Almotriptan

12.1 Mechanism of Action Almotriptan binds with high affinity to 5-HT 1D , 5-HT 1B , and 5-HT 1F receptors. Almotriptan has weak affinity for 5-HT 1A and 5-HT 7 receptors, but has no significant affinity or pharmacological activity at 5-HT 2 , 5-HT 3 , 5-HT 4 , 5-HT 6 ; alpha or beta adrenergic; adenosine (A 1 , A 2 ); angiotensin (AT 1 , AT 2 ); dopamine (D 1 , D 2 ); endothelin (ET A , ET B ); or tachykinin (NK 1 , NK 2 , NK 3 ) binding sites.

1 INDICATIONS AND USAGE Almotriptan tablets are a 5HT 1B/1D receptor agonist (triptan) indicated for: • Acute treatment of migraine attacks in adults with a history of migraine with or without aura ( 1.1 ) • Acute treatment of migraine headache pain in adolescents age 12 to 17 years with a history of migraine with or without aura, and who have migraine attacks usually lasting 4 hours or more ( 1.1 ) Important Limitations: • Use only after a clear diagnosis of migraine has been established ( 1.2 ) • In adolescents age 12 to 17 years, efficacy of almotriptan tablets on migraine-associated symptoms was not established ( 1.2 ) • Not intended for the prophylactic therapy of migraine ( 1.2 ) • Not indicated for the treatment of cluster headache ( 1.2 ) 1.1 Acute Treatment of Migraine Attacks Adults Almotriptan tablets (almotriptan malate) are indicated for the acute treatment of migraine attacks in patients with a history of migraine with or without aura. Adolescents Age 12 to 17 Years Almotriptan tablets are indicated for the acute treatment of migraine headache pain in patients with a history of migraine attacks with or without aura usually lasting 4 hours or more (when untreated). 1.2 Important Limitations Almotriptan tablets should only be used where a clear diagnosis of migraine has been established. If a patient has no response for the first migraine attack treated with almotriptan tablets, the diagnosis of migraine should be reconsidered before almotriptan tablets are administered to treat any subsequent attacks. In adolescents age 12 to 17 years, efficacy of almotriptan tablets on migraine-associated symptoms (nausea, photophobia, and phonophobia) was not established. Almotriptan tablets are not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine [see Contraindications (4.7) ] . Safety and effectiveness of almotriptan tablets have not been established for cluster headache which is present in an older, pr

2 DOSAGE AND ADMINISTRATION • Adults and adolescents age 12 to 17 years: 6.25 mg or 12.5 mg single dose; may repeat after 2 hours if headache returns; benefit of second dose in patients who have failed to respond to first dose has not been established; maximum daily dose 25 mg ( 2.1 ) • Patients with hepatic or severe renal impairment: 6.25 mg starting dose; maximum daily dose 12.5 mg ( 2.2 , 2.3 ) 2.1 Acute Treatment of Migraine Attacks The recommended dose of almotriptan tablets (almotriptan malate) in adults and adolescents age 12 to 17 years is 6.25 mg to 12.5 mg, with the 12.5 mg dose tending to be a more effective dose in adults. As individuals may vary in their response to different doses of almotriptan tablets, the choice of dose should be made on an individual basis. If the headache is relieved after the initial almotriptan tablet dose but returns, the dose may be repeated after 2 hours. The effectiveness of a second dose has not been established in placebo-controlled trials. The maximum daily dose should not exceed 25 mg. The safety of treating an average of more than four migraines in a 30-day period has not been established. 2.2 Hepatic Impairment The recommended starting dose of almotriptan tablets in patients with hepatic impairment is 6.25 mg. The maximum daily dose should not exceed 12.5 mg over a 24-hour period [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.3) ] . 2.3 Renal Impairment The recommended starting dose of almotriptan tablets in patients with severe renal impairment is 6.25 mg. The maximum daily dose should not exceed 12.5 mg over a 24-hour period [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.3) ] .

6 ADVERSE REACTIONS Serious cardiac reactions, including myocardial infarction, have occurred following the use of almotriptan (almotriptan malate) tablets. These reactions are extremely rare and most have been reported in patients with risk factors predictive of CAD. Reactions reported in association with triptans have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation [see Contraindications (4.1) and Warnings and Precautions (5.1) ] . The following adverse reactions are discussed in more detail in other sections of the labeling: • Risk of Myocardial Ischemia and Infarction and Other Adverse Cardiac Events [see Warnings and Precautions (5.1) ] • Sensations of Pain, Tightness, Pressure in the Chest and/or Throat, Neck, and Jaw [see Warnings and Precautions (5.2) ] • Cerebrovascular Events and Fatalities [see Warnings and Precautions (5.3) ] • Other Vasospasm-Related Events, Including Peripheral Vascular Ischemia and Colonic Ischemia [see Warnings and Precautions (5.4) ] • Serotonin Syndrome [see Warnings and Precautions (5.5) ] • Increases in Blood Pressure [see Warnings and Precautions (5.7) ] Adverse events were assessed in controlled clinical trials that included 1840 adult patients who received one or two doses of almotriptan tablets and 386 adult patients who received placebo. The most common adverse reactions during treatment with almotriptan tablets were nausea, somnolence, headache, paresthesia, and dry mouth. In long-term open-label studies where patients were allowed to treat multiple attacks for up to 1 year, 5% (63 out of 1347 patients) withdrew due to adverse experiences. Adverse events were assessed in controlled clinical trials that included 362 adolescent patients who received almotriptan tablets and 172 adolescent patients who received placebo. The most common adverse reactions during treatment with almotriptan tablets were dizziness, somnolence, headache, paresthesia, nausea, and vomiting. In a long-term, open-label study where patients were allowed to treat multiple attacks for up to 1 year, 2% (10 out of 420 adolescent patients) withdrew due to adverse events. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The most common adverse reactions (≥ 1% and greater than placebo) are: • In adults: nausea, dry mouth and paresthesia ( 6.1 ) • In adolescents: dizziness, somnolence, headache, paresthesia, nausea and vomiting ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Almotriptan Tablet Clinical Trials Adults Table 1 lists the adverse events that occurred in at least 1% of the adult patients treated with almotriptan tablets, and at an incidence greater than in patients treated with placebo, regardless of drug relationship. Table 1. Incidence of Adverse Events in Controlled Clinical Trials (Reported in at Least 1% of Adult Patients Treated with Almotriptan Tablets, and at an Incidence Greater than Placebo) System/Organ Class Adverse Event Almotriptan Tablets 6.25 mg (n = 527) % Almotriptan Tablets 12.5 mg (n = 1313) % Placebo (n = 386) % Digestive Disorders Nausea 1 2 1 Dry Mouth 1 1 0.5 Nervous System Disorders Paresthesia 1 1 0.5 The incidence of adverse events in controlled clinical trials was not affected by gender, weight, age, presence of aura, or use of prophylactic medications or oral contraceptives. There were insufficient data to assess the effect of race on the incidence of adverse events. Adolescents Table 2 lists the adverse reactions reported by 1% or more of almotriptan tablet-treated adolescents age 12 to 17 years in one placebo-controlled, double-blind clinical trial. Table 2. Adverse Reactions Reported by ≥ 1% of Adolescent Patients Treated with Almotriptan Tablets in One Placebo-Controlled, Double-Blind Clinical Trial System/Organ Class Adverse Reaction Almotriptan Tablets 6.25 mg (n = 180) % Almotriptan Tablets 12.5 mg (n = 182) % Placebo (n = 172) % Nervous System Disorders Dizziness 4 3 2 Somnolence < 1 5 2 Headache 1 2 1 Paresthesia < 1 1 < 1 Gastrointestinal Disorders Nausea 1 3 0 Vomiting 2 0 < 1 6.2 Other Adverse Reactions Observed in Almotriptan Tablet Clinical Trials In the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. The reports include adverse reactions in five adult controlled studies and one adolescent controlled study. Variability associated with adverse reaction reporting, the terminology used to describe adverse reactions, etc., limit the value of the quantitative frequency estimates provided. Reaction

7 DRUG INTERACTIONS • Do not use almotriptan tablets and ergotamine-containing or ergot-type medications within 24 hours of each other ( 4.5 , 7.1 ) • Do not use almotriptan tablets and other 5-HT 1 agonist (e.g., triptans) within 24 hours of each other ( 4.6 , 7.2 ) • SSRI or SNRI: life-threatening serotonin syndrome reported during combined use with triptans ( 5.5 , 7.3 ) • Ketoconazole: use single dose of almotriptan tablets 6.25 mg; maximum almotriptan tablets daily dose 12.5 mg ( 7.4 ) 7.1 Ergot-Containing Drugs These drugs have been reported to cause prolonged vasospastic reactions. Because, in theory, vasospastic effects may be additive, ergotamine-containing or ergot-type medications (like dihydroergotamine, ergotamine tartrate, or methysergide) and almotriptan tablets (almotriptan malate) should not be used within 24 hours of each other [see Contraindications (4.5) ] . 7.2 5-HT 1 Agonists (e.g., Triptans) Concomitant use of other 5-HT 1 agonists (e.g., triptans) within 24 hours of treatment with almotriptan tablets is contraindicated [see Contraindications (4.6) ] . 7.3 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors Cases of life-threatening serotonin syndrome have been reported during combined use of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.5) , Clinical Pharmacology (12.3) ] . 7.4 Ketoconazole and Other Potent CYP3A4 Inhibitors Co-administration of almotriptan and oral ketoconazole, a potent CYP3A4 inhibitor, resulted in an approximately 60% increase in exposure of almotriptan. Increased exposures to almotriptan may be expected when almotriptan is used concomitantly with other potent CYP3A4 inhibitors [see Clinical Pharmacology (12.3) ] . In patients concomitantly using potent CYP3A4 inhibitors, the recommended starting dose of almotriptan tablets is 6.25 mg. The maximum daily dose should not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan tablets and potent CYP3A4 inhibitors should be avoided in patients with renal or hepatic impairment [see Clinical Pharmacology (12.3) ] .