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Drug Interactions between clarithromycin and Sandimmune

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

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Interactions between your drugs

Major

cycloSPORINE clarithromycin

Applies to: Sandimmune (cyclosporine) and clarithromycin

MONITOR CLOSELY: Coadministration with macrolide antibiotics that are potent inhibitors of CYP450 3A4 may significantly increase the blood concentrations of cyclosporine, which is primarily metabolized by the isoenzyme. The risk of nephro- and neurotoxicity associated with cyclosporine may be increased. There have been numerous reports of significant increases in cyclosporine peak concentration (Cmax) and systemic exposure (AUC) and decreases in its clearance during concomitant administration with macrolide antibiotics, especially erythromycin and clarithromycin. Macrolides that may significantly inhibit CYP450 3A4 include troleandomycin, erythromycin, and clarithromycin. Azithromycin and dirithromycin are generally believed to have little effect, if any, on CYP450 3A4, although azithromycin was implicated in a single case report.

MANAGEMENT: Caution is advised if cyclosporine is used with macrolide antibiotics that are potent inhibitors of CYP450 3A4. Cyclosporine blood levels and renal function should be checked frequently and the dosage adjusted accordingly, particularly following initiation or discontinuation of macrolide therapy in patients who are stabilized on their cyclosporine regimen. Patients should be advised to notify their doctor if they experience possible signs of cyclosporine toxicity such as nausea, vomiting, diarrhea, abdominal pain, dizziness, fatigue, headache, tremors, and convulsions. Alternative antibiotics that do not interfere with cyclosporine metabolism should be considered whenever possible.

References

  1. Ptachcinski RJ, Carpenter BJ, Burckart GJ, Venkataramanan R, Rosenthal J (1985) "Effect of erythromycin on cyclosporine levels." N Engl J Med, 313, p. 1416-7
  2. Grino JM, Sabate I, Castelao AM, et al. (1986) "Erythromycin and cyclosporine." Ann Intern Med, 105, p. 467-8
  3. Wadhwa NK, Schroeder TJ, O'Flaherty E, et al. (1987) "Interaction between erythromycin and cyclosporine in a kidney and pancreas allograft recipient." Ther Drug Monit, 9, p. 123-5
  4. Kessler M, Louis J, Renoult E, et al. (1986) "Interaction between cyclosporin and erythromycin in a kidney transplant patient." Eur J Clin Pharmacol, 30, p. 633-4
  5. Kohan DE (1986) "Possible interaction between cyclosporine and erythromycin." N Engl J Med, 314, p. 448
  6. Freeman DJ, Martell R, Carruthers SG, et al. (1987) "Cyclosporin-erythromycin interaction in normal subjects." Br J Clin Pharmacol, 23, p. 776-8
  7. Murray BM, Edwards L, Morse GD, et al. (1987) "Clinically important interaction of cyclosporine and erythromycin." Transplantation, 43, p. 602-4
  8. Cockburn IT, Krupp P (1989) "An appraisal of drug interactions with sandimmun." Transplant Proc, 21, p. 3845-50
  9. Fabre I, Fabre G, Maurel P, et al. (1988) "Metabolism of cyclosporin A. Interaction of the macrolide antibiotic, erythromycin, using rabbit hepatocytes and microsomal fractions." Drug Metab Dispos, 16, p. 296-301
  10. Yee GC, McGuire TR (1990) "Pharmacokinetic drug interactions with cyclosporin (Part I)." Clin Pharmacokinet, 19, p. 319-32
  11. Gupta SK, Bakran A, Johnson RW, Rowland M (1989) "Cyclosporin-erythromycin interaction in renal transplant patients." Br J Clin Pharmacol, 27, p. 475-81
  12. (2022) "Product Information. SandIMMUNE (cycloSPORINE)." Apothecon Inc
  13. Jensen CW, Flechner SM, Van Buren CT, et al. (1987) "Exacerbation of cyclosporin toxicity by concomitant administration of erythromycin." Transplantation, 43, p. 263-70
  14. Gersema LM, Porter CB, Russell EH (1994) "Suspected drug interaction between cyclosporine and clarithromycin." J Heart Lung Transplant, 13, p. 343-5
  15. Ferrari SL, Goffin E, Mourad M, Wallemacq P, Squifflet JP, Pirson Y (1994) "The interaction between clarithromycin and cyclosporine in kidney transplant recipients." Transplantation, 58, p. 725-7
  16. Zylber-Katz E (1995) "Multiple drug interactions with cyclosporine in a heart transplant patient." Ann Pharmacother, 29, p. 127-31
  17. Ljutic D, Rumboldt Z (1995) "Possible interaction between azithromycin and cyclosporin: a case report." Nephron, 70, p. 130
  18. Amsden GW (1995) "Macrolides versus azalides: a drug interaction update." Ann Pharmacother, 29, p. 906-17
  19. Sketris IS, Wright MR, West ML (1996) "Possible role of the intestinal p-450 enzyme system in a cyclosporine clarithromycin interaction." Pharmacotherapy, 16, p. 301-5
  20. Nahata M (1996) "Drug interactions with azithromycin and the macrolides: an overview." J Antimicrob Chemother, 37 ( Suppl, p. 133-42
  21. Gomez E, Sanchez JE, Aguado S, Grande JA (1996) "Interaction between azithromycin and cyclosporin?" Nephron, 73, p. 724
  22. Spicer ST, Liddle C, Chapman JR, Barclay P, Nankivell BJ, Thomas P, O'Connell PJ (1997) "The mechanism of cyclosporine toxicity induced by clarithromycin." Br J Clin Pharmacol, 43, p. 194-6
  23. Knower MT, LabellaWalker K, McFadden PM, Kantrow SP, Valentine VG (2000) "Clarithromycin for safe and cost-effective reduction of cyclosporine doses in lung allograft recipients." South Med J, 93, p. 1087-92
  24. Homma S, Takahashi KI, Nihei S, Kato F, Sugihara S, Nunoda S (2014) "The successful management of respiratory complications with long-term, low-dose macrolide administration in pediatric heart transplant recipients." Int Heart J
View all 24 references

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Drug and food interactions

Moderate

cycloSPORINE food

Applies to: Sandimmune (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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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.

See also

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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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