Almotriptan

Almotriptan is a an Antimigraine Agent belonging to pharmacology class of Selective serotonin (5-HT1B and 5-HT1D) agonist Class

Almotriptan can be used in the treatment of Migraine, moderate to severe .

It is Well absorbed from the gastrointestinal tract. Bioavailability: Approx 70%. Time to peak plasma concentration: 1-3 hours with Volume of distribution: Approx 180-200 L. Plasma protein binding: Approx 35% and get Metabolised via MAO type A oxidative deamination (approx 27% of dose) and CYP3A4 and CYP2D6 (approx 12% of dose) to inactive metabolites and get excreted Mainly via urine (approx 75%; approx 40%, as unchanged drug); faeces (approx 13%, as unchanged drug and metabolites). Elimination half-life: Approx 3.5 hours.

The common side effects associated with Almotriptan include : Peripheral vascular ischaemia, colonic ischaemia; sensations of tightness, pain, pressure, and heaviness in the precordium, neck, jaw, and throat

Almotriptan is available in the form of tablets.

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

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

The Tmax of Almotriptan was about 1-3 hours.

Almotriptan is available in tablet

Oral: May administer without regard to meals.

Almotriptan can be used in the treatment of Migraine, moderate to severe .

Almotriptan binds with high affinity to 5-HT1D, 5-HT1B, and 5-HT1F receptors. Almotriptan has weak affinity for 5-HT1A and 5-HT7 receptors, but has no significant affinity or pharmacological activity at 5-HT2, 5-HT3, 5-HT4, 5-HT6; alpha or beta adrenergic; adenosine (A1, A2); angiotensin (AT1, AT2); dopamine (D1, D2); endothelin (ETA, ETB); or tachykinin (NK1, NK2, NK3) binding sites.

Almotriptan is approved for use in the following clinical indications

Migraine, moderate to severe, acute treatment: Treatment of migraine with or without aura in adults (with a history of migraine) and adolescents (with a history of migraine lasting ≥4 hours when left untreated).

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: 12.5 mg as a single dose; if symptoms persist or return, may repeat dose after ≥2 hours. Maximum: 12.5 mg/dose; 25 mg per 24 hours.

Tablet:

6.25 mg, 12.5 mg.

Tablet

• Dose Adjustment in Kidney Impairment Patient:

CrCl >30 mL/minute: No dosage adjustment is necessary.

CrCl ≤30 mL/minute: 6.25 mg as a single dose; if symptoms persist or return, may repeat dose after ≥2 hours. Maximum: 12.5 mg per 24 hours.

• Dose Adjustment in Hepatic Patients:

6.25 mg as a single dose; if symptoms persist or return, may repeat dose after ≥2 hours. Maximum: 12.5 mg per 24 hours.

• Dose Adjustment in Pediatric Patients:

Migraine: Children ≥12 years and Adolescents: Oral: Initial: 6.25 to 12.5 mg in a single dose; if headache returns, may repeat the dose after 2 hours; maximum 2 doses/day; maximum daily dose: 25 mg/day. Note: The safety of treating >4 migraines/month has not been established.

The dietary restriction should be individualized as per patient requirements.

Almotriptan may be contraindicated in the following conditions:

Hypersensitivity to almotriptan or any component of the formulation; hemiplegic migraine or migraine with brainstem aura; known or suspected ischemic heart disease (eg, angina pectoris, MI, documented silent ischemia, coronary artery vasospasm, Prinzmetal's variant angina) or other significant underlying cardiovascular disease; cerebrovascular syndromes (eg, stroke, transient ischemic attacks); peripheral vascular disease (including ischemic bowel disease); uncontrolled hypertension; use within 24 hours of another 5-HT₁ agonist; use within 24 hours of ergotamine derivatives and/or ergotamine-containing medications (eg, dihydroergotamine, ergotamine).

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

Concerns related to adverse effects:

• Cardiac events: Coronary artery vasospasm, transient ischemia, myocardial infarction, ventricular tachycardia/fibrillation, cardiac arrest, and death have been reported with 5-HT₁ agonist 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's angina before receiving additional doses; if dosing is resumed and similar symptoms recur, monitor with ECG.

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

• Elevated blood pressure: Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions following 5-HT₁ agonist administration in patients with and without a history of hypertension.

• Headaches: Acute migraine agents (eg, triptans, opioids, ergotamine, or a combination of the agents) used for 10 or more days per month may lead to worsening of headaches (medication overuse headache); withdrawal treatment may be necessary in the setting of overuse.

• Ocular effects: Transient and permanent blindness and partial vision loss have been reported (rare) with 5-HT₁ agonist administration.

• Sulfonamide allergy: Almotriptan contains a sulfonyl group which is structurally different from a sulfonamide. Cross-reactivity in patients with sulfonamide allergy has not been evaluated; however, the manufacturer recommends that caution be exercised in this patient population.

• Vasospasm-related events: Peripheral vascular ischemia and colonic ischemia have been reported with 5-HT₁ agonist administration.

Disease-related concerns:

• Coronary artery disease: Almotriptan should not be given to patients with documented ischemic or vasospastic CAD. Patients with risk factors for CAD (eg, hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, menopause, male >40 years of age) should undergo adequate cardiac evaluation prior to administration; if the cardiac evaluation is “satisfactory,” first dose should be given in the healthcare provider's office (consider ECG monitoring). All patients should undergo periodic evaluation of cardiovascular status during treatment.

• Hepatic impairment: Use with caution in patients with hepatic impairment. Drug clearance may be reduced leading to increased plasma concentrations; dosage reduction is recommended.

• Renal impairment: Use with caution in patients with moderate-to-severe renal failure. Drug clearance may be reduced leading to increased plasma concentrations; dosage reduction is recommended for severe renal impairment.

Concurrent drug therapy issues:

• Serotonin syndrome: Symptoms of agitation, confusion, hallucinations, hyper-reflexia, myoclonus, shivering, and tachycardia may occur with concomitant proserotonergic drugs (ie, SSRIs/SNRIs or triptans) or agents which reduce almotriptan'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.

Other warnings/precautions:

• Appropriate use: Only indicated for treatment of acute migraine; it is not indicated for migraine prophylaxis, or for the treatment of cluster headaches, hemiplegic migraine, or migraine with brainstem aura. If a patient does not respond to the first dose, the diagnosis of acute migraine should be reconsidered.

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

Almotriptan is present in breast milk.

Data related to the presence of 5-HT_1B/1D agonists (triptans) in breast milk is 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 one patient taking almotriptan 12.5 mg. Using the average breast milk concentration observed, authors of the study calculated the estimated exposure of almotriptan to the breastfed infant to be 4.4 mcg/kg/day, providing a relative infant dose (RID) of 1.8% based on the weight-adjusted maternal dose. Using the maximum breast milk concentration, the RID of almotriptan was calculated to be 6.5%. A large interindividual variability among breast milk concentrations was found with all the triptans in the study, even when considering dose and dosage form.

Pregnancy Category C

In animal studies, almotriptan produced developmental toxicity (increased embryolethality and fetal skeletal variations, and decreased offspring body weight) at doses greater than those used clinically. There are no adequate and well-controlled studies in pregnant women; therefore, Almotriptan (almotriptan malate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

When almotriptan (125, 250, 500, or 1000 mg/kg/day) was administered orally to pregnant rats throughout the period of organogenesis, increased incidences of fetal skeletal variations (decreased ossification) were noted at a dose of 250 mg/kg/day or greater and an increase in embryolethality was seen at the highest dose. The no-effect dose for embryo-fetal developmental toxicity in rats (125 mg/kg/day) is approximately 100 times the maximum recommended human dose (MRHD) of 25 mg/day on a body surface area (mg/m2) basis. Similar studies in pregnant rabbits conducted with almotriptan (oral doses of 5, 20, or 60 mg/kg/day) demonstrated increases in embryolethality at the highest dose. The no-effect dose for embryo-fetal developmental toxicity in rabbits (20 mg/kg/day) is approximately 15 times the MRHD on a mg/m2 basis. When almotriptan (25, 100, or 400 mg/kg/day) was administered orally to rats throughout the periods of gestation and lactation, gestation length was increased and litter size and offspring body weight were decreased at the highest dose. The decrease in pup weight persisted throughout lactation. The no-effect dose in this study (100 mg/kg/day) is 40 times the MRHD on a mg/m2 basis.

There is no sufficient scientific evidence traceable regarding use and safety of Almotriptan in concurrent use with any particular food.

The adverse reactions related to Almotriptan can be categorized as

Common Adverse effects: Peripheral vascular ischemia, colonic ischemia, sensations of tightness, pain, pressure, and heaviness in the precordium, neck, jaw, and throat

Less Common Adverse effects: Nausea, vomiting, diarrhea, dyspepsia, dry mouth.

Rare Adverse effects: Increased blood pressure, including hypertensive crisis, transient and permanent blindness, partial vision loss.

The clinically relevant drug interactions of Almotriptan is briefly summarized here

Increased serum concentration with potent CYP3A4 inhibitors (e.g. ketoconazole).

Potentially Fatal: May cause serotonin syndrome with selective SSRIs or selective noradrenaline reuptake inhibitors. May cause prolonged vasospastic reactions with ergot-containing drugs (e.g. dihydroergotamine, ergotamine tartrate, methysergide) and other 5-HT₁ receptor agonists (e.g. triptans).

The common side of Almotriptan include the following

Peripheral vascular ischemia, colonic ischemia; sensations of tightness, pain, pressure, and heaviness in the precordium, neck, jaw, and throat.

Pregnancy

Pregnancy Category C

In animal studies, almotriptan produced developmental toxicity (increased embryolethality and fetal skeletal variations, and decreased offspring body weight) at doses greater than those used clinically. There are no adequate and well-controlled studies in pregnant women; therefore, Almotriptan (almotriptan malate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

When almotriptan (125, 250, 500, or 1000 mg/kg/day) was administered orally to pregnant rats throughout the period of organogenesis, increased incidences of fetal skeletal variations (decreased ossification) were noted at a dose of 250 mg/kg/day or greater and an increase in embryolethality was seen at the highest dose. The no-effect dose for embryo-fetal developmental toxicity in rats (125 mg/kg/day) is approximately 100 times the maximum recommended human dose (MRHD) of 25 mg/day on a body surface area (mg/m2) basis. Similar studies in pregnant rabbits conducted with almotriptan (oral doses of 5, 20, or 60 mg/kg/day) demonstrated increases in embryolethality at the highest dose. The no-effect dose for embryo-fetal developmental toxicity in rabbits (20 mg/kg/day) is approximately 15 times the MRHD on a mg/m2 basis. When almotriptan (25, 100, or 400 mg/kg/day) was administered orally to rats throughout the periods of gestation and lactation, gestation length was increased and litter size and offspring body weight were decreased at the highest dose. The decrease in pup weight persisted throughout lactation. The no-effect dose in this study (100 mg/kg/day) is 40 times the MRHD on a mg/m2 basis.

Labor and Delivery

The effect of Almotriptan on labor and delivery in humans is unknown.

Nursing Mothers

It is not known whether almotriptan is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Almotriptan is administered to a nursing woman. Levels of almotriptan in rat milk were up to 7 times higher than in rat plasma.

Pediatric Use

Safety and efficacy of Almotriptan in pediatric patients under the age of 12 years have not been established. The pharmacokinetics, efficacy, and safety of Almotriptan have been evaluated in adolescent patients, age 12 to 17 years.

In a clinical study, Almotriptan 6.25 mg and 12.5 mg were found to be effective for the relief of migraine headache pain in adolescent patients age 12 to 17 years. Efficacy on migraine-associated symptoms (nausea, photophobia, and phonophobia) was not established. The most common adverse reactions (incidence of ≥1%) associated with Almotriptantreatment were dizziness, somnolence, headache, paresthesia, nausea, and vomiting. The safety and tolerability profile of Almotriptan treatment in adolescents is similar to the profile observed in adults.

Postmarketing experience with other triptans include 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.

Geriatric Use

Clinical studies of Almotriptan did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Clearance of almotriptan was lower in elderly volunteers than in younger individuals, but there were no observed differences in the safety and tolerability between the two populations. In general, dose selection for an elderly patient should be cautious, usually starting at the low dose, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. The recommended dose of Almotriptan for elderly patients with normal renal function for their age is the same as that recommended for younger adults.

Symptoms: Somnolence.

Management: Symptomatic treatment. Monitor vital functions for at least 12 hours or while signs or symptoms persist.

Pharmacodynamics:

Almotriptan is a selective 5-hydroxytryptamine receptor subtype agonist indicated for the acute treatment of migraine attacks with or without aura in adults. Almotriptan is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine. Almotriptan is an agonist for a vascular 5-hydroxytryptamine receptor subtype (probably a member of the 5-HT_1D family) having only a weak affinity for 5-HT_1A, 5-HT_5A, and 5-HT₇ receptors and no significant affinity or pharmacological activity at 5-HT₂, 5-HT₃ or 5-HT₄ receptor subtypes or at alpha1-, alpha2-, or beta-adrenergic, dopamine1,; dopamine2; muscarinic, or benzodiazepine receptors. This action in humans correlates with the relief of migraine headache. In addition to causing vasoconstriction, experimental data from animal studies show that Almotriptan also activates 5-HT₁ receptors on peripheral terminals of the trigeminal nerve innervating cranial blood vessels, which may also contribute to the antimigraine effect of Almotriptan in humans.

Pharmacokinetics:

Absorption: Well absorbed from the gastrointestinal tract. Bioavailability: Approx 70%. Time to peak plasma concentration: 1-3 hours.

Distribution: Volume of distribution: Approx 180-200 L. Plasma protein binding: Approx 35%.

Metabolism: Metabolized via MAO type A oxidative deamination (approx 27% of dose) and CYP3A4 and CYP2D6 (approx 12% of dose) to inactive metabolites.

Excretion: Mainly via urine (approx 75%; approx 40%, as unchanged drug); faeces (approx 13%, as unchanged drug and metabolites). Elimination half-life: Approx 3.5 hours.

1. https://www.uptodate.com/contents/Almotriptan -drug-information?search=Almotriptan &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/Almotriptan _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Almotriptan ?type=full&mtype=generic#mechanism-of-action