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Drug Interactions between Eryzole and Oncovin

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

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Major

erythromycin vinCRIStine

Applies to: Eryzole (erythromycin / sulfisoxazole) and Oncovin (vincristine)

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 and/or P-glycoprotein may significantly increase the plasma concentrations of vinca alkaloids, which are substrates of both the hepatic microsomal isoenzyme and intracellular efflux transporter. Although pharmacokinetic data are not available, the interaction has been associated with severe and life-threatening toxicities in both adult and pediatric cancer patients. Paralytic ileus, intestinal obstruction and perforation, laryngeal nerve paresis requiring mechanical ventilation, neurogenic bladder, paresthesia, paralysis, hypotension, hypertension, heart failure, hyponatremia secondary to SIADH, seizures, profound myelosuppression, and septic shock have been reported. Most cases have involved vincristine or vinblastine in combination with itraconazole. However, the interaction has also been reported with other known potent inhibitors such as clarithromycin, erythromycin, cyclosporine, posaconazole, voriconazole and ritonavir, as well as less potent ones such as nifedipine and isoniazid. In adults with acute lymphoblastic leukemia receiving vincristine as part of their chemotherapeutic regimen, neurotoxicity (paresthesia, muscle weakness, and paralytic ileus) was more severe and occurred earlier and more frequently in 14 patients coadministered itraconazole 400 mg/day for antifungal prophylaxis than in 460 previous patients who did not receive itraconazole (29% vs. 6%). Similarly, in a retrospective cohort study consisting of 25 patients receiving 59 courses of vinorelbine-containing chemotherapy, the incidence of grade 3 or 4 neutropenia was 63.2% in patients who were coadministered clarithromycin, compared to 27.5% in those who did not receive clarithromycin. The incidence of grade 4 neutropenia was also higher in the clarithromycin group, 31.6% vs. 2.5%. Four patients who had received vinorelbine both with and without clarithromycin had lower neutrophil counts during clarithromycin coadministration. A retrospective study to assess vincristine dosing and toxicity in combination with azoles found that vincristine dosing modifications (i.e., dose reductions, dose delays, therapy discontinuation) occurred in 58.6% of patients who received concomitant azole therapy (n=29) compared to 23.8% of patients who did not (n=21). The mean dose reduction of vincristine when combined with an azole was 46.5%. Symptoms of decreased peristalsis were also more common in the azole group, 65.5% vs. 28.6%. The individual incidence was 50%, 75%, and 66.6% in patients receiving fluconazole, voriconazole, and posaconazole, respectively. In addition, patients in the azole group were more likely to have an incomplete course of vincristine, 48.3% vs. 9.5%. Most reported cases of toxicity have been reversible following discontinuation of the CYP450 3A4 inhibitor, and many of the patients tolerated their chemotherapy in the absence of the inhibitor or after dose adjustment. In one incident, however, a patient who had been on itraconazole for fungal pneumonia developed constipation, mucositis, and granulocytopenia within one week after the first dose of vinorelbine and cisplatin, and died 12 days later. No other details were available.

MANAGEMENT: Concomitant use of vinca alkaloids with potent CYP450 3A4 and/or P-glycoprotein inhibitors should be avoided if possible. Some authorities recommend avoiding concomitant use of vinca alkaloids during and for 2 weeks after treatment with itraconazole. Otherwise, conservative dosing of the antineoplastic should be considered, and the patient closely monitored for toxicity. Based on the known half-life of vinca alkaloids (24 to 48 hours), the time course of interaction is expected to be approximately 5 to 7 days. Patients should be advised to seek medical attention if they experience symptoms that could indicate neuro- or myelotoxicity, including constipation, abdominal pain or bloating, urinary retention, paresthesia, paralysis, muscle weakness, hearing loss, seizures, erratic blood pressure changes, unusual or excessive bleeding, easy bruising, pallor, fatigue, dizziness, lightheadedness, fever, chills, and sore throat. Following discontinuation of the potent CYP450 3A4 inhibitor, a washout period of approximately one week should be allowed before the antineoplastic dosage is adjusted upward to the previous dosage.

References

  1. (2002) "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals
  2. Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y (1983) "Potentiation of vincristine and adriamycin effects in human hemopoietic tumor cell lines by calcium antagonists and calmodulin inhibitors." Cancer Res, 43, p. 2267-72
  3. Fedeli L, Colozza M, Boschetti E, et al. (1989) "Pharmacokinetics of vincristine in cancer patients treated with nifedipine." Cancer, 64, p. 1805-11
  4. Tobe SW, Siu LL, Jamal SA, Skorecki KL, Murphy GF, Warner E (1995) "Vinblastine and erythromycin: an unrecognized serious drug interaction." Cancer Chemother Pharmacol, 35, p. 188-90
  5. Carrion C, Espinosa E, Herrero A, Garcia B (1995) "Possible vincristine-isoniazid interaction." Ann Pharmacother, 29, p. 201
  6. Kivisto KT, Kroemer HK, Eichelbaum M (1995) "The role of human cytochrome p450 enzymes in the metabolism of anticancer agents: implications for drug interactions." Br J Clin Pharmacol, 40, p. 523-30
  7. Zhou-Pan XR, Seree E, Zhou XJ, et al. (1993) "Involvement of human liver cytochrome P450 3A in vinblastine metabolism: drug interactions." Cancer Res, 53, p. 5121-6
  8. Bohme A, Ganser A, Hoelzer D (1995) "Aggravation of vincristine-induced neurotoxicity by itraconazole in the treatment of adult ALL." Ann Hematol, 71, p. 311-2
  9. Zhou XJ, Zhou-Pan XR, Gauthier T, Placidi M, Maurel P, Rahmani R (1993) "Human liver microsomal cytochrome P450 3A isozymes mediated vindesine biotransformation. Metabolic drug interactions." Biochem Pharmacol, 45, p. 853-61
  10. (2001) "Product Information. Velban (vinblastine)." Lilly, Eli and Company
  11. (2001) "Product Information. Oncovin (vincristine)." Lilly, Eli and Company
  12. Gillies J, Hung KA, Fitzsimons E, Soutar R (1998) "Severe vincristine toxicity in combination with itraconazole." Clin Lab Haematol, 20, p. 123-4
  13. Chan JD (1998) "Pharmacokinetic drug interactions of vinca alkaloids: summary of case reports." Pharmacotherapy, 18, p. 1304-7
  14. Murphy JA, Ross LM, Gibson BE (1995) "Vincristine toxicity in five children with acute lymphoblastic leukaemia." Lancet, 346, p. 443
  15. Jeng MR, Feusner J (2001) "Itraconazole-enhanced vincristine neurotoxicity in a child with acute lymphoblastic leukemia." Pediatr Hematol Oncol, 18, p. 137-42
  16. Bosque E (2001) "Possible drug interaction between itraconazole and vinorelbine tartrate leading to death after one dose of chemotherapy." Ann Intern Med, 134, p. 427
  17. Sathiapalan RK, El-Solh H (2001) "Enhanced vincristine neurotoxicity from drug interactions: case report and review of literature." Pediatr Hematol Oncol, 18, p. 543-6
  18. Sathiapalan RK, Al-Nasser A, El-Solh H, Al-Mohsen I, Al-Jumaah S (2002) "Vincristine-itraconazole interaction: cause for increasing concern." J Pediatr Hematol Oncol, 24, p. 591
  19. Kajita J, Kuwabara T, Kobayashi H, Kobayashi S (2000) "CYP3A4 is mainly responsibile for the metabolism of a new vinca alkaloid, vinorelbine, in human liver microsomes." Drug Metab Dispos, 28, p. 1121-7
  20. Ariffin H, Omar KZ, Ang EL, Shekhar K (2003) "Severe vincristine neurotoxicity with concomitant use of itraconazole." J Paediatr Child Health, 39, p. 638-9
  21. Antoniou T, Tseng AL (2005) "Interactions between antiretrovirals and antineoplastic drug therapy." Clin Pharmacokinet, 44, p. 111-145
  22. Bermudez M, Fuster JL, Llinares E, Galera A, Gonzalez C (2005) "Itraconazole-related increased vincristine neurotoxicity: case report and review of literature." J Pediatr Hematol Oncol, 27, p. 389-392
  23. Bashir H, Motl S, Metzger ML, et al. (2006) "Itraconazole-enhanced chemotherapy toxicity in a patient with Hodgkin lymphoma." J Pediatr Hematol Oncol, 28, p. 33-35
  24. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  25. Kotb R, Vincent I, Dulioust A, et al. (2006) "Life-threatening interaction between antiretroviral therapy and vinblastine in HIV-associated multicentric Castleman's disease." Eur J Haematol, 76, p. 269-71
  26. Canadian Pharmacists Association (2006) e-CPS. http://www.pharmacists.ca/function/Subscriptions/ecps.cfm?link=eCPS_quikLink
  27. Haddad A, Davis M, Lagman R (2007) "The pharmacological importance of cytochrome CYP3A4 in the palliation of symptoms: review and recommendations for avoiding adverse drug interactions." Support Care Cancer, 15, p. 251-7
  28. Mantadakis E, Amoiridis G, Kondi A, Kalmanti M (2007) "Possible increase of the neurotoxicity of vincristine by the concurrent use of posaconazole in a young adult with leukemia." J Pediatr Hematol Oncol, 29, p. 130
  29. Cerner Multum, Inc. "Australian Product Information."
  30. Takahashi N, Kameoka Y, Yamanaka Y, et al. (2008) "Itraconazole oral solution enhanced vincristine neurotoxicity in five patients with malignant lymphoma." Intern Med, 47, p. 651-3
  31. Porter CC, Carver AE, Albano EA (2009) "Vincristine induced peripheral neuropathy potentiated by voriconazole in a patient with previously undiagnosed CMT1X." Pediatr Blood Cancer, 52, p. 298-300
  32. Yano R, Tani D, Watanabe K, et al. (2009) "Evaluation of potential interaction between vinorelbine and clarithromycin." Ann Pharmacother, 43, p. 453-8
  33. Eiden C, Palenzuela G, Hillaire-Buys D, et al. (2009) "Posaconazole-increased vincristine neurotoxicity in a child: a case report." J Pediatr Hematol Oncol, 31, p. 292-5
  34. Chen S, Wu D, Sun A, et al. (2007) "Itraconazole-enhanced vindesine neurotoxicity in adult acute lymphoblastic leukaemia." Am J Hematol, 82, p. 942
  35. Harnicar S, Adel N, Jurcic J (2009) "Modification of vincristine dosing during concomitant azole therapy in adult acute lymphoblastic leukemia patients." J Oncol Pharm Pract, 15, p. 175-82
  36. Kamaluddin M, McNally P, Breatnach F, et al. (2001) "Potentiation of vincristine toxicity by itraconazole in children with lymphoid malignancies." Acta Paediatr, 90, p. 1204-7
  37. Jain S, Kapoor G (2010) "Severe life threatening neurotoxicity in a child with acute lymphoblastic leukemia receiving posaconazole and vincristine." Pediatr Blood Cancer, 54, p. 783
  38. Leveque D, Santucci R, Pavillet J, Herbrecht R, Bergerat JP (2009) "Paralytic ileus possibly associated with interaction between ritonavir/lopinavir and vincristine." Pharm World Sci, 31, p. 619-21
  39. Moriyama B, Falade-Nwulia O, Leung J, et al. (2011) "Prolonged half-life of voriconazole in a CYP2C19 homozygous poor metabolizer receiving vincristine chemotherapy: avoiding a serious adverse drug interaction." Mycoses, 54, e877-9
  40. van Schie RM, Bruggemann RJ, Hoogerbrugge PM, Te Loo DM (2011) "Effect of azole antifungal therapy on vincristine toxicity in childhood acute lymphoblastic leukaemia." J Antimicrob Chemother, 66, p. 1853-6
  41. Corona G, Vaccher E, Spina M, Toffoli G (2013) "Potential hazard drug-drug interaction between boosted protease inhibitors and vinblastine in HIV patients with Hodgkin's lymphoma." AIDS, 27, p. 1033-5
View all 41 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 (1978) "Bioavailability of erythromycin stearate: influence of food and fluid volume." J Pharm Sci, 67, p. 764-6
  2. Welling PG, Elliott RL, Pitterle ME, et al. (1979) "Plasma levels following single and repeated doses of erythromycin estolate and erythromycin stearate." J Pharm Sci, 68, p. 150-5
  3. Welling PG (1977) "Influence of food and diet on gastrointestinal drug absorption: a review." J Pharmacokinet Biopharm, 5, p. 291-334
  4. Coyne TC, Shum S, Chun AH, Jeansonne L, Shirkey HC (1978) "Bioavailability of erythromycin ethylsuccinate in pediatric patients." J Clin Pharmacol, 18, p. 194-202
  5. Malmborg AS (1979) "Effect of food on absorption of erythromycin. A study of two derivatives, the stearate and the base." J Antimicrob Chemother, 5, p. 591-9
  6. Randinitis EJ, Sedman AJ, Welling PG, Kinkel AW (1989) "Effect of a high-fat meal on the bioavailability of a polymer-coated erythromycin particle tablet formulation." J Clin Pharmacol, 29, p. 79-84
  7. Kanazawa S, Ohkubo T, Sugawara K (2001) "The effects of grapefruit juice on the pharmacokinetics of erythromycin." Eur J Clin Pharmacol, 56, p. 799-803
View all 7 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 (1990) "Influence of alcohol consumption on erythromycin ethylsuccinate kinetics." Int J Clin Pharmacol, 28, p. 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.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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