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Drug Interactions between Eryzole and Gengraf

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

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Major

erythromycin cycloSPORINE

Applies to: Eryzole (erythromycin / sulfisoxazole) and Gengraf (cyclosporine)

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

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Major

cycloSPORINE sulfiSOXAZOLE

Applies to: Gengraf (cyclosporine) and Eryzole (erythromycin / sulfisoxazole)

MONITOR CLOSELY: Sulfonamides may significantly reduce serum cyclosporine concentrations by an unknown mechanism. Allograft rejections have resulted. Hyperkalemia and additive nephrotoxicity has also been reported. The mechanism is unknown. Data are available for intravenous trimethoprim-sulfamethoxazole, intravenous sulfamethazine (no longer marketed), oral sulfadiazine, and sulfasalazine. Oral trimethoprim-sulfamethoxazole reportedly does not affect cyclosporine levels.

MANAGEMENT: Renal function and cyclosporine levels should be closely monitored if these drugs must be used concomitantly.

References

  1. Cockburn IT, Krupp P "An appraisal of drug interactions with sandimmun." Transplant Proc 21 (1989): 3845-50
  2. Yee GC, McGuire TR "Pharmacokinetic drug interactions with cyclosporin (Part I)." Clin Pharmacokinet 19 (1990): 319-32
  3. Berg K, Gjellestad A, Nordby G, et al. "Renal effects of trimethoprim in ciclosporin- and azathioprine-treated kidney-allografted patients." Nephron 53 (1989): 218-22
  4. Wallwork J, McGregor CG, Wells FC, et al. "Cyclosporin and intravenous sulphadimidine and trimethoprim therapy." Lancet 02/12/83 (1983): 366-7
  5. Spes CH, Angermann CE, Stempfle HU, et al. "Sulfadiazine therapy for toxoplasmosis in heart transplant recipients decreases cyclosporine concentration." Clin Investig 70 (1992): 752-4
  6. Ringden O, Myrenfors P, Klintmalm G, Tyden G, Ost L "Nephrotoxicity by co-trimoxazole and cyclosporin in transplanted patients." Lancet 1 (1984): 1016-7
  7. Wallwork J, McGregor CG, Wells FC, Cory-Pearace R, English TA "Cyclosporin and intravenous sulphadimidine and trimethoprim therapy." Lancet 1 (1983): 326-7
  8. Jones DK, Hakim M, Wallwork J, Higenbottam TW "Serious interaction between cyclosporin A and sulphadimidine." Br Med J 292 (1986): 728-9
  9. DuCheyron D, Debruyne D, Lobbedez T, Richer C, Ryckelynck JP, deLigny BH "Effect of sulfasalazine on cyclosporin blood concentration." Eur J Clin Pharmacol 55 (1999): 227-8
View all 9 references

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Drug and food interactions

Moderate

erythromycin food

Applies to: Eryzole (erythromycin / sulfisoxazole)

ADJUST DOSING INTERVAL: Food may variably affect the bioavailability of different oral formulations and salt forms of erythromycin. The individual product package labeling should be consulted regarding the appropriate time of administration in relation to food ingestion. Grapefruit juice may increase the plasma concentrations of orally administered erythromycin. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In an open-label, crossover study consisting of six healthy subjects, the coadministration with double-strength grapefruit juice increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of a single dose of erythromycin (400 mg) by 52% and 49%, respectively, compared to water. The half-life was not affected. The clinical significance of this potential interaction is unknown.

MANAGEMENT: In general, optimal serum levels are achieved when erythromycin is taken in the fasting state, one-half to two hours before meals. However, some erythromycin products may be taken without regard to meals.

References

  1. Welling PG, Huang H, Hewitt PF, Lyons LL "Bioavailability of erythromycin stearate: influence of food and fluid volume." J Pharm Sci 67 (1978): 764-6
  2. Welling PG, Elliott RL, Pitterle ME, et al. "Plasma levels following single and repeated doses of erythromycin estolate and erythromycin stearate." J Pharm Sci 68 (1979): 150-5
  3. Welling PG "Influence of food and diet on gastrointestinal drug absorption: a review." J Pharmacokinet Biopharm 5 (1977): 291-334
  4. Coyne TC, Shum S, Chun AH, Jeansonne L, Shirkey HC "Bioavailability of erythromycin ethylsuccinate in pediatric patients." J Clin Pharmacol 18 (1978): 194-202
  5. Malmborg AS "Effect of food on absorption of erythromycin. A study of two derivatives, the stearate and the base." J Antimicrob Chemother 5 (1979): 591-9
  6. Randinitis EJ, Sedman AJ, Welling PG, Kinkel AW "Effect of a high-fat meal on the bioavailability of a polymer-coated erythromycin particle tablet formulation." J Clin Pharmacol 29 (1989): 79-84
  7. Kanazawa S, Ohkubo T, Sugawara K "The effects of grapefruit juice on the pharmacokinetics of erythromycin." Eur J Clin Pharmacol 56 (2001): 799-803
View all 7 references

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Moderate

cycloSPORINE food

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

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Minor

erythromycin food

Applies to: Eryzole (erythromycin / sulfisoxazole)

Ethanol, when combined with erythromycin, may delay absorption and therefore the clinical effects of the antibiotic. The mechanism appears to be due to slowed gastric emptying by ethanol. Data is available only for erythromycin ethylsuccinate. Patients should be advised to avoid ethanol while taking erythromycin salts.

References

  1. Morasso MI, Chavez J, Gai MN, Arancibia A "Influence of alcohol consumption on erythromycin ethylsuccinate kinetics." Int J Clin Pharmacol 28 (1990): 426-9

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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.

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