Axert

Almotriptan is used to treat the symptoms of migraine headaches (severe, throbbing headaches that sometimes are accompanied by nausea and sensitivity to sound and light). Almotriptan is in a class of medications called selective serotonin receptor agonists. It works by narrowing blood vessels around the brain, stopping pain signals from being sent to the brain, and blocking the release of certain natural substances that cause pain, nausea, and other symptoms of migraine. Almotriptan does not prevent migraine attacks or reduce the number of headaches you have.

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Almotriptan is a headache medicine that narrows blood vessels around the brain. Almotriptan also reduces substances in the body that can trigger headache pain, nausea, sensitivity to light and sound, and other migraine symptoms.

Almotriptan is used to treat migraine headaches in adults and in adolescents who are at least 12 years old. Almotriptan will only treat a headache that has already begun. It will not prevent headaches or reduce the number of attacks.

Almotriptan should not be used to treat a common tension headache, a headache that causes loss of movement on one side of your body, or any headache that seems to be different from your usual migraine headaches. Use this medicine only if your condition has been confirmed by a doctor as migraine headaches.

Almotriptan may also be used for purposes not listed in this medication guide.

You should not take almotriptan if you have ever had heart disease, or if you have coronary artery disease, blood circulation problems, lack of blood supply to the heart, uncontrolled high blood pressure, ischemic bowel disease, a history of a heart attack or stroke (including "mini-stroke"), or if your headache seems to be different from your usual migraine headaches.

Do not take almotriptan within 24 hours before or after using another migraine headache medicine, including other "triptan" medications, or an ergot medicine such as dihydroergotamine, ergotamine, ergonovine, methylergonovine, D.H.E. 45, Migranal, Cafergot, Methergine, and others.

You should not take almotriptan if you are allergic to it, or if you have:

• a history of heart disease;
• a history of heart attack or stroke, including "mini-stroke";
• coronary artery disease, circulation problems, lack of blood supply to the heart;
• uncontrolled high blood pressure;
• ischemic bowel disease; or
• a headache that seems different from your usual migraine headaches.

To make sure almotriptan is safe for you, tell your doctor if you have:

• a sulfa drug allergy;
• liver disease;
• kidney disease;
• high blood pressure, a heart rhythm disorder; or
• risk factors for coronary artery disease (such as diabetes, menopause, smoking, being overweight, having high blood pressure or high cholesterol, having a family history of coronary artery disease, being older than 40 and a man, or being a woman who has had a hysterectomy).

FDA pregnancy category C. It is not known whether almotriptan will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether almotriptan passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Do not give this medicine to anyone under 12 years old.

You should not take almotriptan if you are allergic to it, or if you have:

• severe or uncontrolled high blood pressure;

• past or present heart problems;

• history of coronary artery disease, angina, (chest pain), heart attack, or stroke, including "mini-stroke";

• a blood vessel disorder or circulation problems that cause a lack of blood supply within the body; or

• a headache that seems different from your usual migraine headaches.

To make sure almotriptan is safe for you, tell your doctor if you have ever had:

• a sulfa drug allergy;

• liver or kidney disease;

• kidney disease;

• high blood pressure, a heart rhythm disorder; or

• risk factors for coronary artery disease (such as diabetes, menopause, smoking, being overweight, having high blood pressure or high cholesterol, having a family history of heart disease, or being older than 40 and a man).

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether almotriptan passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Do not give this medicine to anyone under 12 years old.

Selective serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptor agonist (“triptan”).1 2 3 5 12

Metabolized principally by MAO-A, CYP3A4, and CYP2D6.1 19

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (decreased almotriptan metabolism) with concomitant use of CYP3A4 inhibitors.1

When used concomitantly with a potent CYP3A4 inhibitor, recommended initial almotriptan dose is 6.25 mg; do not exceed 12.5 mg within a 24-hour period.1

Avoid concomitant use of almotriptan and potent CYP3A4 inhibitors in patients with renal or hepatic impairment.1

Specific Drugs

Absorption

Bioavailability

Well absorbed from GI tract.19 Absolute bioavailability is approximately 70%.1 19 20

Peak plasma concentrations attained within 1–3 hours after oral administration.1 19 20

Rate and extent of absorption in adolescents 12–17 years of age is similar to that in adults.1

Food

Food does not affect pharmacokinetics.1 10

Distribution

Extent

Appears to be widely distributed throughout the body.20

Distributed into milk in rats; not known whether distributed into milk in humans.1

Plasma Protein Binding

Approximately 35%.1

Elimination

Metabolism

Metabolized to inactive metabolites principally via MAO-mediated oxidative deamination, CYP3A4, and CYP2D6, with minor contribution of flavin monooxygenase.1 19

Elimination Route

Excreted in urine (75%) and feces (13%), with 40% of dose recovered in urine as unchanged drug.1

Half-life

3–4 hours.1 19 20

Special Populations

Pharmacokinetics not evaluated in patients with hepatic impairment.1 Based on mechanism of almotriptan clearance, maximum decrease in clearance of 60% would be expected.1

In patients with moderate or severe renal impairment, clearance is reduced by approximately 40 or 65%, respectively; peak plasma concentrations increased by approximately 80% in these patients.1

In healthy geriatric patients, clearance is decreased, resulting in increases in half-life and AUC compared with younger adults; not considered clinically important.1

• Risk of serious cardiovascular or cerebrovascular events (e.g., MI, stroke) or other vasospastic reactions.1 Importance of seeking medical care if symptoms of such reactions (e.g., shortness of breath, weakness, slurring of speech, or tightness, pain, pressure, or heaviness in chest, throat, neck, or jaw) occur and of not taking almotriptan again until evaluated by clinician.1 22

• Importance of taking almotriptan exactly as prescribed.1

• Importance of providing patient a copy of manufacturer’s patient information.1

• Importance of informing clinician if symptoms suggestive of a hypersensitivity reaction (e.g., rash, itching, difficulty in breathing) occur.1

• Risk of dizziness, somnolence, visual disturbances, and other CNS symptoms that may impair mental or visual performance; avoid driving, operating machinery, and engaging in other hazardous activities until effects on the individual are known.1

• Overuse of drugs indicated for the management of acute migraine attacks may exacerbate headaches; importance of recording headache frequency and drug use to monitor effectiveness of treatment.22 31

• Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease).1

• Importance of informing patients of risk of serotonin syndrome, particularly with concurrent use of almotriptan and an SSRI or SNRI.1 11 Importance of seeking immediate medical attention if symptoms of serotonin syndrome develop.1 11

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. Using too much almotriptan may increase the chance of side effects.

Do not use this medicine for a headache that is not a migraine headache. Talk to your doctor about what to do for regular headaches.

This medicine comes with a patient information leaflet. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For migraine headaches:
    • Adults and teenagers 12 years of age and older—6.25 or 12.5 milligrams (mg) as a single dose. Your doctor may tell you to take another dose if the migraine comes back. However, the maximum dose for a single day (24 hours) is 25 mg.
    • Children younger than 12 years of age—Use and dose must be determined by your doctor.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Axert® (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."

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® 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. 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 Axert® in Adults

Among the 3865 subjects/patients who received Axert® 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 Axert® in Adults

Serious cardiovascular events have been reported in association with the use of Axert®. 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 (6.3)].

Patients with Documented Coronary Artery Disease

Because of the potential of this class of compound (5-HT1 agonists) to cause coronary vasospasm, Axert® should not be given to patients with documented ischemic or vasospastic coronary artery disease [see Contraindications (4.1)].

Patients with Risk Factors for CAD

It is strongly recommended that Axert® 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, Axert® should not be administered [see Contraindications (4.1)].

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 Axert®. 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 Axert®, in these patients 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®. 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®. 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 (4.1) and Warnings and Precautions (5.1)].

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) [see Contraindications (4.2)].

Other Vasospasm-Related Events, Including Peripheral Vascular Ischemia and Colonic Ischemia

Triptans, including Axert®, 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 (4.3)].

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome may occur with triptans, including Axert®, 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 Drug Interactions (7.3)].

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 Axert® 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® is contraindicated in patients with uncontrolled hypertension [see Contraindications (4.4)]. 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® 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® 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 Dosage and Administration (2.2), (2.3) and Clinical Pharmacology (12.3)].

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.