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Frovatriptan Succinate

FDA Drug Information • Also known as: Frovatriptan, Frovatriptan Succinate

Brand Names
Frovatriptan, Frovatriptan Succinate
Dosage Form
TABLET, FILM COATED
Product Type
DRUG FOR FURTHER PROCESSING

Description

11 DESCRIPTION Frovatriptan succinate tablets contain frovatriptan succinate, a selective 5-hydroxytryptamine1 (5-HT 1B / 1D ) receptor subtype agonist, as the active ingredient. Frovatriptan succinate is chemically designated as R-(+) 3-methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole monosuccinate monohydrate and it has the following structure: The molecular formula is C 18 H 23 N 3 O 5 .H 2 O, representing a molecular weight of 379.4 g/mol. Frovatriptan succinate is a white to off-white powder that is soluble in water and very slightly soluble in methanol. Each frovatriptan succinate tablet for oral administration contains 3.91 mg frovatriptan succinate, equivalent to 2.5 mg of frovatriptan base. Each tablet also contains the inactive ingredients anhydrous lactose, colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium starch glycolate (potato), talc, titanium dioxide and triacetin. structure

What Is Frovatriptan Succinate Used For?

1 INDICATIONS AND USAGE Frovatriptan succinate tablets are indicated for the acute treatment of migraine with or without aura in adults. Limitations of Use

  • Use only if a clear diagnosis of migraine has been established. If a patient has no response for the first migraine attack treated with frovatriptan succinate tablets, reconsider the diagnosis of migraine before frovatriptan succinate tablets are administered to treat any subsequent attacks.
  • Frovatriptan succinate tablets are not indicated for the prevention of migraine attacks.
  • Safety and effectiveness of frovatriptan succinate tablets have not been established for cluster headache. Frovatriptan succinate is a serotonin (5-HT 1B/1D ) receptor agonist (triptan) indicated for the acute treatment of migraine with or without aura in adults ( 1 ) Limitations of Use
  • Use only after a clear diagnosis of migraine has been established ( 1 )
  • Not indicated for the prophylactic therapy of migraine ( 1 )
  • Not indicated for the treatment of cluster headache ( 1 )

    • Dosage and Administration

    2 DOSAGE AND ADMINISTRATION Dosing Information The recommended dose is a single tablet of frovatriptan succinate (frovatriptan 2.5 mg) taken orally with fluids. If the migraine recurs after initial relief, a second tablet may be taken, providing there is an interval of at least 2 hours between doses. The total daily dose of frovatriptan succinate tablets should not exceed 3 tablets (3 × 2.5 mg per 24-hour period). There is no evidence that a second dose of frovatriptan succinate tablets is effective in patients who do not respond to a first dose of the drug for the same headache. The safety of treating an average of more than 4 migraine attacks in a 30-day period has not been established.

  • 1 tablet taken with fluids. Second tablet may be taken 2 hours after initial dose if headache recurs following initial relief. Total dose not to exceed 3 tablets in any 24-hour period ( 2 )

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in other sections of the labeling:

  • Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina [see Warnings and Precautions ( 5.1 )]
  • Arrhythmias [see Warnings and Precautions ( 5.2 )]
  • Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure [see Warnings and Precautions ( 5.3 )]
  • Cerebrovascular Events [see Warnings and Precautions ( 5.4 )]
  • Other Vasospasm Reactions [see Warnings and Precautions ( 5.5 )]
  • Medication Overuse Headache [see Warnings and Precautions ( 5.6 )]
  • Serotonin Syndrome [see Warnings and Precautions ( 5.7 )]
  • Increases in Blood Pressure [see Warnings and Precautions ( 5.8 )]
  • Hypersensitivity Reactions [see Contraindications ( 4 ) and Warnings and Precautions ( 5.8 )]
  • Most common adverse reactions (≥2% and >placebo) were dizziness, headache, paresthesia, dry mouth, dyspepsia, fatigue, hot or cold sensation, chest pain, skeletal pain, and flushing ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Frovatriptan was evaluated in four randomized, double-blind, placebo-controlled, short-term trials. These trials involved 2392 patients (1554 on frovatriptan 2.5 mg and 838 on placebo). In these short-term trials, patients were predominately female (88%) and Caucasian (94%) with a mean age of 42 years (range 18 to 69).The treatment-emergent adverse events that occurred most frequently following administration of frovatriptan 2.5 mg ( i.e., in at least 2% of patients), and at an incidence ≥1% greater than with placebo, were dizziness, paresthesia, headache, dry mouth, fatigue, flushing, hot or cold sensation, dyspepsia, skeletal pain, and chest pain. In a long-term, open-label study where 496 patients were allowed to treat multiple migraine attacks with frovatriptan 2.5 mg for up to 1 year, 5% of patients (n=26) discontinued due to treatment-emergent adverse events. Table 1 lists treatment-emergent adverse events reported within 48 hours of drug administration that occurred with frovatriptan 2.5 mg at an incidence of ≥2% and more often than on placebo, in the four placebo-controlled trials. The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these incidence estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Table 1: Adverse Reactions Reported within 48 Hours (Incidence ≥2% and Greater Than Placebo) of Patients in Four Pooled Placebo-Controlled Migraine Trials Adverse Reactions Frovatriptan 2.5 mg (n=1554) Placebo (n=838) Central & peripheral nervous system Dizziness Headache Paresthesia 8% 4% 4% 5% 3% 2% Gastrointestinal system disorders Dry mouth Dyspepsia 3% 2% 1% 1% Body as a whole – general disorders Fatigue Hot or cold sensation Chest pain 5% 3% 2% 2% 2% 1% Musculo-skeletal Skeletal pain 3% 2% Vascular Flushing 4% 2% The incidence of adverse events in clinical trials did not increase when up to 3 doses were used within 24 hours. The incidence of adverse events in placebo-controlled clinical trials was not affected by gender, age, or concomitant medications commonly used by migraine patients. There were insufficient data to assess the impact of race on the incidence of adverse events. Other Events Observed in Association with the Administration of Frovatriptan The incidence of frequently reported adverse events in four placebo-controlled trials are presented below. Events are further classified within...

    • Drug Interactions

    7 DRUG INTERACTIONS 7.1 Ergot-containing Drugs Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and frovatriptan within 24 hours of each other is contraindicated [ see Contraindications ( 4 ) ]. 7.2 5-HT 1B/1D Agonists Because their vasospastic effects may be additive, co-administration of frovatriptan and other 5-HT 1 agonists (e.g., triptans) within 24 hours of each other is contraindicated [ see Contraindications ( 4 ) ]. 7.3 Selective Serotonin Reuptake Inhibitors / Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome Cases of serotonin syndrome have been reported during combined use of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [ see Warnings and Precautions ( 5.7 ) ].

    Contraindications

    4 CONTRAINDICATIONS Frovatriptan succinate tablets are contraindicated in patients with:

  • Ischemic coronary artery disease (CAD) (e.g., angina pectoris, history of myocardial infarction, or documented silent ischemia), or coronary artery vasospasm, including Prinzmetal’s angina [see Warnings and Precautions ( 5.1 )].
  • Wolff-Parkinson-White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see Warnings and Precautions ( 5.2 )].
  • History of stroke, transient ischemic attack (TIA), or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke [see Warnings and Precautions ( 5.4 )].
  • Peripheral vascular disease [see Warnings and Precautions ( 5.5 )].
  • Ischemic bowel disease [see Warnings and Precautions ( 5.5 )].
  • Uncontrolled hypertension [see Warnings and Precautions ( 5.8 )].
  • Recent use (i.e., within 24 hours) of another 5-HT 1 agonist, an ergotamine containing or ergot-type medication such as dihydroergotamine (DHE) or methysergide [see Drug Interactions ( 7.1 , 7.2 )].
  • Hypersensitivity to frovatriptan succinate tablets (angioedema and anaphylaxis seen) [see Warnings and Precautions ( 5.9 )].
  • History of coronary artery disease or coronary artery vasospasm ( 4 )
  • Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders ( 4 )
  • History of stroke, transient ischemic attack, or hemiplegic or basilar migraine ( 4 )
  • Peripheral vascular disease ( 4 )
  • Ischemic bowel disease ( 4 )
  • Uncontrolled hypertension ( 4 )
  • Recent (within 24 hours) use of treatment with another 5-HT 1 agonist, or an ergotamine-containing medication ( 4 )
  • Hypersensitivity to frovatriptan succinate (angioedema and anaphylaxis seen) ( 4 )

    • Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of frovatriptan in pregnant women. In animal studies, frovatriptan produced developmental toxicity (embryofetal lethality, fetal abnormalities, and decreased embryofetal growth) when administered to pregnant rats and rabbits at doses greater than those used clinically [see Animal Data] . In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data have suggested that women with migraines may be at increased risk of preeclampsia during pregnancy. Data Animal Data When pregnant rats were administered frovatriptan (oral doses of 0, 100, 500, or 1000 mg/kg/day) throughout organogenesis, increased embryofetal mortality and an increased incidence of fetal malformations were observed at the high dose; decreased fetal body weights and increased incidences of fetal structural variations associated with growth impairment were observed at all doses. The lowest effect dose for embryofetal developmental toxicity in rats (100 mg/kg/day) is approximately 130 times the maximum recommended human dose (MRHD) of 7.5 mg/day on a body surface area (mg/m 2 ) basis. When pregnant rabbits were administered frovatriptan (oral doses of 0, 5, 20, or 80 mg/kg/day) throughout organogenesis, embryofetal mortality was increased at the mid and high doses. The no-effect dose for embryofetal developmental toxicity in rabbits (5 mg/kg/day) is approximately 13 times the MRHD on a mg/m 2 basis. Oral administration of frovatriptan (0, 100, 500, or 1000 mg/kg/day) to female rats...

    8.2 Lactation Risk Summary There are no data on the presence of frovatriptan in human milk, the effects of frovatriptan on the breastfed infant, or the effects of frovatriptan on milk production. In rats, oral dosing with frovatriptan resulted in levels of frovatriptan and/or its metabolites in milk up to four times higher than in plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for frovatriptan and any potential adverse effects on the breastfed infant from frovatriptan or from the underlying maternal condition.

    Overdosage

    10 OVERDOSAGE The elimination half-life of frovatriptan is 26 hours [ see Clinical Pharmacology ( 12.3 ) ]. Therefore, monitoring of patients after overdose with frovatriptan should continue for at least 48 hours or while symptoms or signs persist. There is no specific antidote to frovatriptan. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of frovatriptan.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING Frovatriptan succinate tablets, containing 2.5 mg of frovatriptan (base) as the succinate, are available as white to off-white, circular biconvex film-coated tablets, debossed with ‘72’ on one side and ‘G’ on the other side. The tablets are available in: Blister card of 9 tablets (NDC 68462-694-40), 1 blister card per carton (NDC 68462-694-97) Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.