frovatriptan succinate

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 )

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 )

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 …

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 )

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 ) ].

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 throughout pregnancy and lactation resulted in increased embryofetal mortality at the high dose. The no effect dose for pre- and postnatal developmental toxicity in rats (500 mg/kg/day) is approximately 650 times the MRHD on a mg/m 2 basis.

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.

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 bod…