Frovatriptan Succinate

Class: Selective Serotonin 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
Brands: Frova

Introduction

Selective serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptor agonist (“triptan”).1 2

Uses for Frovatriptan Succinate

Vascular Headaches

Acute treatment of migraine attacks with or without aura.1 4 5

Slideshow: Living with Your Migraines: Tips for Treatment and Prevention

Not recommended for management of hemiplegic or basilar migraine or for prophylaxis of migraine.1

Safety and efficacy not established for management of cluster headaches.1

Frovatriptan Succinate Dosage and Administration

Administration

Oral Administration

Administer orally with fluids without regard to meals.1

Dosage

Available as frovatriptan succinate; dosage is expressed in terms of frovatriptan.1

Adults

Vascular Headaches
Migraine
Oral

2.5 mg as a single dose.1 Higher dosages provide no additional benefit but may increase risk of adverse effects.1 2

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.1

If patient does not respond to first dose, additional doses are unlikely to provide benefit for the same headache.1

Prescribing Limits

Adults

Vascular Headaches
Migraine
Oral

Maximum 7.5 mg in any 24-hour period.1

Safety of treating an average of >4 headaches per 30-day period has not been established.1

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with mild to moderate hepatic impairment; not studied in patients with severe hepatic impairment.1

Cautions for Frovatriptan Succinate

Contraindications

  • Known or suspected ischemic heart disease (e.g., angina pectoris, history of MI, documented silent ischemia).1

  • Coronary artery vasospasm (e.g., Prinzmetal variant angina).1

  • Uncontrolled hypertension.1

  • Other serious underlying cardiovascular disease.1

  • Cerebrovascular syndromes (e.g., stroke syndrome, TIAs).1

  • Peripheral vascular ischemia or ischemic bowel disease.1

  • Hemiplegic or basilar migraine.1

  • Treatment within previous 24 hours with another 5-HT1 receptor agonist or an ergot alkaloid.1 (See Specific Drugs under Interactions.)

  • Known hypersensitivity to frovatriptan or any ingredient in the formulation.1

Warnings/Precautions

Careful Diagnosis of Migraine

Use only in patients in whom a clear diagnosis of migraine has been established.1

If first migraine attack treated with frovatriptan fails to respond to the drug, reconsider diagnosis before administering frovatriptan to treat subsequent attacks.1

Exclude other potentially serious neurologic disorders before administering frovatriptan to patients not previously diagnosed with migraine or to those with atypical symptoms.21

Cardiac Effects

Possible myocardial ischemia and/or infarction and coronary vasospasm, even in patients without a history of CAD.1 21 Contraindicated in patients with ischemic or vasospastic heart disease.1

Possible fatal or life-threatening cardiac rhythm disturbances (e.g., ventricular tachycardia or fibrillation).1 21 Discontinue if such disturbances occur.21

Tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw occur frequently but usually are noncardiac in origin.1 21 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.1

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.1 21

If evaluation provides evidence of CAD or coronary vasospasm, do not administer the drug.1

If results of evaluation are satisfactory, consider administering the initial dose in a medically supervised setting followed immediately by an ECG.1 21

Periodic cardiovascular evaluation recommended in patients with risk factors for CAD if receiving intermittent long-term therapy.1

Cerebrovascular Events

Possible cerebral or subarachnoid hemorrhage and stroke, sometimes fatal.1 21 (See Careful Diagnosis of Migraine under Cautions.) Discontinue therapy if a cerebrovascular event occurs.1 21

Risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA) may be increased in patients with migraine.1

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);1 21 transient or permanent blindness and partial vision loss reported in patients receiving 5-HT1 receptor agonists.21

If signs or symptoms suggestive of vasospasm occur following administration, evaluate patient to rule out vasospastic reaction before administering additional doses.1 21

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;1 21 transient increases in BP observed following administration of recommended dosage of frovatriptan (2.5 mg) in geriatric patients.1

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.1

Serotonin Syndrome

Potentially life-threatening serotonin syndrome reported in patients receiving 5-HT1 receptor agonists, particularly in those receiving SSRIs or SNRIs concomitantly.1 11 (See Specific Drugs under Interactions.) Also may occur in patients receiving MAO inhibitors or tricyclic antidepressants concomitantly.21

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).1 11

If manifestations of serotonin syndrome occur, discontinue frovatriptan and any concurrently administered serotonergic agents and initiate supportive and symptomatic treatment.33

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.21 31 32

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.21 31 32

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.1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into milk in humans.1 Caution advised if frovatriptan is used.1

Pediatric Use

Safety and efficacy not established in children <18 years of age; use not recommended.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1 (See Special Populations under Pharmacokinetics.)

Hepatic Impairment

Use with caution in patients with mild to moderate hepatic impairment.8 9 (See Special Populations under Pharmacokinetics.)

Not studied in patients with severe hepatic impairment.1

Common Adverse Effects

Dizziness,1 fatigue,1 headache,1 paresthesia,1 flushing,1 dry mouth,1 hot or cold sensation,1 skeletal pain,1 dyspepsia,1 chest pain,1 somnolence,1 nausea.1

Interactions for Frovatriptan Succinate

Appears to be metabolized principally via CYP1A2.1 3 10

Does not inhibit CYP1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 or MAO isoenzymes in vitro; does not induce drug metabolizing enzymes.1 Pharmacokinetic interaction with drugs metabolized by these isoenzymes unlikely.1 9

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (increased plasma frovatriptan concentrations) with concomitant use of CYP1A2 inhibitors; however, effects not considered clinically relevant.8 10

Specific Drugs

Drug

Interaction

Comments

Antidepressants, SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) or SNRIs (e.g., duloxetine, venlafaxine)

Potentially life-threatening serotonin syndrome1 11

Potential increase in blood frovatriptan concentrations with concomitant fluvoxamine administration10

Observe carefully if used concomitantly, particularly during treatment initiation, dosage increases, or when another serotonergic agent is initiated1 11

No dosage adjustment required if fluvoxamine is used concomitantly8 10

Ergot alkaloids (e.g., ergotamine, dihydroergotamine, methysergide [no longer commercially available in the US])

Additive vasospastic effects1

Use within 24 hours contraindicated1

5-HT1 receptor agonists

Additive vasospastic effects1

Use within 24 hours contraindicated1

Oral contraceptives

Possible increased plasma concentrations of frovatriptan8 9

No dosage adjustment required8 9

Propranolol

Possible increased plasma concentrations of frovatriptan1 3 10

No dosage adjustment required8 10

Frovatriptan Succinate Pharmacokinetics

Absorption

Bioavailability

Incompletely absorbed from GI tract; absolute bioavailability of 20 and 30% in males and females, respectively.1 9

Peak plasma concentrations attained approximately 2–4 hours after oral administration.1 9

Food

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

Distribution

Extent

Distributes into cellular fraction of blood, principally erythrocytes (approximately 60% reversibly bound).9

Animal studies indicate limited capacity to cross blood-brain barrier.9

Distributed into milk in rats; not known whether distributed into milk in humans.1

Plasma Protein Binding

Approximately 15%.1 9

Elimination

Metabolism

Appears to be metabolized principally via CYP1A2 to numerous metabolites, including desmethyl frovatriptan, which exhibits lower affinity for 5-HT1B/1D receptors compared with frovatriptan.1 3

Elimination Route

Excreted in urine (32%) and feces (62%) as unchanged drug and metabolites.1

Half-life

Approximately 26 hours.1 9

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.1

In geriatric patients, AUC is 1.5- to 2-fold higher than in younger adults; half-life and time to peak plasma concentrations unchanged.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1 Protect from moisture and light.1

Actions

  • Binds with high affinity to 5-HT1B and 5-HT1D receptors.1

  • Structurally distinct from, but pharmacologically related to, other selective 5-HT1B/1D receptor agonists (e.g., almotriptan, eletriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan).2 7 8

  • Precise mechanism of action not established;6 may ameliorate migraine through selective constriction of certain intracranial blood vessels, inhibition of neuropeptide release, and reduced transmission in trigeminal pain pathway.1 2

Advice to Patients

  • Risk of serious cardiovascular or cerebrovascular events (e.g., MI, stroke) or other vasospastic reactions.1 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.1 8 21

  • Importance of taking frovatriptan exactly as prescribed.1

  • Importance of providing patient a copy of manufacturer’s patient information.1

  • Risk of dizziness or fatigue; importance of exercising caution when driving or operating machinery.1

  • 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.21 31

  • 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).1

  • Importance of informing patients of risk of serotonin syndrome, particularly with concurrent use of frovatriptan and an SSRI or SNRI.1 11 Importance of seeking immediate medical attention if symptoms of serotonin syndrome develop.11

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

Frovatriptan Succinate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

2.5 mg (of frovatriptan)

Frova

Endo

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Frova 2.5MG Tablets (ENDO PHARMACEUTICALS): 9/$299.99 or 27/$883.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 31, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Endo Pharmaceuticals Inc. Frova (frovatriptan succinate) tablets prescribing information. Chadds Ford, PA; 2012 Dec.

2. Tfelt-Hansen P, De Vries P, Saxena PR. Triptans in migraine: a comparative review of pharmacology, pharmacokinetics, and efficacy. Drugs. 2000; 60:1259-87. [PubMed 11152011]

3. Jhee SS, Shiovitz T, Crawford AW et al. Pharmacokinetics and pharmacodynamics of the triptan antimigraine agents: a comparative review. Clin Pharmacokinet. 2001; 40:189-205. [PubMed 11327198]

4. Matchar DB, Young WB, Rosenberg JH et al. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management of acute attacks. From American Academy of Neurology web site ().

5. Silberstein SD, for the US Headache Consortium. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2000; 55:754-63. [IDIS 453389] [PubMed 10993991]

6. GlaxoWellcome. Amerge (naratriptan hydrochloride) tablets prescribing information. Research Triangle Park, NC; 1999 Nov.

7. Deleu D, Hanssens Y. Current and emerging second-generation triptans in acute migraine therapy: a comparative review. J Clin Pharmacol. 2000; 40:687-700. [IDIS 449430] [PubMed 10883409]

8. Elan Pharmaceuticals, South San Francisco, CA: Personal communication.

9. Buchan P, Keywood C, Wade A et al. Clinical pharmacokinetics of frovatriptan. Headache. 2002; 42(Suppl 2):S54-62.

10. Buchan P, Wade A, Ward C et al. Frovatriptan: a review of drug-drug interactions. Headache. 2002; 42(Suppl 2):S63-73.

11. Food and Drug Administration. Public health advisory: combined use of 5-hydroxytryptamine receptor agonists (triptans), selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephirne reuptake inhibitors (SNRIs) may result in life-threatening serotonin syndrome. Rockville, MD; 2006 Jul 19. From the FDA website: ( and ).

21. Merck and Co., Inc. Maxalt (rizatriptan benzoate) tablets and Maxalt-MLT (rizatriptan benzoate) orally disintegrating tablets prescribing information. Whitehouse Station, NJ; 2013 Jan.

31. Tepper SJ, Tepper DE. Breaking the cycle of medication overuse headache. Cleve Clin J Med. 2010; 77:236-42. [PubMed 20360117]

32. Negro A, Martelletti P. Chronic migraine plus medication overuse headache: two entities or not?. J Headache Pain. 2011; 12:593-601. [PubMed 21938457]

33. Bijl D. The serotonin syndrome. Neth J Med. 2004; 62:309-13. [PubMed 15635814]

Hide
(web2)