Frovatriptan (Monograph)

Brand name: Frova
Drug class: Selective Serotonin Agonists
- Antimigraine Agents
- Selective Vascular Serotonin Type 1-Like Receptor Agonists
- 5-HT1 Agonists
VA class: CN105
Chemical name: (+)-(R)-2,3,4,9-tetrahydro-3-(methylamino)-1H-carbazole-6-carboxamide butanedioate monohydrate
Molecular formula: C₁₄H₁₇N₃O•H₂O
CAS number: 158930-17-7

Medically reviewed by Drugs.com on Jul 22, 2024. Written by ASHP.

Introduction

Selective serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptor agonist (“triptan”).

Uses for Frovatriptan

Vascular Headaches

Acute treatment of migraine attacks with or without aura.

Not recommended for management of hemiplegic or basilar migraine or for prophylaxis of migraine.

Safety and efficacy not established for management of cluster headaches.

Frovatriptan Dosage and Administration

Administration

Oral Administration

Administer orally with fluids without regard to meals.

Dosage

Available as frovatriptan succinate; dosage is expressed in terms of frovatriptan.

Adults

Vascular Headaches

Migraine

Oral

2.5 mg as a single dose. Higher dosages provide no additional benefit but may increase risk of adverse effects.

If headache recurs, additional doses may be administered at intervals of ≥2 hours, up to a maximum dosage of 7.5 mg in any 24-hour period.

If patient does not respond to first dose, additional doses are unlikely to provide benefit for the same headache.

Prescribing Limits

Adults

Vascular Headaches

Migraine

Oral

Maximum 7.5 mg in any 24-hour period.

Safety of treating an average of >4 headaches per 30-day period has not been established.

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with mild to moderate hepatic impairment; not studied in patients with severe hepatic impairment.

Cautions for Frovatriptan

Contraindications

• Known or suspected ischemic heart disease (e.g., angina pectoris, history of MI, documented silent ischemia).

• Coronary artery vasospasm (e.g., Prinzmetal variant angina).

• Uncontrolled hypertension.

• Other serious underlying cardiovascular disease.

• Cerebrovascular syndromes (e.g., stroke syndrome, TIAs).

• Peripheral vascular ischemia or ischemic bowel disease.

• Hemiplegic or basilar migraine.

• Treatment within previous 24 hours with another 5-HT₁ receptor agonist or an ergot alkaloid. (See Specific Drugs under Interactions.)

• Known hypersensitivity to frovatriptan or any ingredient in the formulation.

Warnings/Precautions

Careful Diagnosis of Migraine

Use only in patients in whom a clear diagnosis of migraine has been established.

If first migraine attack treated with frovatriptan fails to respond to the drug, reconsider diagnosis before administering frovatriptan to treat subsequent attacks.

Exclude other potentially serious neurologic disorders before administering frovatriptan to patients not previously diagnosed with migraine or to those with atypical symptoms.

Cardiac Effects

Possible myocardial ischemia and/or infarction and coronary vasospasm, even in patients without a history of CAD. Contraindicated in patients with ischemic or vasospastic heart disease.

Possible fatal or life-threatening cardiac rhythm disturbances (e.g., ventricular tachycardia or fibrillation). Discontinue if such disturbances occur.

Tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw occur frequently but usually are noncardiac in origin. Manufacturer states that patients with symptoms suggestive of angina after receiving frovatriptan should be evaluated for presence of CAD or predisposition to Prinzmetal variant angina before receiving additional doses.

Patients at Risk for CAD

Perform cardiovascular evaluation prior to initiating therapy in patients with multiple cardiovascular risk factors (e.g., postmenopausal women; men >40 years of age; patients with risk factors such as hypertension, hypercholesterolemia, smoking, obesity, diabetes, family history of CAD) who have not previously received 5-HT₁ receptor agonist therapy.

If evaluation provides evidence of CAD or coronary vasospasm, do not administer the drug.

If results of evaluation are satisfactory, consider administering the initial dose in a medically supervised setting followed immediately by an ECG.

Periodic cardiovascular evaluation recommended in patients with risk factors for CAD if receiving intermittent long-term therapy.

Cerebrovascular Events

Possible cerebral or subarachnoid hemorrhage and stroke, sometimes fatal. (See Careful Diagnosis of Migraine under Cautions.) Discontinue therapy if a cerebrovascular event occurs.

Risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA) may be increased in patients with migraine.

Other Vasospastic Effects

Possible noncoronary vasospastic reactions (e.g., peripheral vascular ischemia, GI ischemia and infarction with abdominal pain and bloody diarrhea, splenic infarction, Raynaud’s syndrome); transient or permanent blindness and partial vision loss reported in patients receiving 5-HT₁ receptor agonists.

If signs or symptoms suggestive of vasospasm occur following administration, evaluate patient to rule out vasospastic reaction before administering additional doses.

Hypertensive Effects

Substantial increases in BP, including hypertensive crisis with acute impairment of organ systems, reported rarely with 5-HT₁ receptor agonists in patients with or without history of hypertension; transient increases in BP observed following administration of recommended dosage of frovatriptan (2.5 mg) in geriatric patients.

Increases in mean pulmonary arterial pressure observed following administration of a 5-HT₁ receptor agonist to patients with suspected CAD who were undergoing cardiac catheterization.

Serotonin Syndrome

Potentially life-threatening serotonin syndrome reported in patients receiving 5-HT₁ receptor agonists, particularly in those receiving SSRIs or SNRIs concomitantly. (See Specific Drugs under Interactions.) Also may occur in patients receiving MAO inhibitors or tricyclic antidepressants concomitantly.

Symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).

If manifestations of serotonin syndrome occur, discontinue frovatriptan and any concurrently administered serotonergic agents and initiate supportive and symptomatic treatment.

Medication Overuse Headache

Overuse of drugs indicated for management of acute migraine attacks (e.g., use of 5-HT₁ receptor agonists, ergotamine, opiates, or certain analgesic combinations on a regular basis for ≥10 days per month) may result in migraine-like daily headaches or a marked increase in frequency of migraine attacks.

Detoxification, including withdrawal of overused drugs; treatment of withdrawal symptoms (e.g., transient worsening of headaches); and consideration of prophylactic migraine therapy may be necessary.

Ocular Effects

Possible accumulation of frovatriptan and/or its metabolites in melanin-rich tissues (e.g., eye) over time, resulting in potential toxicity in these tissues with extended use.

Specific Populations

Pregnancy

Category C.

Lactation

Distributed into milk in rats; not known whether distributed into milk in humans. Caution advised if frovatriptan is used.

Pediatric Use

Safety and efficacy not established in children <18 years of age; use not recommended.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults. (See Special Populations under Pharmacokinetics.)

Hepatic Impairment

Use with caution in patients with mild to moderate hepatic impairment. (See Special Populations under Pharmacokinetics.)

Not studied in patients with severe hepatic impairment.

Common Adverse Effects

Dizziness, fatigue, headache, paresthesia, flushing, dry mouth, hot or cold sensation, skeletal pain, dyspepsia, chest pain, somnolence, nausea.

Drug Interactions

Appears to be metabolized principally via CYP1A2.

Does not inhibit CYP1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 or MAO isoenzymes in vitro; does not induce drug metabolizing enzymes. Pharmacokinetic interaction with drugs metabolized by these isoenzymes unlikely.

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (increased plasma frovatriptan concentrations) with concomitant use of CYP1A2 inhibitors; however, effects not considered clinically relevant.

Specific Drugs

Frovatriptan Pharmacokinetics

Absorption

Bioavailability

Incompletely absorbed from GI tract; absolute bioavailability of 20 and 30% in males and females, respectively.

Peak plasma concentrations attained approximately 2–4 hours after oral administration.

Food

Food does not affect bioavailability but may delay time to peak plasma concentration by 1 hour.

Distribution

Extent

Distributes into cellular fraction of blood, principally erythrocytes (approximately 60% reversibly bound).

Animal studies indicate limited capacity to cross blood-brain barrier.

Distributed into milk in rats; not known whether distributed into milk in humans.

Plasma Protein Binding

Approximately 15%.

Elimination

Metabolism

Appears to be metabolized principally via CYP1A2 to numerous metabolites, including desmethyl frovatriptan, which exhibits lower affinity for 5-HT_1B/1D receptors compared with frovatriptan.

Elimination Route

Excreted in urine (32%) and feces (62%) as unchanged drug and metabolites.

Half-life

Approximately 26 hours.

Special Populations

In patient with mild to moderate hepatic impairment, AUC is twofold higher than in healthy individuals; pharmacokinetics not studied in patients with severe hepatic impairment.

In geriatric patients, AUC is 1.5- to 2-fold higher than in younger adults; half-life and time to peak plasma concentrations unchanged.

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C). Protect from moisture and light.

Actions

• Binds with high affinity to 5-HT_1B and 5-HT_1D receptors.

• Structurally distinct from, but pharmacologically related to, other selective 5-HT_1B/1D receptor agonists (e.g., almotriptan, eletriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan).

• Precise mechanism of action not established; may ameliorate migraine through selective constriction of certain intracranial blood vessels, inhibition of neuropeptide release, and reduced transmission in trigeminal pain pathway.

Advice to Patients

• Risk of serious cardiovascular or cerebrovascular events (e.g., MI, stroke) or other vasospastic reactions. Importance of seeking medical care if symptoms of such reactions (e.g., shortness of breath, weakness, slurring of speech, or tightness, pain, pressure, or heaviness in chest, throat, jaw, or neck) occur and of not taking frovatriptan again until evaluated by clinician.

• Importance of taking frovatriptan exactly as prescribed.

• Importance of providing patient a copy of manufacturer’s patient information.

• Risk of dizziness or fatigue; importance of exercising caution when driving or operating machinery.

• Overuse of drugs indicated for the management of acute migraine attacks may exacerbate headaches; importance of recording headache frequency and drug use to monitor effectiveness of treatment.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease).

• Importance of informing patients of risk of serotonin syndrome, particularly with concurrent use of frovatriptan and an SSRI or SNRI. Importance of seeking immediate medical attention if symptoms of serotonin syndrome develop.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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