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Drugs

, Volume 62, Issue 2, pp 387–414 | Cite as

Almotriptan

A Review of its Use in Migraine
  • Susan J. KeamEmail author
  • Karen L. Goa
  • David P. Figgitt
Adis New Drug Profile

Summary

Abstract

Almotriptan is a selective serotonin 5-HT1b/1d receptor agonist (‘triptan’). Its efficacy and tolerability have been assessed in a number of randomised, controlled trials in over 4800 adults with moderate or severe attacks of migraine.

Oral almotriptan has a rapid onset of action (significant headache relief is observed 0.5 hours after administration of a 12.5mg dose) and efficacy is sustained in most patients who respond by 2 hours. The drug is significantly more effective than placebo as measured by a number of parameters including 2-hour headache response and pain-free response rates. Other symptoms of migraine, including nausea, photophobia and phonophobia, are also alleviated by almotriptan.

The efficacy of oral almotriptan appears to be maintained over repeated doses for multiple attacks of migraine treated over a long period (up to 1 year). High headache response rates were reported over all attacks without tachyphylaxis.

For the relief of single attacks of migraine, oral almotriptan 12.5mg had similar efficacy to oral sumatriptan 50mg. Patients given almotriptan report less concern with adverse effects than patients given sumatriptan. The lower incidence of chest pain following treatment with almotriptan than with sumatriptan may lead to a reduction in direct costs, with fewer patients requiring management of chest pain.

Almotriptan is well tolerated. Most adverse events were of mild or moderate intensity, transient, and generally resolved without intervention or the need for treatment withdrawal. The most common adverse events associated with oral almotriptan 12.5mg treatment were dizziness, paraesthesia, nausea, fatigue, headache, somnolence, skeletal pain, vomiting and chest symptoms. The incidence of adverse events did not differ from placebo and decreased in the longer term.

Almotriptan can be coadministered with drugs that share a common hepatic metabolic path; in addition, dosage reduction is required only in the presence of severe renal or hepatic impairment.

Conclusions: Almotriptan is an effective drug for the acute treatment of moderate or severe attacks of migraine in adults. An oral dose of almotriptan 12.5mg has shown greater efficacy than placebo; current data indicate that efficacy is similar to that of oral sumatriptan 50mg, and is maintained in the long term (≤ 1 year). Almotriptan has a good adverse event profile and a generally similar overall tolerability profile to sumatriptan; of note, almotriptan is associated with a significantly lower incidence of chest pain than sumatriptan. However, further clinical experience is required to clearly define the place of almotriptan among the other currently available triptans. Nevertheless, because triptans have an important place in various management regimens, and because the nature of individual patient response to triptans is idiosyncratic, almotriptan is likely to become a useful treatment option in the management of adults with moderate or severe migraine headaches.

Pharmacodynamic Properties

Almotriptan has a high and specific affinity for serotonin 5-HT1b/1d receptors, with similar affinity for both 5-HT receptor subtypes demonstrated by specific radioligand displacement assays. The concentration of almotriptan required to inhibit the binding of a ligand by 50% for cloned human 5-HT1b and 5-HT in1d receptors was 0.012 and 0.013 μmol/L, respectively. The drug also has a high affinity for 5-HT1f receptors, and a weak affinity for 5-HT1a and 5-HT7 receptors, but little or low affinity for a wide range of other receptors.

Drugs used in the acute treatment of migraine cause vasoconstriction of the cranial blood vessels and redistribution of cranial blood flow as one of their major effects. Almotriptan induced potent constriction in a number of isolated vascular preparations containing 5-HT1b/1d receptors. The concentration of almotriptan required to produce 50% of maximum contraction in human meningeal and temporal arteries was 0.03 and 0.7 μmol/L respectively. The maximum contraction of coronary and pulmonary arteries with almotriptan was significantly lower than with sumatriptan (p < 0.05), as was that of basilar artery tissue (p < 0.001).

Reduction in carotid arterial blood flow with almotriptan in animal models was caused through constriction of carotid arteriovenous anastomoses. Almotriptan also induced a significant increase in cerebral blood flow and a reduction in blood flow through extracerebral cranial vessels.

The inhibition of neurogenic inflammation is thought to be relevant in managing the pain of migraine headache. Various animal models have shown that almotriptan has the ability to inhibit both peripheral and central trigeminovascular activity, which prevents the release of vasoactive neuropeptides that cause vasodilation and inflammation of the blood vessel walls of the dura mater.

Single doses of oral almotriptan at the optimal therapeutic dose (12.5mg) had no statistically or clinically significant effects on blood pressure, heart rate or ECG parameters in young and elderly healthy volunteers. Although doses of almotriptan 25 and 50mg resulted in small increases in blood pressure, these changes were not clinically important.

Pharmacokinetic Properties

Oral almotriptan is absorbed moderately rapidly in healthy volunteers [maximum plasma concentrations (Cmax) were achieved between 1.4 and 3.8 hours with single doses of almotriptan 5 to 200mg]. After administration of a single dose of oral almotriptan 12.5mg, the Cmax of 29 to 50 μg/L was reached in a time of 2.2 to 2.5 hours. Absorption of oral almotriptan does not appear to be slowed during an acute attack of migraine. Area under the plasma concentration-time curve (AUC) and Cmax values show dose proportionality over the range of almotriptan 5 to 200mg; AUC after a single dose of oral almotriptan 12.5mg was 0.229 to 0.266 mg · h/L. Food had no significant effect on the oral absorption of almotriptan 25mg.

In healthy volunteers, the mean absolute bioavailability of oral almotriptan 25mg is approximately 70%; the relative bioavailability of almotriptan 5 to 200mg is approximately 80%.

Almotriptan is cleared by hepatic metabolism, with faecal and urinary excretion of its metabolites and renal excretion of the unchanged drug occurring in almost equal proportions. It has two major metabolites (a γ-aminobutyric acid and an indoleacetic acid derivative) and three minor metabolites (an N-demethyl, an alcohol and an N-oxide derivative, identified in vitro), all of which appear to be inactive. Almotriptan is primarily metabolised by monoamine oxidase A (MAO-A) and the cytochrome P450 (CYP) isoenzyme 3A subfamily, with some contribution by CYP2D6. Almotriptan is rapidly eliminated from the body. The mean plasma elimination half-life (t½) is about 3.1 to 4 hours, after a single 12.5mg oral dose. Approximately 40 to 50% of a dose of almotriptan is excreted unchanged in urine; renal clearance is about 75% of total body clearance.

Changes in the pharmacokinetics of almotriptan in patients with mild or moderate renal failure are reported not to be clinically important. The pharmacokinetics of almotriptan have not been studied in patients with hepatic impairment because researchers predict that the changes in pharmacokinetic parameters with hepatic impairment are unlikely to exceed those seen with patients who have severe renal impairment. However, patients with severe renal failure [creatinine clearance < 1.8 L/h (< 30 ml/min)] or hepatic failure are likely to have increased systemic exposure to almotriptan, resulting from a prolonged t½ and an increased mean AUC.

Although renal clearance of almotriptan is reduced in the elderly, dosage adjustments are not required. No statistically significant gender-related differences in the pharmacokinetics of almotriptan have been demonstrated.

Clinical Efficacy

The therapeutic efficacy of orally administered almotriptan has been evaluated in more than 4800 adults with moderate to severe attacks of migraine in randomised, controlled trials.

Almotriptan 12.5mg has a rapid onset of action, with significant headache relief reported at 0.5 hours (p < 0.05). A single dose of almotriptan is consistently significantly more effective than placebo in relieving single episodes of moderate or severe migraine headache as measured using a number of endpoints. Headache response rates at 2 hours (the primary efficacy parameter of most migraine trials) after administration of almotriptan 12.5mg ranged between 57 and 65% for single or first attacks of migraine, and were significantly greater than those seen with placebo (32 to 42%).

Pain-free response rates at 2 hours were also increased by almotriptan 12.5mg when compared with placebo (38 and 39 vs 11 and 16%), and efficacy was maintained for 24 hours in a high proportion of patients who responded at 2 hours. Of those who relapsed, the majority responded to a second dose of medication and remained pain free. Nausea, photophobia and phonophobia associated with migraine are significantly improved following almotriptan administration.

The efficacy of almotriptan appears to be maintained after repeated doses for multiple attacks of migraine over a period of up to 12 months with high headache response rates (76 and 84%) reported over all attacks in two noncomparative studies. Almotriptan also appears to be effective in treating mild or moderate migraine headaches, with early intervention reducing the need for rescue or relapse medication. Headache and pain-free response is consistent over time, with no tachyphylaxis to almotriptan treatment developing.

Almotriptan 12.5mg appears to have a similar efficacy to sumatriptan 50mg, the optimal oral dose for each drug. Similar headache response rates were seen at 2 hours (58 vs 57.3%), although almotriptan was less effective than sumatriptan at achieving a pain-free response at 2 hours (17.9 vs 24.6%; p = 0.005). There was no significant difference between the two drugs in alleviation of migraine-related symptoms, the need for rescue medication, or recurrence of moderate or severe headache. According to the results of a Migraine-Specific Quality of Life Questionnaire, adverse effects are of significantly less concern to patients treated with almotriptan when compared with sumatriptan.

Tolerability

Results of several large trials (n > 2000), and two long-term studies (n > 1300), indicate that almotriptan is well tolerated. Adverse events were mainly mild or moderate in intensity, transient, generally did not require intervention or treatment withdrawal and were less frequent with time.

The most common adverse events with almotriptan 12.5mg were dizziness (2.7%), paraesthesia (2.7%), nausea (1.9%), fatigue, headache, somnolence, skeletal pain and vomiting (all 1.6%). The incidence of these events did not differ significantly from that with placebo. When consecutive attacks of migraine were treated with almotriptan or placebo, the incidence of adverse events reported in both study groups decreased with each attack treated.

The adverse events profile of almotriptan and sumatriptan in doses demonstrating equivalent efficacy was similar, the only significant difference being a lower occurrence of chest pain after administration of almotriptan. The frequency of treatment-emergent adverse events in patients given oral almotriptan 12.5mg (n = 591) or oral sumatriptan 50mg (n = 582) was similar (15.2 vs 19.4%), with the most common adverse events in the almotriptan group being nausea (2.2 vs 3.4%), dizziness (2.0 vs 1.7%), headache (1.4 vs 1.5%) and somnolence (1.4 vs 1.9%). Patients treated with oral almotriptan 12.5mg (n = 184) or placebo (n = 99) reported fewer adverse events than the group treated with almotriptan 25mg (n= 191) [10.9 and 10.1%, respectively, vs 20.9%; p< 0.05 for both comparisons]. The incidence of adverse events reported after oral sumatriptan 100mg treatment (23.7%, n = 194) was similar to that with almotriptan 25mg, and significantly greater (p < 0.05) than that with almotriptan 12.5mg or placebo.

The good tolerability of almotriptan appears to persist, and the incidence of adverse events may decrease in the longer term. Over a 1-year period, the most frequent adverse events were vomiting (2.1%), nausea (1.4%), dizziness (1.6%), somnolence (1.7%), fatigue (1.4%) and chest symptoms (1.6%). Very few patients (60 out of 1347 patients) withdrew from long-term clinical trials as a result of adverse events; <1% of withdrawals from the 1-year trial were considered to be because of almotriptan. Almotriptan has not been associated with any clinically significant changes in clinical chemistry, haematology or urinalysis.

Overall, almotriptan was associated with a low incidence of adverse events relating to the cardiovascular system. When oral almotriptan 12.5mg was compared with sumatriptan 50mg (n = 1173), the incidence of chest-related adverse events (including vasodilation, palpitations, tachycardia and abnormal cardiac rhythm) with both treatments was low (<2.5%); chest pain was experienced significantly less often with almotriptan than with sumatriptan (0.3 vs 2.2%; p = 0.004). In a large double-blind study (n = 908), one patient developed transient symptomatic coronary ischaemia after a third dose of almotriptan 6.25mg. Significant risk factors, including a strong family history of heart disease and unsupervised use of oral contraceptives, were thought to have contributed to the event. In a 1-year study (n = 762), nine significant cardiovascular events were reported, including a conduction abnormality, palpitations, tachycardia and hypertension. 31 incidents of chest symptoms were reported in 12 patients; 20 were considered to be almotriptan related. Patients given single doses of almotriptan 5 to 150mg (n = 169) and 12.5mg (n = 591) show no clinically significant changes in ECG parameters or vital signs.

Pharmacoeconomic Studies: Compared with sumatriptan, direct cost savings are more likely when migraine headache is treated with almotriptan because of a lower incidence of chest-related symptoms and the associated costs of investigating them. A retrospective, population-based study using a computer-based model estimated that if patients had been treated with oral almotriptan 12.5mg instead of oral sumatriptan 25 and 50mg, direct annual medical cost savings for managing chest pain would have been $US 11.22 per patient, from the perspective of a health plan with one million covered lives (data reported as an abstract) [estimates based on costs for investigation of chest pain between 1996 and 1998; incidence of chest pain taken from a large (n = 1173) comparative study]. Analysis of data from a large (n = 1173) study using computer-based models (reported as abstracts) indicate that there is potential to reduce the likely direct, annual medical costs of managing chest pain, if patients are treated with oral almotriptan 12.5mg instead of oral sumatriptan 50mg.

Drug Interactions

Coadministration of a single oral dose of almotriptan 12.5mg with various other agents that are commonly used in the prevention of migraine (propranolol, verapamil), with antidepressants (moclobemide, fluoxetine) and with the potent CYP3A4 inhibitor ketoconazole, does not result in any clinically significant drug reactions. Administration of almotriptan with MAO-A or CYP3A4 inhibitors reduces clearance of the drug, but this is not considered clinically significant.

Dosage and Administration

Oral almotriptan is recommended for the acute treatment of migraine with or without aura in adults. According to the manufacturer’s prescribing information, the suggested initial dose of almotriptan tablets in the US is either 6.25 or 12.5mg. The recommended initial dose in the UK and Europe is 12.5mg. For headache recurrence, the dose may be repeated after 2 hours, but should not exceed two doses within a 24-hour period. Treatment should be limited to a maximum of four migraine headaches in any 30-day period.

In patients with severe renal impairment and, in the US, in patients with severe hepatic impairment the recommended initial dose of oral almotriptan is 6.25mg, with a maximum total daily dose of 12.5mg within a 24-hour period; in the UK and Europe treatment with almotriptan is contraindicated in patients with severe hepatic impairment. Almotriptan is contraindicated in patients with ischaemic heart disease, coronary artery vasospasm, any other significant underlying cardiovascular disease, or uncontrolled hypertension. Almotriptan is not recommended for use in patients under the age of 18 years as efficacy and tolerability have not been established in this patient group.

As the reduction in clearance of almotriptan when coadministered with MAO or CYP3A4 inhibitors is not clinically significant, dosage reduction is not required. Like other triptans, almotriptan should not be administered within 24 hours of ergot derivatives, and care should be taken when almotriptan is prescribed with selective serotonin reuptake inhibitors. The UK and European manufacturer’s prescribing information recommends that coadministration with lithium should be avoided.

Keywords

Migraine Sumatriptan Almotriptan Cefditoren Oral Sumatriptan 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Adis International Limited 2002

Authors and Affiliations

  • Susan J. Keam
    • 1
    Email author
  • Karen L. Goa
    • 1
  • David P. Figgitt
    • 1
  1. 1.Adis International LimitedMairangi Bay, AucklandNew Zealand

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