Axert (Almotriptan Malate) - Description and Clinical Pharmacology

DESCRIPTION

AXERT^® (almotriptan malate) Tablets contain almotriptan malate, a selective 5-hydroxytryptamine_1B/1D (5-HT_1B/1D) receptor agonist. Almotriptan malate is chemically designated as 1-[[[3-[2-(Dimethylamino)ethyl]-1H-indol-5-yl]methyl]sulfonyl]pyrrolidine (±)-hydroxybutanedioate (1:1) and its structural formula is:

Its empirical formula is C₁₇H₂₅N₃O₂S-C₄H₆O₅, representing a molecular weight of 469.56. Almotriptan is a white to slightly yellow crystalline powder that is soluble in water. AXERT^® for oral administration contains almotriptan malate equivalent to 6.25 or 12.5 mg of almotriptan. Each compressed tablet contains the following inactive ingredients: carnauba wax, cellulose, FD&C Blue No. 2 (12.5 mg only), hypromellose, iron oxide (6.25 mg only), mannitol, polyethylene glycol, povidone, propylene glycol, sodium starch glycolate, sodium stearyl fumarate and titanium dioxide.

CLINICAL PHARMACOLOGY

Mechanism of Action

Almotriptan binds with high affinity to 5-HT_1D, 5-HT_1B, and 5-HT_1F receptors. Almotriptan has 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.

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-HT_1B/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

Co-administration of almotriptan and moclobemide (150 mg twice daily for 8 days) resulted in a 27% decrease in almotriptan clearance and an increase in C_max of approximately 6%. No dose adjustment is necessary.

Propranolol

Co-administration of almotriptan and propranolol (80 mg twice daily for 7 days) resulted in no significant changes in the pharmacokinetics of almotriptan.

Fluoxetine

Co-administration 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 18%. This difference is not clinically significant.

Verapamil

Co-administration 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

Co-administration 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 hours vs. 3.2 hours) 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 were observed in pharmacokinetic parameters.

Race

No significant differences were 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/hour; creatinine clearance between 10 and 30 mL/min) and approximately 40% lower in patients with moderate renal impairment (Cl/F=34.2 L/hour; creatinine clearance between 31 and 71 mL/min) than in healthy volunteers (Cl/F=57 L/hour). Maximal plasma concentrations of almotriptan increased by approximately 80% in these patients [see Dosage and Administration].

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.

CLINICAL STUDIES

Adults

The efficacy of AXERT^® (almotriptan malate) was established in three 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 no pain, the patient was allowed to take an escape medication. If the pain had decreased to mild or 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^® 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 a significantly better response. These results are summarized in Table 3.

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

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

The estimated probability of achieving pain relief within 2 hours following initial treatment with AXERT^® 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

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^® 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

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^®.

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, and tricyclic antidepressants); or oral contraceptives. There were insufficient data to assess the effect of race on efficacy.

Adolescents Age 12 to 17 Years

The efficacy of AXERT^® in adolescent patients age 12 to 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^® 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 to 17 Years

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

The estimated probability of achieving pain relief within 2 hours following initial treatment with AXERT^® in adolescents age 12 to 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

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^® 6.25 mg or 12.5 mg and those who received placebo.