Drug Interactions

Drug-Drug interactions

• The drug-drug interaction potential of APTIVUS/r when co-administered with other drugs must be considered prior to and during APTIVUS/r use
• Co-administration of APTIVUS/r with drugs that are highly dependent on CYP3A for clearance or are potent CYP3A inducers are contraindicated. These recommendations are based on either drug interaction studies or they are predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy

Drugs That Are Contraindicated With APTIVUS/ Ritonavir

• Combining another PI with APTIVUS/r is not recommended
• Didanosine (EC) administration should be separated from APTIVUS/r dosing by at least 2 hours
• Co-administration of fluticasone propionate and APTIVUS/r is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects
• When co-administered with APTIVUS/r, dosage adjustments or considerations may be recommended for fluconazole, itraconazole, ketoconazole, voriconazole, clarithromycin, rifabutin, trazadone, desipramine, fluoxetine, paroxetine, sertraline, atorvastatin, rosuvastatin, valproic acid, carbamazepine, phenobarbital, phenytoin, meperidine, methadone, ethinyl estradiol, omeprazole, sildenafil, tadalafil, vardenafil, diltiazem, felodipine, nicardipine, nisoldipine, and verapamil

CYP3A Interactions

• APTIVUS co-administered with 200 mg of ritonavir is a net inhibitor of cytochrome P450 (CYP) 3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A
• Co-administration of APTIVUS/r with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated
• Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring
• Co-administration of APTIVUS/r with drugs that inhibit CYP3A may not further increase tipranavir concentrations, because the level of metabolites is low following steady-state administration at the recommended dose
• Co-administration of APTIVUS/r with drugs that induce CYP3A may decrease tipranavir plasma concentrations

P-gp Interactions

• Although ritonavir is a P-glycoprotein (P-gp) inhibitor, data suggest that the net effect of APTIVUS/r is P-gp induction at steady state
• Co-administration of APTIVUS/r with drugs that induce P-gp may decrease tipranavir plasma Concentrations
• Co-administration of APTIVUS/r and drugs that inhibit P-gp may increase tipranavir plasma concentrations because APTIVUS is a substrate of P-gp
• It is difficult to predict the net effect of APTIVUS co-administered with ritonavir on oral bioavailability and plasma concentrations of drugs that are dual substrates of CYP3A and P-gp. The net effect will vary depending on the relative affinity of the co-administered drugs for CYP3A and P-gp, and the extent of intestinal first-pass metabolism/efflux.