Theophylline and Diazepam Rectal: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Diazepam Rectal
Theophylline
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
Decreased benzodiazepine effectiveness
Interaction Deep Dive
Theophylline has been shown to reverse the sedative effects of benzodiazepines3576. A larger dose of benzodiazepine may be needed to produce sedation in a theophylline-treated patient. Respiratory depression may occur if theophylline is discontinued without a reduction of the benzodiazepine dose 10.
Why it happens (mechanism)
Theophylline blocks adenosine receptors
Literature reports
5 reports — tap to read
a) Eight healthy male volunteers participated in a study which demonstrated the antagonistic properties of theophylline on diazepam-induced psychomotor impairment. Subjects received an oral dose of diazepam 0.25 mg/kg, followed 40 minutes later by an intravenous infusion of 100 mL normal saline with or without theophylline 4.4 mg/kg. All subjects were tested twice: one time receiving theophylline and the other time receiving placebo. Theophylline reversed some of the diazepam-induced psychomotor impairment as measured by the digit symbol substitution test, card sorting, and three questionnaires which measured mood, anxiety, and distress. The antagonism caused by theophylline may be attributed to the stimulant action caused by methylxanthines on the central nervous system through adenosine receptor blockade 1.
b) Intravenous theophylline was reported to reverse the sedation produced by intravenous diazepam in patients undergoing genitourinary surgery. Patients were given intravenous doses of diazepam during surgery to maintain deep sedation, followed by administration of intravenous aminophylline (60 to 120 mg) or normal saline postoperatively. Rapid reversal of sedation occurred in aminophylline patients as compared to no response in saline patients 2. Other studies and case reports have also shown that theophylline antagonizes the sedative effects of diazepam 34.
c) Three case reports described patients who had the sedative effects of lorazepam reversed postoperatively by the administration of aminophylline 1 mg/kg intravenously 5. This same aminophylline dose was used to reverse the sedative effects of midazolam in three other patients 6. Theophylline also was demonstrated to reverse the sedative and psychomotor properties of flunitrazepam in healthy volunteers 7.
d) Less successful rates have been reported when utilizing aminophylline to reverse benzodiazepine oversedation . Of the six patients reported, all of whom had received midazolam, five patients showed no change in the level of consciousness after the administration of aminophylline 75 mg. One patient did experience quick and sudden awakening after aminophylline was given. The author suggests that there may be wide individual variations within the population to the effects of aminophylline antagonism on benzodiazepines 8.
e) To determine the mechanism by which theophylline antagonizes benzodiazepines, oral alprazolam 1 mg daily for seven days was administered to six patients who were receiving theophylline and to seven patients who were not receiving theophylline treatment. Serum alprazolam levels were significantly lower in patients on concurrent theophylline therapy, and the levels continued to decrease during each day of the study. In patients who were not receiving theophylline, serum alprazolam levels were within the therapeutic range. The authors concluded that the antagonism of the anxiolytic effects of benzodiazepines by theophylline may be due to decreased serum benzodiazepine levels in these patients 9.
Common questions
Can I take Theophylline and Diazepam Rectal together?
Decreased benzodiazepine effectiveness Always confirm with your pharmacist or prescriber before making any change.
How serious is the Theophylline and Diazepam Rectal interaction?
It is rated moderate. Can be significant — usually manageable with monitoring.
How quickly could this interaction happen?
The documented onset is "rapid". Effects can appear quickly, often within about 24 hours of combining the drugs.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
Questions for your pharmacist
- Does my dose of Theophylline or Diazepam Rectal 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 (10)
- Henauer SA, Hollister LE, Gillespie HK, et al: Theophylline antagonizes diazepam-induced psychomotor impairment. Eur J Clin Pharmacol 1983; 25:743-747. PubMed
- Arvidsson S, Niemand D, Martinell S, et al: Aminophylline reversal of diazepam sedation. Anaesthesia 1984; 39:806-809.
- Stirt JA: Aminophylline is a diazepam antagonist. Anesth Analg 1981; 60:767-768. DOI
- Meyer BH, Weis OF, & Muller FO: Antagonism of diazepam by aminophylline in healthy volunteers. Anesth Analg 1984; 63:900-902. DOI
- Wangler MA & Kilpatrick DS: Aminophylline is an antagonist of lorazepam. Anesth Analg 1985; 64:834-836. DOI
- Gallen JS: Aminophylline reversal of midazolam sedation (letter). Anesth Analg 1989; 69:268. DOI
- Gurel A, Elevli IM, & Hamulu A: Aminophylline reversal of flunitrazepam sedation. Anesth Analg 1987; 66:333-336. DOI
- Sleigh JW: Failure of aminophylline to antagonize midazolam sedation (letter). Anesth Analg 1986; 65:540. PubMed
- Tuncok Y, Akpinar O, Guven H, et al: The effects of theophylline on serum alprazolam levels. Int J Clin Pharmacol Ther 1994; 32:642-645.
- Bonfiglio MF & Dasta JF: Clinical significance of the benzodiazepine-theophylline interaction. Pharmacotherapy 1991; 11:85-87. DOI
Keep reading about Diazepam Rectal
Keep reading about Theophylline
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