Generic Name
Diazoxide
Brand Names
VYKAT, Proglycem
FDA approval date: September 30, 1990
Form: Tablet, Suspension
What is VYKAT (Diazoxide)?
Diazoxide Oral Suspension, USP is useful in the management of hypoglycemia due to hyperinsulinism associated with the following conditions: Adults:Inoperableisletcelladenoma or carcinoma, or extrapancreaticmalignancy. Infants and Children: Leucine sensitivity, islet cell hyperplasia, nesidioblastosis, extrapancreatic malignancy, islet cell adenoma, or adenomatosis. Diazoxide Oral Suspension, USP may be used preoperatively as a temporary measure, and postoperatively, if hypoglycemia persists. Diazoxide Oral Suspension, USP should be used only after a diagnosis of hypoglycemia due to one of the above conditions has been definitely established. When other specific medical therapy or surgical management either has been unsuccessful or is not feasible, treatment with Diazoxide Oral Suspension, USP should be considered.
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Brand Information
VYKAT XR (diazoxide choline)
1INDICATIONS 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).
2DOSAGE 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.
3CONTRAINDICATIONS
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
4ADVERSE REACTIONS
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
- Hyperglycemia
- Risk of Fluid Overload
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
- 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.
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
5DRUG INTERACTIONS
Table 4 displays clinically significant drug interactions with VYKAT XR.
6OVERDOSAGE
An overdosage of VYKAT XR may cause marked hyperglycemia, which may be associated with ketoacidosis
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.
7DESCRIPTION
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
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
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.
8CLINICAL STUDIES
The efficacy of VYKAT XR for the treatment of hyperphagia in adults and pediatric patients ages 4 yearsand older with PWS was established in a 16-week, double-blind, placebo-controlled, randomized withdrawal study period (Study 2-RWP; NCT03714373) that followed an open-label study period of VYKAT XR. During Study 2-RWP, 77 patients with hyperphagia and PWS were randomized in a 1:1 ratio to continue their current oral dosage using a weight-based dosage regimen of VYKAT XR or placebo
Demographic and baseline disease characteristics were similar for the VYKAT XR and placebo groups. The mean age was 14.9 years of age (range 7 to 29 years of age). Most of the participants were White (86%), 7% were Black or African American, and 8% were of multiple races. The majority of participants were non-Hispanic (91%) and female (56%).
The primary efficacy endpoint was the Change from Baseline in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score at Week 16. The HQ-CT is a 9-item, observer-reported outcome measure that assesses a range of hyperphagic and food-related behaviors during the prior 2 weeks. An item score of 0 indicates an absence of behaviors, with a score of 4 indicating the most frequent or severe behaviors. The HQ-CT Total Score may range from 0 to 36, with higher scores indicating greater overall severity of hyperphagic and food-related behaviors.
At the end of the 16-week randomized withdrawal study period, there was statistically significant worsening of hyperphagia in the placebo group relative to the VYKAT XR group, as assessed by the HQ- CT Total Score (see
9HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
VYKAT XR is supplied as follows:
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.
10PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Administration Instructions
Advise patients to swallow tablets whole and not to split, crush, or chew VYKAT XR
Hyperglycemia
Advise the patient or caregiver that VYKAT XR can cause hyperglycemia, sometimes leading to diabetic ketoacidosis, and that the patient will have monitoring of blood glucose before and during VYKAT XR 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
Risk of Fluid Overload
Advise the patient or caregiver that VYKAT XR 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
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