Antimigraine pharmaceutical compositions comprising meloxicam and rizatriptan

Abstract

Disclosed herein are compositions comprising an NSAID such as meloxicam and / or rizatriptan in combination with a cyclodextrin and / or a carbonate or a bicarbonate. These compositions may be orally administered, for example, to improve the bioavailability or pharmacokinetics of the NSAID such as meloxicam for the treatment of pain such as migraine, arthritis, and other conditions. Also disclosed herein are methods of treating pain, such as migraine, comprising administering meloxicam and rizatriptan to a human being suffering from pain, such as migraine. For migraine, these methods may be particularly useful when the meloxicam and rizatriptan are administered while the human being is suffering from an acute attack of migraine pain or migraine aura.

Description

[0001] PCT Patent Application 134057-00001038_7T01PV01-WO PHARMACEUTICAL COMPOSITIONS COMPRISING MELOXICAM

[0002] Inventor: Herriot Tabuteau

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of U. S. Provisional App. Nos. 63 / 730,831, filed December 11, 2024; 63 / 730,838, filed December 11, 2024; 63 / 751,707, filed January 30, 2025; 63 / 751,735, filed January 30, 2025; 63 / 753,357, filed February 3, 2025; 63 / 756,469, filed February 10, 2025; 63 / 761,478, filed February 21, 2025; 63 / 762,305, filed February 24, 2025; 63 / 763,050, filed February 25, 2025; 63 / 770,501, filed March 12, 2025; 63 / 822,108, filed June 11, 2025; 63 / 899,874, filed October 15, 2025; and 63 / 910,526, filed November 3, 2025; all of which are incorporated by reference herein in their entirety.

[0005] BACKGROUND

[0006] Meloxicam, which has the structure:

[0007]

[0008] is a nonsteroidal anti-inflammatory (NSAID) drug that exhibits anti-inflammatory, analgesic, and antipyretic activities. The meloxicam mechanism of action may be related to prostaglandin synthetase (cyclo-oxygenase, COX) inhibition which is involved in the initial steps of the arachidonic acid cascade, resulting in the reduced formation of prostaglandins, thromboxanes and prostacylin.

[0009] SUMMARY

[0010] Meloxicam and some other NSAIDs have poor aqueous solubility which may reduce bioavailability and slow the onset of pain relief resulting from their use. One means of increasing the solubility and bioavailability of meloxicam is through the use of cyclodextrins. PCT Patent Application 134057-00001038_7T01PV01-WO Cyclodextrin (also known as cycloamyloses) are generally cyclic polysaccharides which form a bucket-like shape. Cyclodextrins help to increase bioavailability of other molecules because cyclodextrins are hydrophobic on the inside and hydrophilic on the inside which helps to facilitate the transport of molecules. The naturally occurring cyclodextrins include six, seven, and eight glucose units (a, [3, and y-cyclodextrin, respectively). However, synthetic cyclodextrins containing more or less glucose units are possible. In aqueous solutions, cyclodextrins can form complexes (i.e., an inclusion complex) with drugs by incorporating the drug into the center / hydrophobic portion of the cyclodextrin ring; although cyclodextrin compounds are also known to aggregate around a drug in a micelle-type structure. This ability of cyclodextrins may allow them to act as carriers to increase the bioavailability of less soluble drugs.

[0011] Some embodiments include a method of treating migraine comprising: selecting a human migraine patient with a history of inadequate response to prior migraine treatments, and orally administering a dosage form to the migraine patient, wherein the dosage form comprises a combination of: 1) a complex of meloxicam with a sulfobutyl ether β-cyclodextrin (SBEβCD), 2) a bicarbonate, and 3) a rizatriptan.

[0012] Some embodiments include an inclusion complex of meloxicam in a cyclodextrin. Some embodiments include a dosage form comprising: 1) an inclusion complex of meloxicam and a cyclodextrin, or 2) meloxicam and a carbonate or a bicarbonate.

[0013] Some embodiments include a method of administering meloxicam orally, comprising orally administering a dosage form described herein to a patient in need of treatment.

[0014] Some embodiments include a method of administering meloxicam intravenously, comprising intravenously administering a dosage form described herein to a patient in need of treatment.

[0015] Disclosed herein are formulations for an inclusion complex of cyclodextrin and meloxicam with bicarbonate and methods of use thereof.

[0016] Disclosed herein are formulations and methods for delivering meloxicam with cyclodextrin to a subject by oral, enteral, intravenous, intramuscular, subcutaneous, intranasal, or other parenteral means.

[0017] Disclosed also are methods for treating pain and pain associated with conditions by delivering a dosage form with meloxicam, cyclodextrin, and bicarbonate by oral, enteral, intravenous, intramuscular, subcutaneous, intranasal, or other parenteral means to a subject. PCT Patent Application 134057-00001038_7T01PV01-WO A combination of rizatriptan (e.g. rizatriptan benzoate) and meloxicam (referred to herein for convenience as a "subject combination") may be used to treat a variety of pain conditions.

[0018] Rizatriptan has the structure as shown below.

[0019]

[0020] Rizatriptan can be administered as a pharmaceutically acceptable salt, such as rizatriptan benzoate.

[0021] Some embodiments include a subject combination comprising: 1) an inclusion complex of meloxicam and a cyclodextrin, 2) a rizatriptan, and 3) a bicarbonate for treating migraine in a human being. The migraine may be treatment-resistant migraine. The human being may have a history of inadequate response to prior treatments.

[0022] Some embodiments include a subject combination comprising rizatriptan (e.g., rizatriptan benzoate) and meloxicam that has rapid, sustained, substantial and statistically significant efficacy as compared to placebo, rizatriptan, or meloxicam in the acute treatment of migraine in patients with a history of inadequate response to prior acute treatments.

[0023] Some embodiments include a subject combination comprising rizatriptan, or a pharmaceutically acceptable salt thereof, and meloxicam, or a pharmaceutically acceptable salt thereof, that requires significantly less use of rescue medication as compared to rizatriptan, meloxicam, or placebo.

[0024] Some embodiments include a method of treating migraine, comprising orally administering a combination at least twice a month for at least six months to a human being in need thereof, wherein the combination comprises about 20 mg of meloxicam, or a molar equivalent amount of a salt form of meloxicam, and from about 10 mg to about 15 mg of rizatriptan, or a molar equivalent amount of a salt form of rizatriptan, and wherein the tablet PCT Patent Application 134057-00001038_7T01PV01-WO has a good long-term safety profile in the human being at 6 months after the first time the combination is administered.

[0025] Some embodiments include a method forthe acute treatment of migraine, comprising orally administering a tablet at least one dose to an adult human being following each onset of a migraine forat least 6 months up to 12 months, wherein the human being has a minimum of 2 migraines a month, wherein the tablet comprises about 20 mg of meloxicam, or a molar equivalent amount of a salt form of meloxicam, and about 10 mg of rizatriptan, or a molar equivalent amount of a salt form of rizatriptan, and wherein the tablet has a good long-term safety profile in the human being in 12 months.

[0026] Some embodiments include a method of treating migraine, comprising administering a tablet containing 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan, such as about 14.5 mg of rizatriptan benzoate, to a patient.

[0027] Some embodiments include a method of treating migraine, comprising administering a tablet containing 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan, such as about 14.5 mg of rizatriptan benzoate, to a human patient at the onset of a migraine, wherein the human patient is not experiencing hemiplegic migraine or basilar migraine.

[0028] Some embodiments include a of treating migraine, comprising: administering a tablet containing 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan, such as about 14.5 mg of rizatriptan benzoate, to a human patient with a clear diagnosis of migraine at the onset of a migraine, wherein if the human patient has no response after the tablet is administered, the diagnosis of migraine is reconsidered, and if the clear diagnosis of migraine is confirmed, administering the tablet during a subsequent migraine.

[0029] Some embodiments include a method comprising selecting a human patient who has a negative cardiovascular evaluation, administering a first dose of a tablet in a medically-supervised setting, and performing an electrocardiogram (ECG) on the human patient immediately following administration of the tablet, and administering a second dose of the tablet at the onset of a migraine, wherein the tablet contains 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, such as about 14.5 mg of rizatriptan benzoate, and 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan. PCT Patent Application 134057-00001038_7T01PV01-WO Some embodiments include a method of treating migraine, comprising administering a tablet containing 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan, such as about 14.5 mg of rizatriptan benzoate, to a human patient at the onset of a migraine, wherein the human patient is not experiencing hemiplegic migraine.

[0030] Some embodiments include a method of treating migraine, comprising administering a tablet containing 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan, such as about 14.5 mg of rizatriptan benzoate, to a human patient at the onset of a migraine, wherein the human patient is not experiencing basilar migraine.

[0031] Some embodiments include a method of treating migraine, comprising administering a tablet containing 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan, such as about 14.5 mg of rizatriptan benzoate, to a human patient at the onset of a migraine, wherein the human patient is not experiencing cluster headache.

[0032] Some embodiments include a method of treating migraine, comprising: administering a tablet containing 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan, such as about 14.5 mg of rizatriptan benzoate, to a human patient with a clear diagnosis of migraine at the onset of a migraine, wherein if the human patient has no response after the tablet is administered, the diagnosis of migraine is reconsidered, and if the clear diagnosis of migraine is confirmed, administering the tablet during a subsequent migraine.

[0033] Some embodiments include a method of treating migraine in a human patient being treated with a gepant, comprising: selecting a patient with a confirmed diagnosis of migraine who has been treated with a gepant for the migraine, administering a dosage form comprising 20 mg of meloxicam free acid, or a molar equivalent amount of a meloxicam salt, and 10 mg of rizatriptan free base, or a molar equivalent amount of a rizatriptan salt, such as about 14.5 mg of rizatriptan benzoate, and discontinuing use of the gepant.

[0034] Some embodiments include a method of treating migraine with or without aura in a human patient in need thereof, comprising: selecting a human patient experiencing at least 2 migraine attacks a month, and administering a tablet comprising 20 mg of meloxicam free acid, or a molar equivalent amount of a meloxicam salt, and 10 mg of rizatriptan free base, or PCT Patent Application 134057-00001038_7T01PV01-WO a molar equivalent amount of a rizatriptan salt, such as about 14.5 mg of rizatriptan benzoate, to the human patient, wherein one tablet is orally administered per migraine attack, and wherein the treatment is continued for up to 12 months. A migraine attack is a complex neurological disorder characterized by recurrent episodes of intense, throbbing head pain, often on one side of the head.

[0035] Some embodiments include a method of treating migraine, comprising: administering a tablet containing 20 mg of meloxicam or a molar equivalent amount of a salt of meloxicam, and 10 mg of rizatriptan or a molar equivalent amount of a salt of rizatriptan, such as about 14.5 mg of rizatriptan benzoate, to a human patient with a clear diagnosis of migraine.

[0036] Some embodiments include a method of treating acute migraine in a human patient comprising: selecting a patient with a confirmed diagnosis of migraine, administering a dosage form comprising 20 mg of meloxicam free acid, or a molar equivalent amount of a meloxicam salt, and 10 mg of rizatriptan free base, or a molar equivalent amount of a salt of rizatriptan, such as about 14.5 mg of rizatriptan benzoate, and the treatment is more effective than gepants.

[0037] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a depiction of the results described in Example 2 and contained in Table 6. FIG. 2 is another depiction of the results described in Example 2 and contained in Table 6.

[0038] FIG. 3 is another depiction of the results described in Example 2 and contained in Table 6.

[0039] FIG. 4 is another depiction of the results described in Example 2 and contained in Table 6.

[0040] FIG. 5 is another depiction of the results described in Example 2 and contained in Table 6.

[0041] FIG. 6 is another depiction of the results described in Example 2 and contained in Table 6.

[0042] FIG. 7 is another depiction of the results described in Example 2 and contained in Table 6.

[0043] FIG. 8 is another depiction of the results described in Example 2 and contained in Table PCT Patent Application 134057-00001038_7T01PV01-WO FIG. 9 is another depiction of the results described in Example 2 and contained in Table 6.

[0044] FIG. 10 is another depiction of the results described in Example 2 and contained in Table 6.

[0045] FIG. 11 is a plot of meloxicam plasma concentration at various time points over the first 24 hours for an embodiment of a dosage form described herein and a commercially available meloxicam dosage form.

[0046] FIG. 12 is a plot of meloxicam plasma concentration at various time points over the first 24 hours for a dosage form of meloxicam / rizatriptan described in Example 6 and a commercially available meloxicam dosage form.

[0047] FIG. 13 is a plot of rizatriptan plasma concentration at various time points over the first 12 hours for a dosage form of meloxicam / rizatriptan described in Example 6 and a commercially available meloxicam dosage form.

[0048] FIG. 14 shows plots of the percentages of subjects reporting pain relief at various time points over the first 4 hours post dose of the dosage forms of meloxicam / rizatriptan (e.g., rizatriptan benzoate), rizatriptan (e.g., rizatriptan benzoate), MoSEIC meloxicam, and placebo described in Example 11.

[0049] FIG. 14A shows the percentage of subjects reporting pain relief over placebo for meloxicam, rizatriptan (e.g., rizatriptan benzoate), and meloxicam / rizatriptan (e.g., rizatriptan benzoate) at 1.0 hour and 1.5 hours.

[0050] FIG. 15 shows the percentages of subjects achieving pain freedom at 2 hours, 4 hours, 12 hours, and 16 hours post dose of the dosage forms of meloxicam / rizatriptan (e.g., rizatriptan benzoate), rizatriptan (e.g., rizatriptan benzoate), MoSEIC meloxicam, and placebo described in Example 11.

[0051] FIG. 16A shows the percentages of subjects achieving sustained pain freedom from 2 hours to 24 hours post dose of the dosage forms of meloxicam / rizatriptan (e.g., rizatriptan benzoate), rizatriptan (e.g., rizatriptan benzoate), MoSEIC meloxicam, and placebo described in Example 11.

[0052] FIG. 16B shows the percentages of subjects achieving sustained pain relief from 2 hours to 24 hours post dose of the dosage forms of meloxicam / rizatriptan (e.g., rizatriptan PCT Patent Application 134057-00001038_7T01PV01-WO benzoate), rizatriptan (e.g., rizatriptan benzoate), MoSEIC meloxicam, and placebo described in Example 11.

[0053] FIG. 17A shows the percentages of subjects achieving sustained pain freedom from 2 hours to 48 hours post dose of the dosage forms of meloxicam / rizatriptan (e.g., rizatriptan benzoate), rizatriptan (e.g., rizatriptan benzoate), MoSEIC meloxicam, and placebo described in Example 11.

[0054] FIG. 17B shows the percentages of subjects achieving sustained pain relief from 2 hours to 48 hours post dose of the dosage forms of meloxicam / rizatriptan (e.g., rizatriptan benzoate), rizatriptan (e.g., rizatriptan benzoate), MoSEIC meloxicam, and placebo described in Example 11.

[0055] FIG. 17C shows the percentage of subjects achieving sustained pain freedom over placebo from 2 hours to 48 hours for meloxicam, rizatriptan (e.g., rizatriptan benzoate), and meloxicam / rizatriptan (e.g., rizatriptan benzoate).

[0056] FIG. 17D shows the percentage of subjects achieving sustained pain relief over placebo from 2 hours to 48 hours for meloxicam, rizatriptan (e.g., rizatriptan benzoate), and meloxicam / rizatriptan (e.g., rizatriptan benzoate).

[0057] FIG. 18 shows the percentages of subjects who took rescue medication through hour 24 post dose of the dosage forms of meloxicam / rizatriptan (e.g., rizatriptan benzoate), rizatriptan (e.g., rizatriptan benzoate), MoSEIC meloxicam, and placebo described in Example 11.

[0058] FIG. 19A and FIG. 19B show the percentage of subjects having freedom from pain and resolution of most bothersome symptom for subjects taking meloxicam / rizatriptan (e.g., rizatriptan benzoate) and placebo in Example 12.

[0059] FIG. 20 shows the percentage of subjects achieving pain freedom over time for subjectstaking meloxicam / rizatriptan (e.g., rizatriptan benzoate) and placebo in Example 12.

[0060] FIG. 21 shows the percentage of subjects achieving freedom from most bothersome symptom over time for subjects taking meloxicam / rizatriptan (e.g., rizatriptan benzoate) and placebo in Example 12.

[0061] FIG. 22A and FIG. 22B show the percentage of subjects achieving pain freedom over hours 2-24 and hours 2-48 for subjects taking meloxicam / rizatriptan (e.g., rizatriptan benzoate) and placebo in Example 12. PCT Patent Application 134057-00001038_7T01PV01-WO FIG. 23 shows the percentage of subjects achieving freedom from pain progression over hours 2-24 for subjects taking meloxicam / rizatriptan (e.g., rizatriptan benzoate) and placebo in Example 12.

[0062] FIG. 24 shows the percentage of subjects taking rescue medication for subjects taking meloxicam / rizatriptan (e.g., rizatriptan benzoate) and placebo in Example 12.

[0063] FIG. 25 shows the percentage of subjects having no functional disability at hour 24 for subjectstaking meloxicam / rizatriptan (e.g., rizatriptan benzoate) and placebo in Example 12.

[0064] FIG. 26 shows the percentage of subjects having a Patient Global Impression of Change (PGI-C) of "very much improved" or "much improved" at hour 2 for subjects taking meloxicam / rizatriptan (e.g., rizatriptan benzoate) and placebo in Example 12.

[0065] FIG. 27 shows the probability of subjects experiencing pain relief at different points in time after dosing for subjects taking meloxicam / rizatriptan (e.g., rizatriptan benzoate), rizatriptan (e.g., rizatriptan benzoate), MoSEIC Meloxicam, and placebo in Example 11.

[0066] FIG. 28 shows the percentage of subjects who experienced pain relapse within 48 hours of dosing for subjects taking meloxicam / rizatriptan (e.g., rizatriptan benzoate) and rizatriptan (e.g., rizatriptan benzoate) in Example 11.

[0067] FIG. 29 shows the effects of fixed-dose meloxicam / rizatriptan benzoate on MIDAS (Migraine Disability Assessment) total score, HIT-6 total score, and MSQ domains in Example 14; HIT-6, headache impact test-6; MIDAS, migraine disability assessment; MSQ, migrainespecific quality of life questionnaire.

[0068] FIG. 30 shows the study design of MOVEMENT trial in Example 14.

[0069] FIG. 31A shows the changes in MIDAS total scores over time in Example 14.

[0070] FIG. 31B shows the percentage of participants achieving MCIC in Example 14. MCIC threshold was 4.5 points change. MCIC, minimal clinically important change; MIDAS, migraine disability assessment.

[0071] FIG. 32A shows the changes in HIT-6 total scores over time in Example 14. HIT-6, Headache Impact Test.

[0072] FIG. 32B shows the percentage of participants achieving MCID in Example 14. MOD threshold was 5 points change. MCID, minimal clinically important difference.

[0073] FIG. 33A shows the changes in MSQ total scores and role function-restrictive, role function-preventive, and emotional function subscores over time in Example 14. PCT Patent Application 134057-00001038_7T01PV01-WO FIG. 33B shows the percentage of participants achieving MCID (B) in Example 14. MCID threshold was 5, 5, and 8 points for role function-restrictive, role function-preventive, and emotional function, respectively.aScores were available for 499 participants for the MSQ total and emotional function. MCID, minimal clinically important difference; MSQ, 14-item Migraine Specific Quality of Life Questionnaire Version 2.1.

[0074] FIG. 34 presents the percentage of patients achieving migraine pain freedom within 2 hours following treatment in Study 1 in Example 15.

[0075] FIG. 35 presents the percentage of patients achieving MBS freedom within 2 hours following treatment Study 1 in Example 15.

[0076] FIG. 36 presents the percentage of patients achieving migraine pain freedom within 2 hours following treatment in Study 2 in Example 15.

[0077] FIG. 37 presents the percentage of patients achieving MBS freedom within 2 hours following treatment Study 2 in Example 15.

[0078] FIG. 38 presents the participant disposition in Example 16. The intent-to-treat (ITT) population included all randomized participants with a qualifying migraine episode (pain intensity of 1-mild on a 4-point rating scale [0-none, 1-mild, 2-moderate, or 3-severe]). Efficacy analyses were done in the ITT population. The safety population included all participants who had taken study drug. Analyses grouped participants according to treatment actually received, regardless of the treatment to which they were randomized. All safety analyses were done in the safety population.

[0079] FIG. 39A presents the percentages of participants achieving headache pain freedom at Hour 2 (co-primary efficacy endpoints) in Example 16. Cl, confidence interval; PBO, placebo.

[0080] FIG. 39B presents the percentages of participants achieving absence of most bothersome symptom at Hour 2 (co-primary efficacy endpoints) in Example 16. Cl, confidence interval; MBS, most bothersome symptom; PBO, placebo.

[0081] FIG. 40A presents the time to headache pain freedom (key secondary endpoint) in Example 16. p values are nominal.

[0082] FIG. 40B presents the time to percentage of participants achieving headache pain freedom overtime (ITT population) in Example 16. *p < 0.003 based on Chi-square test. ITT, intent-to-treat. PBO, placebo.

[0083] FIG. 41A presents the percentages of participants using rescue medication in Example 16. *p < 0.001. PBO, placebo. PCT Patent Application 134057-00001038_7T01PV01-WO FIG. 41B presents the time to rescue medication use in Example 16. p values are nominal. PBO, placebo.

[0084] FIG. 42 presents the INTERCEPT study design.

[0085] FIG. 43 presents the efficacy endpoint treatment differences (Meloxicam / Rizatriptan versus placebo) in Example 16. Italicized p values are nominal. Cl, confidence interval; PBO, placebo.aFor consistency with other efficacy endpoints, data reported in Table 2 are shown here as a decrease (improvement) between active treatment and placebo.

[0086] FIG. 44 presents the participants with pain progression (worsening). *p < 0.03. **p < 0.001. p values are nominal in Example 16. Progression (worsening) was defined as a pain intensity of 2 or 3. PBO, placebo.

[0087] FIG. 45 presents the percentage of participants achieving Patient Global Impression of Change (PGI-C) scores at Hour 2 in Example 16. *p < 0.001 using Cochran–Mantel–Haenszel test (only performed for responders), p value is nominal. Responder was defined as "much improved" or "very much improved." PBO, placebo.

[0088] FIG. 46 presents the effects of fixed-dose meloxicam / rizatriptan vs placebo in baseline disability subgroups in Example 16. Cl, confidence interval; MBS, most bothersome symptom.

[0089] FIG. 47A presents the mean baseline MIDAS score across categories in Example 16. MIDAS, migraine disability assessment; Meloxicam / Rizatriptan, 20 mg MoSEIC™ meloxicam and 10 mg rizatriptan.

[0090] FIG. 47B presents the percent with allodynia at baseline across categories in Example 16. MIDAS, migraine disability assessment; Meloxicam / Rizatriptan, 20 mg MoSEIC™ meloxicam and 10 mg rizatriptan.

[0091] FIG. 48 presents the treatment outcomes by baseline MIDAS category at 1-2 Hours post dose in Example 16. MBS, most bothersome symptom; Meloxicam / Rizatriptan, MoSEIC™ meloxicam and rizatriptan. Size of circle represents population size.

[0092] FIG. 49 presents the treatment outcomes 24 hours post dose in Example 16. Meloxicam / Rizatriptan, MoSEIC™ meloxicam and rizatriptan. Size of circle represents population size.

[0093] FIG. 50A presents the pain freedom and freedom from MBS at two hours after single dose in patients with mild migraine pain in Example 17.

[0094] FIG. 50B presents the pain freedom and freedom from MBS at two hours after single dose in patients with moderate to severe migraine pain in Example 17. PCT Patent Application 134057-00001038_7T01PV01-WO FIG. 51A presents the sustained pain freedom 2-24 hours after single dose in patients with mild migraine pain in Example 17.

[0095] FIG. 51B presents the sustained pain freedom 2-24 hours after single dose in patients with moderate to severe migraine pain in Example 17.

[0096] FIG. 52A presents the reduced rescue medication use within 24 hours after single dose in patients with mild migraine pain in Example 17.

[0097] FIG. 52B presents the reduced rescue medication use within 24 hours after single dose in patients with moderate to severe migraine pain in Example 17.

[0098] FIG. 53 presents the tinning of peak plasma levels for Meloxicam / Rizatriptan components align with the increase of key mediators of migraine in Example 17. CGRP = calcitonin gene-related peptide; MoSEIC = Molecular Solubility Enhanced Inclusion Complex; PGE2 = prostaglandin E2.

[0099] FIG. 54A presents the evidence networks in Example 18. Network 1 endpoints: Pain relief at 2h and sustained pain relief from 2-24h, pain freedom at 2h and sustained pain freedom from 2-24h, absence of MBS at 2h, and ability to perform normal activity at 2h.

[0100] FIG. 54B presents the evidence networks in Example 18. Network 2 endpoint: Use of rescue medication from 2-24h.

[0101] FIG. 55A presents the odds ratio for pain freedom in Example 18. Crl = credible interval.

[0102] FIG. 55B presents the additional migraine symptoms and impacts in Example 18. Crl = credible interval; MBS = most bothersome symptoms.

[0103] FIG. 55C presents the odds ratio for pain relief in Example 18. Crl = credible interval. FIG. 56 presents the study design in Example 19. *By migraine episode, without the use of rescue medication.+Most bothersome symptom was photophobia, phonophobia, or nausea. CGRP, calcitonin gene-related peptide; MBS, most bothersome symptom; Meloxicam / Rizatriptan, MoSEIC™ meloxicam and rizatriptan.

[0104] FIG. 57 presents the *mTOQ-4 total score change from baseline to Visit 4 / EOS in Example 19. *mTOQ-4 total score change from baseline to Visit 4 / EOS.+T-test was used to test the null hypothesis of mean change equal to 0. P value is nominal. CGRP, calcitonin gene-related peptide; EOS, end of study; Meloxicam / Rizatriptan, MoSEIC™ meloxicam and rizatriptan; mTOQ-4, Migraine Treatment Optimization Questionnaire, 4-item. PCT Patent Application 134057-00001038_7T01PV01-WO FIG. 58 presents the percentage of patients experiences response compared to oral CGRP inhibitors based on individual mTOQ-4 item scores in Example 19.amTOQ-4 Item 2: " After taking your migraine medication, are you pain free within 2 hours for most attacks?";bmTOQ-4 Item 3: " Does one dose of your migraine medication usually relieve your headache and keep it away for at least 24 hours?";cmTOQ-4 Item 1: " Are you able to quickly return to your normal activities (ie, work, family, leisure, social activities) after taking your migraine medication?";dmTOQ-4 Item 4: " Are you comfortable enough with your migraine medication to be able to plan your daily activities?" Each mTOQ-4 Individual Item was reported half the time or more. *T-test was used to test the null hypothesis of mean change equal to 0. All P values are nominal. CGRP, calcitonin gene-related peptide; EOS, end of study; mTOQ-4, Migraine Treatment Optimization Questionnaire, 4-item.

[0105] FIG. 59 presents the improvements in overall quality of life and daily functioning with Meloxicam / Rizatriptan treatment compared to oral CGRP inhibitors in Example 19. *T-test was used to test the null hypothesis of mean change equal to 0. All P values are nominal. **Role function preventive domain: how migraines prevent social / work activities. Role function restrictive: how migraines restrict social / work activities. EOS, end of study; Meloxicam / Rizatriptan, MoSEIC™ meloxicam, and rizatriptan; MSQ, Migraine-Specific Quality of Life Questionnaire; QoL, quality of life.

[0106] FIG. 60 presents the rates of pain relief, pain freedom, and MBS freedom at 2 hours with Meloxicam / Rizatriptan in Example 19. MBS, most bothersome symptom (nausea, photophobia, or phonophobia); Meloxicam / Rizatriptan, MoSEIC™ meloxicam and rizatriptan.

[0107] FIG. 61A presents the rates of participant-reported improvement in migraine attacks with Meloxicam / Rizatriptan at 30 minutes post-dose in Example 19. Meloxicam / Rizatriptan, MoSEIC™ meloxicam and rizatriptan; PGI-C, Patient Global Impression of Change.

[0108] FIG. 61B presents the rates of participant-reported improvement in migraine attacks with Meloxicam / Rizatriptan at 2 hours post-dose in Example 19. Meloxicam / Rizatriptan, MoSEIC™ meloxicam and rizatriptan; PGI-C, Patient Global Impression of Change.

[0109] FIG. 62 presents the change in pain relief rates over time across treated episodes in Example 19.

[0110] FIG. 63 presents the one-way sensitivity analyses of the difference in healthcare costs between the use of the Meloxicam / Rizatriptan and other migraine treatment products including gepants in third-party commercial heath care in Example 20. PCT Patent Application 134057-00001038_7T01PV01-WO FIG. 64 presents the one-way sensitivity analyses of the difference in healthcare costs between the use of the Meloxicam / Rizatriptan and other migraine treatment products including gepants in Medicare in Example 20.

[0111] FIG. 65 presents the analytical framework in Example 21. DNT, doses needed to treat; NNT, number need to treat.

[0112] FIG. 66 presents the Mullins et al. (2005) definitions in Example 21.

[0113] DETAILED DESCRIPTION

[0114] Provided herein are dosage forms with NSAIDs (such as meloxicam) and cyclodextrin (optionally in an inclusion complex), and / or bicarbonate, and methods of treatment using the dosage form.

[0115] A dosage form may be given enterally including, but not limited to, oral, sublingual, or rectal delivery, or parenterally including, but not limited to, intravenous, intramuscular, intranasal, or subcutaneous delivery.

[0116] Some methods include administration of a product that combines an NSAID that is formulated with: a) a cyclodextrin and / or b) a buffering agent. In some embodiments, the method involves treating a patient with a pharmaceutical formulation comprising meloxicam and a cyclodextrin and / or a carbonate / bicarbonate. Method embodiments may also include treating a patient to increase the bioavailability of meloxicam in the patient or increase the rate at which the meloxicam becomes bioavailable.

[0117] The combination of meloxicam, a cyclodextrin (such as SBEβCD), and a bicarbonate (such as sodium bicarbonate) may substantially increase the solubility and rate of absorption of meloxicam after oral administration, while maintaining its extended plasma concentration half-life in mammals, such as humans after oral administration.

[0118] The combination of meloxicam, a cyclodextrin (such as sulfobutylether-beta-cyclodextrin " SBEβCD" or sulfobutylether-beta-cyclodextrin sodium salt), and a bicarbonate (such as sodium bicarbonate) may substantially increase the oral bioavailability of meloxicam in mammals, such as humans, after oral administration.

[0119] Unless otherwise indicated, any reference to a compound herein, such as meloxicam or rizatriptan, by structure, name, or any other means, includes pharmaceutically acceptable salts, alternate solid forms, such as polymorphs, solvates, hydrates, enantiomers, tautomers, deuterium-modified forms, or any other chemical species, such as precursors, prodrugs, or PCT Patent Application 134057-00001038_7T01PV01-WO any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.

[0120] A subject combination may be given enterally including, but not limited to, oral, sublingual, or rectal delivery, or parenterally including, but not limited to, intravenous, intramuscular, intranasal, or subcutaneous delivery. In some embodiments, both meloxicam and rizatriptan are administered orally. In some embodiments, meloxicam is administered intravenously and rizatriptan is administered orally. In some embodiments, meloxicam is administered intramuscularly and rizatriptan is administered orally.

[0121] Normally, the combination of meloxicam and rizatriptan is administered so that the human being receives the meloxicam and rizatriptan within a short period of time with respect to one another. For example, the meloxicam and rizatriptan (e.g., rizatriptan benzoate) may be administered within about 2 hours, within about 1 hour, within about 30 minutes, within about 20 minutes, within about 15 minutes, within about 10 minutes, within about 5 minutes, or within about 1 minute of one another. In some embodiments, the meloxicam and rizatriptan are administered simultaneously, which for the purpose of this disclosure includes administration within about 5 minutes. In some embodiments, the meloxicam and rizatriptan are administered in a single dosage form.

[0122] The term "treating", or "treatment" broadly includes any kind of treatment activity, including the diagnosis, cure, mitigation, or prevention of disease in man or other animals, or any activity that otherwise affects the structure or any function of the body of man or other animals.

[0123] The dosage form or the subject combination may be used to treat, or provide relief of, any type of pain including, but not limited to, migraine and other types of headache, inflammatory pain, musculoskeletal pain, neuropathic pain, chronic pain, acute pain, localized pain, systemic pain, cancer-related pain, acute pain, pain due to injury, pain due to illness (e.g., fever), post-operative pain, etc. In some instances, pain relief may be palliative, or pain relief may be provided independent of improvement of the disease or condition or the underlying cause of the disease or condition. For example, although the underlying disease may not improve, or may continue to progress, an individual suffering from the disease may experience pain relief. In some embodiments, the pain affects a muscle, nerve, cartilage, bone, ligament, tendon, tendon sheaths, bursae, or joint. PCT Patent Application 134057-00001038_7T01PV01-WO Migraine is a disabling neurological disorder characterized by recurrent attacks of pulsating head pain accompanied by nausea and sensitivity to light and sound. This pain may be moderate to severe, but is often severe and incapacitating, requiring bed rest. The headaches may affect one half of the head, may be pulsating in nature, and may last from 2 to 72 hours. Associated symptoms may include nausea, vomiting, and sensitivity to light (photophobia), sound (phonophobia), or smell. The migraine pain may be accompanied by disturbed vision. The migraine pain can be made worse by physical activity. Migraines may be associated with an aura, which may be a short period of visual disturbance which signals that the headache will soon occur. Some migraine patients may not have aura.

[0124] In some embodiments, the human being who is being treated for migraine pain suffers from allodynia, such as cutaneous allodynia with their migraine attacks. Allodynia, such as cutaneous allodynia, which is pain from normally non-painful stimuli (such as brushing hair, wearing glasses, taking a shower, etc.). Patients having allodynia, such as cutaneous allodynia are believed to be less likely to respond well to triptan medications.

[0125] Current treatments are suboptimal, with more than 70% of sufferers reporting dissatisfaction with existing acute treatments. The most commonly reported reasons for patient dissatisfaction are slow onset of pain relief, inconsistent pain relief, and recurrence of pain during the same day. Suboptimal acute treatment is associated with a significantly increased risk of new-onset chronic migraine, which may be prevented by improving acute treatment outcomes.

[0126] Administering a subject combination to a human being suffering from migraine, such as an acute attack of migraine pain or aura, may quickly result in a reduction in a migraine symptom, such as pain, nausea, vomiting, photophobia, or phonophobia, such as at or within about 5 minutes (intended as a shorthand for "at about 5 minutes, or within about 5 minutes"), at or within about 10 minutes, at or within about 30 minutes, at or within about 1 hour, at or within about 90 minutes, at or within about 2 hours, at or within about 2.5 hours, or at or within about 3 hours. In some embodiments, a human being experiences a reduction of, or complete relief from, pain, such as headache pain or migraine pain, nausea, vomiting, photophobia, and / or phonophobia, at or within about 1 hour, at or within about 90 minutes, at or within about 2 hours, at or within about 2.5 hours, or at or within about 3 hours. In some embodiments, the relief experienced, is greater than would be experienced by receiving the same amount of rizatriptan without meloxicam. In some embodiments, the relief PCT Patent Application 134057-00001038_7T01PV01-WO experienced, is greater than would be experienced by receiving the same amount of meloxicam without rizatriptan.

[0127] The subject combination may be administered at the earliest sign of migraine pain, or soon after the earliest sign of migraine, such as within about 1 minute, within about 5 minutes, within about 10 minutes, within about 15 minutes, within about 20 minutes, within about 30 minutes, or within about 1 hour. At this early state, the pain may still be mild, or before the pain progresses to moderate or severe intensity. For some methods, the subject combination may be administered when the migraine pain has reached moderate or severe intensity.

[0128] In some embodiments, the combination of meloxicam and rizatriptan (e.g., rizatriptan benzoate) is administered to a human migraine patient having, or who is selected for having, functional disability. In some embodiments, the treatment results in the human migraine patient being able to return to normal activities within 24 hours after receiving the treatment.

[0129] The combination of meloxicam and rizatriptan may have distinct dual mechanisms of action for the acute treatment of migraine. Meloxicam is a potent, COX-2 preferential NSAID which is limited by slow absorption. Rizatriptan is a potent 5-HT1B / D agonist believed to have efficacy in migraine.

[0130] Observation of relief or reduction in a symptom at a specific period of time, such as "at 2 hours," is useful because it allows the effectiveness of the treatment to be evaluated at a specific or consistent time point, which facilitates comparison between patients. Observation of relief or reduction in a symptom within a specific period of time, such as "within about 2 hours," is useful because it is desirable for relief or reduction of a symptom to occur as early as possible, and specifying that relief occur within a specified time sets a guideline in which it is desirable that relief occur.

[0131] For some methods, administration of the subject combination may achieve a reduction in migraine pain, nausea, vomiting, photophobia, or phonophobia that lasts at least about one hour, at least about two hours, at least about three hours, at least about four hours, at least about six hours, at least about eight hours, about 8-24 hours, about 24 hours, or more than 24 hours.

[0132] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and two hours after the meloxicam and the rizatriptan (e.g., rizatriptan PCT Patent Application 134057-00001038_7T01PV01-WO benzoate) are administered, the human being experiences greater pain relief than the human being would have experienced two hours after receiving the same amount of meloxicam without the rizatriptan.

[0133] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and twenty-four hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater pain relief than the human being would have experienced twenty-four hours after receiving the same amount of meloxicam without the rizatriptan.

[0134] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and two hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater pain relief than the human being would have experienced two hours after receiving the same amount of rizatriptan without the meloxicam.

[0135] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and twenty-four hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater pain relief than the human being would have experienced twenty-four hours after receiving the same amount of rizatriptan without the meloxicam.

[0136] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and two hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater relief from nausea than the human being would have experienced two hours after receiving the same amount of meloxicam without the rizatriptan.

[0137] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and twenty-four hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater relief from PCT Patent Application 134057-00001038_7T01PV01-WO nausea than the human being would have experienced twenty-four hours after receiving the same amount of meloxicam without the rizatriptan.

[0138] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and two hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater relief from nausea than the human being would have experienced two hours after receiving the same amount of rizatriptan without the meloxicam.

[0139] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and twenty-four hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater relief from nausea than the human being would have experienced twenty-four hours after receiving the same amount of rizatriptan without the meloxicam.

[0140] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and two hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater relief from vomiting than the human being would have experienced two hours after receiving the same amount of meloxicam without the rizatriptan.

[0141] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and twenty-four hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater relief from vomiting than the human being would have experienced twenty-four hours after receiving the same amount of meloxicam without the rizatriptan.

[0142] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and two hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater relief from vomiting than the human being would have experienced two hours after receiving the same amount of rizatriptan without the meloxicam. PCT Patent Application 134057-00001038_7T01PV01-WO In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and twenty-four hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater relief from vomiting than the human being would have experienced twenty-four hours after receiving the same amount of rizatriptan without the meloxicam. In some embodiments, the meloxicam and the rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and two hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater relief from photophobia than the human being would have experienced two hours after receiving the same amount of meloxicam without the rizatriptan.

[0143] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and twenty-four hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater relief from photophobia than the human being would have experienced twenty-four hours after receiving the same amount of meloxicam without the rizatriptan.

[0144] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and two hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater relief from photophobia than the human being would have experienced two hours after receiving the same amount of rizatriptan without the meloxicam.

[0145] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and twenty-four hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater relief from photophobia than the human being would have experienced twenty-four hours after receiving the same amount of rizatriptan without the meloxicam.

[0146] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and two hours after the meloxicam and the rizatriptan (e.g., PCT Patent Application 134057-00001038_7T01PV01-WO rizatriptan benzoate) are administered, the human being experiences greater relief from phonophobia than the human being would have experienced two hours after receiving the same amount of meloxicam without the rizatriptan.

[0147] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and twenty-four hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater relief from phonophobia than the human being would have experienced twenty-four hours after receiving the same amount of meloxicam without the rizatriptan.

[0148] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and two hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater relief from phonophobia than the human being would have experienced two hours after receiving the same amount of rizatriptan without the meloxicam.

[0149] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and twenty-four hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater relief from phonophobia than the human being would have experienced twenty-four hours after receiving the same amount of rizatriptan without the meloxicam.

[0150] In some embodiments, the human being receiving the subject combination has a history of inadequate response to prior migraine treatments. For example, if the human being is asked whether he or she was pain-free within two hours of treatment for most attacks, and given the option of answering "never," "rarely," "less than half the time," or "half the time or more;" and the human being answers "never," "rarely," or "less than half the time," then the human being has had an inadequate response to the treatment. Similarly, if the human being is asked whether one dose of medication usually relieved the human being's headache and kept it away for at least 24 hours, and given the option of answering "never," "rarely," "less than half the time," or "half the time or more;" and the human being answers "never," "rarely," or "less than half the time," then the human being has had an inadequate response to the treatment. PCT Patent Application 134057-00001038_7T01PV01-WO In some embodiments, the human being receiving the subject combination has indicated that he or she was "never" pain-free within two hours of treatment for most attacks. In some embodiments, the human being receiving the subject combination has indicated that he or she was "rarely" pain-free within two hours of treatment for most attacks. In some embodiments, the human being receiving the subject combination has indicated that he or she was pain-free within two hours of treatment for most attacks "less than half the time." In some embodiments, the human being receiving the subject combination has indicated that one dose of medication "never" relieved the respondent's headache and kept it away for at least 24 hours. In some embodiments, the human being receiving the subject combination has indicated that one dose of medication "rarely" relieved the respondent's headache and kept it away for at least 24 hours. In some embodiments, the human being receiving the subject combination has indicated that one dose of medication relieved the respondent's headache and kept it away for at least 24 hours "less than half the time." In some embodiments, the human being receiving the subject combination has a history of inadequate response to prior migraine treatments as assessed by a total mean score of less than 7, less than 6, less than 5, less than 4, less than 3, less than 2, 1-2, 2-3, 3-4, 4-5, 5-6, or 6-7 on the Migraine Treatment Optimization Questionnaire (mTOQ-4). In some embodiments, the human being has had prior triptan use before receives the subject combination, such as a combination comprising meloxicam and rizatriptan.

[0151] In some embodiments, the human being receiving the subject combination, such as a combination comprising meloxicam and rizatriptan, has migraine, and may have a history of inadequate response to prior migraine treatments. In some embodiments, the human being having migraine does not have cluster headaches or other types of migraines. In some embodiments, the human being having migraine does not have chronic daily headache. In some embodiments, the human being having migraine does not have more than 15, 15-20, 20-25, 25-28, 28-30, or 30-31 non-migraine headache days per month. In some embodiments, the human being having migraine does not have a history of significant cardiovascular disease. In some embodiments, the human being having migraine does not have uncontrolled hypertension.

[0152] In some embodiments, the dosage form may also be administered to relieve arthritis pain. In some embodiments the dosage form may be administered to relieve other signs and / or symptoms of arthritis. Examples of arthritis include, but are not limited to, PCT Patent Application 134057-00001038_7T01PV01-WO rheumatoid arthritis, juvenile rheumatoid arthritis (pauciarticular and polyarticular course), osteoarthritis, erosive osteoarthritis, sero-negative (non-rheumatoid), arthropathies, non-articular rheumatism, peri-articular disorders, axial spondyloarthritis, transient osteoarthritis of the hip, vertebral crush fractures, osteoporosis, and neuropathic arthropathies including Charcot's foot, axial spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome. In other embodiments, the arthritis pain may be chronic or acute. In some embodiments the dosage form may be administered to relief the signs and / or symptoms of an arthritis including but not limited osteoarthritis

[0153] For some methods, administration of the dosage form may achieve a reduction in pain that lasts at least about one hour, two hours, three hours, four hours, six hours, at least about eight hours, about eight to about 24 hours, or about 24 hours. In other embodiments, administration of the dosage form may achieve a reduction in pain that is observed at about 10 minutes, at about 30 minutes, at about one hour, at about two hours, at about three hours, at about four hours, at about five hours, at about six hours, at less than 15 minutes, at less than 20 minutes, 30 minutes, at less than one hour, at less than two hours, at less than three hours, at about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60 minutes, or other time period bound by these ranges, after administration of the dosage form.

[0154] In some embodiments, the dosage form may also be administered to relieve neuropathic pain, including diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, sciatica, pudendal neuralgia, and central pain. Other causes of neuropathic pain may include, but are not limited to, cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-associated neuropathy, and radio-therapy or chemotherapy associated neuropathy. The neuropathic pain treated may be chronic or acute.

[0155] In some methods, the dosage form may be administered to relieve inflammatory pain including inflammatory musculoskeletal pain, pain due to injury, arthritis pain, and complex regional pain syndrome. In other embodiments, the inflammatory pain may be chronic or acute.

[0156] Arthritis refers to inflammatory joint diseases that can be associated with pain. Examples of arthritis pain include but are not limited to pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, peri-articular disorders, neuropathic PCT Patent Application 134057-00001038_7T01PV01-WO arthropathies including Charcot's foot, axial spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome. The inflammatory joint disease treated may be chronic or acute.

[0157] For some methods, the meloxicam may be administered to relieve musculoskeletal pain. Examples of musculoskeletal pain may include, but are not limited to, back pain, low back pain (e.g., lumbosacral pain), neck pain, infection, cramps, tendonitis, epidondylitis, carpal tunnel syndrome, joint pain, fibromyalgia, pain due to injury, Tunnel syndromes, pain associated with bone fractures, sprains, fibrous dysplasia, osteogenesis imperfecta, Paget's disease of bone, transient osteoporosis, and transient osteoporosis of the hip. In other embodiments, the musculoskeletal pain may be chronic or acute.

[0158] For some methods, administration of the dosage form orthe subject combination may achieve a reduction in pain that lasts at least about one hour, at least about two hours, at least about three hours, at least about four hours, at least about six hours, at least about eight hours, about 8 to about 24 hours, or about 24 hours. In other embodiments, administration of the subject combination may achieve a reduction in pain that is observed at about 10 minutes, at about 30 minutes, at about one hour, at about two hours, at about three hours, at about four hours, at about five hours, at about six hours, at or within about 5 minutes, at or within about 10 minutes, at or within about 15 minutes, at or within about 20 minutes, at or within about 25 minutes, at or within about 30 minutes, at or within about 35 minutes, at or within about 40 minutes, at or within about 45 minutes, at or within about 50 minutes, or at or within about 60 minutes, at two hours or less, at three hours or less, or other time period bound by these ranges, after administration of the subject combination.

[0159] A human being that is treated for a disease or condition with the dosage forms described herein may be of any age. For example the person may have an age of about 10 years to about 90 years, about 20 years to about 80 years, about 30 years to about 75 years, about 40 years to about 70 years, about 1 year to about 16 years, about 80 years to about 95 years, about 18 years or more, about 20 years or more, about 25 years or more, about 30 years or more, about 40 years or more, about 45 years or more, about 50 years or more, about 55 years or more, about 60 years or more, about 65 years or more, or any other age in a range bounded by, or between, these values.

[0160] In some embodiments, a human being who is treated for migraine with the dosage forms described herein, for example comprising meloxicam, rizatriptan, SBEβCD, and a PCT Patent Application 134057-00001038_7T01PV01-WO bicarbonate such as sodium bicarbonate, may be of 18 years to 65 years of age, about 18-20 years of age, about 20-25 years of age, about 25-30 years of age, about 30-40 years of age, about 40-45 years of age, about 40-50 years of age, about 50-60 years of age, about 60-65 years of age, or any other age in a range bounded by, or between, these values.

[0161] In some embodiments, a human being who is treated for migraine with a dosage forms described herein, such as a dosage form comprising meloxicam, a rizatriptan (e.g., rizatriptan benzoate), a SBEβCD (e.g., SBEβCD sodium), and a bicarbonate such as sodium bicarbonate, may be white, Black, or African American, or Asian.

[0162] In some embodiments, a human being that is treated for a disease or condition with a dosage form comprising meloxicam or another NSAID has suffered from the pain or condition associated with the pain for at least 1 day, at least one week, at least 2 weeks, at least 1 month, at least 6 weeks, at least 2 months, at least 3 months, at least 6 months, or at least 1 year, or any duration in a range bounded by, or between, these values.

[0163] In some embodiments, a human being that is treated for migraine with a dosage form comprising meloxicam and rizatriptan has been diagnosed of migraine with or without aura as defined by the ICHD-3 criteria for at least 3 months, at least 6 months, at least 1 year, at least 2 years, about 1-2 years, 2-3 years, or longer, or at least 1 year, or any duration in a range bounded by, or between, these values.

[0164] In some embodiments, a human being has an average 2 to 8, 2-3, 3-4, 4-5, 5-6, 6-7, or 7-8 moderate to severe migraines per month.

[0165] A cyclodextrin used in a dosage form with meloxicam could include a cyclodextrin, a cyclodextrin derivative, and / or a salt thereof. An inclusion complex of meloxicam and cyclodextrin may be more water-soluble relative to the non-complexed meloxicam. The cyclodextrin may be a naturally-occurring cyclodextrin (e.g., a, [3, or y-cyclodextrins) or a synthetic cyclodextrin. In some embodiments, a-cyclodextrins, derivatives, or salts thereof may be used. a-Cyclodextrins may include, but are not limited to, (2,3,6-tri-O-acetyl)-a-cyclodextrin, (2,3,6-tri-O-methyl)-a-cyclodextrin, (2,3,6-tri-O-octyl)-a-cyclodextrin, 6-bromo-6-deoxy-a-cyclodextrin, 6-iodo-6-deoxy-a-cyclodextrin, (6-O-tertbutyl-dimethylsilyl)-a-cyclodextrin, butyl-a-cyclodextrin, succinyl-a-cyclodextrin, (2-hydroxypropyl)-a-cyclodextrin, or combinations thereof.

[0166] In some embodiments, [3-cyclodextrins, derivatives, or salts thereof may be used. [3-cyclodextrins may include, but are not limited to, hydroxypropyl-[3-cyclodextrin, 6- PCT Patent Application 134057-00001038_7T01PV01-WO monodeoxy-6-monoamino-P-cyclodextrin, glucosyl-[3-cyclodextrin, maltosyl-[3-cyclodextrin, 6-O-a-D-glucosyl-P-cyclodextrin, 6-O-a-maltosyl-[3-cyclodextrin, 6-azido-6-deoxy-[3-cyclodextrin, (2,3-di-O-acetyl-6-O-sulfo)-[3-cyclodextrin, methyl-[3-cyclodextrin, dimethyl-[3-cyclodextrin (DM CD), trimethyl-[3-cyclodextrin (TM CD), (2,3-di-O-methyl-6-O-sulfo)-[3-cyclodextrin, (2,6-di-O-methyl)-[3-cyclodextrin, (2,6-di-O-ethyl)-[3-cyclodextrin, (2,3,6-tri-O-methyl)-[3-cyclodextrin, (2,3,6-tri-O-acetyl)-[3-cyclodextrin, -(2,3,6-tri-O-benzoyl)-[3-cyclodextrin, (2,3,6-tri-O-ethyl)-[3-cyclodextrin, 6-iodo-6-deoxy-[3-cyclodextrin, 6-(dimethyl-tert-butylsilyl)-6-deoxy-[3-cyclodextrin, 6-bromo-6-deoxy-[3-cyclodextrin, monoacetyl-[3-cyclodextrin, diacetyl-[3-cyclodextrin, triacetyl-[3-cyclodextrin, (3-O-acetyl-2,6-di-O-methyl)-[3-cyclodextrin, (6-O-maltosyl)-[3-cyclodextrin, (6-O-sulfo)-[3-cyclodextrin, (6-O-t-butyldimethylsilyl-2,3-di-O-acetyl)-[3-cyclodextrin, succinyl-(2-hydroxypropyl)-[3-cyclodextrin, (2,6-di-O-)ethyl-[3-cyclodextrin, (2-carboxyethyl)-[3-cyclodextrin (CME[3CD), hydro xyethyl- -cyclodextrin (HE CD), (2-hydroxypropyl)-[3-cyclodextrin, (2-hydroxypropyl)-[3-cyclodextrin (HP CD), (3-hydroxypropyl)-[3-cyclodextrin (3HP[3CD), (2,3-hydroxypropyl)-[3-cyclodextrin (DHP CD), butyl-P-cyclodextrin, methyl-[3-cyclodextrin, silyl((6-O-tert-butyldimethyl)-2,3,-di-O-acetyl)-[3-cyclodextrin, succinyl-[3-cyclodextrin, (2-hydroxyisobutyl)- [3-cyclodextrin, randomly methylated-[3-cyclodextrin, branched-[3-cyclodextrin, or combinations thereof.

[0167] In other embodiments, a [3-cyclodextrin may be a sulfoalkyl ether cyclodextrin, derivative, or salt thereof. Examples of sulfoalkyl ether cyclodextrin derivatives may include, but are not limited to, sulfobutyl ether-[3-cyclodextrin (e.g., SBE[3CD, betadex, CAPTISOL®) and sulfobutyl ether-[3-cyclodextrin sodium. In some embodiments, a SBEβCD may have about 4-8, about 5-8, about 4-7, about 6-7, or about 6.5 sulfobutyl ether groups per cyclodextrin molecule.

[0168] In some embodiments, y-cyclodextrins, derivatives, or salts thereof may be used, y-cyclodextrins may include carboxymethyl-y-cyclodextrin, (2,3,6-tri-O-acetyl)-y-cyclodextrin, (2,3,6-tri-O-methyl)-y-cyclodextrin, (2,6-di-O-pentyl)-y-cyclodextrin, 6-(dimethyl-tert-butylsilyl)-6-deoxy-y-cyclodextrin, 6-bromo-6-deoxy-y-cyclodextrin, 6-iodo-6-deoxy-y-cyclodextrin, (6-O-t-butyldimethylsilyl)-y-cyclodextrin, succinyl-y-cyclodextrin, hydroxypropyl-y-cyclodextrin (2-hydroxypropyl)-y-cyclodextrin, acetyl-y-cyclodextrin, butyl-y-cyclodextrin, or combinations thereof.

[0169] In some embodiments, the dosage form may include a bicarbonate, such as sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate, PCT Patent Application 134057-00001038_7T01PV01-WO ammonium bicarbonate, or a combination thereof. A bicarbonate may help to increase bioavailability of the meloxicam.

[0170] In other embodiments, the dosage form may include a carbonate, derivatives, or salts thereof. Examples of carbonates may include aluminum carbonate, ammonium carbonate, barium carbonate, calcium carbonate, cobalt(ll) carbonate, lanthanum carbonate, lithium carbonate, magnesium carbonate, manganese(ll) carbonate, potassium carbonate, sodium carbonate, or combinations thereof.

[0171] In some embodiments, enhanced bioavailability of the dosage form may be achieved in treating one of these conditions by administering a dosage form comprising a salt form of the meloxicam, by creating an inclusion complex with meloxicam and cyclodextrin, and / or by including a bicarbonate. This may allow a reduced molar amount of the meloxicam to be used as compared to other meloxicam dosage forms.

[0172] Unless otherwise indicated, any reference to a compound herein, such as meloxicam or a cyclodextrin, by structure, name, or any other means, includes pharmaceutically acceptable salts, alternate solid forms, such as polymorphs, solvates, hydrates, enantiomers, tautomers, deuterium-modified forms, or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.

[0173] In some embodiments, use of a cyclodextrin, a carbonate, or a bicarbonate may improve the oral bioavailability of meloxicam by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, up to about 100%, up to about 200%, or any amount in a range bounded by, or between, these values as compared to administration of meloxicam alone.

[0174] Due to the improved bioavailability, the dosage form may contain, or a subject may receive, on a molar basis, less of the meloxicam than would otherwise be administered. For example, a dosage form may contain, or a mammal may receive, at least about 10 mole% less, at least about 20 mole% less, at least about 30 mole% less, at least about 40 mole% less, at least about 50 mole% less, at least about 60 mole% less, at least about 70 mole% less, at least about 80 mole% less, at least about 85 mole% less, and / or up to about 90 mole% less, 95 mole% less, or any amount in a range bounded by, or between, these values as would otherwise be administered of meloxicam. PCT Patent Application 134057-00001038_7T01PV01-WO In other embodiments, use of other NSAIDs, opioids, or other pain medications may be reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, up to about 100%, as compared to the use of other NSAIDs, opioids or other pain medications without administration of meloxicam with cyclodextrin, carbonate, and / or bicarbonate.

[0175] In some embodiments, a dosage form may contain meloxicam in an amount from about 1-50 mg; about 1-10 mg; about 1-5 mg; about 10-40 mg; about 1-35 mg; about 1-25 mg; about 1-15 mg; about 5-20 mg; about 5-10 mg; about 5-15 mg; about 10-20 mg; about 20-30 mg; about 30-40 mg; about 40-50 mg; about 5 mg; about 7.5 mg; about 10 mg; about 15 mg; about 30 mg; or any amount in a range bounded by, or between, any of these values. These doses may be a safe dose for repeated administration, such as once hourly dosing to once daily dosing, twice daily dosing, dosing one to 12 times daily, doing 3, 4, 5, or 6 times daily, etc. In some embodiments, the meloxicam may be safely administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times, or about 3 to about 10 times a day, once a day, or less frequently, such as once a week, once every two weeks, once a month, etc.

[0176] For some dosage forms, meloxicam forms a complex with the substituted-[3-cyclodextrin or other cyclodextrin which may be formulated into a solid dosage form. Such a dosage form may be suitable for oral administration. A meloxicam-cyclodextrin inclusion complex may also be dissolved in water or another solvent to form a parenteral formulation. However, physical mixtures of meloxicam and the substituted-[3-cyclodextrin or other cyclodextrins may also be used in oral or parenteral dosage forms.

[0177] Formation of an inclusion complex of meloxicam and a cyclodextrin may help to improve the properties of a dosage form. For some inclusion complexes, the meloxicam and the cyclodextrin (e.g., SBEβCD or SBEβCD sodium) may have a molar ratio of about 0.5-2 (a molar ratio of 0.5 is 0.5 moles of meloxicam to 1 mole of cyclodextrin), about 0.5-0.7, about 0.6-0.8, about 0.7-0.9, about 0.8-1, about 0.9-1.1, about 1-1.2, about 1.1-1.3, about 1.2-1.4, about 1.3-1.5, about 1.4-1.6, about 1.5-1.7, about 1.6-1.8, about 1.7-1.9, about 1.8-2, about 0.8-1.2, about 1, or any ratio in a range bounded by any of these values.

[0178] For some dosage forms, a cyclodextrin (e.g., SBEβCD or SBEβCD sodium) may be employed in a weight ratio to the meloxicam within the range from about 1-1000 (e.g., 1 g of PCT Patent Application 134057-00001038_7T01PV01-WO cyclodextrin per 1 g of meloxicam is a weight ratio of 1); about 1-20; about 1-10; about 1-15; about 2-4, about 3-5, about 4-6, about 5-7, about 6-8, about 7-9, about 8-10, or any weight ratio in a range bounded by, or between, any of these values. For some dosage forms, a cyclodextrin (e.g., SBEβCD, SBEβCD sodium, etc.) may be employed in a weight ratio to the meloxicam within the range from about 0.001-1 (e.g., 0.1 g of cyclodextrin per 1 g of meloxicam is a weight ratio of 0.1); about 0.01-1; about 0.05-1; about 0.1-1; about 0.2-1; about 0.3-1, about 0.4-1, about 0.5-1, about 0.6-1, about 0.7-1, about 0.8-1, or any weight ratio in a range bounded by, or between, any of these values. Each type of cyclodextrin employed may have a different ratio.

[0179] For some dosage forms, the cyclodextrin may be present in an amount from about 1-200 mg; 25-175 mg; about 50-150 mg; about 25-100 mg; about 75-150 mg; about 100-175 mg; about 20-80 mg; about 25-50 mg; about 60-100 mg; about 80-100 mg; about 80-120 mg; about 100-120 mg; about 100-140 mg; about 120-160 mg; about 140-180 mg; about 30-90 mg; about 40-80 mg; about 50-70 mg, about 55-65 mg, about 60-62 mg, or any amount in a range bounded by, or between, any of these values.

[0180] For some methods, the inclusion complex of meloxicam and a cyclodextrin such as a substituted-P-cyclodextrin is delivered orally (for example by tablet, capsule, elixir, or the like). Other potential routes of administration include intravenous, intramuscular, intranasal, lyophilized parenteral, subcutaneous, transdermal, transmucosal, or through other parenteral means. The meloxicam may also be delivered alone or non-complexed with cyclodextrin.

[0181] Some dosage forms contain a bicarbonate (e.g., sodium bicarbonate) in amount from about 1-2000 mg; about 1-1000 mg; about 100-1000 mg; about 200-800 mg; about 1-500 mg; about 1-200 mg; about 1-100 mg; about 50-750 mg; about 500-1000 mg; about 100-500 mg; about 100-300 mg; about 500-1000 mg; about 300-700 mg; about 400-600 mg; about 50-250 mg; about 250-750 mg; about 100-200 mg; about 200-300 mg; about 300-400 mg; about 400-500 mg; about 410-510 mg; about 420-520 mg; about 430-530 mg; about 440-540 mg; about 450-550 mg; about 460-560 mg; about 470-570 mg; about 480-580 mg; about 490-590 mg; about 500-600 mg; about 600-700 mg; about 700-800 mg; about 800-900 mg; about 150-650 mg; about 350-850 mg; or any amount in a range bounded by, or between, any of these values. PCT Patent Application 134057-00001038_7T01PV01-WO Some dosage forms contain a carbonate in amount from about 1-1000 mg; about 1-500 mg; about 1-200 mg; about 1-100 mg; about 50-750 mg; about 500-1000 mg; about 100-500 mg; about 100-300 mg; about 200-800 mg; about 500-1000 mg; about 300-700 mg; about 400-600 mg; about 50-250 mg; about 250-750 mg; about 100-200 mg; about 200-300 mg; about 300-400 mg; about 400-500 mg; about 500-600 mg; about 600-700 mg; about 700-800 mg; about 800-900 mg; about 150-650 mg; about 350-850 mg; or any amount in a range bounded by, or between, any of these values.

[0182] In some embodiments, the daily dose of meloxicam (e.g., an oral dose, a parenteral dose, etc.) is about 2-5 mg, about 2-6 mg, about 2-7 mg, about 2-8 mg, about 2-9 mg, about 2-10 mg, about 2-11 mg, about 2-12 mg, about 2-13 mg, about 2-14 mg, about 2-15 mg, about 2-16 mg, about 2-17 mg, about 2-18 mg, about 2-19 mg, about 2-20 mg, about 2-21 mg, about 2-22 mg, about 2-23 mg, about 2-24 mg, about 2-25 mg, about 2-26 mg, about 2-27 mg, about 2-28 mg, about 2-29 mg, about 2-30 mg, about 2-35 mg, about 2-40 mg, about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-25 mg, about 25-30 mg, about 30-35 mg, or any amount in a range bounded by any of these values.

[0183] In some embodiments, the weekly dose of meloxicam (e.g., an oral dose) is about 1-1000 mg; about 1-500 mg; about 10-250 mg; about 100-300 mg; about 10-100 mg; about 10-150 mg; about 10-300 mg; about 20-150 mg; about 20-60 mg; about 30-70 mg; about 40-60 mg; about 50-70 mg; about 70-90 mg; about 90-110 mg; about 50 mg; about 55 mg; about 100-150 mg; about 30-100 mg; or any amount in a range bounded by, or between, any of these values. The weekly dose may be given as a single dose, given once during the week, or may be given in 2, 3, 4, 5, 6, or 7 individual doses during the week.

[0184] In some embodiments, the monthly dose of meloxicam (e.g., an oral dose), or a dose administered over a period of a month, is about 5000 mg or less; about 4000 mg or less; about 3000 mg or less; about 2000 mg or less; about 1000 mg or less; about 700 mg or less; about 600 mg or less; about 1-4000 mg; about 1-1000 mg; about 10-1000 mg; about 50-1000 mg; about 10-600 mg; about 40-600 mg; about 50-600 mg; about 40-400 mg; about 50-200 mg; about 200-240 mg; about 240-280 mg; about 280-320 mg; about 320-360 mg; about 360-400 mg; about 400-450 mg; about 450-500 mg; about 500-600 mg; about 250-350 mg; about 100-600 mg; about 40-2000 mg; about 40-800 mg; about 100-900 mg; about 100-800 mg; about 40-1000 mg; about 50-1000 mg; about 100-1000 mg; or any monthly dose in a range bounded by, or between, any of these values. A monthly dose may be given as a single dose, or as two PCT Patent Application 134057-00001038_7T01PV01-WO or more individual doses administered during the month. In some embodiments, the monthly dose is administered in 2 or 3 bi-weekly doses. In some embodiments, the monthly dose is administered in 4 or 5 weekly doses. In some embodiments, the monthly dose is administered in 28 to 31 daily doses, or in 56 to 62 daily doses or more. In some embodiments, the monthly dose is administered in 5 to 15 individual doses during the month. The monthly dose may be administered for only 1 month, or may be repeatedly administered for 2 or more months.

[0185] For treatment of migraine, the combination of a meloxicam and a rizatriptan (e.g., rizatriptan benzoate) may be administered to treat at least 2 migraine attacks per month, at least 3 migraine attacks per month, at least 4 migraine attacks per month, at least 5 migraine attacks per month, at least 6 migraine attacks per month, at least 8 migraine attacks per month, at least 10 migraine attacks per month, and / or up to 10 migraine attacks per month, up to 20 migraine attacks per month, up to 30 migraine attacks per month, 2-5 migraine attacks per month, 5-10 migraine attacks per month, 10-15 migraine attacks per month, 15-20 migraine attacks per month, or 20-30 migraine attacks per month. Treatment may be continued for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, at least 24 months, and / or up to 6 months, up to 12 months, up to 18 months, up to 2 years, up to 5 years, up to 10 years, up to 20 years, up to 50 years, up to 80 years, up to 100 years, or longer.

[0186] In other embodiments, the dosage form may be administered weekly for about one, two, three, four, or more consecutive weeks, every other week or bi-weekly, or once every three weeks. This regimen may be repeated once weekly, twice in a month, three times in a month, once monthly, once every two months, once every three months, or as directed by a medical professional.

[0187] In certain embodiments, the pharmaceutical composition results in increased bioavailability (e.g., reduced Tmax, increased Cmax, increased AUC, etc.) of the meloxicam from the dosage form as compared to a dosage form containing meloxicam but not containing a cyclodextrin, an acid inhibitor, or a buffering agent (such as a bicarbonate). In some embodiments, the bioavailability of meloxicam will increase with multiple dosing. For example, the bioavailability of meloxicam in the dosage form may increase after about 1-10 days of dosing; about 2-6 days of dosing; about 3-5 days of dosing; about 4-6 days of dosing; about 5-8 days of dosing; about 5 days of dosing; about 6 days of dosing; about 7 days of PCT Patent Application 134057-00001038_7T01PV01-WO dosing; about 8 days of dosing; about 10 days of dosing; about 15 days of dosing; or time in any range bounded by, or between, any of these values; as compared to the bioavailability of meloxicam in a dosage form not containing a cyclodextrin, an acid inhibitor, or a buffering agent (such as a bicarbonate).

[0188] Some of the dosage forms may result in a desired range for an area under the plasma concentration curve (AUC) of meloxicam. For example the dosage with meloxicam may result in an AUC of meloxicam of about 1-150 pg-hr / mL; about 10-30 pg-hr / mL; about 20-40 pg-hr / mL; about 30-50 pg-hr / mL; about 40-60 pg-hr / mL; about 50-70 pg-hr / mL; about 60-80 pg-hr / mL; about 70-90 pg-hr / mL; about 80-100 pg-hr / mL; about 10-100 pg-hr / mL; about 50-150 pg-hr / mL; about 25-125 pg-hr / mL; about 75-150 pg-hr / mL; about 20-50 pg-hr / mL; about 40-70 pg-hr / mL; about 60-90 pg-hr / mL; about 80-110 pg-hr / mL; about 100-130 pg-hr / mL; about 120-150 pg-hr / mL; or any AUC in a range bounded by, or between, any of these values.

[0189] Unless otherwise indicated, the AUC refers to the AUC calculated to the last measured concentration (AUCo-t), such as, over a period of 6 hours (AUCo-e), over a period of 12 hours (AUC012), over a period of 24 hours (AUC0-24) or extrapolated to infinity (AUCo inf).

[0190] In Example 3 below, the AUCo-24of meloxicam in human beings for an oral dosage form containing sodium bicarbonate and sulfobutylether [3-cyclodextrin (SBEβCD), or a pharmaceutically acceptable salt thereof, was about 27 pg-hr / mL. This dosage form contained 15 mg of meloxicam.

[0191] The 15 mg IV and intramuscular doses also provide an AUCo-24of meloxicam in human beings that is about 27 pg-hr / mL. The AUC of meloxicam is believed to be approximately dose proportional. So, for this oral dosage form, or for an IV or intramuscular dosage form, a meloxicam dose of, for example, approximately 17 mg to about 30 mg would be expected to result in an AUCo-24of meloxicam of about 30-50 pg-hr / mL.

[0192] For some acute pain conditions, such as migraine and other types of headache, the AUC for a short period after oral administration, such as an AUC measured over 6 hours (or AUCo-e), may be of particular interest. For example, some dosage forms may result in an AUCo-6 of at least about 6 pg-hr / mL; at least about 7 pg-hr / mL; at least about 8 pg-hr / mL; at least about 9 pg-hr / mL; about 6-10 pg-hr / mL; about 7-11 pg-hr / mL; about 8-12 pg-hr / mL; about 9-13 pg-hr / mL; or any AUC in a range bounded by, or between, any of these values.

[0193] In some embodiments, the dosage form may result in a Cmaxof meloxicam of about 10-2500 ng / mL; about 100-2250 ng / mL; about 500-2000 ng / mL; about 1000-2500 ng / mL; PCT Patent Application 134057-00001038_7T01PV01-WO about 1000-2000 ng / mL; about 100-900 ng / mL; about 750-1500 ng / mL; about 1250-2000 ng / mL; about 1500-2300 ng / mL; about 800-1200 ng / mL; about 1900-2400 ng / mL; about 50-500 ng / mL; about 400-950 ng / mL; about 900-1500 ng / mL; about 1100-2200 ng / mL; about 1300-1600 ng / mL; about 1200-1500 ng / mL; about 1400-2100 ng / mL; about 1500-1900 ng / mL; about 1600-2100 ng / mL; about 1700-2000 ng / mL; about 1800-2000 ng / mL; about 1900-2500 ng / mL; about 150-1700 ng / mL; about 1600-1800 ng / mL; about 1700-1900 ng / mL; about 1800-2000 ng / mL; about 1900-2100 ng / mL; about 2000-2200 ng / mL; about 2100-2300 ng / mL; about 2200-2400 ng / mL; about 2300-2500 ng / mL; about 2500-3000 ng / mL; or any Cmax in a range bounded by, or between, any of these values.

[0194] For example, a method described herein may reduce the Tmaxof meloxicam. In some embodiments, the method may include treating a patient to achieve the Tmaxof meloxicam in the patient within about 10 minutes; about 20 minutes; about 30 minutes; about 40 minutes; about 50 minutes; about 60 minutes; about 70 minutes; about 80 minutes; about 90 minutes; about 100 minutes; about 110 minutes; about 120 minutes; about 180 minutes; about 1-10 hr; about 2-9 hr; about 3-7 hr; about 4-6 hr; about 1-5 hr; about 2-7 hr; about 3-8 hr; about 4-9 hr; about 1-4 hr; about 2-5 hr; about 3-6 hr; about 4-7 hr; about 5-8 hr; about 6-9 hr; about 7-10 hr; after administration or any Tmaxin a range bounded by, or between, any of these values.

[0195] In some embodiments, an oral dosage form may have a Tmaxof meloxicam that is shorter than would be achieved by administering meloxicam by intramuscular injection. In some embodiments, an oral dosage form may have a Tmaxof meloxicam that is shorter, or may increase meloxicam plasma levels at a faster rate, by a factor of at least about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 12, about 15, about 20, or by a factor of about 1.5-1000, about 2-100, about 3-100, about 4-100, about 5-100, about 6-100, about 7-100, about 8-100, about 9-100, about 10-100, about 12-100, about 15-100, about 20-100, or by a factor in a range bounded by any of these values.

[0196] The oral dosage form of Example 3 below gave a Tmaxof meloxicam of approximately 30 minutes. The reported Tmaxof intravenous meloxicam is approximately 30 minutes for an infusion or 3 minutes for a bolus. The reported Tmaxof intramuscular meloxicam is approximately 60-84 minutes.

[0197] In some embodiments, a dosage form comprising meloxicam may result in a plasma concentration of meloxicam at 12 hours that is about 0.01-0.5 pg / mL; about 0.5-0.7 |ig / mL; PCT Patent Application 134057-00001038_7T01PV01-WO about 0.6-0.8 |ig / mL; about 0.7-0.9 |ig / mL; about 0.8-1 pg / mL; about 0.9-1.1 |ig / mL; about 1-1.2 pg / mL; about 1.1-1.3 pg / mL; about 1.2-1.4 |ig / mL; about 1.3-1.5 |ig / mL; about 1.4-1.6 pg / mL; about 1.5-1.7 pg / mL; about 1.6-1.8 |ig / mL; about 1.7-1.9 pg / mL; about 1.8-2 |ig / mL; about 1.9-2.1 |ig / mL; about 2-2.2 pg / mL; about 2.1-2.3 |ig / mL; about 2.2-2.4 |ig / mL; about 2.3-2.5 |ig / mL; about 2.4-2.6 |ig / mL; about 2.5-2.7 |ig / mL; about 2.6-2.8 |ig / mL; about 2.7-2.9 |ig / mL; about 2.8-3 pg / mL; about 2.9-3.1 pg / mL; about 3-3.2 pg / mL; about 3.1-3.3 |ig / mL; about 3.2-3.4 |ig / mL; about 3.3-3.5 pg / mL; about 3.4-3.6 pg / mL; about 3.5-3.7 |ig / mL; about 3.6-3.8 pg / mL; about 3.7-3.9 |ig / mL; about 3.8-4 |ig / mL; or any plasma concentration in a range bounded by, or between, any of these values.

[0198] In some embodiments, meloxicam is administered at a dose that results in a meloxicam plasma level (such as a Cavg, or average plasma level) of about 0.01-0.5 |ig / mL; about 0.5-0.7 pg / mL; about 0.6-0.8 pg / mL; about 0.7-0.9 |ig / mL; about 0.8-1 pg / mL; about 0.9-1.1 pg / mL; about 1-1.2 |ig / mL; about 1.1-1.3 pg / mL; about 1.2-1.4 |ig / mL; about 1.3-1.5 pg / mL; about 1.4-1.6 |ig / mL; about 1.5-1.7 |ig / mL; about 1.6-1.8 |ig / mL; about 1.7-1.9 |ig / mL; about 1.8-2 |ig / mL; about 1.9-2.1 pg / mL; about 2-2.2 pg / mL; about 2.1-2.3 |ig / mL; about 2.2-2.4 |ig / mL; about 2.3-2.5 |ig / mL; about 2.4-2.6 |ig / mL; about 2.5-2.7 |ig / mL; about 2.6-2.8 pg / mL; about 2.7-2.9 |ig / mL; about 2.8-3 pg / mL; about 2.9-3.1 pg / mL; about 3-3.2 |ig / mL; about 3.1-3.3 |ig / mL; about 3.2-3.4 pg / mL; about 3.3-3.5 pg / mL; about 3.4-3.6 |ig / mL; about 3.5-3.7 |ig / mL; about 3.6-3.8 |ig / mL; about 3.7-3.9 |ig / mL; about 3.8-4 |ig / mL; about 0.1-20 pg / mL; about 0.5-15 |ig / mL; about 0.5-10 pg / mL; about 5-15 |ig / mL; about 10-20 |ig / mL; about 7.5-15 |ig / mL; about 2-10 |ig / mL; about 1-8 |ig / mL; about 1-6 pg / mL; about 1-2 |ig / mL; about 0.5-3.5 |ig / mL; about 0.5-7 pg / mL; about 12-20 |ig / mL; about 8-12 |ig / mL; about 1-4 pg / mL; about 4-7 pg / mL; about 7-11 |ig / mL; about 11-15 pg / mL; about 15-19 |ig / mL; about 16-20 |ig / mL; or any amount of meloxicam plasma level in a range bounded by, or between, any of these values.

[0199] Administration of a dosage form described herein may result in a decreased time to therapeutic plasma concentration of meloxicam. The therapeutic plasma concentration is the Cavg for a 15 mg dose of Mobic® meloxicam. In some embodiments, the time to therapeutic plasma concentration of meloxicam (Tthera) is about 10-30 minutes, about 10-15 minutes, about 15-20 minutes, about 20-25 minutes, about 25-30 minutes, about 10-20 minutes, about 20-30 minutes, about 16-18 minutes, or about 17 minutes. PCT Patent Application 134057-00001038_7T01PV01-WO A method described herein may reduce the Tmaxof rizatriptan. For example, the method may achieve a Tmaxof rizatriptan in the patient within about 50 minutes; within about 60 minutes; within about 70 minutes; within about 80 minutes; or within about 90 minutes; at about 40-60 minutes, at about 40-45 minutes, at about 45-50 minutes, at about 50-55 minutes, or about 55-60 minutes after administration, or any Tmaxin a range bounded by any of these values.

[0200] In some embodiments, the meloxicam and the rizatriptan are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and two hours after the meloxicam and the rizatriptan are administered, the human being experiences greater relief from allodynia, such as cutaneous allodynia than the human being would have experienced two hours after receiving the same amount of meloxicam without the rizatriptan.

[0201] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and twenty-four hours after the meloxicam and a rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater relief from allodynia, such as cutaneous allodynia than the human being would have experienced twenty-four hours after receiving the same amount of meloxicam without the rizatriptan.

[0202] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and two hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater relief from allodynia, such as cutaneous allodynia than the human being would have experienced two hours after receiving the same amount of rizatriptan without the meloxicam.

[0203] In some embodiments, the meloxicam and the rizatriptan, or a pharmaceutically acceptable salt thereof, are administered simultaneously (e.g., in a single dosage form, such as a single oral dosage form), and twenty-four hours after the meloxicam and the rizatriptan (e.g., rizatriptan benzoate) are administered, the human being experiences greater relief from allodynia, such as cutaneous allodynia than the human being would have experienced twenty-four hours after receiving the same amount of rizatriptan without the meloxicam.

[0204] One embodiment is a method for reducing the risk of gastrointestinal side effects in people taking NSAIDs for pain relief and for other conditions, particularly during chronic treatment, and improving the bioavailability of the NSAID. In one embodiment, the method PCT Patent Application 134057-00001038_7T01PV01-WO involves the administration of a product that combines: a) an agent that actively raises intragastric pH; and b) an NSAID that is formulated with a cyclodextrin. In another embodiment, the method involves the administration of a product that combines: a) an agent that actively raises intragastric pH; b) an NSAID that is formulated with a cyclodextrin; and c) a buffering agent. Either short or long acting acid inhibitors can be effectively used in the dosage forms. This method has the added benefit of being able to protect patients from other gastrointestinal ulcerogens whose effect may otherwise be enhanced by the disruption of gastroprotective prostaglandins due to NSAID therapy.

[0205] The meloxicam formulation in an aqueous parenteral form may include a buffer to adjust the pH of an aqueous formulation, within a range of about 2 to about 5; about 3.5 to about 5; about 5 to about 11; about 6 to about 9; about 6 to about 8; about 6 to about 7; or any other pH in a range bounded by, or between, any of these values. The meloxicam formulation in an oral form may include a buffer to adjust the pH of stomach fluid within a range of about 2 to about 5; about 3.5 to about 5; about 5 to about 11; about 6 to about 9; about 6 to about 8; about 6 to about 7; or any other pH in a range bounded by, or between, any of these values. Examples of buffers suitable for use herein include sulfate buffers, phosphate buffers, borate buffers, carbonate buffers, citrate buffers, etc.

[0206] In some embodiments, the dosage form may be formulated for oral administration, for example, with an inert diluent or with an edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly with the food of the diet. For oral therapeutic administration, the active compound may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, coated tablets, troches, capsules, elixirs, dispersions, suspensions, solutions, syrups, wafers, patches, and the like.

[0207] Tablets, troches, pills, capsules, and the like may also contain one or more of the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient, such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose, or saccharin; or a flavoring agent such as peppermint, oil of Wintergreen or cherry flavoring. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coating, for instance, tablets, pills, or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and PCT Patent Application 134057-00001038_7T01PV01-WO propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. It may be desirable for material in a dosage form or pharmaceutical composition to be pharmaceutically pure and substantially non-toxic in the amounts employed.

[0208] Some compositions or dosage forms may be a liquid, or may comprise a solid phase dispersed in a liquid.

[0209] The dosage form may further comprise a second therapeutically active agent, such as an acid inhibitor or an analgesic.

[0210] In some embodiments, the dosage form may further comprise an acid inhibitor present in an amount effective to raise the gastric pH of a patient to at least 2, to at least 2.5, to at least 3, to at least 3.5, to at least 4, and more to at least 5, when one or more unit dosage forms are administered. The term "acid inhibitor" refers to agents that inhibit gastric acid secretion and increase gastric pH. Specific H2 blockers, also referred to as H2 antagonists or histamine H2 blockers or antagonists, which may be used include but are not limited to cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine, famotidine, or combinations thereof.

[0211] Other agents that may be effectively used as acid inhibitors are the proton pump inhibitors such as omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, rabeprazole, pariprazole, leminoprazole and tenatoprazole. In some embodiments the daily dose of the acid inhibitor is about 1-200 mg, about 1-100 mg, about 1-50 mg, about 40-80 mg, about 5-50 mg, about 20-40 mg, about 10-50 mg, about 10-20 mg, about 20-40 mg, about 15-50 mg, about 30-60 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg or any other amount in a range bounded by, or between, any of these values.

[0212] Examples of particular proton pump inhibitors include esomeprazole, present in unit dosage forms in an amount of between 5 mg and 50 mg; omeprazole, present in unit dosage forms in an amount of between 5 mg and 50 mg; lansoprazole, present in unit dosage forms in an amount of between 5 mg and 150 mg (and preferably at between 5 mg and 30 mg); and pantoprazole, present in unit dosage forms in an amount of between 10 mg and 200 mg. In some embodiments, the proton pump inhibitor is present in the dosage form in an amount of about 10-30 mg, about 20-40 mg, about 30-50 mg, about 40-60 mg, about 50-70 mg, about 60-80 mg, about 70-90 mg, or about 80-100 mg. Recently, a newer class of acid inhibitor has been developed which competes with potassium at the acid pump. The compounds in this class have been referred to as "reversible proton pump inhibitors" or "acid pump antagonists" PCT Patent Application 134057-00001038_7T01PV01-WO and may also be used. Examples include AZD-0865, AR-H047108, CS-526, pumaprazole, revaprazan and soraprazan (see WO9605177 and WO9605199). Other compounds in this group are H-335 / 25 (AstraZeneca, Dialog file 128, accession number 020806); Sch-28080 (Schering Plough, Dialog file 128, accession number 009663); Sch-32651 (Schering Plough, Dialog file 128, accession number 006883) and SK& F-96067 (CAS Registry no. 115607-61-9).

[0213] The second therapeutically active agent may include an analgesic such as a second non-steroidal anti-inflammatory drug, an opioid, a steroid, a triptan, etc. In some embodiments, the dosage form or treatment also further comprises administering a second non-steroidal anti-inflammatory drug in an amount effective to reduce or eliminate pain or inflammation. The NSAID may include, but is not limited to, celecoxib, rofecoxib, lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, NS398, aspirin, acetaminophen (considered to be an NSAID for the purposes of the present disclosure), ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, lornoxicam, meloxicam, piroxicam, droxicam, tenoxicam, nabumetone, diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac, tolmetin, fenoprofen, suprofen, benoxaprofen, aceclofenac, tolfenamic acid, oxyphenbutazone, azapropazone, phenylbutazone, or combinations thereof. It will be understood that, for the purposes of the present disclosure, reference to an acid inhibitor, NSAID, or analgesic agent will include all of the common forms of these compounds and, in particular, their pharmaceutically acceptable salts. The amounts of NSAIDs which are therapeutically effective may be lower in the current embodiments than otherwise found in practice due to potential positive kinetic interaction and NSAID absorption in the presence of an acid inhibitor, and or in the presence of a buffering agent.

[0214] In other embodiments, the dosage form or treatment may further comprise administering an opioid in an amount effective to reduce or eliminate pain or inflammation. The opioid may include, but is not limited to, (dextro)propoxyphene, A-methylfentanyl, alfentanil, allylprodine, bezitramide, buprenorphine, butorphanol, carfentanyl, desmethylprodine, dextromoramide, dezocine, diacetylmorphine, dihydrocodeinone, dihydroetorphine, dimorphone, diphenoxylate, dipipanone, etorphine, fentanyl, ketobemidone, lefetamine, levacetylmethadol, levomethorphan, levorphanol, loperamide, meperidine, meptazinol, methadone, methylmorphine, morphine, nalbuphine, nalmefene, naloxone, naltrexone, nicomorphine, ohmefentanyl, oripavine, oxycodone, oxymorphone, PCT Patent Application 134057-00001038_7T01PV01-WO PEPAP, paramorphine, pentazocine, phenazocine, piritramide, prodine, remifentanil, sufentanil, tapentadol, tilidine, tramadol, or combinations thereof.

[0215] Useful triptans may include sumatriptan, rizatriptan, naratriptan, eletriptan, donitriptan, almotriptan, frovatriptan, alvitriptan, zolmatriptan, etc. In some embodiments, the triptan comprises rizatriptan. In some embodiments, the dosage form may contain about 1-5 mg, about 2-6 mg, about 3-7 mg, about 4-8 mg, about 5-10 mg, about 6-11 mg, about 7-12 mg, about 8-13 mg, about 9-14 mg, about 10-15 mg, about 15-20 mg, or about 20-30 mg, of the triptan, such as rizatriptan, or any amount in a range bounded by any of these values.

[0216] In some embodiments; a dosage form comprising the subject combination may contain rizatriptan in an amount of about 1-50 mg; about 1-10 mg; about 10-20 mg; about 20-30 mg; about 30-40 mg; or about 40-50 mg; about 10-40 mg; about 1-35 mg; about 1-25 mg; about 1-15 mg; about 1-10 mg; about 5-20 mg; about 1-5 mg; about 2-6 mg; about 3-7 mg; about 4-8 mg; about 5-10 mg; about 6-11 mg; about 7-12 mg; about 8-13 mg; about 9-11 mg; about 9-14 mg; about 10-15 mg; about 11-16 mg; about 12-17 mg; about 13-18 mg; about 14-19 mg; about 15-20 mg; about 5-15 mg; about 0.5 mg; about 1 mg; about 1.5 mg; about 2 mg; about 2.5 mg; about 3 mg; about 3.5 mg; about 4 mg; about 4.5 mg; about 5 mg; about 6 mg; about 7 mg; about 7.5 mg; about 8 mg, about 9 mg, about 10 mg; about 15 mg; about 20 mg, about 25 mg, about 30 mg; or any amount in a range bounded by, or between, any of these values.

[0217] For acute migraines, the amount of meloxicam and / or rizatriptan in a single dose, or the AUC of the meloxicam and / or rizatriptan associated with a single dose, is of particular interest. For example, after a single dose, the symptoms may be relieved for an extended period of time, such that, in the short term, repeated doses may not be needed. For more continuous conditions, including more chronic, continuous, or frequent migraine symptoms, daily, weekly, or monthly doses may be of particular interest.

[0218] For any amounts of rizatriptan described herein, salt forms of rizatriptan may be present in the amounts recited above, or amounts that are molar equivalents to these amounts for the rizatriptan free base. For example, assuming that the molecular weight of rizatriptan free base is 269.3 g / mol, 10 mg of rizatriptan is 37.1 mmol of rizatriptan. Thus, a molar equivalent of 10 mg of rizatriptan free base would be the mass of 37.1 mmol of that salt form. For example, for the benzoate salt (mw = 391.2 g / mol), the molar equivalent of 10 mg of the free base (or 37.1 mmol), would be 14.5 mg. These doses may be safe for repeated PCT Patent Application 134057-00001038_7T01PV01-WO administration, such as 1, 2, 3, or 4 times a day, or repeated at an interval of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 4 weeks, 4-6 weeks, about 1-2 months, about 6 weeks, about 2-3 months, about 3-4 months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8 months, about 8-9 months, about 9-10 months, about 10-11 months, about 11-12 months, etc.

[0219] A pharmaceutical composition may be in the form of a tablet or capsule that has: (a) the acid inhibitor; and / or (b) a buffering agent; and (c) the non-steroidal anti-inflammatory drug (NSAID) present in an amount effective to reduce or eliminate pain or inflammation in a patient upon administration of one or more of said unit dosage forms. The components of the pharmaceutical composition may be in an immediate or extended release form individually or in total.

[0220] The term "unit dosage form" as used herein refers to a single entity for drug administration. For example, a single tablet or capsule combining both an acid inhibitor and an NSAID would be a unit dosage form. A "unit dosage form" (or "unit dose form") may also be referred to as a "fixed dosage form" (or "fixed dose form") or "fixed dosage combination" (or "fixed dose combination") and are otherwise interchangeable. In one embodiment, the unit dosage form is a multilayer tablet.

[0221] In another embodiment, the unit dosage form is suitable for oral administration to a patient. In yet another embodiment, the unit dosage form is a tablet. In still another embodiment, the unit dosage form is a multilayer tablet comprising a single core and one or more layers outside of the core.

[0222] Some dosage forms may comprise a first layer comprising meloxicam, an SBEβCD, and a bicarbonate; and a second layer comprising a second therapeutically active agent and a bicarbonate.

[0223] The first layer may contain, for example, any amount of meloxicam in one of the ranges recited above. For example, all of the meloxicam in the dosage form may be present in the first layer. The second layer may contain all of the second therapeutically active agent, such that any amount in the ranges recited above with respect to the second therapeutically active agent may apply to the second layer. PCT Patent Application 134057-00001038_7T01PV01-WO In some embodiments, the first layer contains about 10-200 mg, about 50-150 mg, about 50-100 mg, about 70-120 mg, about 90-140 mg, or about 100 mg of the bicarbonate, such as sodium bicarbonate, or any amount of the bicarbonate in a range bounded by any of these values.

[0224] In some embodiments, the second layer contains about 100-500 mg, about 200-500 mg, about 300-500 mg, about 350-450 mg, about 380-420 mg, or about 400 mg of the bicarbonate, such as sodium bicarbonate, or any amount of the bicarbonate in a range bounded by any of these values.

[0225] In some embodiments, the pharmaceutical composition may have an effective amount of meloxicam, a cyclodextrin, and a carbonate or bicarbonate to increase bioavailability of meloxicam. In other embodiments, the pharmaceutical composition may have an effective amount of meloxicam, sulfobutylether-[3-cyclodextrin (SBEPCD), and sodium bicarbonate to increase bioavailability of meloxicam or reduce the Tmaxof meloxicam.

[0226] Some oral dosage forms may have enteric coatings or film coatings. In some embodiments, a dosage form may comprise a tablet or a capsule having an enteric coating. In some embodiments, a dosage form may comprise a tablet or a capsule having a film coating.

[0227] An embodiment of the present disclosure is directed to a pharmaceutical composition in unit dosage form suitable for administration to a patient, comprising:

[0228] esomeprazole, which may or may not be surrounded by an enteric coating;

[0229] (a) sodium or potassium bicarbonate and / or sodium or potassium carbonate; and (b) meloxicam, which may or may not be formulated with a cyclodextrin, and which may or may not be surrounded by an enteric coating

[0230] An embodiment of the present disclosure is directed to a pharmaceutical composition in unit dosage form suitable for administration to a patient for treat a disease, a condition, or disorder, such as migraine, comprising:

[0231] an inclusion complex of a meloxicam and a sulfobutyl ether β-cyclodextrin (SBEβCD); a bicarbonate, such as sodium bicarbonate or potassium bicarbonate; and

[0232] a triptan, such as rizatriptan.

[0233] In certain embodiments, the pharmaceutical composition results in faster release or dissolution of the meloxicam from the dosage form as compared to a dosage form containing meloxicam but not containing the acid inhibitor, or not containing the buffering agent. PCT Patent Application 134057-00001038_7T01PV01-WO A dosage form comprising a combination of rizatriptan and meloxicam (a "subject combination") may be used to treat migraine. The subject combination may be used for the acute treatment of migraine. The subject combination may provide substantially greater and more sustained migraine pain relief compared to rizatriptan, meloxicam, or placebo. The subject combination may provide rapid relief of migraine pain. The subject combination may significantly reduce the use of rescue medication compared to rizatriptan, meloxicam and placebo. The migraine patients being treated with a combination of rizatriptan, and meloxicam described herein may have a history of inadequate response to prior acute treatments. The migraine patients being treated with a combination of rizatriptan, and meloxicam described herein may have allodynia, such as cutaneous allodynia. The migraine patients being treated with a combination of rizatriptan, and meloxicam described herein may have severe pain intensity. The migraine patients being treated with a combination of rizatriptan, and meloxicam described herein may have obesity. The migraine patients being treated with a combination of rizatriptan, and meloxicam described herein may have morning migraine. The migraine patients being treated with a combination of rizatriptan, and meloxicam described herein may have a total mean score of the Migraine Treatment Optimization Questionnaire (mTOQ-4) of less than 7, such as 1-2, 2-3, 3-4, 4-5, 5-6, or 6-7. The migraine patients being treated with a combination of rizatriptan, and meloxicam described herein may have allodynia, such as cutaneous allodynia, severe pain intensity, obesity, morning migraine, a total mean score of the mTOQ-4 of less than 7, and a history of inadequate response to prior acute treatments. A dosage form comprising a combination of rizatriptan and meloxicam described herein is safe and well tolerated in the migraine patients being treated.

[0234] A dosage form comprising a combination of rizatriptan and meloxicam described herein may provide rapid relief of migraine pain in less than 15 minutes, about 15 minutes, less than 30 minutes, 15-30 minutes, less than 1 hour, 0.5-0.75 hour, or 0.75-1 hour post dose. The combination of rizatriptan and meloxicam described herein may provide relief of migraine pain that is numerically greater than rizatriptan at less than 15 minutes, about 5 minutes, about 5-10 minutes, about 10-15 minutes, about 15 minutes, about 15-30 minutes, about 30-45 minutes, about 45-60 minutes, about 1-1.5 hours, about 1.5-2 hours, about 2-2.5 hours, about 2.5-3 hours, about 3-3.5 hours, about 3.5-4 hours, about 4-5 hours, about 5-6 hours, about 6-8 hours, about 8-10 hours, about 10-12 hours, about 12-24 hours, about 24- PCT Patent Application 134057-00001038_7T01PV01-WO 48 hours, or longer, post dose. The percentage of migraine patients reporting pain relief with the treatment of a combination of rizatriptan, and meloxicam described herein may be 1-100%, 3-100%, 4-100%, 5-100%, 3-5%, 5-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, 90-95%, or 95-100%.

[0235] The migraine patients receiving a dosage form comprising a combination of rizatriptan and meloxicam described herein ("subject combination") may achieve pain freedom at less than 2 hours, about 2 hours, about 2-3 hours, about 3-4 hours, about 4-6 hours, about 6-8 hours, about 8-10 hours, about 10-12 hours, about 12-16 hours, about 16-20 hours, about 20-24 hours, about 24-30 hours, about 30-36 hours, about 36-40 hours, about 40-44 hours, about 44-48 hours, or longer post dose.

[0236] The percentage of migraine patients achieving pain freedom increases over time after receiving a dose of a combination of rizatriptan and meloxicam described herein. For example, at 2 h post dose, the percentage of migraine patients achieving pain freedom may be about 15-25%, about 15-20%, about 20%, about 20-25%. At 4 h post dose, the percentage of migraine patients achieving pain freedom may be about 30-50%, about 30-40%, about 40%, about 40-45%, about 45-47%, about 47-50%. At 12 h post dose, the percentage of migraine patients achieving pain freedom may be about 45-70%, about 45-50%, about 50-55%, about 55-60%, about 56-57%, about 60-65%, about 65-70%. At 16 h post dose, the percentage of migraine patients achieving pain freedom may be about 45-70%, about 45-50%, about 50-55%, about 55-60%, about 58-59%, about 60-65%, about 65-70%. The combination of rizatriptan and meloxicam described herein may provide significant improvement over rizatriptan in pain freedom in the migraine patients. There may be about 2-10%, 2-3%, 3-5%, 5-7%, 6-7%, 7-8%, 8-9%, or 9-10% more migraine patients receiving the combination of rizatriptan and meloxicam described herein achieving pain freedom than the migraine patients receiving rizatriptan at 2-16 hours post dose with an improvement of about 10-25%, 10-15%, 14-15%, 15-16%, 16-17%, 17-18%, 18-19%, 19-20%, 20-21%, or 21-25%. For example, at 4 hours post dose, if about 40% migraine patients receiving the subject combination achieve pain freedom, while 33% migraine patients receiving rizatriptan achieve pain freedom, then the improvement of the subject combination is about 21% [((40-33) / 33)x100%]. The improvement with the subject combination over meloxicam may be bigger than over rizatriptan in migraine patients achieving pain freedom. For example, The improvement with the subject combination over meloxicam in migraine patients achieving PCT Patent Application 134057-00001038_7T01PV01-WO pain freedom may be about 25-75%, 25-30%, 27-28%, 28-29%, 30-40%, 40-50%, 50-60%, 55-50%, 60-70%, 65-75%, or 70-75% at 2-16 hours post dose.

[0237] There may be at least 50%, at least 60%, at least 70%, at least 80%, about 70-80%, about 80-90%, about 90-95%, about 80% of migraine patients receiving the combination of rizatriptan and meloxicam described herein ("subject combination") achieving pain freedom at 2 hours may maintain it through 24 hours post dose. The increase of the number of migraine patients (or improvement) achieving sustained pain freedom from 2-24 hours post dose of the subject combination may be about 35-55%, about 35-40%, about 40-45%, about 45-50%, or about 50-55% as compared to administering rizatriptan. The increase of the number of migraine patients (or improvement) achieving sustained pain freedom from 2-24 hours post dose of the subject combination may be about 100-165%, about 100-110%, about 110-120%, about 120-130%, about 130-140%, about 140-150%, about 150-160%, or about 160-165% as compared to administering meloxicam.

[0238] The increase of the number of migraine patients (or improvement) achieving sustained pain relief from 2-24 hours post dose of the subject combination may be about 15-30%, about 15-20%, about 20-25%, about 25-30%, about 20-22%, or about 21% as compared to administering rizatriptan. The increase of the number of migraine patients (or improvement) achieving sustained pain relief from 2-24 hours post dose of the subject combination may be about 20-35%, about 20-25%, about 25-30%, about 30-35%, about 25-26%, about 26-27%, about 27-28%, about 28-30%, or about 27% as compared to administering meloxicam.

[0239] There may be at least 50%, at least 60%, at least 70%, at least 80%, about 70-80%, about 80-90%, about 90-95%, or about 77% of migraine patients receiving the combination of rizatriptan and meloxicam described herein ("subject combination") achieving pain freedom at 2 hours may maintain it through 48 hours post dose. The increase of the number of migraine patients (or improvement) achieving sustained pain freedom from 2-48 hours post dose of the subject combination may be about 60-90%, about 60-70%, about 70-75%, about 75-80%, about 80-90%, or about 75% as compared to administering rizatriptan. The increase of the number of migraine patients (or improvement) achieving sustained pain freedom from 2-48 hours post dose of the subject combination may be about 70-110%, about 70-80%, about 80-90%, about 90-100%, about 100-110%, or about 90% as compared to administering meloxicam. PCT Patent Application 134057-00001038_7T01PV01-WO The increase of the number of migraine patients (or improvement) achieving sustained pain relief from 2-48 hours post dose of the subject combination may be about 20-35%, about 20-25%, about 25-30%, about 30-35%, about 25-26%, about 26-27%, about 27-28%, about 28-20%, or about 27% as compared to administering rizatriptan. The increase of the number of migraine patients (or improvement) achieving sustained pain relief from 2-48 hours post dose of the subject combination may be about 15-30%, about 15-20%, about 20-25%, about 25-30%, about 20-21%, about 21-22%, about 22-23%, about 23-24%, about 24-25%, or about 23% as compared to administering meloxicam.

[0240] There may be at least 50%, at least 60%, at least 70%, about 60-65%, about 65-70%, about 70-75%, about 75-80%, about 80-85%, about 85-90%, about 90-95%, or about 77% of migraine patients receiving the combination of rizatriptan and meloxicam described herein ("subject combination") may not require rescue medication. The decrease of the number of migraine patients who took rescue medication through 24 hours post dose of the subject combination may be about 35-60%, about 35-40%, about 40-45%, about 45-50%, about 50-55%, about 55-60%, about 47-48%, or about 47% as compared to administering placebo. The decrease of the number of migraine patients who took rescue medication through 24 hours post dose of the subject combination may be about 25-45%, about 25-30%, about 30-35%, about 35-40%, about 40-45%, about 34-36%, or about 35% as compared to administering meloxicam. The decrease of the number of migraine patients who took rescue medication through 24 hours post dose of the subject combination may be about 25-40%, about 25-30%, about 30-35%, about 35-40%, about 33-35%, or about 34% as compared to administering rizatriptan. In some embodiments, the migraine patient does not take rescue medication in the 24 hours after the subject combination is administered.

[0241] In some embodiments, this disclosure relates to a combination of meloxicam (an NSAID) and a rizatriptan (a serotonin (5-HT) 1B / 1D receptor agonist or triptan) for the acute treatment of migraine with or without aura in adults. For convenience, dosage form comprising a combination of meloxicam and rizatriptan benzoate as described herein is referred to as the "subject dosage form." In some embodiments, the subject dosage form (e.g., one tablet) is administered by mouth at the onset of a migraine.

[0242] In some embodiments, the maximum daily dose of meloxicam is 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam. In some embodiments, the maximum PCT Patent Application 134057-00001038_7T01PV01-WO daily dose of rizatriptan is 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan.

[0243] In some embodiments, the maximum daily dose is unit of the dosage form or one tablet, or 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan.

[0244] In some embodiments, no more than 7 migraines or migraine attacks are treated in a 30-day period.

[0245] Meloxicam has the molecular formula C14H13N3O4S2and is chemically designated as 4- hydroxy-2-methyl-N-(5 methyl-2-thiazolyl)-2H-l,2-benzothiazine-3-carboxamide-l,l-dioxide. It has a molecular weight of 351.4 g / mole.

[0246] The structural formula is:

[0247] OH 0

[0248] S' '"" V"',1 A H Ji A —CHS

[0249]

[0250] d b

[0251] Meloxicam is a pastel yellow solid, practically insoluble in water, with higher solubility observed in strong acids and bases. It is very slightly soluble in methanol. Meloxicam has an apparent partition coefficient (log P) = 0.1 in n-octanol / buffer pH 7.4. Meloxicam has pKa values of 1.1 and 4.2.

[0252] Rizatriptan benzoate has the molecular formula C15H19N5·C7H6O2and is chemically designated as N, N dimethyl-5-(lH-l,2,4-triazol-l-ylmethyl)-lH indole-3 ethanamine monobenzoate. The molecular weight of the free base rizatriptan is 269.4 g / mole. The structural formula is:

[0253] OTOH

[0254]

[0255] Rizatriptan benzoate is a white to off-white, crystalline solid that is soluble in water at about 42 mg per mL (expressed as free base) at 25°C.

[0256] Unless otherwise indicated, any reference to a compound herein, such as rizatriptan or meloxicam, by structure, name, or any other means, includes pharmaceutically acceptable salts; alternate solid forms, such as polymorphs, crystals, solvates, hydrates, etc.; tautomers; PCT Patent Application 134057-00001038_7T01PV01-WO deuterium-modified compounds, such as deuterium modified dextromethorphan; or any chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.

[0257] A dosage form, such as a tablet, may contain, for example, about 18-22 mg, such as 20 mg of meloxicam free acid, or a molar equivalent amount of a salt form of meloxicam, and about 9-11 mg, such as about 10 mg of rizatriptan free base, or a molar equivalent amount of a salt form of rizatriptan (e.g., about 14-15 mg, such as about 14.5 mg, of rizatriptan benzoate, or a molar equivalent amount of another salt form of rizatriptan).

[0258] A dosage form, such as a tablet, may also contain: colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, partially hydrolyzed polyvinyl alcohol, polyethylene glycol, povidone, pregelatinized starch, sodium bicarbonate, sulfobutyl-ether-P-cyclodextrin sodium, talc, and / or titanium dioxide.

[0259] In some embodiments, the dosage form, such as the tablet, contains colloidal silicon dioxide.

[0260] In some embodiments, the dosage form, such as the tablet, contains crospovidone. In some embodiments, the dosage form, such as the tablet, contains magnesium stearate.

[0261] In some embodiments, the dosage form, such as the tablet, contains microcrystalline cellulose.

[0262] In some embodiments, the dosage form, such as the tablet, contains partially hydrolyzed polyvinyl alcohol.

[0263] In some embodiments, the dosage form, such as the tablet, contains polyethylene glycol.

[0264] In some embodiments, the dosage form, such as the tablet, contains povidone.

[0265] In some embodiments, the dosage form, such as the tablet, contains pregelatinized starch.

[0266] In some embodiments, the dosage form, such as the tablet, contains sodium bicarbonate.

[0267] In some embodiments, the dosage form, such as the tablet, contains sulfobutyl-ether-P-cyclodextrin sodium.

[0268] In some embodiments, the dosage form, such as the tablet, contains talc.

[0269] In some embodiments, the dosage form, such as the tablet, contains titanium dioxide. PCT Patent Application 134057-00001038_7T01PV01-WO In some embodiments, the human patient is screened for a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. In some embodiments, the human patient does not have, or is selected for not having a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal anaphylactic-like reactions to NSAIDs have been reported in such patients.

[0270] In some embodiments, the human patient is screened for history of ischemic heart disease or coronary artery vasospasm. In some embodiments, the human patient does not have, or is selected for not having a history of ischemic heart disease or coronary artery vasospasm.

[0271] In some embodiments, the human patient is screened for a history of stroke or transient ischemic attack. In some embodiments, the human patient does not have, or is selected for not having a history of stroke or transient ischemic attack.

[0272] In some embodiments, the human patient is screened for a peripheral vascular disease. In some embodiments, the human patient does not have, or is selected for not having a peripheral vascular disease.

[0273] In some embodiments, the human patient is screened for an ischemic bowel disease. In some embodiments, the human patient does not have, or is selected for not having an ischemic bowel disease.

[0274] In some embodiments, the human patient is screened for uncontrolled hypertension. In some embodiments, the human patient does not have, or is selected for not having an uncontrolled hypertension.

[0275] In some embodiments, the human patient is screened for moderate to severe renal insufficiency. In some embodiments, the human patient does not have, or is selected for not having a moderate to severe renal insufficiency.

[0276] In some embodiments, the human patient is screened for recent (within 24 hours) use of an ergotamine-containing medication. In some embodiments, the human patient does not have, or is selected for not having a recent (within 24 hours) use of an ergotamine-containing medication. PCT Patent Application 134057-00001038_7T01PV01-WO In some embodiments, the human patient is screened for use of a MAO-A inhibitor in the past 2 weeks. In some embodiments, the human patient does not have, or is selected for not having a used an MAO-A inhibitor in the past 2 weeks.

[0277] In some embodiments, the human patient is screened for hemiplegic or basilar migraine. In some embodiments, the human patient does not have, or is selected for not having a hemiplegic or basilar migraine.

[0278] In some embodiments, a subject combination is not administered in the setting of CABG surgery.

[0279] In some embodiments, if the patient has multiple cardiovascular risk factors, a cardiac evaluation is performed on the patient. For example, the human patient may be evaluated for myocardial ischemia, myocardial infarction, and / or Prinzmetal's angina.

[0280] In some embodiments, the human patient is screened for cluster headaches. In some embodiments, the human patient does not have, or is selected for not having cluster headaches.

[0281] In some embodiments, the human patient is screened for tension headaches. In some embodiments, the human patient does not have, or is selected for not having tension headaches.

[0282] In some embodiments, the human patient is screened for more than eight migraine headaches during either of the past two months. In some embodiments, the human patient does not have, or is selected for not having more than eight migraine headaches during either of the past two months.

[0283] In some embodiments, the human patient is screened for chronic daily headaches, or 15 or more non-migraine headache days / month for the past three months. In some embodiments, the human patient does not have, or is selected for not having chronic daily headaches, or 15 or more non-migraine headache days / month for the past three months.

[0284] In some embodiments, the human patient is screened for hemiplegic or basilar migraine. In some embodiments, the human patient does not have, or is selected for not having a hemiplegic or basilar migraine.

[0285] In some embodiments, the human patient is screened for hemiplegic or basilar migraine. In some embodiments, the human patient does not have, or is selected for not having a hemiplegic or basilar migraine.

[0286] In some embodiments the human patient is, or is selected for being, 18 to 65 years of PCT Patent Application 134057-00001038_7T01PV01-WO age inclusive.

[0287] In some embodiments the human patient has, or is selected for having, an established diagnosis of migraine (history indicating the presence of migraine for at least 1 year) with or without aura as defined by the International Classification of Headache Disorders 3rd edition (ICHD-3) criteria.

[0288] In some embodiments the human patient has, or is selected for having, a diagnosis of migraine attacks with or without aura, presenting before age 50.

[0289] In some embodiments the human patient has, or is selected for having, had a history, on average, of 2 to 8 migraine attacks per month over the past 3 months.

[0290] In some embodiments the human patient has, or is selected for having, at least 1, and no more than 8, migraine attacks in each of the past three months.

[0291] In some embodiments the human patient has, or is selected for having had a history of usual migraine duration of >3 hours untreated (by history) for the past 3 months.

[0292] In some embodiments the human patient has, or is selected for having, had a body weight >45 kg and a BMI ≤40 kg / m2.

[0293] In some embodiments the human patient has not, or is selected for not having, received a selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI); if the human patient is receiving a selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI), the dose had been stable for at least 8 weeks prior to treatment.

[0294] In some embodiments, if female, the human patient is, or is selected for being, either not of childbearing potential (defined as postmenopausal for at least 1 year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy, or hysterectomy]) or nonlactating and nonpregnant (had negative pregnancy test results at screening and baseline), did not plan to get pregnant during the study or for at least 1 month after, and was using a reliable method of contraception, before study drug administration and for the duration of the study. Reliable methods of contraception included hormonal, double-barrier methods (e.g., condom and diaphragm, condom and foam, condom and sponge, each with spermicidal jellies or cream), intrauterine devices, vasectomized partners (>6 months prior to randomization), and abstinence.

[0295] In some embodiments the human patient is, or is selected for being, willing and able to complete a Headache Diary. PCT Patent Application 134057-00001038_7T01PV01-WO In some embodiments, the human patient has not, or is selected for not having, a known history of allergic reaction, hypersensitivity, or clinically significant intolerance to rizatriptan or another triptan, acetaminophen, aspirin, or any NSAIDs, including meloxicam; history of NSAID-induced bronchospasm (participants with the triad of asthma, nasal polyps, and chronic rhinitis were at greater risk for bronchospasm and were to be considered carefully); or hypersensitivity, allergy, or significant reaction to any ingredients of the study drug.

[0296] In some embodiments, the human patient has not, or is selected for not having, experienced >8 migraine attacks monthly during either of the past 2 months.

[0297] In some embodiments, the human patient was not, or is selected for not suffering from cluster headaches (every day or every other day), or other types of migraine.

[0298] In some embodiments, the human patient has not, or is selected for not having experienced chronic daily headache (>15 days per month of non-migraine headaches during each of the prior 3 months).

[0299] In some embodiments, the human patient does not, or is selected for not having a history of brain stem aura, ophthalmoplegic or hemiplegic migraine headache, or any potentially serious neurological condition that was associated with headache.

[0300] In some embodiments, the human patient has not, or is selected for not having confirmed or suspected cardiovascular or cerebrovascular disease.

[0301] In some embodiments, the human patient has not, or is selected for not having history, symptoms, or significant risk factors for ischemic heart (e.g., silent ischemia, angina, myocardial infarction); coronary artery vasospasm; arrhythmia (e.g., atrial fibrillation or flutter, frequent premature ventricular contractions, atrioventricular block); clinically significant findings on ECG; cardiac accessory conduction pathway disorder (e.g., Wolff-Parkinson-White syndrome); or other cardiovascular disease.

[0302] In some embodiments, the human patient has not, or is selected for not having history of stroke, transient ischemic attack, or other cerebrovascular syndrome; peripheral vascular disease; or ischemic bowel disease.

[0303] In some embodiments, the human patient has not, or is selected for not having uncontrolled hypertension (diastolic blood pressure >95 mm Hg or systolic blood pressure >160 mm Hg).

[0304] In some embodiments, the human patient is female, and has not, or is selected for not PCT Patent Application 134057-00001038_7T01PV01-WO having was taking estrogenic contraceptives and, in addition, smoked and had experienced migraine attack with aura.

[0305] In some embodiments, the human patient has not, or is selected for not having a concurrent medical condition(s) that required the chronic (daily or near daily) use of analgesics, narcotic analgesics, steroidal or nonsteroidal anti-inflammatory agents, tranquilizers, sedatives, hypnotics, antipsychotics, or nitrates or their use for prevention of migraine attacks.

[0306] In some embodiments, the human patient has not, or is selected for not having clinically significant abnormalities indicated from the medical history, physical examination, clinical chemistry, hematology, or urine drug screen.

[0307] In some embodiments, the human patient has not, or is selected for not having a diagnosis or suspicion of drug-induced or chronic daily headaches within 1 year.

[0308] In some embodiments, the human patient has not, or is selected for not having used monoamine oxidase (MAO) inhibitor, lithium, methylergonovine, orcimetidine in the 2 weeks before randomization.

[0309] In some embodiments, the human patient has not, or is selected for not having a history or current diagnosis of any clinically significant cardiac, pulmonary, neurological, immunological, hematological, gastrointestinal (Gl), hepatic, renal, or endocrine disease.

[0310] In some embodiments, the human patient has not, or is selected for not having a history or current diagnosis of schizophrenia or another significant psychiatric disorder.

[0311] In some embodiments, the human patient has not, or is selected for not having receiving systemic chemotherapy, had an active malignancy of any type, or had been diagnosed with cancer within the previous 5 years (excluding squamous or basal cell carcinoma of the skin).

[0312] In some embodiments, the human patient has not, or is selected for not having a known or suspected history of alcoholism or drug abuse or misuse within the past 1 year.

[0313] In some embodiments, the human patient has not, or is selected for not currently having, or within 1 year, any clinically significant Gl disorder, including peptic or gastric ulcers or Gl bleeding.

[0314] In some embodiments, the human patient has not, or is selected for not having a medical or surgical condition of the Gl system (including motility dysfunction) or renal system that might significantly alter the absorption, distribution, or excretion of any drug substance. PCT Patent Application 134057-00001038_7T01PV01-WO In some embodiments, the human patient being treated with the subject dosage form is not treated with concurrent analgesic or NSAID.

[0315] In some embodiments, the human patient has not, or is selected for not currently receiving or expecting to use anticoagulants (e.g., heparin, warfarin, nutritional supplements having anticoagulant properties) or having bleeding problems, coagulation abnormalities, active blood dyscrasia, hemorrhagic disease, anemia, porphyria, phenylketonuria, bone marrow suppression, or immunosuppression.

[0316] In some embodiments, the human patient has not, or is selected for not currently receiving propranolol or had received propranolol within the past 2 weeks.

[0317] In some embodiments, the human patient has not, or is selected for not having been treated with agents that could have affected the analgesic response (such as central alpha adrenergic agents [clonidine and tizanidine]) within the past 2 weeks.

[0318] A combination of meloxicam and a rizatriptan (e.g., rizatriptan benzoate) should not be given to patients with ischemic or vasospastic coronary artery disease. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of rizatriptan. Some of these reactions occurred in patients without known coronary artery disease (CAD). 5-HT1 agonists, including a subject combination may cause coronary artery vasospasm (Prinzmetal's Angina), even in patients without a history of CAD.

[0319] In some embodiments, triptan-naive patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) have a cardiovascular evaluation prior to receiving a subject combination. In some embodiments, if there is evidence of CAD or coronary artery vasospasm, a subject combination is not administered. In some embodiments, for a human patient who has a negative cardiovascular evaluation, a treatment method comprises administering a first dose of a subject combination in a medically-supervised setting, and performing an electrocardiogram (ECG) on the human patient immediately following administration of a subject combination. In some embodiments, a treatment method may comprise periodic cardiovascular evaluation wherein the human patient is an intermittent long-term users of a subject combination, and the human patient has cardiovascular risk factors.

[0320] In some embodiments, the use of a subject combination in patients with a recent myocardial infarction (Ml) is avoided unless the benefits are expected to outweigh the risk of PCT Patent Application 134057-00001038_7T01PV01-WO recurrent CV thrombotic events. In some embodiments, if a subject combination is used in a human patient with a recent Ml, the human patient is monitored for signs of cardiac ischemia.

[0321] In some embodiments, the human patient is screened for ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), or other significant underlying cardiovascular disease. In some embodiments, the human patient does not have, or is selected for not having ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), or other significant underlying cardiovascular disease.

[0322] In some embodiments, the human patient is screened for coronary artery vasospasm including Prinzmetal's angina. In some embodiments, the human patient does not have, or is selected for not having coronary artery vasospasm including Prinzmetal's angina.

[0323] In some embodiments, the human patient is screened for a history of stroke or transient ischemic attack (TIA). In some embodiments, the human patient does not have, or is selected for not having a history of stroke or transient ischemic attack (TIA).

[0324] In some embodiments, the human patient is screened for peripheral vascular disease (PVD). In some embodiments, the human patient does not have, or is selected for not having PVD.

[0325] In some embodiments, the human patient is screened for ischemic bowel disease. In some embodiments, the human patient does not have, or is selected for not having ischemic bowel disease.

[0326] In some embodiments, the human patient is screened for uncontrolled hypertension. In some embodiments, the human patient does not have, or is selected for not having uncontrolled hypertension.

[0327] In some embodiments, the human patient is screened for to determine whether they are moderate to severe renal insufficiency patients who are at risk for renal failure due to volume depletion. In some embodiments, the human patient does not have, or is selected for not being moderate to severe renal insufficiency patients who are at risk for renal failure due to volume depletion.

[0328] In some embodiments, the human patient is screened for recent use (i.e., within 24 hours) of an ergotamine-containing medication, or ergot-type medication (such as dihydroergotamine or methysergide). In some embodiments, the human patient has not, or PCT Patent Application 134057-00001038_7T01PV01-WO is selected for not recently used (i.e., within 24 hours) of an ergotamine-containing medication, or ergot-type medication (such as dihydroergotamine or methysergide).

[0329] In some embodiments, the human patient is screened for concurrent administration or recent discontinuation (i.e., within 2 weeks) of a MAO-A inhibitor. In some embodiments, the human patient does not have, or is selected for not having concurrent administration or recent discontinuation (i.e., within 2 weeks) of a MAO-A inhibitor.

[0330] In some embodiments, the human patient is screened for hemiplegic or basilar migraine. In some embodiments, the human patient does not have, or is selected for not having hemiplegic migraine. In some embodiments, the human patient does not have, or is selected for not having basilar migraine.

[0331] In some embodiments, the human patient is monitored for life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, and the subject dosage form is discontinued if these disturbances occur.

[0332] As with other 5-HT1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck and jaw commonly occur after treatment with the subject dosage form and are usually non-cardiac in origin. However, in some embodiments, a cardiac origin is suspected, the human patient is evaluated. In some embodiments, the evaluation reveals that the human patient does not have Coronary Artery Disease (CAD) or Prinzmetal's variant angina, and treatment with the subject dosage form is continued.

[0333] Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not.

[0334] In some embodiments, the human patient is monitored for a cerebrovascular event (e.g., stroke, hemorrhage, transient ischemic attack). If no cerebrovascular event (e.g., stroke, hemorrhage, transient ischemic attack) occurs, treatment with a subject dosage form is continued. If a cerebrovascular event occurs, treatment with the subject dosage form is discontinued.

[0335] In some embodiments, the human patient has not previously been diagnosed as a migraineur, and the human patient is evaluated to exclude other potentially serious neurological conditions before the subject dosage form is administered as described herein. PCT Patent Application 134057-00001038_7T01PV01-WO In some embodiments, the human patient is migraineur who presents with atypical symptoms, and the human patient is evaluated to exclude other potentially serious neurological conditions before the subject dosage form is administered as described herein. In some embodiments, the human patient is evaluated to exclude a history of stroke or transient ischemic attack before the subject dosage form is administered as described herein.

[0336] 5-HT1 agonists, including the subject dosage form, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud's syndrome. In some embodiments, the human patient has experienced symptoms or signs suggestive of non-coronary vasospasm reaction following the use of a 5-HT1 agonist, and the suspected vasospasm reaction is ruled out before receiving the subject dosage form, or before receiving additional doses of the subject dosage.

[0337] NSAIDs, including meloxicam, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs [see SYMBRAVO® (meloxicam and rizatriptan) PRESCRIBING INFORMATION, Drug Interactions (7.1), copied below]. PCT Patent Application 134057-00001038_7T01PV01-WO 7.1 Drugs Having Clinically Important Interactions with SYMBRAVO

[0338] Table 2a: Clinically Important Drug Interactions with SYMBRAVO

[0339] Drugs That Interfere with Hemostasis

[0340] • Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug Clinical alone.

[0341] Impact • Serotonin release by platelets plays an important role in hemostasis.

[0342] Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Monitor patients with concomitant use of SYMBRAVO with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions]. Intervention

[0343] Caution should be used when administering SYMBRAVO with warfarin since patients on warfarin may experience changes in International Normalized Ratio (INR) and an increased risk of bleeding complications when a new medication is introduced.

[0344]

[0345] PCT Patent Application 134057-00001038_7T01PV01-WO Aspirin

[0346] Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect Clinical than the use of NSAIDs alone. In a clinical study, the concomitant use of an Impact NSAID and aspirin was associated with a significantly increased incidence of Gl adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions].

[0347] • Concomitant use of SYMBRAVO and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions].

[0348] • In the setting of concomitant use of low-dose aspirin for cardiac Intervention

[0349] prophylaxis, monitor patients more closely for evidence of Gl bleeding [see Warnings and Precautions].

[0350] • Meloxicam in SYMBRAVO is not a substitute for low dose aspirin for cardiovascular protection.

[0351] SSRIs / SNRIs and Serotonin Syndrome

[0352] Clinical Cases of serotonin syndrome have been reported during co-administration Impact of triptans and SSRIs or SNRIs [see Warnings and Precautions].

[0353] SYMBRAVO treatment should be discontinued if serotonin syndrome is Intervention

[0354] suspected.

[0355]

[0356] PCT Patent Application 134057-00001038_7T01PV01-WO ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers

[0357] • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta blockers.

[0358] • In patients who are elderly, volume-depleted (including those on Clinical

[0359] diuretic therapy), or have renal impairment, co-administration of an Impact

[0360] NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.

[0361] • Propranolol has been shown to increase the plasma AUC of rizatriptan.

[0362] • During concomitant use of SYMBRAVO and ACE-inhibitors, ARBs, or beta blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.

[0363] • During concomitant use of SYMBRAVO and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal Intervention function, monitor for signs of worsening renal function [see Warnings and Precautions].

[0364] • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

[0365] • The concomitant use of SYMBRAVO with propranolol is contraindicated.

[0366]

[0367] PCT Patent Application 134057-00001038_7T01PV01-WO Diuretics

[0368] Clinical studies, as well as postmarketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the Clinical

[0369] NSAID inhibition of renal prostaglandin synthesis. However, studies with Impact

[0370] furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. During concomitant use of SYMBRAVO with diuretics, observe patients for Intervention signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions].

[0371] Lithium

[0372] NSAIDs have produced elevations in plasma lithium levels and reductions in Clinical

[0373] renal lithium clearance. This effect has been attributed to NSAID inhibition Impact

[0374] of renal prostaglandin synthesis.

[0375] During concomitant use of SYMBRAVO and lithium, monitor patients for Intervention

[0376] signs of lithium toxicity.

[0377] Methotrexate

[0378] Concomitant use of NSAIDs and methotrexate may increase the risk for Clinical

[0379] methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal Impact

[0380] dysfunction).

[0381] During concomitant use of SYMBRAVO and methotrexate, monitor patients Intervention

[0382] for methotrexate toxicity.

[0383] Cyclosporine

[0384] Clinical Concomitant use of meloxicam and cyclosporine may increase Impact cyclosporine's nephrotoxicity.

[0385] During concomitant use of SYMBRAVO and cyclosporine, monitor patients Intervention

[0386] for signs of worsening renal function.

[0387]

[0388] PCT Patent Application 134057-00001038_7T01PV01-WO NSAIDs and Salicylates

[0389] Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., Clinical

[0390] diflunisal, salsalate) increases the risk of Gl toxicity, with little or no increase Impact

[0391] in efficacy [see Warnings and Precautions].

[0392] The concomitant use of SYMBRAVO with other NSAIDs or salicylates is not Intervention

[0393] recommended.

[0394] Pemetrexed

[0395] Concomitant use of meloxicam and pemetrexed may increase the risk of Clinical

[0396] pemetrexed-associated myelosuppression, renal, and Gl toxicity (see the Impact

[0397] pemetrexed prescribing information).

[0398] During concomitant use of SYMBRAVO and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL / min, monitor for myelosuppression, renal and Gl toxicity.

[0399] Intervention Patients taking SYMBRAVO should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL / min, the concomitant administration of SYMBRAVO with pemetrexed is not recommended.

[0400] CYP2C9 Inhibitors

[0401] In vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in the metabolic pathway of meloxicam Clinical with a minor contribution of the CYP3A4 isozyme. Thus, concomitant usage Impact of CYP2C9 inhibitors (e.g., amiodarone, fluconazole) may lead to abnormally high plasma levels of meloxicam due to reduced metabolic clearance [see Use in Specific Populations (8.8), Clinical Pharmacology (12.3, 12.5)].

[0402] Use of SYMBRAVO in patients undergoing treatment with CYP2C9 inhibitors Intervention

[0403] is not recommended.

[0404]

[0405] PCT Patent Application 134057-00001038_7T01PV01-WO Ergot-Containing Drugs

[0406] Clinical Ergot-containing drugs have been reported to cause prolonged vasospastic Impact reactions.

[0407] Because these effects may be additive with rizatriptan, use of ergotamine- containing or ergot-type medications (e.g., di hydroergotamine or Intervention

[0408] methysergide) and SYMBRAVO within 24 hours is contraindicated [see Contraindications (4)].

[0409] 5-HTi Agonists

[0410] Clinical Vasospastic effects may be additive with co-administration within 24 hours Impact of another 5-HT1 agonists.

[0411] Use of SYMBRAVO within 24 hours of another 5HT1 agonist is Intervention

[0412] contraindicated [see Contraindications (4)].

[0413] Monoamine Oxidase Inhibitors

[0414] Clinical MAO-A inhibitors increase the systemic exposure of rizatriptan and its Impact metabolite.

[0415] SYMBRAVO is contraindicated in patients taking MAO-A inhibitors and non- Intervention

[0416] selective MAO inhibitors [see Contraindications].

[0417]

[0418] Significant elevation in blood pressure (BP), including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients with and without a history of hypertension receiving 5-HT1 agonists, including rizatriptan. In healthy young adult male and female patients who received maximal doses of rizatriptan (10 mg of the free base every 2 hours for 3 doses or 14.5 mg of rizatriptan benzoate), slight increases in BP (approximately 2-3 mmHg) were observed. In some embodiments, the human patient is monitored or evaluated for uncontrolled hypertension. In some embodiments, the human patient does not have, or is selected for not having, uncontrolled hypertension.

[0419] In some embodiments, the blood pressure of the human patient is monitored during the initiation of the subject dosage form treatment. In some embodiments, the blood pressure of the human patient is monitored throughout the course of therapy. In some PCT Patent Application 134057-00001038_7T01PV01-WO embodiments, the blood pressure of the human patient is monitored during the initiation of the subject dosage form treatment and throughout the course of therapy.

[0420] In some embodiments, the lowest effective dosage of the subject dosage form is administered the shortest possible duration.

[0421] In some embodiments, the subject dosage form is not administered with another NSAID.

[0422] In some embodiments, the subject dosage form is administered to the human patient for treatment of migraine, and the human patient and those responsible for the care of the human patient are advised to remain alert for signs and symptoms of Gl ulceration and bleeding.

[0423] In some embodiments, the human patient is suspected to have a serious Gl adverse event, the human patient is evaluated and treated for a serious Gl adverse event, and the subject dosage form is not administered again until a serious Gl adverse event is ruled out.

[0424] In some embodiments, the subject dosage form is administered to a human patient who is concomitantly using aspirin (such as low-dose aspirin) for cardiac prophylaxis, and the human patient is monitored for evidence of Gl bleeding.

[0425] In some embodiments, the human patient is informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms), and treatment is continued only as long as clinical signs and symptoms consistent with liver disease do not develop, and if systemic manifestations do not occur (e.g., eosinophilia, rash, etc.).

[0426] In some embodiments, the human patient treated with the subject dosage form has a sign or symptom of anemia, and the hemoglobin or hematocrit of the patient is monitored.

[0427] In some embodiments, the human patient has a co-morbid condition such as a coagulation disorder, or is concomitantly using of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), SSRIs, an SNRIs, or a combination thereof, and the human patient is monitored for signs of bleeding.

[0428] The pharmacological activity of the subject dosage form in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

[0429] In some embodiments, the human patient being treated with the subject dosage form is periodically monitored with a complete blood count (CBC) and / or a chemistry profile. PCT Patent Application 134057-00001038_7T01PV01-WO In some embodiments, the human patient being is treated with the subject dosage and concomitant use of anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), SSRIs, and SNRIs is monitored for signs of bleeding.

[0430] In some embodiments, the human patient being treated with the subject dosage form is not receiving concomitant analgesic doses of aspirin.

[0431] In some embodiments, the human patient being treated with the subject dosage form is receiving concomitant low-dose aspirin for cardiac prophylaxis, and the human patient is monitored more closely for evidence of Gl bleeding.

[0432] In some embodiments, the human patient being treated with the subject dosage form, and there is no indication that the human patient is experiencing serotonin syndrome.

[0433] In some embodiments, the human patient is concomitantly treated with the subject dosage form and an ACE-inhibitor, an ARB, or a beta blocker, and the human patient's blood pressure is monitored. In some embodiments, the human patient is hydrated. In some embodiments, the renal function of the human patient is assessed at the beginning of the concomitant treatment and periodically thereafter.

[0434] In some embodiments, the human patient is concomitantly treated with the subject dosage form an ACE-inhibitors or an ARBs, wherein the human patient is elderly, volume-depleted, or has impaired renal function, and the human patient is monitored for signs of worsening renal function. In some embodiments, the human patient is hydrated. In some embodiments, the renal function of the human patient is assessed at the beginning of the concomitant treatment and periodically thereafter.

[0435] In some embodiments, the human patient is concomitantly treated with the subject dosage form and a diuretic, and the human patient is observed for signs of worsening renal function.

[0436] In some embodiments, the human patient is concomitantly treated with the subject dosage form and lithium, and the human patient is monitored for signs of lithium toxicity.

[0437] In some embodiments, the human patient is concomitantly treated with the subject dosage form and methotrexate, and the human patient is monitored for methotrexate toxicity.

[0438] In some embodiments, the human patient is concomitantly treated with the subject dosage form and cyclosporine, and the human patient is monitored for signs of worsening renal function. PCT Patent Application 134057-00001038_7T01PV01-WO In some embodiments, the human patient is treated with the subject dosage form, and the human patient does not receive another NSAID or a salicylate concomitantly.

[0439] In some embodiments, the human patient is concomitantly treated with the subject dosage form and pemetrexed, and the human patient has renal impairment and the human patient's creatinine clearance ranges from 45 to 79 mL / min, and the human patient is monitored for myelosuppression, renal and Gl toxicity.

[0440] Patients taking the subject dosage form should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

[0441] In some embodiments, the human patient being treated with the subject dosage form is not undergoing treatment with a CYP2C9 inhibitor.

[0442] In some embodiments, the human patient being treated with the subject dosage form is not undergoing treatment with an ergotamine-containing or ergot-type medication (like dihydroergotamine or methysergide). In some embodiments, the subject dosage form is not administered within 24 hours of an ergotamine-containing or ergot-type medication (like dihydroergotamine or methysergide).

[0443] In some embodiments, the subject dosage form is not used within 24 hours of another 5HT1 agonist.

[0444] In some embodiments, the human patient being treated with the subject dosage form is not undergoing treatment with a concomitant MAO-A or a concomitant non-selective MAO inhibitor.

[0445] In some embodiments, wherein the human patient is a geriatric patient (age of 65 years or over) who has other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease), the human patient has a cardiovascular evaluation prior to receiving the subject dosage form.

[0446] In some embodiments, the human patient who is being treated using the subject dosage form does not have severe renal impairment and is not at risk for renal failure due to volume depletion or for patients on hemodialysis.

[0447] In some embodiments, the human patient who is being treated using the subject dosage form does not have moderate to severe renal insufficiency and is not at risk for renal failure due to volume depletion.

[0448] In some embodiments, the human patient who is being treated using the subject dosage form has mild to moderate renal impairment. PCT Patent Application 134057-00001038_7T01PV01-WO The term "treating" or "treatment" includes the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals, or any activity that otherwise affects the structure or any function of the body of man or other animals.

[0449] Patients who may benefit from the treatments described herein include pediatric patients, such as patients under about 18 years of age, about 0-5 years of age, about 5-10 years of age, about 10-12 years of age, or about 12-18 years of age; adult patients, such as patients having an age of about 18-65 years, about 18-30 years, about 30-50 years, about 50-65 years; and elderly patients, such as patients 65 years of age and over, about 65-75 years of age, about 75-90 years of age, or over 90 years of age.

[0450] In some embodiments, the human patient who is being treated using the subject dosage form has mild to moderate hepatic impairment.

[0451] The subject dosage form is a combination of rizatriptan and meloxicam formulated to improve the dissolution and absorption of meloxicam. After oral administration of a single dose of the subject dosage form under fasted conditions, meloxicam and rizatriptan are rapidly absorbed. The median Tmax for meloxicam given as the subject dosage form is 0.88 hour which is different compared to standard oral meloxicam (Tmaxof 4-5 hours), and the median Tmax for rizatriptan given as the subject dosage form is 0.75 hour. Meloxicam when given in the subject dosage form has a mean Cmax of approximately 2,900 ng / mL and a mean AUCo -24 of approximately 33,000 ng*hr / mL. Rizatriptan when given in the subject dosage form has a mean Cmax of 32 ng / mL and a mean AUC0-24 of 83 ng*hr / mL.

[0452] The exposures of meloxicam and rizatriptan were comparable after administration of the subject dosage form in the fasted and fed states. Administration of the subject dosage form after a high-fat, high-calorie meal decreased the exposures of meloxicam by approximately 7% for AUC0-24 and 27% for Cmax and increased the AUC0-24 of rizatriptan by approximately 10% with no significant change in Cmax. Food intake delayed the time to maximal plasma concentration for both meloxicam (from 0.875 hours to 5 hours) and rizatriptan (from 0.75 hours to 1.5 hours). Therapeutic concentrations of meloxicam were achieved within 1.5 hours with co-administration of food.

[0453] In some embodiments, the human patient who is being treated using the subject dosage form has mild renal impairment.

[0454] In some embodiments, the human patient who is being treated using the subject dosage form does not have moderate to severe renal impairment is not recommended. PCT Patent Application 134057-00001038_7T01PV01-WO In some embodiments, the human patient who is being treated using the subject dosage form does not have moderate to severe renal insufficiency and is not at risk for renal failure due to volume depletion.

[0455] In some embodiments, the subject dosage form is a tablet, and the tablet comprises a fixed-dose combination of 20 mg meloxicam and 10 mg rizatriptan (or 14.5 mg of rizatriptan benzoate).

[0456] In some embodiments, the human patient who is being treated using the subject dosage form over a period of 1 month, 3 month, 6 month, 9 months, or 12 months may experience improvement in headache-related disability, and headache burden, and a better quality of life with reduced limitations on daily functions.

[0457] In some embodiments, the human patient who is being treated using the subject dosage form over an up to 12-month period, may be more likely to have headache pain relief and relief from their most bothersome symptom within 2 hours, compared with participants who took placebo. In some embodiments, and may experience improvements in their migraine-related disability, headache impact, and quality of life over time. In some embodiments, the subject dosage form is a tablet, and the tablet comprises a fixed-dose combination of 20 mg meloxicam and 10 mg rizatriptan (e.g., 14.5 mg rizatriptan benzoate).

[0458] In the long term treatment, such as over the up to 12-month treatment period, the subject dosage form is well tolerated and the safety profile is consistent with short-term treatment.

[0459] Early treatment with the subject dosage form, while the pain was still mild, may result in statistically significantly improved migraine pain and most bothersome symptoms compared with placebo at 2 hours post-dose. In some embodiments, early treatment with the dosage form may lead to rapid, substantial, and sustained improvements across a broad range of clinically relevant outcomes as compared with placebo.

[0460] In some embodiments, the human patient is being treated with the subject dosage form is an adult who has an average of 2-8 migraine attacks per month, including 1 or more migraine attacks during a 28-day period, with 10 or less migraine days per month over the prior 3 months. Early treatment of migraine, when pain was still mild, with fixed-dose combination meloxicam and rizatriptan, the patient may experience significantly improved ability to resume normal activity, reduced migraine pain and MBS, and avoidance of use of PCT Patent Application 134057-00001038_7T01PV01-WO rescue medication compared with placebo. Improvements may be more pronounced in patients with greater disability at baseline.

[0461] In some embodiments, the human patient is being treated with the subject dosage form, those who had a history of more severe migraine disability may have greater improvement with the treatment of the subject dosage form than those with a history of less migraine disability.

[0462] In some embodiments, the treatment effects may be more pronounced in human patients with greater disability at baseline for freedom from MBS and return to normal function. This may reflect a floor effect for return to normal function, whereby those with minimal disability, being treated early while pain was still mild, may have limited opportunity to improve with treatment. This may also reflect a higher placebo response in the milder severity categories. At later timepoints, the patients with mild disability may exhibit a somewhat greater response, which may indicate that early intervention may prevent progression of migraine.

[0463] The subject dosage form can provide superior efficacy in treatment of migraine across a broad range of migraine severity, from patients treating migraine while initial pain is mild to patients treating migraine of moderate and severe pain intensity, with a history of various responses to prior acute treatments.

[0464] In some embodiments, a single dose of the subject dosage form may provide rapid migraine pain freedom and return to normal functioning within 2 hours, and sustained efficacy through 24 and 48 hours.

[0465] In some embodiments, the percent of human patients experiencing pain freedom and freedom from a most bothersome symptom (MBS) at two hours after a single dose of the subject dosage form may be statistically significantly higherthan placebo in patients both with mild migraine pain and moderate to severe migraine pain.

[0466] In some embodiments, the percent of responders experiencing sustained pain freedom 2-24 hours after a single dose with the subject dosage form in patients with both mild migraine pain and moderate to severe migraine pain may be statistically significantly higherthan placebo in patients both with mild migraine pain and moderate to severe migraine pain.

[0467] In some embodiments, a single dose of the subject dosage form may reduce rescue medication use within 24 hours as compared with placebo in patients both with mild migraine PCT Patent Application 134057-00001038_7T01PV01-WO pain and moderate to severe migraine pain. About 75-95%, about 75-85%, about 80-85%, about 85%, about 85-95%, about 85-90%, about 90-95% of patients with mild migraine pain being treated with a single dose of the subject dosage form may not require rescue medication within 24 hours. About 70-85%, about 70-80%, about 75-80%, about 77%, about 75-85%, about 80-85% of patients with moderate to severe migraine pain being treated with a single dose of the subject dosage form may not require rescue medication within 24 hours, which may be statistically significantly less than meloxicam alone or rizatriptan alone or placebo. In some embodiments, the reduction of or not requiring rescue medication within 24 hours may be statistically significantly less than meloxicam alone. In some embodiments, the reduction of or not requiring rescue medication within 24 hours may be statistically significantly less than rizatriptan alone. In some embodiments, the reduction of or not requiring rescue medication within 24 hours may be statistically significantly less than placebo.

[0468] With the combination of meloxicam and rizatriptan in one tablet, the whole may provide greater efficacy in treating migraine than the sum of the parts (meloxicam alone plus rizatriptan alone) in acute treatment of migraine.

[0469] Patients with acute migraine often experience inadequate treatment response from gepants. A network meta-analysis (NMA) may be used to compare the efficacy of the subject dosage form with gepants, such as rimegepant, ubrogepant, or zavegepant.

[0470] Based on a network meta-analysis approach, the human patients receiving the subject dosage form may be more likely to achieve improved outcomes including 2-hour pain relief, sustained 2-24 hour pain relief, 2-hour pain freedom, sustained 2-24 hour pain freedom, absence of most bothersome symptoms and better ability to perform normal activities at 2 hours, with reduced rescue medication use from 2-24 hour, compared to patients receiving gepants, such as rimegepant, ubrogepant, and zavegepant. For patients with prior inadequate responses, the subject dosage form represents a promising therapeutic alternative for patients with inadequate response to prior treatments, such as gepants.

[0471] Oral calcitonin gene-related peptide (CGRP) inhibitors (gepants) are a newer class of medication approved for the acute treatment of migraine.

[0472] The subject dosage form may be used to treat acute treatment of migraine in patients experiencing inadequate response to an oral calcitonin gene-related peptide (CGRP) inhibitor. PCT Patent Application 134057-00001038_7T01PV01-WO In patients experiencing inadequate response to oral CGRP inhibitors, the subject dosage form may provide statistically significantly greater migraine treatment response compared to oral CGRP inhibitors, as measured by the Migraine Treatment Optimization Questionnaire (mTOQ-4).

[0473] In some embodiments, statistically significant higher percentage of patients receiving a single dose of the subject dosage form experiences 2-hour pain freedom, 24-hourorgreater sustained pain relief, ability to quickly return to normal activities, and improvement of quality of life compared to after receiving oral CGRPs. The improvement in the percentage of the patients experiencing 2-hour pain freedom, 24-hourorgreatersustained pain relief, orability to quickly return to normal activities with the subject dosage form compared to oral CGRP inhibitors may be about 25-60%, about 25-35%, 25-30%, about 30-35%, about 31.2%, about 30-40%, about 35-40%, about 40%, about 40-60%, about 40-50%, about 40-45%, about 45-50%, about 45-60%, about 50-60%, or any value within these ranges or bounded by these ranges.

[0474] The treatment with the subject dosage form with a fixed-dose combination meloxicam and rizatriptan may improve migraine treatment response in patients with a prior inadequate response to oral CGRPs as measured by total score <7 on the mTOQ-4. The treatment effect with the subject dosage form may be associated with substantially higher rates of rapid and sustained pain relief and improved functional recovery, suggesting that the multimechanistic mechanism of action provides therapeutic benefit in multiple subgroups of patients with migraine.

[0475] In human patients experiencing an inadequate response to oral CGRP inhibitors, treatment with the subject dosage form may be associated with significant improvements in migraine treatment response. The treatment with the subject dosage form in patients who has prior inadequate response to oral CGRP inhibitors, may provide higher rates of rapid and sustained pain relief, and improvement of functional recovery and quality of life. In some embodiments, the headache pain relief following treatment with the subject dosage form may be in about 40-60%, about 40-50%, about 50-60%, or about 50% of all migraine attacks 2 hours post-dose, which may reach a maximum at 4 hours, and may be sustained over 48 hours. These results provide additional evidence for efficacy of the subject dosage form across a range of migraine patient populations with varying pain intensities and inadequate responses to a broader range of acute treatments. PCT Patent Application 134057-00001038_7T01PV01-WO Responses to existing acute migraine treatments are often suboptimal (e.g., inconsistent pain relief, slow onset, limited response, high recurrence within 24 hours) and can lead to increased HCRU (healthcare resource utilization) and costs due to medication overuse headache (MOH), medication discontinuation, and progression of migraine frequency from episodic to chronic.

[0476] Due to overall historical increases in acute migraine treatment costs, improved treatments are needed to reduce clinical and economic burden.

[0477] The treatment with a subject dosage form, such as Meloxicam / Rizatriptan, comprising a fixed-dose combination of 20 mg MoSEIC™ meloxicam and 10 mg rizatriptan is estimated to have no to negligible budget impact (PMPM, per member per month) accounted for both HCRU and AE (adverse events) costs for US health plans over a 3-year horizon.

[0478] The favorable cost profile of treatment with Meloxicam / Rizatriptan including reduced HCRU and AE costs and advantages over gepants supports its inclusion on formularies.

[0479] The following embodiments are contemplated:

[0480] Embodiment 1. An inclusion complex of meloxicam in a cyclodextrin.

[0481] Embodiment 2. A dosage form comprising: 1) the inclusion complex of embodiment 1, or 2) meloxicam and a carbonate or a bicarbonate.

[0482] Embodiment 3. The dosage form of embodiment 2 comprising the inclusion complex, wherein the cyclodextrin comprises a substituted [3-cyclodextrin.

[0483] Embodiment 4. The dosage form of embodiment 3, wherein the substituted [3-cyclodextrin is a sulfobutyl ether β-cyclodextrin (SBEβCD), or salt thereof, or hydroxypropyl [3-cyclodextrin (HPBCD), or a salt thereof.

[0484] Embodiment s. The dosage form of embodiment 4, wherein the cyclodextrin is the SBE[3CD, or a salt thereof.

[0485] Embodiment 6. The dosage form of embodiment 5, wherein the SBE[3CD has about 6 to about 7 sulfobutyl ether groups for each molecule of [3-cyclodextrin.

[0486] Embodiment 7. The dosage form of embodiment 6, wherein the meloxicam and the SBE[3CD, or a salt thereof, have a molar ratio of about 0.8 to about 1.2.

[0487] Embodiments. The dosage form of embodiment 6, wherein the meloxicam and the SBE[3CD, or a salt thereof, have a molar ratio of about 1. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 9. The dosage form of embodiment 2, 3, 4, 5, 6, 7, or 8, comprising a bicarbonate.

[0488] Embodiment 10. The dosage form of embodiment 9, wherein the bicarbonate comprises sodium bicarbonate.

[0489] Embodiment 11. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, or 10, which is an oral dosage form.

[0490] Embodiment 12. The dosage form of embodiment 2, 3, 4, 5, 6, 9, 10, or 11, wherein about 50 mg to about 200 mg of SBEβCD, or a salt thereof, is present in the dosage form. Embodiment 13. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein the carbonate or bicarbonate is present in an amount in a range of about 400 mg to about 600 mg.

[0491] Embodiment 14. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the Tmaxof meloxicam is decreased as compared to a dosage form not having a carbonate, a bicarbonate, or a cyclodextrin.

[0492] Embodiment 15. The method of embodiment 14, wherein the Tmaxof meloxicam is achieved in the patient at a time in a range of about 10 minutes to about 180 minutes after administration.

[0493] Embodiment 16. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, having an oral bioavailability of meloxicam that is higher than a dosage form not having a carbonate, a bicarbonate, or a cyclodextrin.

[0494] Embodiment 17. The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, further comprising an acid inhibitor.

[0495] Embodiment 18. The dosage form of embodiment 17, wherein the acid inhibitor is a proton pump inhibitor.

[0496] Embodiment 19. The dosage form of embodiment 18, wherein the proton pump inhibitor is esomeprazole.

[0497] Embodiment 20. The dosage form of embodiment 19, wherein about 30 mg to about 50 mg of esomeprazole is present in the dosage form.

[0498] Embodiment 21. A method of administering meloxicam orally, comprising orally administering a dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 to a patient in need of treatment. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 22. The method of embodiment 21, wherein the dosage form is administered to treat pain.

[0499] Embodiment 23. The method of embodiment 21, wherein the dosage form is administered to treat inflammatory pain.

[0500] Embodiment 24. The method of embodiment 21, wherein the dosage form is administered to treat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoid arthritis.

[0501] Embodiment 25. A method of administering meloxicam intravenously, comprising intravenously administering a dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, or 15, to a patient in need of treatment.

[0502] Embodiment 26. The method of embodiment 21, wherein the dosage form is administered to treat migraine.

[0503] Embodiment 27. A dosage form comprising: 1) the inclusion complex of meloxicam in a cyclodextrin, 2) a bicarbonate, and 3) a triptan.

[0504] Embodiment 28. The dosage form of embodiment 27, wherein the triptan is rizatriptan.

[0505] Embodiment 29. The dosage form of embodiment 27, wherein the bicarbonate comprises sodium bicarbonate.

[0506] Embodiment 30. The dosage form of embodiment 27, wherein the cyclodextrin is a sulfobutyl ether β-cyclodextrin (SBEβCD).

[0507] Embodiment 31. The dosage form of embodiment 30, wherein the SBEβCD, or a salt thereof, has about 6 to about 7 sulfobutyl ether groups for each molecule of [3-cyclodextrin.

[0508] Embodiment 32. The dosage form of embodiment 30, wherein the meloxicam and the SBE[3CD, or a salt thereof, have a molar ratio of about 0.8 to about 1.2.

[0509] Embodiment 33. The dosage form of embodiment 32, wherein the meloxicam and the SBE[3CD, or a salt thereof, have a molar ratio of about 1.

[0510] Embodiment 34. The dosage form of embodiment 27, 28, 29, 30, 31, 32, or 33, which is an oral dosage form.

[0511] Embodiment 35. The dosage form of embodiment 27, 28, 29, 30, 31, 32, 33, or 34, wherein about 50 mg to about 200 mg of SBEβCD, or a salt thereof, is present in the dosage form.

[0512] Embodiment 36. The dosage form of embodiment 27, 28, 29, 30, 31, 32, 33, 34, or 35, wherein the bicarbonate is present in an amount of about 400 mg to about 1000 mg. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 37. A method of treating migraine, comprising administering a dosage form comprising meloxicam, at least 400 mg of a bicarbonate, and a rizatriptan to a human being suffering from migraine; wherein the Tmaxof rizatriptan in the dosage form is shorter than that in a reference dosage form comprising a) same amount of rizatriptan; 2) no meloxicam; and c) no bicarbonate.

[0513] Embodiment 38. A method of treating migraine, comprising administering meloxicam and about 8 mg to about 13 mg of rizatriptan, based upon the weight of the rizatriptan in the free base form,, or a salt thereof, to a human being who is suffering from an acute attack of migraine pain or migraine aura, wherein the meloxicam and the rizatriptan are administered within about 30 minutes of one another, wherein administering the meloxicam to the human being results in a Tmaxof meloxicam of 110 minutes or less, and an AUC0-24of meloxicam of about 30 µg·hr / mL to about 50 µg·hr / mL.

[0514] Embodiment 39. A pharmaceutical dosage form comprising: 1) about 0.028 mmol to about 0.085 mmol of meloxicam in a free acid or a salt form, 2) about 0.019 mmol to about 0.056 mmol of rizatriptan in a free base or a salt form, 3) about 100 mg to about 175 mg of a sulfobutylether-β-cyclodextrin (SBEβCD), and 4) about 400 mg to about 600 mg of sodium bicarbonate.

[0515] Embodiment 40. A method of treating migraine comprising: selecting a human migraine patient with a history of inadequate response to prior migraine treatments, and orally administering a dosage form to the migraine patient, wherein the dosage form comprises a combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether β-cyclodextrin (SBEβCD) or a salt thereof), 2) a bicarbonate, and 3) a rizatriptan.

[0516] Embodiment 41. The method of embodiment 40, wherein the human migraine patient experiences relief of the migraine pain as a result of orally administering the dosage form to the migraine patient.

[0517] Embodiment 42. The method of embodiment 40 or 41, wherein the human migraine patient is free of migraine pain two hours after the dosage form is orally administered to the human migraine patient.

[0518] Embodiment 43. The method of embodiment 40, 41, or 42, wherein the migraine patient experiences a reduction in nausea as a result of orally administering the dosage form to the migraine patient. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 44. The method of embodiment 40, 41, 42, or 43, wherein the human migraine patient is free of nausea two hours after the dosage form is orally administered to the human migraine patient.

[0519] Embodiment 45. The method of embodiment 40, 41, 42, 43, or 44, wherein the migraine patient experiences a reduction in photophobia as a result of orally administering the dosage form to the migraine patient.

[0520] Embodiment 46. The method of embodiment 40, 41, 42, 43, 44, or 45, wherein the human migraine patient is free of photophobia two hours after the dosage form is orally administered to the human migraine patient.

[0521] Embodiment 47. The method of embodiment 40, 41, 42, 43, 44, 45, or 46, wherein the migraine patient experiences a reduction in phonophobia as a result of orally administering the dosage form to the migraine patient.

[0522] Embodiment 48. The method of embodiment 40, 41, 42, 43, 44, 45, 46, or 47, wherein the human migraine patient is free of phonophobia two hours after the dosage form is orally administered to the human migraine patient.

[0523] Embodiment 49. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, or 48, wherein the dosage form contains 400 mg to 600 mg of the bicarbonate.

[0524] Embodiment 50. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49, wherein the dosage form contains about 5 mg to about 50 mg of meloxicam.

[0525] Embodiment 51. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, wherein the dosage form contains about 50 mg to about 200 mg of the SBEβCD, or a salt thereof.

[0526] Embodiment 52. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or 51, wherein the dosage form is a solid oral dosage form having a shorter Tmax of meloxicam in the human being than a reference dosage form that: 1) contains the same amount of meloxicam, 2) does not contain an SBEβCD, and 3) does not contain a bicarbonate.

[0527] Embodiment 53. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52, wherein about 1 mg to about 50 mg of the rizatriptan is present in the oral dosage form based upon the weight of the rizatriptan in the free base form.

[0528] Embodiment 54. The method of embodiment 53, wherein the rizatriptan is present in a salt form in an amount that is a molar equivalent of about 10 mg of the rizatriptan in the free base form. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 55. The method of embodiment 53 or54, wherein the rizatriptan is present as rizatriptan benzoate.

[0529] Embodiment 56. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55, wherein the oral dosage form contains about 10 mg to about 30 mg of meloxicam.

[0530] Embodiment 57. The method of embodiment 56, wherein the oral dosage form contains about 20 mg of meloxicam.

[0531] Embodiment 58. The method of embodiment 56, wherein the oral dosage form contains about 15 mg of meloxicam.

[0532] Embodiment 59. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, or 58, wherein the SBEβCD, has about 6 to about 7 sulfobutyl ether groups for each molecule of [3-cyclodextrin.

[0533] Embodiment 60. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59, wherein the oral dosage form contains about 50 mg to about 150 mg of the SBEβCD, or a salt thereof.

[0534] Embodiment 61. The method of embodiment 60, wherein the oral dosage form contains about 100 mg of the SBEβCD, or a salt thereof.

[0535] Embodiment 62. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, or 61, wherein the molar ratio of the SBEβCD to the meloxicam is about 0.5 to about 2.

[0536] Embodiment 63. The method of embodiment 62, wherein the molar ratio of the SBEβCD to the meloxicam is about 0.8 to about 1.2.

[0537] Embodiment 64. The method of embodiment 62, wherein the molar ratio of the SBEβCD to the meloxicam is about 1.

[0538] Embodiment 65. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, or 64, wherein the oral dosage form contains about 10 mg to about 40 mg of meloxicam, and about 5 mg to about 50 mg of rizatriptan, or a salt thereof.

[0539] Embodiment 66. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65, wherein the oral dosage form contains SBEβCD, or a salt thereof, that is in a weight ratio to rizatriptan, or a salt thereof, that is within a range of about 1 to about 100. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 67. The method of embodiment 66, wherein the oral dosage form contains the SBEPCD that is in a weight ratio to the rizatriptan that is about 10.

[0540] Embodiment 68. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, or 67, wherein the bicarbonate comprises sodium bicarbonate.

[0541] Embodiment 69. The method of embodiment 68, wherein the oral dosage form contains 500 mg of sodium bicarbonate.

[0542] Embodiment 70. The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, or 69, wherein the oral dosage form has been shown to have a median Tmaxof meloxicam that is less than about 90 minutes in fasted human subjects.

[0543] Embodiment 71. The method of embodiment 70, wherein the oral dosage form has been shown to have a median Tmaxof meloxicam that is less than about 2 hours in fasted human subjects.

[0544] Embodiment 72. The method of embodiment 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, or 71, wherein the oral dosage form has been shown to have faster time to therapeutic plasma concentration in the human being as compared to the reference dosage form.

[0545] Embodiment 73. A method of treating migraine comprising: selecting a human migraine patient with a history of inadequate response to prior migraine treatments, and orally administering a dosage form to the migraine patient, wherein the dosage form comprises a combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the human migraine patient experiences relief of the migraine pain as a result of orally administering the dosage form to the migraine patient.

[0546] Embodiment 74. A method of treating migraine comprising: selecting a human migraine patient with a history of inadequate response to prior migraine treatments, and orally administering a dosage form to the migraine patient, wherein the dosage form comprises a combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the human migraine patient is free of migraine pain two hours after the dosage form is orally administered to the human migraine patient. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 75. A method of treating migraine comprising: selecting a human migraine patient with a history of inadequate response to prior migraine treatments, and orally administering a dosage form to the migraine patient, wherein the dosage form comprises a combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the migraine patient experiences a reduction in nausea as a result of orally administering the dosage form to the migraine patient.

[0547] Embodiment 76. A method of treating migraine comprising: selecting a human migraine patient with a history of inadequate response to prior migraine treatments, and orally administering a dosage form to the migraine patient, wherein the dosage form comprises a combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the human migraine patient is free of nausea two hours after the dosage form is orally administered to the human migraine patient.

[0548] Embodiment 77. A method of treating migraine comprising: selecting a human migraine patient with a history of inadequate response to prior migraine treatments, and orally administering a dosage form to the migraine patient, wherein the dosage form comprises a combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the migraine patient experiences a reduction in photophobia as a result of orally administering the dosage form to the migraine patient.

[0549] Embodiment 78. A method of treating migraine comprising: selecting a human migraine patient with a history of inadequate response to prior migraine treatments, and orally administering a dosage form to the migraine patient, wherein the dosage form comprises a combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the human migraine patient is free of photophobia two hours after the dosage form is orally administered to the human migraine patient.

[0550] Embodiment 79. A method of treating migraine comprising: selecting a human migraine patient with a history of inadequate response to prior migraine treatments, and orally administering a dosage form to the migraine patient, wherein the dosage form comprises a combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether [3-cyclodextrin PCT Patent Application 134057-00001038_7T01PV01-WO (SBEβCD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the migraine patient experiences a reduction in phonophobia as a result of orally administering the dosage form to the migraine patient.

[0551] Embodiment 80. A method of treating migraine comprising: selecting a human migraine patient with a history of inadequate response to prior migraine treatments, and orally administering a dosage form to the migraine patient, wherein the dosage form comprises a combination of: 1) meloxicam (optionally in a complex with a sulfobutyl ether β-cyclodextrin (SBEβCD)), 2) a bicarbonate, and 3) a rizatriptan, wherein the human migraine patient is free of phonophobia two hours after the dosage form is orally administered to the human migraine patient.

[0552] Embodiment 81. A method of more rapidly improving migraine pain relief associated with rizatriptan therapy, comprising: orally administering to a human being in need thereof, a combination of: 1) a complex of a meloxicam and a sulfobutylether-β-cyclodextrin, 2) a bicarbonate, and 3) a rizatriptan, wherein one hour after the combination is administered, the human being experiences a greater reduction in migraine pain than the human being would experience one hour after the same amount of the rizatriptan is administered alone.

[0553] Embodiment 82. A method of relieving migraine pain, comprising: orally administering to a human being in need thereof, a combination of: 1) a complex of meloxicam and a sulfobutylether-β-cyclodextrin, 2) a bicarbonate, and 3) a rizatriptan, wherein the combination is orally administered when the human being is suffering from moderate to severe migraine pain of an acute migraine, wherein two hours after the combination is administered, the human being experiences a greater reduction in the human being's most bothersome symptom than the human being would experience two hours after the same amount of the rizatriptan is administered alone.

[0554] Embodiment 83. A method of relieving migraine pain, comprising: orally administering to a human being in need thereof, a combination of: 1) a complex of meloxicam and a sulfobutylether-β-cyclodextrin, 2) a bicarbonate, and 3) a rizatriptan, wherein the combination is orally administered when the human being is suffering from moderate to severe migraine pain of an acute migraine, wherein the human being suffers from migraine with cutaneous allodynia, wherein two hours after the combination is orally administered, the human being experiences a greater reduction in the migraine pain than the human being would experience two hours after the same amount of the meloxicam is administered alone. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 84. A method of relieving migraine pain, comprising: orally administering to a human being in need thereof, a combination of: 1) a complex of meloxicam and a sulfobutylether-β-cyclodextrin, 2) a bicarbonate, and 3) a rizatriptan, wherein the combination is orally administered when the human being is suffering from severe migraine pain of an acute migraine, wherein two hours after the combination is orally administered, the human being experiences a greater reduction in the migraine pain than the human being would experience two hours after the same amount of the meloxicam is administered alone.

[0555] Embodiment 85. A method of relieving migraine pain, comprising: orally administering to a human being in need thereof, a combination of: 1) a complex of meloxicam and a sulfobutylether-β-cyclodextrin, 2) a bicarbonate, and 3) a rizatriptan, wherein the combination is orally administered when the human being is suffering from moderate to severe migraine pain of an acute migraine, wherein the human being is obese, wherein two hours after the combination is orally administered, the human being experiences a greater reduction in the migraine pain than the human being would experience two hours after the same amount of the meloxicam is administered alone.

[0556] Embodiment 86. A method of relieving migraine pain, comprising: orally administering to a human being in need thereof, a combination of: 1) a complex of meloxicam and a sulfobutylether-β-cyclodextrin, 2) a bicarbonate, and 3) a rizatriptan, wherein the combination is orally administered when the human being is suffering from moderate to severe migraine pain of an acute migraine, wherein the human being has morning migraine, wherein two hours after the combination is orally administered, the human being experiences a greater reduction in the migraine pain than the human being would experience two hours after the same amount of the meloxicam is administered alone.

[0557] Embodiment 87. A method of relieving migraine pain, comprising: orally administering to a human being in need thereof, a combination of: 1) a complex of meloxicam and a sulfobutylether-β-cyclodextrin, 2) a bicarbonate, and 3) a rizatriptan, wherein the combination is orally administered when the human being is suffering from moderate to severe migraine pain of an acute migraine, wherein at least one year prior to orally administering the combination to the human being, the human being has been diagnosed as having migraine with aura or migraine without aura as defined by the International Classification of Headache Disorders, third edition (ICHD-3), wherein two hours after the combination is orally administered, the human being experiences a greater reduction in the PCT Patent Application 134057-00001038_7T01PV01-WO migraine pain than the human being would experience two hours after the same amount of the meloxicam is administered alone.

[0558] Embodiment 88. A method of treating migraine comprising: orally administering a dosage form to a human migraine patient, wherein the oral dosage form comprises a combination of: 1) a complex of a meloxicam with a sulfobutyl ether [3-cyclodextrin (SBEβCD), 2) a bicarbonate, and 3) a rizatriptan, wherein the human migraine patient suffers from migraine with cutaneous allodynia at the time the dosage form is administered, wherein the human migraine patient is free of cutaneous allodynia two hours after the dosage form is orally administered to the human migraine patient.

[0559] Embodiment 89. The method of embodiment 81, 82, 83, 84, 85, 86, 87, or 88, wherein the migraine pain is accompanied by disturbed vision.

[0560] Embodiment 90. The method of embodiment 89, wherein the human being achieves absence of the disturbed vision at 2 hours after the combination is orally administered. Embodiment 91. A method of treating migraine, comprising orally administering a combination at least twice a month for at least six months to a human being in need thereof, wherein the combination comprises about 20 mg of meloxicam, ora molar equivalent amount of a salt form of meloxicam, and from about 10 mg to about 15 mg of rizatriptan, or a molar equivalent amount of a salt form of rizatriptan, and wherein the tablet has a good long-term safety profile in the human being at 6 months after the first time the combination is administered.

[0561] Embodiment 92. The method of embodiment 91, wherein the combination further comprises sodium bicarbonate.

[0562] Embodiment 93. The method of embodiment 91 or 92, wherein, upon orally administering the combination, the Tmaxof meloxicam in the human being is less than 60 minutes.

[0563] Embodiment 94. The method of embodiment 91, 92, or 93, wherein, upon orally administering the combination, the Tmaxof meloxicam in the human being is about 5 x 101minutes.

[0564] Embodiment 95. The method of embodiment 91, 92, 93, or 94, wherein, upon orally administering the combination, the Cmaxof meloxicam in the human being is from about 2,500 ng / mL to about 3,000 ng / mL. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 96. The method of embodiment 91, 92, 93, 94, or 95, wherein, upon orally administering the combination, the Cmaxof meloxicam in the human being is about 3 x 103ng / mL.

[0565] Embodiment 97. The method of embodiment 91, 92, 93, 94, 95, or 96, wherein, upon orally administering the combination, the AUC0-infof meloxicam in the human being is from about 50,000 ng*hr / mL to about 70,000 ng*hr / mL.

[0566] Embodiment 98. The method of embodiment 91, 92, 93, 94, 95, 96, or 97, wherein, upon orally administering the combination, the AUC0-infof meloxicam in the human being is from about 50,000 ng*hr / mL to about 60,000 ng*hr / mL.

[0567] Embodiment 99. The method of embodiment 91, 92, 93, 94, 95, 96, 97, or 98, wherein, upon orally administering the combination, the AUC0-infof meloxicam in the human being is about 5 x 104ng*hr / mL.

[0568] Embodiment 100. The method of embodiment 91, 92, 93, 94, 95, 96, 97, 98, or 99, wherein, upon orally administering the combination, the mean elimination half-life in the human being is about 2 x 101hours for meloxicam.

[0569] Embodiment 101. A method for the acute treatment of migraine, comprising orally administering a tablet at least one dose to an adult human being following each onset of a migraine for at least 6 months up to 12 months, wherein the human being has a minimum of 2 migraines a month, wherein the tablet comprises about 20 mg of meloxicam, or a molar equivalent amount of a salt form of meloxicam, and about 10 mg of rizatriptan, or a molar equivalent amount of a salt form of rizatriptan, and wherein the tablet has a good long-term safety profile in the human being in 12 months.

[0570] Embodiment 102. The method of embodiment 101, wherein the human being has low total treatment-emergent adverse events (TEAEs) in 12 months.

[0571] Embodiment 103. The method of embodiment 101 or 102, wherein total serious TEAEs in human subjects is lower than 2% in 12 months.

[0572] Embodiment 104. The method of embodiment 101, 102, or 103, wherein total serious TEAEs in human subjects is lower than 1.5% in 12 months.

[0573] Embodiment 105. The method of embodiment 101, 102, 103, or 104, wherein total serious TEAEs in human subjects is about 1.1% in 12 months.

[0574] Embodiment 106. The method of embodiment 101, 102, 103, 104, or 105, wherein the most frequent adverse event (AE) in the human being is nausea, vomiting or dizziness. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 107. The method of embodiment 106, wherein about 3.1% of the adverse events (AEs) in human subjects is dizziness.

[0575] Embodiment 108. The method of embodiment 106, wherein about 4.7% of the AEs in human subjects is vomiting.

[0576] Embodiment 109. The method of embodiment 106, wherein about 3.1% of the AEs in human subjects is nausea.

[0577] Embodiment 110. The method of embodiment 101, 102, 103, 104, 105, 106, 107, 108, or 109, wherein the human being is 18 to 65 years of age.

[0578] Embodiment 111. The method of embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, or 110, wherein the human being has previously participated in a prior study with the tablet for the acute treatment of migraine.

[0579] Embodiment 112. The method of embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, or 111, wherein the human being records the headache pain intensity in a migraine headache diary when a migraine occurs.

[0580] Embodiment 113. The method of embodiment 112, wherein the human being records the headache pain intensity in a migraine headache diary immediately prior to taking the tablet.

[0581] Embodiment 114. The method of embodiment 112 or 113, wherein the human being records the headache pain intensity in a migraine headache diary at about 30 minutes after taking the tablet.

[0582] Embodiment 115. The method of embodiment 112, 113, or 114, wherein the human being records the headache pain intensity in a migraine headache diary at about 1 hour after taking the tablet.

[0583] Embodiment 116. The method of embodiment 112, 113, 114, or 115, wherein the human being records the headache pain intensity in a migraine headache diary immediately at about 2 hours after taking the tablet.

[0584] Embodiment 117. The method of embodiment 112, 113, 114, 115, or 116, wherein the human being records the headache pain intensity in a migraine headache diary immediately at about 8 hours after taking the tablet.

[0585] Embodiment 118. The method of embodiment 112, 113, 114, 115, 116, or 117, wherein the human being records the headache pain intensity in a migraine headache diary immediately at about 24 hours after taking the tablet. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 119. The method of embodiment 112, 113, 114, 115, 116, 117, or 118, wherein the human being records the headache pain intensity in a migraine headache diary immediately at about 48 hours after taking the tablet.

[0586] Embodiment 120. The method of embodiment 112, 113, 114, 115, 116, 117, 118, or 119, wherein the headache pain intensity is quantified on a scale where 0 is no pain, 1 is mild pain, 2 is moderate pain, and 3 is severe pain.

[0587] Embodiment 121. The method of embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, or 120, wherein the human being is not receiving concomitant propranolol and has not used propranolol within 2 weeks prior to administration of the tablet.

[0588] Embodiment 122. The method of embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, or 121, wherein the human being experiences headache pain relief 2 hours after administration.

[0589] Embodiment 123. The method of embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, or 121, wherein the human being experiences headache pain freedom 2 hours after administration.

[0590] Embodiment 124. The method of embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, or 123, wherein the human being experiences freedom of the most bothersome symptom of nausea, photophobia, phonophobia or a combination thereof 2 hours after administration.

[0591] Embodiment 125. The method of embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, or 124, wherein the human being has no headache pain 2 hours after administration, and has no use of rescue medication and no relapse of headache pain through 24 hours after administration.

[0592] Embodiment 126. The method of embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, or 121, wherein the human being experiences headache pain freedom at 0.5 hours after administration, 1 hour after administration, 8 hours after administration, 24 hours after administration, 48 hours after administration, or a combination thereof.

[0593] Embodiment 127. The method of embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, or 121, wherein the human being experiences headache pain freedom at 0.5 hours after administration, 1 hour after PCT Patent Application 134057-00001038_7T01PV01-WO administration, 8 hours after administration, 24 hours after administration, 48 hours after administration, or a combination thereof.

[0594] Embodiment 128. The method of embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, or 121, wherein the human being experiences headache relief at 0.5 hours after administration, 1 hour after administration, 8 hours after administration, 24 hours after administration, 48 hours after administration, or a combination thereof.

[0595] Embodiment 129. A method of treating migraine, comprising administering a tablet containing 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan, such as about 14.5 mg of rizatriptan benzoate, to a human patient at the onset of a migraine, wherein the human patient is not experiencing hemiplegic migraine or basilar migraine.

[0596] Embodiment 130. A method of treating migraine, comprising: administering a tablet containing 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan, such as about 14.5 mg of rizatriptan benzoate, to a human patient with a clear diagnosis of migraine at the onset of a migraine, wherein if the human patient has no response after the tablet is administered, the diagnosis of migraine is reconsidered, and if the clear diagnosis of migraine is confirmed, administering the tablet during a subsequent migraine.

[0597] Embodiment 131. A method comprising selecting a human patient who has a negative cardiovascular evaluation, administering a first dose of a tablet in a medically-supervised setting, and performing an electrocardiogram (ECG) on the human patient immediately following administration the tablet, and administering a second dose of the tablet at the onset of a migraine, wherein the tablet contains 20 mg of meloxicam, ora molar equivalent amount of a salt of meloxicam, and 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan.

[0598] Embodiment 132. A method of treating migraine, comprising administering a tablet containing 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan, such as about 14.5 mg of rizatriptan benzoate, to a human patient at the onset of a migraine, wherein the human patient is not experiencing hemiplegic migraine. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 133. The method of embodiment 132, wherein the maximum daily dose of meloxicam is 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and the maximum daily dose of rizatriptan is 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan.

[0599] Embodiment 134. The method of embodiment 133, wherein no more than 7 migraines are treated in a 30-day period.

[0600] Embodiment 135. The method of embodiment 132, wherein the human patient is not experiencing basilar migraine.

[0601] Embodiment 136. The method of embodiment 132, wherein the tablet further contains sulfobutyl-ether-P-cyclodextrin sodium.

[0602] Embodiment 137. The method of embodiment 136, wherein the tablet further contains sodium bicarbonate.

[0603] Embodiment 138. The method of embodiment 132, wherein the tablet further contains partially hydrolyzed polyvinyl alcohol.

[0604] Embodiment 139. The method of Embodiment 132, wherein the human patient does not have an ischemic bowel disease.

[0605] Embodiment 140. The method of embodiment 132, wherein the human patient is screened for an ischemic bowel disease.

[0606] Embodiment 141. A method of treating migraine, comprising administering a tablet containing 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan, such as about 14.5 mg of rizatriptan benzoate, to a human patient at the onset of a migraine, wherein the human patient is not experiencing basilar migraine.

[0607] Embodiment 142. The method of embodiment 141, wherein the maximum daily dose of meloxicam is 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and the maximum daily dose of rizatriptan is 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan.

[0608] Embodiment 143. The method of embodiment 142, wherein no more than 7 migraines are treated in a 30-day period.

[0609] Embodiment 144. The method of embodiment 141, wherein the tablet further contains sulfobutyl-ether-P-cyclodextrin sodium. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 145. The method of embodiment 144, wherein the tablet further contains sodium bicarbonate.

[0610] Embodiment 146. The method of embodiment 141, wherein the tablet further contains partially hydrolyzed polyvinyl alcohol.

[0611] Embodiment 147. The method of embodiment 141, wherein the human patient does not have an ischemic bowel disease.

[0612] Embodiment 148. The method of embodiment 141, wherein the human patient is screened for an ischemic bowel disease.

[0613] Embodiment 149. A method of treating migraine, comprising administering a tablet containing 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan, such as about 14.5 mg of rizatriptan benzoate, to a human patient at the onset of a migraine, wherein the human patient is not experiencing cluster headache.

[0614] Embodiment 150. The method of embodiment 149, wherein the maximum daily dose of meloxicam is 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and the maximum daily dose of rizatriptan is 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan.

[0615] Embodiment 151. The method of embodiment 150, wherein no more than 7 migraines are treated in a 30-day period.

[0616] Embodiment 152. The method of embodiment 149, wherein the tablet further contains sulfobutyl-ether-P-cyclodextrin sodium.

[0617] Embodiment 153. The method of embodiment 152, wherein the tablet further contains sodium bicarbonate.

[0618] Embodiment 154. The method of embodiment 149, wherein the tablet further contains partially hydrolyzed polyvinyl alcohol.

[0619] Embodiment 155. The method of embodiment 149, wherein the human patient does not have an ischemic bowel disease.

[0620] Embodiment 156. The method of embodiment 149, wherein the human patient is screened for an ischemic bowel disease.

[0621] Embodiment 157. A method of treating migraine, comprising: administering a tablet containing 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan, such as about 14.5 mg PCT Patent Application 134057-00001038_7T01PV01-WO of rizatriptan benzoate, to a human patient with a clear diagnosis of migraine at the onset of a migraine, wherein if the human patient has no response after the tablet is administered, the diagnosis of migraine is reconsidered, and if the clear diagnosis of migraine is confirmed, the tablet is administered during a subsequent migraine.

[0622] Embodiment 158. The method of embodiment 157, wherein the maximum daily dose of meloxicam is 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and the maximum daily dose of rizatriptan is 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan.

[0623] Embodiment 159. The method of embodiment 158, wherein no more than 7 migraines are treated in a 30-day period.

[0624] Embodiment 160. The method of embodiment 157, wherein the human patient is not experiencing basilar migraine.

[0625] Embodiment 161. The method of embodiment 157, wherein the tablet further contains sulfobutyl-ether-P-cyclodextrin sodium.

[0626] Embodiment 162. The method of embodiment 161, wherein the tablet further contains sodium bicarbonate.

[0627] Embodiment 163. The method of embodiment 157, wherein the tablet further contains partially hydrolyzed polyvinyl alcohol.

[0628] Embodiment 164. The method of embodiment 157, wherein the human patient does not have a peripheral vascular disease.

[0629] Embodiment 165. The method of embodiment 157, wherein the human patient is screened for a peripheral vascular disease.

[0630] Embodiment 166. The method of embodiment 157, wherein the human patient is monitored for a cerebrovascular event; wherein if no cerebrovascular event occurs, the tablet is administered during a subsequent migraine; and wherein if a cerebrovascular event occurs, treatment with the tablet is discontinued.

[0631] Embodiment 167. The method of embodiment 157, wherein the human patient does not have a cerebrovascular event.

[0632] Embodiment 168. A method of treating migraine, comprising selecting a human patient who has a negative cardiovascular evaluation, administering a first dose of a tablet to the human patient in a medically-supervised setting, and performing an electrocardiogram (ECG) on the human patient immediately following administration of the tablet, wherein the tablet PCT Patent Application 134057-00001038_7T01PV01-WO contains 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan.

[0633] Embodiment 169. The method of embodiment 168, wherein the maximum daily dose of meloxicam is 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and the maximum daily dose of rizatriptan is 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan.

[0634] Embodiment 170. The method of embodiment 169, wherein no more than 7 migraines are treated in a 30-day period.

[0635] Embodiment 171. The method of embodiment 168, wherein the human patient is not experiencing basilar migraine.

[0636] Embodiment 172. The method of embodiment 168, wherein the tablet further contains sulfobutyl-ether-P-cyclodextrin sodium.

[0637] Embodiment 173. The method of embodiment 172, wherein the tablet further contains sodium bicarbonate.

[0638] Embodiment 174. The method of embodiment 168, wherein the tablet further contains partially hydrolyzed polyvinyl alcohol.

[0639] Embodiment 175. The method of embodiment 168, wherein the human patient does not have a peripheral vascular disease.

[0640] Embodiment 176. The method of embodiment 168, wherein the human patient is screened for a peripheral vascular disease.

[0641] Embodiment 177. The method of embodiment 168, wherein the human patient is monitored for a cerebrovascular event; wherein if no cerebrovascular event occurs, the tablet is administered during a subsequent migraine; and wherein if a cerebrovascular event occurs, treatment with the tablet is discontinued.

[0642] Embodiment 178. The method of embodiment 168, wherein the human patient does not have a cerebrovascular event.

[0643] Embodiment 179. A method of treating migraine in a human patient being treated with a gepant, comprising: selecting a patient with a confirmed diagnosis of migraine who has been treated with a gepant for the migraine, administering a dosage form comprising 20 mg of meloxicam free acid, or a molar equivalent amount of a meloxicam salt, and 10 mg of rizatriptan free base, or a molar equivalent amount of a salt of rizatriptan, such as about 14.5 mg of rizatriptan benzoate, and discontinuing use of the gepant. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 180. The method of embodiment 179, wherein the dosage form further comprises a bicarbonate.

[0644] Embodiment 181. The method of embodiment of 179 or 180, wherein the dosage form further comprise a cyclodextrin.

[0645] Embodiment 182. The method of embodiment of 179, 180, or 181, wherein the gepant is Rimegepant.

[0646] Embodiment 183. The method of embodiment 179, 180, or 181, wherein the gepant is Ubrogepant.

[0647] Embodiment 184. The method of embodiment 179, 180, or 181, wherein the gepant is Zavegepant.

[0648] Embodiment 185. The method of embodiment 179, 180, 181, 182, 183, or 184, wherein the meloxicam is in the free acid form.

[0649] Embodiment 186. The method of embodiment 179, 180, 181, 182, 183, 184, or 185, wherein the rizatriptan is in a salt form.

[0650] Embodiment 187. The method of embodiment 186, wherein the rizatriptan is rizatriptan benzoate.

[0651] Embodiment 188. The method of embodiment 181, wherein the cyclodextrin is a sulfobutyl ether β-cyclodextrin (SBEβCD).

[0652] Embodiment 189. The method of embodiment 188, wherein the SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of [3-cyclodextrin.

[0653] Embodiment 190. The method of embodiment 188 or 189, wherein the molar ratio of the SBEβCD to meloxicam is about 0.8 to about 1.2.

[0654] Embodiment 191. The method of embodiment 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, or 190, wherein the bicarbonate is sodium bicarbonate.

[0655] Embodiment 192. The method of embodiment 191, wherein about 400 mg to about 600 mg of sodium bicarbonate is present in the dosage form.

[0656] Embodiment 193. The method of embodiment 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, or 192, wherein the migraine is acute migraine.

[0657] Embodiment 194. The method of embodiment 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, or 193, wherein the efficacy for acute migraine treatment is evaluated using a network meta-analysis (NMA). PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 195. The method of embodiment 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, or 194, wherein the efficacy for acute migraine treatment with the dosage form comprising dextromethorphan and bupropion is higher over the comparator gepant, wherein the gepant is rimegepant, ubrogepant, or zavegepant, with respect to releasing the symptoms of migraine.

[0658] Embodiment 196. The method of embodiment 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, or 195, wherein the dosage form comprising dextromethorphan and bupropion is more effective in achieving pain relief by 2h after administration than the comparator gepant.

[0659] Embodiment 197. The method of embodiment 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, or 196, wherein the dosage form comprising dextromethorphan and bupropion is more effective in achieving sustained pain relief and pain freedom from 2 hours to 24 hours than the comparator gepant.

[0660] Embodiment 198. The method of embodiment 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, or 197, wherein the human patient is having inadequate response to prior treatments, and wherein the prior treatments are with gepants.

[0661] Embodiment 199. A method of treating migraine with or without aura in a human patient in need thereof, comprising: selecting a human patient experiencing at least 2 migraine attacks a month, and administering a tablet comprising 20 mg of meloxicam free acid, or a molar equivalent amount of a meloxicam salt, and 10 mg of rizatriptan free base, or a molar equivalent amount of a salt of rizatriptan, such as about 14.5 mg of rizatriptan benzoate, to the human patient, wherein one tablet is orally administered per migraine attack, and wherein the treatment is continued for up to 12 months.

[0662] Embodiment 200. The method of embodiment 199, wherein the tablet further comprises a bicarbonate.

[0663] Embodiment 201. The method of embodiment 199 or 200, wherein the tablet further comprise a cyclodextrin.

[0664] Embodiment 202. The method of embodiment 199, 200, or 201, wherein the human patient has up to 10 migraine attacks per month.

[0665] Embodiment 203. The method of embodiment 199, 200, or 201, wherein the treatment lasts for at least 1 month. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 204. The method of embodiment 199, 200, or 201, wherein the treatment lasts for at least 3 months.

[0666] Embodiment 205. The method of embodiment 199, 200, or 201, wherein the treatment lasts for at least 6 months.

[0667] Embodiment 206. The method of embodiment 199, 200, or 201, wherein the treatment lasts for at least 9 months.

[0668] Embodiment 207. The method of embodiment 199, 200, 201, 202, 203, 204, 205, or 206, wherein the meloxicam is in the free acid form.

[0669] Embodiment 208. The method of embodiment 199, 200, 201, 202, 203, 204, 205, 206, or 207, wherein the rizatriptan is in a salt form.

[0670] Embodiment 209. The method of embodiment 208, wherein the rizatriptan is rizatriptan benzoate.

[0671] Embodiment 210. The method of embodiment 201, wherein the cyclodextrin is a sulfobutyl ether β-cyclodextrin (SBEβCD).

[0672] Embodiment 211. The method of embodiment 210, wherein the SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of [3-cyclodextrin.

[0673] Embodiment 212. The method of embodiment 210 or 211, wherein the molar ratio of the SBEβCD to meloxicam is about 0.8 to about 1.2.

[0674] Embodiment 213. The method of embodiment 200, 201, 202, 203, 204, 205, 206, or 207, 208, 209, 210, 211, or 212, wherein the bicarbonate is sodium bicarbonate.

[0675] Embodiment 214. The method of embodiment 213, wherein about 400 mg to about 600 mg of sodium bicarbonate is present in the tablet.

[0676] Embodiment 215. The method of any preceding embodiment, wherein the human patient has median baseline MIDAS total score of about 17.0 to about 22.5 before treatment.

[0677] Embodiment 216. The method of any preceding embodiment, wherein the human patient has median Baseline HIT-6 total score of about 64 before treatment.

[0678] Embodiment 217. The method of any preceding embodiment, wherein the human patient has moderate to severe impairment before treatment.

[0679] Embodiment 218. The method of any preceding embodiment, wherein the tablet is well tolerated throughout the 12-month period.

[0680] Embodiment 219. The method of any preceding embodiment, wherein the MIDAS total scores of the human patient improves from baseline up to the 12-month. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 220. The method of any preceding embodiment, wherein, at the early termination visit, the (95% Cl) change in MIDAS is about -3.4 to about -7.1.

[0681] Embodiment 221. The method of any preceding embodiment, wherein, at the early termination visit, the average (95% Cl) change in MIDAS is about -5.3.

[0682] Embodiment 222. The method of any preceding embodiment, wherein the probability of the human patient reached an MCIC (minimal clinically important change, with at least 4.5 points) in MIDAS is at least about 40% at 3 months, 6 months, 9 months, or 12 months after oral administration of the tablet.

[0683] Embodiment 223. The method of any preceding embodiment, wherein the HIT-6 total scores in the human patient improves up to the 12-month period.

[0684] Embodiment 224. The method of any preceding embodiment, wherein, at the early termination visit, the (95% Cl) change in HIT-6 is about -3.0 to about -1.9.

[0685] Embodiment 225. The method of any preceding embodiment, wherein, at the early termination visit, the average (95% Cl) change in HIT-6 is about -2.4.

[0686] Embodiment 226. The method of any preceding embodiment, wherein probability of the human patient reaching an MCID (minimal clinically important difference, with 5 points change) in HIT-6 score increases from 21.4% at Month 1 to 34.1% at Month 12.

[0687] Embodiment 227. The method of any preceding embodiment, wherein the MSQ total scores and subscore domains in the human patient improves up to the 12-month.

[0688] Embodiment 228. The method of embodiment 227, wherein the subscore domain comprises role function-restrictive, role function-preventive, and emotional function.

[0689] Embodiment 229. The method of any preceding embodiment, wherein, at the early termination visit, the (95% Cl) change in MSQ total score was about 4.5 to about 7.1.

[0690] Embodiment 230. The method of any preceding embodiment, wherein, at the early termination visit, the average (95% Cl) change in MSQ total score was about 5.8.

[0691] Embodiment 231. The method of any preceding embodiment, wherein the human patient has improvements in quality of life, reduction in headache-related disability, and headache impact.

[0692] Embodiment 232. A method of treating migraine, comprising: administering a tablet containing 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan, such as about 14.5 mg of rizatriptan benzoate, to a human patient with a clear diagnosis of migraine. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 233. The method of embodiment 232, wherein the maximum daily dose of meloxicam is 20 mg of meloxicam, or a molar equivalent amount of a salt of meloxicam, and the maximum daily dose of rizatriptan is 10 mg of rizatriptan, or a molar equivalent amount of a salt of rizatriptan.

[0693] Embodiment 234. The method of embodiment 233, wherein no more than 7 migraines are treated in a 30-day period.

[0694] Embodiment 235. The method of embodiment 232, wherein the tablet further contains sodium bicarbonate.

[0695] Embodiment 236. The method of embodiment 235, wherein the tablet further contains sulfobutyl-ether-β-cyclodextrin sodium.

[0696] Embodiment 237. The method of embodiment 232, wherein the tablet further contains partially hydrolyzed polyvinyl alcohol.

[0697] Embodiment 238. A method of treating acute migraine in a human patient comprising: selecting a patient with a confirmed diagnosis of migraine, administering a dosage form comprising 20 mg of meloxicam free acid, or a molar equivalent amount of a meloxicam salt, and 10 mg of rizatriptan free base, or a molar equivalent amount of a rizatriptan salt, such as about 14.5 mg of rizatriptan benzoate, and the treatment is more effective than a gepant.

[0698] Embodiment 239. The method of embodiment 238, wherein the dosage form further comprises a bicarbonate.

[0699] Embodiment 240. The method of embodiment 238 or 239, wherein the dosage form further comprise a cyclodextrin.

[0700] Embodiment 241. The method of embodiment 238, 239, or 240, wherein the gepant is Rimegepant.

[0701] Embodiment 242. The method of embodiment 238, 239, or 240, wherein the gepant is Ubrogepant.

[0702] Embodiment 243. The method of embodiment 238, 239, or 240, wherein the gepant is Zavegepant.

[0703] Embodiment 244. The method of embodiments 238, 239, 240, 241, 242, or 243, wherein the meloxicam is in the free acid form.

[0704] Embodiment 245. The method of embodiment 238, 239, 240, 241, 242, 243, or 244, wherein the rizatriptan is in a salt form. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 246. The method of embodiment 245, wherein the rizatriptan is rizatriptan benzoate.

[0705] Embodiment 247. The method of embodiment 240, wherein the cyclodextrin is a sulfobutyl ether β-cyclodextrin (SBEβCD) or a pharmaceutically acceptable salt thereof. Embodiment 248. The method of embodiment 247, wherein the SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of [3-cyclodextrin.

[0706] Embodiment 249. The method of embodiment 247 or 248, wherein the molar ratio of the SBEβCD to meloxicam is about 0.8 to about 1.2.

[0707] Embodiment 250. The method of embodiment 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, or 249, wherein the bicarbonate is sodium bicarbonate.

[0708] Embodiment 251. The method of embodiment 250, wherein about 400 mg to about 600 mg of sodium bicarbonate is present in the dosage form.

[0709] Embodiment 252. The method of embodiment 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, or 251, wherein the relative efficacy for acute migraine treatment is evaluated by comparison of doses needed to treat (DNT) and number of patients needed to treat (NNT) to achieve similar clinical effectiveness in 24 h pain-relief and pain-freedom to a gepant comparator after administration.

[0710] Embodiment 253. The method of embodiment 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, or 252, wherein the dosage form comprising dextromethorphan and bupropion provides greater treatment effectiveness for acute migraine with fewer patients to treat (NNT) and fewer doses needed to treat (DNT) to achieve similar clinical effectiveness to a gepant comparator.

[0711] Embodiment 254. The method of embodiment 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, or 253, wherein the dosage form comprising dextromethorphan and bupropion is more effective in achieving 24 h pain relief and pain freedom after administration than a comparator gepant.

[0712] Embodiment 255. The method of embodiment 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, or 254, wherein the dosage form comprising dextromethorphan and bupropion is more effective with fewer doses and patients needed (lower DNT and NNT) to achieve a similar proportion of responders relative to its individual component rizatriptan or meloxicam. PCT Patent Application 134057-00001038_7T01PV01-WO Embodiment 256. The method of embodiment 252, 253, 254, or 255, wherein the gepant is rimegepant, ubrogepant, or zavegepant.

[0713] Embodiment 257. The method of any preceding embodiment, wherein the gepant comprises 75 mg of Rimegepant.

[0714] Embodiment 258. The method of any preceding embodiment, wherein the gepant comprises 50 mg of Ubrogepant.

[0715] Embodiment 259. The method of any preceding embodiment, wherein the gepant comprises 100 mg of Ubrogepant.

[0716] Embodiment 260. The method of any preceding embodiment, wherein the gepant comprises 10 mg of zavegepant.

[0717] EXAMPLES

[0718] Example 1

[0719] The effect of varying amounts of potassium carbonate (K₂CO₃) and sodium bicarbonate (NaHCO₃) on the pH of acidic media was tested. The acidic media was chosen to simulate gastric conditions. K2CO3 or NaHCO₃ was added to 50 mL of a 0.01 N HCl solution (pH 2). The pH of the solution was measured after addition of the K2CO3 or NaHCO3. Deionized water (240 mL) was then added to the mixture and pH was measured again. The results are shown in Tables 1-4.

[0720] Table 1. Results with K₂CO₃ (0.01 N HCl)

[0721] K₂CO₃ (mg) pH

[0722] 25 2.84

[0723] 35 6.29

[0724] 45 8.05

[0725] 50 8.29

[0726] 100 9.43

[0727] 200 10.14

[0728] 300 10.39

[0729] 400 10.55

[0730]

[0731] 450 10.58

[0732] Table 2. Results with K₂CO₃ (0.01 N HCl + Water)

[0733] K₂CO₃ (mg) pH

[0734] 200 10.27

[0735]

[0736] 300 10.46 PCT Patent Application 134057-00001038_7T01PV01-WO 400 10.57

[0737]

[0738] 450 10.63

[0739] Table 3. Results with NaHCO₃ (0.01 N HCl)

[0740] NaHCO₃ (mg) pH

[0741] 200 5.28

[0742] 300 5.90

[0743] 400 6.44

[0744] 450 6.86

[0745] 500 8.23

[0746] 750 8.30

[0747]

[0748] 1000 8.36

[0749]

[0750]

[0751] Tablets containing meloxicam and combinations of a sulfobutylether-β-cyclodextrin (SBEβCD) (a cyclodextrin, containing about 6 to about 7 sulfobutyl ether groups for each molecule of β-cyclodextrin), K2CO3, or NaHCCh were manufactured and tested for dissolution. Tablets containing meloxicam alone (MOBIC®) were purchased and also tested for dissolution. The tested tablets are listed in Table 5. Meloxicam in the form of meloxicam / SBEβCD inclusion complexes was used in the tablets containing meloxicam and SBEβCD. The inclusion complexes were formed by mixing meloxicam and SBEβCD in an aqueous pH- adjusted solution. The pH of the solution was adjusted using buffering agents. The resulting soluble meloxicam / SBEβCD inclusion complexes were then spray dried. This spray-dried dispersion was used in the manufacture of the tablets containing SBEβCD.

[0752] Table 5. Tablets

[0753]

[0754] Tablet A 15 mg meloxicam + 25 mg K2CO3 PCT Patent Application 134057-00001038_7T01PV01-WO Tablet B 15 mg meloxicam + 50 mg K2CO3

[0755] Tablet C 15 mg meloxicam + 100 mg K2CO3

[0756] Tablet D 15 mg meloxicam + 150 mg K2CO3

[0757] Tablet E 15 mg meloxicam + 500 mg NaHCO₃

[0758] Tablet F 15 mg meloxicam + 100 mg SBEβCD

[0759] Tablet G 15 mg meloxicam + 100 mg SBEβCD + 25 mg K₂CO₃

[0760] Tablet H 15 mg meloxicam + 100 mg SBEβCD + 50 mg K₂CO₃

[0761] Tablet I 15 mg meloxicam + 100 mg SBEβCD + 100 mg K₂CO₃

[0762] Tablet J 15 mg meloxicam + 100 mg SBEβCD + 150 mg K₂CO₃

[0763] Tablet K 15 mg meloxicam + 100 mg SBEβCD + 500 mg NaHCO₃

[0764]

[0765] Tablet L 15 g meloxicam (MOBIC®)

[0766] Dissolution testing in acidic medium (chosen to simulate gastric conditions) was performed by placing the tablets in a 0.01 N HCl solution, at an agitation rate of 75 RPM, and vessel temperature of approximately 37 °C. The results are presented in Tables 6 and in Figures 1-10. Results at various time points (0, 15, 30, 45, 60, 90, and 120 minutes) are presented as percent (%) of meloxicam dissolved.

[0767] Table 6. Dissolution Results

[0768] 15 30 45 60 90 120

[0769] 0 mins mins mins mins mins mins mins Tablet A 0% 23% 17% 15% 13% 12% 11%

[0770] Tablet B 0% 27% 20% 17% 16% 17% 15%

[0771] Tablet C 0% 31% 26% 25% 24% 23% 21%

[0772] Tablet D 0% 30% 26% 25% 24% 23% 22%

[0773] Tablet E 0% 50% 66% 77% 84% 92% 95%

[0774] Tablet F 0% 26% 17% 14% 12% 11% 10%

[0775] Tablet G 0% 48% 39% 26% 20% 16% 14%

[0776] Tablet H 0% 44% 30% 22% 17% 16% 13%

[0777] Tablet I 0% 32% 33% 27% 21% 16% 15%

[0778] Tablet J 0% 26% 27% 19% 15% 12% 11%

[0779] Tablet K 0% 85% 86% 86% 86% 86% 86%

[0780]

[0781] Tablet L 0% 2% 2% 2% 2% 2% 2%

[0782] Dissolution of meloxicam was greater with the tablets containing various combinations of meloxicam and SBEβCD, K2CO3, or NaHCO₃, as compared to tablets containing meloxicam alone. For example, after 120 minutes, dissolution of meloxicam tablets containing NaHCO₃ was 95% as compared to 2% for tablets containing meloxicam alone. PCT Patent Application 134057-00001038_7T01PV01-WO Dissolution of meloxicam increases with increasing amounts of K₂CO₃ in the absence of SBEβCD. However, in the presence of SBEβCD, increasing amounts of K2CO3 did not appear to increase meloxicam dissolution. At the highest dose of potassium carbonate tested, meloxicam dissolution in the presence of SBEβCD was reduced by approximately 50% as compared to meloxicam dissolution in the absence of SBEβCD at 120 minutes.

[0783] Dissolution of meloxicam with NaHCCh was significantly greater than that observed with the highest dose of K2CO3 at 15 minutes (50% versus 30%), and at 120 minutes (92% versus 23%). Meloxicam dissolution in the presence of SBEβCD was also significantly greater with NaHCCh as compared to the highest dose of K2CO3 at 15 minutes (85% versus 26%), and at 120 minutes (86% versus 12%). NaHCCh in the presence of SBEβCD increased meloxicam dissolution more at 15 minutes as compared to potassium carbonate, which resulted in a reduction in dissolution.

[0784] Example 3

[0785] A bilayer tablet containing 1) an inclusion complex of SBEβCD with meloxicam, prepared as described below, and 2) sodium bicarbonate was prepared (SBEβCD-Meloxicam / Bicarbonate). The first layer contained an inclusion complex of 15 mg meloxicam and 100 mg SBEβCD, and 100 mg of sodium bicarbonate. The second layer contained 40 mg of esomeprazole and 400 mg of sodium bicarbonate.

[0786] A total of 20 human subjects were randomly assigned in a 1:1 ratio to treatment with the SBEβCD-Meloxicam / Bicarbonate tablets described above or Mobic® tablets (15 mg meloxicam), once daily for 6 days under fasting conditions.

[0787] On the first day of dosing, plasma samples were collected for concentration analysis of meloxicam at several time points. Concentrations of meloxicam were determined using LC-MS / MS. Pharmacokinetic parameters were calculated. The results are depicted in FIG. 11.

[0788] The median Tmaxfor meloxicam, the trial's primary endpoint, was 9 times faster for the SBEβCD-Meloxicam / Bicarbonate tablets as compared to Mobic® (0.5 hour versus 4.5 hours respectively, p<0.0001).

[0789] The SBE[3CD-Meloxicam / Bicarbonate tablets also demonstrated higher mean maximum plasma concentration (Cmax) (p=0.0018), faster time to therapeutic plasma concentration (p<0.0001), and faster time to half-maximal plasma concentration (p<0.0001) as compared to Mobic®. PCT Patent Application 134057-00001038_7T01PV01-WO Meloxicam in the form of meloxicam / SBEβCD inclusion complexes was used in the tablets containing meloxicam and SBEβCD. The inclusion complexes were formed by mixing meloxicam and SBEβCD in an aqueous pH-adjusted solution. The pH of the solution was adjusted using buffering agents. The resulting soluble meloxicam / SBEβCD inclusion complexes were then spray dried. This spray-dried dispersion was used in the manufacture of the tablets containing SBEβCD.

[0790] Example 4

[0791] A monolayer tablet containing 1) the inclusion complex of SBEβCD with meloxicam; 2) rizatriptan; and 3) sodium bicarbonate was prepared (SBEβCD-Meloxicam / rizatriptan / Bicarbonate). The monolayer tablet contained 20 mg of meloxicam, 10 mg of rizatriptan, and 500 mg of sodium bicarbonate. The inclusion complex was the same as the inclusion complex of Example 3.

[0792] Dissolution testing of the tablets in acidic medium (chosen to simulate gastric conditions) was performed by placing the tablets in a 0.01 N HCl solution, at an agitation rate of 75 RPM, and vessel temperature of approximately 37 °C. The results are presented in Table 7. Results at various time points (0, 15, 30, 45, 60, 90, and 120 minutes) are presented as percent (%) of meloxicam, and percent (%) of rizatriptan dissolved.

[0793] Table 7. Dissolution Results

[0794] Time-point (minutes) 0 min 15 min 30 min 45 min 60 min 90 min 120 min Rizatriptan (e.g.,

[0795] 0% 89% 102% 103% 103% 103% 103% rizatriptan benzoate)

[0796] Meloxicam 0% 79% 92% 93% 93% 93% 94%

[0797]

[0798] As shown in Table 7, the dissolution results of the tablets in Example 4 are very similar to the dissolution result of Example 3. Therefore, we expected the pharmacokinetic properties, including bioavailability, Tmaxof meloxicam, etc., of the tablets in Example 4 to be similar to those described in Example 3 and FIG. 11. This expectation turned out to be correct, as shown in the examples below.

[0799] Example 5

[0800] The monolayer tablet of Example 4 was administered to six human subjects. On the first day of dosing, plasma samples were collected for concentration analysis of rizatriptan at several time points. Concentrations of rizatriptan and meloxicam were determined using LC- PCT Patent Application 134057-00001038_7T01PV01-WO MS / MS. Pharmacokinetic parameters were calculated. The results for meloxicam were comparable to those reported for the bilayer dosage form of Example 3. The median Tmaxof rizatriptan was 0.75 hours and the mean Cmaxof rizatriptan was 20.710 ng / mL. By comparison, the reported Tmaxof the commercial rizatriptan dosage form, Maxalt®, is 1.0-1.5 hours.

[0801] Example 6

[0802] A Phase 1, randomized, single-dose, parallel-group clinical study was conducted to evaluate the PK, safety, and tolerability of 1) a combination of meloxicam (20 mg), rizatriptan (10 mg), SBEPCD, and sodium bicarbonate (meloxicam / rizatriptan), as compared to 2) and Maxalt® (10 mg rizatriptan), in healthy human volunteers after oral administration under fasted conditions. A total of 20 healthy, adult male or female volunteers were randomized in a 1:1 ratio to receive a single dose of meloxicam / rizatriptan, or Maxalt® (10 mg rizatriptan).

[0803] Blood samples for PK analysis were collected pre dose and at multiple time points post dose. The pre-specified primary endpoint was Tthera, the time to reach a therapeutic plasma concentration of meloxicam, defined as the Cavgof meloxicam after administration of the highest approved dose (15 mg) of standard meloxicam, which is approximately 1000 ng / mL. PK results for the rizatriptan component of meloxicam / rizatriptan were compared to those for Maxalt® (rizatriptan).

[0804] PK results for the meloxicam (20 mg) component of meloxicam / rizatriptan from this trial were compared to PK results for Mobic® (15 mg meloxicam) from Example 3.

[0805] Phase 1 Results

[0806] Meloxicam was rapidly absorbed after oral administration of meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan), with a median time to therapeutic plasma concentration (Tthera) of 17 minutes, the primary endpoint (Figure 12 and Table 8). Median Tmaxwas 1 hour compared to 4.5 hours for 15 mg standard meloxicam (Mobic®). The very short Tmax suggests the potential for meloxicam / rizatriptan to have rapid onset of action in treating migraine. Mean plasma elimination half-life (T1 / 2) for meloxicam was 18.2 hours after administration of meloxicam / rizatriptan, which compares to 21.5 hours for standard meloxicam. The long elimination half-life suggests the potential for meloxicam / rizatriptan to enhanced and sustained efficacy, and to reduce migraine pain recurrence.

[0807] Table 8. Meloxicam Pharmacokinetic Parameters for Meloxicam / Rizatriptan PCT Patent Application 134057-00001038_7T01PV01-WO Statistic AUC0-infT1 / 2el (hr) Cmax(ng / mL) Tmax(hr)aTthera (hr)a(ng-hr / mL)

[0808] N 10 10 10 10 10 Geometric 46,865 17.5 2,532 1.0 0.29 Mean

[0809] SD 11,965 5.25 607 0.5-2.5 0.20-0.61

[0810]

[0811] aTmaxand Tthera present the value as a median or a range.

[0812] Rizatriptan was rapidly absorbed after oral administration of meloxicam / rizatriptan, with a Tmax of 0.64 hour (38 min), which compares to 0.88 hour for the same dose of standard rizatriptan (Maxalt®) (Figure 13 and Table 9). Systemic exposure measured using Cmaxand AUC were also numerically greater for rizatriptan after administration of meloxicam / rizatriptan versus standard rizatriptan.

[0813] Table 9. Rizatriptan Pharmacokinetic Parameters for Meloxicam / Rizatriptan and Standard Rizatriptan

[0814] Statistic AUC0-infTi / 2el Cmax Tmax(hr)a(pg-hr / mL)

[0815] (hr) (pg / mL) Meloxicam / Rizatriptan N 10 10 10 10 (20 mg meloxicam / 10

[0816] Geometric 83,800 1.98 29,991 0.64 mg rizatriptan) Mean

[0817] SD 22,787 0.28 11,041 0.5-2.5 Standard Rizatriptan N 10 10 10 10 (Maxalt ) (10 mg

[0818] Geometric 71,811 1.81 23,236 0.88 rizatriptan) Mean

[0819] SD 24,287 0.11 9,476 0.5-2

[0820]

[0821] aTmax presents the value as a median or a range.

[0822] Meloxicam / rizatriptan was well tolerated with no relevant differences in safety profile between the two treatment arms. There were no serious adverse events in the study.

[0823] Example 7

[0824] A Phase 3, randomized, double-blind, multicenter, active- and placebo-controlled trial is carried out to assess the efficacy and safety of meloxicam / rizatriptan in the acute treatment PCT Patent Application 134057-00001038_7T01PV01-WO of moderate and severe migraine, in patients with a history of inadequate response to prior acute migraine treatments. Eligible patients are randomized in a 2:2:2:1 ratio to treatment with meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan, with SBEβCD and sodium bicarbonate as described in Example 4 above), rizatriptan (10 mg) (rizatriptan arm), meloxicam (20 mg) with SBEβCD and sodium bicarbonate (meloxicam arm), or placebo. Coprimary endpoints are freedom from headache pain, and freedom from the most bothersome migraine-associated symptom (nausea, photophobia, or phonophobia), two hours after dosing, for meloxicam / rizatriptan as compared to placebo.

[0825] Superiority of meloxicam / rizatriptan to the rizatriptan and the meloxicam arms (component contribution) will be established based on sustained freedom from headache pain from 2 hours to 24 hours after dosing (key secondary endpoint).

[0826] Eligible patients must have a history of inadequate response to prior acute migraine treatments, assessed using the Migraine Treatment Optimization Questionnaire (mTOQ-4). The mTOQ-4 is a validated questionnaire that assesses efficacy response to prior acute treatments based on four aspects (two-hour pain freedom, efficacy for at least 24 hours with one dose, ability to plan daily activities, and disruption of daily activities).

[0827] It is expected that meloxicam / rizatriptan will show significant improvement over placebo and superiority over the rizatriptan and the meloxicam arms because of the rapid absorption and distinct dual mechanisms of action of meloxicam / rizatriptan described herein.

[0828] Example 8

[0829] A female migraine sufferer visits her physician in the hope of having relief from her migraine pain. Her doctor gives her 10 mg rizatriptan (Maxalt®), which she takes during her next acute migraine. It provides some relief of pain, nausea, allodynia, such as cutaneous allodynia, photophobia, and phonophobia, but not complete relief from these symptoms. On her next visit, her doctor gives her 20 mg of meloxicam in a tablet also containing SBEβCD and 500 mg of sodium bicarbonate, which she takes during her next acute migraine. It provides some relief of pain, nausea, allodynia, such as cutaneous allodynia, photophobia, and phonophobia, but not complete relief from these symptoms. On her next visit, her doctor gives her a tablet described in Example 4 above. She reports that at 2 hours and 24 hours after taking the tablet, she has about 10-30% improvement in pain, nausea, allodynia, such as PCT Patent Application 134057-00001038_7T01PV01-WO cutaneous allodynia, photophobia, and / or phonophobia over what she experienced after taking meloxicam or rizatriptan alone.

[0830] Example 9

[0831] A male migraine sufferer visits his physician in the hope of having relief from his migraine pain. His doctor gives him 10 mg rizatriptan (Maxalt®), which he takes during his next acute migraine. It provides some relief of pain, nausea, allodynia, such as cutaneous allodynia, photophobia, and phonophobia, but not complete relief from these symptoms. On his next visit, his doctor gives his 20 mg of meloxicam in a tablet also containing SBEβCD and 500 mg of sodium bicarbonate, which he takes during his next acute migraine. It provides some relief of pain, nausea, allodynia, such as cutaneous allodynia, photophobia, and phonophobia, but not complete relief from these symptoms. On his next visit, his doctor gives him a tablet described in Example 4 above. He reports that at 2 hours and 24 hours after taking the tablet, he has about 30-60% improvement in pain, nausea, allodynia, such as cutaneous allodynia, photophobia, and / or phonophobia over what he experienced after taking meloxicam or rizatriptan alone.

[0832] Example 10

[0833] A female migraine sufferer visits her physician in the hope of having relief from her migraine pain. Her doctor gives her 10 mg rizatriptan (Maxalt®), which she takes during her next acute migraine. It provides some relief of pain, nausea, allodynia, such as cutaneous allodynia, photophobia, and phonophobia, but not complete relief from these symptoms. On her next visit, her doctor gives her 20 mg of meloxicam in a tablet also containing SBEβCD and 500 mg of sodium bicarbonate, which she takes during her next acute migraine. It provides some relief of pain, nausea, allodynia, such as cutaneous allodynia, photophobia, and phonophobia, but not complete relief from these symptoms. On her next visit, her doctor gives her a tablet described in Example 4 above. She reports that at 2 hours and 24 hours after taking the tablet, she has about 60-100% improvement in pain, nausea, allodynia, such as cutaneous allodynia, photophobia, and / or phonophobia over what she experienced after taking meloxicam or rizatriptan alone.

[0834] Example 11

[0835] Over 37 million Americans suffer from migraine according to the Centers for Disease Control, and it is the leading cause of disability among neurological disorders in the United PCT Patent Application 134057-00001038_7T01PV01-WO States according to the American Migraine Foundation. Migraine is characterized by recurrent attacks of pulsating, often severe and disabling head pain associated with nausea, and sensitivity to light and or sound. It is estimated that migraine accounts for $78 billion in direct (e.g., doctor visits, medications) and indirect (e.g., missed work, lost productivity) costs each year in the United States [Gooch CL, Pracht E, Borenstein AR, The burden of neurological disease in the United States: A summary report and call to action. Ann Neurol. 2017 Apr; 81(4):479-484]. Published surveys of migraine sufferers indicate that more than 70% are not fully satisfied with their current treatment, that nearly 80% would try a new therapy, and that they desire treatments that work faster, more consistently, and result in less symptom recurrence [(1) Smelt AF, Louter MA, Kies DA, Blom JW, Terwindt GM, van der Heijden GJ, De Gucht V, Ferrari MD, Assendelft WJ, What do patients consider to be the most important outcomes for effectiveness studies on migraine treatment? Results of a Delphi study. PLoS One. 2014 Jun 16;9(6):e98933, 6; and (2) Lipton RB, Stewart WF, Acute migraine therapy: do doctors understand what patients with migraine want from therapy? Headache.

[0836] 1999;39(suppl 2): S20-S26],

[0837] The World Health Organization classifies severe migraine attacks as among the most disabling illnesses, comparable to dementia, quadriplegia, and active psychosis [(1) Menken et al. Arch Neurol. 2000;57:418-420; and (2) Shapiro and Goadsby. Cephalalgia. 2007;27:991-4]. Debilitating pain, and the often-constant fear of the next migraine attack, damage family life, social life, and employment [Global Burden of Disease Study. Lancet. 2017;390:1211-1259]. Depression and anxiety are twice as common in people with migraine than in healthy individuals [Antonaci et al. J Headache Pain. 2011;12:115-125]. Widespread misperception of the seriousness of migraine contributes to its under-recognition and under-treatment [Global Burden of Disease Study. Lancet. 2017;390:1211-1259]. The majority of patients are not fully satisfied with their current treatment. Thus, there is an urgent need for new treatments that provide improved efficacy for this serious neurological disease.

[0838] A Phase 3, randomized, double-blind, multicenter, placebo- and active-controlled trial was conducted to assess the efficacy and safety of the combination of meloxicam and rizatriptan (meloxicam / rizatriptan) in the acute treatment of moderate and severe migraine. Eligible patients must have an age of 18 to 65 years, an established diagnosis (at least 1 year) of migraine with or without aura as defined by ICHD-3 criteria, an average of 2 to 8 moderate to severe migraines per month, had a history of inadequate response to prior acute migraine PCT Patent Application 134057-00001038_7T01PV01-WO treatments, assessed by a score of 7 using the Migraine Treatment Optimization Questionnaire (mTOQ-4) (the average score was 3.6), corresponding to poor response to prior acute treatments. Exclusion criteria included cluster headaches or other types of migraines, chronic daily headache (> 15 non-migraine headache days per month), history of significant cardiovascular disease, and uncontrolled hypertension. In addition to a history of inadequate response, enrolled patients exhibited a high rate of characteristics that are strongly associated with poor treatment outcomes including cutaneous allodynia (75.4%), severe migraine pain intensity (41.2%), obesity (43.7%), and morning migraine (36.6%). A total of 1,594 patients were randomized in a 2:2:2:1 ratio to the monolayer tablet of Example 4 (20 mg meloxicam / 10 mg rizatriptan, with SBEβCD and sodium bicarbonate), rizatriptan (10 mg), meloxicam (20 mg) with SBEβCD (MoSEIC Meloxicam), or placebo, to treat a single migraine attack of moderate or severe intensity. The two co-primary endpoints of the trial were the proportion of patients who are free from headache pain two hours after dosing, and the proportion of patients who no longer suffered from their most bothersome migraine-associated symptom (nausea, photophobia, or phonophobia) two hours after dosing, for meloxicam / rizatriptan as compared to placebo. Superiority of meloxicam / rizatriptan to the rizatriptan and meloxicam arms (component contribution) was to be established based on sustained freedom from headache pain from two to 24 hours after dosing (key secondary endpoint). The study was conducted pursuant to an FDA Special Protocol Assessment (SPA). Rizatriptan, an active comparator in the trial, is considered to be the fastest acting oral triptan and one of the most effective medications currently available for the acute treatment of migraine. (Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT(lB / lD) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet. 2001 Nov 17;358(9294):1668-75.)

[0839] Meloxicam / rizatriptan provided rapid relief of migraine pain with the percentage of patients achieving pain relief with meloxicam / rizatriptan being numerically greater than with rizatriptan at every time point measured starting at 15 minutes, and statistically significant by 60 minutes (p=0.04) (Fig. 14). The proportions of patients experiencing pain relief 1.5 hours after dosing were 60.5% for meloxicam / rizatriptan compared to 52.5% for rizatriptan and 48.3% for placebo (p=0.019, p=0.04, respectively versus meloxicam / rizatriptan) (Fig. 14). Fig.

[0840] 14A shows the percentage of subjects reporting pain relief over placebo for meloxicam, rizatriptan, and meloxicam / rizatriptan at 1.0 hour and 1.5 hours. PCT Patent Application 134057-00001038_7T01PV01-WO Meloxicam / rizatriptan met the two regulatory co-primary endpoints by demonstrating, with high statistical significance, a greater percentage of patients as compared to placebo achieving pain freedom (19.9% versus 6.7%, p<0.001, Fig. 15), and absence of most bothersome symptom (36.9% versus 24.4%, p=0.002), 2 hours after dosing.

[0841] Superiority of meloxicam / rizatriptan to rizatriptan (active comparator) and MoSEIC™ meloxicam (component contribution) was established as specified in the SPA, by the demonstration of a greater percentage of patients receiving meloxicam / rizatriptan achieving sustained pain freedom from 2 hours to 24 hours after dosing, compared to rizatriptan, MoSEIC™ meloxicam, and placebo (16.1%, 11.2%, 6.8% and 5.3%, respectively; p=0.038, p=0.001, and p<0.001, respectively versus meloxicam / rizatriptan, Fig. 16A), the pre-specified key secondary endpoint to demonstrate component contribution. About 80% of the patients treated with meloxicam / rizatriptan who achieved pain freedom at 2 hours maintained pain freedom through 24 hours. These results demonstrated the significant improvement in pain freedom and superiority of meloxicam / rizatriptan to rizatriptan in treating migraine.

[0842] Meloxicam / rizatriptan provided substantially greater and more sustained migraine pain relief compared to placebo and rizatriptan, which translated to a significant reduction in rescue medication use for meloxicam / rizatriptan compared to placebo and rizatriptan. The percentage of patients experiencing sustained pain relief from 2 hours to 24 hours after dosing was 53.3% for meloxicam / rizatriptan, compared to 33.5% for placebo and 43.9% for rizatriptan (p<0.001, p=0.006, respectively versus meloxicam / rizatriptan) (FIG. 16B).

[0843] Sustained pain relief from 2 hours to 48 hours was also experienced by a statistically significantly greater proportion of meloxicam / rizatriptan patients (46.5%), compared to placebo (31.1%) and rizatriptan (36.5%) patients (p<0.001, p=0.003, respectively versus meloxicam / rizatriptan) (FIG. 17B). Fig. 17D shows the percentage of subjects achieving sustained pain relief over placebo from 2 hours to 48 hours for meloxicam, rizatriptan, and meloxicam / rizatriptan. The sustained pain freedom from 2 hours to 48 hours was also experienced by a statistically significantly greater proportion of meloxicam / rizatriptan patients (15.4%), compared to placebo (5.3%), and rizatriptan (8.8%), and MoSEIC™ meloxicam (8.1%) patients (p<0.001, p=0.003, p=<0.001, respectively versus meloxicam / rizatriptan) (FIG. 17A). Fig. 17C shows the percentage of subjects achieving sustained pain freedom over placebo from 2 hours to 48 hours for meloxicam, rizatriptan, and PCT Patent Application 134057-00001038_7T01PV01-WO meloxicam / rizatriptan. About 77% of patients treated with meloxicam / rizatriptan who achieved pain freedom at 2 hours maintained the pain freedom through 48 hours.

[0844] Rescue medication was used by 23.0% patients received meloxicam / rizatriptan, compared to 43.5% patients received placebo and 34.7% patients received rizatriptan (p<0.001 for each group versus meloxicam / rizatriptan) (FIG. 18). About 77% of patients receiving meloxicam / rizatriptan did not require rescue medication. These results demonstrated the superiority of meloxicam / rizatriptan to rizatriptan, an active comparator, in treating migraine.

[0845] Meloxicam / rizatriptan was statistically significantly superior to rizatriptan on several other secondary endpoints, including Patient Global Impression of Change (PGI-C) (p=0.022), and return to normal functioning at 24 hours (p=0.027).

[0846] Some of the p-values for meloxicam / rizatriptan versus rizatriptan for various endpoints are listed in Table 10 below, demonstrating the statistically significant superiority of meloxicam / rizatriptan over rizatriptan in treating migraine.

[0847] Table 10. P-Values for Meloxicam / Rizatriptan vs Rizatriptan for Various Endpoints Endpoint P-value Meloxicam / Rizatriptan vs Rizatriptan 1 hour Pain Relief 0.04

[0848] 2-24 hour Sustained Pain Relief 0.006

[0849] 2-48 hour Sustained Pain Relief 0.003

[0850] 2-24 hour Sustained Pain Freedom 0.038

[0851] 2-48 hour Sustained Pain Freedom 0.003

[0852] PGI-C 0.022

[0853] Functional Improvement at 24 hours 0.027

[0854] Use of Rescue Medication <0.001

[0855]

[0856] Furthermore, Meloxicam / Rizatriptan showed a greater probability of pain relief with patients who took Meloxicam / Rizatriptan having approximately a 70% percent probability of experiencing pain relief 24 hours after taking Meloxicam / Rizatriptan versus approximately 60% of patients who took rizatriptan or MoSEIC Meloxicam and 50% of patients who took the placebo treatment as illustrated in FIG. 27. The probability of achieving pain relief with Meloxicam / Rizatriptan was greater than with rizatriptan within 30 minutes after dosing, PCT Patent Application 134057-00001038_7T01PV01-WO which resulted in a median time to pain relief that was nearly three times faster for Meloxicam / Rizatriptan compared to rizatriptan at 1.5 hours and 4 hours, respectively.

[0857] Furthermore, the probability of experiencing pain relapse decreased for patients who took Meloxicam / Rizatriptan over patients who took rizatriptan; Meloxicam / Rizatriptan reduced pain relapse by more than 50% compared to rizatriptan over a 48-hour period after dosing with 45.2% of patients experiencing relapse of pain after taking rizatriptan while only 21.2% of patients experienced relapse of pain after taking Meloxicam / Rizatriptan as illustrated in FIG. 28.

[0858] Given that Rizatriptan, an active comparator in the trial, is considered to be the fastest acting oral triptan and one of the most effective medications currently available for the acute treatment of migraine, and that this trial enrolled patients with difficult-to-treat migraine, the observed treatment effects with meloxicam / rizatriptan that provided greater and more lasting migraine pain relief than rizatriptan, is highly significant. Many patients experience a suboptimal response to their current acute migraine treatments, placing them at increased risk of headache related disability and progression to chronic migraine, factors associated with increased healthcare costs. The results of this study suggest that meloxicam / rizatriptan may provide an important treatment option for people with difficult-to-treat migraine.

[0859] Meloxicam / Rizatriptan was generally safe and well-tolerated during the MOMENTUM Phase 3 trials with adverse events occurring in one to three percent of patients. 11.1% of patients experienced any form of treatment-emergent adverse events after taking Meloxicam / Rizatriptan, while 2.7%, 1.6%, and 1.4% of patients experienced nausea, dizziness, and somnolence, respectively, after taking Meloxicam / Rizatriptan (Table 11). The rate at which patients experienced treatment-emergent adverse events after dosing with Meloxicam / Rizatriptan versus any of the other tested treatments was approximately similar (Table 11). PCT Patent Application 134057-00001038_7T01PV01-WO Table 11

[0860] Meloxicam / Rizatriptan Rizatriptan Meloxicam Placebo (N = 441) (N = 434) (N = 433) (N = 218) Any Treatment- 49 (11.1%) 67 (15.4%) 50 (11.5%) 13(6.0%) Emergent Adverse

[0861] Event

[0862] Nausea 12 (2.7%) 21 (4.8%) 14 (3.2%) 8 (3.7%0 Dizziness 7 (1.6%) 9 (2.1%) 5 (1.2%) 5 (1.2%)

[0863]

[0864] Somnolence 6 (1.4%) 9 (2.1%) 10 (2.3%) 6 (1.4%) Data presented as number of subjects (% of subjects)

[0865] The results of this trial demonstrate the ability of meloxicam / rizatriptan to provide unique benefits to migraine patients, with fast, strong, and durable relief of migraine pain as compared to a potent active comparator, rizatriptan, in a stringently designed trial enriched with patients with difficult-to-treat migraine. These results have potentially important implications for patient care based on the high rate of inadequate response to and patient dissatisfaction with current treatments.

[0866] Meloxicam / rizatriptan incorporates multiple mechanisms of action to address various migraine processes with the goal of providing enhanced effectiveness. Meloxicam / rizatriptan is thought to act by inhibiting CGRP release, reversing CGRP-mediated vasodilation, and inhibiting neuro-inflammation, pain signal transmission, and central sensitization. The results of this trial validate this approach, demonstrating that meloxicam / rizatriptan can provide significant benefit that is greater than that of currently available treatments, even in patients with difficult-to-treat migraine. Meloxicam / rizatriptan may be used for the acute treatment of migraine in adults with or without aura effectively.

[0867] Example 12

[0868] A Phase 3, randomized, double-blind, multicenter, placebo-controlled trial was conducted evaluating the early treatment of migraine with meloxicam / rizatriptan. A total of 302 patients were randomized in a 1:1 ratio to treat a single migraine attack with a single dose of meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan, with a SBEβCD (such as SBEPCD sodium) and sodium bicarbonate as described in Example 4 above), or placebo, at the earliest sign of migraine pain, while the pain was mild, before progressing to moderate or severe intensity. PCT Patent Application 134057-00001038_7T01PV01-WO This clinical trial is different from the clinical trial in Example 11. The clinical trial of Example 11 enrolled only patients with a history of inadequate response to prior acute treatments, with patients waiting to treat their attacks only when the migraine pain had reached moderate or severe intensity. The clinical trial in Example 11 is in contrast to this clinical trial, which enrolled all comers and in which patients were instructed to administer meloxicam / rizatriptan at the earliest sign of migraine pain while the pain was mild, before progressing to moderate or severe intensity.

[0869] The patients were adult subjects with an established diagnosis of migraine with or without aura.

[0870] Co-primary endpoints are freedom from headache pain, and freedom from the most bothersome migraine-associated symptom (nausea, photophobia, or phonophobia), two hours after dosing, for meloxicam / rizatriptan as compared to placebo.

[0871] Secondary endpoints included sustained pain freedom, freedom from migraine pain progression, change in functional disability, and use of rescue medication.

[0872] Inclusion criteria included male or female at ages 18-65 inclusive, an established diagnosis (at least 1 year) of migraine with or without aura as defined by the ICHD-3 criteria, and an average of 2 to 8 migraines per month. Exclusion criteria included cluster headaches, tension headaches, or other types of migraines, chronic daily headache (>15 non-migraine headache days per month), history of significant cardiovascular disease, and uncontrolled hypertension.

[0873] Meloxicam / rizatriptan substantially and significantly eliminated migraine pain, and substantially and significantly prevented progression of migraine pain intensity in this Phase 3 trial of meloxicam / rizatriptan in the early treatment of migraine. In the trial, meloxicam / rizatriptan met the co-primary endpoints of freedom from migraine pain and freedom from most bothersome symptoms as compared to placebo.

[0874] Meloxicam / rizatriptan demonstrated statistically significant improvement as compared to placebo on both of the co-primary endpoints of pain freedom (32.6% versus 16.3%, p=0.002), and freedom from most bothersome symptom (43.9% versus 26.7%, p=0.003), 2 hours after dosing (FIG. 19A and FIG. 19B). The most bothersome symptom is nausea, photophobia, or phonophobia.

[0875] Meloxicam / rizatriptan was numerically superior to placebo as early as 30 minutes for migraine pain freedom (FIG. 20) and most bothersome symptom freedom (FIG. 21), achieving PCT Patent Application 134057-00001038_7T01PV01-WO statistical significance for migraine pain freedom at 90 minutes (p=0.003) and at every time thereafter (FIG. 20). At 12 hours, 64% of the patients receiving meloxicam / rizatriptan were pain free as compared to 42% of patients receiving placebo. At 24 hours, 69% of patients receiving meloxicam / rizatriptan were pain free as compared to 47% of patients receiving placebo.

[0876] Meloxicam / rizatriptan durably relieved migraine pain with a statistically significantly greater percentage of patients as compared to placebo achieving sustained pain freedom from 2 to 24 hours after dosing (22.7% versus 12.6%, p=0.030), and from 2 to 48 hours after dosing (20.5% versus 9.6%, p=0.013) (FIG. 22A and FIG. 22B).

[0877] Meloxicam / rizatriptan prevented progression of migraine pain intensity beyond mild in 73.5% of patients versus 47.4% of patients taking placebo from 2 to 24 hours (p<0.001) (FIG. 23). A single dose of meloxicam / rizatriptan prevented migraine pain progression beyond mild.

[0878] The effect on pain progression translated to a significant reduction in the use of rescue medication, with only 15.3% of patients taking meloxicam / rizatriptan required rescue medication through 24 hours after dosing, versus 42.2% of patients taking placebo (p<0.001) (FIG. 24).

[0879] Meloxicam / rizatriptan substantially and significantly reduced functional disability, and demonstrated overall disease improvement. The ability to perform normal activities was achieved by 73.5% of patients taking meloxicam / rizatriptan compared to 47.4% of patients taking placebo at 24 hours (p<0.001) (FIG. 25).

[0880] On the Patient Global Impression of Change (PGI-C) scale, 52.4% of patients taking meloxicam / rizatriptan were very much or much improved compared to 27.7% of patients taking placebo (p<0.001) at hour 2 (FIG. 26).

[0881] Meloxicam / rizatriptan was generally safe and well tolerated in the trial. The most commonly reported adverse events with meloxicam / rizatriptan were somnolence, dizziness, and paresthesia, all of which occurred at a rate of less than five percent (Table 12). There were no serious adverse events in the trial.

[0882] Table 12

[0883] Meloxicam / Rizatriptan Placebo

[0884]

[0885] (N = 140) (N = 143) PCT Patent Application 134057-00001038_7T01PV01-WO Any Treatment-Emergent 25 (17.9%) 11 (7.7%)

[0886] Adverse Event

[0887] Somnolence 6 (4.3%) 3 (2.1%)

[0888] Dizziness 4 (2.9%) 2 (1.4%)

[0889]

[0890] Paraesthesia 3 (2.1%) 0

[0891] Data presented as number of subjects (% of subjects)

[0892] "[This] study demonstrated high rates of freedom from migraine pain with meloxicam / rizatriptan treatment, and utilized an innovative design to evaluate migraine pain progression. It is remarkable that early treatment with meloxicam / rizatriptan prevented migraine pain progression in the vast majority of patients and enabled a similarly high percentage of patients to return to normal functioning," said Dr. Stewart Tepper, Professor of Neurology at the Geisel School of Medicine at Dartmouth. " The multiple mechanisms of meloxicam / rizatriptan address the many disordered physiological processes implicated in migraine attacks. These results, coupled with previous clinical data showing superiority of meloxicam / rizatriptan over an active comparator, provide clinical evidence that this synergistic, multi-mechanistic approach and the rapid absorption of meloxicam / rizatriptan may translate to important benefits for a wide range of patients. As clinicians continue to seek options for their patients with improved efficacy over currently available therapies, meloxicam / rizatriptan may offer an important new treatment for this disabling condition." This Phase 3 trial confirmed the superior and durable efficacy of meloxicam / rizatriptan. The prevention of migraine pain progression, and the substantial increase in the rate of pain freedom demonstrated with early treatment with meloxicam / rizatriptan, expands and enhances its differentiated profile for the acute treatment of migraine. With this Phase 3 trial and the Phase 3 trial described in Example 11 in patients with a history of inadequate response to prior acute treatments, meloxicam / rizatriptan has now been evaluated in two positive well-controlled trials. These trials demonstrated the efficacy of meloxicam / rizatriptan against potent active and placebo comparators, across a spectrum of migraine attack settings, regardless of the timing of migraine treatment, disease severity, or baseline pain intensity.

[0893] " Migraine is one of the most disabling disorders, incapacitating sufferers and seriously damaging home life, social activity and the ability to work. Published surveys have underscored that patients remain dissatisfied with the efficacy of currently available therapies," said Cedric O'Gorman, MD, Senior Vice President of Clinical Development and PCT Patent Application 134057-00001038_7T01PV01-WO Medical Affairs of Axsome. " The results of [this] trial demonstrate for the first time that meloxicam / rizatriptan can halt migraine pain progression before reaching moderate or severe intensity. These data grow the body of clinical evidence in support of the potential of meloxicam / rizatriptan to be a multi-mechanistic treatment for migraine with efficacy that is superior to the current standard of care, and which can rapidly, robustly, and durably alleviate symptoms, and return patients to their normal daily activities."

[0894] Example 13

[0895] A long-term, open-label Phase 3 trial of meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan, with SBEβCD and sodium bicarbonate as described in Example 4 above) was conducted. Treatment with meloxicam / rizatriptan, rapidly, substantially, and durably relieved migraine pain and associated symptoms in this trial, meloxicam / rizatriptan was well tolerated over long-term treatment with a safety profile consistent with that observed in the previously reported controlled trials.

[0896] This clinical trial evaluated the long-term safety of meloxicam / rizatriptan (20 mg MoSEIC™ meloxicam / 10 mg rizatriptan), dosed for up to 12 months, in patients with migraine attacks. The study enrolled patients who had completed the clinical trials described in Example 11 or Example 12. Enrolled patients were allowed to treat up to 10 migraine attacks per month during the up to 12-month period, with one dose of meloxicam / rizatriptan for each migraine that occurred. The safety and efficacy of meloxicam / rizatriptan was assessed during the trial. A total of 706 patients were enrolled. The trial was concluded once at least 300 patients had treated at least 2 migraines a month for 6 months, and approximately 100 patients had treated at least 2 migraines a month for 12 months, as pre-specified. At the time of study conclusion, 515 patients had reached at least 6 months, and 155 patients had reached at least 12 months of treatment. Over 21,000 migraine attacks were treated with meloxicam / rizatriptan during the trial. Efficacy measures included relief of migraine pain and most bothersome symptom (photophobia, phonophobia, nausea), and use of rescue medication.

[0897] In this clinical trial, administration of meloxicam / rizatriptan resulted in rapid, and substantial relief of migraine pain and associated symptoms. Within 1 hour after dosing, 39% (range: 37-41%) of patients achieved relief of migraine pain, demonstrating the rapid onset of meloxicam / rizatriptan. Two hours after administration of meloxicam / rizatriptan, relief of migraine pain was achieved by 68% (range: 65-71%) of patients and pain freedom by 38% PCT Patent Application 134057-00001038_7T01PV01-WO (range: 37-40%) of patients. Freedom from most bothersome symptom (photophobia, phonophobia, nausea) was achieved by 47% (range: 46-49%) of patients within 2 hours after dosing.

[0898] Meloxicam / rizatriptan durably relieved migraine pain with 85% (range: 84-86%) of patients free from rescue medication use through 24 hours, and 83% (range: 82-85%) of patients free from rescue medication use through 48 hours after a single administration of meloxicam / rizatriptan. Rates of sustained pain relief from 2 to 24 hours and from 2 to 48 hours were 60% (range: 59-62%) and 59% (58-60%), respectively. Rates of sustained pain freedom from 2 to 24 hours and from 2 to 48 hours were 33% (range: 33-35%) and 32% (range: 32-34%), respectively.

[0899] Meloxicam / rizatriptan was well tolerated with long-term dosing. The safety profile of meloxicam / rizatriptan over the 12-month treatment period was consistent with that previously reported in short-term controlled trials. The most commonly reported adverse events (>3%) were nausea, dizziness, and vomiting. During the 12-month trial, 1.6% of patients discontinued due to adverse events.

[0900] Example 14

[0901] Protocol and Statistical Analysis Plan for Clinical Trails (NCT04068051)

[0902] An Open-Label Study to Assess the Long-term Safety of Meloxicam / Rizatriptan for the Acute Treatment of Migraine in Adults

[0903] This study will be performed in compliance with Good Clinical Practices and applicable regulatory requirements, including the archiving of essential documents.

[0904] 1. SYNOPSIS

[0905] Table 13 presents synopsis.

[0906] Table 13. Synopsis

[0907] PRODUCT Meloxicam / Rizatriptan

[0908] NAME / NUMBER

[0909] DEVELOPMENT PHASE Phase 3

[0910] PROTOCOL TITLE An Open-Label Study to Assess the Long-term Safety of (meloxicam and rizatriptan) for the Acute Treatment of Migraine in Adults.

[0911] INDICATION Acute treatment of migraine with or without aura in adults.

[0912]

[0913] PCT Patent Application 134057-00001038_7T01PV01-WO OBJECTIVES Primary Objective:

[0914] To evaluate the long term safety of chronic intermittent use of Meloxicam / Rizatriptan.

[0915] Secondary Objectives:

[0916] To assess the effect of Meloxicam / Rizatriptan on migraine symptoms following repeated treatment of migraine attacks. STUDY DESIGN This study is a Phase 3, multicenter, open-label, trial to evaluate the long-term safety of intermittent chronic dosing with meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan, with a SBEβCD and sodium bicarbonate as described in Example 4 above) in subjects with migraine attacks. Eligible subjects will take a dose of Meloxicam / Rizatriptan following the onset of a migraine. Subjects will be enrolled for up to 12 months and encouraged to treat all migraine attacks with Meloxicam / Rizatriptan.

[0917] Subjects are eligible subjects if they have participated in a prior Meloxicam / Rizatriptan study for the acute treatment of migraine with no significant changes in medical history since participation. Subjects who meet all eligibility criteria will be enrolled at Visit 1 and will be dispensed Meloxicam / Rizatriptan for at-home treatment of migraine attacks. Subjects will be instructed to treat each migraine attack with Meloxicam / Rizatriptan and return for clinic visits at Months 1, 3, 6, 9, and 12 (5 return visits).

[0918] Migraine Headache Diary

[0919] For the first 4 migraine attacks, the subject will record their headache pain intensity (measured by a 4-point rating scale; 0- none, 1-mild, 2-moderate, or 3-severe), in the Migraine Headache Diary immediately prior to taking study medication, and at the following time points after taking study medication: 30 minutes, and 1, 2, 8, 24, and 48 hours after dosing.

[0920] Prior to dosing, for the first 4 migraine attacks, the subject will define their most bothersome symptom (nausea, photophobia, phonophobia) and assess the presence or absence of each symptom at the following timepoints: 1 and 2 hours after dosing.

[0921] The subject will be instructed to report any adverse events which occur following each dose of Meloxicam / Rizatriptan. Use of rescue medications will also be recorded. All migraines which occur during the course of the study, regardless of treatment with study drug or not, will be recorded in the Migraine Headache Log.

[0922] Study Visits

[0923]

[0924] PCT Patent Application 134057-00001038_7T01PV01-WO Subjects will come to the clinic for the enrollment visit (Visit 1, Day 1), Month 1, Month 3, Month 6, Month 9, and Month 12. At each in clinic study visit, the subject will undergo the following safety assessments: assessment of adverse events, review of concomitant medications, vital signs, urine pregnancy test (if applicable), clinical laboratory tests and an electrocardiogram. Additionally, the following patient- reported scales will be completed at every visit: Headache Impact Test-6 (HIT- 6), Migraine Disability Assessment Score (MIDAS, not conducted at Month 1), and Migraine- Specific Quality of Life Questionnaire (MSQ).

[0925] PLANNED NUMBER OF The study will end when there are at least 300 subjects that SUBJECTS complete the Month 6 visit and at least 100 subjects that complete the Month 12 visit, treating a minimum of 2 migraines a month. At that time, all remaining uncompleted subjects (those in various interim visits of the study) will be scheduled to come to the site to complete the Month 12 visit procedures. These subjects are considered completing the study.

[0926] STUDY ENTRY CRITERIA Inclusion criteria:

[0927] A subject will be eligible for study participation if the subject meets all of the following criteria:

[0928] 1. Is male or female 18 to 65 years of age inclusive.

[0929] 2. Is willing and able to provide written informed consent to participate in the study, and willing and able to understand and comply with the procedures and study requirements.

[0930] 3. Participated in a prior study with Meloxicam / Rizatriptan for the acute treatment of migraine.

[0931] 4. If female, is either not of childbearing potential (defined as postmenopausal for at least 1 year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy, or hysterectomy]); or is nonlactating and nonpregnant (has negative pregnancy test results at Day 1), does not plan to get pregnant during the study or for at least one month after, and is using a reliable method of contraception, before study drug, administration and for the duration of the trial. Reliable methods of contraception include hormonal, double-barrier methods (e.g., condom and diaphragm, condom and foam,

[0932]

[0933] condom and sponge, each with spermicidal PCT Patent Application 134057-00001038_7T01PV01-WO jellies or cream), abstinence, vasectomized partners and intrauterine devices.

[0934] 5. Is willing and able to complete the Migraine Headache Diary.

[0935] Exclusion criteria:

[0936] A subject will be excluded from the study if the subject meets any of the following criteria:

[0937] 1. Significant change in medical history or concomitant medications since enrolling in the prior Meloxicam / Rizatriptan study.

[0938] 2. Initiation of or a change in concomitant medication to reduce the frequency of migraine episodes since completing the prior Meloxicam / Rizatriptan study.

[0939] 3. Is considered by the investigator, for any reason (including, but not limited to, the risks described as precautions, warnings, and contraindications in the current version of the investigator's brochure for Meloxicam / Rizatriptan tablets), to be an unsuitable candidate to receive Meloxicam / Rizatriptan.

[0940] 4. Is currently receiving propranolol or has received propranolol within 2 weeks prior to enrollment or plans to use during the study. Participation in any clinical trial of an experimental drug or device since completing the prior Meloxicam / Rizatriptan study. INVESTIGATIONAL Meloxicam / Rizatriptan (20 mg meloxicam / 10 mg rizatriptan PRODUCT tablet with a SBEβCD (SBEβCD sodium) and sodium bicarbonate as described in Example 4 above) for oral administration.

[0941] TREATMENT REGIMENS Meloxicam / Rizatriptan is to be taken orally with water at the onset of a migraine attack.

[0942] PRINCIPAL Multi-center

[0943] INVESTIGATOR PLANNED STUDY SITES Up to approximately 80 study sites in North America CRITERIA FOR Primary Outcome Measures

[0944] EVALUATION

[0945] • The primary safety outcome is long-term safety as evaluated by the incidence, severity, and relatedness of AEs following dosing with Meloxicam / Rizatriptan.

[0946]

[0947] PCT Patent Application 134057-00001038_7T01PV01-WO Efficacy Outcome Measures

[0948] • Proportion of subjects with headache pain freedom at Hour 2, with headache pain freedom defined as pain intensity = none.

[0949] • Proportion of subjects with absence of the most bothersome symptom (MBS; nausea, photophobia, or phonophobia) at Hour 2, with the MBS defined at the onset of migraine, prior to drug administration.

[0950] • Proportion of subjects with headache pain relief at Hour 2.

[0951] • Sustained headache pain freedom between Hours 2 and 24, defined as having no headache pain at Hour 2, with no use of rescue medication and no relapse of headache pain through Hour 24.

[0952] • Change from baseline in the MIDAS total score. • Change from baseline in HIT-6 total score.

[0953] • Change from baseline in the scores of each of the three domains of the MSQv2.1.

[0954] • Proportion of subjects with headache pain freedom at Hour 0.5, 1, 8, 24 and 48, with headache pain freedom defined as pain intensity = none.

[0955] • Proportion of subjects with headache pain relief at Hour 0.5, 1, 8, 24 and 48.

[0956] STATISTICAL METHODS Analysis Populations:

[0957] The following analysis populations are planned for this study:

[0958] • Safety Population: The Safety Population will include all subjects who take at least one dose study medication.

[0959] • Intent-to-treat (ITT) Population: The ITT Population will include all subjects who take at least one dose of study medication and report at least one efficacy measurement.

[0960] Descriptive statistics will be used for all variables and all data over time.

[0961] SAMPLE SIZE To assess for long-term safety, this study will enroll enough DETERMINATION subjects to ensure that 300 subjects are treated for at least 6

[0962]

[0963] months and 100 for 12 months, treating at least 2 migraines a PCT Patent Application 134057-00001038_7T01PV01-WO month. Up to 875 subjects may be enrolled to achieve this sample size.

[0964] STUDY AND TREATMENT The duration of participation will be up to 12 months. Subjects DURATION will be allowed to treat each migraine with Meloxicam / Rizatriptan for up to the 12 months following enrollment. Up to six planned study visits will occur over the 12 months.

[0965] Study Description

[0966] Brief Summary: MOVEMENT (Multimechanistic Treatment over Time of Migraine Symptoms) is a Phase 3 study to evaluate the longterm safety of chronic intermittent use of Meloxicam / Rizatriptan and to assess the effect of Meloxicam / Rizatriptan on migraine symptoms following repeated treatment of migraine attacks.

[0967] Detailed Description: This study is a Phase 3, multicenter, open-label, trial to evaluate the long-term safety and efficacy of intermittent chronic dosing with Meloxicam / Rizatriptan in subjects with migraine attacks. Eligible subjects will take Meloxicam / Rizatriptan following the onset of a migraine. Subjects will be treated for up to 12 months.

[0968] Conditions: Migraine

[0969] Study Design

[0970] Study Type: Interventional

[0971] Primary Purpose: Treatment

[0972] Study Phase: Phase 3

[0973] Interventional Study Model: Single Group Assignment

[0974] Number of Arms: 1

[0975] Masking: None (Open Label)

[0976] Enrollment: 706 [Actual]

[0977] Arms and Interventions

[0978]

[0979] Table 14 presents arms and interventions.

[0980] Table 14. Arms and Interventions PCT Patent Application 134057-00001038_7T01PV01-WO Arms Assigned Interventions Experimental: Meloxicam / Rizatriptan Drug: Meloxicam / Rizatriptan Meloxicam / Rizatriptan (20 mg meloxicam / 10 mg rizatriptan, with SBEβCD and sodium bicarbonate as described in Example 4 above) taken by mouth for the acute treatment of

[0981]

[0982] migraine.

[0983] Eligibility

[0984] Minimum Age: 18 Years

[0985] Maximum Age: 65 Years

[0986] Sex: All

[0987] Gender Based: No

[0988] Accepts Healthy Volunteers: No

[0989] Criteria: Inclusion Criteria:

[0990] • Has participated in a prior study with Meloxicam / Rizatriptan for the treatment of migraine

[0991] Exclusion Criteria:

[0992] • Has previously received any investigational drug or device or investigational therapy within 30 days before Screening, other than Meloxicam / Rizatriptan

[0993] • Pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study

[0994] Study Results

[0995] Participant Flow

[0996] Table 15 presents the reporting groups and Table 16 presents the overall study. Table 15. Reporting Groups

[0997] Description

[0998] Meloxicam / Rizatriptan Meloxicam / Rizatriptan (20 mg meloxicam / 10 mg rizatriptan, with SBEβCD and sodium bicarbonate as described in Example

[0999]

[1000] 4 above)) taken by mouth forthe acute treatment of migraine.

[1001] Table 16. Overall Study

[1002] Meloxicam / Rizatriptan

[1003]

[1004] Started 706 PCT Patent Application 134057-00001038_7T01PV01-WO Completed 138

[1005]

[1006] Not Completed 568

[1007] Baseline Characteristics

[1008] Baseline Analysis Population Description:

[1009] Safety Population includes all subjects who received at least one dose of study drug.

[1010] Table 17 presents the reporting groups. Table 18 presents the baseline measures, and Table 19 presents races.

[1011] Table 17. Reporting Groups

[1012] Description

[1013] Meloxicam / Rizatriptan Meloxicam / Rizatriptan (meloxicam / rizatriptan (20 mg meloxicam / 10 mg rizatriptan, with SBEβCD and sodium bicarbonate as described in Example 4 above)) taken by

[1014]

[1015] mouth for the acute treatment of migraine.

[1016] Table 18. Baseline Measures

[1017] Meloxicam / Rizatriptan

[1018] Overall Number of Participants 706

[1019] Age, Continuous

[1020] Number

[1021] Mean (Standard 706 participants

[1022] Analyzed

[1023] Deviation)

[1024] Unit of

[1025] years 42.0 (10.94)

[1026] measure:

[1027] Number

[1028] Sex: Female, Male 706 participants

[1029] Analyzed

[1030] Measure Count of

[1031] Female 580 (82.15%)

[1032] Type: Participants

[1033] Units of..

[1034] participants Male 126 (17.85%)

[1035]

[1036] measure:

[1037] Table 19. Races

[1038] Meloxicam / Rizatriptan

[1039] Number

[1040] Race (NIH / OMB) 706 participants

[1041] Analyzed

[1042] American

[1043] Measure Count of Indian or

[1044] 7 (0.99%)

[1045] type: Participants Alaska

[1046] Native

[1047] Unit of..

[1048] participants Asian 12 (1.7%)

[1049]

[1050] measure: PCT Patent Application 134057-00001038_7T01PV01-WO Native

[1051] Hawaiian

[1052] or Other 0 (0%)

[1053] Pacific

[1054] Islander

[1055] Black or

[1056] African 132 (18.7%)

[1057] American

[1058] White 544 (77.05%)

[1059] More than

[1060] 9 (1.27%)

[1061] one race

[1062] Unknown

[1063] or Not 2 (0.28%)

[1064]

[1065] Reported

[1066] Outcome Measures

[1067] Primary Outcome Measure: (see Table 20)

[1068] Table 20.

[1069] Measure Title Long-term Safety of Chronic Intermittent Use of Meloxicam / Rizatriptan

[1070] Measure Description Long-term safety as measured by:

[1071] Subjects with any TEAEs

[1072] Subjects with suspected to be drug-related TEAEs Subjects with serious TEAEs

[1073] Subjects with TEAEs that led to drug withdrawal

[1074] Subjects with TEAEs that led to withdrawal from study Subjects with TEAEs that resulted in death

[1075] Time Frame Up to 12 months

[1076]

[1077] Note: TEAEs stand for treatment-emergent adverse events.

[1078] Analysis Population Description:

[1079] Safety Population includes all subjects who received at least one dose of study drug.

[1080] Table 21 presents reporting groups, and Table 22 presents measured values.

[1081] Table 21. Reporting Groups

[1082] Description

[1083] Meloxicam / Rizatriptan Meloxicam / Rizatriptan (MoSEIC™ meloxicam and rizatriptan)

[1084]

[1085] taken by mouth for the acute treatment of migraine. PCT Patent Application 134057-00001038_7T01PV01-WO Table 22. Measured Values

[1086] Meloxicam / Rizatriptan Overall Number of Participants Analyzed 706

[1087] Long-term Safety of Chronic Intermittent Use of

[1088] Meloxicam / Rizatriptan

[1089] Measure Type: Count of Participants

[1090] Unit of measure: participants

[1091] Subjects with any TEAEs 293 (41.5%) Subjects with suspected to be drug-related TEAEs 118 (16.71%)

[1092] Subjects with serious TEAEs 8 (1.13%)

[1093] Subjects with TEAEs that led to drug withdrawal 10 (1.42%)

[1094] Subjects with TEAEs that led to withdrawal from study 13 (1.84%)

[1095]

[1096] Subjects with TEAEs that resulted in death 0 (0%)

[1097] Reported Adverse Events

[1098] Table 23 presents the time frame for the reported adverse events. Table 24 presents reporting groups. Table 26 presents all-Cause mortality. Table 27 presents Serious Adverse Events.

[1099] Table 23.

[1100] Time Frame Adverse events were collected after administration of study drug through the final visit (up to 12 months). Any AE was monitored up to a maximum of 30 days after the final visit.

[1101] Adverse Event Reporting Safety Population includes all subjects who received at

[1102]

[1103] Description least one dose of study drug.

[1104] Table 24. Reporting Groups

[1105] Description

[1106] Meloxicam / Rizatriptan Meloxicam / Rizatriptan (MoSEIC™ meloxicam and rizatriptan) taken by mouth for the acute treatment of

[1107]

[1108] migraine.

[1109] Table 25. All-Cause Mortality

[1110] Meloxicam / Rizatriptan

[1111] Affected / At Risk (%) # Events

[1112]

[1113] Total All-Cause Mortality 0 / 706 (0%)

[1114] Table 26. Serious Adverse Events

[1115] Meloxicam / Rizatriptan

[1116]

[1117] Affected / At Risk (%) # Events PCT Patent Application 134057-00001038_7T01PV01-WO Total 8 / 706 (1.13%)

[1118] Cardiac disorders

[1119] Mitral valve incompetenceA* 1 / 706 (0.14%) 1 Gastrointestinal disorders

[1120] Hiatus herniaA* 1 / 706 (0.14%) 1 Hepatobiliary disorders

[1121] Hepatitis acuteA* 1 / 706 (0.14%) 1 Injury, poisoning and procedural

[1122] complications

[1123] Burns third degreeA* 1 / 706 (0.14%) 1 Musculoskeletal procedural 1 / 706 (0.14%) 1

[1124] complicationB*

[1125] Musculoskeletal and connective

[1126] tissue disorders

[1127] ArthralgiaA* 1 / 706 (0.14%) 1 Reproductive system and breast

[1128] disorders

[1129] Endometrial hyperplasiaA* 1 / 706 (0.14%) 1

[1130] Social circumstances

[1131] Victim of crimeA* 1 / 706 (0.14%) 1 Surgical and medical procedures

[1132]

[1133] Skin graftA* 1 / 706 (0.14%) 1

[1134] * Indicates events were collected by non-systematic methods

[1135] ATerm from vocabulary, MedDRA Dictionary

[1136] BTerm from vocabulary, MedDRA Dictionary

[1137] Other Adverse Events

[1138] Table 27 presents other adverse events.

[1139] Table 27. Frequency Threshold Above Which Other Adverse Events are Reported: 3%

[1140] Meloxicam / Rizatriptan

[1141] Affected / At Risk (%) # Events

[1142] Total 95 / 706 (13.46%)

[1143] Gastrointestinal disorders

[1144] NauseaA* 40 / 706 (5.67%) 88 VomitingA* 33 / 706 (4.67%) 48

[1145] Nervous system disorders

[1146]

[1147] DizzinessA* 11 / 706 (3.12%) 45

[1148] Indicates events were collected by non-systematic methods

[1149] ATerm from vocabulary, MedDRA Dictionary

[1150] MOVEMENT Trial

[1151] Long-term effects of Meloxicam / Rizatriptan (fixed-dose combination) on headache burden and quality of life: results of the MOVEMENT trial PCT Patent Application 134057-00001038_7T01PV01-WO Summary:

[1152] In the MOVEMENT trial, open-label, acute treatment of migraine with Meloxicam / Rizatriptan, a fixed-dose combination of 20 mg meloxicam, reformulated using MoSEIC™ technology to improve absorption rate, and rizatriptan 10 mg (e.g., 14.5 mg rizatriptan benzoate), resulted in improved headache-related disability, headache burden, and quality of life over up to 12 months of treatment.

[1153] Background:

[1154] The efficacy and safety of fixed-dose combination meloxicam / rizatriptan for the acute treatment of migraine has been evaluated in two phase 3 trials, MOMENTUM (NCT03896009) and INTERCEPT (NCT04163185). Primary efficacy and safety endpoints have been reported above. The patient-reported outcomes following open-label treatment of migraine symptoms with fixed-dose combination meloxicam / rizatriptan for up to 12 months is reported herewith, to better characterize the impact on participant disability, burden, and quality of life.

[1155] Methods:

[1156] MOVEMENT (NCT04068051) was a phase 3, multicenter, open-label US long-term safety trial in participants who had completed the MOMENTUM and INTERCEPT trials. Participants were required to experience >2 migraine attacks per month and could treat <10 migraine attacks per month during a maximum 12-month period, with one dose of oral fixed-dose meloxicam / rizatriptan per migraine. Participants treated their migraines at home and recorded all migraine attacks in an electronic diary, detailing severity of headache pain, presence / absence of associated symptoms, functional disability and use of rescue medication. Efficacy evaluations were collected for the first 4 migraines.

[1157] Results:

[1158] In the intent-to-treat population (n=704), mean baseline migraine disability assessment (MIDAS) total score was 22.5, headache impact test-6 (HIT-6) total score was 64.1, and the MSG domains of role function-restrictive, role function-preventative, and emotional function were 47.6, 62.2, and 59.0, respectively.

[1159] Over up to 12 months' treatment, MIDAS scores were improved (mean±SD change from baseline: -4.5±20.3, -4.1±19.5, -4.5±22.2, and -0.7±27.9, at 3, 6, 9, and 12 months, respectively). At early termination, the mean±SD change from baseline was -5.3±20.7. There was also a steady improvement in HIT-6 score over time, with mean±SD changes from baseline of -1.4±5.3, -1.5±5.6, -1.8±5.7, -2.8±6.5, and -2.9±8.1, at 1, 3, 6, 9, and 12 months, PCT Patent Application 134057-00001038_7T01PV01-WO respectively. There were improvements across all 3 domains of the 14-item migraine-specific quality of life questionnaire (MSQ): role function-restrictive domain (mean±SD changes from baseline: 4.9±18.5, 6.0±18.8, 8.3±20.5, 9.6±20.1, and 10.7±24.0 at 1, 3, 6, 9, and 12 months, respectively), role function-preventative (mean±SD change from baseline: 3.4±20.0, 5.9±20.4, 7.1±20.4, 9.2±20.8, and 9.9±22.6 at 1, 3, 6, 9, and 12 months, respectively), and emotional function (mean±SD change from baseline: 4.7±20.9, 5.9±22.1, 5.9±22.5, 7.9±23.6, and 6.6±25.7 at 1, 3, 6, 9, and 12 months, respectively) (FIG. 29).

[1160] Over the up to 12-month treatment period, the fixed-dose combination of meloxicam / rizatriptan was well-tolerated and the safety profile was consistent with that reported in short-term controlled trials. The most common adverse events were nausea (5.7%), vomiting (4.7%), dizziness (3.1%), somnolence (2.8%), diarrhea (2.3%), and upper respiratory tract infection (2%).

[1161] Conclusions:

[1162] Over a maximum 12-month period, open-label fixed-dose meloxicam / rizatriptan was generally well-tolerated and was associated with improvement in headache-related disability, and headache burden, and a better quality of life with reduced limitations on daily functions.

[1163] Example 14 - Continued

[1164] Long-Term Effects of Meloxicam / Rizatriptan® (MoSEIC™ Meloxicam and Rizatriptan) on Headache Burden and Quality of Life: Results of the MOVEMENT Trial

[1165] Key Objective

[1166] The key objection is to describe the effects of long-term, open-label treatment with Meloxicam / Rizatriptan (MoSEIC™ meloxicam and rizatriptan (e.g., rizatriptan benzoate)) on patient-reported headache-related disability, headache burden, and quality of life.

[1167] Introduction

[1168] Migraine is a chronic, debilitating neurological disorder characterized by recurrent attacks of throbbing pain, often with nausea, photophobia, and phonophonia.

[1169] A proximately 70% of patients living with migraine report they are not completely satisfied with their current migraine treatments with other drugs.

[1170] Meloxicam / Rizatriptan, a fixed-dose combination of 20 mg MoSEIC™ meloxicam and 10 mg rizatriptan (e.g., 14.5 mg rizatriptan benzoate), is formulated to improve the PCT Patent Application 134057-00001038_7T01PV01-WO pharmacokinetics of meloxicam, as the relatively slow absorption rate of standard meloxicam limits its use for acute treatment of migraine.

[1171] The MOVEMENT (NCT04068051) trial was a long-term trial of Meloxicam / Rizatriptan over up to 1 year in patients living with migraine.

[1172] This analysis describes the patient-reported outcomes (PROs) during long-term, openlabel treatment with Meloxicam / Rizatriptan in the MOVEMENT trial.

[1173] Summary

[1174] In clinical trials, participants who took Meloxicam / Rizatriptan were more likely to have headache pain relief and relief from their most bothersome symptom within 2 hours, compared with participants who took placebo.

[1175] In this study, participants receiving open-label Meloxicam / Rizatriptan for up to 12 months experienced improvements in their migraine-related disability, headache impact, and quality of life over time.

[1176] Methods

[1177] The MOVEMENT trial was a US-based, phase 3, multicenter, open-label, long-term safety study.

[1178] Participants who completed the MOMENTUM or INTERCEPT trials could continue treatment with open-label Meloxicam / Rizatriptan in the MOVEMENT trial (FIG. 30).

[1179] Eligible participants were adults who continued to experience >2 migraine attacks per month.

[1180] Participants could treat up to 10 migraine attacks per month at home for a maximum of 12 months, with 1 oral dose of Meloxicam / Rizatriptan per attack.

[1181] Figure 19 shows the study design of MOVEMENT trial.

[1182] PRO data were collected throughout the trial at intervals specified in Table 28, using the Migraine Disability Assessment (MIDAS) scale, the Headache ImpactTest (HIT-6), and total score and 3 subdomains of the 14-item Migraine Specific Quality of Life Questionnaire Version 2.1 (MSQ):

[1183] 1) Role function-restrictive (7 items assessing how migraine limits daily social and work-related act...

Claims

PCT Patent Application 134057-00001038_7T01PV01-WO CLAIMS1. A method of treating migraine in a human patient being treated with a gepant, comprising: selecting a patient with a confirmed diagnosis of migraine who has been treated with a gepant for the migraine, administering a tablet comprising 20 mg of meloxicam free acid, or a molar equivalent amount of a meloxicam salt, and 10 mg of rizatriptan free base, or a molar equivalent amount of a rizatriptan salt, and discontinuing use of the gepant.

2. The method of claim 1, wherein the gepant is Rimegepant, Ubrogepant, or Zavegepant.

3. The method of claim 1 or 2, wherein the efficacy for acute migraine treatment is evaluated using a network meta-analysis (NMA).

4. The method of claim 1, 2, or 3, wherein the efficacy for acute migraine treatment with the tablet is higher over the gepant, wherein the gepant is rimegepant, ubrogepant, or zavegepant, with respect to releasing the symptoms of migraine.

5. The method of claim 1, 2, 3, or 4, wherein the tablet is more effective in achieving pain relief by 2h after administration than the gepant.

6. The method of claim 1, 2, 3, 4, or 5, wherein the tablet is more effective in achieving sustained pain relief and pain freedom from 2 hours to 24 hours than the gepant.

7. The method of claim 1, 2, 3, 4, 5, or 6, wherein the human patient is having inadequate response to prior treatments, and wherein the prior treatments are with gepants.

8. A method of treating migraine with or without aura in a human patient in need thereof, comprising: selecting a human patient experiencing at least 2 migraine attacks a month, and administering a tablet comprising 20 mg of meloxicam free acid, or a molar equivalent amount of a meloxicam salt, and 10 mg of rizatriptan free base, or a molar equivalent amount of a rizatriptan salt to the human patient, wherein one tablet is orally administered per migraine attack, and wherein the treatment is continued for up to 12 months.

9. The method of claim 8, wherein the human patient has up to 10 migraine attacks per month.

10. The method of claim 8 or 9, wherein the treatment lasts for at least 1 month.PCT Patent Application 134057-00001038_7T01PV01-WO 11. The method of claim 8 or 9, wherein the treatment lasts for at least 3 months.

12. The method of claim 8 or 9, wherein the treatment lasts for at least 6 months.

13. The method of claim 8 or 9, wherein the treatment lasts for at least 9 months.

14. The method of claim 8, 9, 10, 11, 12, or 13, wherein the human patient has median baseline MIDAS total score of about 17.0 to about 22.5 before treatment.

15. The method of claim 8, 9, 10, 11, 12, 13, or 14, wherein the human patient has median baseline HIT-6 total score of about 64 before treatment.

16. The method of claim 8, 9, 10, 11, 12, 13, 14, or 15, wherein the human patient has moderate to severe impairment before treatment.

17. The method of claim 8, 9, 10, 11, 12, 13, 14, 15, or 16, wherein the tablet is well tolerated throughout the 12-month period.

18. The method of claim 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the MIDAS total scores of the human patient improves from baseline up to the 12-month.

19. The method of any one of claims 8 to 18, wherein, at the early termination visit, the (95% Cl) change in MIDAS is about -3.4 to about -7.1.

20. The method of any one of claims 8 to 19, wherein, at the early termination visit, the average (95% Cl) change in MIDAS is about -5.3.

21. The method of any one of claims 8 to 20, wherein the probability of the human patient reached an MCIC (minimal clinically important change, with at least 4.5 points) in MIDAS is at least about 40% at 3 months, 6 months, 9 months, or 12 months after oral administration of the tablet.

22. The method of any one of claims 8 to 21, wherein the HIT-6 total scores in the human patient improves up to the 12-month period.

23. The method of any one of claims 8 to 22, wherein, at the early termination visit, the (95% Cl) change in HIT-6 is about -3.0 to about -1.9.

24. The method of any one of claims 8 to 23, wherein, at the early termination visit, the average (95% Cl) change in HIT-6 is about -2.4.PCT Patent Application 134057-00001038_7T01PV01-WO 25. The method of any one of claims 8 to 24, wherein probability of the human patient reaching an MCID (minimal clinically important difference, with 5 points change) in HIT-6 score increases from 21.4% at Month 1 to 34.1% at Month 12.

26. The method of any one of claims 8 to 25, wherein the MSQ total scores and subscore domains in the human patient improves up to the 12-month.

27. The method of claim 26, wherein the subscore domain comprises role function-restrictive, role function-preventive, and emotional function.

28. The method of any one of claims 8 to 27, wherein, at the early termination visit, the (95% Cl) change in MSQ total score was about 4.5 to about 7.1.

29. The method of any one of claims 8 to 28, wherein, at the early termination visit, the average (95% Cl) change in MSQ total score was about 5.8.

30. The method of any one of claims 8 to 29, wherein the human patient has improvements in quality of life, reduction in headache-related disability, and headache impact.

31. The method of any preceding claim, wherein the human patient does not have an ischemic bowel disease.

32. The method of any preceding claim, wherein the human patient is screened for an ischemic bowel disease.

33. The method of any preceding claim, wherein the human patient does not have a peripheral vascular disease.

34. The method of any preceding claim, wherein the human patient is screened for a peripheral vascular disease.

35. The method of any preceding claim, wherein the human patient is monitored for a cerebrovascular event; wherein if no cerebrovascular event occurs, the tablet is administered during a subsequent migraine; and wherein if a cerebrovascular event occurs, treatment with the tablet is discontinued.

36. The method of any preceding claim, wherein the human patient does not have a cerebrovascular event.PCT Patent Application 134057-00001038_7T01PV01-WO 37. A method of treating acute migraine in a human patient comprising: selecting a patient with a confirmed diagnosis of migraine, administering a tablet comprising 20 mg of meloxicam free acid, or a molar equivalent amount of a meloxicam salt, and 10 mg of rizatriptan free base, or a molar equivalent amount of a rizatriptan salt, and the treatment is more effective than a gepant.

38. The method of claim 37, wherein the gepant is Rimegepant, Ubrogepant, or Zavegepant.

39. The method of claim 37 or 38, wherein the relative efficacy for acute migraine treatment is evaluated by comparison of doses needed to treat (DNT) and number of patients needed to treat (NNT) to achieve similar clinical effectiveness in 24 h pain-relief and painfreedom to a gepant comparator after administration.

40. The method of claim 37, 38, or 39, wherein the tablet comprising dextromethorphan and bupropion provides greater treatment effectiveness for acute migraine with fewer patients to treat (NNT) and fewer doses needed to treat (DNT) to achieve similar clinical effectiveness to a gepant comparator.

41. The method of claim 37, 38, 39, or 40, wherein the tablet comprising dextromethorphan and bupropion is more effective in achieving 24 h pain relief and pain freedom after administration than a comparator gepant.

42. The method of claim 37, 38, 39, 40, or 41, wherein the tablet comprising dextromethorphan and bupropion is more effective with fewer doses and patients needed (lower DNT and NNT) to achieve a similar proportion of responders relative to its individual component rizatriptan or meloxicam.

43. The method of claim 37, 38, 39, 40, 41, or 42, wherein the gepant comprises 75 mg of Rimegepant.

44. The method of claim 37, 38, 39, 40, 41, or 42, wherein the gepant comprises 50 mg of Ubrogepant.

45. The method of claim 37, 38, 39, 40, 41, or 42, wherein the gepant comprises 100 mg of Ubrogepant.PCT Patent Application 134057-00001038_7T01PV01-WO 46. The method of claim 37, 38, 39, 40, 41, or 42, wherein the gepant comprises 10 mg of zavegepant.

47. The method of any preceding claim, wherein the tablet further contains sodium bicarbonate.

48. The method of claim 47, wherein about 400 mg to about 600 mg of sodium bicarbonate is present in the tablet.

49. The method of any preceding claim, wherein the tablet further contains sulfobutyl-ether-P-cyclodextrin (SBEβCD), or a pharmaceutically acceptable salt thereof.

50. The method of claim 49, wherein the SBEβCD is sulfobutyl-ether-β-cyclodextrin sodium.

51. The method of claim 49 or 50, wherein the SBEβCD has about 6 to about 7 sulfobutyl ether groups for each molecule of [3-cyclodextrin.

52. The method of claim 49, 50, or 51 wherein the molar ratio of the SBEβCD to the meloxicam is about 0.8 to about 1.2.

53. The method of any preceding claim, wherein the tablet further contains partially hydrolyzed polyvinyl alcohol.

54. The method of any preceding claim, wherein the meloxicam is in the free acid form.

55. The method of any preceding claim, wherein the rizatriptan is in a salt form.

56. The method of claim 55, wherein the rizatriptan is rizatriptan benzoate.

57. The method of claim 56, wherein the tablet comprises 14.5 mg of rizatriptan benzoate.

58. The method any preceding claim, wherein the migraine is acute migraine.

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