Frova

Generic Name: 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

Introduction

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

Uses for Frova

Vascular Headaches

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

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

Frova 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 Frova

Contraindications

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

  
  


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

  
  


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  Other serious underlying cardiovascular disease (e.g., uncontrolled hypertension).¹

  
  


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

  
  


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  Peripheral vascular ischemia (e.g., ischemic bowel disease).¹

  
  


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  Hemiplegic or basilar migraine.¹

  
  


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

  
  


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

  
  

Warnings/Precautions

Warnings

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

Cardiac Effects

Risk of myocardial ischemia and/or infarction, coronary vasospasm, life-threatening cardiac rhythm disturbances, and death with use of 5-HT₁ receptor agonists.¹

Use not recommended in patients with known or suspected ischemic or vasospastic heart disease or in patients in whom unrecognized CAD is likely (e.g., postmenopausal women; men >40 years of age; patients with risk factors such as hypertension, hypercholesterolemia, smoking, obesity, diabetes, or family history of CAD) unless there is satisfactory evidence from prior cardiovascular evaluation that patient does not have CAD, ischemic heart disease, or other underlying cardiovascular disease.¹

Administer initial dose to patients with risk factors for CAD who have completed satisfactory cardiovascular evaluation under medical supervision (e.g., in clinician’s office, possibly followed by ECG) unless patient previously received the drug.¹

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

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

Cerebrovascular Events

Possible cerebral or subarachnoid hemorrhage, stroke, and other cerebrovascular events, sometimes fatal, with use of 5-HT₁ receptor agonists.¹

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

Other Cardiovascular or Vasospastic Effects

Peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea reported with use of 5-HT₁ receptor agonists.¹ Further evaluation recommended if signs or symptoms of decreased arterial flow (e.g., ischemic colitis, Raynaud’s phenomenon) occur following administration.^{1 6 8}

Substantial increases in BP, including hypertensive crises, reported rarely with 5-HT₁ receptor agonists in patients with or without history of hypertension;^{1 6} transient increases in BP observed following administration of recommended dosage of frovatriptan (2.5 mg) in geriatric patients.¹

Increases in mean pulmonary artery 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 during concurrent therapy with 5-HT₁ receptor agonists (“triptans”) and SSRIs or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs).^{1 11} 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).¹¹ (See Specific Drugs under Interactions.)

General Precautions

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 Frova

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)	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

Frova 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-HT_1B/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

ActionsActions

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  Binds with high affinity to 5-HT_1B and 5-HT_1D receptors.¹

  
  


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  Structurally distinct from, but pharmacologically related to, other selective 5-HT_1B/1D receptor agonists (e.g., almotriptan, eletriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan).^{2 7 8}

  
  


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  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

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  Importance of immediately informing clinician if tightness, pain, pressure, or heaviness in chest, throat, jaw, or neck occurs¹ and of not taking frovatriptan again until evaluated by clinician.⁸

  
  


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  Importance of taking frovatriptan exactly as prescribed.¹

  
  


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

  
  


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

  
  


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  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

  
  


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  Importance of informing patients of risk of serotonin syndrome 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

  
  


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

  
  


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  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 03/2011. 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/$241.99 or 27/$699.93

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions May 2007. 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; 2006 Jun.

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 ).

More Frova resources

• Frova Side Effects (in more detail)
• Frova Dosage
• Frova Use in Pregnancy & Breastfeeding
• Drug Images
• Frova Drug Interactions
• Frova Support Group
• 15 Reviews for Frova - Add your own review/rating

• Frova Prescribing Information (FDA)


• Frova Concise Consumer Information (Cerner Multum)


• Frova Advanced Consumer (Micromedex) - Includes Dosage Information


• Frova MedFacts Consumer Leaflet (Wolters Kluwer)

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