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Drug Interactions between simvastatin and TriCor

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

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Interactions between your drugs

Major

simvastatin fenofibrate

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

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Drug and food interactions

Major

simvastatin food

Applies to: simvastatin

GENERALLY AVOID: Coadministration with grapefruit juice may significantly increase the plasma concentrations of lovastatin and simvastatin and their active acid metabolites. 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 60 mg dose of simvastatin was coadministered with 200 mL of double-strength grapefruit juice three times a day, simvastatin systemic exposure (AUC) increased by 16-fold and simvastatin acid AUC increased by 7-fold. Administration of a single 20 mg dose of simvastatin with 8 ounces of single-strength grapefruit juice increased the AUC of simvastatin and simvastatin acid by 1.9-fold and 1.3-fold, respectively. The interaction has also been reported with lovastatin, which has a similar metabolic profile to simvastatin. 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.

Coadministration with green tea may increase the plasma concentrations of simvastatin. The mechanism of interaction has not been established, but may involve inhibition of organic anion transporting polypeptide (OATP) 1B1- and/or 2B1-mediated hepatic uptake of simvastatin by catechins in green tea. The interaction was suspected in a 61-year-old man who experienced muscle intolerance during treatment with simvastatin while drinking an average of 3 cups of green tea daily. He also experienced similar muscle intolerance (leg cramps without creatine phosphokinase elevation) during treatments with atorvastatin and rosuvastatin while drinking green tea. Pharmacokinetic studies performed during his usual green tea intake demonstrated an approximately two-fold higher exposure to simvastatin lactone (the administered form of simvastatin) than that observed after stopping green tea intake for a month. He was also able to tolerate simvastatin after discontinuing green tea consumption. The authors of the report subsequently conducted two independent studies to assess the effect of different green tea preparations on simvastatin pharmacokinetics. One study was conducted in 12 Italian subjects and the other in 12 Japanese subjects. In the Italian study, administration of a single 20 mg dose of simvastatin following pretreatment with 200 mL of a hot green tea standardized infusion 3 times daily for 14 days (estimated daily intake of 335 mg total catechins and 173 mg epigallocatechin-3-gallate (EGCG), the most abundant and biologically active catechin in green tea) was found to have no significant effect on mean peak plasma concentration (Cmax) or systemic exposure (AUC) of simvastatin lactone and simvastatin acid relative to administration with water. However, green tea increased simvastatin lactone AUC (0-6h) by about two-fold in 3 of the study subjects. In the Japanese study, administration of a single 10 mg dose of simvastatin following pretreatment with 350 mL of a commercial green tea beverage twice daily for 14 days (estimated daily intake of 638 mg total catechins and 322 mg EGCG) did not affect mean simvastatin lactone Cmax or AUC to a statistically significant extent compared to administration with water, but increased mean simvastatin acid Cmax and AUC by 42% and 22%, respectively. Similar to the first study, green tea increased simvastatin lactone AUC (0-6h) by two- to three-fold in 4 of the study subjects. Although not studied, the interaction may also occur with lovastatin due to its similar metabolic profile to simvastatin.

MANAGEMENT: Patients receiving therapy with lovastatin, simvastatin, or red yeast rice (which contains lovastatin) should be advised to avoid the consumption of grapefruit and grapefruit juice. Fluvastatin, pravastatin, pitavastatin, and rosuvastatin are metabolized by other enzymes and may be preferable alternatives in some individuals. All patients receiving statin therapy 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. Also, patients should either refrain from the use of oat bran and pectin, or separate the administration times by at least 2 to 4 hours if concurrent use cannot be avoided. Caution may be advisable when coadministered with green tea or green tea extracts. Dosing reduction of the statin and/or limiting consumption of green tea and green tea products may be required if an interaction is suspected.

References

  1. Richter WO, Jacob BG, Schwandt P (1991) "Interaction between fibre and lovastatin." Lancet, 338, p. 706
  2. (2002) "Product Information. Mevacor (lovastatin)." Merck & Co., Inc
  3. (2001) "Product Information. Zocor (simvastatin)." Merck & Co., Inc
  4. Kantola T, Kivisto KT, Neuvonen PJ (1998) "Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid." Clin Pharmacol Ther, 63, p. 397-402
  5. Bailey DG, Malcolm J, Arnold O, Spence JD (1998) "Grapefruit juice-drug interactions." Br J Clin Pharmacol, 46, p. 101-10
  6. Lilja JJ, Kivisto KT, Neuvonen PJ (1998) "Grapefruit juice-simvastatin interaction: Effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors." Clin Pharmacol Ther, 64, p. 477-83
  7. Thompson PD, Clarkson P, Karas RH (2003) "Statin-associated myopathy." JAMA, 289, p. 1681-90
  8. Neuvonen PJ, Backman JT, Niemi M (2008) "Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin." Clin Pharmacokinet, 47, p. 463-74
  9. Werba JP, Giroli M, Cavalca V, Nava MC, Tremoli E, Dal Bo L (2008) "The effect of green tea on simvastatin tolerability." Ann Intern Med, 149, p. 286-7
  10. Werba JP, Misaka S, Giroli MG, et al. (2014) "Overview of Green Tea Interaction with Cardiovascular Drugs." Curr Pharm Des
  11. Roth M, Timmermann BN, Hagenbuch B (2011) "Interactions of green tea catechins with organic anion-transporting polypeptides." Drug Metab Dispos, 39, p. 920-6
  12. Knop J, Misaka S, Singer K, et al. (2015) "Inhibitory effects of green tea and (-)-epigallocatechin gallate on transport by OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K and P-glycoprotein." PLoS One, 10, e0139370
View all 12 references

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Moderate

simvastatin food

Applies to: simvastatin

MONITOR: Concomitant use of statin medication with substantial quantities of alcohol may increase the risk of hepatic injury. Transient increases in serum transaminases have been reported with statin use and while these increases generally resolve or improve with continued therapy or a brief interruption in therapy, there have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. Active liver disease or unexplained transaminase elevations are contraindications to statin use.

MANAGEMENT: Patients should be counseled to avoid substantial quantities of alcohol in combination with statin medications and clinicians should be aware of the increased risk for hepatotoxicity in these patients.

References

  1. (2001) "Product Information. Pravachol (pravastatin)." Bristol-Myers Squibb
  2. (2001) "Product Information. Zocor (simvastatin)." Merck & Co., Inc
  3. (2001) "Product Information. Lescol (fluvastatin)." Novartis Pharmaceuticals
  4. (2001) "Product Information. Lipitor (atorvastatin)." Parke-Davis
  5. (2002) "Product Information. Altocor (lovastatin)." Andrx Pharmaceuticals
  6. (2003) "Product Information. Crestor (rosuvastatin)." AstraZeneca Pharma Inc
  7. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  8. Cerner Multum, Inc. "Australian Product Information."
  9. (2010) "Product Information. Livalo (pitavastatin)." Kowa Pharmaceuticals America (formerly ProEthic)
View all 9 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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