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Drug Interactions between atorvastatin and conivaptan

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

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Major

atorvastatin conivaptan

Applies to: atorvastatin and conivaptan

GENERALLY AVOID: Coadministration with conivaptan may significantly increase the plasma concentrations of certain HMG-CoA reductase inhibitors and/or their pharmacologically active metabolites. The mechanism is conivaptan inhibition of CYP450 3A4 metabolism. Intravenous conivaptan 30 mg/day has been reported to cause a 3-fold increase in simvastatin systemic exposure (AUC). High levels of HMG-CoA reductase inhibitory activity in plasma (e.g., due to liver disease or interaction with other potent 3A4 inhibitors such as macrolide antibiotics and azole antifungal agents) 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. In clinical trials of oral conivaptan, two cases of rhabdomyolysis occurred in patients who were also receiving a CYP450 3A4-metabolized HMG-CoA reductase inhibitor.

MANAGEMENT: In general, lovastatin, red yeast rice (which contains lovastatin), and simvastatin should be avoided in patients treated with conivaptan due to the potential for severe interaction. Atorvastatin may possibly be used with caution, although clinical data are lacking. Patients currently receiving these agents should consider an interruption during administration of conivaptan, and allow an appropriate amount of time (at least one week) following completion of conivaptan therapy before resuming these medications. Conivaptan is not expected to interact with fluvastatin, pravastatin, and rosuvastatin, since these agents are not significantly metabolized by CYP450 3A4.

References (33)
  1. Spach DH, Bauwens JE, Clark CD, Burke WG (1991) "Rhabdomyolysis associated with lovastatin and erythromycin use." West J Med, 154, p. 213-5
  2. Ayanian JZ, Fuchs CS, Stone RM (1988) "Lovastatin and rhabdomyolysis." Ann Intern Med, 109, p. 682-3
  3. 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
  4. 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
  5. Lees RS, Lees AM (1995) "Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole." N Engl J Med, 333, p. 664-5
  6. Horn M (1996) "Coadministration of itraconazole with hypolipidemic agents may induce rhabdomyolysis in healthy individuals." Arch Dermatol, 132, p. 1254
  7. Jacobson RH, Wang P, Glueck CJ (1997) "Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone." JAMA, 277, p. 296
  8. Jody DN (1997) "Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone." JAMA, 277, p. 296-7
  9. Grunden JW, Fisher KA (1997) "Lovastatin-induced rhabdomyolysis possibly associated with clarithromycin and azithromycin." Ann Pharmacother, 31, p. 859-63
  10. Wong PW, Dillard TA, Kroenke K (1998) "Multiple organ toxicity from addition of erythromycin to long-term lovastatin therapy." South Med J, 91, p. 202-5
  11. Neuvonen PJ, Kantola T, Kivisto KT (1998) "Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole." Clin Pharmacol Ther, 63, p. 332-41
  12. Kivisto KT, Kantola T, Neuvonen PJ (1998) "Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin." Br J Clin Pharmacol, 46, p. 49-53
  13. 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
  14. Dresser GK, Spence JD, Bailey DG (2000) "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet, 38, p. 41-57
  15. Lee AJ, Maddix DS (2001) "Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin." Ann Pharmacother, 35, p. 26-31
  16. Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F (1999) "New insights into the pharmacodynamic and pharmacokinetic properties of statins." Pharmacol Ther, 84, p. 413-28
  17. Garnett WR (1995) "Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors." Am J Health Syst Pharm, 52, p. 1639-45
  18. Omar MA, Wilson JP (2002) "FDA adverse event reports on statin-associated rhabdomyolysis." Ann Pharmacother, 36, p. 288-95
  19. Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al. (2002) "Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047." AIDS, 16, p. 569-577
  20. Piliero PJ (2002) "Interaction between ritonavir and statins." Am J Med, 112, p. 510-1
  21. Cheng CH, Miller C, Lowe C, Pearson VE (2002) "Rhabdomyolysis due to probable interaction between simvastatin and ritonavir." Am J Health Syst Pharm, 59, p. 728-30
  22. Williams D, Feely J (2002) "Pharmacokinetic-Pharmacodynamic Drug Interactions with HMG-CoA Reductase Inhibitors." Clin Pharmacokinet, 41, p. 343-70
  23. Thompson M, Samuels S (2002) "Rhabdomyolysis with simvastatin and nefazodone." Am J Psychiatry, 159, p. 1607
  24. Huynh T, Cordato D, Yang F, et al. (2002) "HMG coA reductase-inhibitor-related myopathy and the influence of drug interactions." Intern Med J, 32(9-10), p. 486-90
  25. Hare CB, Vu MP, Grunfeld C, Lampiris HW (2002) "Simvastatin-nelfinavir interaction implicated in rhabdomyolysis and death." Clin Infect Dis, 35, E111-2
  26. Paoletti R, Corsini A, Bellosta S (2002) "Pharmacological interactions of statins." Atheroscler Suppl, 3, p. 35-40
  27. Sipe BE, Jones RJ, Bokhart GH (2003) "Rhabdomyolysis Causing AV Blockade Due to Possible Atorvastatin, Esomeprazole, and Clarithromycin Interaction." Ann Pharmacother, 37, p. 808-11
  28. Skrabal MZ, Stading JA, Monaghan MS (2003) "Rhabdomyolysis associated with simvastatin-nefazodone therapy." South Med J, 96, p. 1034-5
  29. Jacobson TA (2004) "Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors." Am J Cardiol, 94, p. 1140-6
  30. Chouhan UM, Chakrabarti S, Millward LJ (2005) "Simvastatin interaction with clarithromycin and amiodarone causing myositis." Ann Pharmacother, 39, p. 1760-1
  31. (2006) "Product Information. Vaprisol (conivaptan)." Cumberland Pharmaceuticals Inc
  32. Karnik NS, Maldonado JR (2005) "Antidepressant and statin interactions: a review and case report of simvastatin and nefazodone-induced rhabdomyolysis and transaminitis." Psychosomatics, 46, p. 565-8
  33. Schmidt GA, Hoehns JD, Purcell JL, Friedman RL, Elhawi Y (2007) "Severe rhabdomyolysis and acute renal failure secondary to concomitant use of simvastatin, amiodarone, and atazanavir." J Am Board Fam Med, 20, p. 411-6

Drug and food interactions

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 (7)
  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

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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