eases the risk of myopathy and rhabdomyolysis. According to the manufacturer, if no alternative to a short course of clarithromycin therapy is available, therapy with simvastatin must be suspended during the course of clarithromycin treatment. There are no known adverse effects with short-term discontinuation of simvastatin. Use of a statin that is not dependent of CYP3A4 metabolism should be considered. Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction.
Amprenavir: The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Antacids: Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
Aprepitant, Fosaprepitant: Use caution if simvastatin and aprepitant, fosaprepitant are used concurrently and monitor for an increase in simvastatin-related adverse effects, including myopathy and rhabdomyolysis, for several days after administration of a multi-day aprepitant regimen. |
