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

Active ingredient

Composition

1 tablet contains:

acting substance: 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.

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

How to take, the dosage

The tablets should be taken orally with water.

The recommended dose for a migraine attack is 2.5 mg
(1 tablet). It is recommended to take the drug as soon as possible after the beginning of a headache, but the drug is also effective if taken later after the beginning of the attack.

If migraine symptoms reappear within 24 hours, a second dose of Zolmitriptan-SZ may be taken. Do not take the second dose earlier than 2 hours after the first dose. If there is no clinical effect after the first dose, there is unlikely to be benefit from a second dose during the same seizure.

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

Do not take more than 2 doses of Zolmitriptan-SZ per day. The total dose of Zolmitriptan taken during a day should not exceed 10 mg (4 tablets).

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

Application in special patient groups

Children and adolescents

The efficacy and safety of zolmitriptan in children under 12 years has not been studied. Efficacy of zolmitriptan in a placebo-controlled clinical study in patients aged 12 to 17 years has not been established. The use of Zolmitriptan-SZ in children and adolescents is not recommended.

Elderly age

The efficacy and safety of Zolmitriptan in patients older than 65 years has not been established. Therefore, the use of Zolmitriptan-SZ in elderly patients is not recommended.

Hepatic impairment

Dose adjustment in mild and moderate hepatic impairment is not required. For patients with severe hepatic impairment, the total dose of zolmitriptan taken during a day should not exceed 5 mg.

Renal failure

Dose adjustment is not required if creatinine clearance is above 15 ml/min. The drug is contraindicated in severe renal failure (creatinine clearance less than 15 ml/min).

Interaction with other medicinal products requiring dose adjustment

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

Interaction

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

The results of studies with 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 combined use of these drugs is contraindicated. It is recommended to use zolmitriptan not earlier than 24 hours after taking ergotamine or its derivatives.

A slight increase (26%) in AUC of zolmitriptan and a threefold increase in AUC of its active metabolite were observed after use of moclobemide (MAO-A inhibitor).

After administration of cimetidine, a cytochrome P450 inhibitor, there was a 44 % increase in the half-life of zolmitriptan and a 48 % increase in the AUC. The elimination half-life and AUC of the active
N-desmethylated metabolite were doubled. Therefore, for patients taking cimetidine, the total dose of zolmitriptan taken during a day should not exceed 5 mg. Based on the general interaction profile of zolmitriptan, the possibility of its interaction with CYP1A2 isoenzyme inhibitors of cytochrome P450 cannot be excluded. Therefore, for patients taking selective CYP1A2 isoenzyme inhibitors (e.g., fluvoxamine, ciprofloxacin and other quinolones) the total dose of zolmitriptan taken during a day should not exceed 5 mg.

Pharmacokinetic interaction of zolmitriptan with selegiline (MAO-B inhibitor) and fluoxetine (selective serotonin reuptake inhibitor (SSRI) has not been confirmed. However, cases of serotonin syndrome have been described when using triptans and SSRIs or SSRIs (selective serotonin and noradrenaline reuptake inhibitors) concomitantly (see section “Cautions”).

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

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

Special Instructions

The drug Zolmitriptan-SZ may be used only in cases of clearly diagnosed migraine. Before prescribing zolmitriptan, as well as other drugs for migraine control, it is necessary to exclude other possible serious neurological diseases in patients with previously undiagnosed migraine, as well as in patients with established diagnosis of migraine in the presence of atypical symptoms. Zolmitriptan is not indicated for the treatment of hemiplegic, basilar and ophthalmoplegic migraine. Patients taking serotonin 5HT1B/1D receptor agonists have experienced cerebral circulation disorders, including strokes. Patients with migraine may be at risk of developing certain brain circulatory disorders.

Should not use zolmitriptan in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other accessory pulse pathways.

Very rarely, coronary angiospasm, angina pectoris and myocardial infarction have been reported with this class of drugs (serotonin 5HT1B/1D receptor agonists).

Before prescribing zolmitriptan, patients with risk factors for coronary heart disease (CHD) (e.g., smoking, arterial hypertension, hyperlipidemia, diabetes mellitus, and a strong family history of CHD) should have a cardiovascular evaluation and blood pressure and electrocardiogram monitoring. Particular attention should be given to postmenopausal women and men over 40 years of age in the presence of these risk factors. However, not all patients have cardiovascular disease on examination, 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 heart region have been reported with zolmitriptan. If chest pain or symptoms of coronary heart disease occur, zolmitriptan should be discontinued until appropriate medical evaluation is performed.

As with other serotonin 5HT1B/1D receptor agonists, transient increases in blood pressure have been reported in patients regardless of a history of arterial hypertension (very rarely this increase in blood pressure was clinically significant). The recommended doses of zolmitriptan should not be exceeded.

Side effects may be more frequent if triptans and herbal preparations containing St. John’s Wort (Hypericum perforatum) are taken at the same time.

The development of serotonin syndrome has been noted when triptans and SSRIs or SSRIs are used concomitantly. Serotonin syndrome may include the following signs and symptoms: mental status changes, autonomic and neuromuscular symptoms. We recommend careful monitoring of patients with concomitant administration of Zolmitriptan-SZ and SSRIs or SSRIs, especially during initiation of therapy, dose increase or addition of another drug affecting serotonin metabolism to therapy (see section “Interaction with other medicinal products”).

Excessive use of antimigraine medications may lead to an increase in the frequency of headache, potentially requiring withdrawal of treatment. If a patient has frequent or daily headaches despite regular use of medications to treat this condition, be aware of the possibility of headache development with excessive use of headache therapy medications.

Influence on ability to drive vehicles, mechanisms

There was no significant impairment in performance of psychomotor tests when taking zolmitriptan in dose up to 20 mg. In patients whose activities require high speed psychomotor reactions (e.g., driving or operating machinery), caution is advised because of the possible development of somnolence and other migraine symptoms.

Synopsis

Contraindications

Hypersensitivity to any component of the drug.

Children under 18 years of age.

Elderly age – over 65 years (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.

Ischemic heart disease.

Coronary vasospasm/Prinzmetal angina.

Peripheral artery disease.

A history of cerebral circulation disorders (including stroke or transient ischemic attack).

Parkinson-White syndrome or arrhythmias associated with other accessory pulse pathways.

Severe renal impairment (creatinine clearance less than 15 mL/min).

The co-administration with other serotonin 5NT1B/1D receptor agonists (e.g., sumatriptan, naratriptan), ergotamine or its derivatives (including metizergide), and within 24 hours of their withdrawal.

The co-administration with MAO-A inhibitors and for 14 days after their withdrawal.

Lactose intolerance, lactase deficiency or glucose-galactose malabsorption.

With caution

Severe hepatic impairment

.

Side effects

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 incidence of adverse reactions is presented according to the WHO classification: very common (≥1/10 cases); common (≥1/100 and < 1/10 cases); infrequent (≥1/1000 and < 1/100 cases); rare (≥1/10000 and < 1/1000 cases); very rare (< 1/10000 cases).

From the central nervous system: frequent – sensory disturbances, dizziness, hyperesthesia, paresthesias, somnolence, sensation of “heat” or “cold”, vertigo.

Cardiovascular system disorders:often – feeling of palpitation; infrequently – tachycardia, slight increase in blood pressure, transient increase in blood pressure; very rarely – myocardial infarction, angina pectoris, coronary angiospasm.

Gastrointestinal tract: frequently, abdominal pain; nausea, vomiting, dry mouth, dyspepsia, dysphagia; very rarely, ischemia or infarction (e.g., ischemia or infarction of the colon, spleen infarction), symptoms of which may include diarrhea with blood admixture and abdominal pain.
Muscular system disorders:often – muscle weakness, myalgia.

Since the urinary system: infrequent – polyuria, frequent urination; very rare – urgent urge to urinate.

In immune system disorders: rarely – hypersensitivity reactions, including urticaria, angioedema and anaphylactic reactions.

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

Some of these symptoms may be symptoms of migraine.

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

Overdose

Symptoms

A single oral dose of 50 mg of zolmitriptan in healthy volunteers usually had a sedative effect. The half-life of zolmitriptan is 2.5 to 3 hours, so if there is an overdose, the patient should be monitored for at least 15 hours or until overdose symptoms are present.

Treatment

There is no specific antidote for zolmitriptan. In cases of severe intoxication, intensive care measures are recommended, including restoration and maintenance of airway patency, provision of adequate oxygenation and ventilation, and monitoring and support of cardiovascular function.

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

Pregnancy use

Pregnancy

The safety of using zolmitriptan during pregnancy has not been studied. The results of animal studies have shown no direct teratogenic effects. However, some data from embryotoxicity studies indicate a possible reduction in the viability of embryos. The use of the drug is contraindicated during pregnancy.

Breast-feeding 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 prescribing the drug to women during breastfeeding.

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

Similarities