Migrepam^® (Tablets) Instructions for Use

Marketing Authorization Holder

Aliym, JSC (Russia)

Contact Information

ALIUM JSC (Russia)

ATC Code

N02CC03 (Zolmitriptan)

Active Substance

Zolmitriptan (Rec.INN registered by WHO)

Dosage Form

Migrepam®

Film-coated tablets, 2.5 mg: 2, 3, 4, 5, 6, 10, or 20 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets yellow in color, round, biconvex; the core on the cross-section is white or almost white.

Excipients: anhydrous lactose, microcrystalline cellulose, sodium carboxymethyl starch (sodium starch glycolate), magnesium stearate.

Shell composition hypromellose (hydroxypropyl methylcellulose), macrogol 6000 (polyethylene glycol 6000), titanium dioxide, talc, yellow iron oxide.

2 pcs. – contour cell packaging (1) – cardboard packs.
2 pcs. – contour cell packaging (2) – cardboard packs.
3 pcs. – contour cell packaging (1) – cardboard packs.
3 pcs. – contour cell packaging (2) – cardboard packs.
5 pcs. – contour cell packaging (1) – cardboard packs.
5 pcs. – contour cell packaging (2) – cardboard packs.
10 pcs. – contour cell packaging (1) – cardboard packs.
10 pcs. – contour cell packaging (2) – cardboard packs.

Clinical-Pharmacological Group

Serotonin 5-HT₁ receptor agonist. Agent with antimigraine activity

Pharmacotherapeutic Group

Antimigraine agent

Pharmacological Action

Zolmitriptan is a selective agonist of serotonin 5-HT_1B/1D receptors, stimulation of which leads to vasoconstriction. It has high affinity for recombinant human serotonin 5-HT_1B/1D receptors and moderate affinity for serotonin 5HT_1A receptors. Zolmitriptan has no affinity and does not exhibit significant pharmacological activity towards serotonin 5HT₂-, 5HT₃-, 5HT₄ receptors, α-adrenergic receptors, histamine, muscarinic, and dopamine receptors.

Administration of zolmitriptan to laboratory animals led to vasoconstriction in the carotid artery basin. Furthermore, results from studies on laboratory animals indicate that Zolmitriptan blocks central and peripheral trigeminal nerve activity by inhibiting the release of calcitonin gene-related peptide, vasoactive intestinal peptide, and substance P.

In clinical studies, the effect of zolmitriptan on headache and other migraine symptoms (such as nausea, photophobia, phonophobia) was noted within 1 hour and increased during the period from 2 to 4 hours after drug administration.

Zolmitriptan is equally effective for migraine with aura, migraine without aura, and menstruation-associated migraine. Taking zolmitriptan during the aura did not prevent migraine headache, so the drug should be taken after the onset of the pain attack.

Pharmacokinetics

Absorption

After oral administration, Zolmitriptan is rapidly and completely absorbed (at least 64%). The absorption of zolmitriptan is independent of food intake. The mean absolute bioavailability is approximately 40%. When healthy volunteers took a single dose ranging from 2.5 to 50 mg, Zolmitriptan and its active metabolite exhibited dose-dependent AUC and C_max values in plasma. C_max is reached within 1.5 hours (75% of C_max within 1 hour) and is maintained for the subsequent 4-6 hours. Within 4 hours after oral administration during a migraine attack, the concentration of zolmitriptan and its metabolites in plasma was lower than when the drug was taken during the interictal period. This is likely due to slowed absorption of zolmitriptan associated with delayed gastric emptying during a migraine attack.

Distribution

The mean V_d is 7 L/kg. The degree of binding to plasma proteins is low (approximately 25%). No accumulation of the drug was observed with multiple doses.

Metabolism

Three main metabolites have been identified: indoleacetic acid (the main metabolite found in plasma and urine), N-oxide and N-desmethyl derivatives. The N-desmethylated metabolite is active, while the other two metabolites exhibit no pharmacological activity. The active metabolite of zolmitriptan (N-desmethyl metabolite) is also an agonist of serotonin 5-HT_1B/1D receptors, 2-6 times more potent than Zolmitriptan. The plasma concentration of the N-desmethyl metabolite is approximately half that of zolmitriptan. Therefore, it can be assumed that this metabolite contributes to the therapeutic effect of the drug Migrepam^®.

Elimination

Zolmitriptan is eliminated primarily by hepatic biotransformation followed by excretion of metabolites in the urine.

More than 60% of zolmitriptan administered as a single oral dose is excreted in the urine (primarily as the indoleacetic metabolite) and about 30% is excreted via the intestine, mainly unchanged. The mean total plasma clearance of zolmitriptan is 31.5 ml/min/kg, one-sixth of which is renal clearance. Renal clearance is higher than the glomerular filtration rate, suggesting tubular secretion.

The mean T_1/2 of zolmitriptan and the N-desmethylated metabolite in healthy volunteers is 4.7 hours and 5.7 hours, respectively.

Pharmacokinetics in special patient groups

In patients with impaired liver function, a slowing of zolmitriptan metabolism was observed, proportional to the severity of liver impairment. In patients with severe liver impairment compared to healthy volunteers, an increase in AUC by 226%, C_max by 47%, and T_1/2 up to 12 hours was shown. This was accompanied by a decrease in the concentration of zolmitriptan metabolites, including the active metabolite. In patients with moderate liver impairment, the mean T_1/2 of zolmitriptan and the N-desmethylated metabolite is 7.3 hours and 7.5 hours, respectively; in patients with severe liver impairment – 12 hours and 7.8 hours, respectively.

In patients with moderate and severe renal failure, the renal clearance of zolmitriptan and its metabolites is 7-8 times lower compared to healthy individuals, although the AUC of zolmitriptan and the active metabolite increases slightly (by 16% and 35%, respectively) with an increase in T_1/2 by 1 hour (to 3-3.5 hours). The values of these pharmacokinetic parameters did not exceed the values noted in healthy volunteers.

Pharmacokinetic parameters in healthy elderly individuals are similar to those in young healthy volunteers.

Indications

• Relief of migraine attacks with and without aura.

ICD codes

Dosage Regimen

The drug is taken orally. The tablets should be swallowed whole with water.

The recommended dose of the drug for relieving a migraine attack is 2.5 mg (1 tab.).

It is recommended to take the drug as early as possible from the onset of headache, but the drug is also effective when taken later after the onset of the attack. If migraine symptoms recur within 24 hours, a repeated dose of the drug Migrepam^® can be taken. A repeated dose should not be taken earlier than 2 hours after taking the first dose. If no clinical effect is observed after the first dose, benefit from a repeated dose during the same attack is unlikely.

If a therapeutic effect was not achieved in a patient after taking the drug at a dose of 2.5 mg, for relieving subsequent migraine attacks, the drug Migrepam^® can be used at a dose of 5 mg (2 tabs.).

No more than 2 doses of the drug Migrepam^® should be taken per day. The daily dose of zolmitriptan should not exceed 10 mg (4 tabs.).

The drug Migrepam^® is not indicated for the prevention of migraine.

The efficacy and safety of zolmitriptan use in children under 12 years of age have not been studied. The efficacy of zolmitriptan use in a placebo-controlled clinical study in patients aged 12 to 17 years was not established. The use of the drug Migrepam^® in children and adolescents is not recommended.

The efficacy and safety of zolmitriptan in patients over 65 years of age have not been established. Therefore, the use of the drug Migrepam^® in elderly patients is not recommended.

Dose adjustment for mild and moderate liver impairment is not required. For patients with severe liver impairment, the daily dose of zolmitriptan should not exceed 5 mg.

Dose adjustment in patients with renal failure with CrCl above 15 ml/min is not required. The drug is contraindicated in severe renal failure (CrCl less than 15 ml/min).

Interaction with other medicinal products requiring dose adjustment

For patients taking cimetidine or selective inhibitors of the CYP1A2 isoenzyme (e.g., fluvoxamine, ciprofloxacin and other quinolones), the daily dose of zolmitriptan should not exceed 5 mg.

Adverse Reactions

Adverse reactions when using zolmitriptan usually occur within 4 hours after taking the drug, are transient and resolve spontaneously without treatment. The frequency of adverse reactions does not increase with repeated doses.

The frequency of adverse reactions is presented according to the WHO classification: very common (≥1/10 cases), common (≥1/100 and <1/10 cases), uncommon (≥1/1000 and <1/100 cases), rare (≥1/10,000 and <1/1000 cases) and very rare (<1/10,000 cases).

Nervous system disorders common – sensory disturbances, dizziness, hyperesthesia, paresthesia, somnolence, sensation of warmth or cold, vertigo.

Cardiovascular system disorders common – palpitations; uncommon – tachycardia, slight increase in BP, transient increase in BP; very rare – myocardial infarction, angina pectoris, coronary angiospasm.

Digestive system disorders common – abdominal pain, nausea, vomiting, dry mouth, dyspepsia, dysphagia; very rare – ischemia or infarction (e.g., intestinal ischemia or infarction, splenic infarction), symptoms of which may include bloody diarrhea and abdominal pain.

Musculoskeletal system disorders common – muscle weakness, myalgia.

Urinary system disorders uncommon – polyuria, frequent urination; very rare – imperative urge to urinate.

Immune system disorders rare – hypersensitivity reactions, including urticaria, angioedema and anaphylactic reactions.

Other common – asthenia, inertia, difficulty breathing, pain or tightness in the throat, neck, chest or limbs, increased sweating.

Some of the listed symptoms may be symptoms of migraine.

If any of the adverse reactions listed in the instructions worsen or other adverse reactions not listed in the instructions are noted, the patient must inform the doctor.

Contraindications

• Hemiplegic, basilar and ophthalmoplegic migraine;
• Uncontrolled arterial hypertension;
• Coronary artery disease;
• Coronary vasospasm/Prinzmetal’s angina;
• Peripheral arterial disease;
• Cerebrovascular disorders (including stroke or transient ischemic attack) in history;
• Wolff-Parkinson-White syndrome or arrhythmias associated with other accessory conduction pathways;
• Severe renal failure (CrCl less than 15 ml/min);
• Concomitant use with other serotonin 5-HT_1B/1D receptor agonists (e.g., sumatriptan, naratriptan), ergotamine or its derivatives (including methysergide), as well as within 24 hours after their discontinuation;
• Concomitant use with MAO-A inhibitors and within 14 days after their discontinuation;
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption (the drug contains lactose);
• Pregnancy (safety of use not studied);
• Elderly age over 65 years (efficacy and safety of use not studied);
• Age under 18 years;
• Hypersensitivity to zolmitriptan and other components of the drug.

With caution the drug should be prescribed for severe liver dysfunction.

Use in Pregnancy and Lactation

Pregnancy

The safety of zolmitriptan use during pregnancy has not been studied. Results from animal studies did not reveal direct teratogenic effects. However, some data from embryotoxicity studies indicate a possible decrease in embryo viability. The use of the drug is contraindicated during pregnancy.

Breastfeeding period

Zolmitriptan penetrates into the milk of lactating animals. It is not known whether Zolmitriptan penetrates into the breast milk of women during breastfeeding. Therefore, caution should be exercised when considering prescribing the drug to women during breastfeeding. Discontinuation of breastfeeding for 24 hours allows minimizing the exposure of the breastfed infant to zolmitriptan.

Use in Hepatic Impairment

With caution the drug should be prescribed for severe liver dysfunction.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal failure (CrCl less than 15 ml/min).

Pediatric Use

The use of the drug in children and adolescents under 18 years of age is not recommended.

Geriatric Use

The use of the drug in elderly patients (over 65 years) is not recommended (efficacy and safety of use not studied).

Special Precautions

The drug Migrepam^® should be used only in cases of clearly diagnosed migraine. Before prescribing zolmitriptan, as well as other migraine relief agents, it is necessary to exclude other possible serious neurological diseases in patients with previously undiagnosed migraine, as well as in patients with an established diagnosis of migraine in the presence of atypical symptoms.

Zolmitriptan is not indicated for the treatment of hemiplegic, basilar and ophthalmoplegic migraine.

Cerebrovascular disorders, including strokes, have been observed in patients taking serotonin 5-HT_1B/1D receptor agonists. Patients with migraine may be at risk of developing certain cerebrovascular disorders.

Zolmitriptan should not be used in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other accessory conduction pathways. Very rarely, with the use of this class of drugs (serotonin 5-HT_1B/1D receptor agonists), coronary angiospasm, angina pectoris and myocardial infarction have been reported.

Before prescribing zolmitriptan to patients with risk factors for coronary artery disease (e.g., smoking, arterial hypertension, hyperlipidemia, diabetes mellitus, family history of coronary artery disease), it is recommended to conduct a cardiovascular examination; it is necessary to monitor BP and ECG. Particular attention should be paid to postmenopausal women and men over 40 years of age with the specified risk factors. However, not all patients can be identified with cardiovascular diseases during examination, and in very rare cases, serious cardiovascular complications can develop in patients with no history of cardiovascular disease.

As with the use of other serotonin 5-HT_1B/1D receptor agonists, sensations of heaviness, pressure or tightness in the heart area have been reported with the use of zolmitriptan. If chest pain or symptoms of coronary artery disease occur, zolmitriptan should be discontinued until appropriate medical examination is performed.

As with other serotonin 5-HT_1B/1D receptor agonists, a transient increase in BP has been observed in patients regardless of a history of arterial hypertension (very rarely such an increase in BP was clinically significant).

The recommended doses of zolmitriptan should not be exceeded.

Side effects may be more frequent with concomitant use of triptans and herbal preparations containing St. John’s wort (Hypericum perforatum).

Serotonin syndrome has been reported with the concomitant use of triptans and SSRIs or SNRIs. Serotonin syndrome may include the following signs and symptoms: changes in mental status, autonomic and neuromuscular symptoms. Close monitoring of patients is recommended when co-administering the drug Migrepam^® and SSRIs or SNRIs, especially during the initiation of therapy, dose increase, or addition of another drug affecting serotonin metabolism to the therapy.

Excessive use of anti-migraine drugs can lead to an increase in the frequency of headache occurrence, potentially requiring discontinuation of treatment. If a patient experiences frequent or daily headaches despite regular use of drugs to treat this condition, the possibility of medication-overuse headache should be considered.

Effect on ability to drive vehicles and operate machinery

No significant impairment in psychomotor test performance was observed with zolmitriptan doses up to 20 mg. Patients engaged in activities requiring high speed of psychomotor reactions (e.g., driving vehicles or operating machinery) are recommended to exercise caution due to the possible development of drowsiness and other migraine symptoms.

Overdose

Symptoms when a single oral dose of zolmitriptan 50 mg was taken by healthy volunteers, sedation was usually noted. The T_1/2 of zolmitriptan is 2.5-3 hours, so in case of overdose, patient observation should continue for at least 15 hours or as long as overdose symptoms are present.

Treatment there is no specific antidote for zolmitriptan. In case of severe intoxication, intensive care measures are recommended, including restoration and maintenance of airway patency, ensuring adequate oxygenation and lung ventilation, as well as monitoring and support of cardiovascular function.

The effect of hemodialysis and peritoneal dialysis on the serum concentration of zolmitriptan has not been established.

Drug Interactions

Studies on the interaction of zolmitriptan with caffeine, ergotamine, dihydroergotamine, paracetamol, metoclopramide, pizotifen, fluoxetine, rifampicin, and propranolol did not reveal any clinically significant changes in the pharmacokinetic parameters of zolmitriptan and its active metabolite.

Results from studies involving healthy volunteers indicate the absence of a pharmacokinetic and clinically significant interaction between zolmitriptan and ergotamine. However, due to the theoretical risk of coronary vasospasm, the concomitant use of these drugs is contraindicated. It is recommended to administer Zolmitriptan no earlier than 24 hours after taking ergotamine preparations or its derivatives.

Following the administration of moclobemide (an MAO-A inhibitor), a slight increase (by 26%) in the AUC of zolmitriptan and a threefold increase in the AUC of its active metabolite were observed.

After taking cimetidine, a cytochrome P450 inhibitor, an increase in the T_1/2 of zolmitriptan by 44% and an increase in AUC by 48% were noted. The T_1/2 and AUC of the active N-desmethylated metabolite doubled. Therefore, for patients taking cimetidine, the daily dose of zolmitriptan should not exceed 5 mg.

Based on the overall interaction profile of zolmitriptan, the possibility of its interaction with inhibitors of the cytochrome P450 isoenzyme CYP1A2 cannot be excluded. Therefore, for patients taking selective inhibitors of the CYP1A2 isoenzyme (e.g., fluvoxamine, ciprofloxacin, and other quinolones), the daily dose of zolmitriptan should not exceed 5 mg.

Pharmacokinetic interaction of zolmitriptan with selegiline (an MAO-B inhibitor) and fluoxetine (a selective serotonin reuptake inhibitor (SSRI)) was not confirmed. However, cases of serotonin syndrome have been reported during concomitant use of triptans and SSRIs or SNRIs (serotonin and norepinephrine reuptake inhibitors). Like other agonists of serotonin 5HT_1B/1D receptors, Zolmitriptan may slow the absorption of other drugs.

Side effects may be more frequent with the concomitant use of triptans and herbal preparations containing St. John’s wort (Hypericum perforatum).

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.