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Axert

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Axert

Axert

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 AXERT (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.

AXERT (almotriptan malate) 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 (almotriptan malate) , a causal relationship cannot be excluded. 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.

Premarketing Experience With AXERT (almotriptan malate) in Adults

Among the 3865 subjects/patients who received AXERT (almotriptan malate) in premarketing 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.

Postmarketing experience With AXERT (almotriptan malate) in Adults

Serious cardiovascular events have been reported in association with the use of AXERT (almotriptan malate) . 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 [see ADVERSE REACTIONS].

Patients with documented coronary artery disease

Because of the potential of this class of compound (5-HT1 agonists) to cause coronary vasospasm, AXERT (almotriptan malate) should not be given to patients with documented ischemic or vasospastic coronary artery disease [see CONTRAINDICATIONS].

Patients with risk factors for CAD

It is strongly recommended that AXERT (almotriptan malate) not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors (eg, 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, 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 (almotriptan malate) take place in the setting of a physician's office or similar medically staffed and equipped facility unless the patient has previously received AXERT (almotriptan malate) . Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following AXERT (almotriptan malate) , in these patients with risk factors. It is recommended that patients who are intermittent long-term users of AXERT (almotriptan malate) and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use AXERT (almotriptan malate) .

The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to AXERT (almotriptan malate) . 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 AXERT (almotriptan malate) . 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 [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

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, transient ischemic attack) [see CONTRAINDICATIONS].

Other Vasospasm Related Events including Peripheral Vascular Ischemia and Colonic Ischemia

Triptans, including AXERT (almotriptan malate) , 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 [see CONTRAINDICATIONS].

Serotonin Syndrome

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

Increases in Blood Pressure

As with other triptans, significant elevations in systemic blood pressure have been reported on rare occasions with AXERT (almotriptan malate) use, in patients with and without a history of hypertension; very rarely these increases in blood pressure have been associated with significant clinical events. AXERT (almotriptan malate) is contraindicated in patients with uncontrolled hypertension. [see CONTRAINDICATIONS]. 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 AXERT (almotriptan malate) 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

AXERT (almotriptan malate) 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 [see CLINICAL PHARMACOLOGY].

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, 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

See FDA-Approved Patient Labeling

Inform patients that Patient Information labeling is available as a separate leaflet. Advise the patient to read this information and assist them in understanding its contents. Provide the patient the opportunity to discuss the contents of the Patient Information and answer any questions they may have. The complete text of the Patient Information is attached to the package insert.

Risk of Myocardial Ischemia and/or Infarction, Other Adverse Cardiac Events, Other Vasospasm-related Event, and Cerebrovascular Events

Inform patients that AXERT (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, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Apprise the patient of the importance of this follow-up [see WARNINGS AND PRECAUTIONS].

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome with the use of AXERT (almotriptan malate) or other triptans, particularly during combined use with selective serotonin reuptake inhibitors

(SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [See WARNINGS AND PRECAUTIONS].

Pregnancy

Advise patient to notify their physician if they become pregnant during treatment or intend to become pregnant [see Use in Specific Populations].

Nursing Mothers

Advise patients to notify their physician if they are breast-feeding or plan to breast-feed [see Use in Specific Populations].

Drug Interactions

Advise patients to talk with their physician or pharmacist before taking any new medicines, including prescription and non-prescription drugs and supplements [see CONTRAINDICATIONS and Drug-Drug Interactions].

Ability to Operate Machinery or Vehicles

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

Hypersensitivity

Inform patient to tell their physician if they develop a rash, itching, or breathing difficulties after taking AXERT (almotriptan malate) [see WARNINGS AND PRECAUTIONS].

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, decreased offspring body weight) at doses greater than those used clinically. There are no adequate and well-controlled studies in pregnant women; therefore, AXERT (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/mg/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 AXERT (almotriptan malate) 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 AXERT (almotriptan malate) 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 AXERT (almotriptan malate) in pediatric patients under the age of 12 years have not been established. The pharmacokinetics, efficacy and safety of AXERT (almotriptan malate) have been evaluated in adolescent patients, aged 12-17 years [see CLINICAL PHARMACOLOGY and Clinical Studies].

In a clinical study, AXERT (almotriptan malate) 6.25 mg and 12.5 mg were found to be effective for the relief of migraine headache pain in adolescent patients age 12-17 years. Efficacy on migraine-associated symptoms (nausea, photophobia and phonophobia) was not established.1 The most common adverse reactions (incidence of ≥ 1%) associated with AXERT (almotriptan malate) treatment were dizziness, somnolence, headache, paresthesia, nausea and vomiting [see ADVERSE REACTIONS. The safety and tolerability profile of AXERT (almotriptan malate) 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 AXERT (almotriptan malate) 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]. 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 AXERT (almotriptan malate) 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 AXERT (almotriptan malate) 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 DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Renal Impairment

The recommended starting dose of AXERT (almotriptan malate) 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 DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 5/29/2009
This monograph has been modified to include the generic and brand name in many instances.

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