Zolmitriptan - Drug Monograph

Introduction

Zolmitriptan is a selective serotonin (5-HT1B/1D) receptor agonist belonging to the triptan class of medications. It is specifically designed for the acute treatment of migraine attacks with or without aura in adults. First approved by the FDA in 1997, zolmitriptan represents an important therapeutic option in the management of migraine headaches, offering multiple administration routes including oral tablets, orally disintegrating tablets, and nasal spray formulations.

Mechanism of Action

Zolmitriptan exerts its therapeutic effects through selective agonism at serotonin 5-HT1B and 5-HT1D receptors. This dual mechanism results in:

• Cranial vasoconstriction through 5-HT1B receptor activation
• Inhibition of neurogenic inflammation through 5-HT1D receptor activation
• Reduction of trigeminal nerve transmission

The drug normalizes dilated cerebral and dural arteries, reduces extravasation of plasma proteins, and blocks the release of vasoactive neuropeptides, thereby alleviating migraine symptoms.

Indications

FDA-approved indications:

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

Not approved for:

• Migraine prophylaxis
• Cluster headaches
• Hemiplegic or basilar migraine
• Pediatric migraine (safety and efficacy not established under age 18)

Dosage and Administration

• Oral tablets: 2.5 mg initially; may repeat after 2 hours if needed (maximum 5 mg/24h)
• Orally disintegrating tablets: 2.5 mg placed on tongue
• Nasal spray: 5 mg single spray in one nostril

• Hepatic impairment: Maximum dose 2.5 mg/24h
• Renal impairment (CrCl <25 mL/min): Maximum dose 2.5 mg/24h
• Elderly: Use with caution due to increased cardiovascular risk
• Pregnancy: Category C - use only if potential benefit justifies risk
• Lactation: Not recommended due to secretion in breast milk

Pharmacokinetics

• Oral bioavailability: ~40%
• Tmax: 2-3 hours (oral); 15 minutes (nasal)
• Food delays absorption but does not affect overall bioavailability

• Protein binding: ~25%
• Vd: ~7 L/kg
• Crosses blood-brain barrier

• Extensive first-pass metabolism via CYP1A2
• Active metabolite: N-desmethyl zolmitriptan (2-6 times more potent)
• Minor metabolism via MAO-A

• Half-life: 3 hours (zolmitriptan); 3.5 hours (active metabolite)
• Renal excretion: ~65% (8% unchanged)
• Fecal excretion: ~30%

Contraindications

• History of coronary artery disease (CAD)
• Ischemic heart disease
• Prinzmetal's angina
• Uncontrolled hypertension
• Cerebrovascular syndromes
• Peripheral vascular disease
• Hemiplegic or basilar migraine
• Severe hepatic impairment
• Within 24 hours of another 5-HT1 agonist or ergotamine
• Within 2 weeks of MAOI therapy
• Hypersensitivity to zolmitriptan or components

Warnings and Precautions

• May cause coronary vasospasm and myocardial infarction
• Screen patients for underlying cardiovascular disease
• Perform cardiovascular evaluation in patients with multiple risk factors

• Risk of stroke and cerebral hemorrhage
• Not for use in patients with cerebrovascular syndromes

• Limit use to ≤10 days per month
• Monitor for development of medication-overuse headache

• Risk increased with concomitant serotonergic drugs
• Monitor for autonomic instability, neuromuscular changes, mental status changes

• May cause sensation of chest pain, pressure, or tightness
• Risk of arrhythmias in susceptible patients
• Not recommended in patients with Wolff-Parkinson-White syndrome

Drug Interactions

• MAOIs and within 2 weeks of discontinuation
• Other 5-HT1 agonists (within 24 hours)
• Ergot derivatives (within 24 hours)

• CYP1A2 inhibitors (cimetidine, fluvoxamine): Increase zolmitriptan exposure 2-3 fold
• Oral contraceptives: Increase zolmitriptan AUC by 30%
• SSRIs/SNRIs: Increased risk of serotonin syndrome
• Propranolol: Increases zolmitriptan AUC by 56%

Adverse Effects

• Paresthesia (7-9%)
• Dizziness (4-10%)
• Somnolence (4-8%)
• Nausea (4-9%)
• Asthenia (3-7%)
• Chest/neck/jaw pain (1-5%)
• Throat tightness (1-3%)

• Myocardial infarction
• Coronary artery vasospasm
• Cerebrovascular events
• Serotonin syndrome
• Severe hypertension
• Arrhythmias
• Anaphylaxis

Monitoring Parameters

• Cardiovascular assessment
• Blood pressure
• Medication history for interactions

• Frequency of migraine attacks
• Headache response at 2 hours
• Pain-free response at 2 hours
• Functional ability restoration
• Adverse effects (particularly cardiovascular)
• Medication use frequency (prevent overuse)

• Cardiovascular status annually
• Liver function tests (if long-term use)
• Renal function in elderly

Patient Education

• Use at first sign of migraine headache
• Do not use for more than 10 days per month
• Seek immediate medical attention for chest pain, shortness of breath, or severe dizziness
• Report any unusual sensations or symptoms
• Avoid driving or operating machinery if drowsy or dizzy
• Do not crush or break orally disintegrating tablets
• Store nasal spray away from direct light and heat
• Inform all healthcare providers of zolmitriptan use
• Do not use if pregnant or breastfeeding without medical advice

References

1. Dodick D, Lipton RB, Martin V, et al. Consensus statement: cardiovascular safety profile of triptans (5-HT1B/1D agonists) in the acute treatment of migraine. Headache. 2004;44(5):414-425.

2. Tepper SJ, Rapoport AM, Sheftell FD. Mechanisms of action of the 5-HT1B/1D receptor agonists. Arch Neurol. 2002;59(7):1084-1088.

3. Zolmitriptan prescribing information. FDA-approved labeling. Revised 2022.

4. Ferrari MD, Goadsby PJ, Roon KI, Lipton RB. Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials. Cephalalgia. 2002;22(8):633-658.

5. Rapoport AM, Tepper SJ, Bigal ME, Sheftell FD. The triptan formulations: how to match patients and products. CNS Drugs. 2003;17(6):431-447.

6. Tfelt-Hansen P, De Vries P, Saxena PR. Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy. Drugs. 2000;60(6):1259-1287.

7. American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache. 2019;59(1):1-18.