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Drug Interactions between lonafarnib and Prograf

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

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Interactions between your drugs

Major

tacrolimus lonafarnib

Applies to: Prograf (tacrolimus) and lonafarnib

MONITOR CLOSELY: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the blood concentrations of tacrolimus, which is primarily metabolized by the isoenzyme in both the intestine and liver. There have been numerous reports and pharmacokinetic studies in the medical literature of tacrolimus interaction with various potent CYP450 3A4 inhibitors, including azole antifungal agents, macrolide antibiotics, and protease inhibitors. Nephrotoxicity and other adverse effects (e.g., hyperkalemia, hyperglycemia, hemolytic anemia, hemolytic uremic syndrome, neurotoxicity) in association with significantly elevated tacrolimus blood levels have been reported, necessitating substantial reductions or interruptions in tacrolimus dosing.

MANAGEMENT: Caution is advised when tacrolimus is used with potent CYP450 3A4 inhibitors. Dosage reduction and/or prolongation of the dosing interval for tacrolimus will likely be required. Frequent monitoring of tacrolimus whole blood levels should be performed during and after discontinuation of the CYP450 3A4 inhibitor, and the tacrolimus dosage adjusted accordingly. In addition, patients should be closely monitored for development of serious adverse effects such as nephrotoxicity, lymphoma and other malignancies, infections, diabetes, neurotoxicity (tremor, paraesthesia, encephalopathy, delirium, coma), hyperkalemia, QT prolongation, myocardial hypertrophy, and hypertension. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

References

  1. Mieles L, Venkataramanan R, Yokoyama I, Warty VJ, Starzl TE (1991) "Interaction between FK506 and clotrimazole in a liver transplant recipient." Transplantation, 52, p. 1086-7
  2. Manez R, Martin M, Raman V, et al. (1994) "Fluconazole therapy in transplant recipients receiving FK506." Transplantation, 57, p. 1521-3
  3. Assan R, Fredj G, Larger E, Feutren G, Bismuth H (1994) "FK 506/fluconazole interaction enhances FK 506 nephrotoxicity." Diabete Metab, 20, p. 49-52
  4. (2001) "Product Information. Prograf (tacrolimus)." Fujisawa
  5. Cakaloglu Y, Tredger JM, Devlin J, Williams R (1994) "Importance of cytochrome p-450IIIA activity in determining dosage and blood levels of FK 506 and cyclosporine in liver transplant recipients." Hepatology, 20, p. 309-16
  6. Jensen C, Jordan M, Shapiro R, et al. (1994) "Interaction between tacrolimus and erythromycin." Lancet, 344, p. 825
  7. Wolter K, Wagner K, Philipp T, Fritschka E (1994) "Interaction between FK 506 and clarithromycin in a renal transplant patient." Eur J Clin Pharmacol, 47, p. 207-8
  8. Osowski CL, Dix SP, Lin LS, Mullins RE, Geller RB, Wingard JR (1996) "Evaluation of the drug interaction between intravenous high-dose fluconazole and cyclosporine or tacrolimus in bone marrow transplant patients." Transplantation, 61, p. 1268-72
  9. Furlan V, Perello L, Jacquemin E, Debray D, Taburet AM (1995) "Interactions between FK506 and rifampin or erythromycin in pediatric liver recipients." Transplantation, 59, p. 1217-8
  10. Shaeffer MS, Collier D, Sorrell MF (1994) "Interaction between FK506 and erythromycin." Ann Pharmacother, 28, p. 280-1
  11. Floren LC, Bekersky I, Benet LZ, et al. (1997) "Tacrolimus oral bioavailability doubles with coadministration of ketoconazole." Clin Pharmacol Ther, 62, p. 41-9
  12. Albengres E, Le Louet H, Tillement JP (1998) "Systemic antifungal agents. Drug interactions of clinical significance." Drug Saf, 18, p. 83-97
  13. Olyaei AJ, deMattos AM, Norman DJ, Bennett WM (1998) "Interaction between tacrolimus and nefazodone in a stable renal transplant recipient." Pharmacotherapy, 18, p. 1356-9
  14. Billaud EM, Guillemain R, Tacco F, Chevalier P (1998) "Evidence for a pharmacokinetic interaction between itraconazole and tacrolimus in organ transplant patients." Br J Clin Pharmacol, 46, p. 271-4
  15. Gomez G, Alvarez ML, Errasti P, Lavilla FJ, Garcia N, Ballester B, Garcia I, Purroy A (1999) "Acute tacrolimus nephrotoxicity in renal transplant patients treated with clarithromycin." Transplant Proc, 31, p. 2250-1
  16. Moreno M, Latorre A, Manzanares C, et al. (1999) "Clinical management of tacrolimus drug interactions in renal transplant patients." Transplant Proc, 31, p. 2252-3
  17. Capone D, Gentile A, Imperatore P, Palmiero G, Basile V (1999) "Effects of itraconazole on tacrolimus blood concentrations in a renal transplant recipient." Ann Pharmacother, 33, p. 1124-5
  18. Venkatakrishnan K, von Moltke LL, Greenblatt DJ (2000) "Effects of the antifungal agents on oxidative drug metabolism: clinical relevance." Clin Pharmacokinet, 38, p. 111-80
  19. Vasquez EM, Pollak R, Benedetti E (2001) "Clotrimazole increases tacrolimus blood levels: a drug interaction in kidney transplant patients." Clin Transplant, 15, p. 95-9
  20. Pea F, Furlanut M (2001) "Pharmacokinetic aspects of treating infections in the intensive care unit: focus on drug interactions." Clin Pharmacokinet, 40, p. 833-868
  21. Macias MO, Salvador P, Hurtado JL, Martin I (2000) "Tacrolimus-itraconazole interaction in a kidney transplant patient." Ann Pharmacother, 34, p. 536
  22. Venkataramanan R, Zang S, Gayowski T, Singh N (2002) "Voriconazole inhibition of the metabolism of tacrolimus in a liver transplant recipient and in human liver microsomes." Antimicrob Agents Chemother, 46, p. 3091-3
  23. Jain AK, Venkataramanan R, Shapiro R, et al. (2002) "The interaction between antiretroviral agents and tacrolimus in liver and kidney transplant patients." Liver Transpl, 8, p. 841-5
  24. Ibrahim RB, Abella EM, Chandrasekar PH (2002) "Tacrolimus-clarithromycin interaction in a patient receiving bone marrow transplantation." Ann Pharmacother, 36, p. 1971-1972
  25. Jain AK, Venkataramanan R, Shapiro R, et al. (2002) "Interaction between tacrolimus and antiretroviral agents in human immunodeficiency virus-positive liver and kidney transplantation patients." Transplant Proc, 34, p. 1540-1
  26. Pai MP, Allen S (2003) "Voriconazole inhibition of tacrolimus metabolism." Clin Infect Dis, 36, p. 1089-91
  27. Soltero L, Carbajal H, Rodriguez-Montalvo C, Valdes A (2003) "Coadministration of tacrolimus and ketoconazole in renal transplant recipients: cost analysis and review of metabolic effects." Transplant Proc, 35, p. 1319-21
  28. Schonder KS, Shullo MA, Okusanya O (2003) "Tacrolimus and lopinavir/ritonavir interaction in liver transplantation." Ann Pharmacother, 37, p. 1793-6
  29. Jain AB, Venkataramanan R, Eghtesad B, et al. (2003) "Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients." Liver Transpl, 9, p. 954-60
  30. Kunicki PK, Sobieszczanska-Malek M (2005) "Pharmacokinetic interaction between tacrolimus and clarithromycin in a heart transplant patient." Ther Drug Monit, 27, p. 107-108
  31. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  32. Teicher E, Vincent I, Bonhomme-Faivre L, et al. (2007) "Effect of Highly Active Antiretroviral Therapy on Tacrolimus Pharmacokinetics in Hepatitis C Virus and HIV Co-Infected Liver Transplant Recipients in the ANRS HC-08 Study." Clin Pharmacokinet, 46, p. 941-52
  33. Cerner Multum, Inc. "Australian Product Information."
  34. Pea F, Tavio M, Pavan F, et al. (2008) "Drop in trough blood concentrations of tacrolimus after switching from nelfinavir to fosamprenavir in four HIV-infected liver transplant patients." Antivir Ther, 13, p. 739-42
  35. Mertz D, Battegay M, Marzolini C, Mayr M (2009) "Drug-Drug Interaction in a Kidney Transplant Recipient Receiving HIV Salvage Therapy and Tacrolimus." Am J Kidney Dis
  36. Barau C, Blouin P, Creput C, Taburet AM, Durrbach A, Furlan V (2009) "Effect of coadministered HIV-protease inhibitors on tacrolimus and sirolimus blood concentrations in a kidney transplant recipient." Fundam Clin Pharmacol, 23, p. 423-5
  37. Dodds-Ashley E (2010) "Management of drug and food interactions with azole antifungal agents in transplant recipients." Pharmacotherapy, 30, p. 842-54
  38. Parissis H, Gould K, Dark J (2010) "Dangerous drug interactions leading to hemolytic uremic syndrome following lung transplantation." J Cardiothorac Surg, 5, p. 70
  39. Tsapepas DS, Webber AB, Aull MJ, Figueiro JM, Saal SD (2011) "Managing the atazanavir-tacrolimus drug interaction in a renal transplant recipient." Am J Health Syst Pharm, 68, p. 138-42
  40. 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
  41. Katari SR, Magnone M, Shapiro R, et al. (1997) "Clinical features of acute reversible tacrolimus (FK 506) nephrotoxicity in kidney transplant recipients." Clin Transplant, 11, p. 237-42
View all 41 references

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Drug and food interactions

Major

lonafarnib food

Applies to: lonafarnib

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of lonafarnib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. When a single 50 mg oral dose of lonafarnib was administered following pretreatment with the potent CYP450 3A4 inhibitor ketoconazole (200 mg once daily for 5 days) in healthy study subjects, lonafarnib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 270% and 425%, respectively, compared to lonafarnib administered alone. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to lonafarnib may increase the risk and/or severity of adverse effects such as nausea, vomiting, diarrhea, anorexia, electrolyte disturbances, liver enzyme elevations, myelosuppression, infection, and hypertension.

ADJUST DOSING INTERVAL: Food does not have clinically relevant effects on the oral bioavailability of lonafarnib. When a single 75 mg oral dose of lonafarnib was administered with a high-fat meal (952 calories; approximately 43% from fat) in healthy subjects, lonafarnib Cmax and AUC decreased by 55% and 29%, respectively, compared to administration under fasted conditions. When administered with a low-fat meal (421 calories; approximately 12% from fat), lonafarnib Cmax decreased by 25% and AUC decreased by 21% relative to fasting. However, administration with food may help improve gastrointestinal tolerance to lonafarnib, which may commonly cause nausea, vomiting, diarrhea, and abdominal pain.

MANAGEMENT: Lonafarnib should be administered with the morning and evening meals and an adequate amount of water. Patients should avoid consumption of grapefruit or grapefruit juice and Seville oranges (also known as bitter or sour oranges).during treatment with lonafarnib.

References

  1. (2020) "Product Information. Zokinvy (lonafarnib)." Eiger BioPharmaceuticals

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Moderate

tacrolimus food

Applies to: Prograf (tacrolimus)

ADJUST DOSING INTERVAL: Consumption of food has led to a 27% decrease in the bioavailability of orally administered tacrolimus.

MANAGEMENT: Tacrolimus should be administered at least one hour before or two hours after meals.

GENERALLY AVOID: Grapefruit juice has been reported to increase tacrolimus trough concentrations. Data are limited, but inhibition of the CYP450 enzyme system appears to be involved.

MANAGEMENT: The clinician may want to recommend that the patient avoid ingesting large amounts of grapefruit juice while taking tacrolimus.

References

  1. (2001) "Product Information. Prograf (tacrolimus)." Fujisawa
  2. Hooks MA (1994) "Tacrolimus, a new immunosuppressant--a review of the literature." Ann Pharmacother, 28, p. 501-11

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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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