AHFS Class:

• Anorexigenic Agents and Stimulants, Miscellaneous 28:20.92

Generic Name(s):

• Diazoxide Choline

Diazoxide choline, an adenosine-triphosphate-sensitive potassium (K_ATP) channel activator, is a prodrug and salt formulation of diazoxide, a nondiuretic benzothiadiazine derivative.1,  3,  10

Hyperphagia in Prader-Willi Syndrome

Diazoxide choline is used for the management of hyperphagia in adults and pediatric patients ≥4 years of age with Prader-Willi syndrome (PWS).1 Diazoxide choline has been designated an orphan drug by FDA for this indication.1,  2

Clinical Experience

The safety and efficacy of diazoxide choline were established in a 16-week, phase 3, randomized, double-blind, placebo-controlled, withdrawal study (Study 2-RWP) that followed a 13-week, phase 3, randomized, double-blind, placebo-controlled study (Study 1; DESTINY-PWS) and open-label extension study (Study 2-OLE) in adults and pediatric patients ≥4 years of age with hyperphagia in PWS.1,  3,  4 Prior to enrolling in Study 2-RWP, patients were treated with diazoxide choline in DESTINY-PWS and/or Study 2-OLE for approximately 3.3 years.1

In Study 2-RWP, 77 patients with hyperphagia and PWS were randomized in a 1:1 ratio to continue their current weight-based oral dosage of diazoxide choline or placebo.1 The primary measure of efficacy was the change from baseline in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) total score at Week 16.1 The HQ-CT is an observer-reported outcome that measures hyperphagic and food-related behaviors during the prior 2 weeks; the total score may range from 0-36, with higher scores indicating greater severity of hyperphagic and food-related behaviors.1 Baseline demographics were similar among diazoxide choline- and placebo-treated patients; the mean age was 14.9 years, and the majority of patients were White (86%) and female (56%).1

At the conclusion of the 16-week study, placebo-treated patients experienced a greater increase in the HQ-CT Total Score from baseline, indicating significant worsening of hyperphagia, compared to diazoxide choline-treated patients.1 Placebo-treated patients had a mean baseline HQ-CT Total Score of 8.1 and experienced a least square (LS) mean change from baseline of 7.6, compared to diazoxide choline-treated patients with a mean baseline score of 9.0 and LS mean change from baseline of 2.6.1

Clinical Perspective

Prader-Willi syndrome is a rare, complex, neurodevelopmental genetic disorder associated with hypotonia and feeding difficulties in infancy, accumulation of excess body fat in early childhood, intellectual disability, low muscle mass, neuroendocrine abnormalities, and behavioral problems, including hyperphagia.3,  5 Hyperphagia presents as food obsession, aggressive food seeking, and lack of satiety, and progresses to morbid obesity if access to food is not strictly controlled.3,  5 Hyperphagia typically occurs at a mean age of 9 years.3 While there are treatment guidelines addressing pediatric obesity, there are no guidelines that specifically target hyperphagia in PWS.3,  5,  6,  7 Diazoxide choline is the only approved treatment at this time for hyperphagia in PWS in adults and pediatric patients ≥4 years of age.1,  2

General

Pretreatment Screening

• Evaluate fasting plasma glucose and hemoglobin A1c (HbA1c).1

Patient Monitoring

• Monitor fasting plasma glucose once weekly for the first 2 weeks, then once every 4 weeks, and as clinically indicated.1 In patients with risk factors for hyperglycemia (obesity, elevated fasting glucose, elevated HbA1c, concomitant use of growth hormone, concomitant use of systemic corticosteroids), more frequent fasting glucose monitoring is recommended during the first few weeks of treatment with diazoxide choline.1
• Monitor HbA1c every 3 months and as clinically indicated.1
• Monitor for signs or symptoms of edema or fluid overload.1

Dispensing and Administration Precautions

• Do not substitute diazoxide choline extended-release tablets with diazoxide oral suspension; the pharmacokinetic profiles are different.1

Administration

Administer diazoxide choline orally once daily with or without food.1

The tablets should be swallowed whole and should not be split, crushed, or chewed.1

If a dose of diazoxide choline is missed, take the missed dose as soon as it is remembered.1 Do not take 2 doses at the same time to make up for a missed dose.1 If a dosage interruption of <7 days occurs, resume diazoxide choline at the previous dosage.1 If a dosage interruption of ≥7 days occurs, re-titrate as appropriate per Table 1.1

Store tablets at 20-25°C (excursions permitted to 15-30°C).1 Store in tightly closed container.1 Protect from humidity; do not remove desiccant.1

Dosage

Dosage of diazoxide choline is expressed in terms of diazoxide choline.1

Hyperphagia in Prader-Willi Syndrome

The recommended dosage of diazoxide choline for the treatment of hyperphagia in PWS in adults and pediatric patients ≥4 years of age is weight-based and titrated to a target maintenance dose as described in Table 1.1 The maximum recommended dosage is 5.8 mg/kg per day or 525 mg per day.1

Dosage Modification for Toxicity

Elevations in Fasting Glucose or HbA1c

If clinically significant fasting glucose or HbA1c elevations occur during treatment, temporarily interrupt or reduce the dosage of diazoxide choline until glycemic parameters are appropriately managed.1 Consider initiation or adjustment of antihyperglycemic therapies.1 If elevations in fasting glucose or HbA1c resolve after dosage reduction, re-initiate diazoxide choline and titrate over a longer duration and/or to a lower dosage.1 For patients weighing <30 kg, titrate the dosage in increments of no more than 25 mg every 2 weeks.1 For patients weighing ≥30 kg, titrate the dosage in increments of no more than 75 mg every 2 weeks.1 If clinically significant glucose elevations are noted during titration, titrate over a longer duration and/or to a lower dosage.1 Titrate to a maximum dosage of 5.8 mg/kg per day.1

Fluid Overload

If clinically significant edema or fluid overload occurs during treatment, temporarily interrupt or reduce the dosage of diazoxide choline until resolution.1 If fluid overload resolves after dosage reduction, re-initiate diazoxide choline and titrate over a longer duration and/or to a lower dosage.1 For patients weighing <30 kg, titrate the dosage in increments of no more than 25 mg every 2 weeks.1 For patients weighing ≥30 kg, titrate the dosage in increments of no more than 75 mg every 2 weeks.1 If clinically significant fluid overload is noted during titration, titrate over a longer duration and/or to a lower dosage.1 Titrate to a maximum dosage of 5.8 mg/kg per day.1

Dosage Modification for Concomitant Therapy

Strong CYP1A2 Inhibitors

For concomitant administration with strong cytochrome P-450 (CYP) isoenzyme 1A2 inhibitors, modify diazoxide choline dosage as described in Table 2.1 The maximum recommended dosage is 3.6 mg/kg per day or 325 mg per day.1 No dosage modification is necessary for concomitant administration with moderate CYP1A2 inhibitors.1

Special Populations

Hepatic Impairment

Not recommended in patients with hepatic impairment.1

Renal Impairment

Not recommended in patients with renal impairment.1

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.1

Contraindications

• Known hypersensitivity to diazoxide, other components of diazoxide choline, or thiazides.1 Erythema multiforme has been reported with diazoxide choline.1

Warnings/Precautions

Hyperglycemia

Diazoxide choline increases blood glucose as a result of inhibition of insulin release from the pancreas.1 In DESTINY PWS, 17% of diazoxide choline-treated patients experienced hyperglycemia compared to 5% of placebo-treated patients.1 In 1 patient, hyperglycemia led to discontinuation of diazoxide choline.3 Fasting glucose increased through week 6 (during titration) and ultimately stabilized through the end of blinded treatment.3 HbA1c increased from baseline in diazoxide choline-treated patients by approximately 0.15% compared to no HbA1c increase in placebo-treated patients.3 In a long-term, open-label, maintenance study, 1 patient experienced diabetic ketoacidosis.1

Evaluate fasting blood glucose and HbA1c before initiating diazoxide choline; optimize blood glucose prior to treatment initiation.1 If hyperglycemia occurs during treatment, monitor fasting glucose at least twice weekly and as clinically indicated until glucose returns to normal levels.1 Consider monitoring ketones in worsening hyperglycemia.1 If hyperglycemia necessitates treatment with an anti-hyperglycemic medication, monitor fasting glucose at least weekly for 8 weeks, followed by twice weekly and as clinically indicated.1 Depending on the severity of the hyperglycemia, temporary interruption followed by dosage reduction or permanent discontinuation may be necessary to prevent progression to ketoacidosis.1

Risk of Fluid Overload

Diazoxide choline may cause general, localized, and/or peripheral edema.1 In DESTINY-PWS, 27% of diazoxide choline-treated patients experienced peripheral edema compared to 12% of placebo-treated patients.1 One diazoxide choline-treated patient experienced peripheral and pulmonary edema that was classified as a serious adverse event and determined to be drug related.3

The antidiuretic property of diazoxide may lead to significant fluid retention, which may precipitate congestive heart failure in patients with compromised cardiac reserve.1 Use diazoxide choline with caution in patients with compromised cardiac reserve; it has not been studied in this population.1

Monitor for signs and symptoms of edema or fluid overload.1 Depending on the severity of the edema, temporary interruption followed by dosage reduction or permanent discontinuation may be necessary.1

Specific Populations

Pregnancy

There are insufficient data regarding diazoxide choline use in pregnant women.1 Diazoxide crosses the placenta and has been detected in cord blood.1 Based on data from case reports, in utero exposure of the infant to diazoxide may produce fetal or neonatal hyperbilirubinemia, thrombocytopenia, altered carbohydrate metabolism, and other adverse reactions.1 Alopecia, hypertrichosis lanuginosa, and hyperglycemia have also been reported in a small number of infants whose mothers received diazoxide during the last 19 to 60 days of pregnancy.1 The IV administration of diazoxide (parenteral preparation no longer commercially available in the US) during labor may cause cessation of uterine contractions, requiring administration of oxytocic agents to reinstate labor; this has not been reported with oral diazoxide.1,  8

In animal studies, diazoxide choline was administered to pregnant rats during organogenesis, and decreased fetal body weights, delayed skeletal ossification, and increased fetal resorptions were observed at 160 mg/kg per day (a dose approximately equal to the maximum recommended human dose).1

Lactation

Diazoxide is present in human milk.1 However, effects of diazoxide on breastfed infants or milk production are not known.1 If breastfeeding while receiving diazoxide choline, because of the risk for hyperglycemia, consider monitoring the infant's blood glucose, especially during the neonatal period.1

Females and Males of Reproductive Potential

The manufacturer provides no guidance regarding diazoxide choline use in female and male patients of reproductive potential; based on animal studies, no effects on male or female fertility were observed.1

Pediatric Use

Safety and efficacy of diazoxide choline have been established in pediatric patients ≥4 years of age with hyperphagia and PWS.1 Use of diazoxide choline in this age group is supported by data from a 16-week, randomized, double-blind, placebo-controlled, withdrawal study period that included 77 adults and pediatric patients (ages 7-29 years of age) with hyperphagia and PWS.1 Safety and effectiveness were comparable between pediatric and adult patients in this study.1 Additional safety data supporting use in this population is provided by 3 additional studies (one randomized, double-blind, placebo-controlled study and two long-term, open-label maintenance studies) in adults and pediatric patients with hyperphagia and PWS.1 Safety and efficacy in pediatric patients <4 years of age with hyperphagia and PWS have not been established.1

Geriatric Use

No geriatric patients (≥65 years of age) were included in any studies involving diazoxide choline; the oldest patient was 29 years of age.1 This is reflective of the average lifespan of patients with PWS, with recent data demonstrating a mean age at death of 29.5 years.9

Hepatic Impairment

Safety and efficacy of diazoxide choline have not been established in patients with hepatic impairment.1

Renal Impairment

Safety and efficacy of diazoxide choline have not been established in patients with renal impairment.1

Common Adverse Effects

The most common adverse reactions (incidence ≥10% and ≥2% greater than in placebo) reported with diazoxide choline in clinical studies were hypertrichosis, edema, hyperglycemia, and rash.1

Diazoxide is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 1A2 and to a lesser extent by CYP3A4.1

In vitro studies indicate that diazoxide choline is an inhibitor of CYP1A2.1 Diazoxide choline does not inhibit CYP2B6, 2C19, 2C8, 2C9, 2D6, or 3A4.1 In vitro studies indicate that diazoxide choline does not induce CYP1A2, CYP2B6, or CYP3A4 at the therapeutic dose range.1

In vitro studies indicate that diazoxide choline is a substrate for organic anion transporter (OAT) 1, OAT3, and breast cancer resistance protein (BCRP).1

In vitro studies indicate that diazoxide choline is an inhibitor of OAT1 and OAT3.1 It does not inhibit P-glycoprotein (P-gp), BCRP, multidrug and toxin extrusion (MATE) 1/2-K, organic anion transporting polypeptide (OATP) 1B1/3, or organic cation transporter (OCT) 1/2 at the therapeutic dose range.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Strong CYP1A2 Inhibitors

Diazoxide choline is a CYP1A2 substrate.1 The concomitant use of diazoxide choline with strong CYP1A2 inhibitors increases exposure of diazoxide, which may increase the frequency and/or severity of adverse reactions.1 Reduce the dosage of diazoxide choline when used concomitantly with strong CYP1A2 inhibitors as described in Table 2.1

CYP1A2 Substrates

Diazoxide choline is a CYP1A2 inhibitor.1 The concomitant use of diazoxide choline with CYP1A2 substrates increases exposure of the substrates, which may increase the frequency and/or severity of adverse reactions from the substrates.1 Avoid use of CYP1A2 substrates during diazoxide choline treatment.1

Strong CYP3A4 Inhibitors

Diazoxide choline is a CYP3A4 substrate.1 The concomitant use of diazoxide choline with strong CYP3A4 inhibitors increases exposure of diazoxide, which may increase the frequency and/or severity of adverse reactions.1 Monitor the frequency and severity of adverse reactions; dosage reduction of diazoxide choline may be necessary.1

Dual Strong CYP3A4/Moderate CYP1A2 Inducers

Diazoxide choline is a substrate of CYP3A4 and CYP1A2.1 The concomitant use of diazoxide choline with strong CYP3A4/moderate CYP1A2 inducers may decrease the exposure of diazoxide choline, thus decreasing the efficacy.1 Avoid use of strong CYP3A4/moderate CYP1A2 inducers during diazoxide choline treatment.1

Protein-bound Drugs

Diazoxide is extensively bound to plasma proteins and has the potential to displace other protein-bound drugs, which is clinically important for drugs with a narrow therapeutic index, such as warfarin and phenytoin.1

Warfarin

Protein binding displacement may result in higher blood levels of warfarin, and thus an increased risk of adverse reactions.1 Monitor International Normalized Ratio (INR) in patients using warfarin concomitantly with diazoxide choline; dosage modification of warfarin may be necessary.1

Phenytoin

Protein binding displacement may result in lower exposure of phenytoin, and thus decreased efficacy.1 Monitor serum phenytoin levels in patients using phenytoin concomitantly with diazoxide choline; dosage modification of phenytoin may be necessary.1

Thiazide or Other Diuretics

Diazoxide and thiazides or other diuretics may produce hyperglycemia and hyperuricemia.1 The concomitant use of diazoxide choline with thiazides or other diuretics may potentiate the hyperglycemic and hyperuricemic effects of diazoxide.1 Monitor for signs and symptoms of hyperglycemia and hyperuricemia; dosage adjustment of diazoxide choline or diuretics may be necessary.1

Description

Diazoxide choline, an adenosine-triphosphate-sensitive potassium (K_ATP) channel activator, is a prodrug and salt formulation of diazoxide, a nondiuretic benzothiadiazine derivative.1,  3,  10 The exact mechanism of action of diazoxide choline in the treatment of hyperphagia and Prader-Willi syndrome (PWS) in patients ≥4 years of age is unknown.1 The activation of the K_ATP channel in neuropeptide Y (NPY) and agouti-related protein (AgRP) neurons in the hypothalamus results in reduced secretion of NPY and AgRP, both of which are potent endogenous appetite-stimulatory neuropeptides.3 Additionally, the activation of the K_ATP channel in the dorsal motor nucleus of vagus, pancreatic β cells, and adipocytes reduces hyperinsulinemia, improves insulin and leptin resistance, and increases satiety.3 These actions are thought to be the mechanism by which diazoxide choline exerts its effect in hyperphagia and PWS.3

Following oral administration, diazoxide choline is hydrolyzed to diazoxide prior to absorption.1 Peak plasma concentrations are achieved after 16 hours, and steady state concentrations are expected after 7 days.1 When administered following a high-fat meal, peak plasma concentrations of diazoxide increased by 39% compared to fasted conditions.1 Diazoxide is extensively bound to plasma proteins (91-93%) and crosses the blood-brain barrier.1 Diazoxide is primarily metabolized by CYP1A2 and, to a lesser extent, CYP3A4.1 Metabolism also occurs via oxidation or sulfate conjugation to form two inactive metabolites.1 Diazoxide is largely excreted in the urine as free or conjugated compound.1 In healthy patients, the elimination half-life is approximately 29-32 hours; in patients with PWS, the elimination half-life is approximately 106 hours.1 Age and sex do not have seem to have clinically important effects on the pharmacokinetics of diazoxide choline.1

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide).1
• Advise the patient or caregiver that diazoxide choline can cause hyperglycemia, sometimes leading to diabetic ketoacidosis, and that the patient will have monitoring of blood glucose before and during treatment.1 Advise patients or caregivers on the signs and symptoms of hyperglycemia (e.g., excessive thirst, urinating more often than usual or higher amount of urine than usual, or increased appetite with weight loss) and ketoacidosis (e.g., nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath) and to contact their healthcare provider if these signs or symptoms occur.1
• Advise the patient or caregiver that diazoxide choline may cause edema, including severe adverse reactions associated with fluid overload.1 Advise patients or caregivers on the signs and symptoms of edema and to contact their healthcare provider if signs or symptoms of edema occur.1
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1
• Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

1. Soleno Therapeutics, Inc. VYKAT™ XR (diazoxide choline) extended-release tablets prescribing information. Redwood City, CA; 2025 March.

2. Food and Drug Administration. Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2025 Jul 28.

3. Miller JL, Gevers E, Bridges N, et al. Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: a double-blind, placebo-controlled trial. J Clin Endocrinol Metab. 2023;108(7):1676-1685.

4. Miller JL, Gevers E, Bridges N, et al. Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: results from long-term open-label study. Obesity (Silver Spring). 2024;32(2):252-261.

5. Schwartz L, Caixàs A, Dimitropoulos A, et al. Behavioral features in Prader-Willi syndrome (PWS): consensus paper from the International PWS Clinical Trial Consortium. J Neurodev Disord. 2021;12(1):25. Published 2021 Jun 21.

6. Hampl SE, Hassink SG, Skinner AC, et al. Clinical practice guideline for the evaluation and treatment of children and adolescents with obesity. Pediatrics. 2023;151(2):e2022060640.

7. Styne DM, Arslanian SA, Connor EL, et al. Pediatric obesity-assessment, treatment, and prevention: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(3):709-757.

8. Food and Drug Administration. Search Orange Book. Silver Spring, MD. From FDA website. Accessed 2025 Aug 21.

9. Butler MG, Manzardo AM, Heinemann J, et al. Causes of death in Prader-Willi syndrome: Prader-Willi Syndrome Association (USA) 40-year mortality survey. Genet Med. 2017;19(6):635-642.

10. e5 Pharma, LLC. Diazoxide oral suspension prescribing information. Boca Raton, FL; 2025 Jan.

11. Patient Services Brochure for HCPs. Accessed August 28, 2025. [Web]