Zocor (Simvastatin) Interactions
- Amiodarone
Anti-retroviral protease inhibitors
- Aprepitant
Barbiturates
- Bosentan
- Carbamazepine
- Clarithromycin
- Cyclosporine
- Dalfopristin; Quinupristin
- Danazol
- Daptomycin
- Delavirdine
- Digoxin
- Diltiazem
- Efavirenz
- Erythromycin
Fibric acid derivatives
- Fluconazole
- food
- Fosphenytoin
- grapefruit juice
HMG-CoA reductase inhibitors
- Imatinib, STI-571
- Itraconazole
- Ketoconazole
- Mifepristone, RU-486
- Nefazodone
- Nevirapine
- Niacin, Niacinamide
- Oxcarbazepine
- Phenytoin
- Repaglinide
- Rifabutin
- Rifampin
- Rifapentine
- St. John’s Wort, Hypericum perforatum
- Telithromycin
- Troleandomycin
- Verapamil
- Voriconazole
- Warfarin
- Went Yeast, Monascus purpureus
Zocor (Simvastatin) Interactions
NOTE: Simvastatin is a substrate of CYP3A4 hepatic metabolism. Simvastatin has multiple significant drug interactions with CYP3A4 inhibitors, which may result in increased HMG-CoA reductase inhibition and toxicity including myopathy and rhabdomyolysis (See Adverse Reactions). The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma, and is expected to be increased with higher doses of simvastatin. Any patient receiving a drug known to increase simvastatin serum concentrations or increase the risk of myopathy should be carefully monitored for potential myalgia, myopathy, myasthenia, and/or rhabdomyolysis. Simvastatin does not affect the metabolism CYP3A4 substrates.
Simvastatin should not be administered along with other HMG-CoA reductase inhibitors. The administration of more than one HMG-CoA reductase inhibitor at one time would be duplicative therapy and perhaps increase the risk of drug-related toxicity including myopathy and rhabdomyolysis (See Adverse Reactions). Since compounds in went yeast, Monascus purpureus (Cholestin™) are chemically similar to lovastatin, went yeast should not be used in combination with HMG-CoA reductase inhibitors.
Cyclosporine, fibric acid derivatives (e.g., gemfibrozil, fenofibrate, clofibrate), and antilipemic doses of niacin (i.e., vitamin B3 as nicotinic acid) may increase the risk of myopathy, rhabdomyolysis, and acute renal failure (see Adverse Reactions); however, in some cases simvastatin has been used safely in combination with these agents. This risk may be increased at higher doses of simvastatin. In patients taking gemfibrozil or cyclosporine, the initial simvastatin dose should not exceed 5 mg/day PO, and the total simvastatin dose should not exceed 10 mg/day PO to reduce the risk of myopathy (see Dosage section). The risk of myopathy is increased by gemfibrozil, and to a lesser extent by other fibrates or niacin >= 1 g/day. Fibrates or doses of niacin >= 1 g/day are independently associated with myopathy. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined ‘statin’ and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Simvastatin causes a slight elevation of serum digoxin levels (< 3 ng/ml). Simvastatin should be used cautiously in patients receiving digoxin.
Several statins, including simvastatin, can potentiate the anticoagulant effects of warfarin. The anticoagulant effects of acenocoumarol (not available in the US) are also potentiated by simvastatin. Simvastatin should be prescribed cautiously in patients receiving warfarin, with appropriate INR monitoring.
Macrolide antibiotics such as erythromycin and clarithromycin are not recommended during simvastatin therapy. These macrolides potently inhibit the metabolism of simvastatin via the CYP3A4 isoenzyme and increase the risk of myopathy and rhabdomyolysis. According to the manufacturer, if no alternative to a short course of erythromycin or clarithromycin therapy is available, brief interruption of simvastatin therapy should be considered. A similar interaction is expected with troleandomycin (CYP3A4 inhibitor). There are no known adverse effects with short-term discontinuation of simvastatin.
The concurrent use of telithromycin with simvastatin, lovastatin, or atorvastatin is not recommended. A pharmacokinetic study reported increased simvastatin concentrations due to CYP3A4 inhibition by telithromycin. There was a 5.3-fold increase in simvastatin Cmax, an 8.9-fold increase in the AUC, a 3.2-fold increase in the active metabolite Cmax, and a 4.3-fold increase in the active metabolite AUC. In another study, when simvastatin and telithromycin were administered 12 hours apart, there was a 3.4-fold increase in simvastatin Cmax, a 4-fold increase in AUC, a 3.2-fold increase in the active metabolite Cmax, and a 4.3-fold increase in the active metabolite AUC. A similar interaction may occur with atorvastatin and lovastatin which are also CYP3A4 substrates. Increased serum concentrations of HMG-CoA reductase inhibitors are associated with myopathy. As recommended by the manufacturer, therapy with simvastatin, lovastatin, or atorvastatin should be suspended while taking telithromycin. There are no known adverse effects with short-term discontinuation of statins.
Daptomycin has been associated with elevated CPK in clinical trials. HMG-CoA reductase inhibitors are known to cause myopathy. In a placebo-controlled phase I trial of daptomycin that included 10 healthy subjects stabilized on simvastatin therapy, there was no increase in the incidence of adverse reactions, nor was myopathy reported. However, since data regarding co-administration of daptomycin with HMG-CoA reductase inhibitors are limited, temporary suspension of HMG-CoA reductase inhibitor therapy should be considered in patients receiving daptomycin.
Dalfopristin; quinupristin has been shown to inhibit CYP3A4 and may decrease the elimination of simvastatin (CYP3A4 substrate).
The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as the systemic azole fungals (e.g., fluconazole, itraconazole, ketoconazole, voriconazole). Concurrent use of simvastatin and itraconazole or ketoconazole is contraindicated. There are no known adverse effects with short-term discontinuation of simvastatin; discontinuation of simvastatin may be advisable when concurrent short-term therapy with systemic azole fungals is needed.
The risk of developing myopathy is significantly increased if simvastatin is administered concomitantly with amiodarone (a CYP3A4 inhibitor). In patients taking amiodarone and simvastatin concurrently, the simvastatin dose should not exceed 20 mg/day PO (see Dosage section).
In patients taking verapamil and simvastatin concurrently, the simvastatin dose should not exceed 20 mg/day PO (see Simvastatin Dosage). Verapamil and diltiazem are CYP3A4 inhibitors that may increase the serum concentrations of simvastatin (CYP3A4 substrate). The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A4 metabolism and reduction of first-pass metabolism. In a drug interaction study, verapamil has been reported to increase simvastatin serum concentrations and the AUC. Verapamil has been shown to significantly increase the risk of myopathy due to simvastatin. 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). The risk for myopathy is related to the dose of simvastatin. Diltiazem significantly increases the mean Cmax of simvastatin and simvastatin acid by about 3.6-fold and 3.7-fold, respectively. In addition, diltiazem significantly increases the AUC of simvastatin by 5-fold. Diltiazem has been reported to increase lovastatin (CYP3A4 substrate) serum concentrations (AUC and Cmax), without changing pravastatin serum concentrations.
Food-drug interactions include grapefruit juice. Large quantities of grapefruit juice (>1 quart daily) are contraindicated during simvastatin therapy due to the increased risk of myopathy. Grapefruit juice contains compounds that inhibits the CYP3A4 isozyme in the gut wall. Coadministration with grapefruit juice increases the peak serum concentrations and the AUC of lovastatin and may have a similar effect on the serum concentrations of simvastatin, atorvastatin, and cerivastatin, which are CYP3A4 substrates. Grapefruit juice should be avoided or minimized in patients taking these agents to avoid the potential for drug accumulation and toxicity (ie. myopathy and rhabdomyolysis).
Nefazodone is not recommended during simvastatin therapy due to the increased risk of myopathy. Nefazodone may reduce the metabolism of certain HMG-CoA reductase inhibitors via inhibition of the hepatic CYP3A4 isoenzyme. Both rhabdomyolysis and myositis have been reported in the literature secondary to concurrent administration of nefazodone with either lovastatin or simvastatin. Since pravastatin and rosuvastatin are not substantially metabolized and fluvastatin is a minor CYP3A4 substrate (20%), these statins are less likely to be significantly affected by CYP3A4 inhibitors such as nefazodone.
The coadministration of anti-retroviral protease inhibitors or delavirdine with simvastatin is not recommended. These drugs significantly inhibit the metabolism of simvastatin via the CYP3A4 isoenzyme. Concurrent use of simvastatin with any of these drugs may increase the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Efavirenz has potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates, although in vitro data indicates CYP3A4 inhibitory activity. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be co-administered with simvastatin with caution.
Mifepristone, RU-486 inhibits CYP3A4 in vitro. Coadministration of mifepristone may lead to an increase in serum levels drugs metabolized via CYP3A4, such as simvastatin. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
Imatinib, STI-571 inhibits the metabolism of simvastatin via the cytochrome P450 3A4 isoenzyme. Concurrent use of simvastatin and imatinib resulted in 2- and 3.5-fold increases in simvastatin Cmax and AUC values, respectively.
Phenytoin, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates (atorvastatin, cerivastatin, lovastatin, simvastatin). One case study documented a increase in cholesterol serum concentrations and decrease in gamma-glutamyl transpeptidase levels (returned to normal range) when phenytoin was discontinued during concurrent atorvastatin therapy. Carbamazepine has been reported to reduce the serum concentrations of simvastatin, probably by inducing metabolism via CYP3A4. Other significant CYP3A4 inducers include, but are not limited to: barbiturates, fosphenytoin, nevirapine, oxcarbazepine, rifampin, rifabutin, rifapentine, and St. John’s Wort. Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of simvastatin. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered with HMG-CoA reductase inhibitors which are metabolized by CYP3A4.
Co-administration of bosentan decreases the plasma concentrations of simvastatin (a CYP3A4 substrate), and its active metabolite, by approximately 50%. The plasma concentrations of bosentan are not affected. Bosentan is also expected to reduce plasma concentrations of other statins that have significant metabolism by CYP3A4, such as lovastatin, cerivastatin, and atorvastatin. The possibility of reduced anti-lipemic efficacy should be considered. Patients receiving CYP3A4 metabolized statins should have cholesterol levels monitored after adding bosentan therapy to evaluate the need for anti-lipemic dosage adjustment.
The effects of combined ezetimibe/HMG-CoA reductase inhibitor (’statin’) therapy are synergistic, resulting in greater LDL reductions than either ezetimibe or statin monotherapy. When used in combination with 10 - 80 mg of simvastatin, combined use with ezetimibe reduces LDL-cholesterol by approximately 51% versus 36% with simvastatin monotherapy. No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with simvastatin.
As a moderate inhibitor of hepatic CYP3A4 isoenzymes, aprepitant has the potential to increase serum concentrations of atorvastatin, cerivastatin, lovastatin, or simvastatin (CYP3A4 substrates). Although this interaction has not been studied, monitor for signs and symptoms of myopathy in patients receiving aprepitant concurrently with these HMG-CoA reductase inhibitors.
The risk of myopathy and rhabdomyolysis is increased if danazol is used with simvastatin. A single case report has documented the onset of myositis that progressed to rhabdomyolysis with myoglobinuria after danazol was added to a regimen containing lovastatin. Although other drugs were in use concurrently, a drug interaction between danazol and lovastatin is suspected, as danazol (CYP3A4 inhibitor) is known to inhibit lovastatin metabolism. If concurrent use of simvastatin and danazol is desired, carefully weigh the risk of benefits from simvastatin against the risk of myopathy and rhabdomyolysis. In patients taking danazol, the initial simvastatin dose should not exceed 5 mg/day PO, and the total simvastatin dose should not exceed 10 mg/day PO (see Dosage section).
Coadministration of 20 mg simvastatin and a single dose of 2 mg repaglinide (after 4 days of once daily simvastatin 20 mg and three times daily repaglinide 2 mg) resulted in a 26% increase in repaglinide Cmax from 23.6 ng/ml to 29.7 ng/ml, but the repaglinide AUC was unchanged. Coadministration of simvastatin and repaglinide, given over a 5 day period, resulted in a 26% increase in repaglinide Cmax. This interaction could result in an increased risk of adverse effects associated with repaglinide, specifically hypoglycemia.
[ Last revised: 9/6/2005 6:05:00 PM ]
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