Divalproex (valproate) and Lopinavir and ritonavir interaction

…Non-opioid Analgesic (selective blocker of Nav1.8 sodium channels): suzetrigine PDE5 Inhibitor: sildenafil (Revatio ® ) when used for the treatment of pulmonary arterial hypertension Sedative/Hypnotics: triazolam, orally administered midazolam KALETRA is contraindicated with drugs that are potent CYP3A inducers where significantly reduced lopinavir plasma concentrations…

Postmarketing life-threatening cases of cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving KALETRA oral solution.

Sedative/Hypnotics: triazolam, orally administered midazolam ↑ triazolam ↑ midazolam Contraindicated due to potential for prolonged or increased sedation or respiratory depression [see Contraindications ( 4 )] .

…potential risks, infants should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to KALETRA oral solution including: hyperosmolality, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis.

Anticonvulsants: carbamazepine, phenobarbital, phenytoin ↓ lopinavir ↓ phenytoin KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.

Effects of Co-Administered Drugs on Valproate Clearance Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases (such as ritonavir), may increase the clearance of valproate.

Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance.

Therefore, increased monitoring of valproate and concomitant drug concentrations and dosage adjustment are indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn ( 7.1 )

Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn.

Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy.