almotriptan

1 INDICATIONS AND USAGE Almotriptan tablets, USP are 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, USP 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, USP 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, predominantly male population.

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, USP 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 tablets 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, USP 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, USP 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 )] .

5 WARNINGS AND PRECAUTIONS Serious adverse cardiac events, including acute myocardial infarction and life-threatening disturbances of cardiac rhythm ( 5.1 ) It is strongly recommended that almotriptan tablets not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors. In very rare cases, serious cardiovascular events have been reported in association with almotriptan tablets use in the absence of known cardiovascular disease. If almotriptan tablets are considered, patients should first have a cardiovascular evaluation. If the evaluation is satisfactory, first dose should take place in a physician’s office setting ( 5.1 ) Sensations of pain, tightness, pressure, and heaviness in the chest, throat, neck, and jaw: generally not associated with myocardial ischemia, but patients with signs or symptoms suggestive of angina should be evaluated for the presence of CAD ( 5.2 ) Cerebrovascular events, some fatal ( 5.3 ) Gastrointestinal ischemic events and peripheral vasospastic reactions (e.g., Raynaud’s syndrome) ( 5.4 ) Potentially life-threatening serotonin syndrome, particularly in combination with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). Monitor patients for neurologic changes and gastrointestinal symptoms if concomitant treatment is clinically warranted ( 5.5 , 7.3 ) Medication overuse headache: Detoxification may be necessary ( 5.6 ) Increase in blood pressure, very rarely associated with significant clinical events ( 4.4 , 5.7 ) Use with caution in patients with a known hypersensitivity to sulfonamides ( 5.8 ) 5.1 Risk of Myocardial Ischemia and Infarction and Other Adverse Cardiac Events Cardiac Events and Fatalities with 5-HT 1 Agonists Serious adverse cardiac events, including acute myocardial infarction, have been reported within a few hours following administration of almotriptan tablets. Life-threatening disturbances of cardiac rhythm and death have been reported within a few hours following the administration of other triptans. Considering the extent of use of triptans in patients with migraine, the incidence of these events is extremely low. Almotriptan tablets can cause coronary vasospasm; at least one of these events occurred in a patient with no cardiac history and with documented absence of coronary artery disease. Because of the close proximity of the events to use of almotriptan tablets, a causal relationship cannot be excluded. Patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of coronary artery disease (CAD) or a predisposition to Prinzmetal’s variant angina before receiving additional doses of medication, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur. Premarketing Experience with Almotriptan Tablets in Adults Among the 3865 subjects/patients who received almotriptan tablets in premarketing clinical trials, one patient was hospitalized for observation after a scheduled electrocardiogram (ECG) was found to be abnormal (negative T-waves on the left leads) 48 hours after taking a single 6.25 mg dose of almotriptan. The patient, a 48-year-old female, had previously taken 3 other doses for earlier migraine attacks. Myocardial enzymes at the time of the abnormal ECG were normal. The patient was diagnosed as having had myocardial ischemia and that she had a family history of coronary disease. An ECG performed 2 days later was normal, as was a follow-up coronary angiography. The patient recovered without incident. Postmarketing Experience with Almotriptan Tablets in Adults Serious cardiovascular events have been reported in association with the use of almotriptan tablets. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to definitively determine the proportion of the reported cases that were actually caused by almotriptan or to reliably assess ca…

4 CONTRAINDICATIONS Ischemic heart disease, coronary artery vasospasm, or other significant underlying cardiovascular disease ( 4.1 ) Cerebrovascular syndromes (e.g., history of stroke or TIA) ( 4.2 ) Peripheral vascular disease (including ischemic bowel disease) ( 4.3 ) Uncontrolled hypertension ( 4.4 ) Do not use almotriptan tablets within 24 hours of an ergotamine-containing, or ergot-type medication, or of another 5-HT 1 agonist, e.g., another triptan ( 4.5 , 4.6 ) Hemiplegic or basilar migraine ( 4.7 ) Known hypersensitivity to almotriptan tablets ( 4.8 ) 4.1 Ischemic or Vasospastic Coronary Artery Disease, or Other Significant Underlying Cardiovascular Disease Do not use almotriptan tablets in patients with ischemic heart disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), or in patients who have symptoms or findings consistent with ischemic heart disease, coronary artery vasospasm, including Prinzmetal's variant angina, or other significant underlying cardiovascular disease [see Warnings and Precautions ( 5.1 )] . 4.2 Cerebrovascular Syndromes Do not use almotriptan tablets in patients with cerebrovascular syndromes including (but not limited to) stroke of any type as well as transient ischemic attacks [see Warnings and Precautions ( 5.3 )] . 4.3 Peripheral Vascular Disease Do not use almotriptan tablets in patients with peripheral vascular disease including (but not limited to) ischemic bowel disease [see Warnings and Precautions ( 5.4 )] . 4.4 Uncontrolled Hypertension Because almotriptan tablets may increase blood pressure, do not use almotriptan tablets in patients with uncontrolled hypertension [see Warnings and Precautions ( 5.7 )]. 4.5 Ergotamine-Containing and Ergot-Type Medications Do not use almotriptan tablets and ergotamine-containing or ergot-derived medications like dihydroergotamine, ergotamine tartrate, or methysergide within 24 hours of each other [see Drug Interactions ( 7.1 )] . 4.6 Concomitant Use With 5-HT 1 Agonists (e.g., Triptans) Almotriptan tablets and other 5-HT 1 agonists (e.g., triptans) should not be administered within 24 hours of each other [see Warnings and Precautions ( 5.1 ) and ( 5.2 )] . 4.7 Hemiplegic or Basilar Migraine Do not use almotriptan tablets in patients with hemiplegic or basilar migraine. 4.8 Hypersensitivity Almotriptan tablets are contraindicated in patients with known hypersensitivity to almotriptan or any of its inactive ingredients.

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 agonists (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 should not be used within 24 hours of each other [see Contraindications ( 4.5 )] . 7.2 5-HT1 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 )] .

8.1 Pregnancy Pregnancy Category C In animal studies, almotriptan produced developmental toxicity (increased embryolethality and fetal skeletal variations, and decreased offspring body weight) at doses greater than those used clinically. There are no adequate and well-controlled studies in pregnant women; therefore, almotriptan tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When almotriptan (125, 250, 500, or 1000 mg/kg/day) was administered orally to pregnant rats throughout the period of organogenesis, increased incidences of fetal skeletal variations (decreased ossification) were noted at a dose of 250 mg/kg/day or greater and an increase in embryolethality was seen at the highest dose. The no-effect dose for embryo-fetal developmental toxicity in rats (125 mg/kg/day) is approximately 100 times the maximum recommended human dose (MRHD) of 25 mg/day on a body surface area (mg/m 2 ) basis. Similar studies in pregnant rabbits conducted with almotriptan (oral doses of 5, 20, or 60 mg/kg/day) demonstrated increases in embryolethality at the highest dose. The no-effect dose for embryo-fetal developmental toxicity in rabbits (20 mg/kg/day) is approximately 15 times the MRHD on a mg/m 2 basis. When almotriptan (25, 100, or 400 mg/kg/day) was administered orally to rats throughout the periods of gestation and lactation, gestation length was increased and litter size and offspring body weight were decreased at the highest dose. The decrease in pup weight persisted throughout lactation. The no-effect dose in this study (100 mg/kg/day) is 40 times the MRHD on a mg/m 2 basis.

8.3 Nursing Mothers It is not known whether almotriptan is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when almotriptan tablets are administered to a nursing woman. Levels of almotriptan in rat milk were up to 7 times higher than in rat plasma.

6 ADVERSE REACTIONS Serious cardiac reactions, including myocardial infarction, have occurred following the use of almotriptan 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 tabletswere 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 Ajanta Pharma USA Inc. at 855-664-7744 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Almotriptan Tablets 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 tablets-treated adolescents age 12 to 17 years in 1 placebo-controlled, double-blind clinica…