Axert

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

Almotriptan is well absorbed following oral administration. The mean oral absolute bioavailability is approximately 70%, and peak plasma concentrations of approximately 40 ng/mL are reached 1 to 3 hours after a single 12.5 mg dose. The rate and extent of absorption are not affected by food intake or by administration during a migraine attack. Almotriptan does not undergo substantial first-pass elimination.

AXERT (almotriptan malate) is a selective 5-hydroxytryptamine_1B/1D (5-HT_1B/1D ) receptor agonist. Almotriptan binds with high affinity to 5-HT_1D, 5-HT_1B and 5-HT_1F receptors. Almotriptan has a weak affinity for 5-HT_1A and 5-HT₇ receptors, but has no significant affinity or pharmacological activity at 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₆; alpha or beta adrenergic; adenosine (A₁, A₂); angiotensin (AT₁, AT₂); dopamine (D₁, D₂); endothelin (ET_A, ET_B); or tachykinin (NK₁, NK₂, NK₃) binding sites.

Current theories on the etiology of migraine headaches suggest that symptoms are due to local cranial vasodilatation and/or to the release of vasoactive and pro-inflammatory peptides from the 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 the nerve terminals in the trigeminal system. Activation of these receptors results in cranial vessel constriction, inhibition of the neuropeptide release, and reduced transmission in the trigeminal pain pathways.

These results cannot be validly compared with results of anti-migraine treatments in other studies. Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment responses and the timing of responses may be expected to vary considerably from study to study.

For patients with migraine-associated photophobia, phonophobia, nausea, and vomiting at baseline, there was a decreased incidence of these symptoms following administration of AXERT compared with placebo.

Two to 24 hours following the initial dose of study medication, patients were allowed to take an escape medication or a second dose of study medication for pain response. Escape medication was taken more frequently by patients in the placebo groups than by those in the active almotriptan treatment groups.

The efficacy of AXERT was unaffected by the presence of aura; by gender, weight, or age of the patient; or by concomitant use of common migraine prophylactic drugs (e.g. beta-blockers, calcium channel blockers, tricyclic antidepressants), or oral contraceptives. There were insufficient data to assess the effect of race on efficacy.

No significant differences have been observed in the pharmacokinetic parameters between Caucasian and African-American volunteers.

The mean half-life of almotriptan is between 3 and 4 hours. The primary route of elimination is via renal clearance, accounting for 75% of the administered dose. Approximately 40% of an administered dose is 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.

No significant gender differences have been observed in pharmacokinetic parameters.

The pharmacokinetics of almotriptan have not been evaluated in pediatric patients.

Almotriptan is metabolized by one minor and two major 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 mono-oxygenase 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.

The pharmacokinetics of almotriptan have not been assessed in this population. Based on the known mechanisms of the clearance of almotriptan, the maximum decrease in expected almotriptan clearance due to hepatic impairment would be 60% (see Dosage and Precautions, Hepatic Impairment).

Renal and total clearance, and amount of drug excreted in the urine (10 L/h, 33 L/h and 30% respectively) were lower in elderly non-migraineur volunteers (aged 65 to 76 years) than in younger non-migraineur volunteers (aged 19 to 34 years), resulting in longer terminal half-life (3.7 h vs 3.2 h) and higher area under the plasma concentration-time curve (405 ng·h/mL vs 325 ng·h/mL) in the elderly subjects. However, the differences do not appear to be clinically significant.

The clearance of almotriptan was approximately 65% lower in patients with severe renal impairment (Cl/F=19.8 L/h; creatinine clearance between 10 and 30 mL/min) and approximately 40% lower in patients with moderate renal impairment (Cl/F=34.2 L/h; creatinine clearance between 31 and 71 mL/min) compared to healthy volunteers. Maximum plasma concentrations of almotriptan increased by approximately 80% in these patients (see Dosage and Precautions, Renal Impairment).

All drug interaction studies were performed in healthy volunteers using a single 12.5 mg dose of almotriptan and multiple doses of the other drug.

Ergot-Containing Drugs: These drugs have been reported to cause prolonged vasospastic reactions. As there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (dihydroergotamine or methylsergide) and AXERT within 24 hours of each other should be avoided (see Contraindications).

Monoamine Oxidase Inhibitors: Coadministration of almotriptan and moclobemide (150 mg b.i.d. for 8 days) resulted in a 27% decrease in almotriptan clearance and an increase in Cmax of approximately 6%. No dose adjustment is necessary.

Propranolol: Coadministration of almotriptan and propranolol (80 mg b.i.d. for 7 days) resulted in no significant changes in the pharmacokinetics of almotriptan.

Selective Serotonin Reuptake Inhibitors (SSRIs)/Serotonin Norepinephrine Reuptake Inhibitors (SNRIs): Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans (see Warnings).

Coadministration of almotriptan and fluoxetine (60 mg daily for 8 days), a potent inhibitor of CYP2D6, had no effect on almotriptan clearance, but maximal concentrations of almotriptan were increased by 18%. This difference is not clinically significant.

Verapamil: Coadministration of almotriptan and verapamil (120 mg sustained-release tablets b.i.d. for 7 days), an inhibitor of CYP4503A4, resulted in a 20% increase in the area under the plasma concentration-time curve, and in a 24% increase in maximal plasma concentrations of almotriptan. Neither of these changes is clinically significant.

Other 5-HT_1B/1D Agonists: Concomitant use of other 5-HT_1B/1D agonists within 24 hours of treatment with AXERT is contraindicated (see Contraindications).

Ketoconazole and Other Potent CYP3A4 Inhibitors: Coadministration of almotriptan and the potent CYP3A4 inhibitor ketoconazole (400 mg q.d. for 3 days) resulted in an approximately 60% increase in the area under the plasma concentration-time curve and maximal plasma concentrations of almotriptan. Although the interaction between almotriptan and other potent CYP3A4 inhibitors (e.g. itraconazole, ritonavir, and erythromycin) has not been studied, increased exposures to almotriptan may be expected when almotriptan is used concomitantly with these medications.

When almotriptan was administered orally during organogenesis to pregnant rats at doses of 125, 250, 500 and 1000 mg/kg/day, an increase in embryolethality was seen at the 1000 mg/kg/day dose (maternal exposure [based on plasma AUC of parent drug] was approximately 958 times the human exposure at MRDD of 25 mg). Increased incidences of fetal skeletal variations (decreased ossification) were noted at doses greater than the no-observed-effect level in rats of 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 embryolethality at 60 mg/kg/day (maternal exposure, based on mg/m², 50 times human exposure at MRDD). 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 (maternal exposure, based on mg/m², 160 times human exposure at MRDD). The decrease in pup weight persisted throughout lactation. The no-observed-effect level in this study was 100 mg/kg/day (maternal exposure 40 times human exposure at MRDD).

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

AXERT should be used with caution in patients with hepatic impairment. The maximum daily dose should not exceed 12.5 mg over a 24-hour period, and a starting dose of 6.25 mg is recommended (see Pharmacology, Special Populations and Dosage).

The safety and effectiveness of AXERT in pediatric patients has 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 (under 12 years of age) and adolescent (12-17 years of age) patients who have experienced clinically serious adverse events that are similar in nature to those reported as rare occurrences in adults.

AXERT should be used with caution in patients with severe renal impairment. The maximum daily dose should not exceed 12.5 mg over a 24-hour period, and a starting dose of 6.25 mg should be used (see Pharmacology, Special Populations and Dosage).

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.

Clinical studies of AXERT did not include sufficient numbers of subjects over 65 years of age to determine whether they respond differently from younger subjects. Renal and total clearance, and amount of drug excreted in the urine were lower in elderly non-migraineur volunteers (age 65 to 76 years) than in younger non-migraineur volunteers (age 19 to 34 years), resulting in longer terminal half-life and higher area under the plasma concentration-time curve. Although clearance of almotriptan was lower in elderly volunteers, there were no differences in the safety and tolerability between the two populations (see 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 renal, cardiac, and hepatic function, and of concomitant disease or other drug therapy.

It is not known whether almotriptan is excreted in human milk. Since many drugs are excreted in human milk, caution should be exercised when AXERT is administered to a nursing woman.

Although the abuse potential of AXERT has not been specifically assessed, no abuse of, tolerance to, withdrawal from, or drug-seeking behaviour was observed in patients who received AXERT in clinical trials or their extensions. The 5-HT_1B/1D agonists, as a class, have not been associated with drug abuse.

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 Pharmacology, Special Populations and Dosage).

Caution should be exercised when prescribing almotriptan to patients with known hypersensitivity to sulfonamides.

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 (exposure, based on mg/m², was approximately 40 times exposure in humans receiving the maximum recommended daily dose (MRDD) of 25 mg). No effects on fertility were noted in female rats at 25 mg/kg/day (exposure approximately 10 times human exposure at MRDD). No adverse effects were noted in male rats at 400 mg/kg/day (160 times the human exposure based on mg/m²).

When pigmented rats were given a single oral dose of 5 mg/kg of radiolabelled almotriptan, the elimination half-life of radioactivity from the eye was 22 days, suggesting that almotriptan and/or its metabolites may bind to the melanin of the eye. Because almotriptan could accumulate in the melanin-rich tissues over time, there is the possibility that it could cause toxicity in these tissues over extended use. However, no adverse ocular effects related to treatment with almotriptan were noted in any of the toxicity studies. Although no systemic monitoring of ophthalmic function was undertaken in clinical trials, and no specific recommendations for ophthalmic monitoring are offered, prescribers should be aware of the possibility of long-term ophthalmic effects.

Patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that AXERT does not affect them adversely.

Almotriptan is not known to interfere with any commonly employed clinical laboratory tests. No specific laboratory tests are recommended for monitoring patients.

Care should be taken to exclude other potentially serious neurologic conditions before treating headache in patients not previously diagnosed with migraine or who experience a headache that is atypical for them. There have been rare reports where patients received 5-HT₁ agonists for severe headache that were subsequently shown to have been secondary to an evolving neurological lesion. For newly diagnosed patients or patients presenting with atypical symptoms, the diagnosis of migraine should be reconsidered if no response is seen after the first dose of AXERT.

Almotriptan was not mutagenic, with or without metabolic activation, when tested in two gene mutation assays, the Ames test and the in vitro thymidine locus mouse lymphoma assay. Almotriptan was not determined to be clastogenic in two in vitro cytogenetics assays in human lymphocytes and an in vivo mouse micronucleus assay. Almotriptan produced an equivocal weakly positive response in in vitro cytogenetics assays in human lymphocytes.

The carcinogenic potential of almotriptan was evaluated by oral gavage for up to 103 weeks in mice at doses of 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 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.

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). These events have not been associated with arrhythmias or ischemic ECG changes in clinical trials. Because drugs in this class, including AXERT, 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 the 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 Contraindications and Warnings).

Each white, circular, biconvex tablet, printed in blue with a stylized “A”, contains: almotriptan 12.5 mg. Nonmedicinal ingredients: carnauba wax, cellulose, FD&C Blue No. 2, hydroxypropyl methylcellulose, mannitol, polyethylene glycol, povidone, propylene glycol, sodium starch glycolate, sodium stearyl fumarate and titanium oxide. Unit dose (aluminum blister pack) of 6. Store between 15-30°C.

Each white, circular, biconvex tablet, printed in red with the code 2080, contains: almotriptan 6.25 mg. Nonmedicinal ingredients: carnauba wax, cellulose, hydroxypropyl methylcellulose, iron oxide, mannitol, polyethylene glycol, povidone, propylene glycol, sodium starch glycolate, sodium stearyl fumarate and titanium oxide. Unit dose (aluminum blister pack) of 6. Store between 15-30°C.

In subjects (n=10) with suspected coronary artery disease undergoing angiography, a 5-HT₁ agonist at a subcutaneous dose of 1.5 mg produced an 8% increase in aortic blood pressure, an 18% increase in pulmonary artery blood pressure, and an 8% increase in systemic vascular resistance. In addition, mild chest pain or tightness was reported by four subjects. Clinically significant increases in blood pressure were experienced by three of the subjects (two of whom also had chest pain/discomfort). Diagnostic angiogram results revealed that 9 subjects had normal coronary arteries and 1 had insignificant coronary artery disease.

In an additional study with this same drug, migraine patients (n=35) free of cardiovascular disease were subjected to assessments of myocardial perfusion by positron emission tomography while receiving a subcutaneous 1.5 mg dose in the absence of a migraine attack. Reduced coronary vasodilatory reserve (~10%), increased coronary resistance (~20%), and decreased hyperaemic myocardial blood flow (~10%) were noted. The relevance of these findings to the use of the recommended oral dose of this 5-HT₁ agonist is not known.

Similar studies have not been done with AXERT. However, owing to the common pharmacodynamic actions of 5-HT₁ agonists, the possibility of cardiovascular effects of the nature described above should be considered for any agent of this pharmacological class.

Among the 3865 subjects/patients who received AXERT 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 AXERT. 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.

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. Due to the common pharmacodynamic actions of 5-HT₁ agonists, the possibility of cardiovascular effects of the nature described below should be considered for all agents of this class. 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.

Patients with symptomatic Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders should not receive AXERT.

Rare hypersensitivity (anaphylaxis/anaphylactoid) reactions have occurred in patients receiving other 5-HT₁ agonists. Such reactions can be life threatening or fatal. In general, hypersensitivity reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. Owing to the possibility of cross-reactive hypersensitivity reactions, AXERT should not be used in patients having a history of hypersensitivity to chemically-related 5-HT₁ receptor agonists (see Adverse Effects and Precautions).

Serious cardiovascular events have been reported in association with the use of AXERT. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to definitely determine the proportion of the reported cases that were actually caused by almotriptan or to reliably assess causation in individual cases.

Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans. If concomitant treatment with AXERT and SSRIs (e.g., fluoxetine, paroxetine, sertraline) or SNRIs (e.g., venlafaxine) 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).

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 patients with controlled hypertension, AXERT should be administered with caution, as transient increases in blood pressure and peripheral vascular resistance have been observed in a small portion of patients. 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 AXERT 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 (see Adverse Effects and Precautions).

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.

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 such as: 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 examination 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 evaluations reveal findings indicative of, or consistent with, coronary artery vasospasm, or myocardial ischemia, AXERT should not be administered (see Contraindications).

These evaluations, however, may not identify every patient who has cardiac disease, and in very rare cases, serious cardiac events, such as myocardial infarction or coronary ischemia have occurred in patients without evidence of underlying cardiovascular disease.

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 a clinical setting, such as the physician's office or a similarly staffed medical facility, unless the patient has previously received almotriptan. Because cardiac ischemia can occur in the absence of any 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. However, an absence of drug-induced cardiovascular effects on the occasion of the initial dose does not preclude the possibility of such effects occurring with subsequent administrations.

If symptoms consistent with angina occur after the use of AXERT, ECG evaluation should be carried out to look for ischemic changes.

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 are inadvertently exposed to AXERT.

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 belief that the symptoms experienced were a consequence of migraine, when they were not. Before treating migraine headaches with AXERT, 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. If a patient does not respond to the first dose, the opportunity should be taken to review the diagnosis before a second dose is given. It should be noted, however, that patients who suffer from migraine may have an increased risk of certain cerebrovascular events such as stroke, hemorrhage or transient ischemic attack.

AXERT is generally well tolerated. Most adverse events were mild in intensity and were transient, and did not lead to long-lasting effects. 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.

Infrequent were diarrhea, vomiting, and dyspepsia. Rare were decreased appetite, increased appetite, colitis, gastritis, gastroenteritis, esophageal reflux, increased thirst, and increased salivation.

Infrequent were ear pain, conjunctivitis, eye irritation, hyperacusis, and taste alteration. Rare were diplopia, dry eyes, eye pain, otitis media, parosmia, scotoma, and tinnitus.

In a long term open label study, 762 patients treated 13,751 migraine attacks with AXERT over a period of up to 1 year. Migraine headaches could be treated with either a single dose of 12.5 mg AXERT or an initial 12.5 mg dose followed by a second 12.5 mg dose if needed. In this study, 3% (24 of 762) of patients withdrew due to an adverse experience. The most common adverse events (defined as occurring in more than 3% of patients) in descending order frequency were as follows: back pain (8%), bronchitis (6.4%), influenza-like symptoms (5.8%), pharyngitis (4.6%), vomiting (4.2%), rhinitis (4.1%), skeletal pain (3.4%) and sinusitis (3.4%). Due to the lack of placebo control in this study, the role of AXERT in causation cannot be reliably determined.

Infrequent were pharyngitis, rhinitis, dyspnea, laryngismus, sinusitis, bronchitis, and epistaxis. Rare were hyperventilation, laryngitis, and sneezing.

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 AXERT 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 (see also Contraindications and Warnings).

Infrequent were hyperglycemia and increased serum creatine phosphokinase. Rare were increased gamma glutamyl transpeptidase and hypercholesteremia.

In addition to the adverse experiences reported during clinical trials of AXERT, the following adverse events have been reported in patients receiving marketed AXERT from worldwide use since approval. Due to the uncontrolled nature of post-marketing surveillance, it is not possible to definitely determine the proportion of the reported cases that were actually caused by AXERT or to reliably assess causation.

Serious cardiovascular adverse events, including acute myocardial infarction, coronary vasospasm and angina pectoris have been reported within a few hours following administration of AXERT.

Although very rare, 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 (see Contraindications, Warnings, Adverse Effects and Precautions).

Frequent was headache. Infrequent were abdominal cramp or pain, asthenia, chills, back pain, chest pain, neck pain, fatigue, and rigid neck. Rare were fever and photosensitivity reaction.

Infrequent were myalgia and muscular weakness. Rare were arthralgia, arthritis, and myopathy.

Frequent were dizziness and somnolence. Infrequent were tremor, vertigo, anxiety, hypesthesia, restlessness, CNS stimulation, insomnia, and shakiness. Rare were change in dreams, impaired concentration, abnormal coordination, depressive symptoms, euphoria, hyperreflexia, hypertonia, nervousness, neuropathy, nightmares, and nystagmus.

As with other 5-HT₁ agonists, AXERT has been associated with sensations of heaviness, pressure, tightness or pain which may be intense. These may occur in any part of the body including the chest, throat, neck, jaw and upper limbs.

Dysmenorrhea was infrequent.

The frequencies of less commonly reported adverse events are presented below. However, the role of AXERT in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, etc., limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients who used AXERT in controlled clinical trials and reported an event, divided by the total number of patients exposed to AXERT in these studies. All reported events are included, except the ones already listed in Table 2, and those unlikely to be drug related. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; and rare adverse events are those occurring in fewer than 1/1000 patients.

Infrequent were diaphoresis, dermatitis, erythema, pruritus, and rash.

Infrequent were vasodilation, palpitations, and tachycardia. Rare were intermediate coronary syndrome, abnormal cardiac rhythm, hypertension, and syncope.

Patients and volunteers receiving single oral doses of 100 to 150 mg of AXERT did not experience significant adverse events. During the clinical trials, one patient ingested 62.5 mg in a five-hour period, and another patient ingested 100 mg in a 38-hour period. Neither patients experienced adverse reactions.

Based on the pharmacology of 5-HT₁ agonists, hypertension or other more serious cardiovascular symptoms could occur after overdosage.

Gastrointestinal decontamination (i.e. gastric lavage followed by activated charcoal) should be considered in patients suspected of an overdose with AXERT. Clinical and electrocardiographic monitoring should be continued for at least 20 hours, even if clinical symptoms are not observed.

The effects of hemodialysis or peritoneal dialysis on plasma concentrations of almotriptan are unknown.

The pharmacokinetics of almotriptan have not been assessed in this population. The maximum decrease expected in the clearance of almotriptan due to hepatic impairment is 60%. Therefore, the maximum daily dose should not exceed 12.5 mg over a 24-hour period, and a starting dose of 6.25 mg should be used (see Pharmacology, Special Populations and Precautions).

In patients with severe renal impairment, the clearance of almotriptan was decreased. Therefore, the maximum daily dose should not exceed 12.5 mg over a 24-hour period, and a starting dose of 6.25 mg should be used (see Pharmacology, Special Populations and Precautions).