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Drug Interactions between atorvastatin and clarithromycin

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

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Interactions between your drugs

Major

clarithromycin atorvastatin

Applies to: clarithromycin and atorvastatin

ADJUST DOSE: Some macrolide antibiotics inhibit CYP450 3A4 and may elevate the plasma concentrations of HMG-CoA reductase inhibitors that are metabolized by the isoenzyme. Macrolides that may significantly inhibit CYP450 3A4 include troleandomycin, erythromycin, and clarithromycin. There have been case reports of patients treated with lovastatin or simvastatin who developed severe myopathy or rhabdomyolysis following the addition of a macrolide, usually erythromycin. Plasma levels of HMG-CoA reductase inhibitory activity were significantly elevated in these patients, up to severalfold in many cases. Similar pharmacokinetic changes have been reported in studies with erythromycin and simvastatin and, to a lesser extent, with clarithromycin or erythromycin and atorvastatin. The interaction was also suspected in a patient treated with atorvastatin (more than 1 year) and esomeprazole (6 weeks) who developed rhabdomyolysis with AV block two days after the addition of clarithromycin. The patient reported experiencing symptoms of increased fatigue, mild chest pain, and shortness of breath that coincided with the initiation of esomeprazole approximately six weeks prior to admission.

MANAGEMENT: The benefits of using HMG-CoA reductase inhibitors that are metabolized by CYP450 3A4 in combination with medications that can inhibit the isoenzyme such as clarithromycin and erythromycin should be carefully weighed against the potentially increased risk of myopathy including rhabdomyolysis. A lower dosage of the HMG-CoA reductase inhibitor should be considered if concomitant use is required. Atorvastatin labeling recommends that the dosage not exceed 20 mg/day when used in combination with clarithromycin. Fluvastatin, pitavastatin, and rosuvastatin may be safer alternatives, since they are not metabolized by CYP450 3A4. 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. 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. (2002) "Product Information. Mevacor (lovastatin)." Merck & Co., Inc
  6. (2001) "Product Information. Zocor (simvastatin)." Merck & Co., Inc
  7. (2001) "Product Information. Lipitor (atorvastatin)." Parke-Davis
  8. (2001) "Product Information. Baycol (cerivastatin)." Bayer
  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. Kantola T, Kivisto KT, Neuvonen PJ (1998) "Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations." Clin Pharmacol Ther, 64, p. 177-82
  12. Siedlik PH, Olson SC, Yang BB, Stern RH (1999) "Erythromycin coadministration increases plasma atorvastatin concentrations." J Clin Pharmacol, 39, p. 501-4
  13. Westphal JF (2000) "Macrolide - induced clinically relevant drug interactions with cytochrome P-450 (CYP) 3A4: an update focused on clarithromycin, azithromycin, and dirithromycin." Br J Clin Pharmacol, 50, p. 285-95
  14. Lee AJ, Maddix DS (2001) "Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin." Ann Pharmacother, 35, p. 26-31
  15. Garnett WR (1995) "Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors." Am J Health Syst Pharm, 52, p. 1639-45
  16. Omar MA, Wilson JP (2002) "FDA adverse event reports on statin-associated rhabdomyolysis." Ann Pharmacother, 36, p. 288-95
  17. Amsden GW, Kuye O, Wei GC (2002) "A study of the interaction potential of azithromycin and clarithromycin with atorvastatin in healthy volunteers." J Clin Pharmacol, 42, p. 444-9
  18. Williams D, Feely J (2002) "Pharmacokinetic-Pharmacodynamic Drug Interactions with HMG-CoA Reductase Inhibitors." Clin Pharmacokinet, 41, p. 343-70
  19. 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
  20. 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
  21. Chouhan UM, Chakrabarti S, Millward LJ (2005) "Simvastatin interaction with clarithromycin and amiodarone causing myositis." Ann Pharmacother, 39, p. 1760-1
  22. 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
  23. Cooper JM, Jones AL (2009) "Neuroleptic malignant syndrome or a statin drug reaction? A case report." Clin Neuropharmacol, 32, p. 348-9
View all 23 references

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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

  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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Minor

clarithromycin food

Applies to: clarithromycin

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.

References

  1. Cheng KL, Nafziger AN, Peloquin CA, Amsden GW (1998) "Effect of grapefruit juice on clarithromycin pharmacokinetics." Antimicrob Agents Chemother, 42, p. 927-9

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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.

Further information

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