Diazoxide Choline

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 signs or symptoms of edema or fluid overload. Consider dosage reduction or temporary dosage interruption in the event of clinically significant fluid overload. If clinically significat fluid overload is noted during titration, titrate over a longer duration and/or to a lower dosage [see Warnings and Precautions (5.2) ] . Titration After Resolution of Fluid Overload or Elevation in Fasting Glucose or HbA1c If fluid overload or elevations in fasting glucose or HbA1c resolve after a dosage reduction: For patients weighing less than 30 kg, titrate the dosage in increments of no more than 25 mg every 2 weeks or titrate over longer duration to a maximum dosage of 5.8 mg/kg/day. For patients weighing greater than or equal to 30 kg, titrate the dosage in increments of no more than 75 mg every 2 weeks or titrate over longer duration to a maximum dosage of 5.8 mg/kg/day. For recommendations on resuming VYKAT XR after dosage interruption, see Dosage and Administration (2.5) . 2.4 Dosage Modifications for Concomitant Use with Strong CYP1A2 Inhibitors VYKAT XR dosage modifications for concomitant use with strong CYP1A2 inhibitors are shown in Table 2 [see Drug Interactions (7) ] . Table 2: VYKAT XR Dosage Modifications for Concomitant Use with Strong CYP1A2 Inhibitors Weight VYKAT XR 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 to <30 kg 25 mg 25 mg 50 mg 75 mg 30 to <40 kg 50 mg 100 mg 100 mg 100 mg 40 to <65 kg 50 mg 100 mg 150 mg 150 mg 65 to <100 kg 100 mg 150 mg 200 mg 250 mg 100 to <135 kg 100 mg 200 mg 250 mg 300 mg ≥135 kg 100 mg 200 mg 300 mg 325 mg Based on clinical response, VYKAT XR may be titrated to a maximum recommended dosage of 3.6 mg/kg/day. The VYKAT XR daily dosage should not exceed 325 mg per day. No dosage modification is recommended when VYKAT XR is concomitantly used with moderate CYP1A2 inhibitors. 2.5 Recommendations Regarding Dosage Interruption, Missed Dose, or Discontinuation of Treatment Following a dosage interruption or missed dose of: Less than 7 days, resume VYKAT XR at the previous dosage 7 days or more, re-titrate VYKAT XR according to Table 1 or 2 , as appropriate [see Dosage and Administration (2.2 , 2.4) ] Treatment with VYKAT XR can be discontinued without tapering.

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 Investigations: Increased serum uric acid, transient neutropenia, thrombocytopenia, decreased hemoglobin/hematocrit, eosinophilia Respiratory Disorders: Pulmonary hypertension Special Senses: Cataracts Musculoskeletal and Connective Tissue Disorders: Abnormal facial features Most common adverse reactions (incidence ≥10% and at least 2% greater than in placebo) are hypertrichosis, edema, hyperglycemia, and rash. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Soleno Therapeutics, Inc. at 1-833-765-3661 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

12.3 Pharmacokinetics Absorption Following oral administration, diazoxide choline is hydrolyzed to diazoxide prior to absorption. Peak diazoxide concentrations occur after 16 hours. VYKAT XR is expected to reach steady state after 7 days. Effect of Food Following administration of 150 mg diazoxide choline to healthy subjects, the C max increased by 39% and AUC inf was unchanged with a high-fat meal, compared to fasted conditions. The median T max was 12 hours in the fasted state, and 8 hours in the fed state. Distribution The volume of distribution of diazoxide following oral administration is about 44.9 L. Diazoxide is extensively bound (91% to 93%) to plasma proteins (primarily human albumin), and crosses the blood-brain barrier. Elimination Metabolism Diazoxide is mainly metabolized by CYP1A2 and to a minor extent by CYP3A4. Diazoxide is metabolized by oxidation or sulfate conjugation at the methyl group resulting in two inactive metabolites. Following long term administration in patients with PWS, only metabolite M1(3-hydroxymethyl-7-chloro-1,2,4- benzothiadiazine-1,1-dioxide) is detectable in circulation. Excretion Diazoxide is excreted almost exclusively in urine as free or conjugated compound. In humans, following administration of radiolabeled diazoxide, 85 to 92% of the total dose was recovered in urine, with about 31% eliminated as unchanged drug. About 2% of the dose is eliminated in the feces. The terminal half-life following single-dose administration in healthy subjects was 28.7 to 32.4 hours. In patients with PWS, the estimated terminal half-life is 106 hours. Specific Populations Pediatric Patients Approximately 72% of the patients with PWS were under 17 years of age at enrollment. There were no clinically relevant differences in pharmacokinetics in these participants compared to those observed in adult participants. Male and Female Patients No sex-related differences in pharmacokinetics have been observed in clinical trials of VYKAT XR in patients with PWS who have hyperphagia. Patients with Renal or Hepatic Impairment VYKAT XR has not been studied in patients with renal or hepatic impairment [see Use in Specific Populations (8.6 , 8.7) ] . Drug Interaction Studies Drugs That Inhibit CYP1A2 VYKAT XR is metabolized by CYP1A2 and coadministration with a strong CYP1A2 inhibitor may increase exposure of diazoxide and decrease concentrations of diazoxide metabolites. In a clinical study with fluvoxamine (a strong CYP1A2 inhibitor), coadministration with fluvoxamine at an inhibitory dose increased single dose diazoxide C max by 17.5% and AUC 0-inf by 60% compared to the same parameter measured on single dose in the absence of fluvoxamine co-administration [see Drug Interactions (7) ] . Strong CYP3A4 Inhibitor Physiology-based pharmacokinetic model-based analysis suggests that concomitant use of VYKAT XR with itraconazole (a strong CYP3A4 inhibitor) may increase the AUC inf of VYKAT XR by 1.1 to 2-fold, compared to VYKAT XR alone. Itraconazole did not appreciably affect the C max of VYKAT XR [see Drug Interactions (7) ] . Strong CYP3A4 Inducers Physiology-based pharmacokinetic model-based analysis suggests that concomitant use of VYKAT XR with rifampin (a strong CYP3A4 inducer and moderate CYP1A2 inducer) may decrease the C max and AUC inf of VYKAT XR by 14% to 30% and 40% to 70%, respectively, compared to VYKAT XR alone [see Drug Interactions (7) ] . Drugs that Alter Gastric pH Use of VYKAT XR with gastric pH adjusting-drugs is not expected to affect the pharmacokinetics of diazoxide. Based on population pharmacokinetic modeling, use of VYKAT XR with gastric pH adjusting drugs did not significantly affect relative bioavailability or apparent clearance of diazoxide. Protein Binding Displacement VYKAT XR may also displace bilirubin bound to serum protein, thus resulting in higher blood levels of bilirubin. In Vitro Studies Enzyme systems: Diazoxide choline is an inhibitor of CYP1A2. It is not an inhibitor of CYP2B6, 2C19, 2C8, 2C9, 2D6 or 3A4. It does not induce CYP1A2, CYP2B6 or CYP3A4 at the therapeutic dose range. Transporter systems: Diazoxide choline is a substrate for OAT1, OAT3, and BCRP. It is an inhibitor of OAT1/3. It is not an inhibitor of P-gp, BCRP, MATE1/2-K, OATP1B1/3, OCT1/2 at the therapeutic dose range.