Zolmitriptan-SZ, 2,5mg 10 pcs

Pharmacotherapeutic group:antimigraine medicine

ATX code: N02CC03

Pharmacological properties

Pharmacodynamics

p> Zolmitriptan is a selective agonist of 5HT_1B/1D receptors, stimulation of which leads to vasoconstriction. It has high affinity for recombinant human 5HT_1B/1D receptors and moderate affinity for 5HT_1A receptors. Zolmitriptan has no affinity and no significant pharmacological activity towards 5HT₂, 5HT₃, 5HT₄, adrenergic, histamine, muscarinic and dopaminergic receptors.

The administration of zolmitriptan to laboratory animals resulted in vasoconstriction in the carotid artery basin. In addition, the results of 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 after 1 hour and increased from 2 to 4 hours after taking the drug.

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

Pharmacokinetics

After oral administration, zolmitriptan is rapidly and completely absorbed (minimum 64%). Absorption of zolmitriptan is not dependent on food intake. Mean absolute bioavailability is approximately 40%. Mean volume of distribution is 7.0 l/kg. Binding to plasma proteins is low (approximately 25%). The active metabolite of zolmitriptan
(N-desmethylmetabolite) is also a serotonin 5HT_1B/1D receptor agonist, 2-6 times more potent than zolmitriptan. When administered to healthy volunteers at a single dose ranging from 2.5 to 50 mg, zolmitriptan and its active metabolite have dose-dependent area under the concentration-time curve (AUC) and maximum concentration (Cmax). Cmax is reached within 1.5 hours (75% Cmax within 1 hour); the maximum plasma concentration of the drug is maintained for a further 4-6 hours. No drug cumulation was observed when multiple doses were administered. Within 4 hours after oral administration during a migraine attack, plasma concentrations of zolmitriptan and its metabolites were lower than those during the period between attacks. This is probably due to delayed absorption of zolmitriptan associated with delayed gastric emptying during a migraine attack.

Zolmitriptan is eliminated mainly by hepatic biotransformation with subsequent excretion of metabolites in the urine. Three main metabolites have been identified: indoleacetic acid (the main metabolite detected in plasma and urine), N-oxide- and N-desmethyl derivatives. The N-desmethylated metabolite is active, and the other two metabolites have no pharmacological activity. The plasma concentration of the N-desmethyl metabolite is about 2 times lower than that of zolmitriptan. Therefore, it can be assumed that this metabolite contributes to the therapeutic effect of zolmitriptan. More than 60% of zolmitriptan administered as a single oral dose is excreted in the urine (mainly as an indoleucetic metabolite) and about 30% is excreted through the intestine, mainly unchanged. Mean total plasma clearance of zolmitriptan is
31.5 ml/min/kg, one sixth of which is renal clearance. Renal clearance is higher than glomerular filtration, which suggests the presence of tubular secretion.

The mean half-life of zolmitriptan and the N-deleted metabolite is 4.7 h and 5.7 h in healthy volunteers, 7.3 h and 7.5 h in patients with moderate hepatic impairment and 12 h and 7.8 h in patients with severe hepatic impairment, respectively.

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 the elimination half-life by 1 hour (to 3-3.5 hours). The values of these pharmacokinetic parameters did not exceed the values observed in healthy volunteers.

In patients with impaired liver function there was a delay in metabolism of zolmitriptan in proportion to the severity of liver function impairment. Compared with healthy volunteers, patients with severe hepatic impairment showed a 226% increase in AUC, 47% increase in Cmax, and up to 12 hours increase in the elimination half-life. At the same time there was a decrease in concentrations of metabolites of zolmitriptan, including the active metabolite.

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

Indications

Relief of migraine attacks with or without aura.

Pharmacological effect

Pharmacotherapeutic group: antimigraine drug

ATX code: N02CC03

Pharmacological properties

Pharmacodynamics

Zolmitriptan is a selective agonist of 5HT1B/1D receptors, the stimulation of which leads to vasoconstriction. It has high affinity for recombinant human 5HT1B/1D receptors and moderate affinity for 5HT1A receptors. Zolmitriptan has no affinity and does not exhibit significant pharmacological activity towards 5HT2, 5HT3, 5HT4, adrenergic, histamine, muscarinic and dopaminergic receptors.

Administration of zolmitriptan to laboratory animals led to vasoconstriction in the carotid artery. In addition, 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.

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

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

Pharmacokinetics

After oral administration, zolmitriptan is rapidly and completely absorbed (minimum 64%). Absorption of zolmitriptan is independent of food intake. Average absolute bioavailability is approximately 40%. The average volume of distribution is 7.0 l/kg. Plasma protein binding is low (approximately 25%). Active metabolite of zolmitriptan
(N-desmethyl metabolite) is also a serotonin 5HT1B/1D receptor agonist, 2-6 times more potent than zolmitriptan. When administered to healthy volunteers as a single dose ranging from 2.5 to 50 mg, zolmitriptan and its active metabolite have a dose-dependent area under the concentration-time curve (AUC) and maximum concentration (Cmax). Cmax is reached within 1.5 hours (75% Cmax – within 1 hour); The maximum concentration of the drug in plasma is maintained over the next 4-6 hours. No accumulation of the drug was observed when taking several doses. Within 4 hours after taking the drug orally during a migraine attack, the concentration of zolmitriptan and its metabolites in the blood plasma was lower than when taking the drug in the inter-attack period. This is likely due to the slower absorption of zolmitriptan associated with slower gastric emptying during a migraine attack.

Zolmitriptan is eliminated primarily through hepatic biotransformation followed by excretion of metabolites in the urine. Three main metabolites have been identified: indoleacetic acid (the main metabolite detected in plasma and urine), N-oxide and N-desmethyl derivatives. The N-desmethylated metabolite is active, and the other two metabolites do not exhibit pharmacological activity. The concentration of N-desmethyl metabolite in plasma is approximately 2 times less than the concentration of zolmitriptan. Therefore, it can be assumed that this metabolite contributes to the therapeutic effect of zolmitriptan. More than 60% of zolmitriptan administered as a single oral dose is excreted in the urine (primarily as an indoleacetic metabolite) and about 30% is excreted through the intestines, predominantly unchanged. The average 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 the presence of tubular secretion.

The mean elimination half-lives of zolmitriptan and the N-desmethylated metabolite are 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.

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

In patients with hepatic impairment, a slowdown in the metabolism of zolmitriptan was observed, proportional to the severity of the hepatic impairment. In patients with severe liver dysfunction, compared with healthy volunteers, an increase in AUC was shown by 226%, Cmax by 47%, and half-life by up to 12 hours. At the same time, there was a decrease in the concentration of zolmitriptan metabolites, including the active metabolite.

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

Special instructions

The drug Zolmitriptan-SZ can only be used in cases of clearly diagnosed migraine. Before prescribing zolmitriptan, as well as other drugs for the relief of migraine, 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 or ophthalmoplegic migraine. Cerebrovascular accidents, including strokes, have been reported in patients taking serotonin 5HT1B/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 pathways.

Very rarely, when using this class of drugs (serotonin 5HT1B/1D receptor agonists), coronary vasospasm, angina pectoris and myocardial infarction were observed.

Before prescribing zolmitriptan to patients with risk factors for coronary heart disease (CHD) (for example, smoking, hypertension, hyperlipidemia, diabetes mellitus, family history of CAD), it is recommended to conduct an examination of the cardiovascular system, it is necessary to monitor blood pressure and an electrocardiogram. Particular attention should be paid to postmenopausal women and men over 40 years of age if these risk factors are present. However, not all patients will be diagnosed with cardiovascular disease, and in very rare cases, serious cardiovascular complications may develop in patients with no history of cardiovascular disease.

As with other serotonin 5HT1B/1D receptor agonists, sensations of heaviness, pressure, or tightness in the cardiac region have been reported with zolmitriptan. If chest pain or symptoms of coronary artery disease occur, you should stop taking zolmitriptan until appropriate medical evaluation is performed.

As with other serotonin 5HT1B/1D receptor agonists, transient increases in blood pressure were observed in patients regardless of a history of hypertension (very rarely such increases in blood pressure were clinically significant). Do not exceed recommended doses of zolmitriptan.

Side effects may be more frequent when taking triptans and herbal preparations containing St. John’s wort (Hypericum perforatum) at the same time.

The development of serotonin syndrome has been observed with the combined use of triptans and SSRIs or SSRIs. Serotonin syndrome may include the following signs and symptoms: mental status changes, autonomic symptoms, and neuromuscular symptoms. Careful monitoring of patients is recommended when concomitantly prescribed Zolmitriptan-SZ and an SSRI or SSRI, especially when starting therapy, increasing the dose, or adding another drug that affects serotonin metabolism to therapy (see section “Interaction with other drugs”).

Excessive use of antimigraine drugs may 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 medications to treat the condition, the patient should be aware of the possibility of developing headaches from overuse of headache medications.

Impact on the ability to drive vehicles and machinery

There was no significant deterioration in psychomotor tests when taking zolmitriptan at doses up to 20 mg. Patients whose activities require a high speed of psychomotor reactions (for example, driving a vehicle or operating machinery) are advised to exercise caution due to the possible development of drowsiness and other migraine symptoms.

Active ingredient

Zolmitriptan

Composition

1 tablet contains:

active ingredient: zolmitriptan – 2.5 mg;

excipients: anhydrous lactose (anhydrous milk sugar) – 98.3 mg, microcrystalline cellulose (type 102) – 15.0 mg, sodium carboxymethyl starch – 3.0 mg, magnesium stearate – 1.2 mg.

shell composition: hypromellose – 2.15 mg, polysorbate-80 (Tween-80) – 0.60 mg, talc – 0.60 mg, titanium dioxide E 171 – 0.45 mg, iron dye yellow oxide E 172 – 0.20 mg.

Pregnancy

Pregnancy

The safety of 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.

Breastfeeding period

Zolmitriptan penetrates into the milk of lactating animals. It is not known whether zolmitriptan passes into the breast milk of women during breastfeeding. Therefore, it is necessary to approach the issue of prescribing the drug to women during breastfeeding with caution.

Stopping breastfeeding for 24 hours can minimize the exposure of the infant to zolmitriptan.

Contraindications

Hypersensitivity to any components of the drug.

Children’s age – up to 18 years.

Elderly age – over 65 years (the effectiveness and safety of use have not been studied).

Pregnancy period (safety of use has not been studied).

Hemiplegic, basilar and ophthalmoplegic migraine.

Uncontrolled arterial hypertension.

Coronary heart disease.

Coronary vasospasm/Prinzmetal’s angina.

Peripheral arterial diseases.

A history of cerebrovascular accident (including stroke or transient ischemic attack).

Wolff-Parkinson-White syndrome or arrhythmias associated with other additional impulse pathways.

Severe renal failure (creatinine clearance less than 15 ml/min).

Concomitant use with other serotonin 5HT1B/1D receptor agonists (for example, sumatriptan, naratriptan), ergotamine or its derivatives (including methysergide), as well as within 24 hours after their discontinuation.

Combined use with MAO-A inhibitors and for 14 days after their discontinuation.

Lactose intolerance, lactase deficiency or glucose-galactose malabsorption.

With caution

Severe liver dysfunction

Side Effects

Adverse reactions when using zolmitriptan, as a rule, occur within 4 hours after taking the drug, are transient in nature 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 often (≥1/10 cases); often (≥1/100 and <1/10 cases); uncommon (≥1/1000 and <1/100 cases); rare (≥1/10000 and <1/1000 cases); very rare (< 1/10,000 cases).

From the central nervous system: often – sensory disturbances, dizziness, hyperesthesia, paresthesia, drowsiness, sensation of “warm” or “cold”, vertigo.

From the cardiovascular system: often – palpitations; uncommon – tachycardia, slight increase in blood pressure, transient increase in blood pressure; very rarely – myocardial infarction, angina pectoris, coronary vasospasm.

From the gastrointestinal tract: often – abdominal pain; nausea, vomiting, dry mouth, dyspepsia, dysphagia; very rarely – ischemia or infarction (for example, intestinal ischemia or infarction, splenic infarction), symptoms of which may include bloody diarrhea and abdominal pain.
From the musculoskeletal system: often – muscle weakness, myalgia.

From the urinary system: infrequently – polyuria, frequent urination; very rarely – imperative urge to urinate.

From the immune system: rarely – hypersensitivity reactions, including urticaria, angioedema and anaphylactic reactions.

General disorders: often – asthenia, inertia, feeling of shortness of breath, pain or tightness in the throat, neck, chest or limbs, increased sweating.

Some of the symptoms listed may be symptoms of migraine.

If any of the adverse reactions indicated in the instructions worsen, or you notice other adverse reactions not listed in the instructions, notify your doctor.

Interaction

In studies examining 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.

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

After the use of moclobemide (MAO-A inhibitor), there was a slight increase (26%) in the AUC of zolmitriptan and a threefold increase in the AUC of its active metabolite.

Following administration of cimetidine, a cytochrome P450 inhibitor, there was a 44% increase in zolmitriptan half-life and a 48% increase in AUC. Half-life and AUC of active
N-desmethylated metabolite increased twofold. Therefore, for patients taking cimetidine, the total dose of zolmitriptan taken during the day should not exceed 5 mg. Based on the general 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 (for example, fluvoxamine, ciprofloxacin and other quinolones), the total dose of zolmitriptan taken during the day should not exceed 5 mg.

The pharmacokinetic interaction of zolmitriptan with selegiline (MAO-B inhibitor) and fluoxetine (selective serotonin reuptake inhibitor (SSRI)) has not been confirmed. However, with the simultaneous use of triptans and SSRIs or SSRIs (selective serotonin and norepinephrine reuptake inhibitors), cases of serotonin syndrome have been described (see section “Special instructions”).

Like other serotonin 5HT1B/1D receptor agonists, zolmitriptan may delay the absorption of other drugs.

Side effects may be more common when triptans and herbal preparations containing St. John’s wort (Hypericum perforatum) are taken together.

Overdose

Symptoms

A single 50 mg oral dose of zolmitriptan to healthy volunteers typically resulted in sedation. The half-life of zolmitriptan is 2.5 to 3 hours, so in case of overdose, patient monitoring should continue for at least 15 hours or as long as symptoms of overdose persist.

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 ventilation of the lungs, as well as monitoring and supporting the function of the cardiovascular system.

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

Storage conditions

In a place protected from light, at a temperature not exceeding 25 oC.
Keep out of the reach of children.

Shelf life

3 years.
Do not use after the expiration date stated on the package.

Manufacturer

North Star NAO, Russia