Naratriptan - Drug Monograph

Introduction

Naratriptan is a selective serotonin receptor agonist (triptan) specifically developed for the acute treatment of migraine headaches with or without aura. As a second-generation triptan, it offers a favorable balance of efficacy and tolerability with a longer half-life than sumatriptan. Approved by the FDA in 1998, naratriptan represents an important therapeutic option in migraine management, particularly for patients who experience recurrent headaches or require sustained relief.

Mechanism of Action

Naratriptan exerts its therapeutic effects through selective agonism at serotonin (5-HT) receptors, primarily 5-HT1B and 5-HT1D receptors. This dual mechanism results in:

• Cranial vasoconstriction through 5-HT1B receptor activation
• Inhibition of trigeminal nerve transmission and neuropeptide release through 5-HT1D receptor activation
• Reduction of neurogenic inflammation in the meninges

The drug does not possess general vasoconstrictive properties and shows little affinity for other 5-HT receptor subtypes or adrenergic, dopaminergic, or muscarinic receptors.

Indications

FDA-approved indications:

• Acute treatment of migraine with aura in adults
• Acute treatment of migraine without aura in adults

Off-label uses (limited evidence):

• Cluster headache (alternative when other triptans ineffective)
• Short-lasting unilateral neuralgiform headache attacks (SUNCT)

Dosage and Administration

• Initial dose: 1 mg or 2.5 mg tablet taken at migraine onset
• Maximum dose: 5 mg per 24-hour period (2.5 mg twice daily)
• Minimum dosing interval: 4 hours between doses

• Hepatic impairment: Maximum dose 2.5 mg per 24 hours
• Renal impairment (CrCl 15-39 mL/min): Maximum dose 2.5 mg per 24 hours
• Severe renal impairment (CrCl <15 mL/min): Not recommended
• Elderly: Use with caution due to potential decreased clearance
• Pediatrics: Safety and efficacy not established

• Oral administration with or without food
• Should be taken as early as possible during migraine attack
• Not intended for migraine prophylaxis

Pharmacokinetics

• Oral bioavailability: ~70%
• Tmax: 2-3 hours
• Food delays absorption but does not affect overall bioavailability

• Volume of distribution: ~170 L
• Protein binding: 28-31%
• Crosses blood-brain barrier

• Primarily hepatic via CYP450 enzymes (multiple pathways)
• Forms inactive metabolites
• Not extensively metabolized

• Half-life: 6 hours (longest among triptans)
• Renal excretion: 50% unchanged drug
• Feces: 30% unchanged drug
• Clearance: ~220 mL/min

Contraindications

• History of ischemic heart disease or coronary artery vasospasm
• Uncontrolled hypertension
• History of stroke or transient ischemic attack
• Peripheral vascular disease
• Hemiplegic or basilar migraine
• Severe hepatic impairment
• Within 24 hours of another triptan or ergotamine-containing medication
• Hypersensitivity to naratriptan or any component
• Within 2 weeks of MAO inhibitor therapy

Warnings and Precautions

• May cause coronary artery vasospasm and chest pain
• Screen for cardiovascular risk factors before prescribing
• Not recommended for patients with multiple cardiovascular risk factors

• Risk of cerebral hemorrhage, subarachnoid hemorrhage, and stroke

• Use >10 days per month may lead to medication-overuse headache

• Risk particularly when used with other serotonergic drugs

• May cause gastrointestinal ischemic events
• Potential for increased blood pressure
• Use cautiously in patients with phenylketonuria (contains phenylalanine)

Drug Interactions

• MAO inhibitors: Contraindicated (increased naratriptan levels)
• Other triptans/ergot derivatives: Contraindicated (additive vasoconstriction)
• SSRIs/SNRIs: Increased risk of serotonin syndrome
• Propranolol: Increases naratriptan AUC by 40-50% (dose adjustment needed)
• Oral contraceptives: May increase naratriptan concentrations
• CYP450 inhibitors: Potential increased exposure

Adverse Effects

• Paresthesia (5%)
• Dizziness (4%)
• Fatigue (4%)
• Somnolence (3%)
• Throat/neck discomfort (3%)
• Nausea (2%)

• Chest pain/tightness (1%)
• Coronary artery vasospasm
• Myocardial ischemia
• Hypertension
• Serotonin syndrome
• Seizures
• Visual disturbances

Monitoring Parameters

• Cardiovascular history and risk factors
• Blood pressure
• Renal and hepatic function
• Medication history for potential interactions

• Frequency of migraine attacks and medication use
• Therapeutic response and adverse effects
• Blood pressure in hypertensive patients
• Signs of serotonin syndrome when used with other serotonergic drugs
• Symptoms of cardiac ischemia

• Development of medication-overuse headache
• Changes in migraine pattern
• Cardiovascular risk factors

Patient Education

• Take at first sign of migraine, but may be effective at any time
• Do not exceed recommended dosage
• Wait at least 4 hours between doses
• Do not use for more than 3 headaches per week

• Relief typically within 1-2 hours
• May repeat dose if headache returns (not within 4 hours)
• Lie down in dark, quiet room after taking medication

• Report chest pain, shortness of breath, or severe dizziness immediately
• Inform all healthcare providers of naratriptan use
• Avoid driving if feeling drowsy or dizzy
• Do not use with other migraine medications without medical supervision

• Store at room temperature
• Keep in original container
• Protect from light and moisture

References

1. FDA Prescribing Information: Naratriptan Tablets. (2023) 2. Goadsby PJ, et al. Naratriptan: A review of its use in migraine. Drugs. 2000;59(4):921-949 3. Tepper SJ, et al. Acute treatment of migraine. Headache. 2021;61(2):309-325 4. Ferrari MD, et al. Oral triptans in acute migraine treatment: A meta-analysis of 53 trials. Neurology. 2001;56(3):331-337 5. American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache. 2019;59(1):1-18 6. Lexicomp Online. Naratriptan monograph. Wolters Kluwer Clinical Drug Information. (2023) 7. Micromedex Solutions. Naratriptan drug information. IBM Watson Health. (2023)