Lipitor (Atorvastatin) Interactions
- Amiodarone
Antacids
Anti-retroviral protease inhibitors
- Aprepitant
Barbiturates
- Bosentan
- Carbamazepine
- Clarithromycin
- Clopidogrel
- Colestipol
- 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
Oral contraceptives
- Oxcarbazepine
- Phenytoin
- Pioglitazone
- Rifabutin
- Rifampin
- Rifapentine
- St. John’s Wort, Hypericum perforatum
- Telithromycin
- Troglitazone
- Troleandomycin
- Verapamil
- Voriconazole
- Went Yeast, Monascus purpureus
Lipitor (Atorvastatin) Interactions
NOTE: Atorvastatin is a substrate of CYP3A4 hepatic metabolism. It has potential significant drug interactions with CYP3A4 inhibitors, which may result in increased HMG-CoA reductase inhibition and potential toxicity (ie., myopathy, rhabdomyolysis).
Atorvastatin 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/red yeast rice claim to have HMG-CoA reductase inhibitor activity, went yeast/red yeast rice should not be used in combination with HMG-CoA reductase inhibitors.
The risk of developing myopathy during therapy with HMG-CoA reductase inhibitors (’statins’) such as atorvastatin (CYP3A4 substrate) is increased if coadministered with CYP3A4 inhibitors . Examples of CYP3A4 inhibitors include but are not limited to: clarithromycin, erythromycin, fluconazole, imatinib, STI-571, itraconazole, ketoconazole, troleandomycin, and voriconazole. Itraconazole increases the AUC of atorvastatin by 2.5-fold, which is substantially less than the effect of itraconazole on the AUC of simvastatin and lovastatin (increased 19-fold and 20-fold, respectively). Coadministration of atorvastatin with erythromycin increases atorvastatin plasma concentrations by about 40%. The interaction leading to myopathy is unlikely with normal doses of topically applied erythromycin or azole antifungal agents (i.e., topical ketoconazole cream or shampoo) coadministered with atorvastatin. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. 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.
The risk of myopathy increases when HMG-Co-A reductase inhibitors are administered concurrently with fibric acid derivatives (e.g., gemfibrozil, fenofibrate, clofibrate) or antilipemic doses of niacin (i.e., vitamin B3 as nicotinic acid). When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. 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.
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.
While the manufacturer’s product literature warns of using immunosuppressives with atorvastatin, this warning is based mainly on the interaction with cyclosporine and may not apply to all immunosuppressives. The risk of developing myopathy during therapy with HMG-CoA reductase inhibitors is increased if they are administered concomitantly with cyclosporine. When administered in combination with immunosuppressive therapy including cyclosporine, the incidence of lovastatin-induced myopathy rises to 30%.
Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends that caution should be exercised when atorvastatin is administered concomitantly with drugs (e.g., cimetidine, ketoconazole, spironolactone) that may decrease the concentrations or activity of endogenous hormones. The clinical relevance of these potential interactions has not been established. Cimetidine does not appear to alter the pharmacokinetics of atorvastatin.
Concomitant administration of atorvastatin with antacids (Maalox® TC) reduced the plasma concentrations of atorvastatin by approximately 35%. However, LDL-cholesterol reduction was not altered.
Coadministration of atorvastatin with colestipol resulted in approximately 25% lower plasma concentrations of atorvastatin. However, LDL-cholesterol reduction was greater when atorvastatin and colestipol were administered together than when either drug was given alone.
Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. Area-under-the-curve values for norethindrone and ethinyl estradiol were increased by approximately 30% and 20%, respectively, when atorvastatin was given concurrently. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly.
Coadministration of atorvastatin 80 mg (but not 10 mg) with digoxin resulted in an approximately 20% increase in digoxin plasma concentrations. Patients receiving atorvastatin should be monitored for potential increases in digoxin effects or toxicity.
Dalfopristin; quinupristin has been shown to inhibit CYP3A4 and may decrease the elimination of atorvastatin (CYP3A4 substrate) .
Verapamil and diltiazem may increase the serum concentrations of simvastatin, lovastatin, atorvastatin, and cerivastatin, which are CYP3A4 substrates. The interaction is presumed due to increased simvastatin bioavailability via inhibition of CYP3A4 metabolism and reduction of first-pass metabolism. In one report, diltiazem caused elevations in lovastatin serum concentrations, but did not affect pravastatin serum concentrations. Diltiazem significantly increased the oral AUC and maximum serum concentration (Cmax) of lovastatin but did not affect the elimination half-life. The affect on the active metabolite of lovastatin was not reported. In a drug interaction study with simvastatin, verapamil was reported to increase simvastatin serum concentrations and the AUC.
Food-drug interactions with atorvastatin include grapefruit juice. Grapefruit juice contains a compound that inhibits the CYP3A4 isozyme in the gut wall. Studies have reported that 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 , all of which are CYP3A4 substrates. Grapefruit juice should be avoided in patients taking agents to avoid the potential for drug accumulation and toxicity (ie. myopathy and rhabdomyolysis).
Nefazodone may reduce the metabolism of certain HMG-CoA reductase inhibitors (e.g., atorvastatin, cerivastatin, lovastatin, simvastatin) 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.
Concurrent use of anti-retroviral protease inhibitors or delavirdine with atorvastatin should be done cautiously. These drugs may inhibit the CYP3A4 metabolism of atorvastatin. Coadministration of atorvastatin with any of these drugs may increase the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy increases the AUC of total active atorvastatin by 79%. 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 atorvastatin 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 atorvastatin . Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
Coadministration of pioglitazone for seven days with atorvastatin (80 mg once daily) resulted in a log-transformed AUC ratio of 0.76 for pioglitazone and 0.86 for atorvastatin. The clinical significance of this interaction is unknown, however, patients should be evaluated more frequently with respect to glycemic control and lipid therapy.
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.
Atorvastatin has no clinically significant effect on the prothrombin time when administered to patients receiving chronic warfarin therapy. In a study by the manufacturer, patients chronically maintained on warfarin were administered atorvastatin (80 mg/day) for 2 weeks. Mean prothrombin times decreased slightly, but only for the first few days of treatment.
Rifampin has been reported to significantly increase the plasma clearance and decrease the serum concentrations of simvastatin and fluvastatin, with the potential for reduced antilipemic efficacy. Although not studied, a similar interaction can be expected between other rifamycins (e.g., rifabutin, rifapentine) and other HMG-CoA reductase inhibitors. To evaluate this interaction, monitor serum lipid concentrations during coadministration of rifamycins with HMG-CoA reductase inhibitors.
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. Other significant CYP3A4 inducers include, but are not limited to: barbiturates , carbamazepine , fosphenytoin , nevirapine , oxcarbazepine , rifamycins , troglitazone, and St. John’s Wort . Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered with HMG-CoA reductase inhibitors which are metabolized by CYP3A4.
Amiodarone may inhibit hepatic CYP3A4 isoenzymes, and therefore has the potential to increase serum concentrations of atorvastatin, cerivastatin, lovastatin, or simvastatin (CYP3A4 substrates). Monitor for signs and symptoms of myopathy in patients receiving amiodarone concurrently with these HMG-CoA reductase inhibitors. The risk of developing myopathy has been shown to be significantly increased if simvastatin is administered concomitantly with amiodarone (a CYP3A4 inhibitor).
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.
Atorvastatin has been reported to attenuate the antiplatelet activity of clopidogrel potentially by inhibiting CYP3A4 metabolism to its active metabolite; however, conflicting data exists. The clinical significance of this theoretical interaction is not known. Patients should be monitored for therapeutic effectiveness when clopidogrel is administered with atorvastatin or other HMG Co-A reductase inhibitors metabolized by the CYP 3A4 isozyme (i.e., lovastatin, simvastatin, and cerivastatin).
A single case report has documented the onset of myositis which 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 since danazol (CYP3A4 inhibitor) is known to inhibit lovastatin metabolism. Until more data are available, danazol should be used very cautiously, if at all, in patients receiving statins which are CYP3A4 substrates (atorvastatin, cerivastatin, lovastatin, simvastatin) .
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 atorvastatin, combined use with ezetimibe reduces LDL by approximately 56% versus 44% with atorvastatin monotherapy. No clinically significant pharmacokinetic interactions are seen when ezetimibe is co-administered with atorvastatin.
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.
[ Last revised: 12/5/2005 4:59:00 PM ]
References
. Azie NE, Brater DC, Becker PA, et al. The interaction of diltiazem with lovastatin and pravastatin. Clin Pharmacol Ther 1998;64:369-77.
. Tobert JA, Vega JM, Dobrinska M, et al. Calcium channel blocker-simvastatin interaction. Clin Pharmacol Ther 1999;65:583-5.
. Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 1998;64:177-82.
. Gagne C, Gaudet D, Bruckert E, et al. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 2002;105:2469-75.
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