Xsenza^® (Spray) Instructions for Use

Marketing Authorization Holder

Pharmamed, LLC (Russia)

Manufactured By

PharmVILAR NPO, LLC (Russia)

Or

Pharmamed, LLC (Russia)

Contact Information

PHARMAMED LLC (Russia)

ATC Code

N02CC03 (Zolmitriptan)

Active Substance

Zolmitriptan (Rec.INN WHO registered)

Dosage Form

Xsenza®

Metered nasal spray 2.5 mg/1 dose: 20 dose bottle

Dosage Form, Packaging, and Composition

Metered nasal spray as a light yellow liquid; slight opalescence is allowed.

Excipients: anhydrous citric acid, dexpanthenol, benzalkonium chloride, disodium hydrogen phosphate dihydrate (for pH adjustment), purified water.

20 doses – dark glass bottles (1) with a nasal spray dispenser – 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

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.

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.

Clinical Efficacy and Safety

According to clinical studies, the likelihood of adverse reactions increases with increasing doses of zolmitriptan (see the “Adverse Reactions” section).

Migraine attacks with and without aura

In a clinical study of zolmitriptan involving 1300 migraine patients (with and without aura), when used (to relieve 3 migraine attacks per patient) at a dose of 2.5 mg, Zolmitriptan led to a reduction in headache intensity from severe/moderate to mild/complete relief within 2 hours after administration in 59% of attacks, while pain freedom was achieved in 26% of attacks. The corresponding results for the 5 mg dose were 70% and 36% respectively, and for the placebo group – 31% and 8% respectively. The frequency of a clinically significant effect (reduction in headache intensity by 1 level) 15 minutes after drug administration at both doses statistically significantly exceeded the placebo effect (8% and 11% of attacks in the placebo group compared to 5%). Due to different pharmacokinetic profiles of oral and nasal preparations, patients receiving the 2.5 mg nasal spray may not achieve sufficient efficacy at later time points compared to the 2.5 mg tablet.

Cluster headache attacks

Two controlled clinical studies of zolmitriptan with comparable design involved a total of 121 patients (for the relief of 3 cluster headache attacks).

In a pooled analysis of the results of these 2 studies, 30 minutes after administration led to a reduction in headache intensity from severe/moderate to mild/complete relief in 48.3% compared to 29.5% in the placebo group. Pain freedom was achieved in 34.8% of patients compared to 19.3% in the placebo group. The corresponding results for the 10 mg dose were 63.1% and 44.0% for headache response/pain freedom respectively.

Pharmacokinetics

Absorption

When administered intranasally, Zolmitriptan is rapidly absorbed, with blood concentrations reaching the limit of quantification within 5 minutes. Part of the zolmitriptan dose is rapidly absorbed directly through the nasopharyngeal mucosa. Individual pharmacokinetic profiles are characterized by one or two plasma concentration peaks within the interval of 0.5-5 hours after intranasal administration. The median T_max is about 2 hours. Fifteen minutes after intranasal administration in healthy volunteers, the concentration of zolmitriptan reached on average 40% of C_max.

For the active metabolite N-desmethylzolmitriptan (183C91), the median T_max was slightly higher (about 3 hours after a 2.5 mg dose and about 5 hours after a 5 mg dose). Therapeutic concentrations of zolmitriptan and its active metabolite 183C91 are maintained for up to 6 hours after administration (6 hours after administration, the concentration is 40% of C_max for zolmitriptan and 60% of C_max for 183C91). According to comparative AUC evaluation, the mean relative bioavailability of intranasally administered zolmitriptan 2.5 mg is 102% compared to oral administration of zolmitriptan 2.5 mg in tablet form. No drug accumulation is observed upon repeated administration.

After oral administration in tablet form, Zolmitriptan is rapidly and completely absorbed (at least 64%). The absorption of zolmitriptan is independent of food intake. Within 4 hours after oral administration during a migraine attack, the plasma concentrations of zolmitriptan and its metabolites were 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.

Overall, the main pharmacokinetic parameters of zolmitriptan and its active metabolite after administration as a nasal spray and as tablets are comparable.

Distribution

The V_d of zolmitriptan after IV administration is 2.4 L/kg. Plasma protein binding is 25%.

Metabolism

Three main metabolites of zolmitriptan have been identified: indoleacetic acid (the main metabolite in plasma and urine), N-oxide and N-desmethyl analogues. The N-desmethylated metabolite (183C91) is active, while the other two metabolites are inactive. The N-desmethylated metabolite also has agonist activity at vascular serotonin 5-HT_1B/1D receptors but is 2-6 times more potent than Zolmitriptan.

The metabolism of zolmitriptan is dependent on the cytochrome P450 isoenzyme CYP1A2, and the further metabolism of the N-desmethylated metabolite is mediated by the monoamine oxidase A (MAO-A) enzyme system.

The plasma concentration of the N-desmethylated metabolite is approximately half that of zolmitriptan. Therefore, it can be assumed that this metabolite contributes to the therapeutic effect of the drug.

Elimination

Zolmitriptan is eliminated primarily by hepatic biotransformation followed by excretion of metabolites in the urine. More than 60% of a single oral dose of zolmitriptan is excreted in the urine (mainly as the indoleacetic acid metabolite) and about 30% is excreted via the intestine, mainly unchanged.

The mean total plasma clearance of zolmitriptan is 25.9 mL/min/kg, one-sixth of which is renal clearance. Renal clearance is greater than the glomerular filtration rate, suggesting tubular secretion.

The mean T_1/2 of zolmitriptan and the N-desmethylated metabolite is about 3 hours.

Linearity/non-linearity

The pharmacokinetics of the N-desmethylated metabolite are similar to those of zolmitriptan. After single and multiple dosing in the dose range of 0.1-10 mg, Zolmitriptan and its N-desmethylated metabolite demonstrate linear kinetics.

Pharmacokinetics in specific patient groups

Elderly patients. With oral administration, pharmacokinetic parameters in healthy elderly individuals are similar to those in young healthy volunteers.

Children. Sufficient data on the pharmacokinetics of the drug in children are lacking.

Patients with renal impairment. With oral administration, 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 ranges observed in healthy volunteers.

Patients with hepatic impairment. With oral administration, patients with impaired liver function showed a slowdown in zolmitriptan metabolism proportional to the severity of liver dysfunction. 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 demonstrated. At the same time, a decrease in the concentrations of zolmitriptan metabolites, including the active metabolite, was noted.

Preclinical safety data

In preclinical studies, effects were observed only at drug exposure doses significantly exceeding the maximum, which is clinically insignificant.

Indications

• Relief of migraine attacks with and without aura;
• Relief of acute cluster headache in adults.

ICD codes

Dosage Regimen

The drug Xsenza^® is not indicated for the prevention of migraine or cluster headache.

It is used intranasally. The drug can be used either on an empty stomach or after a meal. Food does not affect the efficacy of the drug.

Migraine

The recommended dose for treating a migraine attack is 2.5 mg or 5 mg. For those patients who do not achieve a satisfactory effect with 2.5 mg, a dose of 5 mg may be effective for subsequent attacks.

It is desirable that the drug Xsenza^® be taken as early as possible after the onset of migraine headache, but the drug is also effective if taken at a later stage.

Sprays of the drug (one or several doses) can be performed in any nostril.

Cluster headache

The recommended dose for treating a cluster headache attack is 5 mg or 10 mg. For those patients who do not achieve a satisfactory effect with 5 mg, a dose of 10 mg may be effective for subsequent attacks.

The total daily dose should not exceed 10 mg, therefore, no more than 4 doses of zolmitriptan 2.5 mg or 2 doses of zolmitriptan 5 mg should be taken in any 24-hour period.

Patients with a cluster headache attack may feel nasal congestion on the side of the pain location. In such cases, it is recommended to administer the drug spray into the nostril on the opposite (contralateral) side.

Special patient groups

The safety and efficacy of the drug Xsenza^® in elderly patients over 65 years have not been established to date. Use is contraindicated.

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

In patients with CrCl above 15 mL/min, dose adjustment is not required. The drug is contraindicated in patients with severe renal impairment.

For patients taking MAO-A inhibitors, the maximum daily dose is 5 mg.

For patients taking cimetidine, the maximum daily dose is 5 mg.

For patients taking CYP1A2 inhibitor drugs such as fluvoxamine and quinolones (e.g., ciprofloxacin), the maximum daily dose is 5 mg.

The safety and efficacy in children under 18 years of age have not been established to date. Use is contraindicated.

A double dose should not be taken to compensate for a missed one.

Method of administration

Before using the drug Xsenza^®, the nostrils should be cleared (blow the nose gently). Before the first use of the drug, press the spray dispenser several times, directing the spray into the air, until a uniform spray cloud is formed. If more than 4 weeks have passed since the last use of the drug, the first spray should be made into the air to prevent the administration of an incomplete dose. Between uses, the bottle with the drug should be stored with the cap tightly closed.

When using, the bottle should be held with the sprayer pointing upwards.

Tilt the head slightly forward, insert the sprayer into the nostril, slightly tilting the tip of the sprayer away from the center of the nose, and press once.

If necessary, repeat the same with the other nostril.

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.

Frequency of occurrence is defined as follows: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10000 and <1/1000), and very rare (<1/10000).

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

Nervous system disorders: very common – dysgeusia; common – sensory disturbances, dizziness, headache, hyperesthesia, paresthesia, somnolence, sensation of warmth or cold, vertigo.

Cardiac disorders: common – palpitations; uncommon – tachycardia; very rare – myocardial infarction, angina pectoris, coronary vasospasm.

Vascular disorders: uncommon – slight increase in BP, transient increases in BP.

Respiratory, thoracic and mediastinal disorders common – epistaxis, nasal discomfort, non-infectious rhinitis (rhinorrhea).

Gastrointestinal 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 or abdominal pain.

Musculoskeletal and connective tissue disorders common – muscle weakness, myalgia.

Renal and urinary disorders uncommon – polyuria, frequent urination; very rare – urgent need to urinate.

General disorders and administration site conditions common – asthenia, lethargy, feeling of tightness in the chest, pain, tension or feeling of tightness in the throat, neck, chest or limbs, increased sweating.

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

Contraindications

• Hypersensitivity to zolmitriptan or to any of the excipients;
• Uncontrolled arterial hypertension;
• Elderly age (over 65 years);
• Coronary artery disease, including history of myocardial infarction;
• Coronary vasospasm/Prinzmetal’s angina;
• Wolff-Parkinson-White syndrome or arrhythmias associated with other accessory conduction pathways;
• Peripheral arterial disease;
• Cerebrovascular disorders (including stroke or transient ischemic attack) in history;
• Severe renal failure (CrCl < 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 (see section “Drug Interactions”);
• Concomitant use with MAO-A inhibitors and within 14 days after their discontinuation (see section “Drug Interactions”);
• Pregnancy;
• Breastfeeding period;
• Childhood and adolescence under 18 years.

Use in Pregnancy and Lactation

Pregnancy

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

Breastfeeding period

According to preclinical studies, Zolmitriptan passes into the milk of lactating animals. There are no data regarding the passage of zolmitriptan into the breast milk of women during breastfeeding. Therefore, the use of the drug Xsenza^® is contraindicated in women during breastfeeding. If the drug has been used, it is recommended to refrain from breastfeeding for 24 hours, which will minimize the risk of zolmitriptan exposure to the infant.

Fertility

There are no data on the effect of zolmitriptan on male and female fertility.

Use in Hepatic Impairment

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

Use in Renal Impairment

Use of the drug is contraindicated in severe renal impairment. In patients with CrCl above 15 mL/min, dose adjustment is not required.

Pediatric Use

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

Geriatric Use

Use of the drug in elderly patients (over 65 years) is not recommended.

Special Precautions

The drug Xsenza^® should be used only in cases of a verified diagnosis of migraine or cluster headache. As with other drugs for the treatment of headache attacks, other possible serious neurological diseases must be ruled out in patients with previously undiagnosed migraine or cluster headache, as well as in patients with atypical symptoms, before prescribing the drug.

The drug Xsenza^® is not indicated for the treatment of hemiplegic, basilar, and ophthalmoplegic migraine (the efficacy and safety of the drug in clinical studies in these patient categories have not been studied).

Cases of cerebrovascular accidents, including strokes, have been described in patients taking serotonin 5-HT_1B/1D receptor agonists. It should be taken into account that patients with migraine may be at risk of developing certain cerebrovascular disorders.

Very rarely, coronary vasospasm, angina pectoris, and myocardial infarction have been reported with the use of this class of drugs (serotonin 5-HT_1B/1D receptor agonists). Before prescribing zolmitriptan to patients with risk factors for coronary artery disease (for example: smoking, arterial hypertension, hyperlipidemia, diabetes mellitus, a family history of coronary artery disease), it is recommended to conduct a cardiovascular system examination; it is necessary to monitor blood pressure and ECG parameters. Particular attention should be paid to postmenopausal women and men over 40 years of age with these risk factors. However, not all patients can be diagnosed with cardiovascular disease during routine examination, and in very rare cases, serious cardiovascular complications may develop in patients with no history of cardiovascular disease.

As with other serotonin 5-HT_1B/1D receptor agonists, cases of a feeling of heaviness, pressure, or tightness in the chest have been reported after the use of zolmitriptan. If a patient experiences chest pain or other symptoms characteristic of coronary artery disease during therapy, further use of zolmitriptan should be discontinued until an appropriate medical examination is performed.

As with other serotonin 5-HT_1B/1D receptor agonists, a transient increase in blood pressure has been observed in patients regardless of a history of arterial hypertension (very rarely such an increase in blood pressure was clinically significant). The recommended doses of zolmitriptan should not be exceeded.

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

The development of serotonin syndrome has been reported with the concomitant use of triptans and selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome may include the following signs and symptoms: changes in mental status, autonomic and neuromuscular disorders. Close monitoring of patients is recommended when Xsenza^® and SSRIs or SNRIs are co-administered, especially during the initiation of therapy, dose increase, or addition of other serotonergic drugs to therapy (see the section “Drug Interactions”).

Excessive (prolonged or exceeding the recommended doses) use of painkillers can lead to an increase in the frequency of headache occurrence, which may potentially require discontinuation of therapy. If a patient experiences frequent or daily headaches despite regular use of drugs to treat this condition, the possibility of a causal relationship between the headaches and excessive use of the relevant drugs should be considered.

Excipients

The medicinal product Xsenza^® contains benzalkonium chloride, which may have an irritating effect on the nasal mucosa.

Effect on the ability to drive vehicles and operate machinery

No significant deterioration in the performance of psychomotor tests was observed in healthy volunteers taking zolmitriptan at doses up to 20 mg. Patients whose activities require 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.

Overdose

Symptoms: a single oral dose of zolmitriptan 50 mg in healthy volunteers usually caused a sedative effect. 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 until the overdose symptoms disappear.

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

Drug Interactions

Pharmacodynamic interactions

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 artery spasm, the concomitant use of these drugs is contraindicated. It is recommended to take Zolmitriptan no earlier than 24 hours after taking ergotamine and its derivatives, and in turn, it is recommended to take ergotamine-containing medicines no earlier than 6 hours after taking zolmitriptan (see the section “Contraindications”).

Pharmacokinetic interactions

MAO-A inhibitors increase the systemic exposure of zolmitriptan (after the use of moclobemide, a small (26%) increase in the AUC of zolmitriptan and a 3-fold increase in the AUC of its active metabolite were noted), therefore, the prescription of the drug Xsenza^® to patients receiving MAO-A inhibitors is contraindicated (see the section “Contraindications”).

After taking cimetidine, a cytochrome P450 inhibitor, an increase in T_1/2 and AUC of zolmitriptan and its active N-desmethylated metabolite (183C91) was noted. Therefore, for patients taking the drug Xsenza^® simultaneously with cimetidine, the maximum daily dose of the drug Xsenza^® should be no more than 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 within 24 hours should not exceed 5 mg.

Pharmacokinetic interaction of zolmitriptan with selegiline (MAO-B inhibitor) and fluoxetine (SSRI) has not been confirmed. However, cases of serotonin syndrome (including changes in mental status, autonomic and neuromuscular disorders) have been reported with the concomitant use of triptans and SSRIs or SNRIs (see the section “Special Precautions”).

When zolmitriptan is taken concomitantly with preparations of St. John’s wort (Hypericum perforatum), an interaction is possible that may increase the risk of side effects (see the section “Special Precautions”).

Like other serotonin 5-HT_1B/1D receptor agonists, Zolmitriptan may slow down the absorption of other medicines.

Concomitant use of zolmitriptan with other serotonin 5-HT_1B/1D receptor agonists (for example, sumatriptan, naratriptan) is contraindicated. The drug Xsenza^® should be used within 24 hours after their discontinuation (see the section “Contraindications”).

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

Prior use of the symptomatic vasoconstrictor xylometazoline does not have a significant effect on the pharmacokinetics of zolmitriptan.

Storage Conditions

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

Shelf Life

The shelf life is 2 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.