Diazoxide Choline (Monograph)

Brand name: Vykat XR
Drug class: Anorexigenic Agents and Stimulants, Miscellaneous

Introduction

Diazoxide choline is an anorexigenic agent.

Uses for Diazoxide Choline

Diazoxide Choline has the following uses:

Diazoxide choline is indicated for the treatment of hyperphagia in adults and pediatric patients 4 years of age and older with Prader-Willi syndrome (PWS).

Diazoxide Choline Dosage and Administration

General

Diazoxide Choline is available in the following dosage form(s) and strength(s):

Extended-release tablets: 25 mg, 75 mg, and 150 mg of diazoxide choline.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Dosage in Adults and Pediatric Patients ≥4 Years of Age

• Prior to initiating therapy, test fasting plasma glucose (FPG) and HbA1c; optimize blood glucose in patients who have hyperglycemia.

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

• Administer diazoxide choline extended-release tablets orally with or without food once daily.

• Recommended starting dosage and titration schedule is based on patient's body weight as shown in Table 1.

• The maximum recommended dosage is 5.8 mg/kg/day or 525 mg per day.

• Interrupt diazoxide choline or reduce dosage for clinically significant elevations in fasting glucose or HbA1c; consider dosage reduction or interruption for clinically significant fluid overload.

• See full prescribing information for diazoxide choline dosage modifications due to drug interactions.

• Following dosage interruption or a missed dose of 7 days or more, re-titrate according to the manufacturer's instructions.

Cautions for Diazoxide Choline

Contraindications

Known hypersensitivity to diazoxide, other components of diazoxide choline, or to thiazides.

Warnings/Precautions

Hyperglycemia

Diazoxide choline increases blood glucose, due primarily to an inhibition of insulin release from the pancreas. Hyperglycemia, including severe adverse reactions associated with diabetic ketoacidosis, occurred in diazoxide choline-treated patients during clinical trials.

Precipitating conditions for diabetic ketoacidosis may include reduction in the dosages of concomitant antihyperglycemic medications, increase in the dosages of concomitant growth hormone, intercurrent illness, surgery, volume depletion or alcohol abuse. Signs and symptoms of ketoacidosis include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath.

Before initiating diazoxide choline, test fasting plasma glucose (FPG) and HbA1c; optimize blood glucose in patients who have hyperglycemia. After initiating treatment with diazoxide choline, regularly monitor fasting glucose (FPG or fasting blood glucose) and HbA1c. Monitor fasting glucose more frequently for the first few weeks of treatment with diazoxide choline in patients with risk factors for hyperglycemia, such as obesity, elevated FPG, HbA1c at the upper limit of normal or above, concomitant use of growth hormone, or concomitant use of systemic corticosteroids.

Advise patients of 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). If a patient experiences hyperglycemia after initiating treatment with diazoxide choline, monitor fasting glucose as clinically indicated, and at least twice weekly until fasting glucose decreases to normal levels. Consider monitoring ketones in patients with worsening hyperglycemia.

If hyperglycemia is treated with anti-hyperglycemic medication during diazoxide choline treatment, continue monitoring fasting glucose at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated. Consider consultation with a healthcare provider with expertise in the treatment of hyperglycemia and counsel patients on lifestyle changes. Based on the severity of the hyperglycemia, diazoxide choline may require dosage interruption, reduction, or discontinuation in order to avoid progression to ketoacidosis.

Risk of Fluid Overload

Edema, including general, localized, and peripheral edema, occurred in 27% of diazoxide choline-treated patients versus 12% of placebo-treated patients in a placebo-controlled trial with treatment-naïve subjects. Severe adverse reactions associated with fluid overload, including pulmonary edema, were reported in diazoxide choline-treated patients during clinical trials.

The antidiuretic property of diazoxide may lead to significant fluid retention, which may precipitate congestive heart failure in patients with compromised cardiac reserve. Diazoxide choline has not been studied in patients with compromised cardiac reserve and should be used with caution in these patients.

Monitor for signs or symptoms of edema or fluid overload and consider appropriate clinical management, which may include diazoxide choline dosage reduction or treatment interruption, if clinically significant.

Specific Populations

Pregnancy

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.

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.

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.

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.

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 diazoxide choline during labor.

Lactation

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 diazoxide choline and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Because of potential adverse reactions, including hyperglycemia, monitoring the infant's blood glucose may be advisable, especially during the neonatal period.

Pediatric Use

The safety and effectiveness of diazoxide choline have been established for the treatment of hyperphagia in pediatric patients 4 years of age and older with PWS. Use of diazoxide choline for this indiction is supported by efficacy data from an adequate and well-controlled study that included pediatric patients with PWS and safety data from additional studies that included pediatric patients with PWS, and the information on this use is described throughout the labeling.

The safety and effectiveness of diazoxide choline have not been established for the treatment of hyperphagia in pediatric patients with PWS less than 4 years of age.

The following postmarketing adverse reactions have been reported with the use of other diazoxide products for the treatment of hyperinsulinemic hypoglycemia, an unapproved population:

• Pulmonary hypertension in pediatric patients less than 6 months of age, including neonates.

• Transient cataracts in association with hyperosmolar coma in a pediatric patient that subsided with correction of the hyperosmolarity.

• Development of abnormal facial features with chronic use in pediatric patients.

Diazoxide choline is not approved and is not recommended for the treatment of hyperinsulinemic hypoglycemia.

Juvenile Animal Toxicity Data: Diazoxide choline was orally administered at doses of 29, 58, and 145 mg/kg/day to juvenile rats from weaning (postnatal day 21) through adulthood (postnatal day 91). Reduced body weight and body weight gains, correlated with decreased food consumption, occurred at doses ≥ 58 mg/kg/day. Delayed sexual maturation occurred in males at ≥ 58 mg/kg/day and in females at all doses. Decreased motor activity was observed in males at ≥ 58 mg/kg/day, but no effect was observed on learning and memory at any dose in both males and females. The no adverse effect level (NOAEL) was 29 mg/kg/day, which results in exposures less than the clinical exposure at the maximum recommended human dose (MRHD) of 525 mg based on AUC.

Geriatric Use

Clinical studies of diazoxide choline did not include any subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

Hepatic Impairment

Diazoxide choline has not been studied in patients with hepatic impairment. Diazoxide choline is not recommended in patients with hepatic impairment.

Renal Impairment

Diazoxide choline has not been studied in patients with renal impairment. Diazoxide choline is not recommended in patients with renal impairment.

Common Adverse Effects

Most common adverse reactions (incidence ≥10% and at least 2% greater than in placebo) are hypertrichosis, edema, hyperglycemia, and rash.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Strong CYP1A2 Inhibitors: Reduce diazoxide choline dosage.

• CYP1A2 Substrates: Concomitant use with diazoxide choline is not recommended.

• Strong CYP1A2 Inhibitors: Monitor the frequency and severity of adverse reactions from diazoxide choline; dosage reduction may be needed.

• Dual Strong CYP3A4/Moderate 1A2 Inducers: Concomitant use not recommended.

• See full prescribing information for additional clinically significant drug interactions.

Actions

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.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide).

• Advise patients to swallow tablets whole and not to split, crush, or chew diazoxide choline.

• 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. 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.

• Advise the patient or caregiver that diazoxide choline may cause edema, including severe adverse reactions associated with fluid overload. Advise patients or caregivers on the signs and symptoms of edema and to contact their healthcare provider if signs or symptoms of edema occur.

Additional Information

AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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