VYKAT XR

1 INDICATIONS AND USAGE VYKAT XR is indicated for the treatment of hyperphagia in adults and pediatric patients 4 years of age and older with Prader-Willi syndrome (PWS). VYKAT XR is indicated for the treatment of hyperphagia in adults and pediatric patients 4 years of age and older with Prader-Willi syndrome (PWS). ( 1 )

2 DOSAGE AND ADMINISTRATION Prior to initiation, test fasting plasma glucose and HbA1c; optimize blood glucose in patients who have hyperglycemia. ( 2.1 ) Do not substitute with diazoxide oral suspension. ( 2.1 ) Administer orally once daily. ( 2.2 ) Recommended starting dosage and titration schedule is based on patient’s body weight. ( 2.2 ) Weight Starting Dosage Titration Dosage Titration Dosage Target Maintenance Dose Weeks 1 and 2 Weeks 3 and 4 Weeks 5 and 6 20 to <30 kg 25 mg 50 mg 75 mg 100 mg 30 to <40 kg 75 mg 150 mg 150 mg 150 mg 40 to <65 kg 75 mg 150 mg 225 mg 225 mg 65 to <100 kg 150 mg 225 mg 300 mg 375 mg 100 to <135 kg 150 mg 300 mg 375 mg 450 mg ≥135 kg 150 mg 300 mg 450 mg 525 mg The maximum recommended dosage is 5.8 mg/kg/day or 525 mg per day. ( 2.2 ) Interrupt VYKAT XR or reduce dosage for clinically significant elevations in fasting glucose or HbA1c; consider dosage reduction or interruption for clinically significant fluid overload. ( 2.3 ) See full prescribing information for VYKAT XR dosage modifications due to drug interactions ( 2.4 ) Following dosage interruption or a missed dose of 7 days or more, re-titrate according to Table 1 or Table 2 . ( 2.5 ) 2.1 Important Recommendations Prior to VYKAT XR Initiation Laboratory Testing Prior to VYKAT XR Initiation Prior to initiating treatment with VYKAT XR, test fasting plasma glucose (FPG) and HbA1c and optimize blood glucose in patients who have hyperglycemia [see Warnings and Precautions (5.1) ] . For fasting glucose and HbA1c monitoring recommendations during VYKAT XR treatment and for dosage modifications based on results, see Dosage and Administration (2.3) . Important Information Regarding Substitution Do not substitute VYKAT XR with diazoxide oral suspension because the pharmacokinetic profiles are different [see Clinical Pharmacology (12.3) ] . 2.2 Dosage and Administration Recommendations Administer VYKAT XR orally with or without food once daily [see Clinical Pharmacology (12.3) ] . Swallow tablets whole. Do not split, crush, or chew the extended-release tablets because doing so may compromise the extended-release characteristics, efficacy, or safety of VYKAT XR. The recommended oral dosage of VYKAT XR is based on body weight. The recommended starting dosage and titration schedule of VYKAT XR are shown in Table 1 . Table 1: Recommended Starting Dosage and Titration Regimen in Adults and Pediatric Patients 4 Years of Age and Older Weight Recommended Once Daily Dosage Starting Dosage Titration Dosage Titration Dosage Target Maintenance Dose Weeks 1 and 2 Weeks 3 and 4 Weeks 5 and 6 20 kg to <30 kg 25 mg 50 mg 75 mg 100 mg 30 kg to <40 kg 75 mg 150 mg 150 mg 150 mg 40 kg to <65 kg 75 mg 150 mg 225 mg 225 mg 65 kg to <100 kg 150 mg 225 mg 300 mg 375 mg 100 kg to <135 kg 150 mg 300 mg 375 mg 450 mg ≥135 kg 150 mg 300 mg 450 mg 525 mg The maximum recommended dosage of VYKAT XR is 5.8 mg/kg/day or 525 mg per day. Dosages above 5.8 mg/kg/day or 525 mg per day have not been evaluated in patients with PWS. 2.3 Monitoring and Dosage Modifications Due to Adverse Reactions Elevations in Fasting Glucose or HbA1c After initiating treatment with VYKAT XR, monitor: Fasting glucose (FPG or fasting blood glucose) at least once every week for the first 2 weeks, then at least once every 4 weeks, and as clinically indicated. HbA1c every 3 months and as clinically indicated. Monitor fasting glucose more frequently during the first few weeks of VYKAT XR treatment in patients with risk factors for hyperglycemia. If clinically significant elevations in fasting glucose of HbA1c occur during treatment, temporarily interrupt VYKAT XR or reduce the dosage until glycemic parameters are appropriately managed. Consider initiation or adjustment of standard antidiabetic therapy(ies). If clinically significant glucose elevations are noted during titration, titrate over a longer duration and/or to a lower dosage [see Warnings and Precautions (5.1) ] . Fluid Overload Monitor for sign …

3 DOSAGE FORMS AND STRENGTHS Extended-release tablets: VYKAT XR 25­mg of diazoxide choline: white, capsule-shaped, film-coated, waxed tablets, debossed with S-25 on one side. VYKAT XR 75 mg of diazoxide choline: white, round, standard convex-shaped, film-coated, waxed tablets, debossed with S-75 on one side. VYKAT XR 150 mg of diazoxide choline: white, oval-shaped, film-coated, waxed tablets, debossed with S-150 on one side. Extended-release tablets: 25 mg, 75 mg, and 150 mg of diazoxide choline. ( 3 )

4 CONTRAINDICATIONS VYKAT XR is contraindicated in patients with known hypersensitivity to diazoxide, other components of VYKAT XR, or to thiazides. Erythema multiforme has been reported with VYKAT XR [see Adverse Reactions (6) ] . Known hypersensitivity to diazoxide, other components of VYKAT XR, or to thiazides. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Hyperglycemia [see Warnings and Precautions (5.1) ] Risk of Fluid Overload [see Warnings and Precautions (5.2) ] Adverse Reactions from Clinical Studies of VYKAT XR in Patients with PWS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the clinical study development program for treatment of hyperphagia in patients aged 4 years and older with PWS, a total of 125 patients received at least 1 dose of VYKAT XR. Patients received dosages of VYKAT XR up to 5.8 mg/kg/day (up to a maximum dosage of 525 mg/day) for up to 4.86 years (median: 3.0 years) in the following studies: Study 1: 13-week, randomized, double-blind, placebo-controlled, parallel-arm study in which 126 patients were randomized in a 2:1 ratio to VYKAT XR or placebo and received at least one dose of VYKAT XR. Study 2-OLE: A long-term, open-label, maintenance treatment period in 115 patients (mean duration 2.6 years; maximum duration 4.3 years) who had previously been enrolled in Study 1. Study 2-RWP: A 16-week, double-blind, placebo-controlled, randomized withdrawal treatment period, in which 77 patients who had completed Study 1 and Study 2-OLE were randomized in a 1:1 ratio to VYKAT XR or placebo [see Clinical Studies (14) ] . Study 3: A long-term, open-label, maintenance study in 77 patients who had completed Study 1 and Study 2-OLE. Adverse reactions leading to discontinuation in VYKAT XR-treated patients included aggression, diabetes mellitus, fluid retention, hirsutism, hyperglycemia, lower respiratory tract infection, peripheral edema, pulmonary edema, and papular rash. The primary safety analyses are based on Study 1. The most common adverse reactions (10% or more and at least 2% greater than in placebo) in Study 1 were hypertrichosis, edema, hyperglycemia, and rash. Table 3 presents adverse reactions that occurred in at least 5% of patients in Study 1 receiving VYKAT XR and 2% more frequently in VYKAT XR-treated patients than placebo. Table 3: Adverse Reactions Occurring in ≥5% of Patients with PWS Receiving VYKAT XR and at Least 2% Greater than Placebo in Study 1 Adverse Reaction VYKAT XR (N=84) Placebo (N=42) Hypertrichosis 36% 14% Edema Edema includes peripheral edema, periorbital edema, swelling face, pulmonary edema, and peripheral swelling. 27% 12% Hyperglycemia Hyperglycemia includes type 2 diabetes mellitus. 17% 5% Rash Rash includes contact dermatitis, erythema multiforme, maculo-papular rash, papular rash, and urticaria. 12% 2% Pyrexia 6% 0% Arthralgia 5% 2% Influenza 5% 2% Nasopharyngitis 5% 2% In Study 2-RWP, the adverse reactions that occurred most frequently (at least 5%) and to a greater extent than placebo included: Immune System Disorders: Seasonal allergy Investigations: Increased weight Nervous System Disorders: Hyperphagia, anxiety, affect lability, anger, compulsive hoarding, suicidal ideation Respiratory Disorders: Streptococcal pharyngitis, upper respiratory infection Skin and Subcutaneous Tissue Disorders: Hirsutism Erythema multiforme was reported in one subject in Study 1. One subject in Study 3 experienced a serious adverse reaction of diabetic ketoacidosis. Adverse Reactions from Clinical Trials or Postmarketing Experience of Diazoxide in An Unapproved Population The following adverse reactions associated with use of diazoxide for an unapproved population have been identified in clinical studies or post-marketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: Hypersensitivity Investigat …

7 DRUG INTERACTIONS Table 4 displays clinically significant drug interactions with VYKAT XR. Table 4: Clinically Significant Drug Interactions with VYKAT XR Strong CYP1A2 Inhibitors See www.fda.gov/CYPandTransporterInteractingDrugs for examples of strong CYP1A2 and CYP3A4 inhibitors, sensitive CYP1A2 substrates, and dual strong CYP3A4 / moderate 1A2 inducers. Prevention or Management Reduce the dosage of VYKAT XR when concomitantly used with strong inhibitors of CYP1A2 [see Dosage and Administration (2.4) ] . Mechanism and Clinical Effect(s) VYKAT XR is a CYP1A2 substrate. Concomitant use of VYKAT XR with strong CYP1A2 inhibitors increases exposure of diazoxide, which may increase the frequency and/or severity of adverse reactions from VYKAT XR [see Clinical Pharmacology (12.3) ] . CYP1A2 Substrates Prevention or Management Concomitant use of VYKAT XR with CYP1A2 substrates is not recommended. Mechanism and Clinical Effect(s) VYKAT XR is an inhibitor of CYP1A2. Concomitant use of VYKAT XR with CYP1A2 substrates increases exposure of these substrates. This may increase the frequency and/or severity of adverse reactions from such substrates. Strong CYP3A4 Inhibitors Prevention or Management Monitor the frequency and severity of adverse reactions from VYKAT XR. A dosage reduction of VYKAT XR may be needed when used concomitantly with strong CYP3A4 inhibitors. Mechanism and Clinical Effect(s) Concomitant use of VYKAT XR with strong CYP3A4 inhibitors increases exposure of diazoxide, which may increase the frequency and/or severity of adverse reactions from VYKAT XR [see Clinical Pharmacology (12.3) ] . Dual Strong CYP3A4 / Moderate 1A2 Inducers Prevention or Management Concomitant use of VYKAT XR with dual strong CYP3A4/moderate CYP1A2 inducers is not recommended. Mechanism and Clinical Effect(s) VYKAT XR is a substrate of CYP3A4 and CYP1A2. Concomitant use of VYKAT XR with strong CYP3A4/moderate 1A2 inducers may decrease exposure of VYKAT XR. This may decrease the efficacy of VYKAT XR [see Clinical Pharmacology (12.3) ] . Drugs Highly Bound to Protein Prevention or Management Monitor international normalized ratio (INR) in patients who use coumarin or its derivatives concomitantly with VYKAT XR. Dosage modification of coumarin or its derivatives may be needed when used concomitantly with VYKAT XR. Monitor diphenylhydantoin serum levels when VYKAT XR is used concomitantly with diphenylhydantoin. Dosage modification of diphenylhydantoin may be needed when used concomitantly with VYKAT XR. Mechanism and Clinical Effect(s) Diazoxide is highly bound to serum proteins. Diazoxide may displace other drugs which are also highly bound to protein resulting in higher or lower blood levels of the concomitantly used drugs. The impact of protein binding displacement is expected to be clinically important for drugs with narrow therapeutic range such as coumarin or its derivatives and diphenylhydantoin. Protein binding displacement may result in an increased risk of adverse reactions due to higher blood levels of coumarin or its derivative or loss of efficacy due to lower exposures of diphenylhydantoin. Thiazide or Other Diuretics Prevention or Management Monitor for signs and symptoms of hyperglycemia [see Warnings and Precautions (5.1) ] and hyperuricemia when VYKAT XR is used concomitantly with thiazides or other diuretics. Dosage adjustment of VYKAT XR or diuretics may be needed when VYKAT XR is concomitantly used with diuretics. Mechanism and Clinical Effect(s) Both diazoxide and thiazides or other diuretics may produce hyperglycemia and hyperuricemia. The concomitant use of VYKAT XR with thiazides or other diuretics may potentiate the hyperglycemic and hyperuricemic effects of diazoxide [see Adverse Reactions (6) and Clinical Pharmacology (12.2) ] . Strong CYP1A2 Inhibitors: Reduce VYKAT XR dosage. ( 2.4 , 7 ) CYP1A2 Substrates: Concomitant use with VYKAT XR is not recommended. ( 7 ) See full prescribing information for additional clinically …

8 USE IN SPECIFIC POPULATIONS Renal Impairment or Hepatic Impairment: Use is not recommended. ( 8.6 , 8.7 ) 8.1 Pregnancy Risk Summary Available data from case reports with diazoxide use during pregnancy are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal outcomes. Adverse reactions, including hyperglycemia, alopecia, and hypertrichosis lanuginosa, have been reported in neonates exposed to diazoxide in utero prior to delivery (see Clinical Considerations ) . In animal reproduction studies, oral gavage administration of diazoxide choline to pregnant rats during organogenesis at dose exposures equal to the human exposure of 525 mg resulted in no malformations. Maternal and fetal toxicities were observed at a dose approximately equal to the maximum recommended human dose (MRHD) of 525 mg based on AUC (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Diazoxide crosses the placenta and has been detected in cord blood. Based on adverse reactions reported in adults, in utero exposure of the infant prior to delivery may produce fetal or neonatal hyperbilirubinemia, thrombocytopenia, altered carbohydrate metabolism, and possibly other adverse reactions. Monitor infants who were exposed to diazoxide in utero for adverse reactions and treat accordingly. Alopecia and hypertrichosis lanuginosa have occurred in a small number of infants whose mothers received oral diazoxide during the last 19 to 60 days of pregnancy. Abnormal hair growth was first noted at the age of one week and persisted when the infants were last seen at the ages of 5 months to one year. An infant born to a mother who was treated with oral diazoxide, 150 mg daily for 47 days prior to delivery, developed hyperglycemia which resolved after a 6-hour insulin infusion. Because there was an inappropriately low plasma insulin concentration for the degree of hyperglycemia, it was considered compatible with transplacental transfer of diazoxide causing inhibition of release of insulin from the neonatal pancreas. Labor or Delivery Intravenous administration of diazoxide during labor may cause cessation of uterine contractions, which may require administration of oxytocic agents to reinstate labor. However, this has not been reported with diazoxide when administered orally. Use caution in administering VYKAT XR during labor. Data Animal Data Diazoxide choline was administered orally to pregnant rats during the period of organogenesis at doses of 40, 100, and 160 mg/kg/day (0.3, 0.6, and 1.2 times the MRHD of 525 mg based on AUC). No malformations were observed; however, decreased fetal body weights, delayed skeletal ossification, and increased fetal resorptions were observed at 160 mg/kg/day (a dose approximately equal to the MRHD based on AUC) which was a maternally toxic dose. In a study in which rabbits were administered diazoxide intravenously, evidence of skeletal and cardiac teratogenic effects was noted at unknown multiples of the MRHD for diazoxide choline. 8.2 Lactation Risk Summary Diazoxide is present in human milk. There are no data on the effects of diazoxide on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VYKAT XR and any potential adverse effects on the breastfed child from VYKAT XR or from the underlying maternal condition. Clinical Considerations Because of potential adverse reactions, including hyperglycemia, monitoring the infant’s blood glucose may be advisable, especially during the neonatal period. 8.4 P …

12.1 Mechanism of Action The exact mechanism of action of diazoxide choline in the treatment of hyperphagia in patients 4 years of age and older with Prader-Willi syndrome (PWS) is unknown.

11 DESCRIPTION VYKAT XR contains diazoxide choline. Diazoxide choline is very slightly soluble to soluble in solvents dichloromethane, tetrahydrofuran, acetonitrile, and methanol and practically insoluble in solvents methyl tert -butyl ether. The pKa is 8.44 ± 0.01 Diazoxide choline is 7-Chloro-3-methyl-1λ6, 2,4-benzothiadiazin-2-ide 1,1-dioxide 2- hydroxyethyl(trimethyl)azanium. The empirical formula is C 8 H 6 ClN 2 O 2 S•C 5 H 14 NO and the molecular weight is 333.83 g/mole. The structural formula is: VYKAT XR is for oral administration and is available as extended-release tablets in the following strengths: 25 mg tablet contains diazoxide choline 25 mg, equivalent to 17.2 mg diazoxide; 75 mg tablet contains diazoxide choline 75 mg, equivalent to 51.6 mg diazoxide; and 150 mg tablet contains diazoxide choline 150 mg, equivalent to 103.2 mg diazoxide. Each tablet contains the following inactive ingredients: carnauba wax, colloidal silicon dioxide, dibasic calcium phosphate dihydrate, hypromellose, magnesium stearate, polyethylene oxide, silicified microcrystalline cellulose, talc, titanium dioxide, and triacetin. Chemical Structure

10 OVERDOSAGE An overdosage of VYKAT XR may cause marked hyperglycemia, which may be associated with ketoacidosis [see Warnings and Precautions (5.1) ] . No specific antidotes for VYKAT XR are known. Monitor ketones in patients with severe hyperglycemia following overdose and consider insulin treatment if necessary. Treat severe hyperglycemia associated with ketoacidosis with prompt insulin administration and restoration of fluid and electrolyte balance. Because of VYKAT XR’s long half-life (approximately 106 hours) in patients with PWS, the symptoms of overdosage (hyperglycemia, with or without ketoacidosis) require prolonged surveillance for periods up to three weeks or until blood sugar levels stabilize within the patient’s normal range. Consider contacting a Poison Help line (1-800-222-1222) or a medical toxicologist for overdosage management recommendations for VYKAT XR.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied VYKAT XR is supplied as follows: Strength Description Package Configuration NDC Number 25 mg diazoxide choline White, capsule-shaped tablets, debossed with "S-25" on one side 30-count bottles 83860-025-01 75 mg diazoxide choline White, round, standard convex tablets, debossed with "S-75" on one side 30-count bottles 83860-075-01 150 mg diazoxide choline White, oval-shaped tablets, debossed with “S-150” on one side. 30-count bottles 83860-150-01 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Keep in tightly closed container. Protect from humidity. Do not remove desiccant.