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Drug Interactions between ombitasvir / paritaprevir / ritonavir and Versed

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

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Interactions between your drugs

Major

midazolam ritonavir

Applies to: Versed (midazolam) and ombitasvir / paritaprevir / ritonavir

CONTRAINDICATED: Coadministration with protease inhibitors (PIs) may significantly increase the plasma concentrations and pharmacologic effects of orally administered midazolam and triazolam. The mechanism is PI inhibition of intestinal and hepatic CYP450 3A4, the isoenzyme primarily responsible for the metabolic clearance of these benzodiazepines. Within the class, ritonavir is the most potent CYP450 3A4 inhibitor, while saquinavir is considered one of the weaker ones. In six healthy volunteers, ritonavir (200 mg twice a day for 2 days) nearly doubled the peak plasma concentration (Cmax) of triazolam (0.125 mg single dose) and increased its systemic exposure (AUC) and elimination half-life by 20- and 14-fold, respectively, compared to placebo. Ritonavir also decreased triazolam clearance to less than 4% of control values. In 12 healthy volunteers, the Cmax and AUC of oral midazolam (7.5 mg single dose) increased by more than 2- and 5-fold, respectively, during coadministration with saquinavir (soft gelatin capsule 1200 mg three times a day for 5 days) relative to placebo, while oral bioavailability increased from 41% to 90%. The AUC of intravenous midazolam (0.05 mg/kg single dose) increased 2.4-fold, and mean plasma clearance decreased by 56%. In both studies, the pharmacokinetic changes were accompanied by increased sedation and impairment of psychomotor performance.

MANAGEMENT: Given the potential for prolonged and/or increased sedation and respiratory depression associated with excessive benzodiazepine blood levels, concomitant use of oral midazolam or triazolam with protease inhibitors is considered contraindicated. Caution and close clinical monitoring are recommended when administering parenteral midazolam in combination with protease inhibitors. Appropriate medical management should be readily available in case of respiratory depression and/or prolonged sedation. Dosage adjustment for midazolam may be appropriate, especially if more than a single dose of midazolam is administered.

References

  1. (2001) "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical
  2. (2001) "Product Information. Crixivan (indinavir)." Merck & Co., Inc
  3. Merry C, Mulcahy F, Barry M, Gibbons S, Back D (1997) "Saquinavir interaction with midazolam: pharmacokinetic considerations when prescribing protease inhibitors for patients with HIV disease." AIDS, 11, p. 268-9
  4. (2001) "Product Information. Viracept (nelfinavir)." Agouron Pharma Inc
  5. Eagling VA, Back DJ, Barry MG (1997) "Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir." Br J Clin Pharmacol, 44, p. 190-4
  6. Michalets EL (1998) "Update: clinically significant cytochrome P-450 drug interactions." Pharmacotherapy, 18, p. 84-112
  7. Malaty LI, Kuper JJ (1999) "Drug interactions of HIV protease inhibitors." Drug Safety, 20, p. 147-69
  8. Decker CJ, Laitinen LM, Bridson GW, Raybuck SA, Tung RD, Chaturvedi PR (1998) "Metabolism of amprenavir in liver microsomes: role of CYP3A4 inhibition for drug interactions." J Pharm Sci, 87, p. 803-7
  9. (2001) "Product Information. Agenerase (amprenavir)." Glaxo Wellcome
  10. Barry M, Mulcahy F, Merry C, Gibbons S, Back D (1999) "Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection." Clin Pharmacokinet, 36, p. 289-304
  11. Palkama VJ, Ahonen J, Neuvonen PJ, Olkkola KT (1999) "Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam." Clin Pharmacol Ther, 66, p. 33-9
  12. Dresser GK, Spence JD, Bailey DG (2000) "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet, 38, p. 41-57
  13. Greenblatt DJ, von Moltke LL, Harmatz JS, et al. (2000) "Differential impairment of triazolam and zolpidem clearance by ritonavir." J Acquir Immune Defic Syndr, 24, p. 129-36
  14. (2001) "Product Information. Fortovase (saquinavir)." Roche Laboratories
  15. Gill J, Feinberg J (2001) "Saquinavir soft gelatin capsule - A comparative safety review." Drug Safety, 24, p. 223-32
  16. Mangum EM, Graham KK (2001) "Lopinavir-Ritonavir: a new protease inhibitor." Pharmacotherapy, 21, p. 1352-63
  17. (2003) "Product Information. Reyataz (atazanavir)." Bristol-Myers Squibb
  18. (2003) "Product Information. Lexiva (fosamprenavir)." GlaxoSmithKline
  19. (2006) "Product Information. Prezista (darunavir)." Ortho Biotech Inc
View all 19 references

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Drug and food interactions

Moderate

midazolam food

Applies to: Versed (midazolam)

GENERALLY AVOID: The pharmacologic activity of oral midazolam, triazolam, and alprazolam may be increased if taken after drinking grapefruit juice. The proposed mechanism is CYP450 3A4 enzyme inhibition. In addition, acute alcohol ingestion may potentiate CNS depression and other CNS effects of many benzodiazepines. Tolerance may develop with chronic ethanol use. The mechanism may be decreased clearance of the benzodiazepines because of CYP450 hepatic enzyme inhibition. Also, it has been suggested that the cognitive deficits induced by benzodiazepines may be increased in patients who chronically consume large amounts of alcohol.

MANAGEMENT: The manufacturer recommends that grapefruit juice should not be taken with oral midazolam. Patients taking triazolam or alprazolam should be monitored for excessive sedation. Alternatively, the patient could consume orange juice which does not interact with these drugs. Patients should be advised to avoid alcohol during benzodiazepine therapy.

References

  1. (2002) "Product Information. Xanax (alprazolam)." Pharmacia and Upjohn
  2. (2002) "Product Information. Valium (diazepam)." Roche Laboratories
  3. (2001) "Product Information. Halcion (triazolam)." Pharmacia and Upjohn
  4. (1995) "Grapefruit juice interactions with drugs." Med Lett Drugs Ther, 37, p. 73-4
  5. Kupferschmidt HHT, Ha HR, Ziegler WH, Meier PJ, Krahenbuhl S (1995) "Interaction between grapefruit juice and midazolam in humans." Clin Pharmacol Ther, 58, p. 20-8
  6. Hukkinen SK, Varhe A, Olkkola KT, Neuvonen PJ (1995) "Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice." Clin Pharmacol Ther, 58, p. 127-31
  7. Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR (2000) "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients." Clin Pharmacol Ther, 68, p. 468-77
View all 7 references

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Moderate

ritonavir food

Applies to: 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: 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.

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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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