f oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant).
Trandolapril; Verapamil: Verapamil has been shown to significantly increase the risk of myopathy due to simvastatin; the risk for myopathy is related to the dose of simvastatin. If verapamil and simvastatin must be administered together, do not exceed 10 mg/day simvastatin in adults. For patients chronically receiving simvastatin 80 mg/day who need to be started on verapamil, the manufacturer of simvastatin recommends switching to an alternative statin with less potential for interactions. In an analysis of clinical trials treated with simvastatin 20-80 mg/day, the incidence of myopathy was higher in patients receiving verapamil and simvastatin (0.63%; 4 of 635 patients) than in patients taking simvastatin without a calcium channel blocker (0.061%; 13 patients of 21,224 patients). Verapamil increases simvastatin serum concentrations (increased Cmax and AUC). The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A4 metabolism and reduction of first-pass metabolism.
Ulipristal: In vitro data indicate that ulipristal may be an inhibitor of P-glycoprotein (P-gp) at clinically relevant concentrations. Thus, co-administration of ulipristal and P-gp substrates such as simvastatin may increase simvastatin concentrations; use caution. With single doses of ulipristal for emergency contraception it is not clear this interaction will have clinical consequence. In the absence of clinical data, co-administration of ulipristal (when given daily) and P-gp substrates is not recommended.
Vandetanib: Use caution if coadministration of vandetanib with simvastatin is necessary, due to a possible increase in simvastatin-related adverse reactions. Simvastatin is partially a substrate of P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of digoxin, another P-gp substrate, by 29% and 23%, respectively.
Vemurafenib: Concomitant use of vemurafenib and simvastatin may result in altered concentrations of simvastatin and increased concentrations of vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4, a substrate/inhibitor of P-glycoprotein (PGP), and a weak inhibitor of CYP2D6. Simvastatin is a substrate of CYP3A4 and CYP2D6 and a substrate/inhibitor of PGP. Use caution and monitor patients for toxicity and efficacy.
Venetoclax: Avoid the concomitant use of venetoclax and simvastatin. Venetoclax is a substrate of P-glycoprotein (P-gp) and may be a P-gp inhibitor at therapeutic dose levels in the gut; simvastatin is a substrate and an inhibitor of P-gp. Consider alternative agents. If concomitant use of these drugs is required, reduce the venetoclax dosage by at least 50% (maximum dose of 200 mg/day) and consider administering simvastatin at least 6 hours before venetoclax. If simvastatin is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were increased by 106% and 78%, respectively, when a P-gp inhibitor was co-administered in healthy subjects.
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