AXERT® (almotriptan malate) Tablets should only be used where a clear diagnosis of migraine has been established.

Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events

Because of the potential of this class of compounds (5-HT_1B/1D agonists) to cause coronary vasospasm, AXERT® should not be given to patients with documented ischemic or vasospastic coronary artery disease (see CONTRAINDICATIONS). It is strongly recommended that 5-HT₁ agonists (including AXERT®) not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors (e.g., hypertension, hyper cholesterolemia, 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 diseases or predisposition to coronary artery vasospasm is modest at best. If, during the cardiovascular evaluation the patient's medical history, electrocardiogram (ECG), or other investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, AXERT® should not be administered (see CONTRAINDICATIONS). 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 AXERT® take place in the setting of a physician's office or similar medically staffed and equipped facility, unless the patient has previously received almotriptan.Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining an ECG during the interval immediately following the first use of AXERT® in a patient with risk factors.

It is recommended that patients who are intermittent long-term users of AXERT® and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use AXERT®.

The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to AXERT®.

Cardiac Events and Fatalities Associated With 5-HT₁ Agonists

Serious adverse cardiac events, including acute myocardial infarction, have been reported within a few hours following administration of almotriptan. Life-threatening disturbances of cardiac rhythm and death have been reported within a few hours following the administration of other 5-HT₁ agonists.Considering the extent of use of 5-HT₁ agonists in patients with migraine, the incidence of these events is extremely low. AXERT® 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 AXERT®, a causal relationship cannot be excluded.

Pre marketing Experience With AXERT®

Among the 3865 subjects/patients who received AXERT® in pre marketing clinical trials, one patient was hospitalized for observation after a scheduled 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 it was also found 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.

Post marketing Experience With AXERT®

Serious cardiovascular events have been reported in association with the use of AXERT®. The uncontrolled nature of post marketing 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.

Cerebrovascular Events and Fatalities With 5-HT₁ Agonists

Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with other 5-HT₁ agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack).

Other Vasospasm Related Events

5-HT₁ agonists may cause vasospastic reactions other than coronary artery vasospasm. Both peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea have been reported with 5-HT₁ agonists.

Increases in Blood Pressure

Significant elevations in systemic blood pressure, including hypertensive crisis, have been reported on rare occasions in patients with and without a history of hypertension treated with other 5-HT₁ agonists. AXERT® is contraindicated in patients with uncontrolled hypertension (see CONTRAINDICATIONS). In volunteers, small increases in mean systolic and diastolic blood pressure relative to placebo were seen over the first 4 hours after administration of 12.5 mg of almotriptan (0.21 and 1.35 mm Hg, respectively).The effect of almotriptan on blood pressure was also assessed in patients with hypertension controlled by medication. In this population, mean increases in systolic and diastolic blood pressure relative to placebo over the first 4 hours after administration of 12.5 mg of almotriptan were 4.87 and 0.26 mm Hg, respectively. The slight increases in blood pressure in both volunteers and controlled hypertensive patients were not considered clinically significant.

An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5-HT1 agonist in a study evaluating subjects undergoing cardiac catheterization.

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome may occur with triptans, including AXERT® treatment, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with AXERT® 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) (see PRECAUTIONS: DRUG INTERACTIONS).

General

As with other 5-HT_1B/1D agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw have been reported after treatment with AXERT® (almotriptan malate) Tablets. These events have not been associated with arrhythmias or ischemic ECG changes in clinical trials. Because drugs in this class, including almotriptan, may cause coronary artery 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 recur. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud's syndrome following the use of any 5-HT₁ agonist are candidates for further evaluation (see WARNINGS).

AXERT® should also 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 (see CLINICAL PHARMACOLOGY, Special Populations).

For a given attack, if a patient does not respond to the first dose of AXERT®, the diagnosis of migraine headache should be reconsidered before the administration of a second dose.

Binding to Melanin-Containing Tissues

When pigmented rats were given a single oral dose of 5 mg/kg of radio labeled 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 the melanin of the eye. Because almotriptan could accumulate in melanin-rich tissues over time, there is the possibility that it could cause toxicity in these tissues over 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 systemic exposure [plasma AUC] to parent drug approximately 20 times that in humans receiving the maximum recommended daily dose of 25 mg).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, 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 in the affected dog at 12.5 mg/kg/day after a 4-week drug-free period. 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 daily dose of 25 mg.A no-effect dose was not established.

Information for Patients

See PATIENT INFORMATION at the end of this labeling for the text of the separate leaflet provided for patients.

Patients should be cautioned about the risk of serotonin syndrome with the use of AXERT® or other triptans, especially during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).

Laboratory Tests

No specific laboratory tests are recommended for monitoring patients.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

The carcinogenic potential of almotriptan was evaluated by oral gavage for up to 103 weeks in mice at doses up to 250 mg/kg/day and in rats for up to 104 weeks at doses up to 75 mg/kg/day. These doses were associated with plasma exposures (AUC) to parent drug that were approximately 40 and 78 times, in mice and rats respectively, the plasma AUC observed in humans receiving the maximum recommended daily dose (MRDD) of 25 mg. 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, with or without metabolic activation, in two in vitro gene mutation assays, the Ames test, and the thymidine locus mouse lymphoma assay. Almotriptan was not clastogenic in an in vivo mouse micronucleus assay. Almotriptan produced an equivocal weakly positive response in in vitro cytogenetics assays in human lymphocytes.

Impairment of Fertility

When female rats received almotriptan by oral gavage prior to and during mating and up to implantation at doses of 25, 100, and 400 mg/kg/day, prolongation of the estrous cycle was observed at a dose of 100 mg/kg/day (40 times the maximum recommended daily dose [MRDD] of 25 mg on a mg/m² basis). No effects on fertility were noted in female rats at 25 mg/kg/day (approximately 10 times the MRDD on a mg/m² basis).

Pregnancy: Pregnancy Category C

When almotriptan was administered by oral gavage to pregnant rats throughout the period of organogenesis at doses of 125, 250, 500, and 1000 mg/kg/day, an increase in embryo lethality was seen at the highest dose (maternal exposure, based on plasma AUC of parent drug, was approximately 958 times the human exposure at the maximum recommended daily dose [MRDD] of 25 mg). Increased incidences of fetal skeletal variations (decreased ossification) were noted at doses greater than 125 mg/kg/day (maternal exposure 80 times human exposure at MRDD).Similar studies in rabbits conducted with almotriptan at doses of 5, 20, and 60 mg/kg/day demonstrated increases in embryo lethality at the high dose (50 times the MRDD on a mg/m² basis). When almotriptan was administered to rats throughout the periods of gestation and lactation at doses of 25, 100, and 400 mg/kg/day, gestation length was increased and litter size and offspring body weight were decreased at the high dose (160 times the MRDD on a mg/m² basis). The decrease in pup weight persisted throughout lactation. The no-observed-effect level in this study was 100 mg/kg/day (40 times the MRDD on a mg/m² basis).

There are no adequate and well-controlled studies in pregnant women; therefore, AXERT® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 AXERT® is administered to a nursing woman. Lactating rats dosed with almotriptan had milk levels equivalent to maternal plasma levels at 0.5 hours and 7 times higher than plasma levels at 6 hours after dosing.

Pediatric Use

Safety and effectiveness of AXERT® in pediatric patients have not been established; therefore, AXERT® is not recommended for use in patients under 18 years of age.

Post marketing 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.The long-term safety of almotriptan in pediatric patients has not been studied.

Geriatric Use

Clinical studies of AXERT® did not include sufficient numbers of subjects aged 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 (see CLINICAL PHARMACOLOGY, Special Populations). In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.The recommended dose of AXERT® for elderly patients with normal renal function for their age is the same as that recommended for younger adults.

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