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Drug Interactions between dasabuvir / ombitasvir / paritaprevir / ritonavir and tacrolimus

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

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Interactions between your drugs

Major

tacrolimus ritonavir

Applies to: tacrolimus and dasabuvir / ombitasvir / paritaprevir / ritonavir

MONITOR CLOSELY: Coadministration with protease inhibitors (PIs) may significantly increase the blood concentrations of tacrolimus. The proposed mechanism is PI inhibition of intestinal and hepatic CYP450 3A4, the isoenzyme responsible for the metabolic clearance of tacrolimus. Enhanced tacrolimus oral bioavailability due to inhibition of intestinal P-glycoprotein (P-gp) efflux transporter may also contribute. There have been numerous reports of tacrolimus interaction with various PI-containing regimens in the medical literature, which necessitated substantial (> 10-fold) reductions or interruptions in tacrolimus dosing.

MANAGEMENT: Caution is advised when tacrolimus is used with protease inhibitors (PIs). Dosage reduction and/or prolongation of the dosing interval for tacrolimus will likely be required. Tacrolimus blood levels and renal function should be checked frequently and the dosage adjusted accordingly, particularly following initiation or discontinuation of PI therapy. 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. (2001) "Product Information. Prograf (tacrolimus)." Fujisawa
  2. 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
  3. (2001) "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical
  4. (2001) "Product Information. Crixivan (indinavir)." Merck & Co., Inc
  5. (2001) "Product Information. Viracept (nelfinavir)." Agouron Pharma Inc
  6. (2001) "Product Information. Agenerase (amprenavir)." Glaxo Wellcome
  7. (2001) "Product Information. Fortovase (saquinavir)." Roche Laboratories
  8. 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
  9. 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
  10. (2003) "Product Information. Reyataz (atazanavir)." Bristol-Myers Squibb
  11. (2003) "Product Information. Lexiva (fosamprenavir)." GlaxoSmithKline
  12. Schonder KS, Shullo MA, Okusanya O (2003) "Tacrolimus and lopinavir/ritonavir interaction in liver transplantation." Ann Pharmacother, 37, p. 1793-6
  13. 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
  14. (2006) "Product Information. Prezista (darunavir)." Ortho Biotech Inc
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
View all 19 references

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Major

tacrolimus paritaprevir

Applies to: tacrolimus and dasabuvir / ombitasvir / paritaprevir / ritonavir

CONTRAINDICATED: Coadministration of ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, may significantly increase the blood concentrations of tacrolimus, sirolimus, and everolimus. The proposed mechanism involves ritonavir inhibition of intestinal and hepatic CYP450 3A4, the isoenzyme responsible for the metabolic clearance of these immunosuppressants. Enhanced oral bioavailability due to inhibition of intestinal P-glycoprotein (P-gp) efflux transporter by ritonavir, paritaprevir, and dasabuvir may also contribute. When a single dose of tacrolimus was administered with ombitasvir/paritaprevir/ritonavir in healthy study subjects, tacrolimus peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) increased by approximately 4.3-, 85.8- and 24.6-fold, respectively, compared to tacrolimus administered alone. Likewise, sirolimus Cmax, AUC and Cmin increased by approximately 6.4-, 38.0- and 19.6-fold, respectively, while everolimus Cmax, AUC and Cmin increased by approximately 4.7-, 27.1- and 16.1-fold, respectively, when coadministered with ombitasvir/paritaprevir/ritonavir plus dasabuvir. Single-dose tacrolimus Cmax, AUC and Cmin increased by approximately 4.0-, 57.1-fold and 16.6-fold when coadministered with ombitasvir/paritaprevir/ritonavir plus dasabuvir

MANAGEMENT: Concomitant use of tacrolimus, sirolimus, or everolimus in combination with ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, is considered contraindicated.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. (2022) "Product Information. Viekira Pak (dasabuvir/ombitasvir/paritaprev/ritonav)." AbbVie US LLC
  3. (2015) "Product Information. Technivie (ombitasvir/paritaprevir/ritonavir)." AbbVie US LLC
  4. Badri P, Dutta S, Coakley E, et al. (2015) "Pharmacokinetics and dose recommendations for cyclosporine and tacrolimus when coadministered with ABT-450, ombitasvir, and dasabuvir." Am J Transplant, 15, p. 1313-22
View all 4 references

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Drug and food interactions

Moderate

tacrolimus food

Applies to: 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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Moderate

ritonavir food

Applies to: dasabuvir / ombitasvir / paritaprevir / ritonavir

ADJUST DOSING INTERVAL: Administration with food may modestly affect the bioavailability of ritonavir from the various available formulations. When the oral solution was given under nonfasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution (within one hour of dosing) with 240 mL of chocolate milk or a nutritional supplement (Advera or Ensure) did not significantly affect the extent and rate of ritonavir absorption. When a single 100 mg dose of the tablet was administered with a high-fat meal (907 kcal; 52% fat, 15% protein, 33% carbohydrates), approximately 20% decreases in mean peak concentration (Cmax) and systemic exposure (AUC) were observed relative to administration after fasting. Similar decreases in Cmax and AUC were reported when the tablet was administered with a moderate-fat meal. In contrast, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate) relative to fasting.

MANAGEMENT: Ritonavir should be taken with meals to enhance gastrointestinal tolerability.

References

  1. (2001) "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical

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Moderate

paritaprevir food

Applies to: dasabuvir / ombitasvir / paritaprevir / ritonavir

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of ombitasvir, paritaprevir, ritonavir, and dasabuvir. Relative to fasting conditions, administration of ombitasvir, paritaprevir, ritonavir, and dasabuvir with a moderate-fat meal (approximately 600 Kcal; 20% to 30% calories from fat) increased the mean systemic exposure (AUC) by 82%, 211%, 49%, and 30%, respectively. Relative to fasting conditions, administration of ombitasvir, paritaprevir, ritonavir, and dasabuvir with a high-fat meal (approximately 900 Kcal; with 60% calories from fat) increased the mean AUC by 76%, 180%, 44%, and 22%, respectively.

MANAGEMENT: Ombitasvir/paritaprevir/ritonavir plus dasabuvir should always be administered with a meal. The fat or calorie content does not matter.

References

  1. (2022) "Product Information. Viekira Pak (dasabuvir/ombitasvir/paritaprev/ritonav)." AbbVie US LLC

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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.

Further information

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