Skip to main content

Drug Interactions between darunavir and midazolam

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

Edit list (add/remove drugs)

Interactions between your drugs

Major

midazolam darunavir

Applies to: midazolam and darunavir

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

Switch to consumer interaction data

Drug and food interactions

Moderate

midazolam food

Applies to: 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

Switch to consumer interaction data

Moderate

darunavir food

Applies to: darunavir

ADJUST DOSING INTERVAL: Food enhances the absorption and oral bioavailability of darunavir administered in combination with low-dose ritonavir. The mechanism is unknown. When administered with food, the peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of darunavir were approximately 30% higher than when administered in the fasting state. Darunavir exposure was similar for the range of meals studied. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 grams fat) to 928 Kcal (56 grams fat).

MANAGEMENT: To ensure maximal oral absorption, darunavir coadministered with ritonavir should be taken with food. The type of food is not important.

References

  1. (2006) "Product Information. Prezista (darunavir)." Ortho Biotech Inc

Switch to consumer interaction data

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

Report options

Loading...
QR code containing a link to this page

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.

Medical Disclaimer