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Drug Interactions between cyclosporine and pravastatin

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

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Major

cycloSPORINE pravastatin

Applies to: cyclosporine and pravastatin

ADJUST DOSE: Coadministration with cyclosporine may increase the oral bioavailability of pravastatin. The proposed mechanism is cyclosporine inhibition of the intestinal efflux of pravastatin via MRP2 transporter. In studies of adult and pediatric organ transplant patients receiving immunosuppressive therapy containing cyclosporine, plasma concentrations of pravastatin were approximately 5 to 10 times higher than in control patients receiving pravastatin without cyclosporine. No significant adverse effects or elevations in plasma creatinine, liver enzymes, or creatine kinase levels were reported in the studies. In three reports involving a total of 100 post-transplant patients treated for up to two years concurrently with pravastatin 10 to 40 mg and cyclosporine, neither myopathy nor significant increases in creatine kinase levels have been observed. However, high levels of HMG-CoA reductase inhibitory activity in plasma has been 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. Pravastatin does not affect the plasma concentrations of cyclosporine.

MANAGEMENT: The benefits of the use of pravastatin in combination with cyclosporine should be carefully weighed against the potential risks. Pravastatin dosage should start at 10 mg/day and generally not exceed 20 mg/day when used in combination with cyclosporine. Higher dosages should be used with caution. All patients treated with HMG-CoA reductase inhibitors should be advised to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. 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 (18)
  1. Yoshimura N, Oka T, Okamoto M, Ohmori Y (1992) "The effects of pravastatin on hyperlipidemia in renal transplant recipients." Transplantation, 53, p. 94-9
  2. 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
  3. 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
  4. 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
  5. (2001) "Product Information. Pravachol (pravastatin)." Bristol-Myers Squibb
  6. Regazzi MB, Iacona I, Campana C, Raddato V, Lesi C, Perani G, Gavazzi A, Vigano M (1993) "Altered disposition of pravastatin following concomitant drug therapy with cyclosporin A in transplant recipients." Transplant Proc, 25, p. 2732-4
  7. Kobashigwa JA, Katznelson S, Laks H, et al. (1995) "Effect of pravastatin on outcomes after cardiac transplantation." N Engl J Med, 333, p. 621-7
  8. Castelao AM, Grinyo JM, Castineiras MJ, Fiol C, Gilvernet S, Seron D, Torras J, Cruzado JM, Alsina J (1995) "Effect of pravastatin in the treatment of hypercholesterolemia after renal transplantation under cyclosporine and prednisone." Transplant Proc, 27, p. 2217-20
  9. 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
  10. Lill J, Bauer LA, Horn JR, Hansten PD (2000) "Cyclosporine-drug interactions and the influence of patient age." Am J Health Syst Pharm, 57, p. 1579-84
  11. 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
  12. Park JW, Siekmeier R, Merz M, et al. (2002) "Pharmacokinetics of pravastatin in heart-transplant patients taking cyclosporin A." Int J Clin Pharmacol Ther, 40, p. 439-50
  13. Hedman M, Neuvonen PJ, Neuvonen M, Holmberg C, Antikainen M (2004) "Pharmacokinetics and pharmacodynamics of pravastatin in pediatric and adolescent cardiac transplant recipients on a regimen of triple immunosuppression." Clin Pharmacol Ther, 75, p. 101-9
  14. Launay-Vacher V, Izzedine H, Deray G (2005) "Statins' dosage in patients with renal failure and cyclosporine drug-drug interactions in transplant recipient patients." Int J Cardiol, 101, p. 9-17
  15. Cuenca-Estrella M, Mellado E, Diaz-Guerra TM, Monzon A, Rodriguez-Tudela JL (2000) "Susceptibility of fluconazole-resistant clinical isolates of Candida spp. to echinocandin LY303366, itraconazole and amphotericin B." J Antimicrob Chemother, 46, p. 475-7
  16. Bancalari E (2006) "Caffeine for apnea of prematurity." N Engl J Med, 354, p. 2179-81
  17. Holtzman CW, Wiggins BS, Spinler SA (2006) "Role of P-glycoprotein in statin drug interactions." Pharmacotherapy, 26, p. 1601-7
  18. Cerner Multum, Inc. "Australian Product Information."

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 (13)
  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
Moderate

pravastatin food

Applies to: pravastatin

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 (9)
  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)

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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