Drug Criteria & Outcomes: Almotriptan Formulary Evaluation 

By Melissa Headrick, PharmD 
Written while on clinical rotation at Huntsville (AL) Hospital, Harrison School of Pharmacy at Auburn (AL) University

Triptans

• Almotriptan (Axert) — Pharmacia

• Sumatriptan (Imitrex) — GlaxoSmithKline

• Naratriptan (Amerge) — GlaxoSmithKline

• Rizatriptan (Maxalt, Maxalt MLT) — Merck

• Zolmitriptan (Zomig) — AstraZeneca

• Frovatriptan (Frova) — Elan

Description

Almotriptan malate (Axert) a selective 5-hydroxytryptamine1B/1D (5-HT1B/1D) receptor agonist, otherwise known as a "triptan," was approved by the U.S. Food and Drug Administration (FDA) in May 2001. Almotriptan is indicated for the acute treatment of migraine with or without aura in adults 18 years of age or older.

Mechanism of action

Almotriptan, like the other triptans, binds with high affinity to 5-HT1B/1D receptors on the extra-cerebral, intracrancial blood vessels that become dilated during a migraine attack. Activation of these receptors results in cranial vessel constriction, inhibition of neuropeptide release, and reduced transmission in trigeminal pain pathways.

Pharmacokinetics

Almotriptan has the highest oral bioavailability of all the current triptans. This drug undergoes metabolism in the liver to inactive metabolites. The remaining pharmacokinetic parameters of almotriptan and the triptans currently on the Huntsville Hospital formulary are shown in Table 1.

Clinical studies

Efficacy

Efficacy of almotriptan was based on three multicenter, randomized, double-blind, placebo-controlled trials conducted in Europe. Patients enrolled in study one were mostly female (85.3%) with a mean age of 40.5 years.

Study one

Patients were asked to treat a moderate- to-severe migraine headache with placebo, almotriptan 6.25 mg, or almotriptan 12.5 mg.

The percentage of patients achieving a response two hours after treatment was significantly greater in patients who received almotriptan 6.25 mg or 12.5 mg, compared to those patients who received placebo. A higher percentage of patients reported pain relief after taking the 12.5 mg dose than with the 6.25 mg dose, but statistical significance was not assessed (no P value reported).

Another endpoint was pain relief at measured time intervals. Almotriptan 6.25 mg was significantly superior in providing pain relief at hour 1, 1.5, and 2 as compared to placebo. This dose also showed significant pain freedom as compared to placebo at two hours after treatment initiation. Almotriptan 12.5 mg was significantly superior to placebo on all four measured time intervals. Patients who received this dose also had significantly better pain freedom compared to placebo at hour 1, 1.5, and 2 after treatment initiation. Patients in the almotriptan 6.25 mg group had significantly less migraine-associated symptoms (nausea, vomiting, photophobia, and phonophobia) at two hours compared to placebo.

Almotriptan 12.5 mg showed significantly less photophobia and phonophobia only. The results for study one are shown in Table 2.

Study two

Patients enrolled in study two were mostly female (86.5%) with a mean age of 42.1 years. Patients were asked to take almotriptan 12.5 mg or sumatriptan 100 mg for moderate or severe migraine pain. Patients who received almotriptan and sumatriptan showed a significantly better response two hours after treatment as compared to placebo. Patients in the almotriptan group had significantly more pain relief and pain freedom at two hours as compared to placebo (see Table 3). Sumatriptan and almotriptan response rates were not statistically compared. Almotriptan-treated patients showed significantly less migraine-associated symptoms two hours after treatment initiation. Sumatriptan significantly decreased nausea, photophobia, and phonophobia only. Equipotent doses of almotriptan and sumatriptan were not used in this study.

Study three

The population for study three was similar to the previous two studies (85.6% female with mean age of 40.6 years). Patients were asked to take almotriptan 6.25 mg or 12.5 mg for moderate or severe migraine pain. This study showed similar results as the two previous studies.

Both almotriptan 6.25 mg and 12.5 mg showed significantly better response rates two hours after treatment as compared to placebo, with the 12.5 mg dose showing higher response rates than the 6.25 mg dose. Both study groups also showed significantly better pain relief and pain freedom at hours 1.5 and 2 as compared to placebo. Patients in both active treatment groups had significantly less nausea, photophobia, and phonophobia two hours after treatment initiation. Results from this study are summarized in Table 4.

All almotriptan groups demonstrated significantly higher response rates than placebo in the three studies. Also, a higher percentage of patients reported pain relief after treatment with the 12.5 mg dose than with the 6.25 mg dose. The results from these trials with almotriptan doses higher than 12.5 mg are reported not to be significantly superior to this dose, but specific data are not available. Overall, the incidence of migraine-associated photophobia, phonophobia, nausea, and vomiting decreased in the almotriptan groups compared with the placebo group.

Meta-analysis

A meta-analysis of four double-blind, placebo-controlled clinical trials was reported in an abstract. A total of 2,294 patients were included. Patients taking almotriptan showed greater pain relief and pain freedom compared to placebo. The results of the meta-analysis are shown in Table 5.

The pooling of results for this meta-analysis could lead to bias because nonsignificant findings may not have been included. Specific patient data are not available to evaluate, which is another weakness.

Comparative efficacy

A single pre-release study that was performed to assess the efficacy of almotriptan also compared almotriptan to sumatriptan. The results are shown in the previous tables. As illustrated in Table 3, 57.1% of patients on almotriptan 12.5 mg tablets had pain relief after taking the drug, as compared to 63.2% of patients who took sumatriptan 100 mg. This difference was not statistically significant.

The only post-release published trial that compares almotriptan to another member of the triptan class is a randomized, double-blind, parallel-group, optimum-dose comparison of almotriptan versus sumatriptan conducted by Spierings, et al. This study included 1,173 patients with a history of migraine headaches with or without aura. The results of the two study medications’ ability to produce headache relief (defined as a decrease in pain intensity from moderate or severe at baseline to mild or no pain at the time of post-baseline assessment) and headache freedom (defined as a decrease in pain intensity from moderate or severe at baseline to no pain at the time of post-baseline assessment) are summarized in Table 6, below.

The difference between the two study medications’ ability to reduce migraine-associated symptoms (nausea, vomiting, photophobia, and phonophobia) was not statistically significant. Of the responders in the almotriptan-treated group, 27.4% had recurrence of moderate or severe migraine headache within 24 hours, as compared with 24.0% of patients in the sumatriptan-treated group. This difference was not statistically significant. A slightly greater percentage of patients in the almotriptan group required escape medication a well.

Treatment-emergent adverse events occurred in 15.2% of patients in the almotriptan group and 19.4% of patients in the sumatriptan group. This difference was not statistically significant. The authors of this trial concluded that almotriptan is similarly effective as compared to sumatriptan in the abortive treatment of moderate or severe migraines.

The study also concluded that almotriptan showed similar tolerability and safety. Patient randomization was not fully explained in the article, which is a possible weakness.

Percent of patients who experienced headache relief and freedom

Indications and dosing

The only FDA-approved indication for almotriptan is the acute treatment of migraine with or without aura in adults. This is the same indication that the other triptans have, except subcutaneous sumatriptan also is indicated for the treatment of cluster headache episodes.

The choice to administer the 6.25 mg dose or the 12.5 mg dose to adults with acute migraine should be made on an individual basis; however, in clinical studies, the 12.5 mg dose showed a greater increase in response rates. If the headache returns, the dose may be repeated after two hours, but should not exceed two doses (25 mg) in 24 hours.

Hepatic impairment: Pharmacokinetics have not been studied in this population. The decrease expected in the clearance of almotriptan in this population is 60%. Therefore, the starting dose of 6.25 mg should be used, and the maximum daily dose should not exceed 12.5 mg over a 24-hour period.

Renal impairment: The starting dose for this population is 6.25 mg. The maximum daily dose should not exceed 12.5 mg over a 24-hour period.

Adverse events

Incidence of adverse events in controlled clinical trials (reported in at least 1% of patients treated with almotriptan and at an incidence greater than placebo) is listed in Table 7. The numbers are the percentage of people reporting the event (as reported in the package insert).

Adverse events

Table 8, below, compares the adverse effects of the current triptans in the Huntsville Hospital formulary interchange program, including almo-triptan. Reported adverse effects are similar among the five drugs. A complete list of adverse events can be found in the package insert.

Adverse effects of five triptans in the Huntsville Hospital formulary interchange program

The manufacturer of almotriptan has focused on the decreased incidence of chest pain associated with almotriptan as compared to sumatriptan. In the previously mentioned study by Spierings et al., with patients randomized to either almotriptan 12.5 mg or sumatriptan 50 mg, treatment-emergent adverse events that involve the cardiovascular system were evaluated. The occurrence of these adverse events was low in both treatment groups.

No P values were reported for this information. Symptoms of chest pain also were specifically reported in this study in both treatment groups. The difference between the two groups for chest pain was significantly less for the almotriptan group (almotriptan 12.5 mg: 0.3% vs. sumatriptan 50 mg: 2.2%, P = 0.004); however, almotriptan is contraindicated in patients with any type of ischemic heart disease, as are the other triptans.

Contraindications

Almotriptan shares several contraindications with other triptans, such as its use in ischemic heart disease, concurrent ergotamine use, and concurrent serotonin agonist use (see Table 9); however, its use is not contraindicated with concomitant MAO inhibitors.

Contraindications of triptans (Almotriptan + Huntsville Hospital Formulary Exchange Drugs

Drug interactions

Drug-drug interactions involving the triptans are summarized in Table 10.

Cost/usage

Current cost of almotriptan to the hospital is approximately 25% less than the current formulary triptan zolmitriptan. Almotriptan’s hospital usage has been low up to this time. (The main usage of this drug class is for employee outpatient prescriptions.)

Summary and recommendations

Almotriptan’s pharmacokinetic profile does not differ to a great extent from the other triptans currently in the formulary interchange program. There are no controlled trials that directly compare almotriptan to the current workhorse triptan zolmitriptan. However, there are several trials that compare almotriptan to sumatriptan, to which both drugs showed similar efficacy and safety.

Almotriptan 6.25 mg and 12.5 mg tablets currently are less expensive to purchase than zolmitriptan 2.5 mg and 5 mg. Almotriptan use at Huntsville Hospital has up to now been extremely low. Also, the majority of zolmitriptan that has been dispensed was for outpatient use (from the pharmacy for hospital employees) and does not reflect use in actual hospital inpatients.

Because almotriptan is a newly released drug, and there has been little experience with it at Huntsville Hospital, almotriptan should be added to the current triptan formulary interchange program (see Table 11). Until additional outpatient experience with almotriptan is gained, zolmitriptan should remain the triptan workhorse drug.

References

• Agents for Migraine: Serotonin 5-HT1 Receptor Agonists. Drug Facts and Comparisons. Facts and Comparisons 2001; 849-856.

• Almotriptan. Drugdex Drug Evaluations. Vol. 2 Update (cited Oct. 2, 2001). Available at: www.micromedex.com.

• Baty S. Huntsville Hospital Triptan Formulary Evaluation. Presented to Huntsville Hospital Pharmacy and Therapeutics Committee; 2000.

• Cada DJ, Levien T, Baker DE. Almotriptan malate. Hospital Pharmacy 2001; 36:1066-1074.

• Kehoe WA. New drug: Almotriptan (Axert). Pharmacist’s Letter 2001; 17:39.

• Spierings EL, Gomez-Mancilla B, Grosz DE, et al. Oral almotriptan versus oral sumatriptan in the abortive treatment of migraine: A double-blind, randomized, parallel-group, optimum-dose comparison. Arch Neur 2001; 58:944-950.

• Hall C. Personal communication. Pharmacy buyer. Huntsville (AL) Hospital System Pharmacy; October 2001.

• Pharmacia. Almotriptan package insert. Kalamazoo, MI; 2001.

• Pharmacia. Almotriptan (Axert) product information. Kalamazoo, MI; 2001.