Use of solriamfetol for the treatment of orphan diseases

Abstract

The present invention relates to a method of treating an orphan disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of certain carbamate compounds, particularly solriamfetol and even more particularly solriamfetol hydrochloride.

Description

[0001] USE OF SOERIAMFETOL FOR THE TREATMENT OF ORPHAN DISEASES

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a method of treating an orphan disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of certain carbamate compounds, particularly solrianifetoL

[0004] BACKGROUND

[0005] Orphan diseases, including orphan diseases, are neglected conditions whose treatments are often not considered profitable due to their cost to develop and limited patient population. Orphan diseases include more familiar conditions such as cystic fibrosis, Lou Gehrig’s disease and Tourete’s syndrome, as well as less familiar conditions such as Duncan’s Syndrome, Madelung’ s disease and acromegaly / gigantism. The prevalence of orphan diseases is often an estimate and may change o ver time. These conditions are complex and often not well understood, causing many patients to encounter greater challenges in being properly diagnosed or having access to effective treatments.

[0006] While most orphan diseases are genetic in origin, many causes are not well understood. Even if the cause of an orphan disease is identified, researchers may still not understand how the disease functions or how to properly treat it. The Institute of Medicine’s 2010 report on orphan diseases and orphan products outlines four potential causes for orphan diseases.

[0007] Genetic causes: 80% or more of orphan diseases are genetic in origin. Infectious agents: Some infections are thought to be rare worldwide, while others are rare in wealthy countries but common in less economically developed countries. Toxic agents: Exposure to natural or manufactured toxic substances can also cause orphan diseases. Other causes: orphan conditions ha ve a variety of other causes such as nutritional deficiencies, injuries, adverse effects of treatment and many others. Financial strain from orphan diseases can affect, both patients and their caregivers. The diagnosis process can be time-consuming and expensive.

[0008] Lost producti vity, lost wages or lack of manageable work with crucial benefits can impact individuals living with an orphan or rare disease. Caregivers experience financial impacts from caring for patients with oiphan diseases, with 86% reporting that they cut back on household savings, did not save for long-term goals, used personal savings and took on more personal debt.

[0009] Patients with orphan diseases often seek treatment in clinics where the condition has never been seen before, and absent, masked, misunderstood or confused symptoms can contribute to delayed diagnosis. For one-third of individuals with an orphan disease, it can take between one and five years to receive a proper diagnosis.

[0010] Early detection, diagnosis and intervention is critical to prevent death or disability for many orphan diseases. Half of all patients diagnosed with an orphan disease are children, and as many as three in ten children with an orphan disease will not live to see their fifth birthday. Newborn screening, routinely provided to 4,1 million babies each year in the United States, can identify genetic, endocrine and metabolic disorders. Each year, 4,000 babies are diagnosed as having a congenital disorder, and approximately 1,000 go undetected,

[0011] Orphan and rare disease treatments range in effectiveness from curing the disease, modifying how the disease functions or treating the symptoms of the disease. Truly curative treatments are rare. Disease modifying therapies target the underlying pathology of a disease to prevent it from worsening. Symptomatic treatments seek to temper symptoms or maintain physical, emotional and mental functioning. Treatments may include medications, nutritional agents, surgical procedures, psychotherapy, physical and occupational therapy and medical devices.

[0012] Many patients with orphan diseases require medical devices to diagnose and treat their conditions, such as genetic tests, pediatric implants that grow with a child and pediatric intrathecal ports for drug delivery. The U.S. Food and Drug Administration (FDA) and the National Institutes of Health’s National Center for Advancing Translational Sciences / Office of Oiphan diseases Research reported that 917 clinicians cited unmet medical device needs in 2015, with many noting the need for entirely new diagnostic and therapeutic devices. Accordingly, there exists a strong need for more treatments to help alleviate the suffering and other issues associated with orphan diseases.

[0013] SUMMARY OF EMBODIMENTS OF THE INVENTION

[0014] The present invention is directed to a method of treating orphan diseases in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of solriamfetol or a pharmaceutically acceptable salt or ester thereof. A preferred form of solriamfetol is solriamfetol hydrochloride.

[0015] In some embodiments, solriamfetol structure is given below as the compound of Formula la: or a pharmaceutically acceptable salt or ester thereof. In some embodiments, solriamfetol structure is given below as the compound of Formula lb: or a pharmaceutically acceptable salt or ester thereof. This compound is also named (R)-(beta- amino- benzenepropyl) carbamate or O-carbamoyl-(D)-phenylaianinol and has alternatively been called solriamfetol, ADX-N05, SKL-N05, YKP10A, and R.228060. A preferred form is solriamfetol hydrochloride.

[0016] Embodiments of the in vention include the use of solriamfetol, for the preparation of a medicament for the treatment of an orphan disease, an enantiomer of solriamfetol of Formula I substantially free of other enantiomers or an enantiomeric mixture wherein one enantiomer of Formula 1 predominates and pharmaceutical compositions comprising solriamfetol for the treatment of orphan diseases.

[0017] DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

[0018] The present invention now will be described hereinafter with reference to the accompanying drawings and examples, in which embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey t he scope of the in vention to those skilled in the art. In addition, any references cited herein are incorporated by reference in their entireties.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The term inology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. All publications, patent applications, patents, patent publications and other references cited herein are incorporated by reference in their entireties for the teachings relevant to the sentence and / or paragraph in which the reference is presented.

[0020] Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination. Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a composition comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination.

[0021] Definitions

[0022] As used herein, “a,” “an,” or “the” can mean one or more than one. For example, “a” cell can mean a single cell or a multipl icity of cells.

[0023] Also as used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0024] The term “about,” as used herein when referring to a measurable value such as an amount of dose (e.g., an amount of a compound) and the like, is meant to encompass variations of ± 20%, ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of the specified amount.

[0025] The terms “comprise,” “comprises,” and “comprising” as used herein, specify the presence of the stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0026] As used herein, the transitional phrase “consisting essentially of’ means that the scope of a claim is to be interpreted to encompass the specified materials or steps recited in the claim “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention, See, In re Hers, 537 F.2d 549, 551 -52, 190 U.S.P.Q. 461, 463 (CCPA 1976) (emphasis in the original); see a / so MPEP § 2111.03. Thus, the term “consisting essentially of’ when used in a claim or the description of this invention is not intended to be interpreted to be equivalent to “comprising

[0027] As used herein, the terms “increase,” “increases,” “increased,” “increasing,” and similar terms indicate an elevation of at least about 25%, 50%, 75%, 100%, 150%, 200%, 300%, 400%, 500% or more.

[0028] As used herein, the terms “reduce,” “reduces,” “reduced,” “reduction,” and similar terms mean a decrease of at least about 5%, 10%, 15%, 20%, 25%, 35%, 50%, 75%, 80%, 85%, 90%, 95%, 97% or more. In particular embodiments, the reduction results in no or essentially no (Ze,, an insignificant amount e.g., less than about 10% or even 5%) detectable activity or amount.

[0029] “Effective amount” or “therapeutically effective amount” as used herein refers to an amount of a compound, composition and / or formulation of the invention that is sufficient to produce a desired effect, which can be a therapeutic and / or beneficial effect. The effective amoun t will vary with the age, general condition of the subject, the severity-' of the condition being treated, the particular agent administered, the duration of the treatment, the nature of any concurrent treatment, the pharmaceutically acceptable carrier used, and like factors within the know ledge and experti se of those skilled in the art. As appropriate, an “effective amount” in any individual case can be determined by one of skill in the art by reference to the pertinent texts and literature and / or by using routine experimentation.

[0030] “Pharmaceutically acceptable carrier” (sometimes referred to as a “carrier”) refers to a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic and includes a carrier that is acceptable for veterinary and / or human pharmaceutical or therapeutic use. The terms “carrier” or “pharmaceutically acceptable carrier” can. include, but are not limited to, phosphate buffered saline solution, water, emulsions (such as an oil / water or water / oil emulsion) and / or various types of wetting agents. As used herein, the term “carrier” encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations and as described further herein.

[0031] A “subject” of the invention includes any animal that has or is suspected of having an orphan disease. Such a subject is generally a mammalian subject (e.g., a laboratory animal such as a rat, mouse, guinea pig, rabbit, primate, etc. ), a farm or commercial animal (e.g., a cow, horse, goat, donkey, sheep, etc.), or a domestic animal (e.g., cat, dog, ferret, etc. ). In particular embodiments, the subject is a primate subject, a con-human primate subject (e.g., a chimpanzee, baboon, monkey, gorilla, etc.) or a human, In certain embodiments, a subject of the invention can be a subject known to have or believed to have an orphan disease. A subject of the invention can be a subject known or believed to be at risk of developing an orphan disease. Alternatively, a subject according to the invention can also include a subject not previously known or suspected to have an orphan disease. Subjects include males and / or females of any age, including neonates, juvenile, mature and geriatric subjects, “Treat,” “treating” and similar terms as used herein in the context of treating a subject refer to providing medical and / or surgical management of a subject. Treatment may include, but is not limited io, administering an agent or composition (e.g., a pharmaceutical composition) to a subject. Treatment is typically undertaken in an effort to alter the course of a disease (which term is used to indicate any disease, disorder, syndrome, or undesirable condition warranting or potentially warranting therapy) in a manner beneficial to the subject. The effect of treatment may include reversing, alleviating, reducing severity of, delaying the onset of, curing, inhibiting the progression of, and / or reducing the like lihood of occurrence or recurrence of the disease or one or more symptoms or manifestations of the disease. A therapeutic agent may be administered to a subject who has a disease or is at increased risk of developing a disease relati ve to a member of the general population . In some embodiments a therapeutic agent may be administered to a subject who has had a disease but no longer shows evidence of the disease. The agent may be administered e.g., to reduce the likelihood of recurrence of evident disease. A therapeutic agent may be administered prophy I actically, i.e., before development of any symptom or manifestation of a disease. “Prophylactic treatment” refers to providing medical and / or surgical management to a subject who has not developed a disease or does not show evidence of a disease in order, e.g., to reduce die likelihood that the disease will occur, delay the onset of the disease, or to reduce the severity of the disease should it occur. The subject may have been identified as being at risk of developing the disease (e.g, at increased risk relative to the general population or as having a risk factor that increases the likelihood of developing the disease.

[0032] Grammatical variations of “administer,” “administration,” and “administering” to a subjec t include any route of introducing or delivering to a subject an agent. Administration can be carried out by any suitable route, including oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesioaal, intranasal, rectal, vaginal, by inhalation, via aa implanted reservoir, parenteral subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intraperitoneal, intrahepatic, intralesional, and intracranial injections or infusion techniques), and the like. “Concurrent administration ,” “administration in combination,” “simultaneous administration,” or “administered simultaneously” as used herein, means that the compounds are administered at the same point in time, overlapping in time, or one following the other. In the latter case, the two compounds are administered at times sufficiently close that the results observed are indistinguishable from those achieved when the compounds are administered at the same point in time. “Systemic administration” refers to the introducing or delivering to a subject an agent via a route which introduces or delivers the agent to extensive areas of the subject’s body (e.g,» greater than 50% of the body ), for example through entrance into the circulatory or lymph systems. By contrast, “local administration” refers to the introducing or delivery to a subject an agent via a route which introduces or delivers the agent to the area or area immediately adjacent to the point of administration and does not introduce the agent systemically in a therapeutically significant amount. For example, locally administered agents are easily detectable in the local vicinity of the point of administration but are undetectable or detectable at negligible amounts in distal parts of the subject’s body. Administration includes self-administration and the administration by another.

[0033] A “subject in need” of the methods of the invention can be a subject known to have an orphan disease, suspected of having an orphan disease, or having an increased risk of developing an orphan disease.

[0034] The term “pharmaceutically acceptable salts or esters” shall mean non-toxic salts or esters of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base or the free base with a suitable organic or inorganic acid. Examples of such salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsaailate, hexyhesorc inate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, laetobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, mefhylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate, palmitate, panthothenate, phosphate / diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate. succinate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.

[0035] As used herein the term “concomitant administration” or “combination administration” of a compound, therapeutic agent or kno wn drug with a compound of the present invention means administration of a known medication or drug and, in addi tion, the one or more compounds of the invention at such time that both the known drug and the compound will have a therapeutic effect. In some cases this therapeutic effect will be synergistic. Such concomitant administration can involve concurrent (i.e., at the same time), prior, or subsequent administration of the known drug with respect to the administration of a compound of the present invention. A person of skill in the art, would have no difficulty determining the appropriate timing, sequence and dosages of administration for particular drugs and compounds of the present invention.

[0036] As used herein the term “orphan disease” or “orphan diseases” includes but is not limited to any one or more of the following:

[0037] Reduction of Chronic Drooling In Patients Aged 3 - 16 With Neurologic Conditions Associated With Problem Drooling (E.G. Cerebral Palsy)

[0038] Treatment Of Non- Infectious Uveitis Affecting The Posterior Segment Of The Eye

[0039] Treatment, of Infantile Spasms

[0040] Treatment Of Patients With Subependymal Giant. Cell Astrocytoma (Sega) Associated With Tuberous Sclerosis Who Require Therapeutic Intervention But Are Not Candidates For Curative Surgical Resection

[0041] Treatment Of Cyanide Poisoning That Is Judged To Be Life-Threatening

[0042] Management Of Postherpetic Neuralgia

[0043] Reduction of the Risk Of Preterm Birth In Women With Singleton Pregnancy Who Have A History Of Singleton Spontaneous Preterm Birth

[0044] Treatment Of Severe Hypercalcemia In Patients With Primary Hypeiparathyroidism Who Are Unable To Undergo Parathyroidectomy

[0045] Treatment Of Asymptomatic Or Progressive Medullary Thyroid Cancer In Patients With Unresectable Locally Advanced Or Metastatic Disease

[0046] Use In Combination Chemotherapy With 5-FIuorouracil In The Palliative Treatment Of Patients With Advanced Metastatic Colorectal Cancer

[0047] Treatment Of Progressive Neuroendocrine Tumors Of Pancreatic Origin (Pnet) In Patients With Unresectable, Locally Advanced Or Metastatic Disease

[0048] Treatment Of Peripheral T-Cell Lymphoma (Ptcl) In Patients Who Have Received At Least One Prior Therapy

[0049] Treatment Of Unresectable Or Metastatic Melanoma With The Braf V600e Mutation As

[0050] Detected By An Fda-Approved Test

[0051] Treatment Of Acute Attacks Of Hereditary Angioedema In Adults 18 Years Of Age And Older

[0052] Treatment Of Patients With Locally Advanced Or Metastatic Non-Small Cell Lung Cancer (Nsclc) That Is Anaplastic Lymphoma Kinase (Alk)-Positive As Detected By An Fda Approved Test

[0053] Treatment Of Patients With Transfusional Iron Overload Due To Thalassemia Syndromes When Current Chelation Therapy Is Inadequate

[0054] Adjunctive Treatment Of Seizures Associated With Lennox-Gastaut Syndrome In Patients 2 Years Of Age Or Older

[0055] Adjunctive Treatment Of Seizures Associated With L.ennox-Gastaut Syndrome Inpatients 2 Years Of Age Or Older

[0056] Treatment Of Patients With Intermediate Or High-Risk M yelofibrosis, Including Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis And Post-Essential Thrombocythemia Myelofibrosis

[0057] Treatment Of Cystic Fibrosis (Cf) In Patients Age 6 Years And Older Who Have A G551d Mutation In The Cftr Gene,

[0058] An Adjunct To Ab Extemo Glaucoma. Surgery

[0059] For The Control Of Hyperglycemia Secondary To Hypercortisolism In Adult Patients With Endogenous Cushing’s Syndrome Who Have Type 2 Diabetes Mellitus Or Glucose Intolerance And Have Failed Surgery Or Are Not Candidates For Surgery

[0060] Advanced Soft Tissue Sarcoma (Sts) Who Have Received Prior Chemotherapy

[0061] Treatment Of Adults With Renal Angiomyolipoma And Tuberous Sclerosis Complex (Tse) Not Requiring Immediate Surgery

[0062] Management Of Postherpetic Neuralgia In Adults.

[0063] Treatment Of Endogenous Anterior Uveitis

[0064] Treatment Of Patients With Multiple Myeloma Who Have Received At Least Two Prior Therapies Including Bortezomib And An Immunomodulatory Agent And Have Demonstrated Disease Progression On Or Within 60 Days Of Completion Of The Last Therapy

[0065] Treatment Of Adult Patients With Philadelphia Chromosome-Negative (Ph-) Acute Lymphoblastic Leukemia (All) In Second Or Greater Relapse Or Whose Disease Has Progressed Following Two Or .More Anti-Leukemia Therapies

[0066] Localization Of Lymph Nodes Draining A Primary TumorIn Patients With Melanoma When Used With A Hand-Field Gamma Counter

[0067] Treatment Of Adult Patients With Chronic, Accelerated Or Blast Phase Philadelphia Chromosome-Positive (Ph+) Chronic Myelogenous Leukemia (Cml) With Resistance, Or Intolerance To Prior Therapy

[0068] Treatment Of Corneal Cystine Crystal Accumulation In Patients With Cystinosis

[0069] Treatment Of Adult Patients With Chronic Or Accelerated Phase Chronic Myeloid Leukemia (Cml) With Resistance And / Or Intolerance To Two Or More Tyrosine Kinase Inhibitors (Tki)

[0070] Treatment Of Progressive, Metastatic Medullary Thyroid Cancer (Mtc)

[0071] Treatment Of Adult Patients With Cushing’s Disease For Whom Pituitary Surgery Is Not An Option Or Has Not Been Curative

[0072] Treatment Of Adult Patients With Philadelphia Chromosome Positive Acute Lymphoblastic

[0073] Leukemia (Ph+All) That Is Resistant Or Intolerant To Prior Tyrosine Kinase Inhibitor 'Therapy. Adjunct To A Low-Fat Diet And Other Lipid-Lowering Treatments, Including Ldl Apheresis Where Available, To Reduce Ldl-C, Tc, Apolipoprotein B, & Non-Hdl-C In Patients With Homozygous Familial Hypercholesterolemia

[0074] Treatment Of Adult Patients With Short Bowel Syndrome (Sbs) Who Are Dependent On Parenteral Support

[0075] Part Of Combination Therapy In Adults (Greater Than Or Equal To 18 Years) With Pulmonary Multi -Drug Resistant Tuberculosis (Mdr-Tb)

[0076] Treatment Of Chronic Iron Overload In Patients 10 Yrs, & Older With Non-Transfusion

[0077] Dependent Thalassemia (Ntdt) Syndromes And With A Liver Iron Concentration Of At Least 5 Mg Of Iron Per Gram Of Liver Dry Weight & Serum Ferritin Greater Than 300 McgZL,

[0078] Treatment Of Pediatric Patients With Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ All) In Combination With Chemotherapy, Approved Under Nda #21588 / S-037

[0079] Adjunct To Lipid-Lowering Medications And Diet To Reduce Ldl-C, Apolipoprotein B (Apo B), Total Cholesterol (Tc), And Nou-High Density Lipoproteia-Cholesterol (Non-Hdl-C) In

[0080] Patients With Homozygous Familial Hypercholesterolemia (Hofh)

[0081] Use As A Nitrogen-Binding Adjunctive Therapy For Chronic Mgmt Of Adult And Pediatric Patients At Least 2 Yrs With Urea Cycle Disorders That Cannot Be Managed By Dietary Protein Restriction And / Or Amino Acid Supplementation Alone

[0082] Treatment Of Patients With Multiple Myeloma Who Have Recei ved At Least Two Prior Therapies Including Lenalidomide And Bortezomib And Have Demonstrated Disease Progression On Or Within 60 Days Of Completion Of The Last Therapy.

[0083] Treatment Of Patients With Locally Advanced, Unresectable Or Metastatic Gastrointestinal Stromal Tumor (Gist) Who Have Been Previously Treated With Imatinib Mesylate And Sunitinfb Malate.

[0084] Management Of Nephropathic Cystinosis In Adults And Children Ages 6 Years And Older,

[0085] Impro vement Of Neurological Outcome By Reducing The Incidence And Severity Of Ischemic Deficits In Adult Patients With Subarachnoid Hemorrhage From Ruptured Intracranial Berry Aneurysms Regardless Of Their Post-Ictus Neurological Condition

[0086] Treatment Of Patients With Unresectable Or Metastatic Melanoma With Braf V600e Mutation As Detected By An Fda Approved Test.

[0087] Treatment Of Patien ts With Unresectable Or Metastatic Melanoma With Braf V600e Or VbOOk Mutations As Detected By An Fda Approved Test

[0088] Treatment Of Mantle Cell Lymphoma Whose Disease Has Relapsed Or Progressed A fter Two Prior Therapies, One Of Which Included Bortez.omib

[0089] First-Line Treatment Of Patients With Metastatic Non-Smail Cell Lung Cancer (Nsclc) Whose Tumors Have Epidermal Growth Factor Receptor (Egfr) Exon 19 Deletions Or Exon 21 (L858r) Substitution Mutations As Detected By An Fda-Approved Test.

[0090] Topical Treatment Of Stage la And lb Mycosis Fungoides-Type Cutaneous T-Cell Lymphoma In Patients Who Have Received Prior Skin-Directed Therapy

[0091] Treatment Of Metastatic Adenocarcinoma Of The Pancreas As First-Line Treatment, In Combination With Gemcitabine.

[0092] Treatment Of Adults With Pulmonary Arterial Hypertension (Pah) Who Group 1 , To Improve Exercise Capacity, Who Functional Class And To Delay Clinical Worsening.

[0093] Tx Of Pah To Delay Disease Progression, Disease Progression Included: Death, Initiation Of Tv Or Sc Prostanoids, Or Clinical Worsening Of Pah (Decreased 6-Minute Walk Distance, Worsened Pah Symptoms And Need For Additional Pah Treatment).

[0094] Treatment Of Patients With Mantle Cell Lymphoma (Mid) Who Have Received At Least One Prior Therapy

[0095] Treatment Of Patien ts With Locally Recurrent Or Metastatic, Progressive, Differentiated Thyroid Carcinoma (Det) That Is Refractory To Radioactive Iodine Treatment.

[0096] Trametinib In Combo With Dabrafenib For Tx. Of Pts With Unresectable Or Metastatic

[0097] Melanoma With Braf V600e Or V600k .Mutations As Detected By An Fda-Approved Test. This Indication Is Based On The Demonstration Of Durable Response Rate Dabrafenib In Combo With Trametinib For Tx. Of Pts With Unresectable Or Metastatic

[0098] Melanoma With Braf V600e Or V600k Mutations As Detected By An Fda-Approved Test. This

[0099] Indication Is Based On The Demonstration Of Durable Response Rate

[0100] Treatment Of Non-24-Hour Sleep-Wake Disorder

[0101] Treatment Of Patients With Chronic Lymphocytic Leukemia (Cll) Who Have Received At Least One Prior Therapy

[0102] Treatment Of Neurogenic Symptomatic Orthosta tic Hypotension In Patients With Primary Autonomic Failure, Dopamine-Beta-Hydroxylase Deficiency, And Nondiabetic Autonomic Neuropathy

[0103] Treatment Of Proliferating Infantile Hemangioma Requiring Systemic Therapy.

[0104] Treatment Of Visceral Leishmaniasis Due To Leishmania Donovani; Cutaneous Leishmaniasis Due To Leishmania Braziliensis, Leishmania Guyanensis, And Leishmania Pauamensis; And Mucosal Leishmaniasis Due To Leishmania Braziliensis.

[0105] Selective Hepatic Intra-Arterial Use For Imaging Tumors In Adults With Known Hepatocellular Carcinoma (Hcc)

[0106] Treatment Of Patients With Acute Lymphoblastic Leukemia As Part Of A Combination Regimen.

[0107] Treatment Of Patients With Anaplastic Lymphoma Kinase (Aik)- Positive Metastatic Nou-Small Cell Lung Cancer (Nsclc) Who Have Progressed On Or Are Intolerant To Crizotinib.

[0108] Guiding Sentinel Lymph Node Biopsy , Using A Hand-Held Gamma Counter In Patients With Clinically Node Negative Squamous Cell Carcinoma Of The Oral Cavity

[0109] Treatment Of Patients With Relapsed Or Refractory Peripheral T-Cell Lymphoma

[0110] Treatment Of Malignant Hyperthermia In Conjunction With Appropriate Supportive Measures

[0111] And For The Prevention Of Malignant Hyperthermia In Pat ients At High Risk

[0112] Relapsed Cll, In Combo. With Rituximab, In Patients For Whom Rituximab Alone Would Be Considered Appropriate Therapy Due To Other Co-Morbidities; And Relapsed Sil In Patients Who Have Received At Least 2 Prior Systemic Therapies

[0113] Relapsed Follicular B-Cell Non-Hodgkin Lymphoma (Fl) In Patients Who Have Received At Least Two Prior Systemic Therapies

[0114] Treatment Of Patients With Chron ic Lymphocytic Leukemia With I7p Deletion Who Have Not Received At Least One Prior Therapy

[0115] Long-Term Treatment Of Adult Pati ents W ith Gaucher Disease Type 1 Who Are Cyp2d6

[0116] Extensive Metabolizers (Ems), Intermediate Metabolizers (Ims), Or Poor Metabolizes (Pms) As Detected By An Fda-Cleared Test

[0117] Treatment Of Patients With Severe Aplastic Anemia Who Ha ve Had An Insufficient Response To Immunosuppressive Therapy

[0118] Treatment Of Patients With Severe Aplastic Anemia Who Have Had An Insufficient Response To Immunosuppressive Therapy,

[0119] Treatment Of Patients With Mantle Cell Lymphoma Who Have Not Recei ved At Least 1 Prior Therapy

[0120] Treatment Of Idiopathic Pulmonary Fibrosis

[0121] Treatment Of Hypercalcemia In Adult Patients With Primary Hyperparathyroidism For Whom Parathyroidectomy Would Be Indicated On The Basis Of Serum Calcium Levels, But Who Are Unable To Undergo Parathyroidectomy,

[0122] Treatment Of Patients With Polycythemia Vera Who Have Had An Inadequate Response To Or Are Intolerant Of Hydroxyurea

[0123] Treatment Of Pediatric Patients With Tourette's

[0124] Treatment Of Patients With Acromegaly Who Have Had An Inadequate Response To Surgery And / Or For Whom Surgery Is Not An Option

[0125] Treatment Of Patients With Unresectable.Well- Or Moderately-Differentiated Locally Advanced Or Metastatic Gastroenteropancreatic Neuroendocrine Tumors To improve Progression-Free Survival Use Of As Monotherapy For Patients With Deleterious Or Suspected Del eterious Germlin e Brea Mutated (As Detected By An Pda- Approved lest) Advanced Ovarian Cancer Who Have Been Treated With Three Or More Prior Lines Of Chemotherapy

[0126] Treatment Of Motor Fluctuations In Patients With .Advanced Parkinson's Disease

[0127] As A Replacement Solution In Continuous Renal Replacement Therapy (Crrt) And In Case Of Drag Poisoning When Crrt Is Used To Remove Dialyzable Substances

[0128] Treatment Of Patients With Waldenstrom's Macroglobulinemia

[0129] Treatment Of Patients With Locally Recurrent Or Metastatic, Progressive, Radioactive Iodine Refractory Differentiated Thyroid Cancer

[0130] For Use In Combination With Dexamethasone For The Treatment Of Patients With Multiple Myeloma Who Have Not Received At Least One Prior Therapy (First Line Treatment)

[0131] Treatment Of Patients With Multiple Myeloma Who Have Received At Least 2 Prior Regimens, Including Bortezomib And An Immunomodulatory Agent

[0132] Treatment Of Invasive Mucormycosis In Patients 18 Years Of Age And Older

[0133] Treatment. Of Bile Acid Synthesis Disorders Due To Single Enzyme Defects

[0134] Treatment Of Lymphangioleiomyomatosis (Lam)

[0135] Treatment Of Cystic Fibrosis In Patients Age 12 Years And Older Who Are Homozygous For F508del Mutation In The Cftr Gene

[0136] Prophylaxis Of Organ Rejection In Kidney Transplant Patients Converted From Tacrolimus Immediate-Release Formulations In Combination With Other Immunosuppressants

[0137] For The First-Line Treatment Of Patients With Metastatic Non-Small Cell Lung Cancer (Nsclc) Whose 'rumors Have Epidermal Growth Factor Receptor (Egfr) Exon 19 Deletions Or Exon 21 (L858r) Substitution Mutations As Detected By An Fda-Approved Test

[0138] Treatment Of Primary Hyperkalemic Periodic Paralysis, Primary Hypokalemic Period Paralysis,

[0139] And Related Variants To Expand The Indi cation To Pediatric Patien ts 2-6 Years Of Age With Nephropathic Cystinosis

[0140] Treatment Of Heredi tary Orotic Aciduria

[0141] For Use In Combination With 5-Fluorouracil And Leucovorin, For The Treatment Of Patients With Metastatic Adenocarcinoma Of The Pancreas That Has Progressed Following Gemcitabine-Based Therapy

[0142] For The Treatment Of Patients With Unresectable Or Metastatic Liposarcoma Or Leiomyosarcoma Who Received A Prior Anthracycline-Containing Regimen

[0143] For The Treatment Of Patients With Unresectable Or Metastatic Melanoma With Braf V600e Or V6000k Mutation, In Combination With Vemurafenib, CoteBic Is Not Indicated For Treatment Of Patients With Wild-Type Braf Melanoma

[0144] For Treatment Of Patients With Metastatic Epidermal Growth Factor Receptor (Egfr) T790m Mutation-Positive Non-Small Cell Lung Cancer (Nsclc), As Detected By An Fda-Approved Test, Who Have Progressed On Or After Egfr Tki Therapy

[0145] Use In Combination With Lenalidomide And Dexamethasone For The Treatment Of Patients With Multiple Myeloma Who Have Received At Least One Prior Therapy

[0146] Emergency Tx. Of Pts Following A Fu Or Capecitabine Od, Or Who Exhibit Early-Onset, Severe Or Life-Threatening Toxicity Affecting The Cardiac System Or Cns, And / Or Early-Onset, Unusually Severe Ar W / In 96 His Following The End Of Fu Or Capecitabine Admin.

[0147] Treatment Of Patients With Anaplastic Lymphoma Kinase (Alk)-Positive Metastatic Non-Small

[0148] Cell Lung Cancer (Nsclc), Who Have Progressed On Or Are Intolerant To Crizotinib

[0149] For Use Of Uptravi ( Selexipag) Tablets, 200, 400, 600, 800, 1000, 1200, 1400, And 1600 Mcg For Treatment Of Pulmonary Arterial Hypertension (Pah, Who Group I) To Reduce The Risks Of Disease Progression And Hospitalization For Pah

[0150] Treatment Of Patients With Unresectable Or Metastatic Liposarcoma Who Have Received A Prior Anthracyclne-Coutaiuing Regimen

[0151] Treatment Of Adult Patients With Progressive, Well-Differentiated, Non-Functioaal, Neuroendocrine Tumors (Net) Of Gastrointestinal (Gi) Or Lung Ori gin , (Excluding Pancreatic) With Unresectable, Locally Advanced Or Metastatic Disease

[0152] Indicated For The Treatment Of Patients With Chronic Lymphocytic Leukemia Without 17p Deletion Who Have Not Received At Least One Prior Therapy (First Line Therapy)

[0153] For High-Dose Conditioning Treatment Prior To Hematopoietic Progenitor (Stem) Cell Transplantation In Patients With Multiple Myeloma

[0154] Treatment Of Patients With Metastatic Non-Small Cell Lung Cancer Whose Tumors Are Ros-1 Positive.

[0155] For The Treatment Of Adult And Pediatric Patients With Hepatic Veno-Occlusive Disease (Vod), Also Known As Sinusoidal Obstruction. Syndrome (Sos), With Renal Or Pulmonary Dysfunction Following Hematopoietic Stem Cell Transplantation (Hsct).

[0156] For Treatment Of Pediatric And Adult Patients With Acquired Methemoglobinemia.

[0157] Treatment Of Patients 'With Chron ic Lymp hocytic Leukemia (Cil) W ith 17p Deletion, As Detected By An Fda Approved Test, Who Have Received At Least One Prior Therapy

[0158] Treatment Of Patients With Metastatic, Squamous, Non- Small Cell Lung Cancer Progressing

[0159] After Platinum-Based Chemotherapy

[0160] Treatment Of Progressive Keratoconus

[0161] For Treatment Of Patients With Small Lymphocytic Lymphoma (SIl)

[0162] An Adjunct To Diet To Reduce Ldl-C, Total-C, Nonhdl-C And Apob In Children And Adolescents 7 To 17 Years Of Age With Homozygous Familial Hypercholesterolemia, Either Alone Or With Other Lipid-Lowering Treatments (E.G., Ldl Apheresis)

[0163] Treatment Of Primary Biliary Cholangitis (Pbc) In Combination With Ursodeoxycholic Acid (Udca) In Adults With An Inadequate Response To Udca, Or As Monotherapy In Adults Unable To Tolerate Udca

[0164] For Use After Radiolabeling With Ga 68, With Positron Emission Tomography (Pet) For Localization Of Somatostatin Receptor Positive Neuroendocrine Tumors (Nets) In Adult And Pediatric Patients. Treatment Of Corneal Ectasia Following Refractive Surgery

[0165] 'Treatment Of Duchenne Muscular Dystrophy (Dmd) In Patients Who Have A Confirmed Mutation Of The Dmd Gene That Is Amenable To Exon 51 Skipping

[0166] Treatment Of Cystic Fibrosis (Cf) In Patients Age 6-11 Year Old Who Are Homozygous For The F508del Mutation In The Cftr Gene

[0167] Replacement Therapy For Oral Carbamazepine Formulations, When Oral Administration Is Temporarily Not Feasible, In Adults With The Following Seizure Types: Partial With Complex Symptomology, Generalized Clonic-Tonic, And Mixed

[0168] Indicated In Pediatric Patients 10 Years And Older For The Prevention And Treatment Of

[0169] Secondary Hyperparathyroidism Associated ‘With Chronic Kidney Disease (Ckd) Stages 3 And 4 And Ckd Stage 5 In Patients On Hemodialysis Or Peritoneal Dialysis

[0170] As Monotherapy For The Treatment Of Patients With Deleterious Brea Mutation (Germline And Or Somatic) Associated Advanced Ovarian Cancer Who Have Been Treated With Two Or More Chemotherapies

[0171] Treatment Of Spinal Muscular Atrophy In Pediatric And Adult Patients

[0172] Treatment Of Patients With Marginal Zone l ymphoma (Mzl) Who Require Systemic Therapy And Have Received At Least One Prior Anti-Cd20-Based Therapy

[0173] Indicated For Reducing The Risk Of Graft Rejection When Used In Conjunction With High- Dose Busulfan & Cyclophosphamide As A Preparative Regimen For Allogenic Hematopoietic Progenitor Cell Transplantation For Peds. Patients With Class 3 Beta-Thalassemia

[0174] Treatment Of Duchenne Muscular Dystrophy In Patients 5 Years Of Age And Older

[0175] Treatment Of Multiple Myeloma (Mm), As Maintenance Following Autologous Hematopoietic Stem Cell Transplantation (Auto-Hsct)

[0176] Treatment Of Carcinoid Syndrome Diarrhea In Combination With Somatostatin Analog (Ssa) Therapy In Adults Inadequately Controlled By Ssa Therapy

[0177] Indicated For Maintenance Treatment Of Adult Patients With Recurrent Epithelial Ovarian, Fallopian Tube, Or Primary Peritoneal Cancer Who Are In A Complete Or Partial Response To Platinum-Based Chemotherapy

[0178] Treatment Of Chorea Associated With Huntington's Disease

[0179] Treatment Of Chronic Hcv Genotype 2 Or 3 Infection In Pediatric Patients 12 Years Of Age And Older Or Weighing At Least 35 Kg Without Cirrhosis Or With Compensated Cirrhosis For Use In Combination With Ribavirin

[0180] Treatment Of Pediatric Patients 12 Years Of Age And Older Or Weighing At Least 35 Kg With Chronic Hepatitis C Virus Genotype 1 , 4, 5, Or 6 Infection. Without Cirrhosis Or With Compensated Cirrhosis

[0181] Treatment Of Oligoarticuiar Juvenile Idiopathic Arthritis (Persistent Oligoarthritis, Psoriatic Juvenile Idiopathic Arthritis, Enthesitis-Related Arthritis, Or Undifferentiated Arthritis) & Polyarticular Juvenile idiopathic Arthritis In Children 0-16 Yrs

[0182] Treatment Of Pediatric Patients With Acute Lymphoblastic Leukemia As A Component Of A Combination Cheomotherapy Maintenance Regimen

[0183] Treatment Of Patients With Hepatocellular Carcinoma (Hcc Or Liver Cancer) Who Have Been Previously Treated With The Drug Sorafenib.

[0184] Treatment Of Adult Patients With Aggressive Systemic Mastocytosis ( Asm), Systemic Mastocytosis With Associated Hematological Neoplasm (Sm-Ahn), Or Mast Cell Leukemia (Mcl)

[0185] Treatment Of Adult Patients With Newly Diagnosed Acute Myeloid Leukemia (Ami) That Is Flt3 Mutation-Positive As Detected By An Fda Approved Test, In Combination With Standard Cytarabine And DaunorubicIn Induction And Cytarabine Consolidation

[0186] Treatment Of Patien ts With Anaplastic Lymphoma Kinase (Aik)- Positive Metastatic NomSniall Cell Lung Cancer (Nsclc) Who Have Progressed On Or Are Intolerant To Crizotinib

[0187] To Decrease The Recurrence Of Pneumothorax In Adults

[0188] Treatment Of Amyotrophic Lateral Sclerosis (Als) Treatment Of Patients 'With Metastatic Non-Small Cell Lung Cancer (Nsclc) Whose Tumors Are

[0189] Anaplastic Lymphoma Kinase (Alk)-Positive As Detected By An Fda-Approved Test

[0190] Optical Imaging Agent Indicated In Patients With Glioma (Suspected World Health

[0191] Organization Grades lii Or Iv On Preoperative Imaging) As An Adjunct For The Visualization Of Malignant Tissue During Surgery

[0192] Dabrafenib In Combination With Trametinib, For The Tx, Of Pts With Metastatic Non-Small Cell Lung Cancer With Braf V600e Mutation As Detected By An Fda- Approved Test

[0193] Trametinib In Combination With Dabrafenib, For The Tx. Of Pts With Metastatic Non-Small

[0194] Cell Lung Cancer With Braf V600e Mutation As Detected By An Fda-Approved Test

[0195] Treatment Of Pediatr ic Pat ients 2 Years Of Age A nd Older With Centra l Precocious Puberty

[0196] To Reduce The Acute Complications Of Sickle Cell Disease In Adult And Pediatric Patients 5 Years Of Age And Older.

[0197] Treatment Of Adult Patients With Relapsed Or Refractory Acute Myeloid Leukemia With An

[0198] Isocitrate Dehydrogenase -2 (Idh2) Mutation As Detected By An Fda-Approved Test

[0199] Treatment Of Adult Patients With Chronic Graft Versus Host Disease (Cgvhd)

[0200] Treatment Of Dyskinesia In Patients With Parkinson’s Disease Receiving Levodopa-Based

[0201] Therapy With Or Without Concomitant Dopaminergic Medications

[0202] For Use In Children Ages 2 To 12 Years Old With Chagas Disease

[0203] Treatment Of Adult Patients With Relapsed Follicular Lymphoma Who Have Received At Least Two Prior Systemic Therapies

[0204] Treatment Of Adults With Carcinoid Syndrome; When Used, It Reduces The Frequency Of

[0205] Short-Acting Somatostatin Analog Rescue Therapy

[0206] For Use As A Nitrogen-Binding Agent For Chronic Management Of Pediatric Patients >=2

[0207] Months And < 2 Years Of Age With Urea Cycle Disorders (Ucds) Who Cannot Be Managed By

[0208] Dietary Protein Restriction And / Or Amino Acid Supplementation Alone

[0209] Treatment Of Patients With Erdheim-Chester Disease With Braf V600 Mutation For Treatment Of Patients With Anaplastic Lymphoma Kinase (Aik) Positive, Metastatic Non- Small-Cell Lung Cancer (Nsclc) As Detected By An Fda Approved Test, Excluding Patients Who Have Progressed On Or Are intolerant To Crizotmib

[0210] For Treatment Of Scurvy In Adult And Pediatric Patients Age 5 Months And Older For Whom Oral Administration Is Not Possible, Insufficient Or Contraindicated

[0211] Treatment Of Pulmonary Arterial Hypertension (Pah) (Who Group 1 ) In Pediatric Patients Aged 3 Yrs And. Older With Idiopathic Or Congenital Pah To Improve Pulmonary Vascular Resistance (Pvr), Which Is Expected To Result In An Improvement In Exercise Ability

[0212] Treatment Of Nephropathic Cystinosis In Pediatric Patients 1 Year Of Age To Less Than 2 Years Of Age

[0213] Treatment Of Adult Patients With Newly-Diagnosed Chronic Phase (Cp) Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia (PhT Cml)

[0214] Treatment Of Pediatric Patients With Philadelphia Chromosome-Positive (Ph-r) Chronic Myeloid Leukemia (Cml) In Chronic Phase

[0215] Prophylaxis Of Cytomegalovirus (Cmv) Infection And Disease In Adult Cmv-Seroposltive Recipients [RT] Of An Allogeneic Hematopoietic Stem Cell Transplant (Hsct)

[0216] Treatment Of Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors (Gep-Nets) Including Foregut, Midgut, And Hindgut Neuroendocrine Tumors In Adults

[0217] Arsenic Trioxide For Use In Combination With Tretinoin For Treatment Of Adults With Newly- Diagnosed Low-Risk Acute Promyelocytic Leukemia (Apl) Whose Apl Is Characterized By The Presence Of The T(15;17) Translocation Or Pml / Rar-Alpha Gene Expression

[0218] For The Maintenance Treatment Of Adult Patients With Recurrent Epithelial O varian, Fallopian Tube. Or Primary Peritoneal Cancer Who Are In A Complete Or Partial Response To Platinum- Based Chemotherapy

[0219] For The Adjunctive Treatment Of Adult And Pediatric Patients Aged 2 Years And Older With Tuberous Sclerosis Complex (Tsc)- Associated Partial-Onset Seizures

[0220] For The Diagnosis Of Adult Growth Hormone Deficiency (Aghd) Treatment Of Pediatric Patients Greater Than Or Equal To 1 Year Of Age Wit h N ewly

[0221] Diagnosed Philadelphia Chromosome Positive Chronic Myeloid Leukemia (Ph+Cml) In Chronic

[0222] Phase

[0223] Treatment Of Pediatric Patients Greater Than Or Equal To 1 Year Of Age With Chronic Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia With Resistance Or Intolerance To Prior Tyrosine-Kinase Inhibitor Therapy

[0224] Treatment Of Patien ts With Cystic Fibrosis Aged 12 Years And Older Who Are Homozygous For The F5O8del Mutation Or Who Have At Least One Mutation In The Cystic Fibrosis Transmembrane Conductance Regulator Gene Responsive To Tezacaftor / lvacaftor

[0225] For The Treatment Of Thrombocytopenia In Adult Patients With Chronic Immune Thrombocytopenia (lip) Who Have Had An Insufficient Response To A Previous Treatment

[0226] Treatment Of Adult Patients With Mantle Cell Lymphoma (Mcl) Who Have Received At Least One Prior Therapy

[0227] Indicated For The First-Line Treatment Of Patients With Metastatic Non-Small Cell Lung Cancer (Nsclc) Whose Tumors Have Epidermal Growth Factor Receptor (Egfr) Exon 19 Deletions Or Exon 21 L858r Mutations, As Detected By An Fda-Approved Test

[0228] To Reduce The Frequency Of Painful Crises And To Reduce The Need For Blood Transfusions hr Pediatric Patients. 2 Years Of Age And Older, With Sickle Cell Anemia With Recurrent Moderate To Severe Painful Crisis

[0229] Indicated To Slo w Kidney Function Decline In Adults At Risk Of Rapidly Progressing Autosomal Dominant Polycystic Kidney Disease (Adpkd)

[0230] Treatment Of Patients With C11 And Treatment Of Patients With Indolent B-Cell Nhl That Has Progressed During Or Within Six Months Of Treatment With Rituximab Or A Rituximab Con tain ing Regimen

[0231] Maintenance Treatment Of Adul t Patients With Recurrent Epithelial Ovarian, Fallopian Tube Or Primary Peritoneal Cancer, Who Are In A Complete Or Partial Response To Platinum-Based Chemotherapy Treatment Of Adult Patients With Deleterious Or Suspected Deleterious Germline Brea-Mutated Advanced Ovarian Cancer Who Ha ve Been Treated With Three Or More Prior Lines Of

[0232] Chemotherapy

[0233] Trametinib Is Indicated, In Combination With Dabrafetub, For The Adjuvant Treatment Of Patients With Melanoma With Braf V600e Or V600k Mutations, As Detected By An Fda- Approved Test, And Involvement Of Lymph Node(S), Following Complete Resection

[0234] Trametinib And Dabrafenib In Combination, For The Treatment Of Patients With Locally Advanced Or Metastatic Anaplastic Thyroid Cancer (Atc) With Braf V600e Mutation And With

[0235] No Satisfactory Locoregional Treatment Options

[0236] Indicated In Combination With Other Antiretroviral Agents For The Treatment Of Pediatric Patients With Hiv-l Infection

[0237] Indicated For The Treatment Of Patients With Chronic Lymphocytic Leukemia (Cll) Or Small Lymphocytic Lymphoma (SIl), With Or Without 17p Deletion, Who Have Received At Least One Prior Therapy

[0238] Treatment Of C ystic Fibrosis (Cf) In Patients Age 6 Years And Older Who Have One Of The Following Mutations In The Cftr Gene: Gl244e, G1349d, G178r, G551s, S1251n, S1255p, S549n, Or S549r

[0239] Treatment Of Cystic Fibrosis (Cf) In Patients Age 6 Years And Older Who Have An R117h Mutation In The Cftr Gene

[0240] Treatment Of Cystic Fibrosis (Cf) In Patients Ages 2 To Less Than 6 Years Who Have One Of The Following Mutations In The Cftr Gene: G55ld, G1244e, G1349d, G178r, G551s, S1251n, S1255p, S549n, S549r, And RH7h

[0241] Treatment Of Cystic Fibrosis (Cf) in Patients Age 2 Years And Older Who Have One Of The Following Mutations In The Cftr Gene: 711+3a-G, E831x, 2789-H5g-A, 3272-26a-G, And 3849+10kbc-T

[0242] Tx Of Cf In Pts 2 Yrs And Older Who Have One Of The Following Mutations In The Cftr Gene: E56k, P67I, R74w, D110e, D1 10h, R117c, E193k, L206w, R347h, R352q, A455e, D579g, S9451, S977f, F1052v, K1060t, A1067t, G1069r, R1070q, R1070w, F10741, D1152h, D1270n To Decrease The Recurrence Of Malignant Pleural Effusions In Symptomatic Patients Following Maximal Drainage Of The Pleural Effusion

[0243] Indicated To Induce Controlled Cardiac Septal Infraction To Improve Exercise Capacity In Adults With Symptomatic Hypertrophic Obstructive Cardiomyopathy Who Are Not Candidates For Surgical Myectomy

[0244] Indicated For The Treatment Of Onchocerciasis Due To Onchocerca Volvulus In Patients Aged 12 Years And Older

[0245] For The Treatment Of Cystic Fibrosis (CI) In Patients Age 2 Through 5 Years Old Who Are Homozygous For The F508del Mutation In The Cftr Gene

[0246] Indicated For The First-Line Treatment Of Patients With Unresec table Hepatocellular Carcinoma (Hcc)

[0247] Indicated For The Treatment Of The Polyneuropathy Of Hereditary Transthyreti n-Mediated Amyloidosis In Adults

[0248] Indicated For The Treatment Of Seizures Associated With Dravet Syndrome (Ds) In Patients 2 Years Of Age And Older Taking Clobazam

[0249] The Treatment Of Cystic Fibrosis (Cf) In Patients Age 12 Months And Older Who Have One Mutation In The Cftr Gene That Is Responsive To Ivacaftor Potentiation Based On Clinical And Or In Vitro Assay Data

[0250] Indicated For The Treatment Of Human Smallpox Disease Caused By Variola Virus In Adults And Pediatric Patients Weighing At Least 13 Kg

[0251] Indicated For The Radical Cure (Prevention Of Relapse) Of Plasmodium Vivax Malaria In Patients Aged 16 Years And Older Who Are Receiving Appropriate Antimalarial Therapy For Acute P. Vivax Infection

[0252] Indicated As A Source Of Calories And Fatty Acids In Pediatric Patients With Parenteral Nutrition-Associated Cholestasis (Pnac)

[0253] Indicated For The Treatment Of Adult Patients With Relapsed Or Refractory' Acute Myeloid Leukemia (Ami) With A Susceptible Isocitrate Dehydrogenase- 1 (Idhl) Mutation As Detected By An Fda-Approved Test

[0254] Treatment Of Adult And Pediatric Patients 12 Years And Older With lobenguane Scan Positive;

[0255] Uaresectable, Locally Advanced Or Metastatic Pheochromocytoma Or Paraganglioma Who Require Systemic .Anticancer Therapy

[0256] Indicated For The Treatment Of Adults With A Confirmed Diagnosis Of Fabry Disease And An Amenable Galactosidase Alpha Gene (Gia) Variant Based On In Vit.ro Assay Data

[0257] First-Line Treatment Of Patients With Metastatic Non-Small Cell Lung Cancer (Nsclc) With Epidermal Growth Factor Receptor (Egfr) Exon 19 Deletion Or Exon 2.1 L858r Substitution Mutations As Detected By An Fda-Approved Test

[0258] Treatment Of Status Epilepticus In Adults

[0259] Treatment Of Adult Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia (Oil) Or Small Lymphocytic Lymphoma (Sil) After At Least Two Prior Therapies

[0260] Treatment Of Adult Patients With Relapsed Or Refractory Follicular Lymphoma (Fl) After At Least Two Prior Systemic Therapies

[0261] Indicated In Combination With Standard Immunosuppressive Therapy For The First-Line

[0262] Treatment Of Adult And Pediatric Patients 2 Years And Older With Severe Aplastic Anemia

[0263] Indicated In Combo With Azacitidine, Or Decitabine, Or Low-Dose Cytarabine For The Tx Of Newly-Diagnosed Acute Myeloid Leukemia In Adults Who Are Age 75 Years Or Older, Or Who Have Comorbidities That Preclude Use Of Intensive Induction Chemotherapy

[0264] Indicated For The Treatment O f The Polyneuropathy Of Hereditaiy Transthyretin-Merli.ated .Amyloidosis In Adults

[0265] Indicated For The First-Line Treatment Of Patients With Metastatic Non-Small Cell Lung Cancer (Nsclc) With Epidermal Growth Factor (Egfr) Exon 19 Deletion Or Exon 21 L858r Substitution Mutations As Detected By An Fda-Approved Test

[0266] Tx Of Mac Lung Disease In Adults With Limited Or No Alternative Tx Options As Part Of A Combo Antibacterial Drug Regimen Who Do Not Achieve Negative Sputum Cultures After A Minimum Of 6 Consecutive Months Of A Multi drug Background Regimen Therapy Indicated For The Treatment Of Adult And Pediatric Patients With Solid Tumors That Have A Neurotrophic Receptor Tyrosine Kinase (Ntrk) Gene Fusion Without A Known Acquired Resistance Mutation

[0267] Indicated For The Treatment Of Seizures Associated With Lennox-Gastaut Syndrome (Lgs) Or Dravet Syndrome (Ds) In Patients 2 Years Of Age And Older

[0268] Indicated For The Treatment O f Patients With Anaplastic Lymphoma Kinase (Alk)-Positive Metastatic Non-Small Cell Lung Cancer (Nsclc) Whose Disease Has Progressed On Crizotinib And At Least One Other Aik Inhibitor For Metastatic Diesase

[0269] Indicated For The Treatment Of Patients With Anaplastic Lymphoma Kinase (Alk)-Positive Metastatic Non-Small Cell Lung Cancer (Nsclc) Whose Disease Has Progressed On Alectinib As The First Alk Inhibitor Therapy For Metastatic Disease

[0270] Indicated For The Treatment Of Patients With Anaplastic Lymphoma Kinase (Alk)-Positive

[0271] Metastatic Non-Small Cell Lung Cancer (Nsclc) Whose Disease Has Progressed On Ceritinib As The First Alk Inhibitor Therapy For Metastatic Disease

[0272] Indicated For The Treatment Of Adult And Pediatric Patients With Solid Tumors That Are Metastatic Or Where Surgical Resection Is Likely To Resul t In Severe Morbidity

[0273] Indicated For The Treatment Of Adult And Pediatric Patients With Solid Tumors That Have No Satisfactory Alternative Treatments Or That Have Progressed Following Treatment

[0274] Indicated For The Treatment Of Adult Patients Who Have Relapsed Or Refractory Acute Myeloid Leukemia (Aml) With A Fms-Like Tyrosine Kinase 3 (Flt3) Mutation As Detected By An Fda-Approved Test

[0275] Treatment Of Lambert-Eaton Myasthenic Syndrome (Lems)

[0276] Indicated, In Combination With Low-Dose Cytarabine, For The Treatment Of Newly-Diagnosed Acute Myeloid Leukemia (Aml) In Adult Patients Who Are >=75 Years Old Or Who Have Comorbidities That Preclude Use Of Intensive Induction Chemotherapy

[0277] Indicated For The Treatment Of Pediatric Patients 1 Year Of Age And Older With Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (All) In Combination With Chemotherapy

[0278] Maintenance Treatment Of Adults With Deleterious Or Suspected Deleterious Germline Or Somatic Brea-Mutated Advanced Epithelial Ovarian, Fallopian Tube, Or Primary Peritoneal Cancer In Complete Or Partial Response To First-Line Platinum-Based Chemotherapy

[0279] Indicated For Treatment Of Patients With Hepatocellular Carcinoma (Hcc) Who Have Been Previously Treated With Sorafenib

[0280] Indicated For The Treatment Of Fascioliasis In Patients 6 Years Of Age And Older

[0281] Treatment Of Adult Patients With Metastatic Gastric Or Gastroesophageal Junction Adenocarcinoma Previously Treated With At Least Two Prior Lines Of Chemotherapy, And If Appropriate, Her2 / Neu-Targeted Therapy

[0282] First-Line Treatment Of Metastatic Non-Small Cell Lung Cancer Whose Tumors Have Non- Resistant Epidermal Growth Factor (Egfr) Mutations Other Than Exon 19 Deletions Or Exon 21 (L858r) Substitution Mutations As Detected By An Fda-Approved Test

[0283] Indicated For The Treatment Of Cataplexy Or Excessive Daytime Sleepiness (Eds) In Pediatric Patients 7 Years Of Age And Older With Narcolepsy

[0284] Treatment Of Pediatric Patients 12 Years And Older Or Weighing At Least 45 Kg With Chronic Hepatitis C Virus (Hcv) Genotype 1,2, 3,4,5 Or 6 Infection Without Cirrhosis Or With Compensated Cirrhosis (Child- Pugh A)

[0285] Treatment Of Pediatric Patients 12 Years And Older Or Weighing At Least 45 Kg With Hev Genotype 1 Infection, Who Previously Have Been Treated With A Regimen Containing An Hcv Ns5a Inhibitor Or An Ns3 / 4a Protease Inhibitor (Pi), But Not Both

[0286] Indicated For The Treatment Of Stable Symptomatic Heart Failure Due To Dilated Cardiomyopathy (Dcm) In Pediatric Patients Aged 6 Months And Older, Who Are In Sinus Rhythm With An Elevated Heart Rate

[0287] Indicated For The Treatment Of Acute Herpetic Keratitis (Dendritic Ulcers) In Patients With Herpes Simplex (Hsv-1 And Hsv-2) Vims

[0288] Treatment Of Cystic Fibrosis (Cf) In Patients Age 6 Months To Less Than 12 Months Who Have One Mutation In The Cftr Gene That Is Responsive To Ivacaftor Potentiation Based On Clinical And. Or In Vitro Assay Data

[0289] Treatment Of The Cardiomyopathy Of Wild Type Or Hereditary Transthyretin-Mediated Amyloidosis (.Atr-Cm) In Adults To Reduce Cardiovascular Mortality And Cardiovascular- Related Hospitalization

[0290] Treatment Of Steroid-Refractory Acute Graft- Versus-Host Disease (Gvhd) In Adult And Pediatric Patients 12 Years And Older

[0291] Treatment Of Previously Untreated Adult Patients With Chronic Lymphocytic Leukemia (Cll) Or Small Lymphocytic Lymphoma (S1I)

[0292] Treatm ent Of Pediatric Patients I Year Of Age And Older With Short Bowel Syndrome (Sbs ) Who Are Dependent On Parenteral Support

[0293] Indicated In Combination With A Rituximab Product For The Treatment Of Adult Patients With Previously Treated Follicular Lymphoma (Fl)

[0294] Tx Of Newly-Diagnosed Acute Myeloid Leukemia With A Susceptible Isocitrate Dehydrogenase- 1 .Mutation As Detected By An Fda- Approved Test In Adult Pts Who Are >-75 Yrs Old Or Who Have Comorbidities That Preclude Use Of Intensive Induction Chemotherapy

[0295] Acute Treatment. Of Intermittent, Stereotypic Episodes Of Frequent Seizure Activity (I.E., Seizure Clusters, Acute Repetitive Seizures) That Are Distinct From A Patient's Usual Seizure Pattern In Patients With Epilepsy 12 Years Of Age And Older

[0296] Treatment Of Lambert-Eaton Myasthenic Syndrome (Lems) In Patients 6 To Less Than 17

[0297] Years Of Age

[0298] Indicated In Combination With A Rituximab Product For The Treatment Of Adult Patients With Previously Treated Marginal Zone Lymphoma (Mzl)

[0299] Treatment Of Thrombocytopenia In Adult Patients With Chronic Immune Thrombocytopenia Who Have Had An Insufficient Response To A Previous Treatment

[0300] Tx Of Pts W7 Cystic Fibrosis (Cf) Age 6 To <12 Yrs Who Are Homozygous For The F508deI

[0301] Mutation Or W / At Least 1 Mutation In Cf Transmembrane Conductance Regulatory Gene Responsive To Tezacaftor / lvacaftor Based On In Vitro Data And / Or Clinical Evidence

[0302] Treatment Of Adult Patients With Oral Ulcers Associated With Behcets Disease

[0303] Treatment Of Patients With Cystic Fibrosis (Cf) Age 6 Years To Less Than 12 Years Who Are Homozygous For F508del Mutation Or Who Have At Least One Mutation In The Cf Transmembrane Conductance Regulator Gene That Is Responsive To Tezacaftor / Ivacaftor

[0304] Indicated For The Treatment Of Adult Patients With Symptomatic Tenosynovial Giant Cell Tumor (Tgct) Associated With Severe Morbidity Or Functional Limitations And Not Amenable To Improvement With Surgery

[0305] Indicated As Part Of Combination Therapy In The Treatment O f Pedi atric Patients (12 To Less Than 18 Years Of Age And Weighing At Least 30 Kg) W ith Pulmonary Multi-Drag Resistant Tuberculosis

[0306] Treatment Of Duchene Muscular Dystrophy In Patients 2 Years Of Age To Less Than 5 Years Of A ge

[0307] Indicated As Part Of A Combination Regimen With Bedaquiline And Linezolid For The Treatment Of Adults With Pulmonary Extensively Drug Resistant (Xdr) Or Treatment-Intolerant Or Nonresponsive Multidnig-Resistant (Mdr) Tuberculosis (Tb)

[0308] Indicated To Improve Wakefulness In Adult Patients With Excessive Daytime Sleepiness Associated With Narcolepsy

[0309] Indicated For The Treatment Of Excessive Daytime Sleepiness (Eds) In Adult Patients With Narcolepsy

[0310] For Hiv-1 Infection In Pediatric Pts At Least 25 Kg W / No Antiretroviral (Arv) Tx H x Or To Replace Current Arv Regimen For Virologically-Suppressed On Stable Arv W7 No Hx Tx Failure And No Known Substitutions Associated W / Resistance To Bic. Ftc, Or Taf In Combo W / Dexamethasone For Adults W / Relapsed Or Refractory Multiple Myeloma Who Received At Least 4 Prior Therapies And Refractory To At Least 2 Proteasome Inhibitors, At Least 2 Immunomodulatory Agents, And An Anti-Cd38 Monoclonal Antibody

[0311] For The Treatment. Of Chronic Hepatitis C Virus (Hcv) Genotype 2 Or 3 Infection In Pediatric Patients Between 3 Years Of Age And 12 Years Of Age Or Weighing 35 Kg Without Cirrhosis

[0312] Or With Compensated Cirrhosis For Use In Combination With Ribavirin

[0313] Indicated For The Treatment Of Adult Patients With Intermediate-2 Or High-Risk Primary Or Secondary (Post-Polycythemia Vera Or Post-Essential Thrombocythemia) Myelofibrosis (Mf)

[0314] Indicated To Increase Systemic Exposure Of Atazanavir In Combination With Other Antiretroviral Agents In The Treatment Of Hiv-1 Infection In Pediatric Patients Weighing At Least 35 Kg

[0315] Indicated To Slow The Rate Of Decline In Pulmonary Function In Patients With Systemic Sclerosis-Associated Interstitial Lung Disease (Ssc-Ild)

[0316] Treatment Of Pediatric Patients Between 3 Years Of Age And 12 Years Of Age Or Weighing 35

[0317] Kg With Chronic Hepatitis C Virus (Hcv) Genotype 1 , 4, 5, Or 6 Infection Without Cirrhosis Or With Compensated Cirrhosis

[0318] Treatment Of Pediatric Patients 3 Years Of Age And Older With Chronic Hcv Genotype 1

[0319] Infection With Decompensated Cirrhosis, For Use In Combination With Ribavirin

[0320] Treatment Of Pediatric Patients 3 Years Of Age And Older With Chronic Hcv Genotype 1 Or 4 Infection Who Are Liver Transplant Recipients Without Cirrhosis Or With Compensated

[0321] Cirrhosis, For Use In Combination With Ribavirin

[0322] Indicated For The Treatment Of Adult Patients With Metastatic Non-Small Cell Lung Cancer (Nsclc) Whose Tumors Are Ros 1 -Positive

[0323] Adult & Ped >=12yrs Old W / Solid Tumors That Have Ntrk W / O Known Acquired Resistance Mutation, Are Metastatic Or Where Surgical Resection Is Likely To Result In Severe Morbidity & Have Either Progressed Following Tx Or Have No Satisfactory Alternative Tx

[0324] Indicated In Combination With High Fluid Intake, Alkali, And Diet Modification, For The Prevention Of Cy stine Sto ne Formation In Pediatric Patients 2 dkg To 9 Y ears O f Age W / Severe Homozygous Cystinuria, Who Are Not Responsive To These Measures Alone

[0325] Indicated For Treatment Of Patients With Cushing’s Disease For Whom Pituitary Surgery Is Not An Option Or Has Not Been Curative Prophylaxis Of Organ Rejection In Pediatric Patients Receiving Allogeneic Kidney Transplant, Liver Transplants, And Heart Transplant, In Combination With Other Immunosuppressants

[0326] Indicated To Increase Pain Free Light Exposure In Adult Patients With A History Of Photo toxic Reactions From Erythropoietic Protopoiphyria (Epp)

[0327] Indicated In Combination With Other Anti-Myeloma Products For The Treatment Of Adults With Multiple Myeloma (Mm)

[0328] Indicated For The Treatment Of Pulmonary Arterial Hypertension (Pah) (Who Group I) To Delay Disease Progression

[0329] Indicated For The Treatment Of Adults With Acute Hepatic Porphyria (Ahp)

[0330] Indicated For The Treatment Of Adult Patients With Chronic Lymphocytic Leukemia (Cll) Or Small Lymphocytic Lymphoma (SII)

[0331] Indicated For The Treatment Of Cystic Fibrosis (Cf) In Patients Aged 12 Years And Older Who Have At Least One F508de1 Mutation In The Cystic Fibrosis Transmembrane Conductance Regulator (C'ftr) Gene

[0332] Indicated For The Treatment Of Adult Patients With Mantle Cell Lymphoma (Mel) Who Have Received At Least One Prior Therapy

[0333] Tx Of Adults W / Adv Ovarian, Fallopian Tube, Or Primary Peritoneal Cancer Treated WZ >=3 Prior Chemo Regimens & Cancer Associated WZ Hrd+ Status Defined By A Deleterious Or Suspected Deleterious Brea Mutation

[0334] Tx Of Adults W / Adv Ovarian, Fallopian Tube, Or Primary Peritoneal Cancer Treated WZ Prior Chemo Regimens & Cancer Associated WZ Hrd+ Stains Defined By Genomic Instability & Progressed >6 Months After Response To The Last Platinum-Based Chemotherapy

[0335] Indicated For The Acute Tx Of Intermittent, Stereotypic Episodes Of Frequent Seizure Activity (I.E. Seizure Clusters, Acute Repetitive Seizures) That Are Distinct From A Patient’s Usual Seizure Pattern In Patients With Epilepsy 6 Years Of Age And Older

[0336] Indicated For The Treatment Of Duchenne Muscular Dystrophy (Dmd) In Patients Who Have A Confirmed Mutation Of The Dmd Gene That Is Amenable To Exon 53 Skipping Indicated For The Treatment Of Sickle Cell Disease (Scd) In Adults And Pediatric Patients 12 Years Of Age And Older

[0337] Indicated To Selectively Stain The Internal Limiting Membrane (IIm)

[0338] Maintenance Tx Of Adults W / Deleterious Or Suspected Deleterious Gbrcatn Metastatic Pancreatic Adenocarcinoma Whose Dz Has Not Progressed On >= 1 dwks Of 1st Line Platinum Based Chemo Regimen. Select Pts For Therapy Based On Approved Companion Diagnostic

[0339] In Combination With Other Antiretroviral Agents, For The Treatment Of Hi v-i Infection In Pediatric Patients Under 12 Years Of Age Weighing At Least 35kg

[0340] In Combination With Other Antiretroviral Agents Other Than Protease inhibitors That Require A Cyp3a Inhibitor, For The Treatment Of Hiv-1 Infection In Pediatric Patients Under 12 Years Of Age Weighing At Least 25kg And Less Than 35kg

[0341] Indicated For The Treatment Of Adult Patients With Cushing’s Disease For Whom Pituitary Surgery Is Not An Option Or Has Not Been Curative

[0342] Treatment. Of Adults With Newly Diagnosed Therapy -Related Acute Myeloid Leukemia (T- Aml) Or Ami With Myelodysplasia-Related Changes (Aml-Mrc)

[0343] Indicated For The Treatment Of Pediatric Patients 2 Years Of Age And Older With Nemofibromatosis Type 1 (Nfl) Who Have Symptomatic, Inoperable Plexiform Neurofibromas (Pn)

[0344] Indicated For The Treatment Of Adult Patients With Low-Grade Upper Tract Urothelial Cancer (Lg-Utuc)

[0345] Indicated For The Initial Treatment Of Severe Malaria In Adult And Pediatric Patients To

[0346] Always Be Followed By A Complete Treatment Course Of An Appropriate Oral Antimalarial Regimen

[0347] Indicated For The Treatment Of Adult Patients With Metastatic Non-Small Cell Lung Cancer (Nsclc) Whose Tumors Have A Mutation That Leads To Mesenchymal-Epithelial Transition ( Met) Exon 14 Skipping As Detected By An Fda- Approved Test

[0348] Indicated For The Treatment Of Adults With Previously Treated, Unresectable Locally Advanced Or Metastatic Cholangiocatcinoma With A Fibroblast Growth Factor Receptor 2 (Fgfr2) Fusion Or Other Rearrangement As Detected By An Fda-Apptoved Test.

[0349] Tx Of Ped Pts 6 Yrs Of Age & Older Or Weighing At Least 17 Kg With Chronic Hepatitis C Virus Genotype 1, 2, 3, 4, 5, Or 6 Infection; Without Cirrhosis Or With Compensated Cirrhosis;

[0350] Or With Decompensated Cirrhosis For Use In Combination With Ribavirin

[0351] Prophylaxis Of Organ Rejection In Pediatric Patients Recei ving Allogeneic Kidney Or Heart Transplants, In Combination With Other Immunosuppressants

[0352] Indicated For The Maintenance Treatment Of Adult Patients With Advanced Epithelial Ovarian Cancer Who Are In A Complete Or Partial Response To First-Line Platinum-Based Chemotherapy

[0353] Indicated For T he Treatment Of Adult Patients With Aids-Related Kaposi Sarcoma (Ks) After Failure Of Highly Active Antiretroviral Therapy (Haart)

[0354] For The Treatment Of Kaposi Sarcoma (Ks) In Adult Patients Who Are Hiv-Negaiive

[0355] Indicated For The Treatment Of Adult Patients With Advanced Gastrointestinal Stromal Tumor (Gist) Who Have Received Prior Treatment With 3 Or More Kinase Inhibitors, Including Imatinib

[0356] Indicated For The Treatment Of Adults And Pediatric Patients Aged 16 Years And Older With Metastatic Or Locally Advanced Epithelioid Sarcoma Not Eligible For Complete Resection

[0357] For The Treatment Of Adult Patients With Anaplastic Lymphoma Kinase (Alk)-Positive Metastatic Non-Small Cell Lung Cancer (Nsclc) As Detected By An Fda-Approved Test, Not Including Patients Who Have Progressed On Or Are Intolerant To Crizotinib

[0358] Indicated For The Treatment Of Adult Patients With Metastatic Ret Fusion-Positive Non-Small Cell Lung Cancer (Nsclc)

[0359] Indicated For The Treatment Of Adult And Pediatric Pa tients 12 Years Of Age And Older With Advanced Or Metastatic Ret-Mutant Medullary Thyroid Cancer (Mtc) Who Require Systemic Therapy Adult And Pediatric Patients 12 Years Of Age And O lder W ith Advan ced Or Metastatic Ret Fusion-Positive Thyroid Cancer Who Require Systemic Therapy And Who Are Radioactive

[0360] Iodine-Refractory (If Radioactive Iodine Is Appropriate)

[0361] Indicated For The Treatment Of Adult Patients With Metastatic Small Cell Lung Cancer (Sclc) With Disease Progression On Or After Platinum-Based Chemotherapy

[0362] Treatm ent Of Invasive Aspergillosis

[0363] W / Bevacizumab For Maint Tx Of Adults W / Adv Epithelial Ovarian, Fallopian Tube, Or Primary Peritoneal Ca In Complete Or Partial Response To 1st Line Pt Based Chemo & Whose Ca Is Assoc W / Homologous Recomb Def + Status Defined By Genomic Instability

[0364] Indicated As Part Of Combination Therapy In The Treatment Of Pediatric Patients 5 Years And Older To Less Than 12 Years Of Age And Weighing At Least 15 Kg With 'Pulmonary M ulti - Drug Resistant Tuberculosis (Mdr-Tb)

[0365] Treatment Of Pulmonary Arterial Hypertension (Pah) (Who Group I) To Improve Exercise Capacity

[0366] Indicated For Use In Combination With Trastuzumab And Capecitabine For Treatment Of Adult Patients With Metastatic H.er2~Positive Breast Cancer And Brain Metastases, Who Have Received One Or More Prior Anti-Her2 -Based Regimens In The Metastic Setting

[0367] Indicated For The Treatment Of Adult Patients With Relapsed Or Refractory Diffuse Large B- Cell Lymphoma (Dlbcl), Not Otherwise Specified, Including Dlbcl Arising From Follicular Lymphoma, After At Least 2 Lines Of Systemic Therapy

[0368] Indicated As A Source Of Calories And Fatty Acids For The Treatment Of Pediatric And Adult Patients With Molecularly Confirmed Long-Chain Fatty Acid Oxidation Disorders (Lc-Faod)

[0369] Indicated For The Treatment Of Seizures Associated With Dravet Syndrome In Patients 2 Years Of Age And Older

[0370] Indicated For The Treatment Of Adult And Pediatric Pa tients 12 Years Of Age And Older With Solid Tumors That Have A Neurotrophic Tyrosine Receptor Kinase (Ntrk) Gene Fusion Without A Known Acquired Resistenaee Mutation, Are Metastatic Or Where Surgical Resection Is Likely To Result In Severe Morbidity, And Have Either Progressed Following Treatment Or Have No Satisfactory Alternative Therapy

[0371] Indicated For The Treatment Of Adult Patients With Relapsed Or Refractory Follicular Lymphoma Whose Tumors Are Positive For An Ezh2 Mutation As Detected By An Fda- Approved Test And Who Have Received At Least 2 Prior Systemic Therapies, And For The Treatment Of Adult Patients With Relapsed Or Refractory Follicular Lymphoma Who Have No Satisfactory Alternative Treatment Options

[0372] For Cl eans ing Of The Colon As A Preparation For Colonoscopy In Pediatri c Patients 12 Years Of Age And Older

[0373] Treatment Of Adult Patients With Myelodysplastic Syndromes (Mds), Including Previously Treated And Untreated, De Novo And Secondary Mds With The Following French-American- British Subtypes (Refractory Anemia, Refractory Anemia With Ringed Sideroblasts, Refractory Anemia With Excess Blasts, And Chronic Myelomonocytic Leukemia [Cmml]) And Intermediate- 1 , Intermediate-2, And High-Risk International Prognostic Scoring System Groups.

[0374] For Use With Positron Emission Tomography (Pet) For Localization Of Somatostatin Receptor Positive Neuroendocrine Tumors (Nets) In Adult Patients

[0375] Treatment. Of Adult Patients Wi th Metastatic Ret Fusion-Positive Non-Small Cell Lung Cancer (Nsdc) As Detected By An Fda Approved Test

[0376] Indicated In Pediatric Patients (Birth To Less Than 18 Years Of Age And Weighing At Least 2,5 Kg) For The Treatment Of Chagas Disease (American Trypanosomiasis) Caused By

[0377] Trypanosoma Cruzi

[0378] Indicated For Continued Treatment: Of Adult Patients With Acute Myeloid Leukemia Who Achieved First Complete Remission (Cr) Or Complete Remission With Incomplete Blood Count Recovery (Cri) Following Intensive Induction Chemotherapy And Are Not Able To Complete Intensive Curative Therapy

[0379] Treatment Of Cystic Fibrosis (Cf) In Patients Age 4 Months To Less Than 6 Months Who Have One Mutation In The Cftr Gene That Is Responsive To Ivacaftor Potentiation Based On Clinical And / Or In Vitro Assay Data

[0380] Treatment Of Cystic Fibrosis (Cf) In Patients Aged 12 Years And Older W ho Have A Mutation In The Cystic Fibrosis Transmembrane Conductance Regulator (Cftr) Gene That Is Responsive Based On In Vitro Data

[0381] Treatment Of Hutchinson-Gilford Progeria Syndrome (Hgps) And Progeroid Laminopathies

[0382] Treatment Of Adult Patients With Metastatic Non-Small Cell Lung Cancer (Nsclc) Harboring Mesenchymal-Epithelial Transition (Met) Exon 14 Skipping Alterations

[0383] Treatment Of Seizures Associated With Lennox -Gastaut Syndrome (Lgs) Or Dravet Syndrome (Ds) In Patients Between 1 And 2 Years Of Age

[0384] Add-On M aintenance Therapy To Improve Pulmonary' Function In Adult Patients 18 Year's Of Age And Older With Cystic Fibrosis And Who Have Passed The Bronchitol Tolerance Test

[0385] Treatment Of Pediatric Patients 1 Year Of Age And Older And Young Adults With Relapsed Or Refractory, Systemic Anaplastic Large Cell Lymphoma (Alcl) That Is Aik-Positive

[0386] For The Treatment Of Nighttime Sleep Disturbances In Smith-Magenis Syndrome (Sms) In Pediatric Patients 3 To 15 Years Of Age

[0387] The Treatment Of Nighttime Sleep Disturbances In Smith-Magenis Syndrome (Sms) In Patients 16 Years Of Age And Older

[0388] Treatment Of Seizures Associated With Tuberous Sclerosis Complex (Tse) In Patients 1 Year Of Age And Older

[0389] Prophylaxis To Prevent Attacks Of Hereditary Angioedema (Hae) In Adults And Pediatric Patients 12 Years Of Age And Older

[0390] Treatment O f Spinal Muscular Atrophy (Sma) In Patients 2 Months Of Age And Older

[0391] For Treatment Of Cystic Fibrosis (Cf) In Patients Age 6 Years And Older Who Have At Least One Of The Additional Mutations In The Cystic Fibrosis Transmembrane Conductance Regulator (Cftr) Gene That Have Been Identified As Responsive To Tezacaftor / Ivacaftor Based

[0392] On In Vitro Data And Identified In The Approval On December 21, 2020

[0393] Indicated For Chronic Weight Management In Adult And Pediatric Patients 6 Years Of Age And

[0394] Older With Obesity Due To Proopiomelanocortin (Pome), Proprotein Convertase Subtilisin / Kexin Type I (PcskI ), Or Leptin Receptor (Lepr) Deficiency Confirmed By Genetic Testing Demonstrating Variants In Pomc, PcskL Or Lepr Genes That Are Interpreted As Pathogenic, Likely Pathogenic, Or Of Uncertain Significance (Vus)

[0395] For Adjuvant Therapy After Tumor Resection In Adult Patients With Non- Small Cell Lung Cancer (Nsclc) Whose Tumors Have Epidermal Growth Factor Receptor (E-gfr) Exon 19 Deletions Or Exon 21 L858r Mutations, As Detected By An Fda-Approved Test

[0396] For The Treatment Of Cystic Fibrosis (Cl) In Patients Age 4 Months And Older Who Have One Of The Additional Mutations In T he Cystic Fibrosis Transmembrane Conductance Regulator (Cftr) Gene That Have Been Identified As Responsi ve To Ivacaftor Potentiation Based On In Vitro Data And Identified In The Approval On December 21 , 2020

[0397] Treatment Of Primary Hyperoxaluria Type 1 (Ph 1) To Lower Urinary Oxalate Levels In Pediatric And Adult Patients

[0398] Treatment Of Adult And Pediatric Patients 12 Years Of Age And Older With Advanced Or Metastatic Ret-Mutant Medullary Thyroid Cancer (Mtc) Who Require Systemic Therapy

[0399] Treatment Of Adult And Pediatric Patients 12 Years Of Age And Older With Advanced Or Metastatic Ret Fusion-Positive Thyroid Cancer Who Require Systemic Therapy And Who Are Radioactive Iodine- Refractory (If Radioactive Iodine Is Appropriate)

[0400] Indicated To Reduce The Risk Of Mortality In Patients With Molybdenum Cofactor Deficiency (Mocd) Type A

[0401] For Treatment Of Adult Patients With Relapsed Or Refractory Marginal Zone Lymphoma (Mzl) Who Have Received At Least One Prior Anti-Cd20-Based Regimen

[0402] For Treatment Of Adult Patients With Relapsed Or Refractory Follicular Lymphoma (Fl) Who Have Received At Least Three Prior Lines Of Systemic Therapy

[0403] In Pediatric And Adult Patients As Adjunctive Therapy To Standard Of Care For The Treatment Of Acute Hyperammonemia Due To Propionic Acidemia (Pa) Or Methylmalonic Acidemia (Mma)

[0404] For The Treatment Of Adult Patients With Multiple Myeloma Who Have Received At Least One Prior Therapy, Excluding Adult Patients Covered By Xpovio's Previous Indication For Multiple Myeloma Approved On July 3, 2019

[0405] Treatment Of Duchenne Muscular Dystrophy (Dmd) .In Patients Who Have A Confirmed Mutation Of The Dmd Gene That Is Amenable To Exon 45 Skipping

[0406] Treatment Of Adult Patients With Relapsed Or Refractory Multiple Myeloma Who Have Received At Least Four Prior Lines Of Therapy And Whose Disease Is Refractory To At Least. One Proteasome Inhibitor, One Immunomodulatory Agent, And One Cd-38 Directed Monoclonal Antibody

[0407] Treatment Of Adult Patients With Metastatic Non-Small Cell Lung Cancer (Nsclc) Whose Tumors Are Anaplastic Lymphoma Kinase (Alk)-Positive As Detected By An Fda-Approved Test, Excluding Patients Whose Disease Has Progressed On Crizotinib And At Least One Other Aik Inhibitor For Metastatic Disease; Or Alectinib Or Ceritinib As The First Aik Inhibitor Therapy For Metastatic Disease

[0408] Treatment Of Newly-Diagnosed Therapy-Related Acute Myeloid Leukemia (T-AmI) Or Ami With Myelodysplasia-Related Changes (Aml-Mrc) In Pediatric Patients Ages I Year And Older

[0409] Treatment Of Adult Patients Wi th Paroxysmal Nocturnal Hemoglobinuria (Pnh)

[0410] Treatment Of Adult Patients With Kras G12c-Mutated Locally A dvanced Or Metastatic NonSmall Cell Lung Cancer (Nsclc), As Determined By An Fda-Approved Test, Who Have Received At Least One Prior Systemic Therapy

[0411] For Treatment Of Adults With Previously Treated, Unresectable Locally Advanced Or Metastatic Cholangiocarcinoma With A Fibroblast Growth Factor Receptor 2 (Fgfr2) Fusion Or Other Rearrangement As Detected By An Fda-Approved Test

[0412] Treatment Of Human Smallpox Disease Caused By Variola Virus In Adult And Pediatric Patients, Including Neonates

[0413] For The Treatment Of Invasive Aspergillosis In Adults And Pediatric Patients 13 Years Of Age And Older

[0414] For The Treatment Of Adult Patients With Advanced Systemic Mastocytosis (Advsm). Advsm Includes Patients With Aggressive Systemic Mastocytosis (Asm), Systemic Mastocytosis With

[0415] An. Associated Hematological Neoplasm (Sm-Ahn), And Mast Cell Leukemia (Mel)

[0416] For The Treatment Of Cystic Fibrosis (Cf) In Patients Aged 6 Through 11 Years Old Who Have At Least One F508deI Mutation In The Cystic Fibrosis Transmembrane Conductance Regulator (Cftr) Gene Or A. Mutation In The Cftr Gene That Is Responsive Based On In Vitro Data

[0417] For The Treatment Of Verna! Keratoconjunctivitis (Vkc) In Children And Adults

[0418] For The Treatment Of Both The First-Stage (Hemolymphatic) And Second-Stage (Meningoencephalitic) Human Aftican Trypanosomiasis (Hat) Due To Trypanosoma Brunei Gambiense In Patients 6 Years Of Age And Older And Weighing At Least 20 Kg

[0419] For Prophylaxis Of Organ Rejection In Adult And Pediatric Patients Receiving Allogeneic Lung Transplant

[0420] Treatment Of Adult And Pediatric Patients 12 Years And Older With Chronic Graft- Versus- Host Disease (Chronic Gvhd) After Failure Of At Least Two Prior Lines Of Systemic Therapy

[0421] Treatment. Of Pruritus In Patients 3 Months Of Age And Older With Progressive Familial Intrahepatic Cholestasis (Pile)

[0422] Treatment Of Adult Patients With Von Hippel-Liudau (Vhl) Disease Who Require Therapy For Associated Renal Cell Carcinoma (Rcc), Central'Nervous System (Cns) Hemangioblastomas, Or Pancreatic Neuorendocrine Tumors (Pnet), Not Requiring Immediate Surgery

[0423] Treatment Of Adult Patients With Von Hippel-Lindau ( Vhl) Disease Who Require Therapy For Associated Renal Cell Carcinoma (Rcc), Central Nervous System (Cns) Hemangioblastomas, Or Pancreatic Neuroendocrine Tumors (Pnet), Not Requiring Immediate Surgery

[0424] Indicated For The Treatment Of Adults With Unresectable Or Metastatic Gist Harboring A Platelet- Derived Growth Factor Receptor Alpha (Pdgfta) Exon 18 Mutation, Including Pdgfra D842v Mutations

[0425] Pediatric Patients Aged 6 Months And Older For The Treatment Of C. Difficile-Associated Diarrhea (Cdad)

[0426] Treatment Of Adult Patients With Previously Treated, Locally Advanced Or Metastatic Cholangiocarcinoma With An Isocitrate Dehydrogenase- 1 (Idhl) Mutation As Detected By An Fda- Approved Test.

[0427] The Treatment Of Idiopathic Hypersomnia (Ih) In Adults

[0428] Treatment Of Adult Patients With Relapsed Or Refractory Marginal Zone Lymphoma (Mzl) Who Have Recei ved At Least One Anti-CdTO-Based Regimen

[0429] Treatment Of Adult Patients With Waldenstrom’s Macroglobulinemia (Wm)

[0430] For Treatment Of Pediatric Patients 3 Years Of Age To Less Than 12 Years Of Age Weighing Less Than 45 Kg With Chronic Hepatitis C Virus (Hcv) Genotype L 2, 3, 4, 5 Or 6 Infection Without Cirrhosis Or With Compensated Cirrhosis (Child-Pugh A); And Treatment Of Pediatric Patients 3 Years Of Age To Less Than 12 Years Of Age Weighing Less Than 45 Kg With Hcv Genotype 1 Infection, Who Previously Have Been Treated With A Regimen Containing An Hcv Ns5a Inhibitor Or An Ns3 / 4a Protease Inhibitor (Pi), But Not Both

[0431] Treatment Of Chronic Graft-Versus-Host Disease (Cgvhd) After Failure Of One Or Two Lines Of Systemic Therapy In Adult And Pediatric Patients 12 Years And Older

[0432] Treatment Of Adult Patients With Locally Advanced Or Metastatic Nou-Small Cell Lung Cancer (Nsclc) With Epidermal Growth Factor Receptor (Egfr) Exon 20 Insertion Mutations, As Detected By An Fda-Approved Test, Whose Disease Has Progressed On Or After Platinum- Based Chemotherapy

[0433] The Treatment Of Adult And Pediatric Patients 12 Years Of Age And Older With Locally Advanced Or Metastatic Differentiated Thyroid Cancer (Die) That Has Progressed Following Prior Vegfr-Targeied Therapy And Who Are Radioactive Iodine-Refractory Or Ineligible

[0434] For Treatment Of Pediatric Patients 3 Years Of Age To Less Than 6 Years Of A ge Weighing Less Than 17 Kg With Chronic Hepatitis C Virus (Hcv) Genotype 1, 2, 3, 4, 5, Or 6 Infection: Without Cirrhosis Or With Compensated Cirrhosis; Or With Decompensated Cirrhosis For Use In Combination With Ribavirin

[0435] As An Adjunctive Treatment Of Adult. Patients With Severe Active Anti-Neutrophil Cytoplasmic Autoantibody (Anca)-Associated Vasculitis (Granulomatosis With Polyangiitis [Gpa] And Microscopic Polyangiitis [Mpa]) A Complete Regimen For The Treatment Of Human Immunodeficiency Virus Type 1 (Hiv-1) Infection In Pediatric Patients Weighing 14 Kg To Less Than 25 Kg Who Have No Antiretroviral Treatment History Or To Replace The Current Antiretroviral Regimen In Those Who Are Virofogically-Suppressed (Hiv-1 Rna Less Than 50 Copies Per Ml) On A Stable Antiretroviral Regimen With No History Of Treatment Failure And No Known Substitutions Associated With Resistance To The Individual Components Of Biktarvy

[0436] For Treatment Of Cholestatic Pruritus In Patients With Alagille Syndrome (Algs) 1 Year Of Age And Older

[0437] Treatment Of Pediatric Patients Greater Than Or Equal To I Year Of Age With Accelerated Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia (Ph+ Cml) With Resistance Orintolerance To Prior Tyrosine-Kinase Inhibitor (Tki) Therapy

[0438] Treatment Of Adul t Patients With Philadelphia Chromosome-Positive Chroni c Myeloid Leukemia (PM- Cml) In Chronic Phase (Cp) With The T315i Mutation

[0439] Treatment Of Adult. Patients With Philadelphia Chromosome- Positive Chronic Myeloid Leukemia (PM- Cml) In Chronic Phase (Cp), Previously Treated With Two Or More Tyrosine Kinase Inhibitors (This)

[0440] For Use With Positron Emission Tomography (Pet) For The Localization Of Known Somatostatin Receptor Positive Neuroendocrine Tumors (Nets) In Adult And Pediatric Patients

[0441] To Reduce The Risk Of Ototoxicity Associated With Cisplatin In Pediatric Patients I Month Ofage And Older With Localized, Non-Metastatic Solid Tumors

[0442] For Treatment Of Endogenous Hypercortisolemia In .Adult Patients With Cushing's Syndrome For Whom Surgery Is Not An Option Or Has Not Been Curative

[0443] For The Treatment Of Adult Patients With Locally Advanced Unresectable Or Metastatic Malignant Perivascular Epithelioid Cell Tumor (Pecoma)

[0444] To Increase Linear Growth In Pediatric Patients With Achondroplasia Who Are 5 Years Of Age And Older With Open Epiphyses

[0445] For The Treatment Of Adults And Pediatric Patients (12 Years O f Age And Older And Weighing At Least 35 Kg) With Past-Transplant Cytomegalovirus (Cmv) Intection / Disease That Is Refractory To Treatment (With Or Without Genotypic Resistance) With Ganciclovir, Valganciclovir, Cidofovir Or Foscar.net

[0446] To Reduce Proteinuria In Adults With Primary Immunoglobulin A Nephropathy (Igan) At Risk Of Rapid Disease Progression, Generally A Urine Protein-To-Creatinine Ratio (Upcr) > Or = 1 .5 G / G

[0447] As An Adjunct For Intraoperative Identification Of Malignant Lesions In Adult Patients With Ovarian Cancer

[0448] Treatment Of Facial Angiofibroma Associated With Tuberous Sclerosis In Adults And Pediatric Patients 6 Years Of Age And Older

[0449] Treatment Of Hemolytic Anemia In Adults With Pyruvate Kinase (Pk) Deficiency

[0450] Treatment Of Seizures Associated With Lennox-Gastaut Syndrome (Lgs) In Patients 2 Years Of Age And Older

[0451] For Treatment Of Sickle Cell Disease (Scd) In Pediatric Patients 4 Years Of Age To Less Than 1.2 Years Of Age

[0452] Treatment Of Seizures Associated With Cyclin-Dependent Kinase-Like 5 (Cdkl5) Deficiency Disorder (Cdd) In Patients 2 Years Of Age And Older

[0453] Treatment Of Adult And Pediatric Patients 2 Years Of Age And Older With Severe Manifestations Of Pik3ca-Related Overgrowth Spectrum (Pros) Who Require Systemic Therapy

[0454] Treatment Of Adults With Intermediate Or High-Risk Primary Or Secondary (Post- Polycythemia Vera Or Post-Essential Thrombocythemia) Myelofibrosis (Ml) With A Platelet Count Below 50 X 10^9 / L

[0455] Treatment Of Adults With Symptomatic New York Heart Association (Nyha) Class li-Iii Obstructive Hypertrophic Cardiomyopathy (Hcm) To Improve Functional Capacity And Symptoms

[0456] Treatment Of Pediatric Patients Aged One Month And Older With Newly Diagnosed Juvenile Myelomonocytic Leukemia (Jmml) Treatment Of Spinal Muscular Atrophy (Sma) In Pediatric Patients Between Birth And 2 Mouths Of Age

[0457] Treatment Of Adult Patients With Stable Wilson’s Disease Who Are De-Coppered And Tolerant To Penicillamine

[0458] For Chronic Weight Management In Adult And Pediatric Patients 6 Years Of Age And Older With Monogenic Or Syndromic Obesity Due To Bardet-Biedl Syndrome (Bbs)

[0459] Treatment Of Seizures Associated With Dravet Syndrome (Ds) In Patients Taking Clobazam

[0460] Who Are 6 Months To Less Than 2 Years Of Age And Weighing 7 Kg Or More

[0461] Treatment Of Adults With Relapsed Or Refractory MyeloidZLymphoid Neoplasms (Mlns) With

[0462] Fibroblast Growth Factor Receptor 1 (Fgfrl ) Rearrangement

[0463] Treatment Of Pediatric Patients Age 1 Year And Older With Chronic Graft-Versus-Host Disease (Cgvhd) After Failure Of One Or More Lines Of Systemic Therapy

[0464] To Improve Kidney Function In Adults With Hepatorenal Syndrome With Rapid Reduction In Kidney Function

[0465] Treatment Of Adult And Pediatr ic Pati en ts 1 Year Of Age And Older With Unresectable, Recurrent, Or Refractory Inflammatory Myoflbroblastic Tumor (Imt) That Is Aik-Positive

[0466] Treatment Of Cystic Fibrosis (C-f) In Patients Aged 1 Year To Less Than 2 Years Who Are Homozygous For The F508del Mutation In The Cftr Gene

[0467] Treatment Of Adult Patients With Locally Advanced Or Metastatic Solid Tumors With A Ret Gene Fusion That Have Progressed On Or Following Prior Systemic Treatment Or Who Have No Satisfactory Alternative Treatment Options

[0468] Treatment Of Adult Patients With Previously Treated, Unresectable, Locally Advanced Or

[0469] Metastatic Intrahepatic Cholangiocarcinoma Harboring Fibroblast Growth Factor Receptor 2 (Fgfr2) Gene Fusions Or Other Rearrangements

[0470] Treatment Of Amyotrophic Lateral Sclerosis (Als) In Adults

[0471] Treatment Of Adult Patients With Locally Advanced Non-Small Cell Lung Cancer (Nsclc) With A Rearranged During Transfection (Ret) Gene Fusion, As Detected By An Fda-Approved Test Treatment Of Adult Patients With Relapsed Or Refractory Acute Myeloid Leukemia (Ami) With

[0472] A Susceptible Isocitrate Dehydrogenase- 1 (Idhl ) Mutation As Detected By An Fda-Approved Test

[0473] Treatm ent Of N eonatal Seizures In Term And Preterm Infants

[0474] Treatment Of Pr imary Hyperoxaluria Type 1 (PhI ) To Lower Plasma Oxalate Levels In

[0475] Pediatric And Adult Patients

[0476] Treatment Of Adult Patients With Histiocytic Neoplasms

[0477] Treatment Of Transfnsional Iron Overload In Adult Patients With Thalassemia Syndromes

[0478] Excluding Adult Patients Covered By The Indication For Thalassemia Syndromes Approved On October 14, 2011

[0479] Treatment Of Transfusional Iron Overload In Pediatric Patients 3 Years Of Age And Older With Thalassemia Syndromes

[0480] Treatment Of Transfuslonal Iron Overload In Adult And Pediatric Patients 3 Years Of Age And Older With Sickle Cell Disease Or Other Anemias

[0481] Treatment Of Transfusional Iron Overload In Pediatric Patients 8 Years Of Age And Older With Thalassemia Syndromes

[0482] Treatment Of Transfusional Iron Overload In Adult And Pediatric Patients 8 Years Of Age And Older With Sickle Cell Disease Or Other Anemias

[0483] Treatment Of Adult Patients With Ras Wild-Type, Her2-Positive Unresectable Or Metastatic

[0484] Colorectal Cancer That Has Progressed Following Treatment With Fluoropyrimidine-, Oxaliplatin-, And Irinotecan-Based Chemotherapy

[0485] For Prophylaxis Of Cytomegalovirus (Cmv) Disease In Adult Kidney Transplant Recipients At High Risk (Donor Cmv SeropositiveZRecipient Cmv Seronegative [D+7R-])

[0486] Treatment Of Adult Patients With Relapsed Or Refractory Mantle Cell Lymphoma (Mcl) After At Least Two Lines Of Systemic Therapy, Including A Btk Inhibitor Treatment Of Ret Syndrome In Adults And Pediatric Patien ts 2 Years Of Age And Older

[0487] For Use In Patients 18 Years Of Age Or Older Who Have Limited Or No Alternative Options For The Treatment Of Candidemia And Invasive Candidiasis

[0488] Treatment Of Friedreich’s Ataxia In Adults And Adolescents Aged 16 Years And Older

[0489] Treatment Of Pediatric Patients I Year Of Age And Older With Low-Grade Glioma. (Lgg) With A Braf V600e Mutation Who Require Systemic Therapy

[0490] Treatment Of Cholestatic Pruritus In Patients 3 Months Of Age To Less Than I Year Of Age With Alagille Syndrome (Algs)

[0491] Treatment Of Activated Phosphoinositide 3-Kinase Delta (Pi3k Delta) Syndrome (Apds) In Adult And Pediatric Patients 12 Years Of Age And Older

[0492] Treatment Of Cataplexy Or Excessive Daytime Sleepiness (Eds) In Adults With Narcolepsy

[0493] Treatment Of Amyotrophic Lateral Sclerosis (Als) In Adults Who Have A Mutation In The Superoxide Dismutase 1 (Sodl) Gene

[0494] Treatment Of Cystic Fibrosis (Cf) In Patients Aged 2 Years To Less Than 6 Years Who Have At Least One F508del Mutation In The Cystic Fibrosis Transmembrane Conductance Regulator (Citr) Gene Or A Mutation In The Cftr Gene That Is Responsive Based On In Vitro Data

[0495] Treatment Of Adult Patients With Indolent Systemic Mastocytosis (Ism)

[0496] The Treatment Of Cystic Fibrosis (Cf) In Patients I Month To Less Than 4 Months Of Age Who Have At Least One Mutation In The Cftr Gene That Is Responsive To Ivacaftor Potentiation Based On Clinical And / Or to Vitro Assay Data

[0497] Treatment Of Cholestatic Pruritus In Patients 12 Months Of Age And Older With Alagiile Syndrome (Algs)

[0498] For Use In Combination With Standard Induction And Consolidation, And As Maintenance Therapy Following Consolidation Chemotherapy, For The Treatment Of Adult Patients With Newly Diagnosed Acute Myeloid Leukemia ( Ami) That Is Flt3 Internal Tandem Duplication (Itd)-Positive As Detected By An Fda-Approved Test. In addition, in some embodiments, the compounds of this invention wil l be used, either alone or in combination with each other or in combination with one or more other therapeutic medications as described above, or their salts or esters, for manufocturing a medicament for the purpose of providing treatment an orphan disease in a patient or subject in need thereof

[0499] The present invention is based in part on the discovery that phenylalkylamino carbamates of Formula I, particularly solriamfetol, even more particularly solriamfetol hydrochloride have novel and unique pharmacological properties. These compounds have a beneficial effect on orphan diseases. Thus, these compounds can be safely used for this purpose to provide effective treatment of an orphan disease or orphan diseases regardless of the precise etiology of the disorder.

[0500] One aspec t of the invention relates to a method of treating an orphan disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula la: or a pharmaceutically acceptable salt or ester thereof.

[0501] In one embodiment the compound of Formula lb. or a pharmaceutically acceptable salt or ester thereof This compound is the (R) enantiomer, if named by structure and is therefore (R)-(beta-amino-benzenepropyl) carbamate. This compound is the dextrorotary enantiomer and can therefore also be named O-carbamoyi-tD)- phenylalaninol. The compound is also named ADX-N05. These names and solriamfetol may be used interchangeably in this specification. Particularly preferred is the use of solriamfetol hydrochloride.

[0502] The present invention includes the use of isolated enantiomers of the compound of Formula I compounds of Formula la or lb). In one embodiment, a pharmaceutical composition comprising the isolated S-enantiomer of Formula 1 is used to provide treatment to a subject. In another embodiment a pharmaceutical composition comprising the isolated R- enan tiomer of Formula 1 is used to provide treatment, to a subject.

[0503] The present invention also includes the use of mixtures of enantiomers of Formula 1. In one aspect of the present invention, one enantiomer will predominate. An enantiomer that predominates in the mixture is one that is present in the mixture in an amount greater than any of the other enantiomers present in the mixture, e.g., in an amount greater than 50%. In one aspect, one enantiomer will predominate to the extent of 90% or to the extent of 93%, 92%, 93%, 94%, 95%, 96%, 97% or 98% or greater. In one embodiment, the enantiomer that predominates in a composition comprising a compound of Formula I is the S~enantiomer of Formula I.

[0504] The present invention provides methods of using enantiomers and enantiomeric mixtures of compounds represented by Formula I. A carbamate enantiomer of Formula I contains an asymmetric chiral carbon at the benzylic position, which is the second aliphatic carbon adjacent to the phenyl ring.

[0505] An enantiomer tha t is isolated is one that is substantially tree of the corresponding enantiomer. Thus, an isolated enantiomer refers to a compound that is separated via separation techniques or prepared free of the corresponding enantiomer.

[0506] The term “substanti ally free,” as used herein, mean s that the compound is made up of a significantly greater proportion of one enantiomer. In preferred embodiments, the compound includes at least about 90% by weight of one enantiomer. In other embodiments of the invention, the compound includes at least about 99% by weight of one enantiomer.

[0507] The compounds of Formula I can be synthesized by methods known to the skilled artisan. The salts and esters of the compounds of Formula I can be produced by treating the compound with a suitable mineral or organic acid (HX) in suitable solvent or by other means well known to those of skill in the art,

[0508] Details of reaction schemes for sy nthesizing compo unds of Formula I as well as representative examples cm the preparation of specific compounds have been described in U.S, Pat, No. 10,829,443, U.S. Pat. No. 5,705,640, U.S. Pat. No. 5,756,817, U.S. Pat. No.

[0509] 5,955,499, U.S. Pat. No. 6,140,532, all incorporated herein by reference in their entirety.

[0510] Unless otherwise indicated, any reference to a compound herein, such as solriamfetol, by structure, name, or any other means, includes pharmaceutically acceptable salts; free acids or bases; alternate solid forms, such as polymorphs, solvates, hydrates, etc,; tautomer’s; enantiomers; deuterium modified compounds, or any chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.

[0511] From Formula I it Is evident that some of the compounds of the invention have at least one and possibly more asymmetric carbon atoms. It is intended that the present invention include within its scope the stereochemical ly pure isomeric forms of the compounds as well as their racemates, Stereochenucally pure isomeric forms may be obtained by the application of art known principles. Diastereoisomers may be separated by physical separation methods such as fractional crystallization and chromatographic techniques, and enantiomers may be separated from each other by the selective crystallization of the diastereomeric salts with optically active acids or bases or by chiral chromatography. Pure stereoisomers may also be prepared synthetically from appropriate stereochemically pure starting materials, or by using stereoselective reactions.

[0512] Duri ng any of the processes for preparation of the compounds of the present invention, it. may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed, J. F. W, McOntie, Plenum Press, 1973; and T. W. Greene & P. G. M, Writs, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. The protecting groups may be removed at a convenient subsequent stage using methods known in the art.

[0513] The compound may be part of a pharmaceutical composition, w herein the pharmaceutical composition is administered to a subject by any conventional route of administration, including, but not limited to, oral buccal, topical, systemic (e.g,, transdermal. intranasal, or by suppository), or parenteral (e.g., intramuscular, subcutaneous, or intravenous injection.) Administration of the compounds directly to the nervous system can include, for example, administration to intracerebral, intraventricular, intracerebralventricular, intrathecal, intraeistemal, intraspinal or peri-spinal routes of administration by delivery via intracranial or intravertebral needles or catheters with or without pump devices. Depending on the route of administration, compounds of Formula 1 can be constituted into any form. For example, forms suitable for oral administration include solid forms, such as pills, gelcaps, tablets, caplets. capsules, granules, and powders (each including immediate release, timed release and sustained release formulations). Forms suitable for oral administration also include liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions, In addition, forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

[0514] In certain embodiments, pharmaceutical compositions of this invention comprise one or more compounds of Formula I or a salt or ester thereof without any pharmaceutical carriers or excipients. In other embodiments, pharmaceutical compositions of this invention comprise one or more compounds of formula I or a salt or ester thereof intimately adm ixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.

[0515] Carriers are inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorings, sweeteners, preservatives, dyes, and coatings. In preparing compositions in oral dosage form, any of the usual pharmaceutical carriers may be employed. For example, for liquid oral preparations, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.

[0516] Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, emulsions, syrups, elixirs, aerosols, or any other appropriate compositions; and comprise at least one compound of this invention, optionally in combination with at least one pharmaceutically acceptable excipient. Suitable excipients are well known to persons of ordinary skill in the art, and they, and the methods of formulating the compositions, can be found in such standard references as Alfonso AR: Remington's Pharmaceutical Sciences, 17th ed.. Mack Publishing Company, Easton Pa., 1985, the disclosure of which is incorporated herein by reference in its entirety and for all purposes. Suitable liquid carriers, especially for injectable solutions, include water, aqueous saline solution, aqueous dextrose solution, and glycols.

[0517] The carbamate compounds can be provided as aqueous suspensions. Aqueous suspensions of the invention can contain a carbamate compound in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients can include, for example, a suspending agent, such as sodium carboxymethylcellulose, metliylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partia l ester derived fiom a fatty acid and a hexitol (e.g, , polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester deri ved from faty acid and a hexi tol anhydride (e.g., polyoxyethylene sorbitan mono-oleate).

[0518] The aqueous suspension can also contain one or more preservatives such as ethyl or n- propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity.

[0519] Oil suspensions for use in the present methods can be formulated by suspending a carbamate compound in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin, or a mixture of these. The oil suspensions can contain a. thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281 :93 (1997). The pharmaceutical formulations of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, as described above, or a mixture of these.

[0520] Suitable emulsifying agents include naturally occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent

[0521] The compound of choice, alone or in combin ation with other suitable components can be made into aerosol formulations (i.e., they can be “nebulized”) to be“ administered via inhalation. Aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.

[0522] Formulations of the present invention suitable for parenteral administration, such as, for example, by intraarticular ( in the joints), intravenous, intra.muscular, intradermal, intraperitoneal, and subcutaneous routes, can include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. Among the acceptable vehicles and solvents that can be employed are water and Ringer’s solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides, In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter.

[0523] Where the compounds are sufficiently soluble they can be dissolved directly in normal saline with or without the use of suitable organic solvents, such as propylene glycol or polyethylene glycol. Dispersions of the finely divided compounds can be made-up in aqueous starch or sodium carboxymethyl cellulose solution, or in suitable oil, such as arachis oil. These formulations can be sterilized by conventional, well-known sterilization techniques. The formulations can contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g,, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.

[0524] The concentration of a carbamate compound in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art. using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as a solution of 1,3- butanediol. The formulations of commends can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials. Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

[0525] A carbamate compound suitable for use in the practice of this invention can be administered orally. The amount of a compound of the present invention in the composition can vary widely depending on the type of composition, size of a unit dosage, kind of excipients, and other factors well known to those of skill in the art. In general, the final composition can comprise, for example, from 0.000001 percent by weight (% w) to 100% w of the carbamate compound, e.g., 0.00001% w to 50% w, with the remainder being the excipient or excipients.

[0526] Pharmaceutical formulations for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for oral administration. Such carriers enable the pharmaceutical formulations to be formulated in unit dosage forms as tablets, pills, powder, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc. suitable for ingestion by the patient, In other embodiments, pharmaceutical formulations for oral administration can be formulated without using any pharmaceutically acceptable carriers.

[0527] Formulations sui table for oral administration can consist of (a) liquid solutions, such as an effective amount of the pharmaceutical formulation suspended in a diluents, such as water, saline or PEG 400; (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin; (c) suspensions in an appropriate liquid; and (d) suitable emulsions.

[0528] Pharmaceutical preparations for oral use can be obtained through combination of the compounds of the presen t invention with a soli d exc ipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores. Suitable solid excipients are carbohydrate or protein fillers and include, but are not limited to sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxymethyl cell ulose, hydroxypropy Imethyl-cellulose or sodium carboxymethylcellulose; and gums including arable and tragacanth; as well as proteins such as gelatin and collagen.

[0529] If desired, disintegrating or solubilizing agents can be added, such as cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof such as sodium alginate. Tablet forms can include one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffering agents, moistening agents, preservatives, flavoring agents, dyes, disintegrating agents, and pharmaceutically compatible carrier's. Lozenge forms can comprise the active ingredient in a flavor, e,g., sucrose, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, carriers known in the art.

[0530] The compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug. These formulations can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperatures and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[0531] The compounds of the present invention can also be administered by intranasal, intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35: 1187 (1995); Tjwa, Ann. Allergy Asthma Immunol. 75: 107 (1995)),

[0532] The compounds of the present invention can be delivered transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0533] Encapsulating materials can also be employed with the compounds of the present invention and the term “composition” can include the active ingredient in combination with an encapsulating material as a formulation, with or without other carriers. For example, the compounds of the present invention can also be delivered as microspheres for slow release in the body. In one embodiment, microspheres can be administered via intradermal injection of drug (e.g.. mifepristone)-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater. Sci. Polyrn. Ed. 7:623 (1995); as biodegradable and injectable gel formulations (see, e.g.. Gao. Pharm. Res. 12:857 (1995)); or. as microspheres for oral administration (see, e,g,, Eyles, J. Pharm. Pharmacol. 49:669 (1997)). Both transdermal and intradermal routes afford constant delivery for weeks or months. Cachets can also be used in the deli very of the compounds of the present invention.

[0534] In another embodiment, the compounds of the present invention can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i. e., by employing ligands attached to the liposome that bind to surface membrane protein receptors of the cell resulting in endocytosis. The active drug can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

[0535] By using liposomes, particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the carbamate compound into target cells in vivo (see, e.g., Al -Muhammed, J. Microencapsul. 13:293 (1996); Chonn, Curr. Opin, Biotechnol, 6:698 (1995); Ostro, Am, J. Hosp. Pharm. 46:1576 (1989)).

[0536] Active drug may also be delivered by the use of monoclonal antibodies as individual earners to which the compound molecules are coupled. Acti ve drug may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydioxy-ethyl-aspartamide- phenol, or polyethyleneoxide-poiylysine substituted with palmitoyl residues. Furthermore, active drug may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogeIs,

[0537] In certain embodiments the compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-iujector devices or suppositories, for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.

[0538] Alternatively, the composition maybe presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.

[0539] The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful, suppository and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. For example, the pharmaceutical compositions herein can contain, per unit dosage unit, from about 10 to about 1000 mg of the active ingredient, eg., from about 25 to about 600 mg of the active ingredient,e.g., from about 75 to about 400 mg of the active ingredient, e.g., about 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, or 600 mg or more or any range therein.

[0540] In some embodiments of the present invention, carbamate compounds suitable for use

[0541] In the practice of this invention will be administered either singly or concomitantly with at least one or more other compounds or therapeutic agents, e.g. , with other agents that treat an orphan disease and / or other disorders or symptoms associated with an orphan disease.

[0542] The method includes the step of administering to a patient in need of treatment an effective amount of one of the carbamate compounds disclosed herein in combination with an effective amount of one or more other compounds or therapeutic agents that have the ability to provide advantageous combined effects such as the ability to augment the effects of the compounds of the invention.

[0543] Pharmaceutically acceptable salts and esters refers to salts and esters that are pharmaceutically acceptable and have the desired pharmacological properties. Such salts include salts that may be formed where acidic protons present in the compounds are capable of reacting with inorganic or organic bases. Suitable inorganic salts include those formed with the alkali metals, sodium and potassium, magnesium, calcium, and aluminum. Suitable organic salts include those formed with organic bases such as the amine bases, e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N methylglucamine, and the like. Pharmaceutically acceptable salts can also include acid addition salts formed from the reaction of amine moieties in the parent compound with inorganic acids (e.g., hydrochloric and hydrobromic acids) and organic acids (c.g., acetic acid, citric acid, maleic acid, and the alkane- and arenesulfonic acids such as methanesulfonic acid and benzenesulfonic acid). Pharmaceutically acceptable esters include esters formed from carboxy, sulfonyloxy, and phosphonoxy groups present in the compounds. When there are two acidic groups present, a pharmaceutically acceptable salt or ester may be a mono-acid-mono-salt or ester or a di-salt or ester; and similarly where there are more than two acidic groups present, some or all of such groups can be salified or esierified.

[0544] Compounds named in this invention can be present in unsalified or unesterriied form, or in salified and / or esterified form, and the naming of such compounds is intended to include both the original (unsalified and unesterified) compound and its pharmaceutically acceptable salts and esters. The present invention includes pharmaceutically acceptable salt and ester forms of Formula I. More than one crystal form of an enantiomer of Formula I can exist and as such are also included in the present invention.

[0545] A pharmaceutical composition of the invention can optionally contain, in addition to a carbamate compoun d, at least one other therapeuti c agent useful in the treatment of an orphan disease. For example the carbamate compounds of Formula I can be combined physically with other compounds in fixed dose combinations to simplify their administration.

[0546] Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets. Second Edition. Revised and Expanded. Volumes 1-3, edited by Lieberman et at; Pharmaceutical Dosage Forms: Parenteral Medications. Volumes 1-2, edited by Avis et at; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et at; published by Marcel Dekker, Inc, the disclosure of each of which are herein incorporated by reference in their entireties and for all purposes.

[0547] The pharmaceutical compositions are generally formulated as sterile, substantially isotonic and in foil compliance with all Good Manufacturing Practice (GMP) regulations of the U.S. Food and Drug Administration.

[0548] The present in vention provides methods of providing treatment for an orphan disease in a mammal using carbamate compounds. The amount of the carbama te compound necessary to provide treatment for an orphan disease is defined as a therapeutically or a pharmaceutically effective dose. The dosage schedule and amounts effective for this use, i.e., the dosing or dosage regi men will depend on a variety of factors includi ng the stage of the disease, the pati ent's physical status, age and the like. In calculating the dosage regimen for a patient, the mode of administration is also taken into account.

[0549] A person of skill in the art will be able without undue experimentation, having regard to that skill and this disclosure, to determine a therapeutically effective amount of a particular substituted carbamate compound for practice of this invention ( see. e.g.. Lieberman, Pharmaceutical Dosage Fotins (Vols. 1-3, 1992); Lloyd, 1999, The Art, Science and Technology of Pharmaceutical Compounding; and Pickar, 1999, Dosage Calculations). A therapeutically effective dose is also one in which any toxic or detrimental side effects of the acti ve agent is outweighed in clinical terms by therapeutically beneficial effects. It is to be further noted that for each particular subject, specific dosage regimens should be evaluated and adjusted over time according to the indi vidual need and professional judgmen t of the person administering or supervising the administration of the compounds.

[0550] For treatment purposes, the compositions or compounds disclosed herein can be administered to the subject in a single bolus delivery, via continuous delivery over an extended time period, or in a repeated administration protocol (e,g., by an hourly, daily or weekly, repeated administration protocol). The pharmaceutical formulations of the present invention can be administered, for example, one or more times daily, 3 times per week, or weekly, in one embodiment of the present invention, the pharmaceutical formulations of the present invention are orally administered once or twice daily.

[0551] In this context, a therapeutically effective dosage of the biologically active agent(s) can include repeated doses within a prolonged treatment regimen that will yield clinically significant results to provide treatment for an orphan disease. Determination of effective dosages in this context is typically based on animal model studies followed up by human clinical trials and is guided by determining effective dosages and administration protocols that significantly reduce the occurrence or severity of targeted exposure symptoms or conditions in the subject. Suitable models in this regard include, for example, murine, rat, porcine, feline, non-human primate, and other accepted animal model subjects known in the art. Alternatively, effective dosages can be determined using in vitro models (e.g., immunologic and histopathologic assays).

[0552] Using such models, only ordinary calculations and adjustments are typically required to determine an appropriate concentration and dose to administer a therapeutically effective amount, of the biologically active agent(s) (e.g., amounts that are orally effective intranasally effective, transdermally effective, intravenously effective, or intramuscularly effective to elicit a desired response). The effective amount, however, may be varied depending upon the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and rime of administration, will result in the need to adjust dosages.

[0553] In an exemplary embodiment of the present invention, unit dosage forms of the compounds are prepared for standard administration regimens. In this way, the composition can be subdivided readily into smaller doses at the physician’s direction. For example, unit dosages can be made up in packeted powders, vials or ampoules and preferably in capsule or tablet form.

[0554] Eff ective administration of the carbamate compounds of this invention can be, for example, at an oral or parenteral dose of from about 0.01 mg / kg / dose to about 150 mg / kg / dose. For example, administration can be from about 0.1 / mg / kg / dose to about 25 mg / kg / dose, e.g.,from about 0.2 to about 18 mg / kg / dose, eg. , from about 0.5 to about 10 mg / kg / dose. Therefore, the therapeutically effective amount of the active ingredient can be, lor example, from about 1 mg / day to about 7000 mg / day for a subject having, for example, an average weight of 70 kg, e.g., from about 10 to about 2000 mg / day, c.g;, from about 50 to about 600 mg / day, c,g;, about 10, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, or 600 mg / day or more or any range therein. In one embodiment, the compound of Formula I is administered in the form of a capsule at a dose of about 150 nig to about 300 mg without any excipients.

[0555] The methods of this invention also provide for kits for use in providing treatment for an orphan disease. After a pharmaceutical composition comprising one or more carbamate compounds of this invention, with the possible addition of one or more other compounds of therapeutic benefit, has been formulated in a suitable carrier, it can be placed in an appropriate container and labeled for providing treatment for an orphan disease. Additionally, another pharmaceutical comprising at least one other therapeutic agent can be placed in the container as well and labeled for treatment of the indicated disease. Such labeling can include, for example, instructions concerning the amount, frequency and method of administration of each pharmaceutical.

[0556] Embodiments according to the present invention are described in non-limiting examples below.

[0557] Example 1.

[0558] Clinical Trial With Patients Having an Orphan Disease

[0559] A study of the safety and efficacy of Soltiamfetol in the treatment of subjects having an. orphan disease is carried out. The study includes an exploratory analysis of the efficacy of Solriamfetol in subjects in this study who have an orphan disease.

[0560] The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.

[0561] All publications, patent applications, patents and other references cited herein are incorporated by reference in their entireties for the teachings relevant to the sentence and / or paragraph in wh ich the reference is presented.

Claims

We claim.1 . A method of treating an orphan disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of solriamfetol or a pharmaceutically acceptable salt or ester thereof.

2. The method of claim 1 wherein solriamfetol is solriamfetol hydrochloride.

3. The method of claim 1 wherein the orphan disaease is idiopathic Hypersomnia.

4. A pharmaceutical composition comprising solriamfetol for treating an orphan disease.

5. The pharmaceutical composition of claim 4 comprising 75 mg of solriamfetol hydrochloride.6 The pharmaceutical composition of claim 4 comprising 150 mg of solriamfetol hydrochloride.

7. The pharmaceutical composition of claim 4 in the form of a tablet.

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