Frovatriptan Succinate

Prescription

Ticari adlar: frovatriptan succinate

Farmasötik Form

Tablet

Uygulama Yolu

ORAL

Üretici

Glenmark Pharmaceuticals Inc., USA

About This Medication

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

Etken Maddeler

Bileşen	Güç
Frovatriptan Succinate	-

Endikasyonlar ve Kullanım

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 )

Nasıl çalışır

12.1 Mechanism of Action Frovatriptan binds with high affinity to 5-HT 1B/1D receptors. The therapeutic activity of frovatriptan is thought to be due to the agonist effects at the 5-HT 1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

Dozaj ve Uygulama

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 Overview

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 body system categories. Frequent adverse events are those occurring in at least 1/100 patients. Central and peripheral nervous system: dysesthesia and hypoesthesia. Gastrointestinal: vomiting, abdominal pain and diarrhea. Body as a whole: pain. Psychiatric: insomnia and anxiety. Respiratory: sinusitis and rhinitis. Vision disorders: vision abnormal. Skin and appendages: sweating increased. Hearing and vestibular disorders: tinnitus. Heart rate and rhythm: palpitation. 6.2 Postmarketing Experience The following adverse reactions were identified during post approval use of frovatriptan. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Central and peripheral nervous system : Seizure.

Uyarılar ve Önlemler

5 WARNINGS AND PRECAUTIONS • Myocardial ischemia/infarction or Prinzmetal’s angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors ( 5.1 ) • Arrhythmias: Discontinue frovatriptan succinate if occurs ( 5.2 ) • Chest/throat/neck/jaw pain, tightness, pressure, or heaviness: Generally not associated with myocardial ischemia; evaluate high risk patients for coronary artery disease ( 5.3 ) • Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue frovatriptan succinate if occurs ( 5.4 ) • Gastrointestinal ischemic reactions and peripheral vasospastic reactions: Discontinue frovatriptan succinate if occurs (5.5) • Medication overuse headache: Detoxification may be necessary ( 5.6 ) • Serotonin syndrome: Discontinue frovatriptan succinate if occurs ( 5.7 , 7.3 ) 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina Frovatriptan succinate tablets are contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of frovatriptan. Some of these reactions occurred in patients without known CAD. Frovatriptan may cause coronary artery vasospasm (Prinzmetal’s angina), even in patients without a history of CAD. Perform a cardiovascular evaluation in triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving frovatriptan. Do not administer frovatriptan if there is evidence of CAD or coronary artery vasospasm [ see Contraindications ( 4 ) ]. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administrating the first frovatriptan dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following frovatriptan administration. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of frovatriptan. 5.2 Arrhythmias Life-threatening disturbances of cardiac rhythm including ventricular tachycardia and ventricular fibrillation leading to death have been reported within a few hours following the administration of 5-HT 1 agonists. Discontinue frovatriptan if these disturbances occur. Frovatriptan succinate tablets are contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see Contraindications ( 4 )]. 5.3 Chest, Throat, Neck, and Jaw Pain/Tightness/Pressure Sensations of pain, tightness, pressure, and heaviness have been reported in the chest, throat, neck, and jaw after treatment with frovatriptan and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of frovatriptan succinate tablets are contraindicated in patients with CAD and those with Prinzmetal’s angina [ see Contraindications ( 4 ) ]. 5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with 5-HT 1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical of migraine, other potentially serious neurological conditions need to be excluded. Frovatriptan succinate tablets are contraindicated in patients with a history of stroke or TIA [see Contraindications ( 4 )]. 5.5 Other Vasospasm Reactions Frovatriptan, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of a vasospastic reaction following the use of any 5-HT 1 agonist, rule out a vasospastic reaction before using frovatriptan [ see Contraindications ( 4 ) ]. Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT 1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT 1 agonists have not been clearly established. 5.6 Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary. 5.7 Serotonin Syndrome Serotonin syndrome may occur with frovatriptan, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase (MAO) inhibitors [ see Drug Interactions (7.3) ]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue frovatriptan if serotonin syndrome is suspected. 5.8 Increase in Blood Pressure Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT 1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with frovatriptan. Frovatriptan succinate tablets are contraindicated in patients with uncontrolled hypertension [see Contraindications ( 4 )]. 5.9 Hypersensitivity Reactions There have been reports of reactions including anaphylaxis and angioedema, in patients receiving frovatriptan. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. Frovatriptan succinate tablets are contraindicated in patients with a history of hypersensitivity reaction to frovatriptan [see Contraindications ( 4 )].

Kontrendikasyonlar

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 )

Farmakokinetik

12.3 Pharmacokinetics The pharmacokinetics of frovatriptan are similar in migraine patients and healthy subjects. Absorption Mean maximum blood concentrations (C max ) in patients are achieved approximately 2 to 4 hours after administration of a single oral dose of frovatriptan 2.5 mg. The absolute bioavailability of an oral dose of frovatriptan 2.5 mg in healthy subjects is about 20% in males and 30% in females. Food has no significant effect on the bioavailability of frovatriptan, but delays t max by one hour. Distribution Binding of frovatriptan to serum proteins is low (approximately 15%). Reversible binding to blood cells at equilibrium is approximately 60%, resulting in a blood: plasma ratio of about 2:1 in both males and females. The mean steady state volume of distribution of frovatriptan following intravenous administration of 0.8 mg is 4.2 L/kg in males and 3 L/kg in females. Metabolism In vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan. Following administration of a single oral dose of radiolabeled frovatriptan 2.5 mg to healthy male and female subjects, 32% of the dose was recovered in urine and 62% in feces. Radiolabeled compounds excreted in urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, together with several other minor metabolites. Desmethyl frovatriptan has lower affinity for 5-HT 1B/1D receptors compared to the parent compound. The N-acetyl desmethyl metabolite has no significant affinity for 5-HT receptors. The activity of the other metabolites is unknown. Elimination After an intravenous dose, mean clearance of frovatriptan was 220 and 130 mL/min in males and females, respectively. Renal clearance accounted for about 40% (82 mL/min) and 45% (60 mL/min) of total clearance in males and females, respectively. The mean terminal elimination half-life of frovatriptan in both males and females is approximately 26 hours. Special Populations Hepatic Impairment The AUC of frovatriptan in patients with mild (Child-Pugh 5 to 6) to moderate (Child-Pugh 7 to 9) hepatic impairment was about twice that of young, healthy subjects, but within the range observed in healthy elderly subjects and was considerably lower than the values attained with higher doses of frovatriptan (up to 40 mg), which were not associated with any serious adverse effects. There is no clinical or pharmacokinetic experience with frovatriptan in patients with severe hepatic impairment . Renal Impairment The pharmacokinetics of frovatriptan following a single oral dose of 2.5 mg was not different in patients with renal impairment (5 males and 6 females, creatinine clearance 16 to 73 mL/min) compared to subjects with normal renal function. Age Mean AUC of frovatriptan was 1.5- to 2-fold higher in healthy elderly subjects (age 65 to 77 years) compared to those in healthy younger subjects (age 21 to 37 years). There was no difference in t max or t 1/2 between the two populations. Sex There was no difference in the mean terminal elimination half-life of frovatriptan in males and females. Bioavailability was higher, and systemic exposure to frovatriptan was approximately 2-fold greater, in females than males, irrespective of age. Race The effect of race on the pharmacokinetics of frovatriptan has not been examined. Drug Interaction Studies Frovatriptan is not an inhibitor of human monoamine oxidase (MAO) enzymes or cytochrome P450 (isozymes 1A2, 2C9, 2C19, 2D6, 2E1, 3A4) in vitro at concentrations up to 250 to 500- fold higher than the highest blood concentrations observed in man at a dose of 2.5 mg. No induction of drug metabolizing enzymes was observed following multiple dosing of frovatriptan to rats or on addition to human hepatocytes in vitro . Although no clinical trials have been performed, it is unlikely that frovatriptan will affect the metabolism of co-administered drugs metabolized by these mechanisms. Oral Contraceptives Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean C max and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives compared to those not taking oral contraceptives. Ergotamine The AUC and C max of frovatriptan (2 × 2.5 mg dose) were reduced by approximately 25% when co-administered with ergotamine tartrate [see Contraindications (4), Drug Interactions ( 7.1 )]. Propranolol Propranolol increased the AUC of frovatriptan 2.5 mg in males by 60% and in females by 29%. The C max of frovatriptan was increased 23% in males and 16% in females in the presence of propranolol. The t max as well as half-life of frovatriptan, though slightly longer in the females, were not affected by concomitant administration of propranolol. Moclobemide The pharmacokinetic profile of frovatriptan was unaffected when a single oral dose of frovatriptan 2.5 mg was administered to healthy female subjects receiving the MAO-A inhibitor, moclobemide, at an oral dose of 150 mg twice a day for 8 days.

Frequently Asked Questions

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 …

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 …

5 WARNINGS AND PRECAUTIONS • Myocardial ischemia/infarction or Prinzmetal’s angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors ( 5.1 ) • Arrhythmias: Discontinue frovatriptan succinate if occurs ( 5.2 ) • Chest/throat/neck/jaw pain, tightness, pressure, or heaviness: Generally not associated with myocardial ischemia; evaluate high risk patients for coronary artery disease ( 5.3 ) • Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue frovatriptan succinate if occurs ( 5.4 ) • Gastrointestinal ischemic reactions and peripheral vasospastic reactions: …

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 …

Frovatriptan Succinate is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

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References & Data Sources

• DailyMed — Frovatriptan Succinate drug label (National Library of Medicine)
• openFDA — Frovatriptan Succinate label data (U.S. Food & Drug Administration)
• RxNorm — RXCUI 349462 (NLM Normalized Drug Names)
• NDC Directory — Frovatriptan Succinate (FDA National Drug Code)

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