Compounds and combinations thereof for treating neurological and psychiatric conditions

Abstract

This disclosure relates to administration of a combination of: 1) about 100-110 mg, about 104-106 mg, or about 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion; and 2) about 40-50 mg, about 44-46 mg, or about 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of the free base form or another salt form of dextromethorphan in certain patient populations, such as patients having severe renal impairment.

Description

[0001] COMPOUNDS AND COMBINATIONS THEREOF FOR TREATING NEUROLOGICAL AND PSYCHIATRIC CONDITIONS

[0002] Inventor: Herriot Abuteau

[0003] CROSS REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of U. S. Provisional Application No.63 / 715,455, filed November 1, 2024; U. S. Provisional Application No. 63 / 715,485, filed November 1, 2024; and U. S. Provisional Application No. 63 / 725,482, filed November 26, 2024; all of which are incorporated by reference herein in their entireties.

[0005] SUMMARY

[0006] This disclosure relates to administration of a combination of: 1) about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride, or a molar equivalent amount of a free base form or another salt form of bupropion; and 2) about 40-50 mg, about 44-46 mg, or about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of a free base form or another salt form of dextromethorphan in certain patient populations.

[0007] Some embodiments include a method of treating major depressive disorder in a patient having severe renal impairment, comprising, administering a daily dose of: (i) about 105 mg of bupropion hydrochloride and (ii) about 45 mg of dextromethorphan hydrobromide to a human patient who has severe renal impairment and is experiencing major depressive disorder.

[0008] Some embodiments include a method of treating a patient having a nervous system condition by administering a combination of dextromethorphan and bupropion, the method comprising:

[0009] orally administering to the patient, once a day, a dosage form comprising: 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan, wherein the molar ratio of the bupropion to the dextromethorphan in the dosage form is about the ratio of the molar amount bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide;

[0010] wherein the patient is selected for; 1) having the nervous system condition and 2) having severe renal impairment, wherein the patient is determined to have severe renal impairment by an assay on a biological sample from the patient; and wherein a risk of somnolence or dizziness for the patient who has severe renal impairment is lower following orally administering the dosage form containing the combination once a day to the patient than it would be if a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide were administered twice a day to the patient for the same number of days.

[0011] Some embodiments include a method of treating a patient with a combination of dextromethorphan and bupropion, wherein the patient is experiencing a nervous system condition, the method comprising the steps of:

[0012] determining whether the patient has severe renal impairment by:

[0013] obtaining or having obtained a biological sample from the patient; and performing or having performed an assay on the biological sample to determine if the patient has severe renal impairment; and if the patient has severe renal impairment, then orally administering once a day to the patient, a dosage form containing a combination of 105 mg or less of bupropion hydrochloride., or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan, wherein the molar ratio of the bupropion to the dextromethorphan is about the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide;

[0014] if the patient does not have renal impairment, then orally administering twice a day to the patient, a dosage form containing a combination of 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan; wherein a risk of somnolence or dizziness for a patient who has severe renal impairment is lower following orally administering the dosage form containing the combination once a day to the patient than it would be if a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide were administered twice a day to the patient for the same number of days.

[0015] Some embodiments include a method of treating a patient who is experiencing a nervous system condition, the method comprising the steps of:

[0016] a) determining whether the patient is at risk of an adverse event associated with overexposure to dextromethorphan by:

[0017] obtaining or having obtained a biological sample from the patient; and performing or having performed an assay on the biological sample to determine if the patient has severe renal impairment, wherein a result that the patient has severe renal impairment indicates that the patient is at risk of an adverse event associated with overexposure to dextromethorphan; and

[0018] b) if the patient is at risk of an adverse event associated with overexposure to dextromethorphan, then orally administering once a day to the patient, a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan, wherein the molar ratio of the bupropion to the dextromethorphan is about the ratio the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; and

[0019] c) if the patient is not at risk of an adverse event associated with overexposure to dextromethorphan, then orally administering twice a day to the patient, a dosage form containing a combination of 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan.

[0020] Some embodiments include a method of treating a nervous system condition with a combination of dextromethorphan and bupropion, comprising: orally administering to a patient, once a day, a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is about the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; and

[0021] wherein the patient is selected for: 1) having the nervous system condition and 2) having severe renal impairment, wherein the patient is determined to have severe renal impairment by an assay on a biological sample from the patient and wherein the patient has a reduced risk of an adverse event as compared with the risk of the adverse event that the patient would have if the dosage form were administered twice daily to the patient,

[0022] Some embodiments include a method of treating a patient with a combination of dextromethorphan and bupropion, wherein the patient is experiencing a nervous system condition, the method comprising the steps of:

[0023] determining whether the patient has severe renal impairment by:

[0024] obtaining or having obtained a biological sample from the patient; and performing or having performed an assay on the biological sample to determine if the patient has severe renal impairment; and

[0025] if the patient has severe renal impairment, then orally administering once a day to the patient, a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is about the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; and

[0026] if the patient does not have renal impairment, then orally administering twice a day to the patient, a dosage form containing a combination of 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan.

[0027] Some embodiments include a method of treating a patient having a nervous system condition by administering a combination of dextromethorphan and bupropion, the method comprising:

[0028] orally administering to the patient, once a day, a dosage form comprising: 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan, wherein the molar ratio of the bupropion to the dextromethorphan in the dosage form is about the ratio of the molar amount bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide;

[0029] wherein the patient is selected for; 1) having the nervous system condition and 2) having severe renal impairment, wherein the patient is determined to have severe renal Impairment by an assay on a biological sample from the patient; and wherein a risk of somnolence and dizziness for the patient who has severe renal impairment is lower following orally administering the dosage form containing the combination once a day to the patient than it would be if a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide were administered twice a day to the patient for the same number of days.

[0030] Some embodiments include a method of treating a patient with a combination of dextromethorphan and bupropion, wherein the patient is experiencing a nervous system condition, the method comprising the steps of:

[0031] determining whether the patient has severe renal impairment by:

[0032] obtaining or having obtained a biological sample from the patient; and performing or having performed an assay on the biological sample to determine if the patient has severe renal impairment; and if the patient has severe renal impairment, then orally administering once a day to the patient, a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan, wherein the molar ratio of the bupropion to the dextromethorphan is about the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide;

[0033] if the patient does not have renal impairment, then orally administering twice a day to the patient, a dosage form containing a combination of 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan;

[0034] wherein a risk of somnolence and dizziness for a patient who has severe renal impairment is lower following orally administering the dosage form containing the combination once a day to the patient than it would be if a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide were administered twice a day to the patient for the same number of days.

[0035] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 depicts the effects of renal impairment, hepatic impairment, and CYP2D6 poor metabolizer status on the pharmacokinetics of a tablet containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride.

[0036] FIG. 2 depicts the change from baseline in MADRS total score by week for human patients receiving a tablet containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride twice per day.

[0037] DETAILED DESCRIPTION

[0038] As mentioned above, this disclosure relates to administration of a combination of: 1) about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride, or a molar equivalent amount of a free base form or another salt form of bupropion; and 2) about 40-50 mg, about 44-46 mg, or about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of a free base form or another salt form of dextromethorphan. This combination is referred to for convenience herein as the "subject combination." In every instance where the subject combination is referred to herein, the combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is specifically contemplated.

[0039] Dextromethorphan hydrobromide is an uncompetitive NMDA receptor antagonist and a sigma-1 receptor agonist.

[0040] The chemical name of dextromethorphan hydrobromide is morphinan, 3-methoxy-17-methyl-, (9a, 13a, 14a), hydrobromide monohydrate. Dextromethorphan hydrobromide has the empirical formula C18H25NO·HBr·H2O and a molecular weight of 370.33. The structural formula is:

[0041]

[0042] Dextromethorphan hydrobromide powder is white or almost white, crystalline, and sparingly soluble in water.

[0043] Bupropion hydrochloride is an aminoketone and CYP4502D6 inhibitor.

[0044] The chemical name of bupropion hydrochloride is: (+)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. Bupropion hydrochloride has the empirical formula C13H18ClNO·HCl and a molecular weight of 276.2, The structural formula is:

[0045]

[0046] Bupropion hydrochloride powder is white and highly soluble in water.

[0047] The subject combination may be contained in an oral dosage form, including a tablet, such as an extended-release tablet, In some embodiments, the subject combination is contained in a dosage form for oral administration and is available as round bilayer tablets.

[0048] In some embodiments, each tablet containing the subject combination contains 45 mg of dextromethorphan hydrobromide in an immediate-release formulation, in some embodiments, each tablet of the subject combination contains 105 mg of bupropion hydrochloride in an extended-release formulation, in some embodiments, each tablet of the subject combination contains 45 mg of dextromethorphan hydrobromide in an immediate-release formulation and 105 mg of bupropion hydrochloride in an extended-release formulation.

[0049] In some embodiments, a tablet containing the subject combination contains I-cysteine hydrochloride monohydrate. In some embodiments, a tablet containing the subject combination contains carbomer homopolymer. In some embodiments, a tablet containing the subject combination contains microcrystalline cellulose, in some embodiments, a tablet containing the subject combination contains colloidal silicon dioxide. In some embodiments, a tablet containing the subject combination contains crospovidone. In some embodiments, a tablet containing the subject combination contains stearic acid. In some embodiments, a tablet containing the subject combination contains magnesium stearate.

[0050] In some embodiments, a tablet containing the subject combination contains the following inactive ingredients: l-cysteine hydrochloride monohydrate, carbomer homopolymer, microcrystalline cellulose, colloidal silicon dioxide, crospovidone, stearic acid, and magnesium stearate.

[0051] In some embodiments, the starting dosage of the subject combination is 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride in one tablet that is administered once daily in the morning. In some embodiments, after 3 days, the dosage is increased to one tablet (or one dosage form containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) twice daily, e.g., given at least 8 hours apart, in some embodiments, no more than two doses containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride are administered in the same day. The subject combination may be administered orally with or without food. In some embodiments, the tablets are swallowed whole, and not crushed, divided, or chewed,

[0052] Patients having renal impairment may require special dosing.

[0053] In some embodiments, for moderate renal impairment, one tablet may be administered by mouth once daily in the morning. In some embodiments, for a severe renal impairment, one tablet may be administered by mouth once daily in the morning may be administered. In some embodiments, the dosage of the subject combination for patients with moderate renal impairment (eGFR 30 to 59 ml / minute / 1,73 m2) can one tablet once daily in the morning.in some embodiments, the recommended dosage of the subject combination for patients with severe renal impairment (eGFR 15 to 29 mL / minute / i.73 m2) is one tablet once daily in the morning.

[0054] In some embodiments, the renal impairment status of the subject may be determined by measuring the “estimated glomerular filtration rate" or “eGFR" of the individual. The eGFR in mL / min / 1.73 m2is calculated by the Modification of Diet In Renal Disease [MDRD] equation:

[0055]

[0056] Further details regarding the calculation of the eGFR may be found in, e.g., Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, Van Lente F: Chronic Kidney Disease Epidemiology Collaboration. Expressing the Modification of Diet in Renal Disease Study Equation for Estimating Glomerular Filtration Rate with Standardized Serum Creatinine Values. Ann Intern Med. 2009;150(9):604-12.

[0057] Renal impairment status based on Food and Drug Administration (FDA) guidance is as follows.

[0058] • Normal: eGFR >90 ml / min / 1.73 m2

[0059] • Mild: eGFR 60 - 89 ml / min / 1.73 m2(i.e., >60 to 90)

[0060] • Moderate: eGFR 30 - 59 ml / min / 1.732(i.e., £30 to <60)

[0061] ♦ Severe: eGFR 15 ~ 29 ml / min / 1.73 m3(z,e,, £15 to <30) and not on hemodialysis ♦ End-stage renal disease (ESRD): eGFR <15 ml / min / 1.73 m2and not on hemodialysis or on hemodialysis

[0062] See, Guidance for industry Pharmacokinetics in Patients with Impaired Renal Function -Study Design, Data Analysis and Impact on Dosing and Labeling. U. S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (ODER) Center for Biologics Evaluation and Research (CBER) February 2010. As used herein, a "renally impaired subject" may have mild, moderate, or severe renal impairment, or may have ESRD.

[0063] In some embodiments, the recommended dosage of the subject combination for patients with moderate renal impairment (estimated glomerular filtration rate (eGFR) or glomerular filtration rate (GFR) of 30 to 59 ml / minute / 1.73 m2) is a daily dose of 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride, or a molar equivalent amount of another form of dextromethorphan and / or bupropion, such as administration of one tablet (or one dosage form containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) once daily, such as one tablet or other oral dosage form daily in the morning, or twice daily oral administration of a combination of 52.5 mg of bupropion hydrochloride and about 22.5 mg of dextromethorphan hydrobromide. In some embodiments, the patients are monitored for adverse reactions potentially attributable to dextromethorphan, such as somnolence and dizziness.

[0064] Moderate renal impairment may be determined by an assay, such as an assay that determines creatinine levels, on a biological sample from the patient, such as a blood sample. Serum creatinine levels from a blood sample can be used to estimate GFR.

[0065] In some embodiments, the recommended dosage of the subject combination for patients with severe renal impairment (estimated glomerular filtration rate (eGFR) or glomerular filtration rate (GFR) of 15 to 29 mL / minute / 1.73 m2) is a daily dose of 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride, or a molar equivalent amount of another form of dextromethorphan and / or bupropion, such as administration of one tablet (or one dosage form containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) once daily, such as one tablet or other oral dosage form daily in the morning, or twice daily oral administration of a combination of 52,5 mg of bupropion hydrochloride and about 22.5 mg of dextromethorphan hydrobromide. In some embodiments, the patients are monitored for adverse reactions potentially attributable to dextromethorphan, such as somnolence and dizziness.

[0066] Severe renal impairment may be determined by an assay, such as an assay that determines creatinine levels, on a biological sample from the patient, such as a blood sample. Serum creatinine levels from a blood sample can be used to estimate GFR.

[0067] Based on animal studies, the subject combination may cause fetal harm when administered during pregnancy, if a female becomes pregnant while being treated with the subject combination, discontinue treatment and counsel the patient about the potential risk to a fetus. In some embodiments, neurotoxicity findings are observed in juvenile rats treated with dextromethorphan / bupropion on postnatal day,.g„ (PND) 7, which corresponds to the third trimester of gestation through the first few months of life and may extend through the first three years of life in humans.

[0068] In oral studies conducted in mice and rabbits, dextromethorphan / bupropicm did not demonstrate fetal or developmental toxicity, in pregnant mice, dextromethorphan / bupropson caused CNS-related effects at only the high-dose of 68 / 150 mg / kg / day, approximately 3.6 times the MRHD of dextromethorphan / bupropion on a mg / nv basis, and not at the mid-dose of 34 / 75 mg / kg / day, approximately 1.8 times the MRHD on a mg / W basis. In the mice offspring, mating was slowed at the high- and mid-dose groups, however there was no impact on mating or fertility outcomes at any dose level. Neurotoxicity findings were observed in juvenile rets treated with a combination of dextromethorphan / bupropion (in male rats at approximately 1.1 / 6.9 times, respectively, the MRHD on a mg / mg2basis, and in female rats at approximately 3.2 / 6.9 times, respective!' / , the MRHD on a mg / m2basis) on postnatal day (PND) 7, which corresponds to the third trimester of gestation through the first few months of life and may extend through the first three years of life in humans. Based on these findings, the subject combination may cause fetal harm when administered to pregnant women.

[0069] The avaiiabie clinical data on the use of the subject combination during pregnancy is insufficient to evaluate for a drug-associated risk of major birth malformations, miscarriage, or other adverse maternal or feta! outcomes. However, there are available data on one of the Individual components of the subject combination, bupropion. Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenita! maiformations overall There are risks to the mother associated with untreated depression in pregnancy.

[0070] The estimated background risk of major birth defects and miscarriage for the i dicated popuiation is unknown. Aii pregnancies have a background risk of birth defect, loss, or other adverse outcomes, In the U. S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

[0071] In an oral study in pregnant mice, dextromethorphan / bupropion was administered during the period of organogenesis. Administration of dextromethorphan / bupropion did not affect body weight, weight gain, food consumption, or pregnancy, and did not produce gross pathologic findings or placental or fetal findings up to 68 / 150 mg / kg / day, the highest dose tested, approximately 3.6 times the MRHD for the subject combination on a mg / * basis. The no-effect: level for reproductive organ findings in mice was 68 / 150 mg / kg in both sexes,

[0072] In an oral study in pregnant rabbits, dextromethorphan / bupropion was administered during the period of organogenesis. Administration of dextromethorphan / bupropion did not cause feta! or developmental toxicity at up to 42.9 / 100 mg / kg / day, the highest dose tested, approximately 9.2 times the MRHD on a mg / m2basis. Decreases in body weight and food consumption were observed in pregnant rabbits in the mid-dose group (23.4 / 54.5 mg / kg / day, approximately 5.0 times the MRHD on a mg / m2basis) and the high-dose group, but were not considered adverse.

[0073] In an oral study in pregnant mice, dextromethorphan / bupropion was administered during pregnancy and lactation. Administration of dextromethorphan / bupropion caused CN5-related effects in the dams at the high-dose of 68 / 150 mg / kg / day, approximately 3.6 times the MRHD on a mg / m2basis, but not at the mid-dose of 34 / 75 mg / kg / day, approximately 1.8 times the MRHD on a mg / m2basis, in the mice offspring, mating was slowed at the mid- and high-dqse groups but there was no impact on pup survival, weight, mating, or fertility outcomes at any dose level up to 68 / 150 mg / kg / day, the highest dose tested.

[0074] In an oral study in juvenile mice given dextromethorphan / bupropion from postnatal day (PND) 22 to 63, no toxicity or neurobehavioral effects were observed at up to 51 / 112.5 mg / kg / day, approximately 2.7 times the MRHD for aduits on a mg / m2basis.

[0075] When dextromethorphan / bupropion was orally administered at doses of 0 / 0, 3 / 150, 10 / 150 / 30 / 150 mg / kg / day, respectively, to male and female rats on postnatal day (PND) 7, the mid-dose of 10 / 150 mg / kg / day in males (approximately 1.1 / 6.9 times, respectively, the MRHD on a mg / m2basis) and the high-dose of 30 / 150 mg / kg / day in females (approximately 3.2 / G.9 times, respectively, the MRHD on a mg / m:basis) resulted in increased apoptotlc neurodegeneration in the brain (cerebral cortex, pons, midbrain, and thalamus). PND 7 in rat corresponds to the third trimester of gestation through the first several months of life but may extend to approximately three years of age in humans.

[0076] Data from published literature report the presence of bupropion and its metabolites in human milk. There are no data on the effects of bupropion or its metabolites on milk production. Limited data from postmarketing reports of bupropion use in lactating patients have not identified a clear association of adverse reactions in the breastfed infant.

[0077] Neurotoxicity findings were observed in juvenile rats treated with a combination of dextromethorphan / bupropion on postnatal day (PND) 7, which corresponds to the third trimester of gestation through the first few months of life and may extend through the firstthree years of life in humans, It is not known whether dextromethorphan is present in human milk. There are no data on the effects of dextromethorphan on the breastfed infant or the effects on milk production. Because of the potential for neurotoxicity, advise patients that breastfeeding is not recommended during treatment with the subject combination and for 5 days following final dose,

[0078] In some embodiments, dosage adjustment of the subject combination cart be considered for patients with moderate renal impairment (eGFR 30 to 59 mL / minute / 1.73 m2). In some embodiments, dosage adjustment of the subject combination can be considered for patients with severe renal impairment (eGFR 15 to 29 mL / minute / 1.73 n ).

[0079] Dextromethorphan / bupropion administered once daily for 7 weeks in mice at doses of 0 / 0, 26 / 57, 34 / 75, and 68 / 150 mg / kg / day to male and female mice prior to and during mating, and continuing to Day 7 of gestation in females, showed no effect on fertility up to 68 / 150 mg / kg / day (approximately 3.6 times the MRHD on a mg / m basis), the highest dose tested. General toxicity (primarily CNS-related findings and slightly longer estrous cycling which was likely secondary to general toxicity) was observed at the mid-dose of 34 / 75 mg / kg / day (approximately 1,8 times the MRHD on a mg / m2basis), and the high-dose of 68 / 150 mg / kg / day with no adverse effects on fertility or reproduction.

[0080] There is data that reports the presence of bupropion and its metabolites in human milk. There is no data on the effects of bupropion or its metabolites on milk production. Limited data related to bupropion use in lactating patients have not identified a clear association of adverse reactions in the breastfed infant. Neurotoxicity findings were observed in juvenile rats treated with a combination of dextromethorphan / quiriidine on postnatal day (PND) 7, which corresponds to the third trimester of gestation through the first few months of iife and may extend through the first three years of life in humans. It is not known whether dextromethorphan is present in human milk. There are no data on the effects of dextromethorphan on the breastfed infant or the effects on milk production. Because of the potential for neurotoxicity, in some embodiments, patients should be advised that breastfeeding is not recommended during treatment with a combination of dextromethorphan and bupropion and for 5 days following final dose.

[0081] In some embodiments, the human child of a patient receiving the subject combination is at risk of seizure. In some embodiments, the human child is about three years old or younger. In some embodiments, the human child of a patient receiving the subject combination is at risk of neurotoxicity.

[0082] For lactating human mothers, the combination of about 45 mg of dextromethorphan hydrobromide and about IOS mg of bupropion hydrochloride may be taken twice daily for about 1 week to about 6 weeks, about 6 weeks, or at least 6 weeks, before stopping the treatment at least 5 days before beginning breastfeeding the child.

[0083] In some embodiments, the human patient produces milk that is substantially free of dextromethorphan after 5 days from the fina l dose of the combination.

[0084] In some embodiments, the human patient produces milk that is substantially free of bupropion after 5 days from the final dose of the combination.

[0085] In some embodiments, the human child of a patient receiving the subject combination is not exposed to a detectable amount of dextromethorphan during breastfeeding.

[0086] In some embodiments, the human child of a patient receiving the subject combination is not exposed to a detectable amount of bupropion during breastfeeding.

[0087] In some embodiments, the subject combination is administered to the human patient twice daily until the human patient experiences a reduction from baseline of at least about 7, at least about 11, at least about 13, or at least about 15.9 in the human patient's total MADRS score. When the desired reduction in the MADRS score is reached, the human patient may stop the treatment, wait at least 5 day, and then begin breastfeeding her child.

[0088] In some embodiments, the human child is a breastfed infant.

[0089] In some embodiments, the human patient experiences a reduction from baseline in total MADRS score in the human patient for administering the subject combination that is more than the patient would experience if a placebo were administered. The human patient taking the subject combination may experience the greater reduction in MADRS score than taking a placebo at, for example, after 1 week of administration, after 2 weeks of administration, after 3 weeks of administration, after 4 weeks of administration, after 5 weeks of administration, after 6 weeks of administration, or at other times.

[0090] In the subject combination, bupropion inhibits the metabolism of dextromethorphan via CYP2D6. Dextromethorphan, when co-administered with bupropion, displays nonlinear pharmacokinetics at steady state, with greater than doseproportional changes in AUG and Cm3i< for varying doses of dextromethorphan (30 to 60 mg) and less than dose-proportional changes for varying doses of bupropion (75 to 150 mg).

[0091] Steady state plasma concentrations of dextromethorphan and bupropion when given as the subject combination are achieved within 8 days. The accumulation ratios for dextromethorphan at steady state are about 20 and about 32, respectively based on Cmax and AUCO-12. The accumulation ratios for bupropion at steady state are 1.1 and 1.5, respectively based

[0092]

[0093] After administration of the subject combination, the median TmaKof dextromethorphan is about 3 hours and the median Tmax of bupropion is about 2 hours. The Cmax of hydroxy bupropion metabolite occurs approximately 3 hours post-dose and is approxi ately 14 times the peak level of bupropion. The AUCo-ia hydroxybupropion is about 19 times that of bupropion. The

[0094]

[0095] of the erythrohydroxybupropion and threohydroxybupropion metabolites occurs approximately 4 hours post-dose and is approximately equal to and about 5 times that of bupropion, respectively. The AUCa-n values of erythrohydroxybupropion and threohydroxybupropion are about 1.2 and about 7 times that of bupropion, respectively.

[0096] The subject combination can be taken with or without food. Dextromethorphan Cmax and AUCQ-12 were unchanged and decreased by 14%, respectively, and bupropion Cmaxand AUCo-ij were increased by 3% and 6%, respectively, when the subject combination was administered with food.

[0097] The plasma protein binding of dextromethorphan is approximately 60-70% and bupropion is 84%. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion; whereas the extent of protein binding of the th reohydroxy bupropion metabolite is about half that seen with bupropion.

[0098] Following 8 days of administration of the subject combination in extensive metabolizers, the mean elimination half-life of dextromethorphan was increased approximately 3-fold to about 22 hours, as compared to dextromethorphan given without bupropion.

[0099] The mean elimination half-life of dextromethorphan and bupropion was 22 hours and 15 hours, respectively. The apparent elimination half-life of hydroxybupropion, erythrohydroxybupropion and threohydroxy bupropion metabolites were approximately 35, 44 and 33 hours, respectively.

[0100] The subject combination may be used for adjunctive treatment of major depressive disorder or depression.

[0101] In addition to major depressive disorder, the subject combination may be used to treat other diseases in conditions in the patient populations or circumstances described herein. For example, the subject combination may be used to treat pain or a neurological disorder. Examples of neurological disorders that may be treated with the subject combination include, but are not limited to: affective disorders, psychiatric disorders, cerebral function disorders, movement disorders, dementias, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.

[0102] Affective disorders that may be treated by the subject combination include, but are not limited to, depression, major depression, treatment resistant depression, treatment resistant bipolar depression, bipolar disorders including cyclothymia, seasonal affective disorder, mood disorders, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrua! dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit disorder with hyperactivity (ADDH), and attention def icit / hy peract ivity disorder (AD / HD), bipolar and manic conditions, obsessive-compuisive disorder, bulimia, obesity or weight-gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psycho-sexual dysfunction, pseudobulbar affect, and emotional lability.

[0103] Depression may be manifested by depressive symptoms. These symptoms may include psychological changes such as changes in mood, feelings of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, suicidal thoughts, or attempts, and / or self-deprecation. Physical symptoms of depression may include insomnia, anorexia, appetite loss, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, aches, pains, headaches, cramps, digestive issues, and / or abnormal hormonal circadian rhythms.

[0104] Psychiatric disorders that may be treated by the subject combination, include, but are not limited to, anxiety disorders, including but not limited to, phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD); mania, manic depressive illness, hypomania, unipolar depression, depression, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizotypy, aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease. Alzheimer's disease may also be referred to as dementia of the Alzheimer's type. Other neurobehavioral symptoms of Alzheimer's disease that may be treated Include dislnhibition and apathy.

[0105] Agitation in Alzheimer's disease occurs as the disease progresses. Agitation may present itself as inappropriate verba!, emotional, and / or physical behaviors, inappropriate behaviors may include, but are not limited to, incoherent babbling, inappropriate emotional response, demands for attention, threats, irritability, frustration, screaming, repetitive questions, mood swings, cursing, abusive language. physical outbursts, emotional distress, restlessness, shredding, sleeping disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive body motions, hoarding, shadowing, hitting, scratching, biting, combativeness, hyperactivity, and / or kicking.

[0106] Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, and behavioral and psychological symptoms including agitation, AD is the most common form of dementia and afflicts an estimated 6 million individuals in the United States, a number that is anticipated to increase to approximately 14 million fay 2050, Agitation is reported in up to 70% of patients with AD and is characterized by emotional distress, aggressive behaviors, disruptive irritability, and disinhibition, Managing agitation is a priority in AD. Agitation in patients with AD has been associated with increased caregiver burden, decreased functioning, accelerated cognitive decline, earlier nursing home placement, and increased mortality. There are currently no therapies approved by the FDA for the treatment of agitation in patients with AD.

[0107] Neurobehavioral symptoms have been known to appear during dementia and may be treated by the combination. Caregivers or families may feel more overwhelmed by patients' behavioral / psychological symptoms than by their cognitive impairment. Common forms of the syndrome are Alzheimer’s disease, vascular dementia, dementia with Lewy bodies (abnormal aggregates of protein that develop inside nerve ceils), and a group of diseases that contribute to frontotemporal dementia (degeneration of the frontal lobe of the brain). The symptoms that dementia patients have are similar to those of psychiatric disorders, but some are slightly different from each other. Neurobehavioral symptoms associated with dementia include depression, apathy, agitation, disinhibition, hallucinations, delusions, psychosis, impulsiveness, aggressiveness, compulsion, excessive sex drive, and personality disorders. Neurobehavioral symptoms such as disinhibition may also be found in other conditions such as traumatic brain injury.

[0108] Agitation in patients with Alzheimer's disease may be assessed using the Cohen Mansfield Agitation Inventory or CMAI. The CMA! assesses various behaviors including, Hitting (including self), Kicking, Grabbing onto people, Pushing, Throwing things, BitingfScratching, Spitting, Hurting self or others. Tearing things or destroying property, Making physical sexual advances, Pacing, aimless wandering, Inappropriate dress or disrobing, Trying to get to a different place, Intentional falling, Eating / drinking inappropriate substances, Handling things inappropriately, Hiding things, Hoarding things, Performing repetitive mannerisms, General restlessness, Screaming, Making verbal sexual advances, Cursing or verbal aggression, Repetitive sentences or questions, Strange noises (weird laughter or crying), Complaining, Negativism, Constant unwarranted request for attention or help.

[0109] Schizophrenia may be treated by the combination including positive symptoms and / or negative symptoms of schizophrenia, or residual symptoms of schizophrenia. Other conditions that may be treated include intermittent explosive disorder.

[0110] Cerebral function disorders that may be treated by the subject combination include, but are not limited to, disorders involving Intellectual deficits such as senile dementia, Alzheimer's type dementia, memory loss, amnesia / arnnestic syndrome, epilepsy, disturbances of consciousness, coma, lowering of attention, speech disorders, voice spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperkinetic syndrome, and schizophrenia. Cerebral function disorders also include disorders caused by cerebrovascular diseases including, but not limited to, stroke, cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis, head injuries, and the like where symptoms include disturbance of consciousness, senile dementia, coma, lowering of attention, and speech disorders.

[0111] Substance addiction abuse that may be treated by the subject combination includes, but is not limited to, drug dependence, addiction to cocaine, psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, anxiolytic and hypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes nicotine addiction of all known forms, such as smoking cigarettes, cigars and / or pipes, e-cigarettes or vaping, and addiction to chewing tobacco.

[0112] Movement disorders that may be treated by the subject combination include, but are not limited to, akathisia, akinesia, associated movements, athetosis, ataxia, bailismus, hemiballismus, bradykinesia, cerebral palsy, chorea, Huntington's disease. Huntington s disease chorea, rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor, and Tourette's syn rome, and Wilson's disease.

[0113] Dementias that may be treated by the subject combination include, but are not limited to, Alzheimer’s disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies, mixed dementia, fronto-temporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington’s disease, Wernicke-Korsakoff Syndrome, and Pick's disease.

[0114] Motor neuron diseases that may be treated by the subject combination include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophies, Tay-Sach's disease, Sandhoff disease, and hereditary spastic paraplegia.

[0115] eurodegenerative diseases that may be treated the subject combination include, but are not limited to, Alzheimer’s disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewy body disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant artenopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophies, Charcot-Marie-Tooth disease (CMT), familial spastic paraparesis, neurofibromatosis, ollvopontine cerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barre syndrome, and spastic paraplesia.

[0116] Seizure disorders that may be treated by the subject combination include, but are not limited to, epileptic seizures, nonepileptic seizures, epilepsy, febrile seizures; partial seizures including, but not limited to, simple partial seizures, Jacksonian seizures, complex partial seizures, and epilepsia partialis continua; generalized seizures including, but not limited to, generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

[0117] Types of headaches that may be treated by the subject combination include, but are not limited to, migraine, tension, and cluster headaches,

[0118] Other neurological disorders that may be treated by the subject combination include, Rett Syndrome, autism, tinnitus, disturbances of consciousness disorders, sexual dysfunction, intractable coughing, narcolepsy, cataplexy; voice disorders due to uncontrolled laryngeal muscle spasms, including, but not limited to, abductor spasmodic dysphonia, adductor spasmodic dysphonia, muscular tension dysphonia, and vocal tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity, such as methotrexate neurotoxicity; incontinence including, but not limited, stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.

[0119] In some embodiments, the subject combination may be used to treat pain, joint pain, pain associated with sickle cell disease, pseudobulbar affect, depression (including treatment resistant depression), disorders related to memory and cognition, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rhett's syndrome, seizures, cough (Including chronic cough), etc.

[0120] In some embodiments, the subject combination may be administered orally to relieve musculoskeletal pain including low back pain, and pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, sero-negative (non-rheumatoid) arthropathies, non-articuiar rheumatism, peri-articular disorders, axial spondyioarthritis including ankylosing spondylitis, Paget’s disease, fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip, vertebral crush f ractures, osteoporosis, etc.

[0121] In some embodiments, the subject combination may be administered to relieve inflammatory pain including musculoskeletal pain, arthritis pain, and complex regional pain syndrome.

[0122] Arthritis refers to inflammatory joint diseases that can be associated with pain. Examples of arthritis pain Include pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatoid) arthropathies, non-articular rheumatism, peri-articular disorders, neuropathic arthropathies including Charcot's foot, axial spondyloarthntis including ankylosing spondylitis, and SAPHO syndrome.

[0123] In some embodiments, the subject combination is used to treat chronic musculoskeletal pain.

[0124] In some embodiments, the subject composition may be administered to relieve complex regional pai syndrome, such as com lex regional pain syndrome type I (CRPS-Ij, complex regional pain syndrome type II (CRPS-II), CRP5-NOS, or another type of CRPS. CRPS is a type of inflammatory pain. CRPS can also have a neuropathic component. Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by severe pain In a limb that can be accompanied by edema, and autonomic, motor, and sensory changes.

[0125] In some embodiments, the subject composition may be administered orally to relieve neuropathic pain.

[0126] Examples of neuropathic pain include pain due to diabetic peripheral neuropathy or diabetic peripheral neuropathic pain, post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, central pain, pain due to multiple sclerosis, etc. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal card injury, post-stroke pain, central multiple sclerosis pain, HIV-associated neuropathy, and radio* or chemotherapy associated neuropathy, etc.

[0127] In some embodiments, the subject composition may be administered to relieve fibromyalgia.

[0128] In some embodiments, the subject composition may be co-administered with one or more strong Inhibitors of CYP2D6. It has been found that the concomitant use of the subject combination with one or mare strong CYP2D6 inhibitors Increases plasma concentrations of dextromethorphan. It is thus recommended to monitor patients for adverse effects or adverse reactions potentially attributable to dextromethorphan, such as somnolence and dizziness. The dosage adjustment may be necessary when the subject composition is coadministered with one or more strong inhibitors of CYP2D6. Adjusting to a lower dose amount of the bupropion and / or the dextromethorphan in the subject combinat ion or less frequent dosing of the subject combination may reduce adverse effects or adverse reactions, such as, but not limited to, somnolence, dizziness, or a combination thereof in a patient. For example, a recommended dosage of the subject combination when coadministered with one or more strong CYP2D6 inhibitors, Is one tablet containing 45 mg or less of dextromethorphan hydrobromide and 105 mg or less of bupropion hydrochloride once daily, such as once daily in the morning.

[0129] Administration of the subject combination once a day to patients who are receiving a concomitant strong CYP2D6 inhibitor may reduce the adverse effects, such as, but not limited to, somnolence, dizziness, ora combination thereof, as compared to administration of the subject combination twice a day for the same number of days. In some embodiments, reducing the dose amount or dose frequency of the subject combination may reduce somnolence, In some embodiments, reducing the dose amount or dose frequency may reduce dizziness. As dizziness may link to falls, adjusting the dosage to lower amount or lower dose frequency of the subject combination may reduce the risk of fails for a patient taking the subject combination. For example, taking the subject combination once a day may reduce the risk of fails for a patient as compared to taking the subject combination twice a day for the same number of days. This may be important, for example, to elderly patients or patients suffering from a dementia, such as Alzheimer's disease.

[0130] In some embodiments, the subject composition may be administered to a patient who has moderate renal impairment. As explained herein, it has been found that administering the subject composition to CYP2D6 poor metabolizers increases plasma concentrations of dextromethorphan as compared to patients who are not CYP2D6 poor metabolizers. it is thus recommended to monitor patients for adverse effects or adverse reactions potentially attributable to dextromethorphan, such as somnolence and dizziness.

[0131] Dosage adjustment may be necessary when the patient has moderate renal impairment. Adjusting to a lower dose amount of the bupropion and / or the dextromethorphan in the subject combination or Jess frequent dosing of the subject combination may reduce adverse effects or adverse reactions, or a risk of adverse effects or adverse reactions, such as, but not limited to, somnolence, dizziness, or a combination thereof in a patient. For example, a recommended dosage of the subject combination when administered to a patient who has moderate renal impairment, is one tablet containing 45 mg or less of dextromethorphan hydrobromide and 105 mg or less of bupropion hydrochloride once dally, such as once daily In the morning.

[0132] Administration of the subject combination once a day to patients who have moderate renal impairment may reduce the adverse effects, or the risk of adverse effects, such as, but not limited to, somnolence, dizziness, or a combination thereof, as compared to administration of the subject combination twice a day for same number of days. In some embodiments, reducing the dose amount or dose frequency of the subject combination may reduce somnolence. In some embodiments, reducing dose amount or dose frequency may reduce dizziness. As dizziness may link to falls, adjusting the dosage to lower amount or lower dose frequency of the subject combination may reduce the risk of falls for a patient taking the subject combination. For example, taking the subject combination once a day may reduce the risk of falls for a patient as compared to taking the subject combination twice a day for same number of days, This may be important, for example, to elderly patients or patients suffering from a dementia, such as Alzheimer's disease.

[0133] In some embodiments, the subject composition may be administered to a patient who has severe renal impairment. As explained herein, it has been found that administering the subject composition to CYP2D6 poor metabolizers increases plasma concentrations of dextromethorphan as compared to patients who are not CYP2D6 poor metabolizers. It is thus recommended to monitor patients for adverse effects or adverse reactions potentially attributable to dextromethorphan, such as somnolence and dizziness.

[0134] Dosage adjustment may be necessary when the patient has severe renal impairment. Adjusting to a lower dose amount of the bupropion and / or the dextromethorphan in the subject combination or less frequent dosing of the subject combination may reduce adverse effects or adverse reactions, or a risk of adverse effects or adverse reactions, such as, but not limited to, somnolence, dizziness, or a combination thereof in a patient. For example, a recommended dosage of the subject combination when administered to a patient who has severe renal impairment, is one tablet containing 45 mg or less of dextromethorphan hydrobromide and 105 mg or less of bupropion hydrochloride once daily, such as once daily in the morning.

[0135] Administration of the subject combination once a day to patients who have severe renal impairment may reduce the adverse effects, or the risk of adverse effects, such as, but not limited to, somnolence, dizziness, or a combination thereof, as compared to administration of the subject combination twice a day for same number of days, in some embodiments, reducing the dose amount or dose frequency of the subject combination may reduce somnolence. In some embodiments, reducing dose amount or dose frequency may reduce dizziness. As dizziness may link to fails, adjusting the dosage to lower amount or lower dose frequency of the subject combination may reduce the risk of falls for a patient taking the subject combination. For example, taking the subject combination once a day may reduce the risk of falls for a patient as compared to taking the subject combination twice a day for same number of days, This may be important, for example, to elderly patients or patients suffering from a dementia, such as Alzheimer's disease.

[0136] 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.

[0137] Example 1

[0138] Tablets are prepared for oral administration. They are round bilayer tablets. Each tablet contains 45 mg dextromethorphan hydrobromide (equivalent to 32.98 mg of ths dextromethorphan free base) in an immediate-release formulation and 105 mg bupropion hydrochloride (equivalent to 91,14 mg of the bupropion free base) in an extended-release formulation. Each tablet contains the following inactive ingredients: carbomer homopolymer, colloidal silicon dioxide, crospovidone, glyceryl monocapryloca rate, L-cysteine hydrochloride monohydrate, magnesium stearate. microcrystalline cellulose, polyvinyl alcohol, red iron oxide, sodium lauryl sulfate, stearic acid, talc, titanium dioxide, and / or yellow iron oxide.

[0139] Example 2

[0140] The properties of the tablets of Example 1, containing a combination of dextromethorphan hydrobromide, which Is ah uncompetitive NMOA receptor antagonist and sigma-1 receptor agonist, and bupropion hydrochloride, which Is an aminoketone and CYP4502D6 inhibitor, were studied.

[0141] The effects of renal impairment, hepatic impairment, and CYP2D6 poor metabollzer status on the exposure to the tablets of Example 1 are summarized In Figure 1.

[0142] Results depicted in FIG. 1 are based on plasma concentrations in human patients after 8 days of twice daily dosing of a tablet containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride. Data are GMRs and 90% Cis. References used are the matched healthy subjects for renal and hepatic impairment studies, and extensive or ultra-extensive CYP2D6 metabolizers respectively. AUC represents the area under the plasma concentration-time curve from zero to 12 hours; BMP represents bupropion; Cl is confidence interval; Cmax is maximum plasma concentration; DM represents dextromethorphan; GMRs represents geometric mean ratios; PK represents pharmacokinetics.

[0143] In FIG. 1, the results for patients with moderate Renal Impairment are identified as "Group 1," the results for patients with severe Renal Impairment are identified as Group 2," the results for patients with Moderate Hepatic Impairment are identified as ’’Group 3," and the results for patients who are CYP2D6 Poor Metabolizers are identified as "Group 4," The resuits are summarized in Table 1 below.

[0144] Table 1

[0145]

[0146]

[0147] For patients having moderate renal impairment, a 2,21-fold increase in dextromethorphan AUCe

[0148]

[0149] a 2- 10-fold increase in dextromethorphan C a 1, 80-fold increase in bupropion AUCo-, and a 1,87-fold increase in bupropion CmMwere observed.

[0150] Based upon these results, dosage adjustment is recom ended in patients known to have moderate renal impairment because these patients have higher dextromethorphan and bupropion concentrations than patients with healthy renal function. The recommended total daily dose for patients known to have moderate renal impairment is about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride (e,g. one tablet containing about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride for administration once daily, such as in the morning), or an equivalent dose of another form dextromethorphan and / or bupropion.

[0151] For patients having severe renal impairment, a 2,78-fold increase in dextromethorphan AUCMJ, a 2,68-fold increase in dextromethorphan Cmax, a 1, 22-fold increase in bupropion AUC0.2., and a 1,17-fold increase in bupropion Cmax were observed.

[0152] Based upon these results, dosage adjustment is also recommended in patients known to have severe renal impairment because these patients have higher dextromethorphan and bupropion concentrations than patients with healthy renal function. The recommended total daily dose for patients known to have severe renal impairment is about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride (e,g. one tablet containing about 45 mg of dextromethorphan hydrobromide and about 105 mg of bupropion hydrochloride for administration once daily, such as in the morning), or an equivalent dose of another form dextromethorphan and / or bupropion.

[0153] Example 3

[0154] An open-label, multiple-dose, two-cohort, PK study was conducted at a single center in 16 subjects, 8 with severe renal Impairment (eGFR of < 30 ml / min / 1.73m2) and 8 matched healthy controls (eGFR > 90 mL / min / 1.73 m2), matched for similar age, gender, and weight. Subjects received open-label the subject combination (45 mg dextromethorphan HBr / 105 mg bupropion HCI) once-daily in the morning (QAM) for 8 days, aligning with the dosing recommendation for patients with moderate renal impairment in the subject combination prescribing information. Intensive PK sampling occurred on Day 1 and Day 8, and trough PK samples were collected each morning prior to the next dose. Safety assessments included electrocardiogram (ECG), clinical labs, physical exam, adverse event (AE) monitoring, and vital signs.

[0155] An increase in exposure of bupropion (Cmax 1,0-fold and ADCs 1. -fold) and of dextromethorphan (Cmax 1.8-fold and AUCs 2.9-fold) was noted in subjects with severe renal impairment relative to matched healthy controls following single and multiples doses of the subject combination. Exposure to the metabolites of bupropion (hydroxybupropion, erythrohydroxybupropion, and threohydroxy-bupropion) and of dextromethorphan (dextrorphan and dextrorphan O-glucuronide) also increased in subjects with severe renal impairment relative to matched healthy controls following single and multiples doses of the subject combination. Refer to the PK data below.

[0156] Pharmacokinetics

[0157] Table 2 below present the PK results of healthy and renally impaired subjects:

[0158] Table 2: Ratio of Arithmetic Mean of PK Parameters between Moderate Renal Impairment, Severe Renal Impairment, and Healthy Control Subjects on Day 1 and Day 8

[0159]

[0160]

[0161] Prior studies with the subject combination have demonstrated that steady state is reached by Day 8 of dosing. The objective of the current analysis is to compare the pharmacokinetics of the subject combination in healthy, moderately renal impaired, and severely renal impaired subjects at steady state in order to recommend appropriate longterm dosing of the subject combination in patients with severe renal impairment.

[0162] For dextromethorphan:

[0163] After daily dosing for 8 days, both moderate- and severe renal impairment subjects had exposures approximately 2-3 times higher than healthy controls. On Da 8 both moderate and severe impairment subjects experienced a shorter Tma* (approximately 0.5 hours and 0,8 hours, respectively) and approximately 1.6 times longer bupropion:

[0164] • After daily dosing for 8 days, subjects with moderate renal impairment results

[0165] in exposures (AUG and Cmax) approximately 1.7 times higher than healthy controls, compared to exposures in subjects with severe renal impairment 1.0-1.4 times higher than healthy controls. Both moderate and severe impairment subjects experienced a shorter Tmax relative to healthy controls (approximately 0.5 hours and 1.0 hours, respectively), and similar Ty^s (0.9 times and 1.1 times, respectively).

[0166] Overall, the results from these studies demonstrate that both moderate and severe renal sufficiency would be expected to have a similar effect on the pharmacokinetics of the subject combination when dosed once daily.

[0167] Safety

[0168] In these studies treatment with the subject combination was safe and weli-tolerated in both severe renal impairment subjects and healthy controls. No subjects withdrew from the study, and there were no subject deaths, serious, or significant AEs reported during this study.

[0169] A total of 12 treatment-emergent AEs (TEAEs) were reported by 7 (43.8%) of the 16 subjects who received the study drug. The TEAEs reported in both groups were consistent with the known safety profile of the subject combination. Only one TEAE, diarrhoea was reported in >2 subjects in a single group. Overall, 7 subjects reported TEAEs that were judged related to the treatment: 4 (50%) subjects in the healthy control group and 3 (37.5%) subjects in the severe impaired group (Table 3).

[0170] Table 3: Frequency of Subjects Experiencing Treatment-Emergent Adverse Events

[0171] by System Organ Class and Preferred Term

[0172]

[0173]

[0174] MedDRA*: Medical Dictionary for Regulatory Activities,

[0175] Of the 12 TEAEs reported, 11 were graded as mild and 1 as moderate (dizziness, healthy control subject). No TEAEs were graded as severe in either healthy control or severe impairment groups, The efficacy of the tablets of Example 1 for the treatment of major depressive disorder in adults was demonstrated in a placebo-controlled clinical study (Study 1). In this study, adult patients (18 to 65 years of age) who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for MDD were randomized to receive the tablets of Example 1 ("DM / BU," 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) twice daily ( =156) or placebo twice daily (N=162) for 6 weeks. Patients in Study 1 had a median age of 41 years and were 67% female, 55% Caucasian, 35% Black, and 5% Asian. Here, "N" represents number of adult patients.

[0176] The primary outcome measure was the change from baseline to Week 6 in the total score of the Montgomery-Asberg Depression Rating Scale (MADRS). The MADRS is a clinician-rated scale used to assess the severity of depressive symptoms. Patients are rated on 10 items to assess feelings of sadness, inner tension, reduced sleep or appetite, difficulty concentrating, lassitude, lack of interest, pessimism, and suicidality. Scores on the MADRS range from 0 to 60, with higher scores indicating more severe depression. DM / BU was statistically significantly superior to placebo in improvement of depressive symptoms as measured by decrease in MADRS total score at Week 6 (see Table 4), Table 4: Primary Efficacy Results for Change from Baseline in MADRS Total Score at Week 6 in Adult Patients with MDD

[0177]

[0178] SD = standard deviation; SE ~ standard error; IS Mean = least-squares mean; Cl ” confidence interval.

[0179] adrug - placebo

[0180] The change from baseline in MADRS total score by week is displayed in Figure 1. The change in MADRS total score from baseline to Week 1 and from baseline to Week 2 were pre-specified secondary efficacy endpoints. The difference between DM / BU and placebo in change from baseline in MADRS total score was statistically significant at Week 1 and at Week 2.

[0181] Examination of demographic subgroups by age, sex, and race did not suggest differences in response.

[0182] examples

[0183] The purpose of this study was to determine the potential toxicity and toxicokinetic profile of the subject combination (coadministration of dextromethorphan / buprapion) when administered once daily for 6 weeks (postnatal day 22 to 63 or 64) via oral gavage to juvenile male and female CD-I mice. Five hundred and fifty-four (280 males and 274 females) CD-I mice were assigned to groups and dosed once daily via oral gavage for up to 43 consecutive days with vehicle or the subject combination (dextromethorphan / bupropion) at 26 / 57, 34 / 75, and 51 / 112.5 mg / kg / day.

[0184] Results

[0185] Treatment with the subject combination at doses up to 51 / 112.5 mg / kg / day had no effect on mortality, physical examinations, cageside observations, food consumption, estrus cycling, acoustic startle, locomotor activity, learning and memory, ophthalmic examinations, clinical pathology (hematology, coagulation, and clinical chemistry), macroscopic pathology observations, bone length and density, absolute and relative organ weights, sperm motility and density, or microscopic pathology observations. Observed reductions in body weights and body weight gains were considered to be test article related, but not adverse. Delays in developmental markers (vaginal opening and preputial separation) were dose responsive and considered to be treatment related, but not adverse, due to the lack of correl ati ve fi ndings in androgen- and estrogen dependent tissue weights.

[0186] Once daily oral administration of the subject combination at 26 / 57, 34 / 75, or 51 / 112,5 mg / kg to juvenile CD-I mice over a 6-week. period resulted in minimal increases in glucose in males at 2: 34 / 75 mg / kg and females at all dose levels. This finding generally resolved by the end of the recovery period. Therefore, the no observed adverse effect level (NOAEL) for the subject combination when administered to juvenile male and female CD-I mice for six weeks was 51 / 112.5 mg / kg / day, the highest dose tested. .£xa filg„6

[0187] The purpose of this study was to determine the potential maternal and / or developmental toxicity and toxicokinetic profile of the subject combination in pregnant New Zealand White rabbits when administered via oral gavage during the embryo-fetal development period. Animals were dosed once daily from gestational day (GD) 7 to GD 19 with vehicle or the subject combination (dextromethorphan / bupropion) at 8.6 / 20, 23.4 / 54.5, and 42.9 / 100 mg / kg / day.

[0188] Results

[0189] Pregnant rabbits tolerated daily oral doses of the subject combination during the period of organogenesis at 8.6 / 20, 23.4 / 54.5, and 42.9 / 100 mg / kg / day, albeit with reduced body weight gain and food consumption at the mid- and high-dose levels. These effects were minima! at the mid-dose level and statistically significant at the high-dose level, and were considered test article-related but not adverse due to lack of correlative clinical observations indicating declining maternal health. The effects resolved when dosing stopped. In dams examined 10 days after the last dose, there were no macroscopic pathologic findings. Administration of the subject combination did not affect maintenance of pregnancy, litter size, or the rates or pre- and post-implantation loss at any dose level. Administration of the subject combination also did not affect fetal body weight or sex ratio and did not produce fetal defects at any dose level. Therefore, the NOAEL for the subject combination when administered to pregnant New Zealand White rabbits during the period of organogenesis for maternal effects as well as effects on pregnancy or embryofetal development was 42.9 / 100 mg / kg / day, the highest dose tested.

[0190] example 7

[0191] The objectives of this study were to test for effects on reproductive function resulting from administration of the subject combination (dextromethorphan / bupropion) to Cri: CDI(! CR) male and female mice before cohabitation, through mating and implantation. Animals were dosed once daily beginning 28 and 14 days before cohabitation in males and females, respectively, with vehicle or the subject combination (dextromethorphan / bupropion) at 26 / 57, 34 / 75, and 68 / 150 mg / kg / day. Result:

[0192] Males

[0193] Most male mice tolerated daily ora! doses of the subject combination at dextromethorphan / bupropion dose levels of 26 / 57, 34 / 75, and 68 / 150 mg / kg for 7 weeks; be., beginning 28 days before cohabitation, through cohabitation, and continuing until the day before euthanasia. However, a few mates at each dose level (3, 2, and 6, respectively) died or were euthanized early due to adverse clinical signs or body weight loss, and these deaths were considered to be related to the subject combination. The oniy other the subject combination-related findings were clinical signs at 2:34 / 75 mg / kg / day that were chiefly central nervous system (CNS)-related and that occurred primarily at 10 to 20 minutes after dose administration. Based on these results, a no-observed-ad verse-effect level (NOAEL) for general toxicity in males was not identified. There were no the subject combination-related effects on the number of days cohabitated prior to mating (1.8 to 2.4 days), the number of mates that mated (95.5% to 100%), or the fertility index of mated females (86.4% to 95.5%) at any dose level. The litter averages for implantation rate, pre- and post-implantation loss rates, and the number of viable and nonviable embryos were unaffected by the subject combination at any dose level. No dam had a litter consisting of only nonviable embryos. Based on these results, the NOAELfor reproductive toxicity in males was 68 / 150 mg / kg / day, the highest dose level tested.

[0194] Females

[0195] Female mice tolerated daily oral doses of the subject combination at dextrornethorphan / bupropion dose levels of 26 / 57, 34 / 75, and 68 / 150 mg / kg for at least 3 weeks; i.e., beginning 14 days before cohabitation, through cohabitation, and continuing until GD 7. The only the subject combination-related findings were:

[0196] • Clinical signs at 2:34 / 75 mg / kg / day that were chiefly CNS-related and that occurred primarily at 10 to 20 minutes after dose administration.

[0197] • Slightly (15% to 16%) longer mean estrous cycle duration during the pre- cohabltatlon dose period at 2:34 / 75 mg / kg / day than in the control group. Because estrus cycling is highly sensitive to stress-related perturbation in rodents, this finding was likely secondary to general toxicity and not a direct effect of the subject combination.

[0198] Based on these resuits, the NOAEL for general toxicity in females was 26 / 57 mg / kg / day. There were no the subject combination-related effects on the number of days cohabitated prior to mating (1.8 to 2.4 days), the number of females that mated (95.5% to 100%), or the fertility index of mated females (86.4% to 95.5%) at any dose level. The litter averages for implantation rate, pre- and post-implantation loss rates, and the number of viable and nonviable embryos were unaffected by the subject combination at any dose level, No dam had a litter consisting of only nonviabie embryos. Based on these results, the NOAEL for reproductive toxicity in females was 68 / 150 mg / kg / day, the highest dose level tested.

[0199] Example 8

[0200] The purpose of this study was to test for effects of the subject combination, on Crl: CDI(ICR) mice and development of the offspring consequent to exposure of the female from implantation through lactation and weaning via oral gavage. Observations were continued through sexual maturity of the Fi generation offspring. Presumed pregnant mice were dosed daily via oral gavage from GD 6 through lactation day (ID) 20 and then were euthanized and necropsied. Offspring (Fl) mice were observed from birth through at least postnatal day 90. At that point, Fl males and females were paired and allowed up to 14 days to mate. Males were euthanized and necropsied after mating. Females were observed until GD 13 and then were euthanized and necropsied. Dams were dosed with vehicle or the subject combination (dextromethorphan / bupropion) at 26 / 57, 34 / 75, and 68 / 150 mg / kg / day.

[0201] Results

[0202] in the FO generation dams dosed from GD 6 through ED 20, administration of the subject combination caused CNS-related clinical signs at the high dose level. However, the subject combination did not affect gestation, parturition, lactation, or maternal behavior at any dose level. Therefore, the maternal NOAEL for maternal toxicity is 34 / 75 mg / kg / day. in the Fl generation offspring exposed to simulated the subject combination in utero or while nursing, there was no effect on survival, growth, sexual maturation, or development; however, there was an effect on reproductive function, F 1 generation mice exposed to the subject combination at 2:34 / 75 mg / kg / day were slower to mate. It was unciear if the slowness reflected an effect on their desire to mate or their ability to copulate successfully, and it also was unclear if one or both sexes were affected. Although mating was slowed, there was no effect on mating index or fertility in either sex and no effect on ovarian or uterine parameters in F 1 generation femaies at any dose level; therefore, the delayed mating was not considered adverse. Therefore, the NOAEL for viability and growth in the Fl offspring is 68 / 150 mg / kg / day, the highest dose tested.

[0203] Example 9

[0204] The purpose of this study was to determine the neurotoxic potential of dextromethorphan when administered once via oral gavage to male and female CrL: CD(SD) Sprague Dawely rats on Postnatal Day 7. Dextromethorphan was administered to rats of an age range and stage of development that are comparable to the third trimester of gestation through the first several months of life. Dose levels of dextromethorphan were 30 mg / kg alone or 3, 10, or 30 mg / kg in conjunction with bupropion at 150 mg / kg. Bupropion 150 mg / kg was added because it is known to cause enzyme inhibition and increase the exposure levels to dextromethorphan. Animals were necropsied approximately 24 hours following dosing. In addition, the toxicokinetic characteristics of dextromethorphan and bupropion were determined.

[0205] Results

[0206] There were no test article related findings besides neuronal necrosis in the 2:10 / 150 mg / kg males and 30 / 150 mg / kg males and females which was characterized by small well-delineated clusters of necrotic neurons that stained positive with aminocupric silver, and occasionally positive with Caspase 9, and which presented as shrunken neurons with pyknotic or karyorrhectic nuclei on H& E stain. The aminocupric sliver generally revealed a higher density and number of these necrotic / apoptotic cells than the Caspase 9. Neuronal necrosis was not identified on the NeuN or Thionine stains.

[0207] Neuronal necrosis was Identified in multiple subanatomic sites including:

[0208] i) the cerebral cortex (septal nucleus, accumbens nucleus, lateral septal nuclei, and cingulate, retrosplenial, frontal, parietal, entorhinai cortices); ii) the thalamus;

[0209] iii) pons; and

[0210] iv) midbrain (most notably in the caudal colliculus and lateral geniculate). The highest incidence and severity of the lesions were noted in the cerebral cortex, followed by the thalamus, and then midbrain and pons. In the 10 / 150 mg / kg group, 1 male was noted with mild necrosis, and in the 30 / 150 mg / kg group, 7 males and females each were noted with mild to moderate necrosis.

[0211] Neuronal necrosis was graded In a semi-quantitative manner based primarily on the aminocupric silver stain: Neuronal necrosis was minimal if approximately 10-25 aminocupric silver positive (i.e., necrotic) cell bodies were present in a single cluster in a sub-anatomic site. Neuronal necrosis was graded as mild if approximately 26-75 necrotic cell bodies were clustered in anyone site or if there were multiple smaller clusters present In that subanatomic site. Neuronal necrosis was graded moderate if 76-100 necrotic neurons were present in any single cluster; and marked if the cluster contained more than 100 necrotic positive-staining cell bodies. The Caspase 9 and the H& E stained serial sections were evaluated to help confirm the diagnosis of neuronal necrosis, but was not relied upon for grading severity of neuronal necrosis.

[0212] One control female (0 mg / kg; No. 1504) had marked neuronal necrosis in the brain, with the cerebral cortex {frontal, motor, retrosplenial, parietal and entorhinal cortices and striatum), thalamus, pons, and midbrain affected. The midbrain { caudal colliculus) bad marked necrosis; the thalamus and cerebral cortex had moderate necrosis; and the pons had mild necrosis. The necrosis was visible on both aminocupric silver and H& E stained sections, and increase in Caspase 9 positive staining was also detected in a few of the moderately to markedly affected areas. The cause for this necrosis was unclear, but the severity was much greater than that seen in any of the 30 / 150 mg / kg males or females or in the affected 10 / 150 mg / kg male. The finding of neuronal necrosis in a control animal was considered an outlier: The degree of neuronal necrosis in this one control animal was not considered to be a background finding. An investigation of the dosing / perfusion records did not provide any reasoning for the marked neuronal necrosis noted in this animal. In conclusion, dextromethorphan in combination with bupropion caused neurodegeneration at a dose level of 2:10 / 150 mg / kg in males and at a dose level of 30 / 150 mg / kg in females, when administered once via oral gavage to Crl; CD(SD) Sprague Dawley rats on Postnatal Day 7 with necropsy approximately 24 hours post-dose.

[0213] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as amounts, percentage, and so forth used in the specification and claims are to be understood in all instances as indicating both the exact values as shown and as being modified by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0214] Use of the term "comprising" or "comprises" herein also contemplates that use of "consisting essentially of," “consists essentially of," "consisting of," or "consists of" in its place.

[0215] Affirmative recitation of an element anywhere herein should be understood to contemplate both including and excluding that element.

[0216] The terms "a," “an," "the" and similar referents used in the context of describing the embodiments (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of any claim. No language in the specification should be construed as indicating any non-ciaimed element essential to the practice of the claims.

[0217] Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from a group, for reasons of convenience and / or to expedite prosecution. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups if used in the appended claims.

[0218] Certain embodiments are described herein, including the best mode known to the inventors for carrying out the claimed embodi ments. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the claimed embodiments to be practiced otherwise than specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

[0219] In closing, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims, BackThus, by way of example, but not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to embodiments precisely as shown and described.

Claims

CLAIMS1. A method of treating a patient: having a nervous system condition by administering a combination of dextromethorphan and bupropion, the method comprising:orally administering to the patient, once daily, a dosage form comprising: 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan; wherein the patient has severe renal impairment.

2. The method of claim 1, wherein the patient has an eGFR of 15 mL / minute / 1.73 mg?to 29 mL / minute / 1.73 mg2.

3. The method of claim 1, wherein the dosage form contains 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide.

4. The method of claim 1, wherein a combination of about 52.5 mg of bupropion hydrochloride and about 22.5 mg of dextromethorphan hydrobromide is orally administered twice a day to the patient.

5. A method of treating a human patient with a combination of dextromethorphan and bupropion, wherein the human patient is experiencing a nervous system condition, the method comprising the steps of:determining whether the human patient has severe renal impairment by:obtaining or having obtained a biological sample from the patient; and performing or having performed an assay on the biological sample to determine if the human patient has severe renal impairment; and if the human patient has severe renal impairment, then orally administering once a day to the patient, a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg or iess of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan, wherein the molar ratio of the bupropion to the dextromethorphan is about the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide;if the human patient does not have renal impairment, then orally administering twice a day to the patient, a dosage form containing a combination of 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan;wherei n a risk of somnolence and dizziness for a hu man patient who has severe renal impairment is lower following orally administering the dosage form containing the combination once a day to the human patient than it would be if a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide were administered twice a day to the human patient for the same number of days,6, A method of treating a human patient who is experiencing a nervous system condition, the method comprising the steps of:a) determining whether the human patient is at risk of an adverse event associated with overexposure to dextromethorphan by:obtaining or having obtained a biological sample from the patient; and performing or having performed an assay on the biological sample to determine if the human patient has severe renal impairment, wherein a result that the human patient has severe renal Impairment i dicates that the human patient is at risk of an adverse event associated with overexposure to dextromethorphan; andb) if the human patient is at risk of an adverse event associated with overexposure to dextromethorphan, then orally administering once a day to the patient, a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan, wherein the molar ratio of the bupropion to the dextromethorphan Is about the ratio the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; andc) if the human patient is not at risk of an adverse event associated with overexposure to dextromethorphan, then orally administering twice a day to the patient, a dosage form containing a combination of 105 mg of bupropion hydrochloride, or a molarequivalent amount of the free base or another salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan.

7. A method of treating a nervous system condition with a combination of dextromethorphan and bupropion, comprising:orally administering to a patient, once a day, a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg or iess of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan, wherein the molar ratio of bupropion to dextromethorphan in the dosage form is about the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; and wherein the human patient is selected for: 1) having the nervous system condition and 2} having severe renal impairment, wherein the human patient is determined to have severe renal impairment by an assay on a biological sample from the patient; and wherein the human patient has a reduced risk of an adverse event as compared with the risk of the adverse event that the human patient would have if the dosage form were administered twice daily to the patient.

8. A method of treating a human patient with a combination of dextromethorphan and bupropion, wherein the human patient is experiencing a nervous system condition, the method comprising the steps of:determining whether the human patient has severe renal impairment by:obtaining or having obtained a biological sample from the patient; and performing or having performed an assay on the biological sample to determine if the human patient has severe renal impairment; andif the human patient has severe renal impairment, then orally administering once a day to the patient, a dosage form containing a combination of 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan, wherein the molar ratioof bupropion to dextromethor han in the dosage form is about the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide; andif the human patient does not have renal impairment, then orally administering twice a day to the patient, a dosage form containing a combination of 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion,, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan.

9. A method of treating a human patient having a nervous system condition by administering a combination of dextromethorphan and bupropion, the method comprising:orally administering to the patient, once a day, a dosage form comprising: 105 mg or less of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan, wherein the molar ratio of the bupropion to the dextromethorphan in the dosage form is about the ratio of the molar amount bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide;wherein the human patient is selected for: 1) having the nervous system condition and 2) having severe renal impairment, wherein the human patient is determined to have severe renal impairment by an assay on a biological sample from the patient; and wherei n a risk of somnolence or dizziness for the human patient who has severe renal impairment is lower following orally administering the dosage form containing the combination once a day to the human patient than it would be if a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide were administered twice a day to the human patient for the same number of days,10. The method of claim 8, wherein a combi nation of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is orally administered once a day to the patient.

11. The method of claim 8, wherein a combination of about 52.5 mg of bupropion hydrochloride and about 22.5 mg of dextromethorphan hydrobromide is orally administered twice a day to the patient.

12. A method of treating a human patient with a combination of dextromethorphan and bupropion, wherein the human patient is experiencing a nervous system condition, the method comprising the steps of:determining whether the human patient has severe renal impairment by:obtaining or having obtained a biological sample from the patient and performing or having performed an assay on the biological sample to determine if the human patient has severe renal impairment; and if the human patient has severe rena! impairment, then orally administering once a day to the patient, a dosage form containing a combination of.1.05 mg or iess of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg or less of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan, wherein the molar ratio of the bupropion to the dextromethorphan is about the ratio of the molar amount of bupropion in 105 mg of bupropion hydrochloride to the molar amount of dextromethorphan in 45 mg of dextromethorphan hydrobromide;if the human patient does not have renal impairment, then orally administering twice a day to the patient, a dosage form containing a combination of 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base or another salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base or another salt form of dextromethorphan;wherein a risk of somnolence or dizziness for a human patient who has severe renal impairment is lower following orally administering the dosage form containing the combination once a day to the human patient than it would be if a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide were administered twice a day to the human patient for the same number of days,13. The method of claim 11, wherein if the human patient has severe renal impairment, a dosage form containing a combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is orally administered once a day to the patient.

14. The method of claim 11, wherein if the human patient has severe renal impairment, a dosage form containing a combination of about 52.5 mg of bupropion hydrochloride andabout 22,5 mg of dextromethorphan hydrobromide is orally administered twice a day to the patient.

15. A method of treating major depressive disorder in a human patient who has severe renal impairment comprising administering a daily dose of: (i) about 100 mg to about 110 mg of bupropion hydrochloride, or a molar equivalent amount of a free base form or another salt form of bupropion; and ( ii > about 40 mg to about 50 mg of dextromethorphan hydrobromide, or a molar equivalent amount of a free base form or another salt form of dextromethorphan to the human patient who has severe renal i mpairment and is experiencing major depressive disorder, wherein the daily dose is optionally administered in a dosage form,16. The method of claim 14, wherein the bupropion and the dextromethorphan are in a tablet, and wherein one tablet containing about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide is administered once daily by mouth.

17. The method of claim 14, wherein the bupropion and the dextromethorphan are in a tablet, and wherein one tablet containing about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide is administered daily by mouth.

18. A method of treating major depressive disorder In a human patient who has severe renal impairment, comprising administering a daily dose of: (i) about 105 mg of bupropion hydrochloride and (ii) about 45 mg of dextromethorphan hydrobromide to the human patient who has severe renal impairment and is experiencing major depressive disorder, wherein the daily dose is optionally administered in a dosage form.

19. The method of any preceding claim, wherein the Tmsxof dextromethorphan is about 3 hours.

20. The method of any preceding claim, wherein the human patient has a glomerular filtration rate that is between about 15 ml / min / 1.72m2and 29 ml / min / 1.72mT21. The method of any preceding claim, wherein the administering is achieved by once daily administration, by mouth, of one tablet containing about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide.

22. The method of any preceding claim, wherein steady state plasma concentrations of dextromethorphan and bupropion are achieved within 8 days, and wherein the accumulation ratio for dextromethorphan at steady state is about 20 based on the23. The method of any preceding claim, wherein steady state plasma concentrations of dextromethorphan and bupropion are achieved within 8 days, and wherein the accumulation ratio for dextromethorphan at steady state is about 32 based on the AUCt.

24. The method of any preceding claim, wherein the once-daily administration avoids the human patient having an about 2.78-fold increase in AUC012 of dextromethorphan as compared to the AUCo-? of dextromethorphan that would result from twice daily administration of the tablet for 8 days to a human patient who has no renal impairment.

25. The method of any preceding claim, wherein the once-daily administration avoids the human patient having an about 2.68-fold increase inof dextromethorphan as compared to the Cnwtx of dextromethorphan that would result from twice daily administration of the tablet for 8 days to a human patient who has no renal impairment.

26. The method of any preceding claim, wherein the once-daily administration avoids the human patient having an about 1.22-fold increase in AUCo-i? of bupropion as compared to the AUCoi? of bupropion that would result from twice daily administration of the tablet for 8 days to a human patient who has no renal impairment,27. The method of any preceding claim, wherein the once-daily administration avoids the human patient having an about 1.17-fold increase in Cm3Xof bupropion as compared to the Cmaxof bupropion that would result from twice daily administration of the tablet for 8 days to a human patient who has no renal impairment.

28. The method of any preceding claim, wherein the nervous system condition is major depressive disorder.

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