1 INDICATIONS AND USAGE FROVA is 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 FROVA, reconsider the diagnosis of migraine before FROVA is administered to treat any subsequent attacks. FROVA is not indicated for the prevention of migraine attacks. Safety and effectiveness of FROVA have not been established for cluster headache. FROVA is a serotonin (5-HT1B/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)
3 DOSAGE FORMS AND STRENGTHS 2.5 mg Tablets: Round, white, film-coated tablets debossed with 2.5 on one side and "E" on the other side. Tablets: 2.5 mg (3)
4 CONTRAINDICATIONS FROVA is 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 [s ee Warnings and Precautions (5.4)]. Peripheral vascular disease [s ee Warnings and Precautions (5.5)]. Ischemic bowel disease [s ee Warnings and Precautions (5.5)]. Uncontrolled hypertension [see Warnings and Precautions (5.8)]. Recent use (i.e., within 24 hours) of another 5-HT1 agonist, an ergotamine containing or ergot-type medication such as dihydroergotamine (DHE) or methysergide [see Drug Interactions (7.1, 7.2)]. Hypersensitivity to FROVA (angioedema and anaphylaxis seen) [s ee 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-HT1 agonist, or an ergotamine-containing medication (4) Hypersensitivity to FROVA (angioedema and anaphylaxis seen) (4)
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 FROVA 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 FROVA if occurs (5.4) Gastrointestinal ischemic reactions and peripheral vasospastic reactions: Discontinue FROVA if occurs (5.5) Medication overuse headache:Detoxification may be necessary (5.6) Serotonin syndrome:Discontinue FROVA if occurs (5.7, 7.3) 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina FROVA is 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 FROVA. Some of these reactions occurred in patients without known CAD. FROVA 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 FROVA. Do not administer FROVA 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 FROVA dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following FROVA administration. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of FROVA. 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-HT1 agonists. Discontinue FROVA if these disturbances occur. FROVA is 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 FROVA and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of FROVA is 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-HT1 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. FROVA is contraindicated in patients with a history of stroke or TIA [see Contraindications (4)]. 5.5 Other Vasospasm Reactions FROVA, 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-HT1 agonist, rule out a vasospastic reaction before using FROVA [see Contraindications (4)]. Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 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 FROVA, 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 FROVA 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-HT1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with FROVA. FROVA is contraindicated in patients with uncontrolled hypertension [see Contraindications (4)]. 5.9 Anaphylactic/Anaphylactoid Reactions There have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving FROVA. 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. FROVA is contraindicated in patients with a history of hypersensitivity reaction to FROVA [see Contraindications (4)].
6 ADVERSE REACTIONS The following 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 Endo Pharmaceuticals Inc. at 1-800-462-3636 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. FROVA was evaluated in four randomized, double-blind, placebo-controlled, short-term trials. These trials involved 2392 patients (1554 on FROVA 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 - 69).The treatment-emergent adverse events that occurred most frequently following administration of FROVA 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 FROVA 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 FROVA 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 Treatment-Emergent Adverse Events Reported within 48 Hours (Incidence ≥ 2% and Greater Than Placebo) of Patients in Four Pooled Placebo-Controlled Migraine Trials Adverse events FROVA 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 FROVA 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 FROVA. 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.
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 FROVA within 24 hours of each other is contraindicated [see Contraindications (4)]. 7.2 5-HT1B/1D Agonists Because their vasospastic effects may be additive, co-administration of FROVA and other 5-HT1 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 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.1) 8.1 Pregnancy Pregnancy Category C: There are no adequate and well-controlled trials in pregnant women; therefore, frovatriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When pregnant rats were administered frovatriptan during the period of organogenesis at oral doses of 100, 500 and 1000 mg/kg/day (equivalent to 130, 650 and 1300 times the maximum recommended human dose [MRHD] of 7.5 mg/day on a mg/m2 basis) there were dose related increases in incidences of fetuses with dilated ureters, unilateral and bilateral pelvic cavitation, hydronephrosis, and hydroureters. A no-effect dose for renal effects was not established. This signifies a syndrome of related effects on a specific organ in the developing embryo in all treated groups, which is consistent with a slight delay in fetal maturation. This delay was also indicated by a treatment related increased incidence of incomplete ossification of the sternebrae, skull and nasal bones in all treated groups. Reduced fetal weights and an increased incidence of embryolethality were observed in treated rats; an increase in embryolethality occurred in both the embryo-fetal developmental study and in the prenatal-postnatal developmental study. No increase in embryolethality was observed at the lowest dose level studied (100 mg/kg/day, equivalent to 130 times the MRHD on a mg/m2 basis). When pregnant rabbits were dosed throughout organogenesis at oral doses up to 80 mg/kg/day (equivalent to 210 times the MRHD on a mg/m2 basis), no effects on fetal development were observed. 8.3 Nursing mothers It is not known whether frovatriptan is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from FROVA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 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. 8.4 Pediatric use The safety and effectiveness in pediatric patients have not been established. Therefore, FROVA is not recommended for use in patients under 18 years of age. There are no additional adverse reactions identified in pediatric patients based on postmarketing experience that were not previously identified in adults. 8.5 Geriatric use Mean blood concentrations of frovatriptan in elderly patients were 1.5- to 2-times higher than those seen in younger adults [see Clinical Pharmacology (12.3)]. No dosage adjustment is necessary. 8.6 Patients with Hepatic Impairment No dosage adjustment is necessary when FROVA is given to patients with mild to moderate hepatic impairment. There is no clinical or pharmacokinetic experience with FROVA in patients with severe hepatic impairment. Because a greater than two-fold increase in AUC is predicted in patients with severe hepatic impairment, there is a greater potential for adverse events in these patients, and FROVA should therefore be used with caution in that population.