Midazolam Injection and Saquinavir: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Saquinavir
No brand names on recordMidazolam Injection
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
An increased risk of midazolam toxicity (excessive sedation, respiratory depression)
Interaction Deep Dive
The AUC and Cmax of oral midazolam increased by 1144% and 327%, respectively, when coadministered with saquinavir/ritonavir. Because of the potential for serious and/or life-threatening prolonged sedation and respiratory depression that can occur with increased plasma concentrations of midazolam, the concurrent use of saquinavir and midazolam is contraindicated. Saquinavir and midazolam are both metabolized by CYP3A4 enzymes, and the competition for metabolism could result in an increased plasma concentration of midazolam. If concurrent use with parenteral midazolam is required, close monitoring for respiratory depression or prolonged sedation is recommended along with dose adjustments as necessary1.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated midazolam metabolism by saquinavir
Literature reports
3 reports — tap to read
a) Coadministration of oral midazolam with saquinavir/ritonavir resulted in significantly increase exposure and plasma concentrations of midazolam. Oral saquinavir 1000 mg/ritonavir 100 mg twice daily were administered for 15 days followed by a single-dose of oral midazolam 7.5 mg in 16 healthy volunteers. The geometric mean AUC and Cmax of midazolam increased by 1144% (95% confidence interval (CI), 975% to 1339%) and 327% (95% CI, 264% to 402%), respectively 1.
b) In a double-blind, randomized, two-phase crossover study involving 12 healthy volunteers, saquinavir was found to significantly inhibit the metabolism of oral and intravenous midazolam. Each study participant received saquinavir 1200 mg as the soft-gelatin capsule formulation 3 times daily for 5 days. On day 3, half of the subjects received oral midazolam 7.5 mg and half received intravenous midazolam 0.05 mg/kg. On day 5, the second dose of midazolam was administered but the route of administration was switched. Saquinavir increased the maximum concentration (Cmax) of oral midazolam from 26.9 nanograms (ng)/mL to 63.2 ng/mL. The area under the concentration-time curve (AUC) also increased from 108 ng/mL/hr to 559 ng/mL/hr. The half-life of oral midazolam was extended from 4.3 hours to 10.9 hours, and the oral bioavailability rose from 41% to 90%. For intravenous midazolam, saquinavir caused a 56% reduction of the mean plasma clearance and increased the half-life from 4.1 hours to 9.5 hours. Pharmacodynamically, the higher midazolam concentrations experienced during the saquinavir phase were associated with profound sedation. Cytochrome P450 3A4 (CYP3A4) enzymes are expressed in both the gut wall and the liver, so inhibition of CYP3A4 by saquinavir may occur at both sites, depending on the route of administration. Accordingly, the AUC of oral midazolam was increased more than 5-fold while the AUC of intravenous midazolam was increased by 2.4-fold 2.
c) In a placebo-controlled study involving 12 patients, saquinavir 1200 mg three times daily for 5 days was administered with intravenous midazolam 0.05 mg/kg and a 56% reduction in the clearance of midazolam resulted. The midazolam half-life increased approximately 2-fold 3.
Common questions
Can I take Midazolam Injection and Saquinavir together?
An increased risk of midazolam toxicity (excessive sedation, respiratory depression) Always confirm with your pharmacist or prescriber before making any change.
How serious is the Midazolam Injection and Saquinavir interaction?
It is rated contraindicated. These should generally not be used together.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How strong is the evidence for this interaction?
The evidence is graded "established". Well documented — supported by controlled studies or strong clinical data.
Questions for your pharmacist
- Does my dose of Midazolam Injection or Saquinavir need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (3)
- Product Information: INVIRASE(R) oral capsules and oral tablets, saquinavir mesylate oral capsules and oral tablets. F.Hoffmann-La Roche Ltd. Basel, Switzerland, 2010. DailyMed
- Palkama VJ, Ahonen J, Neuvonen PJ, et al: Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. Clin Pharmacol Ther 1999; 66:33-39. PubMed
- Product Information: NOVAPLUS(R) midazolam hydrochloride intramuscular injection, intravenous injection, midazolam hydrochloride intramuscular injection, intravenous injection. Hospira, Lake Forest, IL, 2004.
Keep reading about Saquinavir
Keep reading about Midazolam Injection
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Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
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