Active ingredient: Eletriptan - Brands, Medical Use, Clinical Data

Brands, Medical Use, Clinical Data

Drug Category

• Anti-migraine Agents
• Vasoconstrictor Agents
• Anti-inflammatory Agents
• Selective Serotonin Agonists

Dosage Forms

• Tablet for oral administration (24.2 or 48.5 mg)

Brands / Synonyms

Eletriptan [INN:BAN]; Relpax; Relpax

Indications

For the acute treatment of migraine with or without aura in adults.

Pharmacology

Eletriptan is a selective 5-hydroxytryptamine 1B/1D receptor agonist. In the anesthetized dog, eletriptan has been shown to reduce carotid arterial blood flow, with only a small increase in arterial blood pressure at high doses. While the effect on blood flow was selective for the carotid arterial bed, decreases in coronary artery diameter were observed. Eletriptan has also been shown to inhibit trigeminal nerve activity in the rat.

Mechanism of Action

Eletriptan binds with high affinity to 5-HT1B, 5-HT1D and 5-HT1F receptors, has modest affinity for 5-HT1A, 5-HT1E, 5-HT2B and 5-HT7 receptors, and little or no affinity for 5-HT2A, 5-HT2C, 5-HT3, 5-HT4, 5-HT5A and 5-HT6 receptors. Eletriptan has no significant affinity or pharmacological activity at adrenergic alpha1, alpha2, or beta; dopaminergic D1 or D2; muscarinic; or opioid receptors. Two theories have been proposed to explain the efficacy of 5-HT receptor agonists in migraine. One theory suggests that activation of 5-HT1 receptors located on intracranial blood vessels, including those on the arteriovenous anastomoses, leads to vasoconstriction, which is correlated with the relief of migraine headache. The other hypothesis suggests that activation of 5-HT1 receptors on sensory nerve endings in the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release.

Absorption

Well absorbed after oral administration with a mean absolute bioavailability of approximately 50%.

Toxicity

Based on the pharmacology of the 5-HT1B/1D agonists, hypertension or other more serious cardiovascular symptoms could occur on overdose.

Biotrnasformation / Drug Metabolism

In vitro studies indicate that eletriptan is primarily metabolized by cytochrome P-450 enzyme CYP3A4. The N-demethylated metabolite of eletriptan is the only known active metabolite.

Contraindications

RELPAX Tablets should not be given to patients with ischemic heart disease (e.g., angina pectoris, history of myocardial infarction, or documented silent ischemia) or to patients who have symptoms, or findings consistent with ischemic heart disease, coronary artery vasospasm, including Prinzmetal's variant angina, or other significant underlying cardiovascular disease. RELPAX Tablets should not be given to patients with cerebrovascular syndromes including (but not limited to) strokes of any type as well as transient ischemic attacks. RELPAX Tablets should not be given to patients with peripheral vascular disease including (but not limited to) ischemic bowel disease. Because RELPAX Tablets may increase blood pressure, it should not be given to patients with uncontrolled hypertension. RELPAX Tablets should not be administered to patients with hemiplegic or basilar migraine. RELPAX Tablets should not be used within 24 hours of treatment with another 5-HT₁ agonist, an ergotamine-containing or ergot-type medication such as dihydroergotamine (DHE) or methysergide. RELPAX Tablets should not be used in patients with known hypersensitivity to eletriptan or any of its inactive ingredients. RELPAX Tablets should not be given to patients with severe hepatic impairment.

Drug Interactions

Ergot-containing drugs: Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine [DHE] or methysergide) and eletriptan within 24 hours of each other is not recommended.

CYP3A4 Inhibitors: Eletriptan is metabolized primarily by CYP3A4.

Monoamine Oxidase Inhibitors: Eletriptan is not a substrate for monoamine oxidase (MAO) enzymes, therefore there is no expectation of an interaction between eletriptan and MAO inhibitors.

Propranolol:The C_max and AUC of eletriptan were increased by 10 and 33% respectively in the presence of propranolol. No interactive increases in blood pressure were observed. No dosage adjustment appears to be needed for patients taking propranolol.

Selective serotonin reuptake inhibitors (SSRIs): SSRIs (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with 5-HT1 agonists. If concomitant treatment with eletriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised.

Other 5-HT₁ agonists: Concomitant use of other 5-HT₁ agonists within 24 hours of RELPAX treatment is not recommended .

Drug/Laboratory Test Interactions: RELPAX Tablets are not known to interfere with commonly employed clinical laboratory tests.

Carcinogenesis: Lifetime carcinogenicity studies, 104 weeks in duration, were carried out in mice and rats by administering eletriptan in the diet. In rats, the incidence of testicular interstitial cell adenomas was increased at the high dose of 75 mg/kg/day. The estimated exposure (AUC) to parent drug at that dose was approximately 6 times that achieved in humans receiving the maximum recommended daily dose (MRDD) of 80 mg, and at the no-effect dose of 15 mg/kg/day it was approximately 2 times the human exposure at the MRDD. In mice, the incidence of hepatocellular adenomas was increased at the high dose of 400 mg/kg/day. The exposure to parent drug (AUC) at that dose was approximately 18 times that achieved in humans receiving the MRDD, and the AUC at the no-effect dose of 90 mg/kg/day was approximately 7 times the human exposure at the MRDD.

Mutagenesis: Eletriptan was not mutagenic in bacterial or mammalian cell assays in vitro, testing negative in the Ames reverse mutation test and the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) mutation test in Chinese hamster ovary cells. It was not clastogenic in two in vivo mouse micronucleus assays. Results were equivocal in in vitro human lymphocyte clastogenicity tests, in which the incidence of polyploidy was increased in the absence of metabolic activation (-S9 conditions), but not in the presence of metabolic activation.

Impairment of Fertility: In a rat fertility and early embryonic development study, doses tested were 50, 100 and 200 mg/kg/day, resulting in systemic exposures to parent drug in rats, based on AUC, that were 4, 8 and 16 times MRDD, respectively, in males and 7, 14 and 28 times MRDD, respectively, in females. There was a prolongation of the estrous cycle at the 200 mg/kg/day dose due to an increase in duration of estrus, based on vaginal smears. There were also dose-related, statistically significant decreases in mean numbers of corpora lutea per dam at all 3 doses, resulting in decreases in mean numbers of implants and viable fetuses per dam. This suggests a partial inhibition of ovulation by eletriptan. There was no effect on fertility of males and no other effect on fertility of females.

Pregnancy: Pregnancy Category C: In reproductive toxicity studies in rats and rabbits, oral administration of eletriptan was associated with developmental toxicity (decreased fetal and pup weights and an increased incidence of fetal structural abnormalities). Effects on fetal and pup weights were observed at doses that were, on a mg/m² basis, 6 to 12 times greater than the clinical maximum recommended daily dose (MRDD) of 80 mg. The increase in structural alterations occurred in the rat and rabbit at doses that, on a mg/m² basis, were 12 times greater than (rat) and approximately equal to (rabbit) the MRDD. When pregnant rats were administered eletriptan during the period of organogenesis at doses of 10, 30 or 100 mg/kg/day, fetal weights were decreased and the incidences of vertebral and sternebral variations were increased at 100 mg/kg/day (approximately 12 times the MRDD on a mg/m² basis). The 100 mg/kg dose was also maternally toxic, as evidenced by decreased maternal body weight gain during gestation. The no-effect dose for developmental toxicity in rats exposed during organogenesis was 30 mg/kg, which is approximately 4 times the MRDD on a mg/m² basis.

When doses of 5, 10 or 50 mg/kg/day were given to New Zealand White rabbits throughout organogenesis, fetal weights were decreased at 50 mg/kg, which is approximately 12 times the MRDD on a mg/m² basis. The incidences of fused sternebrae and vena cava deviations were increased in all treated groups. Maternal toxicity was not produced at any dose. A no-effect dose for developmental toxicity in rabbits exposed during organogenesis was not established, and the 5 mg/kg dose is approximately equal to the MRDD on a mg/m² basis. There are no adequate and well-controlled studies in pregnant women; therefore, eletriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: Eletriptan is excreted in human breast milk. In one study of 8 women given a single dose of 80 mg, the mean total amount of eletriptan in breast milk over 24 hours in this group was approximately 0.02% of the administered dose. The ratio of eletriptan mean concentration in breast milk to plasma was 1:4, but there was great variability. The resulting eletriptan concentration-time profile was similar to that seen in the plasma over 24 hours, with very low concentrations of drug (mean 1.7 ng/mL) still present in the milk 18-24 hours post dose. The N-desmethyl active metabolite was not measured in the breast milk. Caution should be exercised when RELPAX is administered to nursing women.

Pediatric Use: Safety and effectiveness of RELPAX Tablets in pediatric patients have not been established; therefore, RELPAX is not recommended for use in patients under 18 years of age.

The efficacy of RELPAX Tablets (40 mg) in patients 11-17 was not established in a randomized, placebo-controlled trial of 274 adolescent migraineurs. Adverse events observed were similar in nature to those reported in clinical trials in adults. Postmarketing experience with other triptans includes a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events that are similar in nature to those reported rarely in adults. Long-term safety of eletriptan was studied in 76 adolescent patients who received treatment for up to one year. A similar profile of adverse events to that of adults was observed. The long-term safety of eletriptan in pediatric patients has not been established.

Geriatric Use: Eletriptan has been given to only 50 patients over the age of 65. Blood pressure was increased to a greater extent in elderly subjects than in young subjects. The pharmacokinetic disposition of eletriptan in the elderly is similar to that seen in younger adults (see CLINICAL PHARMACOLOGY). In clinical trials, there were no apparent differences in efficacy or the incidence of adverse events between patients under 65 years of age and those 65 and above (n=50).

There is a statistically significantly increased half-life (from about 4.4 hours to 5.7 hours) between elderly (65 to 93 years of age) and younger adult subjects (18 to 45 years of age).