Diazepam Rectal and Fluoxetine: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Fluoxetine
Diazepam Rectal
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
Increased diazePAM exposure
Interaction Deep Dive
During coadministration of FLUoxetine with diazePAM, the FLUoxetine area under the concentration-time curve (AUC) was increased, but this was not associated with increased impairment2. Conversely, a controlled study observed significant decreases in psychomotor performance when diazePAM was added to FLUoxetine 7. The metabolism of diazePAM is mediated by several P450 enzymes which may be inhibited by FLUoxetine 465. Concurrent administration of FLUoxetine with diazePAM may prolong the half-life of diazePAM in some patients 1.
Why it happens (mechanism)
Inhibition of the hepatic P450 metabolism of diazePAM
Literature reports
5 reports — tap to read
a) Coadministration of FLUoxetine and diazePAM resulted in prolonged half-life, reduced plasma clearance, and increased AUC for diazePAM. Oral diazePAM 10 mg was given alone, after a single dose of oral FLUoxetine 60 mg, and after 8 daily doses of FLUoxetine 60 mg. Psychometric data demonstrated no effect of FLUoxetine on the psychomotor response to diazePAM. Thus, although FLUoxetine decreases the clearance of diazePAM, this does not appear to be of clinical relevance and dosing adjustments are not required during combined therapy 2.
b) Combined therapy with diazePAM and FLUoxetine caused an increase in the half-life of the metabolite desmethyldiazePAM, but this did not appear to be clinically significant. diazePAM had no effect on the disposition of FLUoxetine or norFLUoxetine 3.
c) To date, in-vitro studies have found that diazePAM demethylation occurs via P450 1A2, 3A4, 2C9, and 2C19. Evidence with drugs known to be metabolized by these enzymes suggests that FLUoxetine strongly inhibits 2C9, moderately inhibits 2C19 and 3A4, and has no effect on 1A2 456.
d) In a controlled study of performance of 90 healthy volunteers, the effects of FLUoxetine, amitriptyline, or placebo with diazePAM were studied. Volunteers received one of six treatment combinations, and were given performance tests including a critical tracking test, divided attention test, visual search task, memory test, and vigilance test. FLUoxetine alone did not affect performance, but when FLUoxetine was added to diazePAM, there was a significant increase in the divided attention tracking error and significant impairment on the vigilance test. For amitriptyline alone and during coadministration with diazePAM, significant impairment was observed. On most tests, the combination of amitriptyline and diazePAM resulted in additive effects. The authors concluded that the combination of diazePAM and an antidepressant may increase an individual's risk during driving and while performing other complex tasks 7.
e) A case was reported in which an 83-year old man developed delirium after the addition of FLUoxetine and diazePAM to a regimen of warfarin, lisinopril, furosemide, potassium, digoxin, and acetaminophen. The patient was given FLUoxetine 20 mg per day and diazePAM 2.5 mg three to four times per day for symptoms of depression, anxiety, and insomnia. The patient then developed symptoms of drug delirium, including confusion, incoherence, and irrational speaking. The patient also developed an increased international normalized ratio (INR), after which FLUoxetine was discontinued. The patient presented to the hospital with left-sided weakness and later died from complications of a large interparenchymal hemorrhage. The authors proposed that the addition of FLUoxetine to the patient's regimen resulted in increased serum levels of both warfarin and diazePAM, resulting in drug-induced delirium and loss of anticoagulant control 8.
Common questions
Can I take Diazepam Rectal and Fluoxetine together?
Increased diazePAM exposure Always confirm with your pharmacist or prescriber before making any change.
How serious is the Diazepam Rectal and Fluoxetine interaction?
It is rated moderate. Can be significant — usually manageable with monitoring.
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 "probable". Good supporting evidence, though not definitively proven.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Diazepam Rectal or Fluoxetine 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 anything you'd monitor while I'm on both?
References (8)
- Product Information: PROZAC(R) oral capsules, fluoxetine oral capsules. Lilly USA LLC (per FDA), Indianapolis, IN, 2023. DailyMed
- Lemberger L, Rowe H, Bosomworth JC, et al: The effect of fluoxetine on the pharmacokinetics and psychomotor responses of diazepam. Clin Pharmacol Ther 1988; 43:412-419. PubMed
- Lemberger L, Bergstrom RF, Wolen RL, et al: Fluoxetine: clinical pharmacology and physiologic disposition. J Clin Psychiatry 1985; 46:14-19.
- Riesenman C: Antidepressant drug interactions and the cytochrome P450 system: a critical appraisal. Pharmacotherapy 1995; 15(6 part 2):84S-99S. DOI
- Nemeroff CB, DeVane CL, & Pollock BG: Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 1996; 153:311-320. PubMed
- Shen WW: Cytochrome P450 monooxygenases and interactions of psychotropic drugs: a five-year update. Int J Psychiatry Med 1995; 25:277-290. DOI
- Moskowitz H & Burns M: The effects on performance of two antidepressants, alone and in combination with diazepam. Prog Neuropsychopharmacol Biol Psychiatry 1988; 12:783-792. PubMed
- Dent LA & Orrock MW: Warfarin-fluoxetine and diazepam-fluoxetine interaction. Pharmacother 1997; 17:170-172. DOI
Keep reading about Fluoxetine
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