Migrenet

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

Composition:

active substance: sumatriptan;

1 tablet contains sumatriptan succinate equivalent to 50 mg or 100 mg of sumatriptan;

excipients:

for 50 mg tablets:

microcrystalline cellulose, calcium hydrogen phosphate, sodium hydrogencarbonate, sodium croscarmellose, magnesium stearate;

coating: hypromellose, polyethylene glycol 6000, titanium dioxide (E 171), iron oxide red (E 172);

for 100 mg tablets:

microcrystalline cellulose, calcium hydrogen phosphate, sodium hydrogencarbonate, sodium croscarmellose, magnesium stearate;

coating: hypromellose, polyethylene glycol 6000, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Basic physicochemical properties: round, biconvex tablets with a score line, film-coated, pink in colour.

Pharmacotherapeutic group

Selective serotonin 5-HT₁ receptor agonist. Medicinal products used in the treatment of migraine. ATC code N02CC01.

Pharmacological Properties

Pharmacodynamics

Sumatriptan has been shown to be a selective agonist of serotonin 5-hydroxytryptamine-1 (5-HT_1D) receptors, with no effect on other subtypes of 5-HT receptors (5-HT₂–5-HT₇).

The vascular 5-HT_1D receptor is predominantly located in cranial blood vessels and mediates vasoconstriction. In animals, sumatriptan selectively constricts blood flow in the carotid arteries without affecting cerebral blood flow. The carotid arterial system supplies blood to extra- and intracranial tissues, such as the meninges; dilation and/or edema formation in these vessels are believed to be a primary mechanism of migraine in humans. In addition, animal studies indicate that sumatriptan inhibits trigeminal nerve activity. Both of these actions (constriction of cranial vessels and inhibition of trigeminal nerve activity) may contribute to the antimigraine effect of sumatriptan in humans.

Sumatriptan remains effective in treating menstrual migraine, i.e., migraine without aura occurring from 3 days before the onset of menstruation to 5 days after. Sumatriptan should be taken as soon as possible during an attack.

Clinical effect is observed within 30 minutes after oral administration of 100 mg of the drug.

Although the recommended oral dose of sumatriptan is 50 mg, migraine attacks vary in severity both within an individual patient and between patients. Doses of 25–100 mg have demonstrated greater efficacy than placebo in clinical trials, but the 25 mg dose is statistically significantly less effective than the 50 mg and 100 mg doses.

The safety and efficacy of oral sumatriptan tablets were evaluated in several placebo-controlled clinical trials involving over 650 children and adolescents aged 10 to 17 years with migraine. These studies did not demonstrate a statistically significant difference in headache relief at 2 hours between placebo and any dose of sumatriptan. The adverse reaction profile of oral sumatriptan in children and adolescents aged 10 to 17 years was similar to that reported in adult studies.

Pharmacokinetics

After oral administration, sumatriptan is rapidly absorbed, reaching 70% of maximum concentration (C_max) within 45 minutes. Following a 100 mg dose, the mean peak plasma concentration is 54 ng/mL. The mean absolute bioavailability after oral administration is 14%, partly due to presystemic metabolism and partly due to incomplete absorption. The elimination half-life is approximately 2 hours, although evidence suggests a longer terminal phase. Plasma protein binding is low (14–21%), and the mean volume of distribution is 170 L. Mean total plasma clearance is approximately 1160 mL/min, and mean renal clearance is approximately 260 mL/min. Extrarenal clearance accounts for approximately 80% of total clearance. Sumatriptan is primarily eliminated via oxidative metabolism mediated by monoamine oxidase A.

Special Patient Groups

Hepatic Impairment

The pharmacokinetics of sumatriptan after oral (50 mg) and subcutaneous (6 mg) administration were studied in 8 patients with mild to moderate hepatic impairment, matched by sex, age, and body weight with 8 healthy volunteers. After oral administration, plasma exposure (AUC and C_max) of sumatriptan nearly doubled (increased by approximately 80%) in patients with mild to moderate hepatic impairment compared to control subjects with normal liver function. After subcutaneous administration, no differences were observed between patients with hepatic impairment and the control group. This indicates that mild to moderate hepatic impairment reduces presystemic clearance and increases bioavailability and systemic exposure of sumatriptan compared to healthy volunteers.

After oral administration, presystemic clearance is reduced in patients with mild to moderate hepatic impairment, and systemic exposure is nearly doubled.

The pharmacokinetics of sumatriptan in patients with severe hepatic impairment have not been studied (see sections "Contraindications" and "Special Warnings and Precautions for Use").

The primary metabolite, indole acetic acid analog of sumatriptan, is excreted predominantly in urine as free acid and glucuronide conjugate. It has no known 5-HT₁ or 5-HT₂ activity. Minor metabolites have not been identified. The pharmacokinetics of oral sumatriptan does not appear to be significantly influenced by migraine attacks.

In a pilot study, no significant differences in pharmacokinetic parameters were observed between elderly patients and young healthy volunteers.

Preclinical Safety Data

Sumatriptan showed no genotoxic or carcinogenic activity in in vitro systems and animal studies.

In a rat fertility study, oral doses of sumatriptan resulting in plasma levels approximately 200 times higher than in humans after a 100 mg oral dose were associated with reduced fertility success.

This effect was not observed in a subcutaneous administration study, where maximum plasma levels reached approximately 150 times higher than in humans after oral administration.

Embryolethality was observed in rabbits without evident teratogenic defects. The significance of these findings for humans is unknown.

Clinical Characteristics

Indications

Migrenet tablets are indicated for the acute relief of migraine attacks, with or without aura. Migrenet should be used only when a clear diagnosis of migraine has been established.

Contraindications

Hypersensitivity to sumatriptan or to any of the excipients of the medicinal product.

Sumatriptan should not be administered to patients who have suffered myocardial infarction or who have ischemic heart disease, coronary vasospasm (Prinzmetal's angina), peripheral vascular disease, or patients who have symptoms or signs consistent with ischemic heart disease.

Sumatriptan is contraindicated in patients with a history of cerebrovascular accident or transient ischemic attack.

The use of sumatriptan is contraindicated in patients with moderate to severe arterial hypertension, as well as in those with mild uncontrolled arterial hypertension.

Sumatriptan should not be administered to patients with severe hepatic impairment.

Concomitant use of ergotamine or its derivatives (including methysergide) or any other triptan/5-HT₁ receptor agonist with sumatriptan is contraindicated (see section "Interaction with other medicinal products and other types of interactions").

Concomitant administration of monoamine oxidase inhibitors (MAOIs) and sumatriptan is contraindicated. Migrenet should not be used within 2 weeks of discontinuing MAOIs.

Interaction with other medicinal products and other types of interactions

Studies in healthy volunteers show that sumatriptan does not interact with propranolol, flunarizine, pizotifen, or alcohol.

Data regarding interaction with medicinal products containing ergotamine or other triptan/5-HT₁ receptor agonists are limited. An increased risk of coronary vasospasm is theoretically possible; therefore, such concomitant use is contraindicated (see section "Contraindications").

The required time interval between administration of sumatriptan and medicinal products containing ergotamine or other triptan/5-HT₁ receptor agonists is unknown and may depend on the doses and types of medicinal products used. Because these effects may be potentiated by Migrenet, a 24-hour interval should be maintained between administration of ergotamine-containing products or other triptan/5-HT₁ receptor agonists and Migrenet. Conversely, it is recommended to wait at least 6 hours after administration of sumatriptan before administering an ergotamine-containing product, and at least 24 hours before administering another triptan/5-HT₁ receptor agonist. Interaction may occur between sumatriptan and MAO inhibitors; therefore, their concomitant use is contraindicated (see section "Contraindications").

Post-marketing studies have reported cases of serotonin syndrome (including mental status changes, autonomic instability, neuromuscular abnormalities) in patients taking selective serotonin reuptake inhibitors (SSRIs) and sumatriptan. Cases of serotonin syndrome have also been reported with concomitant use of triptans and serotonin-norepinephrine reuptake inhibitors (SNRIs) (see section "Special precautions for use").

Special precautions for use

Migrenet tablets should be used only when migraine has been clearly diagnosed.

Migrenet is not indicated for the treatment of hemiplegic, basilar, or ophthalmoplegic migraine.

Prior to initiating therapy with sumatriptan, potentially serious neurological disorders (e.g., cardiovascular disease, transient ischemic attack) should be ruled out in patients presenting with atypical symptoms or in whom a diagnosis of migraine has not been clearly established.

Sumatriptan may cause transient symptoms such as pain and sensations of tightness or pressure in the chest, which may be intense and radiate to the throat (see section "Adverse reactions"). If such symptoms suggest ischemic heart disease, appropriate cardiac evaluation should be performed.

Sumatriptan should not be administered to patients with risk factors for ischemic heart disease, including heavy smokers or those using nicotine replacement therapy, without prior cardiovascular evaluation (see section "Contraindications"). Particular caution is required in postmenopausal women and men over 40 years of age with these risk factors. However, such evaluation may not always detect underlying heart disease, and severe cardiovascular complications have been reported in rare cases in patients with undiagnosed cardiac conditions.

Migrenet should be used with caution in patients with mild, well-controlled arterial hypertension, as transient increases in blood pressure and peripheral vascular resistance may occur in a small number of patients (see section "Contraindications").

Rare cases of serotonin syndrome (including mental status changes, autonomic instability, and neuromuscular abnormalities) have been reported in post-marketing surveillance following concomitant use of SSRIs and sumatriptan. There have also been reports of serotonin syndrome with concomitant use of triptans and SNRIs. If concomitant use of Migrenet and SSRIs/SNRIs is clinically justified, careful patient monitoring is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Migrenet should be used with caution in patients with significant impairment in absorption, metabolism, or excretion of drugs, such as those with hepatic (Child–Pugh class A or B, see section "Pharmacological properties") or renal dysfunction (see section "Pharmacological properties"). A dose of 50 mg should be considered in patients with hepatic impairment.

Migrenet should be used with caution in patients with a history of seizures or risk factors for reduced seizure threshold, as seizures have been reported in association with sumatriptan use (see section "Adverse reactions").

Allergic reactions may occur in patients with known hypersensitivity to sulfonamides following administration of Migrenet. Reactions may range from skin hypersensitivity to anaphylaxis. Cross-sensitivity is limited, but caution should be exercised when prescribing the drug to such patients.

Adverse reactions may occur more frequently during concomitant use of triptans and medicinal products containing St. John's wort (Hypericum perforatum).

Prolonged use of any analgesic medicinal products may exacerbate headache. If such symptoms occur or are suspected, medical advice should be sought and treatment discontinued. Patients who experience frequent or daily headaches due to regular use of analgesics may be diagnosed with medication-overuse headache.

This medicinal product contains 40 mg of sodium bicarbonate per dose. Caution is advised when administering sumatriptan to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding

Pregnancy

Post-marketing data are available on the use of sumatriptan during the first trimester of pregnancy in over 1000 women. Although these data are insufficient to draw definitive conclusions, they do not indicate an increased risk of congenital malformations. Experience with sumatriptan use during the second and third trimesters of pregnancy is limited.

Animal studies do not indicate a direct teratogenic effect or adverse effects on peri- and postnatal development. However, embryofetal viability may be impaired in rabbits (see section "Pharmacological properties"). Sumatriptan should be used only if the expected benefit to the mother outweighs any potential risk to the fetus.

Breastfeeding

Sumatriptan has been shown to be excreted into breast milk following subcutaneous administration. Infant exposure can be minimized by avoiding breastfeeding for 12 hours after treatment; any expressed breast milk during this period should be discarded.

Ability to affect reaction speed when driving or operating machinery

Somnolence may result from migraine itself or from its treatment with Migrenet. Therefore, patients should avoid driving or operating machinery during an attack or while taking this medication.

Method of Administration and Dosage

Tablets Migranet cannot be used for the prevention of migraine attacks.

Migranet is recommended to be taken as early as possible after the onset of a migraine attack, although it is equally effective at any stage of the attack.

The recommended dose of Migranet for adults is 50 mg. In individual cases, the dose may be increased to 100 mg.

The medicinal product Migranet can be used for new migraine attacks; however, if the first dose proves ineffective, the drug should not be repeated during the same attack.

If the patient responds to the first dose but symptoms recur, a second dose may be administered within the next 24 hours, provided that the total daily dose does not exceed 300 mg.

Tablets should be swallowed whole with water.

Elderly patients (aged 65 years and older)

There is insufficient experience with the use of sumatriptan for the treatment of patients aged 65 years and older. Although the pharmacokinetics of the drug do not differ from those in younger individuals, until additional clinical data are available, the use of Migranet in elderly patients is not recommended.

Children

The efficacy and safety of sumatriptan for the treatment of children have not been established; therefore, Migranet is not recommended for use in this patient population.

Overdose

Doses exceeding 400 mg (orally) have not caused any adverse effects other than those listed below.

Treatment: supportive therapy and monitoring of the patient for at least 10 hours.

The effect of hemodialysis or peritoneal dialysis on plasma levels of Migranet has not been established.

Adverse reactions

Adverse reactions are listed below by system organ classes and frequency. Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10000 to <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data). Some of the symptoms reported as adverse reactions may be concomitant symptoms of migraine.

Reporting of suspected adverse reactions

Reporting adverse reactions following registration of the medicinal product is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life

2 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging

10 tablets per blister; 1 blister per cardboard box.

Prescription status

Prescription only.

Manufacturer

ASTRAFARM LLC

Manufacturer's address and location of its business activities

6, Kyivska Street, city of Vyshneve, Bucha district, Kyiv region, 08132, Ukraine