FROVATRIPTAN: 193 Adverse Event Reports & Safety Profile

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

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 )

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 x 2.5 mg per 24-hour period). There is no evidence that a second dose of frovatriptan succinate tablets are 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 )

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 )

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.

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 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 frovatriptan succinate. Some of these reactions occurred in patients without known CAD. Frovatriptan succinate 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 succinate. Do not administer frovatriptan succinate if there is evidence of CAD or coronary artery vasospasm <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administrating the first frovatriptan succinate dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following frovatriptan succinate administration. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of frovatriptan succinate.

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 succinate if these disturbances occur. Frovatriptan succinate is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

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 succinate 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 is contraindicated in patients with CAD and those with Prinzmetal’s angina <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

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 is contraindicated in patients with a history of stroke or TIA <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.5 Other Vasospasm Reactions Frovatriptan succinate 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 succinate <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . 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 succinate, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase (MAO) inhibitors <span class="opacity-50 text-xs">[see Drug Interactions (7.3) ]</span> . 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 succinate 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 succinate. Frovatriptan succinate is contraindicated in patients with uncontrolled hypertension <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.9 Hypersensitivity Reactions There have been reports of reactions, including anaphylaxis and angioedema, in patients receiving frovatriptan succinate. 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 tablet is contraindicated in patients with a history of hypersensitivity reaction to frovatriptan succinate <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

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 succinate within 24 hours of each other is contraindicated <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . 7.2 5-HT 1B/1D Agonists Because their vasospastic effects may be additive, co-administration of frovatriptan succinate and other 5-HT 1 agonists (e.g., triptans) within 24 hours of each other is contraindicated <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>.

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.7 )]</span>.