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Axert

"Migraine medications overview

Migraine is a serious, potentially life-threatening neurological disease that affects nearly 32 million Americans, the majority of whom are women. The hallmark symptom of migraine is an escalating, often "...

Axert

Axert

CLINICAL PHARMACOLOGY

Mechanism of Action

Almotriptan binds with high affinity to 5-HT1D, 5-HT1B, and 5-HT1F receptors. Almotriptan has weak affinity for 5-HT1A 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 (ETA, ETB); or tachykinin (NK1, NK2, NK3) binding sites.

Pharmacodynamics

Current theories on the etiology of migraine headache suggest that symptoms are due to local cranial vasodilatation and/or to the release of vasoactive and pro-inflammatory peptides from sensory nerve endings in an activated trigeminal system. The therapeutic activity of almotriptan in migraine can most likely be attributed to agonist effects at 5-HT1B/1D receptors on the extracerebral, intracranial blood vessels that become dilated during a migraine attack, and on nerve terminals in the trigeminal system. Activation of these receptors results in cranial vessel constriction, inhibition of neuropeptide release, and reduced transmission in trigeminal pain pathways.

Pharmacokinetics

Absorption

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

Distribution

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

Metabolism

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

Excretion

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

Drug-Drug Interactions

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.

Monoamine Oxidase Inhibitors: coadministration of almotriptan and moclobemide (150 mg twice daily 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 twice daily for 7 days) resulted in no significant changes in the pharmacokinetics of almotriptan.

Fluoxetine: Coadministration of almotriptan and fluoxetine (60 mg daily for 8 days), a potent inhibitor almotriptan were increased 18%. This difference is not clinically significant.

Verapamil: Coadministration of almotriptan and verapamil (120 mg sustained release tablets twice daily for 7 days), an inhibitor of CYP3A4, 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. No dose adjustment is necessary.

Ketoconazole and Other Potent CYP3A4 Inhibitors: Coadministration of almotriptan and ketoconazole, a potent CYP3A4 inhibitor, resulted in an approximately 60% increase in exposure of almotriptan. Increased exposures to almotriptan may be expected when almotriptan is used with other potent CYP3A4 inhibitors.

Special Populations

Geriatric

Renal and total clearance, and amount of drug excreted in the urine were lower in elderly healthy volunteers (age 65 to 76 years) than in younger healthy volunteers (age 19 to 34 years), resulting in longer terminal half-life (3.7 h vs. 3.2 h) and a 25% higher area under the plasma concentration-time curve in the elderly subjects. The differences, however, do not appear to be clinically significant.

Pediatric

A pharmacokinetics study of almotriptan was conducted in adolescents (12 to 17 years) and adults (18 to 55 years) with or without a history of migraine. No differences were observed in the rate or extent of absorption of almotriptan in adolescents compared with adults.

Gender

No significant gender differences have been observed in pharmacokinetic parameters.

Race

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

Hepatic Impairment

The pharmacokinetics of almotriptan have not been assessed in patients with hepatic impairment. Based on the known mechanisms of clearance of almotriptan, the maximum decrease expected in almotriptan clearance due to hepatic impairment would be 60% [see DOSAGE AND ADMINISTRATION].

Renal Impairment

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) than in healthy volunteers (Cl/F= 57 L/h). Maximal plasma concentrations of almotriptan increased by approximately 80% in these patients [see DOSAGE AND ADMINISTRATION].

Clinical Studies

Adults

The efficacy of AXERT (almotriptan malate) was established in 3 multi-center, randomized, double-blind, placebo-controlled European trials. Patients enrolled in these studies were primarily female (86%) and Caucasian (more than 98%), with a mean age of 41 years (range of 18 to 72). Patients were instructed to treat a moderate to severe migraine headache. Two hours after taking one dose of study medication, patients evaluated their headache pain. If the pain had not decreased in severity to mild or to no pain, the patient was allowed to take an escape medication. If the pain had decreased to mild or to no pain at 2 hours but subsequently increased in severity between 2 and 24 hours, it was considered a relapse and the patient was instructed to take a second dose of study medication. Associated symptoms of nausea, vomiting, photophobia, and phonophobia were also evaluated.

In these studies, the percentage of patients achieving a response (mild or no pain) 2 hours after treatment was significantly greater in patients who received either AXERT (almotriptan malate) 6.25 mg or 12.5 mg, compared with those who received placebo. A higher percentage of patients reported pain relief after treatment with the 12.5 mg dose than with the 6.25 mg dose. Doses greater than 12.5 mg did not lead to significantly better response. These results are summarized in Table 3.

Table 3. Response Rates 2 Hours Following Treatment of Initial Headache

  Placebo AXERT
6.25 mg
AXERT
12.5 mg
Study 1 33.8%
(n = 80)
55.4%*
(n = 166)
58.5%
(n = 164)
Study 2 40.0%
(n = 95)
--- 57.1%
(n =175)
Study 3 33.0%
(n = 176)
55.6%
(n = 360)
64.9%
(n = 370)
* p value 0.002 in comparison with placebo
p value < 0.001 in comparison with placebo
p value 0.008 in comparison with placebo

The estimated probability of achieving pain relief within 2 hours following initial treatment with AXERT (almotriptan malate) in adults is shown in Figure 1.

Figure 1. Estimated Probability of Achieving an Initial Headache Response (mild or no pain) in 2 Hours in adults

Estimated Probability of Achieving an Initial Headache Response (mild or no pain) in 2 Hours in adults - Illustration

This Kaplan-Meier plot is based on data obtained in the three placebo-controlled clinical trials that provided evidence of efficacy (Studies 1, 2, and 3). Patients not achieving pain relief by 2 hours were censored at 2 hours.

For patients with migraine-associated photophobia, phonophobia, nausea, and vomiting at baseline, there was a decreased incidence of these symptoms following administration of AXERT (almotriptan malate) 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. The estimated probability of patients taking escape medication or a second dose of study medication over the 24 hours following the initial dose of study medication is shown in Figure 2.

Figure 2. Estimated Probability of Adult Patients Taking Escape Medication or a Second Dose of Study Medication Over the 24 Hours Following the Initial Dose of Study Treatment

Estimated Probability of Adult Patients Taking Escape Medication or a Second Dose of Study Medication Over the 24 Hours Following the Initial Dose of Study Treatment - Illustration

This Kaplan-Meier plot is based on data obtained in the three placebo-controlled trials that provided evidence of efficacy (Studies 1, 2, and 3). Patients not using additional treatment were censored at 24 hours. Remedication was not allowed within 2 hours after the initial dose of AXERT (almotriptan malate) .

The efficacy of AXERT (almotriptan malate) 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.

Adolescents age 12-17 years

The efficacy of AXERT (almotriptan malate) in adolescent patients age 12-17 years was evaluated in a double-blind, randomized, placebo-controlled, study. Patients enrolled in that study had at least a 1-year history of migraine attacks with or without aura usually lasting 4 hours or more (when untreated). Patients enrolled in the study were primarily females (60%) and Caucasian (75%), while 15% of patients were black, and 10% were of other races. Patients were instructed to treat a moderate to severe migraine headache. Two hours after taking one dose of study medication, patients evaluated their headache pain. Associated symptoms of nausea, photophobia, and phonophobia were also evaluated.

In this study, the percentage of patients achieving a pain relief response (mild or no pain) 2 hours after treatment was statistically significantly greater in patients who received AXERT (almotriptan malate) 6.25 mg or 12.5 mg compared with those who received placebo. There was no additional benefit on pain relief provided by the 12.5 mg dose. The 2-hour pain relief results are summarized in Table 4.

Table 4.: Response Rates 2 Hours Following Treatment of Initial Headache in Adolescents age 12-17 years

  Placebo AXERT 6.25 mg AXERT 12.5 mg
Study 1 55.3%
(n/N = 94/170)
71.8%*
(n/N = 127/177)
72.9%
(n/N = 132/181)
* p value 0.001 in comparison with placebo
p value < 0.001 in comparison with placebo

The estimated probability of achieving pain relief within 2 hours following initial treatment with AXERT (almotriptan malate) in adolescents age 12-17 years is shown in Figure 3.

Figure 3. Estimated Probability of Achieving an Initial Headache Response (mild or no pain) in 2 Hours in the adolescent study

Estimated Probability of Achieving an Initial Headache Response (mild or no pain) in 2 Hours in the adolescent study - Illustration

The prevalence of the migraine-associated symptoms (nausea, photophobia, and phonophobia) at 2 hours after taking the dose was not significantly different between patients who received AXERT (almotriptan malate) 6.25 mg or 12.5mg and those who received placebo.

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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