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Drug Interactions between atorvastatin and cyclosporine

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

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Major

cycloSPORINE atorvastatin

Applies to: cyclosporine and atorvastatin

GENERALLY AVOID: Coadministration with cyclosporine may significantly increase the plasma concentrations of some HMG-CoA reductase inhibitors and/or their pharmacologically active metabolites. The proposed mechanism is cyclosporine inhibition of intestinal and hepatic CYP450 3A4, the isoenzyme responsible for the metabolic clearance of HMG-CoA reductase inhibitors like atorvastatin, lovastatin, simvastatin. In addition, atorvastatin, its metabolites, and the active beta-hydroxyacid form of simvastatin, simvastatin acid, are substrates of the hepatic uptake transporter, organic anion transporting polypeptide (OATP) 1B1, which is also inhibited by cyclosporine. The AUC of atorvastatin increased 8.7-fold during concurrent administration of atorvastatin 10 mg/day and cyclosporine 5.2 mg/kg/day. High levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Use of cyclosporine with atorvastatin or other HMG-CoA reductase inhibitors has resulted in 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.

MANAGEMENT: Concomitant use of atorvastatin with cyclosporine should generally be avoided. Fluvastatin or pravastatin may be considered as alternatives in patients receiving cyclosporine, as they are not extensively metabolized by CYP450 3A4. However, the benefits of using these medications in combination with cyclosporine should be carefully weighed against the potential risks, and dosages titrated with caution. The product labeling for fluvastatin recommends that the dosage not exceed 20 mg twice a day when given with cyclosporine. The product labeling for pravastatin recommends initiating treatment at 10 mg/day and generally not exceeding 20 mg/day when given with cyclosporine. 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.

References

  1. Corpier CL, Jones PH, Suki WN, et al. (1988) "Rhabdomyolysis and renal injury with lovastatin use. Report of two cases in cardiac transplant recipients." JAMA, 260, p. 239-41
  2. East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA (1988) "Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation." N Engl J Med, 318, p. 47-8
  3. Norman DJ, Illingworth DR, Munson J, Hosenpud J (1988) "Myolysis and acute renal failure in a heart-transplant recipient receiving lovastatin." N Engl J Med, 318, p. 46-7
  4. (2002) "Product Information. Mevacor (lovastatin)." Merck & Co., Inc
  5. (2001) "Product Information. Pravachol (pravastatin)." Bristol-Myers Squibb
  6. (2001) "Product Information. Zocor (simvastatin)." Merck & Co., Inc
  7. (2001) "Product Information. Lescol (fluvastatin)." Novartis Pharmaceuticals
  8. Vanhaecke J, Vancleemput J, Vanlierde J, Daenen W, Degeest H (1994) "Safety and efficacy of low dose simvastatin in cardiac transplant recipients treated with cyclosporine." Transplantation, 58, p. 42-5
  9. Arnadottir M, Eriksson LO, Germershausen JI, Thysell H (1994) "Low-dose simvastatin is a well-tolerated and efficacious cholesterol-lowering agent in ciclosporin-treated kidney transplant recipients: double-blind, randomized, placebo-controlled study in 40 patients." Nephron, 68, p. 57-62
  10. Campana C, Iacona I, Regassi MB, et al. (1995) "Efficacy and pharmacokinetics of simvastatin in heart transplant recipients." Ann Pharmacother, 29, p. 235-9
  11. (2001) "Product Information. Lipitor (atorvastatin)." Parke-Davis
  12. Southworth MR, Mauro VF (1997) "The use of HMG-CoA reductase inhibitors to prevent accelerated graft atherosclerosis in heart transplant patients." Ann Pharmacother, 31, p. 489-91
  13. Rodriguez JA, CrespoLeiro MG, Paniagua MJ, Cuenca JJ, Hermida LF, Juffe A, CastroBeiras A (1999) "Rhabdomyolysis in heart transplant patients on HMG-CoA reductase inhibitors and cyclosporine." Transplant Proc, 31, p. 2522-3
  14. Gruer PJK, Vega JM, Mercuri MF, Dobrinska MR, Tobert JA (1999) "Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin." Am J Cardiol, 84, p. 811-5
  15. Gullestad L, Nordal KP, Berg KJ, Cheng H, Schwartz MS, Simonsen S (1999) "Interaction between lovastatin and cyclosporine A after heart and kidney transplantation." Transplant Proc, 31, p. 2163-5
  16. Maltz HC, Balog DL, Cheigh JS (1999) "Rhabdomyolysis associated with concomitant use of atorvastatin and cyclosporine." Ann Pharmacother, 33, p. 1176-9
  17. Jardine A, Holdaas H (1999) "Fluvastatin in combination with cyclosporin in renal transplant recipients: a review of clinical and safety experience." J Clin Pharm Ther, 24, p. 397-408
  18. Kusus M, Stapleton DD, Lertora JJL, Simon EE, Dreisbach AW (2000) "Rhabdomyolysis and acute renal failure in a cardiac transplant recipient due to multiple drug interactions." Am J Med Sci, 320, p. 394-7
  19. Arnadottir M, Eriksson LO, Thysell H, Karkas JD (1993) "Plasma concentration profiles of simvastatin 3-hydroxy- 3-methylglutaryl-coenzyme A reductase inhibitory activity in kidney transplant recipients with and without ciclosporin." Nephron, 65, p. 410-3
  20. Capone D, Stanziale P, Gentile A, Imperatore P, Pellegrino T, Basile V (1999) "Effects of simvastatin and pravastatin on hyperlipidemia and cyclosporin blood levels in renal transplant recipients." Am J Nephrol, 19, p. 411-5
  21. Paoletti R, Corsini A, Bellosta S (2002) "Pharmacological interactions of statins." Atheroscler Suppl, 3, p. 35-40
  22. Holtzman CW, Wiggins BS, Spinler SA (2006) "Role of P-glycoprotein in statin drug interactions." Pharmacotherapy, 26, p. 1601-7
  23. Cerner Multum, Inc. "Australian Product Information."
  24. Francis L, Bonilla E, Soforo E, et al. (2008) "Fatal toxic myopathy attributed to propofol, methylprednisolone, and cyclosporine after prior exposure to colchicine and simvastatin." Clin Rheumatol, 27, p. 129-31
  25. 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
  26. Rifkin SI (2008) "Multiple drug interactions in a renal transplant patient leading to simvastatin-induced rhabdomyolysis: a case report." Medscape J Med, 10, p. 264
  27. Kalliokoski A, Niemi M (2009) "Impact of OATP transporters on pharmacokinetics." Br J Pharmacol, 158, p. 693-705
  28. Najafian B, Franklin DB, Fogo AB (2007) "Acute renal failure and myalgia in a transplant patient." J Am Soc Nephrol, 18, p. 2870-4
View all 28 references

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Drug and food interactions

Moderate

cycloSPORINE food

Applies to: cyclosporine

GENERALLY AVOID: Administration with grapefruit juice (compared to water or orange juice) has been shown to increase blood concentrations of cyclosporine with a relatively high degree of interpatient variability. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

GENERALLY AVOID: Administration with red wine or purple grape juice may decrease blood concentrations of cyclosporine. In 12 healthy volunteers, 12 ounces total of a merlot consumed 15 minutes prior to and during cyclosporine administration (single 8 mg/kg dose of Sandimmune) decreased cyclosporine peak blood concentration (Cmax) and systemic exposure (AUC) by 38% and 30%, respectively, compared to water. The time to reach peak concentration (Tmax) doubled, and oral clearance increased 50%. Similarly, one study were 12 healthy patients were administered purple grape juice and a single dose of cyclosporine showed a 30% and a 36% decrease in cyclosporine systemic exposure (AUC) and peak blood concentration (Cmax), respectively. The exact mechanism of interaction is unknown but may involve decreased cyclosporine absorption.

MONITOR: Food has been found to have variable effects on the absorption of cyclosporine. There have been reports of impaired, unchanged, and enhanced absorption during administration with meals relative to the fasting state. The mechanisms are unclear. Some investigators found an association with the fat content of food. In one study, increased fat intake resulted in significantly increased cyclosporine bioavailability and clearance. However, the AUC and pharmacodynamics of cyclosporine were not significantly affected, thus clinical relevance of these findings may be minimal.

MANAGEMENT: Patients receiving cyclosporine therapy should be advised to either refrain from or avoid fluctuations in the consumption of grapefruits and grapefruit juice. Until more data are available, the consumption of red wine or purple grape juice should preferably be avoided or limited. All oral formulations of cyclosporine should be administered on a consistent schedule with regard to time of day and relation to meals so as to avoid large fluctuations in plasma drug levels.

References

  1. Honcharik N, Yatscoff RW, Jeffery JR, Rush DN (1991) "The effect of meal composition on cyclosporine absorption." Transplantation, 52, p. 1087-9
  2. Ducharme MP, Provenzano R, Dehoornesmith M, Edwards DJ (1993) "Trough concentrations of cyclosporine in blood following administration with grapefruit juice." Br J Clin Pharmacol, 36, p. 457-9
  3. Bailey DG, Arnold JMO, Spence JD (1994) "Grapefruit juice and drugs - how significant is the interaction." Clin Pharmacokinet, 26, p. 91-8
  4. Hollander AAMJ, Vanrooij J, Lentjes EGWM, Arbouw F, Vanbree JB, Schoemaker RC, Vanes LA, Vanderwoude FJ, Cohen AF (1995) "The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients." Clin Pharmacol Ther, 57, p. 318-24
  5. (1995) "Grapefruit juice interactions with drugs." Med Lett Drugs Ther, 37, p. 73-4
  6. Tan KKC, Trull AK, Uttridge JA, Metcalfe S, Heyes CS, Facey S, Evans DB (1995) "Effect of dietary fat on the pharmacokinetics and pharmacodynamics of cyclosporine in kidney transplant recipients." Clin Pharmacol Ther, 57, p. 425-33
  7. Yee GC, Stanley DL, Pessa LJ, et al. (1995) "Effect of grrapefruit juice on blood cyclosporin concentration." Lancet, 345, p. 955-6
  8. Ducharme MP, Warbasse LH, Edwards DJ (1995) "Disposition of intravenous and oral cyclosporine after administration with grapefruit juice." Clin Pharmacol Ther, 57, p. 485-91
  9. Ioannidesdemos LL, Christophidis N, Ryan P, Angelis P, Liolios L, Mclean AJ (1997) "Dosing implications of a clinical interaction between grapefruit juice and cyclosporine and metabolite concentrations in patients with autoimmune diseases." J Rheumatol, 24, p. 49-54
  10. Min DI, Ku YM, Perry PJ, Ukah FO, Ashton K, Martin MF, Hunsicker LG (1996) "Effect of grapefruit juice on cyclosporine pharmacokinetics in renal transplant patients." Transplantation, 62, p. 123-5
  11. Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR (2000) "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients." Clin Pharmacol Ther, 68, p. 468-77
  12. Tsunoda SM, Harris RZ, Christians U, et al. (2001) "Red wine decreases cyclosporine bioavailability." Clin Pharmacol Ther, 70, p. 462-7
  13. Oliveira-Freitas VL, Dalla Costa T, Manfro RC, Cruz LB, Schwartsmann G (2010) "Influence of purple grape juice in cyclosporine availability." J Ren Nutr, 20, p. 309-13
View all 13 references

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Moderate

atorvastatin food

Applies to: 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 (1991) "Interaction between fibre and lovastatin." Lancet, 338, p. 706
  2. McMillan K (1996) "Considerations in the formulary selection of hydroxymethylglutaryl coenzyme a reductase inhibitors." Am J Health Syst Pharm, 53, p. 2206-14
  3. (2001) "Product Information. Lipitor (atorvastatin)." Parke-Davis
  4. Boberg M, Angerbauer R, Fey P, Kanhai WK, Karl W, Kern A, Ploschke J, Radtke M (1997) "Metabolism of cerivastatin by human liver microsomes in vitro. Characterization of primary metabolic pathways and of cytochrome P45 isozymes involved." Drug Metab Dispos, 25, p. 321-31
  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 (1999) "Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin." Clin Pharmacol Ther, 66, p. 118-27
  7. 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
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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