Axert

Dosage Forms And Strengths

AXERTR^® (almotriptan malate) Tablets are available as white, coated, circular, biconvex tablets in the following dosage strengths:

6.25 mg tablet with red code imprint “2080”

12.5 mg tablet with blue stylized imprint “A.”

Storage And Handling

AXERT^® (almotriptan malate) Tablets are available as follows:

6.25 mg: White, coated, circular, biconvex tablets with red code imprint “2080.”

Unit Dose (aluminum blister pack)

6 tablets - NDC 50458-211-01

12.5 mg: White, coated, circular, biconvex tablets with blue stylized imprint “A.”

Unit Dose (aluminum blister pack)

12 tablets - NDC 50458-210-01

Store at °C (77°F); excursions permitted to 15°-30°C (59°-86°F).

Manufactured by: Janssen-Ortho, LLC Gurabo, Puerto Rico 00778. Revised : May 2017.

Acute Treatment Of Migraine Attacks

Adults

AXERTR^® (almotriptan malate) is 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 AXERTR^® is 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

AXERTR^® 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 AXERTR^®, the diagnosis of migraine should be reconsidered before AXERTR^® is administered to treat any subsequent attacks.

In adolescents age 12 to 17 years, efficacy of AXERTR^® on migraine-associated symptoms (nausea, photophobia, and phonophobia) was not established. AXERTR^® is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine.

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

Acute Treatment Of Migraine Attacks

The recommended dose of AXERTR^® (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 AXERTR^®, the choice of dose should be made on an individual basis.

If the headache is relieved after the initial AXERTR^® 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 AXERTR^® 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 AXERTR^® 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.

Ischemic Or Vasospastic Coronary Artery Disease, Or Other Significant Underlying Cardiovascular Disease

Do not use AXERTR^® (almotriptan malate) 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.

Cerebrovascular Syndromes

Do not use AXERTR^® in patients with cerebrovascular syndromes including (but not limited to) stroke of any type as well as transient ischemic attacks.

Peripheral Vascular Disease

Do not use AXERTR^® in patients with peripheral vascular disease including (but not limited to) ischemic bowel disease.

Uncontrolled Hypertension

Because AXERTR^® may increase blood pressure, do not use AXERTR^® in patients with uncontrolled hypertension.

Ergotamine-Containing And Ergot-Type Medications

Do not use AXERTR^® and ergotamine-containing or ergot-derived medications like dihydroergotamine, ergotamine tartrate, or methysergide within 24 hours of each other.

Concomitant Use With 5-HT₁ Agonists (e.g., Triptans)

AXERTR^® and other 5-HT₁ agonists (e.g., triptans) should not be administered within 24 hours of each other.

Hemiplegic Or Basilar Migraine

Do not use AXERTR^® in patients with hemiplegic or basilar migraine.

Hypersensitivity

AXERTR^® is contraindicated in patients with known hypersensitivity to almotriptan or any of its inactive ingredients.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Risk Of Myocardial Ischemia And Infarction And Other Adverse Cardiac Events

Cardiac Events And Fatalities With 5-HT₁ Agonists

Serious adverse cardiac events, including acute myocardial infarction, have been reported within a few hours following administration of AXERTR^® (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.

AXERTR^® 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 AXERTR^®, 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 AXERTR^® in Adults

Among the 3865 subjects/patients who received AXERTR^® 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 AXERTR^® in Adults

Serious cardiovascular events have been reported in association with the use of AXERTR^®. 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-HT₁ agonists) to cause coronary vasospasm, AXERTR^® 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 AXERTR^® 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, AXERTR^® 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 AXERTR^® take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received AXERTR^®. 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 AXERTR^® , in these patients with risk factors. It is recommended that patients who are intermittent long-term users of AXERTR^® and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use AXERTR^®.

The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to AXERTR^®. 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-HT₁ agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw have been reported after treatment with AXERTR^®. Because 5-HT₁ 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-HT₁ 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 AXERTR^®, 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 AXERTR^®, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with AXERTR^® 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 AXERTR^® use in patients with and without a history of hypertension; very rarely these increases in blood pressure have been associated with significant clinical events. AXERTR^® is 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 AXERTR^® to patients with known hypersensitivity to sulfonamides. The chemical structure of almotriptan contains a sulfonyl group, which is structurally different from a sulfonamide. Cross-ensitivity to almotriptan in patients allergic to sulfonamides has not been systematically evaluated.

Impaired Hepatic Or Renal Function

AXERTR^® 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, 5, 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.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Drug Interactions

Advise patients to talk with their physician or pharmacist before taking any new medicines, including prescription and non-prescription drugs and supplements.

Hypersensitivity

Inform patients to tell their physician if they develop a rash, itching, or breathing difficulties after taking AXERTR^®.

Risk Of Myocardial Ischemia And/Or Infarction, Other Adverse Cardiac Events, Other Vasospasm-Related Events, And Cerebrovascular Events

Inform patients that AXERTR^® (almotriptan malate) may cause serious cardiovascular side effects such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, or slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Apprise the patient of the importance of this follow-up.

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome with the use of AXERTR^® or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).

Medication Overuse Headache

Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary).

Pregnancy

Advise patients to notify their physician if they become pregnant during treatment or intend to become pregnant.

Nursing Mothers

Advise patients to notify their physician if they are breastfeeding or plan to breastfeed.

Ability To Operate Machinery Or Vehicles

Counsel patients that AXERTR^® may cause dizziness, somnolence, visual disturbances, and other CNS symptoms that can interfere with driving or operating machinery. Accordingly, advise the patient not to drive, operate complex machinery, or engage in other hazardous activities until they have gained sufficient experience with AXERTR^® to gauge whether it affects their mental or visual performance adversely.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Almotriptan was administered to mice and rats for up to 103-104 weeks at oral doses up to 250 mg/kg/day and 75 mg/kg/day, respectively. These doses were associated with plasma exposures (AUC) to parent drug that were approximately 40 and 80 times, in mice and rats respectively, the plasma AUC in humans at the maximum recommended human dose (MRHD) of 25 mg/day. Because of high mortality rates in both studies, which reached statistical significance in high-dose female mice, all female rats, all male mice, and high-dose female mice were terminated between weeks 96 and 98. There was no increase in tumors related to almotriptan administration.

Mutagenesis

Almotriptan was not mutagenic in two in vitro gene mutation assays, the Ames test, and the mouse lymphoma tk assay. Almotriptan was not clastogenic in an in vivo mouse micronucleus assay.

Impairment Of Fertility

When male and female rats received almotriptan (25, 100, or 400 mg/kg/day) orally prior to and during mating and gestation, prolongation of the estrous cycle was observed at the mid-dose and greater, and fertility was impaired at the highest dose. Subsequent mating of treated with untreated animals indicated that the decrease in fertility was due to an effect on females. The no-effect dose for reproductive toxicity in rats (25 mg/kg/day) is approximately 10 times the MRHD on a mg/m² basis.

Use In Specific Populations

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, AXERTR^® (almotriptan malate) 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/m²) 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/m² 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/m² basis.

Labor And Delivery

The effect of AXERTR^® on labor and delivery in humans is unknown.

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 AXERTR^® is administered to a nursing woman. Levels of almotriptan in rat milk were up to 7 times higher than in rat plasma.

Pediatric Use

Safety and efficacy of AXERTR^® in pediatric patients under the age of 12 years have not been established. The pharmacokinetics, efficacy, and safety of AXERTR^® have been evaluated in adolescent patients, age 12 to 17 years.

In a clinical study, AXERTR^® 6.25 mg and 12.5 mg were found to be effective for the relief of migraine headache pain in adolescent patients age 12 to 17 years. Efficacy on migraine-associated symptoms (nausea, photophobia, and phonophobia) was not established. The most common adverse reactions (incidence of ≥1%) associated with AXERTR^® treatment were dizziness, somnolence, headache, paresthesia, nausea, and vomiting. The safety and tolerability profile of AXERTR^® treatment in adolescents is similar to the profile observed in adults.

Postmarketing experience with other triptans include a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events that are similar in nature to those reported rarely in adults.

Geriatric Use

Clinical studies of AXERTR^® did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Clearance of almotriptan was lower in elderly volunteers than in younger individuals, but there were no observed differences in the safety and tolerability between the two populations. In general, dose selection for an elderly patient should be cautious, usually starting at the low dose, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. The recommended dose of AXERTR^® for elderly patients with normal renal function for their age is the same as that recommended for younger adults.

Hepatic Impairment

The recommended starting dose of AXERTR^® 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 AXERTR^® 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.

SIDE EFFECTS

Serious cardiac reactions, including myocardial infarction, have occurred following the use of AXERTR^® (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 myocardialischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation.

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
• Sensations of Pain, Tightness, Pressure in the Chest and/or Throat, Neck, and Jaw
• Cerebrovascular Events and Fatalities
• Other Vasospasm-Related Events, Including Peripheral Vascular Ischemia and Colonic Ischemia
• Serotonin Syndrome
• Increases in Blood Pressure

Adverse events were assessed in controlled clinical trials that included 1840 adult patients who received one or two doses of AXERTR^® and 386 adult patients who received placebo. The most common adverse reactions during treatment with AXERTR^® 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 AXERTR^® and 172 adolescent patients who received placebo. The most common adverse reactions during treatment with AXERTR^® 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.

Commonly-Observed Adverse Reactions In Double-Blind, Placebo- Controlled AXERTR^® Clinical Trials

Adults

Table 1 lists the adverse events that occurred in at least 1% of the adult patients treated with AXERTR^®, 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 AXERTR^®, and at an Incidence Greater than Placebo)

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 AXERTR^®-treated adolescents age 12 to 17 years in 1 placebo-controlled, double-blind clinical trial.

Table 2. Adverse Reactions Reported by ≥1% of Adolescent Patients Treated with AXERTR^® in 1 Placebo-Controlled, Double-Blind Clinical Trial

Other Adverse Reactions Observed In AXERTR^® Clinical Trials

In the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. The reports include adverse reactions in 5 adult controlled studies and 1 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 frequencies are calculated as the number of patients who used AXERTR^® and reported a reaction divided by the total number of patients exposed to AXERTR^® (n=3047, all doses). All reported reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Reactions are further classified within system organ class and enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are those occurring in 1/100 or more patients, infrequent adverse reactions are those occurring in fewer than 1/100 to 1/1000 patients, and rare adverse reactions are those occurring in fewer than 1/1000 patients.

Body: Frequent: Headache. Infrequent: Abdominal cramp or pain, Asthenia, Chills, Back pain, Chest pain, Neck pain, Fatigue, and Rigid neck. Rare: Fever and Photosensitivity reaction.

Cardiovascular: Infrequent: Vasodilation, Palpitations, and Tachycardia. Rare: Hypertension and Syncope.

Digestive: Infrequent: Diarrhea, Vomiting, Dyspepsia, Gastroenteritis, and Increased thirst. Rare: Colitis, Gastritis, Esophageal reflux, and Increased salivation.

Metabolic: Infrequent: Hyperglycemia and Increased serum creatine phosphokinase. Rare: Increased gamma glutamyl transpeptidase and Hypercholesteremia.

Musculo-Skeletal: Infrequent: Myalgia. Rare: Arthralgia, Arthritis, Myopathy, and Muscle weakness.

Nervous: Frequent: Dizziness and Somnolence. Infrequent: Tremor, Vertigo, Anxiety, Hypoesthesia, Restlessness, CNS stimulation, and Shakiness. Rare: Change in dreams, Impaired concentration, Abnormal coordination, Depressive symptoms, Euphoria, Hyperreflexia, Hypertonia, Nervousness, Neuropathy, Nightmares, Nystagmus, and Insomnia.

Respiratory: Infrequent: Pharyngitis, Rhinitis, Dyspnea, Laryngismus, Sinusitis, and Bronchitis. Rare: Hyperventilation, Laryngitis, Sneezing, and Epistaxis.

Skin: Infrequent: Diaphoresis, Pruritus, and Rash. Rare: Dermatitis and Erythema.

Special Senses: Infrequent: Ear pain and Tinnitus. Rare: Diplopia, Dry eyes, Eye pain, Otitis media, Parosmia, Scotoma, Conjunctivitis, Eye irritation, Hyperacusis, and Taste alteration.

Urogenital: Infrequent: Dysmenorrhea.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of AXERTR^®. Because these reactions 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.

Immune System Disorders: Hypersensitivity reactions (including angioedema, anaphylactic reactions and anaphylactic shock)

Psychiatric Disorders: Confusional state, Restlessness

Nervous System Disorders: Hemiplegia, Hypoesthesia, Seizures

Eye Disorders: Blepharospasm, Visual impairment, Vision blurred

Ear and Labyrinth Disorders: Vertigo

Cardiac Disorders: Acute myocardial infarction, Coronary artery vasospasm, Angina pectoris, Tachycardia

Gastrointestinal Disorders: Abdominal discomfort, Abdominal pain, Abdominal pain upper, Colitis, Hypoesthesia oral, Swollen tongue

Skin and Subcutaneous Tissue Disorders: Cold sweat, Erythema, Hyperhidrosis

Musculoskeletal, Connective Tissue, and Bone Disorders: Arthralgia, Myalgia, Pain in extremity

Reproductive System and Breast Disorders: Breast pain

General Disorders: Malaise, Peripheral coldness.

DRUG INTERACTIONS

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 AXERTR^® (almotriptan malate) should not be used within 24 hours of each other.

5-HT₁ Agonists (e.g., Triptans)

Concomitant use of other 5-HT₁ agonists (e.g., triptans) within 24 hours of treatment with AXERTR^® 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 AXERTR^® is 6.25 mg. The maximum daily dose should not exceed 12.5 mg within a 24hour period. Concomitant use of AXERTR^® and potent CYP3A4 inhibitors should be avoided in patients with renal or hepatic impairment.

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, AXERTR^® (almotriptan malate) 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/m²) 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/m² 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/m² basis.

Serious cardiac reactions, including myocardial infarction, have occurred following the use of AXERTR^® (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 myocardialischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation.

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
• Sensations of Pain, Tightness, Pressure in the Chest and/or Throat, Neck, and Jaw
• Cerebrovascular Events and Fatalities
• Other Vasospasm-Related Events, Including Peripheral Vascular Ischemia and Colonic Ischemia
• Serotonin Syndrome
• Increases in Blood Pressure

Adverse events were assessed in controlled clinical trials that included 1840 adult patients who received one or two doses of AXERTR^® and 386 adult patients who received placebo. The most common adverse reactions during treatment with AXERTR^® 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 AXERTR^® and 172 adolescent patients who received placebo. The most common adverse reactions during treatment with AXERTR^® 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.

Commonly-Observed Adverse Reactions In Double-Blind, Placebo- Controlled AXERTR^® Clinical Trials

Adults

Table 1 lists the adverse events that occurred in at least 1% of the adult patients treated with AXERTR^®, 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 AXERTR^®, and at an Incidence Greater than Placebo)

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 AXERTR^®-treated adolescents age 12 to 17 years in 1 placebo-controlled, double-blind clinical trial.

Table 2. Adverse Reactions Reported by ≥1% of Adolescent Patients Treated with AXERTR^® in 1 Placebo-Controlled, Double-Blind Clinical Trial

Other Adverse Reactions Observed In AXERTR^® Clinical Trials

In the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. The reports include adverse reactions in 5 adult controlled studies and 1 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 frequencies are calculated as the number of patients who used AXERTR^® and reported a reaction divided by the total number of patients exposed to AXERTR^® (n=3047, all doses). All reported reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Reactions are further classified within system organ class and enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are those occurring in 1/100 or more patients, infrequent adverse reactions are those occurring in fewer than 1/100 to 1/1000 patients, and rare adverse reactions are those occurring in fewer than 1/1000 patients.

Body: Frequent: Headache. Infrequent: Abdominal cramp or pain, Asthenia, Chills, Back pain, Chest pain, Neck pain, Fatigue, and Rigid neck. Rare: Fever and Photosensitivity reaction.

Cardiovascular: Infrequent: Vasodilation, Palpitations, and Tachycardia. Rare: Hypertension and Syncope.

Digestive: Infrequent: Diarrhea, Vomiting, Dyspepsia, Gastroenteritis, and Increased thirst. Rare: Colitis, Gastritis, Esophageal reflux, and Increased salivation.

Metabolic: Infrequent: Hyperglycemia and Increased serum creatine phosphokinase. Rare: Increased gamma glutamyl transpeptidase and Hypercholesteremia.

Musculo-Skeletal: Infrequent: Myalgia. Rare: Arthralgia, Arthritis, Myopathy, and Muscle weakness.

Nervous: Frequent: Dizziness and Somnolence. Infrequent: Tremor, Vertigo, Anxiety, Hypoesthesia, Restlessness, CNS stimulation, and Shakiness. Rare: Change in dreams, Impaired concentration, Abnormal coordination, Depressive symptoms, Euphoria, Hyperreflexia, Hypertonia, Nervousness, Neuropathy, Nightmares, Nystagmus, and Insomnia.

Respiratory: Infrequent: Pharyngitis, Rhinitis, Dyspnea, Laryngismus, Sinusitis, and Bronchitis. Rare: Hyperventilation, Laryngitis, Sneezing, and Epistaxis.

Skin: Infrequent: Diaphoresis, Pruritus, and Rash. Rare: Dermatitis and Erythema.

Special Senses: Infrequent: Ear pain and Tinnitus. Rare: Diplopia, Dry eyes, Eye pain, Otitis media, Parosmia, Scotoma, Conjunctivitis, Eye irritation, Hyperacusis, and Taste alteration.

Urogenital: Infrequent: Dysmenorrhea.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of AXERTR^®. Because these reactions 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.

Immune System Disorders: Hypersensitivity reactions (including angioedema, anaphylactic reactions and anaphylactic shock)

Psychiatric Disorders: Confusional state, Restlessness

Nervous System Disorders: Hemiplegia, Hypoesthesia, Seizures

Eye Disorders: Blepharospasm, Visual impairment, Vision blurred

Ear and Labyrinth Disorders: Vertigo

Cardiac Disorders: Acute myocardial infarction, Coronary artery vasospasm, Angina pectoris, Tachycardia

Gastrointestinal Disorders: Abdominal discomfort, Abdominal pain, Abdominal pain upper, Colitis, Hypoesthesia oral, Swollen tongue

Skin and Subcutaneous Tissue Disorders: Cold sweat, Erythema, Hyperhidrosis

Musculoskeletal, Connective Tissue, and Bone Disorders: Arthralgia, Myalgia, Pain in extremity

Reproductive System and Breast Disorders: Breast pain

General Disorders: Malaise, Peripheral coldness.

Signs And Symptoms

Patients and volunteers receiving single oral doses of 100 to 150 mg of almotriptan did not experience significant adverse events. Six additional normal volunteers received single oral doses of 200 mg without serious adverse events. During clinical trials with AXERTR^® (almotriptan malate), one patient ingested 62.5 mg in a 5-hour period and another patient ingested 100 mg in a 38-hour period. Neither patient experienced adverse reactions.

Based on the pharmacology of triptans, hypertension or other more serious cardiovascular symptoms could occur after overdosage.

Recommended Treatment

There is no specific antidote to AXERTR^®. In cases of severe intoxication, intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system.

Clinical and electrocardiographic monitoring should be continued for at least 20 hours even if clinical symptoms are not observed.

It is unknown what effect hemodialysis or peritoneal dialysis has on plasma concentrations of almotriptan.

Current theories on the etiology of migraine headache suggest that symptoms are due to local cranial vasodilatation and/or to the release of vasoactive and pro-inflammatory peptides from sensory nerve endings in an activated trigeminal system. The therapeutic activity of almotriptan in migraine can most likely be attributed to agonist effects at 5-HT_1B/1D receptors on the extracerebral, intracranial blood vessels that become dilated during a migraine attack and on nerve terminals in the trigeminal system. Activation of these receptors results in cranial vessel constriction, inhibition of neuropeptide release, and reduced transmission in trigeminal pain pathways.

Absorption

The absolute bioavailability of almotriptan is about 70%, with peak plasma levels occurring 1 to 3 hours after administration; food does not affect pharmacokinetics.

Distribution

Almotriptan is minimally protein bound (approximately 35%) and the mean apparent volume of distribution is approximately 180 to 200 liters.

Metabolism

Almotriptan is metabolized by two major and one minor pathways. Monoamine oxidase (MAO)-mediated oxidative deamination (approximately 27% of the dose), and cytochrome P450-mediated oxidation (approximately 12% of the dose) are the major routes of metabolism, while flavin monooxygenase is the minor route. MAO-A is responsible for the formation of the indoleacetic acid metabolite, whereas cytochrome P450 (3A4 and 2D6) catalyzes the hydroxylation of the pyrrolidine ring to an intermediate that is further oxidized by aldehyde dehydrogenase to the gamma-aminobutyric acid derivative. Both metabolites are inactive.

Excretion

Almotriptan has a mean half-life of 3 to 4 hours. Almotriptan is eliminated primarily by renal excretion (about 75% of the oral dose), with approximately 40% of an administered dose excreted unchanged in urine. Renal clearance exceeds the glomerular filtration rate by approximately 3-fold, indicating an active mechanism. Approximately 13% of the administered dose is excreted via feces, both unchanged and metabolized.