Diazepam (nasal)

7 DRUG INTERACTIONS CYP2C19 and CYP3A4 Inhibitors: Elimination of diazepam could be decreased with concurrent administration; therefore, adverse reactions with VALTOCO may be increased. ( 7.3 ) Inducers of CYP2C19 and CYP3A4 Inducers: Exposure of diazepam with concurrent administration may be decreased; therefore, efficacy with VALTOCO may be decreased. ( 7.3 )

7.1 Effect of Concomitant Use of Benzodiazepines and Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABA- A sites, and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists [see Warnings and Precautions (5.1) ]. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation.

7.2 CNS Depressants and Alcohol Coadministration of other CNS depressants (e.g., valproate) or consumption of alcohol may potentiate the CNS-depressant effects of diazepam [see Warnings and Precautions (5.4) ].

7.3 Effect of Other Drugs on VALTOCO Metabolism Potential interactions may occur when diazepam is given concurrently with agents that affect CYP2C19 and CYP3A4 activity. Inhibitors of CYP2C19 and CYP3A4 Inhibitors of CYP2C19 (e.g., cimetidine, quinidine, and tranylcypromine) and CYP3A4 (e.g., ketoconazole, troleandomycin, and clotrimazole) could decrease the rate of diazepam elimination; therefore, adverse reactions to VALTOCO may be increased. Inducers of CYP2C19 and CYP3A4 Inducers of CYP2C19 (e.g., rifampin) and CYP3A4 (e.g., carbamazepine, phenytoin, dexamethasone, and phenobarbital) could increase the rate of diazepam elimination; therefore, efficacy of VALTOCO may be decreased.

7.4 Effect of VALTOCO on the Metabolism of Other Drugs Diazepam is a substrate for CYP2C19 and CYP3A4; therefore, it is possible that VALTOCO may interfere with the metabolism of drugs which are substrates for CYP2C19 (e.g., omeprazole, propranolol, and imipramine) and CYP3A4 (e.g., cyclosporine, paclitaxel, theophylline, and warfarin) leading to a potential drug-drug interaction.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as VALTOCO, during pregnancy. Healthcare providers are encouraged to recommend that pregnant women who are taking VALTOCO during pregnancy enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org. Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.7) and Clinical Considerations ] .

Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Human Data ) . In animal studies, administration of diazepam during the organogenesis period of pregnancy resulted in increased incidences of fetal malformations at doses greater than those used clinically. Data for diazepam and other benzodiazepines suggest the possibility of increased neuronal cell death and long-term effects on neurobehavioral and immunological function based on findings in animals following prenatal or early postnatal exposure at clinically relevant doses (see Animal 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 U.S. 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 Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to VALTOCO during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems.

Monitor neonates exposed to VALTOCO during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.7) ] . Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort…