Is concomitant use of propranolol and rizatriptan contraindicated in a patient without known cardiovascular disease, uncontrolled hypertension, or a history of ischemic heart disease?

Concomitant Use of Propranolol and Rizatriptan

Concomitant use of propranolol and rizatriptan is NOT contraindicated, but requires a mandatory dose reduction of rizatriptan from 10 mg to 5 mg when used together. 1, 2

Pharmacokinetic Interaction

• Propranolol significantly increases rizatriptan plasma concentrations by approximately 67% for AUC and 75% for Cmax through inhibition of monoamine oxidase-A (MAO-A), the primary enzyme responsible for rizatriptan metabolism. 2

• This interaction is specific to propranolol among beta-blockers—neither nadolol nor metoprolol produce clinically significant changes in rizatriptan pharmacokinetics, so no dose adjustment is required with those agents. 2, 3

• The mechanism involves propranolol (or its metabolite) inhibiting MAO-A in the gut wall and liver, thereby reducing first-pass metabolism of rizatriptan and increasing systemic exposure. 2, 3

FDA-Mandated Dose Adjustment

• The FDA drug label for rizatriptan explicitly states: "Especially tell your doctor if you take propranolol containing medicines such as Inderal®, Inderal® LA, or Innopran® XL" and mandates use of the 5 mg dose when propranolol is prescribed concomitantly. 1

• Do not exceed 15 mg of rizatriptan in 24 hours (maximum three 5 mg doses) when the patient is taking propranolol, compared to the standard 30 mg maximum in patients not on propranolol. 1

Safety Profile of the Combination

• Clinical trials demonstrated no serious adverse events, untoward clinical effects, or laboratory abnormalities attributable to the pharmacokinetic interaction between propranolol and rizatriptan when the 5 mg dose was used. 2

• The increased rizatriptan exposure from propranolol co-administration does not translate into increased cardiovascular risk or triptan-related adverse events when the dose is appropriately reduced. 2

Cardiovascular Contraindications (Unrelated to Propranolol)

• Rizatriptan remains absolutely contraindicated in patients with ischemic heart disease, previous myocardial infarction, coronary artery vasospasm, uncontrolled hypertension, cerebrovascular disease, history of stroke or TIA, or basilar/hemiplegic migraine—regardless of propranolol use. 1

• In a patient without these cardiovascular contraindications, the propranolol–rizatriptan combination is safe when the 5 mg rizatriptan dose is prescribed. 1, 2

Practical Algorithm for Prescribing

1. Confirm the patient is taking propranolol (any formulation: immediate-release, long-acting, or extended-release). 1

2. Prescribe rizatriptan 5 mg (not 10 mg) for acute migraine treatment. 1, 2

3. Instruct the patient to take no more than three 5 mg doses in 24 hours (maximum 15 mg/day). 1

4. Do not attempt to separate dosing times between propranolol and rizatriptan—studies show that delaying rizatriptan administration by 1–2 hours after propranolol does not eliminate the interaction. 2

5. If the patient is taking nadolol or metoprolol instead of propranolol, use the standard 10 mg rizatriptan dose without adjustment. 2, 3

Alternative Triptan Considerations

• If a higher triptan dose is required for efficacy, consider switching from propranolol to metoprolol or nadolol for migraine prophylaxis, which do not interact with rizatriptan and allow use of the full 10 mg dose. 2, 3

• Alternatively, switch to a different triptan (e.g., sumatriptan, eletriptan, naratriptan) that may have less pronounced interaction with propranolol, though all triptans undergo some degree of MAO-A metabolism. 3

Critical Pitfall to Avoid

• Do not withhold rizatriptan solely because the patient is on propranolol—the interaction is manageable with dose reduction and is not a contraindication. 1, 2

• Do not prescribe the 10 mg rizatriptan dose to a patient taking propranolol, as this results in excessive triptan exposure equivalent to approximately 17 mg. 2