Despite the widespread use of triptans ... REPORTS... Almotriptan: A Review of Pharmacology, Clinical Efficacy, and Tolerability

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1 ... REPORTS... Almotriptan: A Review of Pharmacology, Clinical Efficacy, and Tolerability Randal L. Von Seggern, PharmD, BCPS Abstract Objective: This article summarizes preclinical and clinical data for almotriptan. Methods: Almotriptan has been evaluated in more than 3500 acute migraine patients in phase 2 and 3 double-blind, randomized trials and in 1500 patients in long-term open-label trials. Results: Controlled clinical trials show that almotriptan 12.5 mg is significantly more effective than placebo. These results are observed across different endpoints examined, including pain relief at 2 hours, pain-free outcome at 2 hours, recurrence rate, use of escape medication, and sustained pain-free outcome. The onset of pain relief is observed as early as 30 minutes after administration. Results from a multiple-attack study show that almotriptan maintains a consistency of response across 3 attacks, and results from long-term studies confirm that patients continue to respond to almotriptan for up to 1 year. Results from 2 comparative studies show that almotriptan 12.5 mg has comparable efficacy to sumatriptan 50 or 100 mg, but almotriptan has a superior tolerability profile. Early use of almotriptan results in a higher proportion of patients achieving pain relief or complete freedom from pain. Conclusions: Because almotriptan has a tolerability profile comparable to that of placebo, it may be more acceptable for early administration. The incidence of treatment-related adverse events with almotriptan is comparable to that of placebo and significantly lower than recorded with sumatriptan. In addition, almotriptan has a low incidence of chest symptoms, an adverse event associated with triptan use. Because of its comparable efficacy and superior tolerability profile, almotriptan offers a potential improvement over existing triptans for the treatment of acute migraine. (Am J Manag Care 2002;8:S74 S79) Despite the widespread use of triptans for acute migraine treatment and a favorable response by the majority of patients, many patients continue to report unmet needs for acute migraine. 1 When surveyed about their treatment expectations for acute migraine, patients report a need for therapy that is rapidly effective, relieves pain completely, has a low recurrence rate, and is well tolerated. 1 Although triptans offer many of these attributes, a recent survey from the National Headache Foundation indicated that patients remain dissatisfied (see article by Gallagher and Cutrer in this supplement). Almotriptan is the most recent 5- HT 1B/1D receptor agonist marketed for the treatment of acute migraine. Preclinical studies indicate that almotriptan is highly selective for meningeal arteries, with a lower affinity for cardiac, pulmonary, and other peripheral arterial beds. 2 Almotriptan has been evaluated in more than 3500 acute migraine patients in phase 2 and 3 double-blind, randomized trials and in an additional 1500 patients in long-term openlabel trials. Results from these trials indicate that almotriptan 12.5 mg is effective for the treatment of acute migraine, with a rapid onset of activity and a tolerability profile comparable to placebo. This article summarizes the preclinical and clinical data for almotriptan. Pharmacology Similar to other triptans, almotriptan exerts potent vasoconstrictor activity on 5- HT 1B/1D receptor sites in meningeal arteries. 3 According to studies in isolated human arteries, almotriptan was at least as potent as sumatriptan in meningeal arteries but significantly less potent than sumatriptan in coronary and pulmonary arteries. 2 S74 THE AMERICAN JOURNAL OF MANAGED CARE FEBRUARY 2002

2 Almotriptan: A Review of Pharmacology, Clinical Efficacy, and Tolerability Almotriptan is well absorbed after oral administration, with an oral bioavailability of 70%. 4 The absorption of almotriptan is not affected by food, age, gender, or administration during or after a migraine attack. 5-7 Although peak plasma levels of almotriptan occur at 2.5 hours, the onset of pain relief has been observed within 30 minutes of administration. 8 Almotriptan is eliminated by both renal elimination and hepatic metabolism. 9 Approximately 55% is excreted unchanged via urine and stool and the remaining 45% is metabolized by monoamine oxidase-a and the cytochrome P-450 system. The elimination half-life of almotriptan is 3 to 4 hours. 4 The drug-interaction potential of almotriptan coadministered with fluoxetine, verapamil, propranolol, and moclobemide, a monoamine oxidase-a inhibitor, has been evaluated in human volunteers No clinically relevant change in the pharmacokinetic profile of almotriptan was noted, and no dosage modification is recommended when almotriptan is taken with other drugs. Almotriptan has been evaluated in a number of phase 1 studies in healthy volunteers. 6,7,9,14 Almotriptan was found to be well tolerated in elderly patients and in those with varying degrees of renal impairment. 6,7 Further, no clinically relevant adverse effects on the cardiovascular system were observed at doses up to 200 mg in either healthy volunteers or patients with acute migraine. 9,14,15 Clinical Efficacy The efficacy of almotriptan has been evaluated in 4 double-blind, randomized trials of patients satisfying International Headache Society (IHS) criteria for moderate-to-severe acute migraine (Table 1). 8,16-18 Three trials were placebo controlled, including 1 trial that had a sumatriptan 100-mg comparator group 17 and 1 trial that assessed the response across 3 successive episodes of acute migraine. 18 A fourth trial compared almotriptan 12.5 mg and sumatriptan 50 mg. 16 In a dose-finding study, patients with moderate-to-severe acute migraine were randomized to placebo or oral almotriptan 2, 6.25, 12.5, or 25 mg. 8 Of 742 patients evaluated, pain relief at 2 hours was 32.5% with placebo and 30%, 56.3%, 58.5%, and 66.5% with almotriptan 2-, 6.25-, 12.5-, and 25-mg doses, respectively (P <.05 for 6.25, 12.5, and 25 mg versus placebo). The onset of pain relief was observed at 30 minutes with almotriptan 12.5 mg. The percentage of patients who were completely pain free at 2 hours was 37.8% and 45.3% in the 12.5 and 25 mg almotriptan groups, respectively, compared with 11.3% in the placebo group (Figure 1). The incidence of adverse events with the almotriptan 2-, 6.25-, and 12.5-mg groups was comparable to that with the placebo group. Almotriptan 12.5 mg had the most favorable ratio between efficacy and tolerability. The efficacy and tolerability of single doses of almotriptan 6.25 and 12.5 mg were evaluated in 722 patients who were treated for 3 consecutive moderate-tosevere migraine attacks. 18 Significant pain relief was noted as early as 1 hour with almotriptan. Across all migraine attacks, pain relief at 2 hours was achieved in 60% of patients with almotriptan 6.25 mg, 70% with almotriptan 12.5 mg, and 38% with placebo (P <.001). Pain relief at 2 hours Table 1. Summary of Double-Blind, Randomized Trials of Almotriptan for the Treatment of Moderate-to-Severe Acute Migraine Reference Treatment Regimens Number of Patients Dahlöf et al, Placebo 80 Almotriptan 2 mg 170 Almotriptan 6.25 mg 167 Almotriptan 12.5 mg 164 Almotriptan 25 mg 161 Dowson, Placebo 99 Almotriptan 12.5 mg 183 Almotriptan 25 mg 191 Sumatriptan 100 mg 194 Pascual et al, Placebo 131 Almotriptan 6.25 mg 287 Almotriptan 12.5 mg 304 Spierings et al, Almotriptan 12.5 mg 591 Sumatriptan 50 mg 582 VOL. 8, NO. 3, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S75

3 REPORTS was achieved in 75% of patie nts for 2 of 3 attacks and in 49% of patients for 3 of 3 attacks. Across all attacks, 38.8% of patients with almotriptan 12.5 mg and 29.9% with almotriptan 6.25 mg were pain free at 2 hours compared with 15.5% with placebo (P <.001; Figure 2). Recurrence Figure 1. Percentage of Patients Pain Free After Treatment With Almotriptan or Placebo Patients (%) Placebo Almotriptan 2 mg Almotriptan 6.25 mg Almotriptan 12.5 mg Almotriptan 25 mg Assessment Time (Hours) P <.0001, Cochran-Mantel-Haenszel test for all doses of almotriptan at 1, 1.5, and 2 hours. Figure 2. Percentage of Patients Pain Free at 2 Hours Across 3 Consecutive Migraine Attacks With Almotriptan and Placebo P <.001 for comparisons of almotriptan 6.25 and 12.5 mg versus placebo. Source: Reference 18. rates were 28.7% and 30.1% with almotriptan 6.25 and 12.5 mg, respectively, and 23.3% with placebo. The incidence of treatment-related adverse events and discontinuation for adverse events with almotriptan was comparable to that of placebo. Thus, almotriptan 12.5 mg demonstrated a consistent response across multiple migraine attacks and offered the optimal balance of efficacy and tolerability. Almotriptan 12.5 and 25 mg and sumatriptan 100 mg were compared in a placebo-controlled trial of 668 patients. 17 At 2 hours, pain relief was recorded in 58% to 64% of patients in active treatment groups compared with 42% of patients on placebo (Figure 3). Freedom from pain at 2 hours was noted in 28%, 35%, and 34% of patients in the almotriptan 12.5-, 25-, and sumatriptan 100-mg groups, respectively, and in 15% of patients in the placebo group. The recurrence rate was 18.0% and 15.4% with almotriptan 12.5 and 25 mg, respectively, 24.6% with sumatriptan, and 19.5% with placebo. The incidence of any adverse event was comparable with almotriptan 12.5 mg (8.7%) and placebo (6.1%). Spierings et al 16 reported the results from a comparison of almotriptan 12.5 mg and sumatriptan 50 mg in 1173 patients. At 2 hours, pain relief was recorded in 58.0% of almotriptan-treated and 57.3% of sumatriptan-treated patients. No significant differences among groups were observed in recurrence rate (27.4% almotriptan and 24.0% sumatriptan), use of rescue medication, or incidence of migraine-associated symptoms. Significantly more patients treated with sumatriptan were pain free at 2 hours (24.6% versus 17.9%, P =.005). Whereas the incidence of all treatment-related adverse events was 15.5% with sumatriptan and 9.1% with almotriptan (P =.001), the incidence of chest pain was 2.2% with sumatriptan and 0.3% with almotriptan (P =.004). Thus, almotriptan and sumatriptan exhibited comparable efficacy, but almotriptan was better tolerated (Figure 4). Sustained pain-free outcome has been identified by the IHS as more relevant than pain relief to patient needs. 19 S76 THE AMERICAN JOURNAL OF MANAGED CARE FEBRUARY 2002

4 Almotriptan: A Review of Pharmacology, Clinical Efficacy, and Tolerability Sustained pain-free outcome is defined as a decrease in pain severity from moderate or severe at baseline to no pain at 2 hours postdose and without relapse or the use of escape medication between 2 and 24 hours. A pooled analysis of 3 randomized, double-blind, placebo-controlled trials of almotriptan was conducted to examine the sustained pain-free outcome. 20 Among 1791 patients, the proportion achieving a sustained pain-free state was significantly (P <.05) higher in the almotriptan 6.25 mg (21.7% to 22.5%) and 12.5 mg (24.6% to 27.6%) groups than in the placebo group (7.5% to 12.1%). The proportion of patients achieving a sustained pain-free state was comparable between the almotriptan mg (24.6%) and sumatriptan 100-mg (28.5%) groups. Thus, almotriptan 12.5 mg was significantly better than placebo and comparable to sumatriptan 100 mg for achieving a sustained pain-free state. Two open-label, long-term trials have been completed with almotriptan. 21,22 One study, which included 762 patients, evaluated 13,751 migraine attacks of any intensity treated with almotriptan 12.5 mg over a 1-year period. 21 Pain relief and pain-free rates at 2 hours were 84% and 58% of attacks, respectively. Treatment-related adverse events were reported in 29% of patients, but most were of mild intensity and were transient. A post hoc analysis from this study was performed in 118 patients who had been treated for at least 3 attacks of mild intensity and 3 of moderate or severe intensity (J. Pascual, unpublished data, 2001). At 1 hour, 47% of mild attacks and 14% of moderate-tosevere attacks were pain free (P <.001). In addition, lower recurrence rates and use of escape medication were observed with mild attacks. This study suggests that early intervention with almotriptan when migraine pain is of mild, rather than moderate or severe, intensity results in an improved response. The second study was a 6-month openlabel trial of almotriptan 12.5 mg. 22 Among 582 patients, the most frequent drug-related adverse events were nausea (3.1%) and dizziness (2.4%). Adverse events led to discontinuation of treatment in 36 (6.2%) patients. Drug-related chest pain was reported in 9 (1.5%) patients. No serious drug-related adverse events were reported and no deaths occurred. Pain relief at 2 hours was reported for 76% of all migraine attacks, and 49% were pain free at 2 hours after the first drug dose. Figure 3. Percentage of Patients With Pain Relief or Pain Free at 2 Hours All active groups significantly (P <.05) different from placebo. Source: Reference 17. Figure 4. Results From Efficacy and Tolerability Assessments of Sumatriptan 50 mg and Almotriptan 12.5 mg AE = adverse event. Source: Reference 16. VOL. 8, NO. 3, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S77

5 REPORTS Table 2. Incidence of Adverse Events Occurring in at Least 1% of Patients in Placebo-Controlled Trials of Almotriptan ALM ALM ALM SMT Placebo 6.25 mg 12.5 mg 25 mg 50 mg (N = 386) (N = 527) (N = 1313) (N = 387) (N = 582) Adverse Event n (%) n (%) n (%) n (%) n (%) Body Asthenia 3 (0.8) 4 (0.8) 9 (0.7) 10 (2.6) 2 (0.3) Chest pain 1 (0.3) 1 (0.2) 3 (0.2) 5 (1.3) 13 (2.2) Headache 4 (1.0) 4 (0.8) 15 (1.1) 3 (0.8) 9 (1.5) Localized pain 1 (0.3) 2 (0.4) 8 (0.6) 5 (1.3) 3 (0.5) Cardiovascular Palpitation 2 (0.5) 4 (0.8) 3 (0.2) 7 (1.8) 0 Vasodilation 0 2 (0.4) 9 (0.7) 4 (1.0) 8 (1.4) Digestive Dry mouth 2 (0.5) 6 (1.1) 9 (0.7) 4 (1.0) 4 (0.7) Nausea 5 (1.3) 4 (0.8) 26 (2.0) 6 (1.6) 20 (3.4) Nervous Dizziness 7 (1.8) 7 (1.3) 22 (1.7) 8 (2.1) 10 (1.7) Paresthesia 2 (0.5) 6 (1.1) 16 (1.2) 4 (1.0) 5 (0.9) Somnolence 4 (1.0) 3 (0.6) 17 (1.3) 9 (2.3) 11 (1.9) ALM = almotriptan; SMT = sumatriptan. Source: Reference 23. Tolerability Overall, almotriptan demonstrates a tolerability profile comparable to placebo. A pooled analysis assessed the safety and tolerability of almotriptan from phase 1, 2, and 3 studies. 15 Phase 2 and 3 studies included more than 2500 patients who were treated for over 15,000 migraine attacks. Adverse events occurring in at least 1% of patients treated with almotriptan are listed in Table Most adverse events were of mild-to-moderate intensity. The incidence of adverse events with almotriptan 12.5 mg and placebo was comparable. In both comparative trials of almotriptan and sumatriptan, the incidence of treatment-related adverse events was significantly higher with sumatriptan. 16,17 In phase 3 trials, the incidence of chest symptoms with almotriptan was 0.2%. In phase 1 trials in healthy volunteers, no significant cardiovascular safety issues were recorded, including electrocardiographic abnormalities or clinically relevant changes in blood pressure. 15 Conclusion Based on results from controlled clinical trials in more than 3000 patients, almotriptan 12.5 mg is significantly more effective than placebo. These results are observed across different endpoints examined, including pain relief at 2 hours, pain free at 2 hours, recurrence rate, use of escape medication, and sustained painfree outcome. The onset of pain relief is observed as early as 30 minutes after administration. Results from a multipleattack study show that almotriptan maintains a consistency of response across 3 attacks, and results from long-term studies confirm that patients continue to respond to almotriptan for up to 1 year. Results from 2 comparative studies show that almotriptan 12.5 mg has comparable efficacy to sumatriptan 50 or 100 mg, but almotriptan has a superior tolerability profile. Early use of almotriptan results in a higher proportion of patients achieving pain relief or complete freedom from pain. The incidence of treatment-related adverse events with almotriptan is comparable to that of placebo and significantly lower than that recorded with sumatriptan. In addition, almotriptan has a low incidence of chest symptoms. Because of its comparable efficacy and superior tolerability profile, almotriptan offers a potential improvement over existing triptans for the treatment of acute migraine.... REFERENCES Lipton RB, Stewart WF. Acute migraine therapy: Do doctors understand what patients with migraine want from therapy? Headache 1999;39(suppl 2):S20- S Bou J, Gras J, Cortijo J, Morcillo EJ, Llenas J, Palacios JM. Vascular effects of the new anti-migraine agent almotriptan on human cranial and peripheral arteries. Cephalalgia 2001;21: Bou J, Domenech T, Puig J, et al. Pharmacological characterization of almotriptan: An indolic 5-HT receptor agonist for the treatment of migraine. Eur J Pharmacol 2000;410: Fernandez FJ, Jansat JM, Cabarrocas X, Costa J, Salva P. Absolute bioavailability of oral and subcutaneous almotriptan [abstract]. Cephalalgia 1999;19:363. S78 THE AMERICAN JOURNAL OF MANAGED CARE FEBRUARY 2002

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