Diazoxide

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 significant drug interactions. ( 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…