Almotriptan tablets, USP contain almotriptan malate, a selective 5-hydroxytryptamine 1B/1D (5-HT 1B/1D ) receptor agonist. Almotriptan malate is chemically designated as 1-[[[3-[2-(Dimethylamino)ethyl]-1H-indol-5-yl]methyl]sulfonyl]pyrrolidine (±)-hydroxybutanedioate (1:1) and its structural formula is: Its molecular formula is C 17 H 25 N 3 O 2 S•C 4 H 6 O 5 , representing a molecular weight of 469.56. Almotriptan malate, USP is a white to light yellow color crystalline powder that is soluble in water. Almotriptan tablets for oral administration contain 8.75 mg or 17.50 mg of almotriptan malate equivalent to 6.25 mg or 12.5 mg of almotriptan, respectively. Each compressed tablet contains the following inactive ingredients: hypromellose, mannitol, microcrystalline cellulose, polyethylene glycol, povidone, sodium starch glycolate (potato), sodium stearyl fumarate and titanium dioxide. Almotriptan Malate Structural Formula

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 • 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 Important Limitations: • Use only after a clear diagnosis of migraine has been established • In adolescents age 12 to 17 years, efficacy of almotriptan tablets on migraine-associated symptoms was not established • Not intended for the prophylactic therapy of migraine • Not indicated for the treatment of cluster headache 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)

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 . Safety and effectiveness of almotriptan tablets have not been established for cluster headache which is present in an older, predominantly male population.

Almotriptan Tablets, USP are available containing 8.75 mg or 17.50 mg of almotriptan malate, USP equivalent to 6.25 mg or 12.5 mg of almotriptan, respectively. • The 6.25 mg tablets are white to off-white, film-coated, round, unscored tablets debossed with M on one side of the tablet and AL1 on the other side. • The 12.5 mg tablets are white to off-white, film-coated, round, unscored tablets debossed with M on one side of the tablet and AL2 on the other side. Tablets: 6.25 mg and 12.5 mg

• 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 • Patients with hepatic or severe renal impairment: 6.25 mg starting dose; maximum daily dose 12.5 mg 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

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

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 .

• Serious adverse cardiac events, including acute myocardial infarction and life-threatening disturbances of cardiac rhythm • 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 tablet 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 • 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 • Cerebrovascular events, some fatal • Gastrointestinal ischemic events and peripheral vasospastic reactions (e.g., Raynaud’s syndrome) • 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 • Medication overuse headache: Detoxification may be necessary • Increase in blood pressure, very rarely associated with significant clinical events • Use with caution in patients with a known hypersensitivity to sulfonamides 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 (almotriptan malate). 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 three 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 causation in individual cases . Patients with Documented Coronary Artery Disease Because of the potential of this class of compound (5-HT 1 agonists) to cause coronary vasospasm, almotriptan tablets should not be given to patients with documented ischemic or vasospastic coronary artery disease . Patients with Risk Factors for CAD It is strongly recommended that almotriptan tablets not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient’s medical history, electrocardiographic or other investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, almotriptan tablets should not be administered . For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of almotriptan tablets take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received almotriptan tablets. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an ECG during the interval immediately following almotriptan tablets, in these patients with risk factors. It is recommended that patients who are intermittent long-term users of almotriptan tablets and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use almotriptan tablets. The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to almotriptan tablets. The ability of cardiac diagnostic procedures to detect all cardiovascular diseases or predisposition to coronary artery vasospasm is modest at best. Cardiovascular events associated with triptan treatment have occurred in patients with no cardiac history and with documented absence of coronary artery disease

Sensations of Pain, Tightness, Pressure in the Chest and/or Throat, Neck, and Jaw As with other 5-HT 1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw have been reported after treatment with almotriptan tablets. Because 5-HT 1 agonists may cause coronary vasospasm, patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of 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 occur. Patients shown to have CAD and those with Prinzmetal’s variant angina should not receive 5-HT 1 agonists

Cerebrovascular Events and Fatalities Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with other triptans and some events have resulted in fatalities. In a number of cases, it appeared possible that the cerebrovascular events were primary, the triptan having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, and transient ischemic attack)

Other Vasospasm-Related Events, Including Peripheral Vascular Ischemia and Colonic Ischemia Triptans, including almotriptan tablets, may cause vasospastic reactions other than coronary artery vasospasm, such as peripheral and gastrointestinal vascular ischemia with abdominal pain and bloody diarrhea. Very rare reports of transient and permanent blindness and significant partial vision loss have been reported with the use of triptans. Visual disorders may also be part of a migraine attack. Patients who experience symptoms or signs suggestive of decreased arterial flow following the use of any triptan, such as ischemic bowel syndrome or Raynaud’s syndrome, are candidates for further evaluation

Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome may occur with triptans, including almotriptan tablets, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with almotriptan tablets and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. 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)

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

Increases in Blood Pressure As with other triptans, significant elevations in systemic blood pressure have been reported on rare occasions with almotriptan tablet use in patients with and without a history of hypertension; very rarely these increases in blood pressure have been associated with significant clinical events. Almotriptan tablets are contraindicated in patients with uncontrolled hypertension . In normotensive healthy subjects and patients with hypertension controlled by medication, small, but clinically insignificant, increases in mean systolic (0.21 and 4.87 mm Hg, respectively) and diastolic (1.35 and 0.26 mm Hg, respectively) blood pressure relative to placebo were seen over the first 4 hours after oral administration of 12.5 mg of almotriptan. An 18% increase in mean pulmonary artery pressure was seen following dosing with another triptan in a study evaluating subjects undergoing cardiac catheterization

Hypersensitivity to Sulfonamides Caution should be exercised when prescribing almotriptan tablets to patients with known hypersensitivity to sulfonamides. The chemical structure of almotriptan contains a sulfonyl group, which is structurally different from a sulfonamide. Cross-sensitivity to almotriptan in patients allergic to sulfonamides has not been systematically evaluated

Impaired Hepatic or Renal Function Almotriptan tablets should be administered with caution to patients with diseases that may alter the absorption, metabolism, or excretion of drugs, such as those with impaired hepatic or renal function

Binding to Melanin-Containing Tissues When pigmented rats were given a single oral dose of 5 mg/kg of radiolabeled almotriptan, the elimination half-life of radioactivity from the eye was 22 days. This finding suggests that almotriptan and/or its metabolites may bind to melanin in the eye. Because almotriptan could accumulate in melanin-rich tissues over time, there is the possibility that it could cause toxicity in these tissues with extended use. However, no adverse retinal effects related to treatment with almotriptan were noted in a 52-week toxicity study in dogs given up to 12.5 mg/kg/day (resulting in exposure [AUC] to parent drug approximately 20 times that in humans receiving the maximum recommended human dose of 25 mg/day). Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, prescribers should be aware of the possibility of long-term ophthalmologic effects

Corneal Opacities Three male dogs (out of a total of 14 treated) in a 52-week toxicity study of oral almotriptan developed slight corneal opacities that were noted after 51 weeks, but not after 25 weeks of treatment. The doses at which this occurred were 2 mg/kg/day, 5 mg/kg/day, and 12.5 mg/kg/day. The opacity reversed after a 4-week drug-free period in the affected dog treated with the highest dose. Systemic exposure (plasma AUC) to parent drug at 2 mg/kg/day was approximately 2.5 times the exposure in humans receiving the maximum recommended human daily dose of 25 mg. A no-effect dose was not established.

• Do not use almotriptan tablets and ergotamine-containing or ergot-type medications within 24 hours of each other • Do not use almotriptan tablets and other 5-HT 1 agonist (e.g., triptans) within 24 hours of each other • SSRI or SNRI: life-threatening serotonin syndrome reported during combined use with triptans • Ketoconazole: use single dose of almotriptan tablets 6.25 mg; maximum almotriptan tablets daily dose 12.5 mg 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

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

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)

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 . 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 .