Zolmigren® spray

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOLMIGREN® SPRAY (ZOLMIGREN SPRAY)

Composition:

Active substance: zolmitriptan;

1 dose contains zolmitriptan 2.5 or 5 mg;

Excipients: benzalkonium chloride; citric acid, anhydrous; sodium hydrogen phosphate, dihydrate; dexpanthenol; purified water.

Pharmaceutical form. Metered nasal spray.

Main physicochemical properties:

2.5 mg/dose: light yellow liquid. Slight opalescence may occur.

5 mg/dose: yellow liquid. Slight opalescence may occur.

Pharmacotherapeutic group.

Medicinal products used in migraine. Selective serotonin 5-HT1-receptor agonists. Zolmitriptan. ATC code N02C C03.

Pharmacological Properties

Pharmacodynamics

Antimigraine agent. Zolmitriptan is a selective agonist of recombinant human 5-HT_1B/1D vascular serotonin receptors. It has moderate affinity for 5-HT_1A serotonin receptors and lacks significant affinity or pharmacological activity at 5-HT₂-, 5-HT₃-, 5-HT₄-serotonin receptors, α₁-, α₂-, β₁-adrenergic receptors, H₁-, H₂-histamine receptors, M-cholinergic receptors, D₁-, D₂-dopaminergic receptors.

Due to its agonist activity at 5-HT_1B/1D vascular receptors, zolmitriptan induces vasoconstriction primarily of cranial blood vessels, associated with inhibition of the release of calcitonin gene-related peptide, vasoactive intestinal peptide, and substance P.

In addition to its peripheral action, zolmitriptan affects brainstem nuclei involved in the pathogenesis of migraine attacks, which explains the sustained effect of repeated administration in treating a series of several migraine attacks in a single patient. During a migraine attack, vasodilation occurs due to reflex activation mediated by orthodromic fibers of the trigeminal nerve and parasympathetic innervation of cerebral circulation, primarily via release of vasoactive intestinal peptide as the main effector neurotransmitter. Zolmitriptan blocks this reflex activation and the release of vasoactive intestinal peptide, thereby halting the progression of a migraine attack without exerting direct analgesic effects.

In addition to aborting migraine attacks, zolmitriptan reduces nausea, vomiting (especially during left-sided attacks), photophobia, and phonophobia. It is highly effective in the comprehensive treatment of migraine status (a series of several severe, consecutive migraine attacks lasting 2–5 days). It alleviates menstrually associated migraine.

Clinical Efficacy and Safety

One controlled clinical study in 696 adolescents with migraine did not demonstrate superiority of zolmitriptan tablets at doses of 2.5 mg, 5 mg, and 10 mg compared to placebo. Efficacy was not demonstrated.

Pharmacokinetics

Absorption. Zolmitriptan is rapidly absorbed via the nasal mucosa following intranasal administration, as confirmed by positron emission tomography studies using radiolabeled [carbonyl-¹¹C] zolmitriptan. The mean relative bioavailability of Zomigreen® nasal spray is 102% compared to oral zolmitriptan tablets. In healthy volunteers, following single and repeated intranasal doses, zolmitriptan and its active metabolite N-desmethyl-zolmitriptan show dose-proportional area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C_max) over the dose range of 1 to 5 mg. On average, 40% of the C_max of the parent zolmitriptan is achieved within 15 minutes. The appearance of the active metabolite N-desmethyl-zolmitriptan in plasma, partially formed via first-pass metabolism, is delayed by 15–60 minutes after dosing. Zolmitriptan is detectable in plasma within 5 minutes, and the time to reach peak plasma concentration (T_max) is 3 hours. After administration, therapeutic plasma concentrations are maintained for 4–6 hours. No drug accumulation occurs with repeated dosing.

Plasma concentrations and elimination pharmacokinetics of zolmitriptan and its three major metabolites are similar between the nasal spray and conventional tablet formulations.

It has been established that the absorption of zolmitriptan nasal spray in healthy volunteers is not altered by concomitant use of the sympathomimetic nasal decongestant xylometazoline.

Distribution. The mean apparent volume of distribution for Zomigreen® nasal spray is 8.4 L/kg. Plasma protein binding is 25%.

Metabolism. Three major metabolites of zolmitriptan have been identified: indoleacetic acid (the primary metabolite in plasma and urine), N-oxide, and N-desmethyl analogs. The N-desmethyl metabolite (183C91) is pharmacologically active, while the other two metabolites are inactive. The N-desmethyl metabolite also acts as an agonist at 5-HT_1B/1D vascular serotonin receptors, with 2–6 times greater activity than zolmitriptan.

The pharmacokinetics of the N-desmethyl metabolite are similar to those of zolmitriptan. After single and repeated doses in the range of 0.1–10 mg, both zolmitriptan and its N-desmethyl metabolite exhibit linear kinetics.

Zolmitriptan metabolism is mediated by CYP1A2, while the metabolism of the active metabolite N-desmethyl-zolmitriptan occurs via monoamine oxidase A (MAO-A) enzyme system.

The N-desmethyl metabolite appears in plasma within 15 minutes, and its T_max is 3 hours.

Excretion. Elimination of zolmitriptan and its active metabolite N-desmethyl-zolmitriptan is similar after both oral and intranasal administration. The mean elimination half-life of zolmitriptan and its N-desmethyl metabolite is approximately 3 hours.

In an oral administration study, 65% of the administered dose was excreted in urine (primarily as the indoleacetic acid metabolite), and approximately 30% was excreted in feces, mainly as unchanged drug.

The mean total plasma clearance of Zomigreen® nasal spray is 25.9 ml/min/kg, of which renal clearance accounts for 1/6. Renal clearance exceeds the glomerular filtration rate, suggesting the presence of tubular secretion.

Pharmacokinetics in Specific Patient Populations

Elderly Patients

Following oral administration of zolmitriptan in healthy elderly volunteers (65–76 years) without migraine headache, pharmacokinetic parameters were similar to those observed in healthy young volunteers (18–39 years) without migraine headache.

Patients with Renal Impairment

Renal clearance of zolmitriptan and all its metabolites is reduced by 7–8 fold in patients with moderate to severe renal impairment, although AUC of the parent compound and active metabolite is only slightly increased (by 16% and 35%, respectively), and elimination half-life is prolonged by 1 hour, reaching 3–3.5 hours. These pharmacokinetic parameters remained within the range observed in healthy volunteers. These data were obtained from studies using zolmitriptan tablets.

Patients with Hepatic Impairment

Studies on the effect of liver disease on zolmitriptan pharmacokinetics following oral administration have shown that in patients with impaired liver function, compared to healthy volunteers, AUC and C_max are increased: by 94% and 50%, respectively, in patients with moderate hepatic impairment, and by 226% and 47%, respectively, in patients with severe hepatic impairment. The residence time of metabolites, including the active metabolite, is prolonged. For the metabolite N-desmethyl-zolmitriptan, AUC and C_max were reduced by 33% and 44%, respectively, in patients with moderate hepatic impairment, and by 82% and 90%, respectively, in patients with severe hepatic impairment.

The half-life (T_1/2) of zolmitriptan was 4.7 hours in healthy volunteers, 7.3 hours in patients with moderate hepatic impairment, and 12 hours in patients with severe hepatic impairment. Corresponding T_1/2 values for the N-desmethyl-zolmitriptan metabolite were 5.7, 7.5, and 7.8 hours, respectively. No studies have been conducted to characterize the pharmacokinetics of intranasal zolmitriptan in patients with hepatic impairment.

Patients with Cardiovascular Hypertensive Disease

Following oral administration of zolmitriptan in patients with mild to moderate arterial hypertension, no effect on pharmacokinetics or blood pressure parameters was observed compared to healthy volunteers with normal blood pressure.

Pharmacokinetic Interactions

In a small group of healthy volunteers, no pharmacokinetic interaction was observed with ergotamine. Concomitant administration of zolmitriptan with ergotamine/caffeine was well tolerated and did not lead to increased adverse effects or changes in blood pressure compared to zolmitriptan monotherapy. These data were obtained from studies with zolmitriptan tablets.

From a pharmacokinetic standpoint, selegiline (an MAO-B inhibitor) and fluoxetine (a selective serotonin reuptake inhibitor, SSRI) do not interact with zolmitriptan. These data were obtained from studies with zolmitriptan tablets.

Following rifampicin administration, no clinically significant differences in the pharmacokinetics of zolmitriptan or its active metabolite were observed. These data were obtained from studies with zolmitriptan tablets.

Clinical characteristics.

Indications.

Acute treatment of migraine attacks with aura and without aura.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients;
• Uncontrolled hypertension;
• Ischemic heart disease;
• Angina pectoris due to coronary vasospasm (Prinzmetal's angina);
• History of cerebrovascular disorders or transient ischemic attack (TIA);
• Concomitant use of ergotamine, ergotamine derivatives, or other 5HT1 receptor agonists.

Interaction with other medicinal products and other forms of interaction.

Interaction studies of oral zolmitriptan with ergotamine, paracetamol, and metoclopramide did not reveal any clinically significant changes in zolmitriptan's pharmacokinetic parameters or tolerability.

Studies with oral zolmitriptan have not shown evidence that concomitant use of migraine prophylactic medications affects the efficacy or adverse effects of zolmitriptan nasal spray (e.g., beta-blockers, oral dihydroergotamine, and pizotifen).

Based on data obtained from healthy volunteers, there is no pharmacokinetic interaction or any clinically significant interaction between zolmitriptan and ergotamine. However, since the risk of coronary spasm may increase, Zomig® nasal spray should be administered no sooner than 24 hours after using ergotamine-containing medications. Conversely, ergotamine-containing medications should not be administered earlier than 6 hours after using Zomig® nasal spray.

Following co-administration of moclobemide, a specific MAO-A inhibitor, and oral zolmitriptan, a slight increase (26%) in zolmitriptan AUC and a threefold increase in AUC of the active metabolite were observed. Therefore, in patients taking an MAO-A inhibitor, the recommended maximum daily dose of zolmitriptan nasal spray should not exceed 5 mg.

Concomitant administration of Zomig® nasal spray with other 5HT1B/1D receptor agonists is contraindicated due to the risk of vasospastic reactions within 24 hours.

Following co-administration of cimetidine, a general P450 inhibitor, and oral zolmitriptan, elimination half-life increased by 44% and AUC by 48%. Furthermore, cimetidine doubled the elimination half-life and AUC of the active N-desmethyl metabolite. Therefore, in patients receiving Zomig® nasal spray concomitantly with cimetidine, the maximum daily dose of Zomig® nasal spray should be limited to 5.0 mg.

Based on the general interaction profile, possible interactions with specific inhibitors of cytochrome P450 CYP1A2 cannot be excluded. Therefore, dose reduction is also recommended when using such compounds as fluvoxamine and quinolones (e.g., ciprofloxacin).

Fluoxetine did not affect the pharmacokinetic parameters of zolmitriptan in a study using oral zolmitriptan. Therapeutic doses of selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, sertraline, paroxetine, and citalopram, do not inhibit CYP1A2. However, cases of serotonin syndrome have been reported following concomitant use of triptans and SSRIs (e.g., fluoxetine, paroxetine, sertraline) or serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine and duloxetine.

Concomitant use of zolmitriptan with St. John's wort (Hypericum perforatum) may result in an interaction that could increase the risk of adverse effects (similar to that observed with other 5HT1B/1D serotonin receptor agonists).

Absorption and pharmacokinetics of the medicinal product are not altered if a vasoconstrictor, such as the sympathomimetic xylometazoline, was used prior to administration.

Special precautions for use.

Zomig® nasal spray should only be used when a diagnosis of migraine has been clearly established. Prior to initiating treatment for headache, potentially serious neurological conditions should be ruled out in patients. The medication should not be prescribed in cases of hemiplegic or basilar migraine.

Cerebrovascular events (hemorrhagic stroke, subarachnoid hemorrhage, ischemic stroke) have been reported with the use of 5HT1B/1D agonists, indicating an increased risk.

Zomig® nasal spray should not be administered to patients with symptomatic Wolff-Parkinson-White syndrome or arrhythmias associated with other accessory cardiac conduction pathways.

In rare cases, as with other 5HT1B/1D agonists, coronary artery spasm, angina pectoris, and myocardial infarction may occur. Zolmitriptan should not be used in patients with risk factors for ischemic heart disease without prior evaluation for cardiovascular disorders. However, such evaluation cannot identify all patients with underlying heart disease, and serious cardiac events have occurred in patients with no prior history of cardiovascular disorders.

Some patients, as with other 5HT1B/1D agonists, may experience chest tightness, pressure, or heaviness after taking zolmitriptan. If chest pain or symptoms suggestive of ischemic heart disease occur, zolmitriptan should be discontinued until appropriate medical evaluation has been performed.

Transient increases in blood pressure may occur in patients with or without a history of hypertension. Very rarely, such blood pressure elevations are associated with serious clinical manifestations.

Cases of serotonin syndrome have been reported with concomitant use of triptans and SSRIs or SNRIs. Serotonin syndrome may be life-threatening and may present with the following signs and symptoms (when using a serotonergic drug):

• spontaneous clonus;
• induced or ocular clonus with agitation or diaphoresis;
• tremor and hyperreflexia;
• hypertonia and elevated body temperature >38°C with induced or ocular clonus.

Careful monitoring is recommended in patients receiving concomitant treatment with Zomig® nasal spray and SSRIs or SNRIs, particularly at the start of therapy, when the dose is increased, or when another serotonergic agent is added to the treatment regimen (see section "Interaction with other medicinal products and other types of interactions").

Discontinuation of serotonergic drugs usually leads to rapid improvement. Treatment depends on the type and severity of symptoms.

Prolonged use of any analgesic for headache may worsen headache. In such cases, treatment should be discontinued and medical advice sought. Medication-overuse headache should be suspected in patients with frequent or daily headaches that do not respond to regular medication.

As with other 5HT1B/1D agonists, rare cases of anaphylaxis/anaphylactoid reactions have been reported in patients using Zomig® nasal spray.

The product contains benzalkonium chloride. When used topically, it may cause irritation and may provoke skin reactions.

Use during pregnancy or breastfeeding.

The safety of zolmitriptan use during pregnancy has not been established; therefore, the use of the drug in pregnant women is only recommended if the expected therapeutic benefit to the woman outweighs the potential risk to the fetus/child. Animal studies have not revealed direct teratogenic effects.

There are no data on the passage of zolmitriptan into human breast milk; therefore, the drug should be used with caution in breastfeeding women. Animal studies have shown that zolmitriptan is excreted into the milk of lactating animals.

Effect on ability to drive or operate machinery.

Studies have shown that oral administration of zolmitriptan at a dose of 20 mg does not affect psychomotor test performance. Zomig® nasal spray has no or negligible effect on the ability to drive or operate machinery. However, patients whose activities require rapid psychomotor responses should be warned that during a migraine attack, symptoms such as drowsiness and other migraine-related symptoms may occur.

Method of Administration and Dosage

Zomigren® spray is not intended for use in the prevention of migraine attacks. After the onset of a migraine attack, the medication should be used as early as possible. The recommended initial dose is 2.5 mg, corresponding to one spray of Zomigren® spray at a dose of 2.5 mg/dose. The maximum recommended dose is 5 mg, which corresponds to one spray of Zomigren® spray at a dose of 5 mg/dose or two sprays at a dose of 2.5 mg/dose. If there is no therapeutic effect or if pain recurs, a repeat dose may be administered, but not earlier than 2 hours after the first dose. The maximum daily dose is 10 mg.

Elderly patients

The safety and efficacy of Zomigren® spray in patients aged 65 years and older have not been systematically studied.

Hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of zolmitriptan nasal spray has not been studied. In patients with moderate to severe hepatic impairment, the metabolism of zolmitriptan is reduced following oral administration. For patients with moderate and severe hepatic impairment, the recommended maximum dose is 5 mg per day.

Renal impairment

Dosage adjustment is not required.

For interactions requiring dosage adjustments, see section "Interaction with other medicinal products and other forms of interaction."

Instructions for use

For optimal effectiveness, the nasal passages should be cleared (gently blown) before using Zomigren® spray.

Before the first use, prime the pump by pressing it several times into the air until a fine, consistent mist is produced. The device is now ready for use.

If more than four weeks have passed since the last use of the medication, the first spray should be administered into the air to ensure delivery of a full dose. Between uses, store the bottle with the cap securely closed.

When using, hold the bottle with the spray nozzle upright.

Tilt the head slightly forward, insert the spray nozzle into one nostril, slightly angling the tip away from the center of the nose, and press once. If necessary, repeat the same procedure in the other nostril.

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Children

The safety and efficacy of the medicinal product in pediatric patients under 12 years of age have not been established; therefore, use is recommended from the age of 12 years. The safety profile of the nasal spray in pediatric patients aged 12 to 17 years is similar to that observed in adults.

Overdose

Symptoms. No cases of overdose with zolmitriptan nasal spray have been reported. In volunteers who received a single oral dose of 50 mg of zolmitriptan, sedative effects were observed. The elimination half-life of zolmitriptan after intranasal administration is approximately 3 hours. Monitoring of patients in case of overdose should continue for at least 15 hours or until symptoms and signs have resolved.

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

Adverse Reactions

Zolmitriptan is generally well tolerated. Adverse reactions are usually mild or moderate in severity, transient, non-serious, and occur within 4 hours after drug administration. They do not occur more frequently with repeated use and resolve spontaneously without additional treatment.

Adverse reactions are classified according to their frequency and effects on organs or body systems. The following adverse reactions have been reported, categorized by frequency as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Cardiac disorders:

Common – palpitations;
Uncommon – tachycardia;
Very rare – myocardial infarction, angina pectoris, coronary spasm.

Vascular disorders:

Uncommon – transient increase in blood pressure.

Nervous system disorders:

Very common – taste disturbance;
Common – hypoesthesia, dizziness, headache, hyperesthesia, paresthesia, somnolence, sensation of warmth.

Gastrointestinal disorders:

Common – abdominal pain, dry mouth, dysphagia, nausea, vomiting;
Very rare – diarrhea with blood, intestinal infarction or necrosis, ischemic events in the gastrointestinal tract, ischemic colitis, splenic infarction.

Renal and urinary disorders:

Uncommon – polyuria, increased frequency of urination;
Very rare – urinary urgency.

Musculoskeletal and connective tissue disorders:

Common – muscle weakness, muscle pain.

Immune system disorders:

Rare – hypersensitivity reactions, anaphylactic/anaphylactoid reactions.

Skin and subcutaneous tissue disorders:

Rare – angioneurotic edema, urticaria.

Respiratory, thoracic and mediastinal disorders:

Common – epistaxis, nasal discomfort.

General disorders and administration site conditions:

Common – asthenia, sensation of heaviness, tightness, pain or pressure in the throat, neck, chest, and extremities.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging. Do not freeze.

Keep out of reach and sight of children.

Packaging. 2 ml (20 doses) in a light-protective glass bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Address of manufacturer’s location and place of business.
74, Kyrylivska Street, Kyiv, 04080, Ukraine.

Marketing Authorization Holder. JSC "Farmak".

Address of Marketing Authorization Holder.
63, Kyrylivska Street, Kyiv, 04080, Ukraine.