Drug Interaction Report

Primidone and Midazolam Injection: Interaction Details

A pharmacist-reviewed analysis of the Primidone and Midazolam Injection interaction: the documented clinical effects, severity rating, onset, mechanism, and management considerations, with cited references throughout.

AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature

Primidone

Mysoline
+

Midazolam Injection

Nayzilam Versed® Injection
Dr. Brian Staiger, PharmD, BCPS
Medically reviewed by
Dr. Brian Staiger, PharmD, BCPS
Updated Aug 8, 2026
Editorial policy · Data sources
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Interaction severity
Major
Potentially serious — often needs a change or close monitoring.
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.

Of 204 documented Primidone interactions, 190 are rated major — including this one.
Worried about symptoms right now? Contact your pharmacist or prescriber, or call Poison Control at 1-800-222-1222 (US). Call 911 for an emergency.
Onset
unspecified
Evidence
theoretical
Severity
Major

What happens

An increased risk of CNS depression, reduced midazolam exposure and reduced efficacy of midazolam

Interaction Deep Dive

Primidone is metabolized to PHENobarbital2 (a CNS depressant and a CYP3A4 inducer). Concomitant use of PHENobarbital with certain CYP3A4 substrates, such as midazolam, may result in decreased exposure of midazolam which may reduce the efficacy of midazolam. Additionally, when used in combination, these drugs may have sedation and additive CNS and respiratory depressant effects 3. Concomitant use of midazolam with other central nervous system depressants like PHENobarbital or primidone may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect. Anticipated effects range from mild sedation to deep levels of sedation equivalent to a state of general anesthesia where the patient may require external support of vital functions. Monitor closely and be prepared to manage serious cardiorespiratory adverse reactions, including airway management 1. If concomitant use cannot be avoided, closely monitor neonates and consider increasing the midazolam dosage accordingly. Also, closely monitor patients for signs and symptoms of respiratory depression and sedation 3.

Why it happens (mechanism)

Additive CNS depression; induction of CYP3A4-mediated midazolam metabolism

Literature reports

2 reports — tap to read

a) It has been noted in several studies that combinations of clonazePAM and primidone or PHENobarbital tend to produce more severe side effects (drowsiness, irritability, hyperactivity), while clonazePAM in combination with hydantoins or carBAMazepine are better tolerated 45678.

b) Concomitant administration of intravenous midazolam and thiopental resulted in synergistic (supraadditive) effects during induction of anesthesia 9. The combination of intravenous thiopental and midazolam had 1.8 times the expected potency of the individual drugs, and the dose of thiopental required to produce anesthesia was reduced by 50% in another study 10. A 15% reduction in the thiopental induction dose requirement has been observed if it follows intramuscular premedication with midazolam 11. The interaction between midazolam and thiopental may in part be dependent on thiopental dosing 12.

Common questions

Can I take Primidone and Midazolam Injection together?

An increased risk of CNS depression, reduced midazolam exposure and reduced efficacy of midazolam Always confirm with your pharmacist or prescriber before making any change.

How serious is the Primidone and Midazolam Injection interaction?

It is rated major. Potentially serious — often needs a change or close monitoring.

How quickly could this interaction happen?

The documented onset is "unspecified". The timing of this interaction is not well characterized.

How strong is the evidence for this interaction?

The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.

From our Q&A

Real reader questions about these medications, each personally answered by our pharmacist:

Questions for your pharmacist

  • Does my dose of Primidone or Midazolam Injection 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 (12)

  1. Product Information: SEIZALAM(TM) intramuscular injection, midazolam HCl intramuscular injection. Meridian Medical Technologies, Inc (per DailyMed), Columbia, MD, 2018.
  2. Product Information: Mysoline(R) oral tablets, primidone oral tablets. Valeant Pharmaceuticals North America (per DailyMed), Aliso Viejo, CA, 2010. DailyMed
  3. Product Information: SEZABY(TM) intravenous injection, phenobarbital sodium intravenous injection. Sun Pharmaceutical Industries Inc (per manufacturer), Cranbury, NJ, 2022. DailyMed
  4. Birket-Smith E & Mikkelsen B: Preliminary observations on the effect of a new benzodiazepine (RO-5-4023) in epilepsy. Acta Neurol Scand 1972; 48(suppl):385-395. PubMed
  5. Aarli J: Effect of clonazepam (RO5-4023) on epileptic seizures. Acta Neurol Scand 1973; 49(suppl 53):11.
  6. Mikkelsen B & Birket-Smith E: A clinical study of the benzodiazepine RO5-4023 (clonazepam) in the treatment of epilepsy. Acta Neurol Scand 1973; 49(suppl 53):91-96.
  7. Munthe-Kaas A: Clonazepam in the treatment of epileptic seizures. Acta Neurol Scand 1973; 49(suppl 53):97. PubMed
  8. Hooshmond H: Trial of a new anticonvulsant for uncontrollable minor motor seizures. Epilepsia 1971; 12:277.
  9. Tverskoy M, Fleyshman G, Bradley EL, et al: Midazolam-thiopental anesthetic interaction in patients. Anesth Analg 1988; 67:342-345. DOI
  10. Short TG, Galletly DC, & Plummer JL: Hypnotic and anaesthetic action of thiopentone and midazolam alone and in combination. Br J Anaesth 1991; 66:13-19. PubMed
  11. Product Information: Versed(R), midazolam. Roche Laboratories Inc. Nutley, NJ, 2000. DailyMed
  12. Wilder-Smith OHG, Ravussin PA, Decosterd LA, et al: Hypnotic and anaesthetic action of thiopentone and midazolam alone and in combination. Br J Anaesth 1999; 83:590-595.
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Primidone

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Beyond drug–drug

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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:

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This information is for education, not a substitute for professional medical advice. Do not start, stop, or change any medication without talking to your pharmacist or prescriber.