Zolmitriptan-SZ (Tablets) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

N02CC03 (Zolmitriptan)

Active Substance

Zolmitriptan (Rec.INN registered by WHO)

Dosage Form

Zolmitriptan-SZ

Film-coated tablets, 2.5 mg: 2, 4, 6, 8, 10 or 20 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets yellow with a brownish tint, round, biconvex; on the cross-section, the tablet core is white or almost white.

Excipients: lactose anhydrous (anhydrous milk sugar), microcrystalline cellulose (type 102), sodium carboxymethyl starch, magnesium stearate.

Shell composition: hypromellose, polysorbate-80 (tween-80), talc, titanium dioxide (E171), iron oxide yellow dye (E172).

2 pcs. – blister packs (1) – cardboard packs.
4 pcs. – blister packs (1) – cardboard packs.
6 pcs. – blister packs (1) – cardboard packs.
8 pcs. – blister packs (1) – cardboard packs.
10 pcs. – blister packs (1) – cardboard packs.
10 pcs. – blister packs (2) – cardboard packs.
20 pcs. – polymer jars (1) – cardboard packs.
20 pcs. – polymer bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Serotonin 5-HT₁ receptor agonist. Agent with antimigraine activity

Pharmacotherapeutic Group

Analgesics; antimigraine preparations; selective agonists of serotonin 5-HT₁ receptors

Pharmacological Action

Mechanism of action

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

Pharmacodynamic effects

Administration of zolmitriptan to laboratory animals led to vasoconstriction in the carotid artery basin. Furthermore, results from studies in 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.

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.

Clinical efficacy and safety

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

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 in the range of 2.5 to 50 mg, Zolmitriptan and its active metabolite have dose-dependent AUC and C_max. C_max is reached within 1.5 hours (75% of C_max – within 1 hour); the drug’s C_max in plasma is maintained for the next 4-6 hours. No accumulation of zolmitriptan was observed with multiple doses. Within 4 hours after oral administration during a migraine attack, the concentration of zolmitriptan and its metabolites in blood plasma was lower than when the drug was taken in the interictal period. This is probably due to the slowed absorption of zolmitriptan associated with delayed gastric emptying during a migraine attack.

Distribution

The mean V_d is 7.0 L/kg. The degree of binding to plasma proteins is low (approximately 25%).

Metabolism

Zolmitriptan is eliminated primarily by hepatic biotransformation followed by excretion of metabolites in the urine. 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 show no pharmacological activity. 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 zolmitriptan. The active metabolite of zolmitriptan (N-desmethyl metabolite) is also an agonist of serotonin 5HT_1B/1D receptors, 2-6 times more potent than Zolmitriptan.

Excretion

More than 60% of zolmitriptan administered as a single oral dose is excreted in the urine (mainly as the indoleacetic metabolite) and about 30% is excreted through 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 is 4.7 hours and 5.7 hours in healthy volunteers, 7.3 hours and 7.5 hours in patients with moderate hepatic impairment, and 12 hours and 7.8 hours in patients with severe hepatic impairment, respectively.

Pharmacokinetics in special patient groups

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

Renal impairment. The renal clearance of zolmitriptan and its metabolites is 7-8 times lower in patients with moderate and severe renal impairment 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.

Hepatic impairment. In patients with impaired liver function, a slowdown in the metabolism of zolmitriptan was noted, proportional to the severity of liver dysfunction. In patients with severe hepatic 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. At the same time, a decrease in the concentration of zolmitriptan metabolites, including the active metabolite, was noted.

Indications

Adults aged 18 to 65 years

• Relief of migraine attacks with or 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 tablet). 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 Zolmitriptan-SZ 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, a repeated dose during the same attack is unlikely to be beneficial.

If a therapeutic effect is not achieved in a patient after taking a dose of 2.5 mg, Zolmitriptan-SZ can be used at a dose of 5 mg (2 tablets) to relieve subsequent migraine attacks.

No more than 2 doses of Zolmitriptan-SZ should be taken per day. The total dose of zolmitriptan taken during the day should not exceed 10 mg (4 tablets).

Zolmitriptan-SZ is not indicated for the prevention of migraine.

Special patient groups

Elderly patients (≥65 years)

The efficacy and safety of zolmitriptan in patients over 65 years of age have not been established to date. Therefore, the use of Zolmitriptan-SZ in elderly patients is contraindicated (see section “Contraindications”).

Patients with renal impairment

In patients with CrCl >15 ml/min, dose adjustment is not required. Zolmitriptan-SZ is contraindicated in patients with severe renal failure (CrCl <15 ml/min) (see section “Contraindications”).

Patients with hepatic impairment

The biotransformation of zolmitriptan is reduced in patients with impaired liver function (see section “Pharmacokinetics”). Therefore, in patients with moderate or severe hepatic impairment, the maximum daily dose should not exceed 5 mg of zolmitriptan. In patients with mild hepatic insufficiency, dose adjustment is not required.

Interactions 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 maximum daily dose of zolmitriptan should not exceed 5 mg.

Children

Zolmitriptan-SZ is contraindicated for use in children and adolescents aged 0 to 18 years (see section “Contraindications”).

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.

Adverse reactions are distributed by system-organ class with an indication of the frequency of their occurrence: very common (≥1/10); common (≥1/100 but <1/10); uncommon (≥1/1000 but <1/100); rare (≥1/10000 but <1/1000); very rare (<1/10000), frequency not known (cannot be estimated from available data).

Some of the listed symptoms may be symptoms of migraine.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk ratio of the drug. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to zolmitriptan or to any of the excipients included in the drug;
• Hemiplegic, basilar and ophthalmoplegic migraine;
• Uncontrolled arterial hypertension;
• Ischemic heart disease;
• Coronary vasospasm/Prinzmetal’s angina;
• Peripheral arterial disease (PAD);
• Cerebrovascular disorders, including history of stroke or transient ischemic attack (TIA);
• Wolff-Parkinson-White syndrome or arrhythmias associated with other accessory conduction pathways;
• Severe renal failure (CrCl <15 ml/min);
• Concomitant use with other serotonin 5HT_1B/1D receptor agonists (e.g., sumatriptan, naratriptan), ergotamine or its derivatives (including methysergide), as well as within 24 hours after their withdrawal (see section “Drug Interactions”);
• Concomitant use with MAO-A inhibitors and within 14 days after their withdrawal;
• Pregnancy;
• Children under 18 years of age;
• Elderly age ≥65 years.

With caution severe hepatic impairment.

Use in Pregnancy and Lactation

Pregnancy

The safety of using zolmitriptan 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 (see section “Contraindications”).

Breastfeeding period

Zolmitriptan passes into the milk of lactating animals. There are no data on the passage of zolmitriptan into the breast milk of women during lactation. Therefore, caution should be exercised when prescribing the drug to women during breastfeeding. If it is necessary to use zolmitriptan, it is recommended to refrain from breastfeeding for 24 hours, which will minimize exposure to the breastfed infant.

Use in Hepatic Impairment

In patients with moderate or severe hepatic impairment, the maximum daily dose should not exceed 5 mg of zolmitriptan. In patients with mild hepatic insufficiency, dose adjustment is not required.

Use in Renal Impairment

In patients with CrCl >15 ml/min, dose adjustment is not required. Zolmitriptan-SZ is contraindicated in patients with severe renal failure (CrCl <15 ml/min).

Pediatric Use

Zolmitriptan-SZ is contraindicated for use in children and adolescents aged 0 to 18 years.

Geriatric Use

The use of the drug in elderly patients is contraindicated.

Special Precautions

Zolmitriptan-SZ 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.

Zolmitriptan should not be used in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other accessory conduction pathways.

Cerebrovascular disorders, including strokes, very rarely – coronary angiospasm, angina and myocardial infarction have been reported in patients taking serotonin 5-HT_1B/1D receptor agonists. Migraine patients may be at risk of developing certain cerebrovascular disorders. As with the use of other serotonin 5-HT_1B/1D receptor agonists, the following have been reported with the use of zolmitriptan

• Sensations of heaviness, pressure or tightness in the heart area (if chest pain or symptoms of coronary artery disease occur, zolmitriptan should be discontinued until appropriate medical examination is performed);
• Transient increase in blood pressure in patients, regardless of a history of arterial hypertension (very rarely such an increase in blood pressure was clinically significant);
• Rare cases of anaphylaxis/anaphylactoid reactions in patients.

The recommended doses of zolmitriptan should not be exceeded.

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, and blood pressure and ECG should be monitored. Particular attention should be paid to postmenopausal women and men ≥40 years of age with the specified risk factors. However, not all patients can be identified with cardiovascular disease during examination, and in very rare cases, serious cardiovascular complications can develop in patients with no history of cardiovascular disease.

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

Serotonin syndrome has been reported with the combined 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 Zolmitriptan-SZ and SSRIs/SNRIs are co-administered, especially during the initiation of therapy, dose increase, or addition of another drug affecting serotonin metabolism (see section “Drug Interactions”).

Excessive use of anti-migraine drugs can lead to an increase in the frequency of headaches, 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.

Excipients

Zolmitriptan-SZ contains lactose monohydrate. Patients with rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this drug.

Effect on ability to drive vehicles and operate machinery

No significant impairment in psychomotor test performance was observed when taking zolmitriptan in doses up to 20 mg. Patients whose activities require high speed of psychomotor reactions (for example, driving a vehicle or machinery) are advised 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 therapy measures are recommended, including restoration and maintenance of airway patency, ensuring adequate oxygenation and lung ventilation, as well as monitoring and support of the cardiovascular system function. The effect of hemodialysis and peritoneal dialysis on the serum concentration of zolmitriptan has not been established.

Drug Interactions

Pharmacodynamic Interaction

Results of studies involving healthy volunteers indicate the absence of pharmacokinetic and clinically significant interaction between zolmitriptan and ergotamine. However, due to the theoretical risk of coronary angiospasm, the concomitant use of these drugs is contraindicated (see section “Contraindications”). It is recommended to use Zolmitriptan no earlier than 24 hours after taking ergotamine preparations or its derivatives.

Pharmacokinetic Interaction

After the use 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 noted.

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. For patients taking cimetidine, the total dose of zolmitriptan taken within 24 hours 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 maximum daily dose should not exceed 5 mg.

Pharmacokinetic interaction of zolmitriptan with selegiline (an MAO-B inhibitor) and fluoxetine (SSRI) was not confirmed. However, cases of serotonin syndrome development, including changes in mental status, autonomic and neuromuscular disorders, have been described with the concomitant use of triptans and SSRIs/SNRIs.

When triptans and herbal preparations containing St. John’s wort (Hypericum perforatum) are taken concomitantly, an interaction that increases the risk of adverse reactions is possible (see section “Special Instructions”).

Like other serotonin 5-HT_1B/1D receptor agonists, Zolmitriptan may slow down the absorption of other medicinal products. Concomitant use of zolmitriptan with other serotonin 5-HT_1B/1D receptor agonists (e.g., sumatriptan, naratriptan) is contraindicated. The drug Zolmitriptan-SZ should be used no earlier than 24 hours after their discontinuation.

In studies on the interaction of zolmitriptan with caffeine, ergotamine, dihydroergotamine, paracetamol, metoclopramide, pizotifen, fluoxetine, rifampicin, and propranolol, no clinically significant changes in the pharmacokinetic parameters of zolmitriptan and its active metabolite were identified.

Storage Conditions

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

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the package.

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.