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Drug Interactions between Lipitor and TriCor

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Major

atorvastatin fenofibrate

Applies to: Lipitor (atorvastatin) and TriCor (fenofibrate)

GENERALLY AVOID: Severe myopathy and rhabdomyolysis have been reported during concomitant use of HMG-CoA reductase inhibitors and fibric acid derivatives, especially gemfibrozil. Gemfibrozil has been reported to significantly increase the plasma concentrations of some HMG-CoA reductase inhibitors and/or their active metabolites, including lovastatin, simvastatin, pravastatin, cerivastatin, and rosuvastatin (but not fluvastatin). High levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death. Other fibrates have not been shown to significantly affect the pharmacokinetics of HMG-CoA reductase inhibitors. However, the use of fibrates alone has also been associated with development of myopathy, thus a pharmacodynamic interaction could conceivably occur.

MANAGEMENT: Concurrent use of fibric acid derivatives and HMG-CoA reductase inhibitors should generally be avoided unless the benefit of further alterations in lipid levels is anticipated to outweigh the potential risks. Addition of fibrates to HMG-CoA reductase inhibitor therapy typically provides little additional reduction in LDL cholesterol, but further reductions of triglycerides and increases in HDL cholesterol may be attained. If the combination is prescribed, a fibrate other than gemfibrozil may be preferable, along with lower initial dosages of the HMG-CoA reductase inhibitor. If gemfibrozil is used, rosuvastatin daily dosage should not exceed 10 mg. Lovastatin labeling recommends that the dosage not exceed 20 mg daily when prescribed with gemfibrozil or other fibrates. All patients treated with HMG-CoA reductase inhibitors and/or fibrates should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed. In addition, patients should be closely monitored for hepatotoxicity.

References

  1. Pierce LR, Wysowski DK, Gross TP "Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy." JAMA 264 (1990): 71-5
  2. Schwandt P "Drug interactions and side effects of hypolipidemic drugs." Int J Clin Pharmacol Biopharm 17 (1979): 351-6
  3. "Product Information. Mevacor (lovastatin)." Merck & Co., Inc PROD (2002):
  4. "Product Information. Pravachol (pravastatin)." Bristol-Myers Squibb PROD (2001):
  5. "Product Information. Zocor (simvastatin)." Merck & Co., Inc PROD (2001):
  6. Lozada A, Dujovne CA "Drug interactions with fibric acids." Pharmacol Ther 63 (1994): 163-76
  7. Spence JD, Munoz CE, Hendricks L, Latchinian L, Khouri HE "Pharmacokinetics of the combination of fluvastatin and gemfibrozil." Am J Cardiol 76 (1995): a80-3
  8. Abdul-Ghaffar NU, el-Sonbaty MR "Pancreatitis and rhabdomyolysis associated with lovastatin-gemfibrozil therapy." J Clin Gastroenterol 21 (1995): 340-1
  9. "Product Information. Atromid-S (clofibrate)." Wyeth-Ayerst Laboratories PROD (2001):
  10. "Product Information. Lipitor (atorvastatin)." Parke-Davis PROD (2001):
  11. "Product Information. Baycol (cerivastatin)." Bayer PROD (2001):
  12. "Product Information. Tricor (fenofibrate)." Abbott Pharmaceutical PROD (2001):
  13. Duell PB, Connor WE, Illingworth DR "Rhabdomyolysis after taking atorvastatin with gemfibrozil." Am J Cardiol 81 (1998): 368-9
  14. Tal A, Rajeshawari M, Isley W "Rhabdomyolysis associated with simvastatin-gemfibrozil therapy." South Med J 90 (1997): 546-7
  15. Miller DB, Spence JD "Clinical pharmacokinetics of fibric acid derivatives (fibrates)." Clin Pharmacokinet 34 (1998): 155-62
  16. Pogson GW, Kindred LH, Carper BG "Rhabdomyolysis and renal failure associated with cerivastatin-gemfibrozil combination therapy." Am J Cardiol 83 (1999): 1146
  17. Murdock DK, Murdock AK, Murdock RW, Olson KJ, Frane AM, Kersten ME, Joyce DM, Gantner SE "Long-term safety and efficacy of combination gemfibrozil and HMG-CoA reductase inhibitors for the treatment of mixed lipid disorders." Am Heart J 138 (1999): 151-5
  18. Bermingham RP, Whitsitt TB, Smart ML, Nowak DP, Scalley RD "Rhabdomyolysis in a patient receiving the combination of cerivastatin and gemfibrozil." Am J Health Syst Pharm 57 (2000): 461-4
  19. Rodriguez ML "Cerivastatin-induced rhabdomyolysis." Ann Intern Med 132 (2000): 598
  20. Backman JT, Kyrklund C, Kivisto KT, Wang JS, Neuvonen PJ "Plasma concentrations of active simvastatin acid are increased by gemfibrozil." Clin Pharmacol Ther 68 (2000): 122-9
  21. Alexandridis G, Pappas GA, Elisaf MS "Rhabdomyolysis due to combination therapy with cerivastatin and gemfibrozil." Am J Med 109 (2000): 261-2
  22. Garcia-Valdecasas-Campelo E, Gonzalez-Reimers E, Lopez-Lirola A, Rodriguez-Rodriguez E, Santolaria-Fernandez F "Acute rhabdomyolysis associated with cerivastatin therapy." Arch Intern Med 161 (2001): 893
  23. Mastroianni CM, dEttorre G, Forcina G, Lichtner M, Corpolongo A, Coletta S, Vullo V "Rhabdomyolysis after cerivastatin-gemfibrozil therapy in an HIV-infected patient with protease inhibitor-related hyperlipidemia." AIDS 15 (2001): 820-1
  24. Tomlinson B, Lan IW "Combination therapy with cerivastatin and gemfibrozil causing rhabdomyolysis: Is the interaction predictable?." Am J Med 110 (2001): 669
  25. Kyrklund C, Backman JT, Kivisto KT, Neuvonen M, Laitila J, Neuvonen PJ "Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate." Clin Pharmacol Ther 69 (2001): 340-5
  26. Bruno-Joyce J, Dugas JM, MacCausland OE "Cerivastatin and gemfibrozil-associated rhabdomyolysis." Ann Pharmacother 35 (2001): 1016-9
  27. Staffa JA, Chang J, Green L "Cerivastatin and reports of fatal rhabdomyolysis." N Engl J Med 346 (2002): 539-40
  28. Roca B, Calvo B, Monferrer R "Severe rhabdomyolysis and cerivastatin-gemfibrozil combination therapy." Ann Pharmacother 36 (2002): 730-1
  29. Prueksaritanont T, Zhao JJ, Ma B, et al. "Mechanistic Studies on Metabolic Interactions between Gemfibrozil and Statins." J Pharmacol Exp Ther 301 (2002): 1042-51
  30. Williams D, Feely J "Pharmacokinetic-Pharmacodynamic Drug Interactions with HMG-CoA Reductase Inhibitors." Clin Pharmacokinet 41 (2002): 343-70
  31. Backman JT, Kyrklund C, Neuvonen M, Neuvonen PJ "Gemfibrozil greatly increases plasma concentrations of cerivastatin." Clin Pharmacol Ther 72 (2002): 685-91
  32. "Product Information. Crestor (rosuvastatin)." AstraZeneca Pharma Inc (2003):
  33. Kyrklund C, Backman JT, Neuvonen M, Neuvonen PJ "Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance." Clin Pharmacol Ther 73 (2003): 538-44
  34. Prueksaritanont T, Tang C, Qiu Y, Mu L, Subramanian R, Lin JH "Effects of fibrates on metabolism of statins in human hepatocytes." Drug Metab Dispos 30 (2002): 1280-7
  35. Fujino H, Shimada S, Yamada I, Hirano M, Tsunenari Y, Kojima J "Studies on the interaction between fibrates and statins using human hepatic microsomes." Arzneimittelforschung 53 (2003): 701-7
  36. Schneck DW, Birmingham BK, Zalikowski JA, et al. "The effect of gemfibrozil on the pharmacokinetics of rosuvastatin." Clin Pharmacol Ther 75 (2004): 455-63
  37. Jacob SS, Jacob S, Williams C, Deeg MA "Simvastatin, fenofibrate, and rhabdomyolysis." Diabetes Care 28 (2005): 1258
  38. Wang JS, Neuvonen M, Wen X, Backman JT, Neuvonen PJ "Gemfibrozil inhibits CYP2C8-mediatd cerivastatin metabolism in human liver microsomes." Drug Metab Dispos 30 (2002): 1352-6
  39. Ireland JH, Eggert CH, Arendt CJ, Williams AW "Rhabdomyolysis with cardiac involvement and acute renal failure in a patient taking rosuvastatin and fenofibrate." Ann Intern Med 142 (2005): 949-50
  40. Davidson MH "Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions." Exp Opin Drug Saf 5 (2006): 145-56
  41. Neuvonen PJ, Backman JT, Niemi M "Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin." Clin Pharmacokinet 47 (2008): 463-74
  42. Unal A, Torun E, Sipahioglu MH, et al. "Fenofibrate-induced acute renal failure due to massive rhabdomyolysis after coadministration of statin in two patients." Intern Med 47 (2008): 1017-9
View all 42 references

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Drug and food interactions

Moderate

atorvastatin food

Applies to: Lipitor (atorvastatin)

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of atorvastatin. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. When a single 40 mg dose of atorvastatin was coadministered with 240 mL of grapefruit juice, atorvastatin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 16% and 37%, respectively. Greater increases in Cmax (up to 71%) and/or AUC (up to 2.5 fold) have been reported with excessive consumption of grapefruit juice (>=750 mL to 1.2 liters per day). Clinically, high levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death.

ADJUST DOSING INTERVAL: Fibres such as oat bran and pectin may diminish the pharmacologic effects of HMG-CoA reductase inhibitors by interfering with their absorption from the gastrointestinal tract.

MANAGEMENT: Patients receiving therapy with atorvastatin should limit their consumption of grapefruit juice to no more than 1 liter per day. Patients should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed. In addition, patients should either refrain from the use of oat bran and pectin or, if concurrent use cannot be avoided, to separate the administration times by at least 2 to 4 hours.

References

  1. Richter WO, Jacob BG, Schwandt P "Interaction between fibre and lovastatin." Lancet 338 (1991): 706
  2. McMillan K "Considerations in the formulary selection of hydroxymethylglutaryl coenzyme a reductase inhibitors." Am J Health Syst Pharm 53 (1996): 2206-14
  3. "Product Information. Lipitor (atorvastatin)." Parke-Davis PROD (2001):
  4. Boberg M, Angerbauer R, Fey P, Kanhai WK, Karl W, Kern A, Ploschke J, Radtke M "Metabolism of cerivastatin by human liver microsomes in vitro. Characterization of primary metabolic pathways and of cytochrome P45 isozymes involved." Drug Metab Dispos 25 (1997): 321-31
  5. Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions." Br J Clin Pharmacol 46 (1998): 101-10
  6. Lilja JJ, Kivisto KT, Neuvonen PJ "Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin." Clin Pharmacol Ther 66 (1999): 118-27
  7. Neuvonen PJ, Backman JT, Niemi M "Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin." Clin Pharmacokinet 47 (2008): 463-74
View all 7 references

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

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