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

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

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Interactions between your drugs

Major

rifabutin ritonavir

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

ADJUST DOSE: Coadministration with ritonavir may significantly increase the plasma concentrations of rifabutin and its pharmacologically active 25-O-desacetyl metabolite. The mechanism is ritonavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of rifabutin and 25-O-desacetylrifabutin. In five healthy volunteers, administration of rifabutin (150 mg once daily) with ritonavir (300 mg twice a day titrated up to 500 mg twice a day) for 10 days increased mean steady-state rifabutin peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by approximately 2.5-, 4- and 6-fold, respectively, compared to administration of rifabutin alone. Mean steady-state Cmax, AUC, and Cmin of 25-O-desacetylrifabutin increased by 16-, 35-, and 200-fold, respectively. The combination has been associated with increased risk of rifabutin-related adverse effects such as leukopenia, uveitis, arthralgia, joint disorder, and skin discoloration.

MANAGEMENT: To minimize the risk of rifabutin toxicity, the manufacturers suggest that rifabutin dosage be reduced to 150 mg every other day or three times per week in patients treated with ritonavir; however, specific dosage adjustment recommendations are not available for the use of ritonavir-boosted nirmatrelvir in the treatment of COVID-19 infection. More recently, U.S. HIV treatment guidelines and some infectious disease experts have been recommending a rifabutin dosage of 150 mg once daily or 300 mg three times per week when prescribed with ritonavir-boosted protease inhibitor regimens, as lower dosages of rifabutin have been associated with potentially subtherapeutic plasma levels in some studies. Therapeutic drug monitoring for rifabutin is advisable. Patients should be monitored closely for adverse effects of rifabutin, and a complete blood count should be performed at least weekly and as clinically indicated to monitor for development of neutropenia. Further dosage adjustments should be guided by therapeutic response and patient tolerance.

References

  1. "Product Information. Mycobutin (rifabutin)." Pharmacia and Upjohn PROD (2001):
  2. "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical PROD (2001):
  3. Cato A, Cavanaugh J, Shi H, Hsu A, Leonard J, Granneman R "The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin." Clin Pharmacol Ther 63 (1998): 414-21
  4. Fournier S, Deplus S, Janier M, Poinsignon Y, Decazes JM, Modai J "Anterior uveitis in 3 HIV-infected patients treated with antiprotease." Presse Med 27 (1998): 844-8
  5. Burman WJ, Jones BE "Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy." Am J Respir Crit Care Med 164 (2001): 7-12
  6. "Notice to readers: updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibiotrs." MMWR Morb Mortal Wkly Rep 49 (2000): 185-9
  7. American Thoracic Society, CDC, Infectious Diseases Society of America "Treatment of tuberculosis." MMWR Morb Mortal Wkly Rep 52(RR-11) (2003): 1-77
  8. Lin HC, Lu PL, Chang CH "Uveitis associated with concurrent administration of rifabutin and lopinavir/ritonavir (Kaletra)." Eye 21 (2007): 1540-1
  9. Jenny-Avital ER, Joseph K "Rifamycin-resistant Mycobacterium tuberculosis in the highly active antiretroviral therapy era: a report of 3 relapses with acquired rifampin resistance following alternate-day rifabutin and boosted protease inhibitor therapy." Clin Infect Dis 48 (2009): 1471-4
  10. Khachi H, O'Connell R, Ladenheim D, Orkin C "Pharmacokinetic interactions between rifabutin and lopinavir/ritonavir in HIV-infected patients with mycobacterial co-infection." J Antimicrob Chemother 64 (2009): 871-3
  11. Boulanger C, Hollender E, Farrell K, et al. "Pharmacokinetic evaluation of rifabutin in combination with lopinavir-ritonavir in patients with HIV infection and active tuberculosis." Clin Infect Dis 49 (2009): 1305-11
  12. Zhang J, Zhu L, Stonier M, et al. "Determination of rifabutin dosing regimen when administered in combination with ritonavir-boosted atazanavir." J Antimicrob Chemother 66 (2011): 2075-82
  13. Tanuma J, Sano K, Teruya K, et al. "Pharmacokinetics of rifabutin in Japanese HIV-infected patients with or without antiretroviral therapy." PLoS One 8 (2013): e70611
  14. Ramachandran G, Bhavani PK, Hemanth Kumar AK, et al. "Pharmacokinetics of rifabutin during atazanavir/ritonavir co-administration in HIV-infected TB patients in India." Int J Tuberc Lung Dis 17 (2013): 1564-8
  15. US Food and Drug Administration "FACT SHEET FOR HEALTHCARE PROVIDERS EMERGENCY USE AUTHORIZATION FOR PAXLOVID. https://www.fda.gov/media/155050/download" (2021):
View all 15 references

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Drug and food interactions

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. "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical PROD (2001):

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

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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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