Eletriptan

Eletriptan is an Antimigraine Agent belonging to pharmacology class of Serotonin 5-HT1B, 1D Receptor Agonist Class.

Eletriptan can be used in the treatment of Migraine.

It is Rapidly and well absorbed from the gastrointestinal tract. Bioavailability: Approx 50%; increased with a high-fat meal. Time to peak plasma concentration: Approx 1.5-2 hours and Enters breast milk. Plasma protein binding: Approx 85% and get Metabolised in the liver mainly by the CYP3A4 isoenzyme to the active, N-demethylated metabolite and get excreted Mainly via metabolism (approx 90%); urine (approx 10%). Elimination half-life: Approx 4 hours.

The common side effects associated with Eletriptan include Sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw; elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems; non-coronary vasospastic reactions

Eletriptan is available in the form of tablets

The molecule is available in India, USA, Japan, Germany.

Selective agonist for serotonin (5-HT_1B, 5-HT_1D, and 5-HT_1F receptors) in cranial arteries; causes vasoconstriction and reduces sterile inflammation associated with antidromic neuronal transmission correlating with relief of migraine

The Tmax of Eletriptan was about 1-3 hours.

Onset of Action was about 30 minutes.

Eletriptan is available in tablet

Oral: May administer without regard to meals.

Eletriptan can be used in the treatment of Migraine.

Eletriptan is a selective agonist of serotonin (5-HT_1B/1D/1F receptors). Its exact mechanism of action in the management of migraine has yet to be established, however, current data suggest that it causes constriction of certain intracranial blood vessels, inhibits pro-inflammatory neuropeptide release, and reduces transmission in the trigeminal pain pathway, thereby relieving migraine.

Eletriptan is approved for use in the following clinical indications

Migraine, moderate to severe, acute treatment: Acute treatment of migraine, with or without aura in adults.

Migraine, moderate to severe, acute treatment:

Note: Do not use within 24 hours of an ergotamine preparation or a different triptan. Limit use to <10 days per month to avoid medication-overuse headache. Administration early in the course of a migraine attack, at the first sign of pain, may improve response to treatment. When attack is complicated by severe nausea or vomiting, a non-oral medication may be more effective.

Oral: 20 to 40 mg as a single dose; some experts prefer 40 mg as a single dose due to greater efficacy. If symptoms persist or return, may repeat dose after ≥2 hours. Maximum: 40 mg/dose; 80 mg per 24 hours. Dosages of 80 mg/dose and 160 mg per 24 hours have been evaluated; however, use was associated with increased adverse effects and similar efficacy compared to lower doses.

Tablet:

20 mg, 40 mg

Tablet

The dietary restriction should be individualized as per patient requirements.

Eletriptan may be contraindicated in the following conditions:-

Ischemic coronary artery disease (eg, angina pectoris, history of myocardial infarction, documented silent ischemia); coronary artery vasospasm, including Prinzmetal angina; Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders; history of stroke, transient ischemic attack, or history or current evidence of hemiplegic migraine or migraine with brainstem aura (basilar migraine); peripheral vascular disease; ischemic bowel disease; uncontrolled hypertension; recent use (within 24 hours) of treatment with another 5-HT₁ agonist, or an ergotamine-containing or ergot-type medication (eg, dihydroergotamine or methysergide); recent use (within at least 72 hours) of the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, or nelfinavir; known hypersensitivity to eletriptan or any component of the formulation (including anaphylaxis and angioedema).

Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Concerns related to adverse effects:

• Anaphylactic/Anaphylactoid reactions: Anaphylaxis, anaphylactoid, and hypersensitivity reactions (including angioedema) have occurred; may be life-threatening or fatal.

• Cardiac events: Coronary artery vasospasm, transient ischemia, myocardial infarction, ventricular tachycardia/fibrillation, cardiac arrest, and death have been reported with 5-HT₁ agonist administration; some events have occurred within a few hours of administration. Patients who experience sensations of chest pain/pressure/tightness or symptoms suggestive of angina following dosing should be evaluated for coronary artery disease or Prinzmetal angina before receiving additional doses; if dosing is resumed and similar symptoms recur, monitor with ECG.

• Cerebrovascular events: Cerebral/subarachnoid hemorrhage and stroke (some fatal) have been reported with 5-HT₁ agonist administration.

• Elevated BP: Significant elevation in BP, including hypertensive crisis with acute impairment of organ systems, has also been reported on rare occasions in patients with and without a history of hypertension.

• Serotonin syndrome: Symptoms of agitation, confusion, hallucinations, hyper-reflexia, myoclonus, shivering, and tachycardia may rarely occur with concomitant proserotonergic drugs (ie, SSRIs/SNRIs or triptans) or agents which reduce eletriptan's metabolism. Concurrent use of serotonin precursors (eg, tryptophan) is not recommended. If concomitant administration with SSRIs is warranted, monitor closely, especially at initiation and with dose increases.

• Vasospasm-related events: Peripheral vascular ischemia, gastrointestinal vascular ischemia/infarction, and Raynaud syndrome have been reported with 5-HT₁ agonists.

Disease-related concerns:

• Coronary artery disease: Should not be given to patients who have risk factors for CAD (eg, hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, menopause, male >40 years of age) without adequate cardiac evaluation. Patients with suspected CAD should have cardiovascular evaluation to rule out CAD before considering use; if cardiovascular evaluation is “satisfactory,” first dose should be given in the healthcare provider's office (consider ECG monitoring). Periodic evaluation of cardiovascular status should be done in all patients.

There is no sufficient scientific evidence traceable regarding use and safety of Eletriptan in concurrent use with alcohol.

Eletriptan is present in breast milk.

Data related to the presence of 5-HT_1B/1D agonists (triptans) in breast milk are available from a study of 19 lactating women (6 weeks to 30 months postpartum) treated for migraine headaches. During the study, infants were fed previously expressed breast milk. Breast milk was sampled prior to and at intervals up to 24 hours after the dose in patients taking eletriptan 40 mg/day (n = 2) or eletriptan 20 mg/day (n = 1). Using the average breast milk concentrations observed, authors of the study calculated the estimated exposure of eletriptan to the breastfed infant to be 3.5 to 3.6 mcg/kg/day, providing a relative infant dose (RID) of 0.6% to 0.8% based on the weight adjusted maternal dose of 40 mg/day. The estimated exposure to the breastfed infant was 0.9 mcg/kg/day (RID 0.3%) based on a maternal dose of 20 mg/day. Using the maximum breast milk concentrations, the RID of eletriptan was 2% (range: 0.8% to 3.3%). The active metabolite of eletriptan was not included in the calculations (concentrations were near or below the limit of quantification). A large interindividual variability among breast milk concentrations was found with all the triptans in the study, even when considering dose and dosage form (Amundsen 2021). In general, breastfeeding is considered acceptable when the RID of a medication is <10%).

Treatment for migraine headaches in lactating patients should be individualized. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Withholding breastfeeding for 24 hours after the maternal dose will minimize infant exposure via breast milk. The decision to withhold breastfeeding following a dose of eletriptan should be part of a shared decision-making process.

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. In reproductive toxicity studies in pregnant animals, oral administration of eletriptan was associated with developmental toxicity (decreased fetal and pup weights and an increased incidence of fetal structural abnormalities) at clinically relevant plasma exposures. Eletriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus

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 maximum recommended human dose [MRHD] of 80 mg/day on a mg/m2 basis). The 30 and 100 mg/kg/day doses were also maternally toxic, as evidenced by decreased maternal body weight gain during gestation. The no-effect dose for developmental toxicity in rats was 30 mg/kg/day, which is approximately 4 times the MRHD on a mg/m2 basis.

When doses of 5, 10, or 50 mg/kg/day were given to pregnant rabbits throughout organogenesis, fetal weights were decreased at 50 mg/kg/day, which is approximately 12 times the MRHD on a mg/m2 basis. The incidences of fused sternebrae and vena cava deviations were increased at all doses. Maternal toxicity was not evident at any dose. A no-effect dose for developmental toxicity in rabbits was not established; the lowest dose tested (5 mg/kg/day) is similar to the MRHD on a mg/m2 basis.

A high-fat meal increases bioavailability. Management: Administer without regard to meals.

The adverse reactions related to Eletriptan can be categorized as

• Common Adverse effects: Sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw; elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems; non-coronary vasospastic reactions
• Less Common Adverse effects: Abdominal pain or discomfort, nausea, dry mouth, dyspepsia, dysphagia, vomiting.
• Rare Adverse effects: Paranesthesia, somnolence, headache, dizziness, tingling or abnormal sensation, hypertonia, hypoaesthesia, myasthenia. Rarely, syncope, CVA.

The clinically relevant drug interactions of Eletriptan is briefly summarized here

Increased risk of serotonin syndrome with SSRIs, SNRIs, TCAs, and MAOIs.

Potentially Fatal: May result in additive vasospastic effect when taken within 24 hours of using ergot alkaloids (e.g. ergotamine, dihydroergotamine, methysergide) or other 5-HT₁ receptor agonists. Potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) significantly increase the exposure of eletriptan when used within at least 72 hours of each other.

The common side of Eletriptan include the following

Sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw; elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems; non-coronary vasospastic reactions.

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. In reproductive toxicity studies in pregnant animals, oral administration of eletriptan was associated with developmental toxicity (decreased fetal and pup weights and an increased incidence of fetal structural abnormalities) at clinically relevant plasma exposures. Eletriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus

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 maximum recommended human dose [MRHD] of 80 mg/day on a mg/m2 basis). The 30 and 100 mg/kg/day doses were also maternally toxic, as evidenced by decreased maternal body weight gain during gestation. The no-effect dose for developmental toxicity in rats was 30 mg/kg/day, which is approximately 4 times the MRHD on a mg/m2 basis.

When doses of 5, 10, or 50 mg/kg/day were given to pregnant rabbits throughout organogenesis, fetal weights were decreased at 50 mg/kg/day, which is approximately 12 times the MRHD on a mg/m2 basis. The incidences of fused sternebrae and vena cava deviations were increased at all doses. Maternal toxicity was not evident at any dose. A no-effect dose for developmental toxicity in rabbits was not established; the lowest dose tested (5 mg/kg/day) is similar to the MRHD on a mg/m2 basis.

Labor and Delivery

There is no FDA guidance on use of Eletriptan during labor and delivery.

Nursing Mothers

Eletriptan is excreted in human milk. Caution should be exercised when Eletriptan is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

The efficacy of Eletriptan Tablets (40 mg) in patients 11–17 was not established in a randomized, placebo-controlled trial of 274 adolescent migraineurs. Adverse reactions 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 reactions 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 reactions to that of adults was observed. The long-term safety of eletriptan in pediatric patients has not been established.

Geriatic Use

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. In clinical trials, there were no apparent differences in efficacy or the incidence of adverse reactions between patients under 65 years of age and those 65 and above.

Gender

There is no FDA guidance on the use of Eletriptan with respect to specific gender populations.

Race

There is no FDA guidance on the use of Eletriptan with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Eletriptan in patients with renal impairment.

Hepatic Impairment

The effect of severe hepatic impairment on Eletriptan metabolism has not been evaluated. Eletriptan is not recommended for use in patients with severe hepatic impairment.

Symptoms: Hypertension or other more serious CV symptoms.

Management: Supportive treatment.

Pharmacodynamics:

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.

Pharmacokinetics:

Absorption: Rapidly and well absorbed from the gastrointestinal tract. Bioavailability: Approx 50%; increased with a high-fat meal. Time to peak plasma concentration: Approx 1.5-2 hours.

Distribution: Enters breast milk. Plasma protein binding: Approx 85%.

Metabolism: Metabolized in the liver mainly by the CYP3A4 isoenzyme to the active, N-demethylated metabolite.

Excretion: Mainly via metabolism (approx 90%); urine (approx 10%). Elimination half-life: Approx 4 hours.

1. https://www.uptodate.com/contents/Eletriptan -drug-information?search=Eletriptan &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/Eletriptan _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Eletriptan ?type=full&mtype=generic#mechanism-of-action