Migretan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MIGRETAN (MIGRETAN)

Composition:

active substance: almotriptan;

1 film-coated tablet contains almotriptan 12.5 mg, equivalent to almotriptan malate 17.5 mg;

excipients: microcrystalline cellulose pH 101; mannitol (E 421); sodium starch glycolate, type A; povidone K 29-32; sodium stearyl fumarate;

Opadry white 02B580001, including: hypromellose (E 464); titanium dioxide (E 171); polyethylene glycol 400 (E 1521); carnauba wax.

Pharmaceutical form. Film-coated tablets.

Basic physicochemical properties: round, biconvex, film-coated tablets, white to almost white in color.

Pharmacotherapeutic group. Medicinal products used in migraine. Selective 5-HT₁ serotonin receptor agonist. Almotriptan.

ATC code: N02C C05.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Almotriptan is a selective agonist of 5-HT_1B and 5-HT_1D receptors. These receptors mediate vasoconstriction of certain cerebral blood vessels, as demonstrated in studies using isolated human tissue preparations. Almotriptan also interacts with the trigeminovascular system, inhibiting plasma protein extravasation from dural blood vessels following stimulation of the trigeminal ganglion—a sign of neuronal inflammation believed to be involved in the pathophysiology of migraine. Almotriptan has no significant activity at other 5-HT receptor subtypes and shows no significant affinity for adrenergic, adenosine, angiotensin, dopaminergic, endothelin, or tachykinin binding sites.

Pharmacodynamic Effects

The efficacy of almotriptan in the treatment of acute migraine attacks was established in four multicenter, placebo-controlled clinical trials involving over 700 patients receiving almotriptan 12.5 mg. Pain relief began within 30 minutes after administration, and the response rate (reduction of headache from moderate or severe to mild or absent) at 2 hours was 57–70% with almotriptan and 32–42% with placebo. In addition, almotriptan alleviated nausea, photophobia, and phonophobia associated with migraine attacks.

Pharmacokinetics

Absorption. Almotriptan is well absorbed, with an oral bioavailability of approximately 70%. Peak plasma concentration (C_max) is reached about 1.5–3.0 hours after administration. The rate and extent of absorption are not affected by concomitant food intake. In healthy volunteers receiving single oral doses ranging from 5 mg to 200 mg, C_max and area under the pharmacokinetic curve (AUC) were dose-proportional, indicating linear pharmacokinetics. The elimination half-life (T_1/2) is approximately 3.5 hours in healthy individuals. There is no evidence that gender influences the pharmacokinetics of almotriptan.

Over 75% of the administered dose is excreted in urine, and the remainder in feces. Approximately 50% of the excreted amount in urine and feces consists of unchanged almotriptan. The primary metabolic pathway is oxidative deamination by monoamine oxidase-A (MAO-A) to form indole acetic acid metabolite. Other enzymes involved in almotriptan metabolism include cytochrome P450 (isoenzymes 3A4 and 2D6) and flavin monooxygenase. None of the metabolites exhibit significant pharmacological activity.

Elimination. Following intravenous administration of almotriptan to healthy volunteers, mean values for volume of distribution, total clearance, and elimination half-life were 195 L, 40 L/h, and 3.4 hours, respectively. Renal clearance (CLR) accounted for about two-thirds of total clearance, suggesting that renal tubular secretion also contributes to elimination. CLR correlates well with renal function in patients with mild (creatinine clearance: 60–90 mL/min), moderate (creatinine clearance: 30–59 mL/min), and severe (creatinine clearance: < 30 mL/min) renal impairment. A statistically and clinically significant increase in mean T_1/2 (up to 7 hours) occurs only in patients with severe renal impairment. Compared to healthy individuals, increases in maximum plasma concentration (C_max) of almotriptan were 9%, 84%, and 72% in patients with mild, moderate, and severe renal impairment, respectively, while increases in exposure (AUC) were 23%, 80%, and 195%, respectively.

Based on these findings, reductions in total almotriptan clearance were -20%, -40%, and -65% in patients with mild, moderate, and severe renal impairment, respectively. As expected, both total (CL) and renal (CLR) clearances were reduced in elderly healthy volunteers compared to younger controls, but not to a clinically significant extent.

Based on the known clearance mechanisms of almotriptan in humans, approximately 45% of almotriptan elimination occurs via hepatic metabolism. Therefore, even if these clearance pathways were completely blocked or impaired, plasma almotriptan concentrations would increase by no more than twofold compared to control conditions, assuming renal function (and renal clearance of almotriptan) remains unaffected by hepatic impairment. In patients with severe renal impairment, C_max is doubled and AUC is increased approximately threefold compared to healthy volunteers. The maximum changes in pharmacokinetic parameters observed in patients with significant hepatic impairment do not exceed these ranges. For this reason, pharmacokinetic studies of almotriptan in patients with hepatic impairment have not been conducted.

Clinical characteristics

Indications

For the acute treatment of migraine attacks, with or without aura.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• History of ischemic heart disease or symptoms or signs of existing (myocardial infarction, angina pectoris, documented silent ischemia, Prinzmetal's angina), severe hypertension, or uncontrolled mild or moderate hypertension.
• History of cerebrovascular disorders, transient ischemic attack (TIA), or peripheral vascular disorders.
• Concomitant use of ergotamine, ergotamine derivatives (including methysergide), or other 5-HT_1B/1D receptor agonists.
• Severe hepatic impairment (see section "Dosage and method of administration").

Interaction with other medicinal products and other forms of interaction

Interaction studies were conducted with monoamine oxidase A (MAO-A) inhibitors, beta-blockers, selective serotonin reuptake inhibitors (SSRIs), calcium channel blockers, or inhibitors of cytochrome P450 isoenzymes 3A4 and 2D6. No in vivo interaction studies assessing the effect of almotriptan on other medicinal products have been conducted.

As with other 5-HT₁ receptor agonists, a potential risk of serotonin syndrome due to pharmacodynamic interaction cannot be excluded when used concomitantly with monoamine oxidase inhibitors (MAO).

There have been reports of patients experiencing symptoms consistent with serotonin syndrome (including mental status changes, autonomic instability, and neuromuscular abnormalities) following concomitant use of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) and triptans (see section "Special precautions for use").

Repeated administration with the calcium channel blocker verapamil, a CYP3A4 substrate, resulted in a 20% increase in almotriptan C_max and AUC. This increase is not considered clinically significant. No clinically significant interactions were observed.

Repeated administration with propranolol did not alter the pharmacokinetics of almotriptan. No clinically significant interactions were observed.

In vitro studies conducted to evaluate the ability of almotriptan to inhibit major CYP enzymes in human liver microsomes and human monoamine oxidase (MAO) showed that almotriptan is not expected to alter the metabolism of medicinal products metabolized by CYP enzymes or by MAO-A and MAO-B enzymes.

Special precautions for use

Migretan should be used only for a clearly established diagnosis of migraine. Migretan should not be used to treat basilar, hemiplegic, or ophthalmoplegic migraine.

As with other agents for the acute treatment of migraine, other potentially serious neurological disorders should be excluded prior to initiating treatment for headache in patients who have not previously been diagnosed with migraine, as well as in patients with migraine who present with atypical symptoms. Cerebrovascular disorders have been reported in patients receiving 5-HT1B/1D agonists. It should be noted that patients with migraine may have an increased risk of certain cerebrovascular disorders (e.g., stroke, transient ischemic attack).

In very rare cases, as with other 5-HT1B/1D receptor agonists, coronary artery spasm and myocardial infarction have been reported. Therefore, almotriptan should not be administered to patients who may have undiagnosed coronary artery disease without prior evaluation for potential underlying cardiovascular disease. Such patients include postmenopausal women, men aged 40 years and older, and patients with other risk factors for coronary artery disease, such as uncontrolled arterial hypertension, hypercholesterolemia, obesity, diabetes, smoking, or a family history of cardiovascular disease. However, such preliminary evaluations cannot identify all patients with heart disease, and in very rare cases, serious cardiac complications have occurred in patients without underlying cardiovascular disease during treatment with 5-HT1 agonists.

Following almotriptan administration, transient symptoms may occur, including chest pain and chest tightness, which may be intense and radiate to the throat (see section "Adverse reactions").

If such symptoms raise suspicion of ischemic heart disease, the drug should be discontinued and appropriate investigations should be performed.

Caution should be exercised when prescribing almotriptan to patients with known hypersensitivity to sulfonamides.

Serotonin syndrome (including mental status changes, autonomic instability, and neuromuscular abnormalities) has been reported following concomitant use of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). These reactions may be severe. If concomitant treatment with almotriptan and SSRIs or SNRIs is clinically warranted, careful patient monitoring is recommended, especially at the beginning of treatment, during dose escalation, or when adding another serotonergic agent (see section "Interaction with other medicinal products and other forms of interaction").

At least 6 hours should elapse after almotriptan administration before taking ergotamine. Before administering almotriptan, it must be ensured that at least 24 hours have passed since the last dose of any ergotamine-containing medication. Although in a clinical study involving 12 healthy volunteers who received oral almotriptan and ergotamine, no additive vasospastic effects were observed, such effects are theoretically possible (see section "Contraindications").

Patients with severe renal impairment should not take more than one 12.5 mg tablet within 24 hours.

Caution is recommended in patients with mild to moderate hepatic impairment, and treatment is contraindicated in patients with severe hepatic impairment (see section "Pharmacokinetics").

Adverse effects occur more frequently with concomitant use of triptans and herbal products containing St. John's wort (Hypericum perforatum).

Like other 5-HT1B/1D receptor agonists, almotriptan may cause mild, transient increases in blood pressure, which may be more pronounced in elderly patients.

Medication-overuse headache.

Prolonged use of any analgesic for headache may worsen its course. If such a situation occurs (or is suspected), medical advice should be sought and treatment discontinued. Medication-overuse headache should be suspected in patients who experience frequent or daily headaches despite regular use of headache medications.

The maximum recommended dose of almotriptan should not be exceeded.

Sodium content. The medicinal product Migretan contains less than 1 mmol sodium (23 mg) per film-coated tablet (12.5 mg almotriptan), and is therefore considered essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

Data on the safety of almotriptan use in pregnant women are very limited. Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonal/fetal development, parturition, or postnatal development.

Almotriptan should be used with caution in pregnant women.

Breastfeeding period

There are no data on the excretion of almotriptan into human breast milk. Animal studies in rats have shown that almotriptan and/or its metabolites are excreted into milk.

Therefore, Migretan should be administered to breastfeeding women with caution. Exposure to the infant should be minimized by avoiding breastfeeding for 24 hours after drug administration.

Ability to affect reaction speed when driving or operating machinery

Studies on the effect of almotriptan on the ability to drive or operate machinery have not been conducted. Since somnolence may occur as an adverse effect during a migraine attack or during treatment with almotriptan, patients performing skilled tasks should exercise caution.

Method of Administration and Dosage

Almotriptan should not be used for the prevention of migraine.

Dosage

Adults (18–65 years)

The recommended dose is 1 tablet containing 12.5 mg of almotriptan.

A second dose may be taken no sooner than 2 hours after the first dose (1 tablet – 12.5 mg almotriptan) if symptoms persist or recur; no more than two doses should be taken within a 24-hour period.

The efficacy of a second dose for treating the same attack when the first dose was ineffective has not been evaluated in controlled clinical trials. Therefore, if the patient does not experience a therapeutic effect after taking the first dose, a second dose should not be taken for the same attack.

The maximum recommended dose within 24 hours is two tablets (two doses).

Elderly patients (65 years and older)

Dosage adjustment in elderly patients is not required. However, the safety and efficacy of almotriptan in patients aged 65 years and older have not been systematically studied.

Patients with renal impairment

Dose adjustment is not necessary in patients with mild or moderate renal impairment. Patients with severe renal impairment should not take more than 1 tablet (12.5 mg) within 24 hours.

Patients with hepatic impairment

There are no data on the use of almotriptan in patients with hepatic impairment (see section "Contraindications" and section "Special warnings and precautions for use").

Method of administration

The medicinal product Migrétan should be taken with liquid as early as possible after the onset of migraine-related headache, although it remains equally effective when taken at later stages.

The tablets may be taken with or without food.

Children

Children and adolescents (under 18 years of age)

There are no data on the efficacy and safety of almotriptan in children and adolescents; therefore, its use in this age group is not recommended.

Overdose

The most commonly reported adverse event in patients who received a 150 mg dose (the highest dose administered to patients) was somnolence.

Overdose should be treated symptomatically, and vital functions should be supported. Since the elimination half-life is approximately 3.5 hours, patient monitoring should continue for at least 12 hours or until symptoms and signs have resolved.

Adverse Reactions

The use of almotriptan has been evaluated in over 2700 patients in clinical studies lasting up to one year. The most commonly reported adverse reactions following administration of the therapeutic dose were dizziness, somnolence, nausea, vomiting, and fatigue. The incidence of any adverse reaction did not exceed 1.5%.

The adverse reactions listed below were reported in clinical studies and are presented by system organ class (SOC) and in order of decreasing frequency. The frequency of adverse reactions is defined as follows: very common (>1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), including isolated case reports, and not known (cannot be estimated from the available data).

* However, visual disturbances may be a consequence of the migraine attack itself.

Reporting of suspected adverse reactions

Reporting of adverse reactions following registration of the medicinal product is of significant importance. It enables continuous monitoring of the benefit-risk balance of the use of this medicinal product. Medical and pharmaceutical personnel, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 36 months.

Storage conditions. The medicinal product does not require special storage conditions.

Keep out of reach of children.

Packaging

3 tablets per blister, 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer

Shanell Medical Unlimited Company / Chanelle Medical Unlimited Company.

Manufacturer's address and place of business

Dublin Road, Loughrea, Co. Galway, H62 FH90, Ireland / Dublin Road, Loughrea, Co. Galway, H62 FH90, Ireland.

Marketing Authorisation Holder

UAB "Farmlyga" / JSC "Farmliga".

Address of the Marketing Authorisation Holder

Antakalnio g. 48A-304, Vilnius, Republic of Lithuania / Antakalnio St., 48A-304, Vilnius, Republic of Lithuania.