Instructions Zolmigren spray nasal spray dosed 2.5 mg/dose bottle 2 ml 20 doses
Composition
active ingredient: zolmitriptan;
1 dose contains zolmitriptan 5 mg;
Excipients: benzalkonium chloride; citric acid, anhydrous; sodium hydrogen phosphate, dihydrate; dexpanthenol; purified water.
Dosage form
Nasal spray dosed.
Main physical and chemical properties: yellow liquid. Slight opalescence is allowed.
Pharmacotherapeutic group
Drugs 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 vascular serotonin 5-HT1B/1D receptors. It has moderate affinity for serotonin 5-HT1A receptors, and has no significant affinity or pharmacological activity for 5HT2, 5HT3, 5HT4 serotonin receptors, α1-, α2-, β1-adrenergic receptors, H1-, H2-histamine receptors, M-choline receptors, D1-, D2-dopaminergic receptors.
Due to its vascular 5-HT1B/1D receptor agonist properties, zolmitriptan causes vasoconstriction, predominantly of cranial vessels, associated with blocking the release of calcitonin gene-related peptide, vasoactive intestinal peptide, and substance P.
In addition to its peripheral action, zolmitriptan acts on the brainstem nuclei involved in the mechanism of migraine attacks, which explains the persistent effect of repeated administration in the treatment of a series of several migraine attacks in one patient. During a migraine attack, vasodilation is noted due to the activation of reflex excitation supported by orthodromic fibers of the trigeminal nerve and parasympathetic innervation of the cerebral circulation through the release of vasoactive intestinal peptide as the main effector neurotransmitter. Zolmitriptan blocks reflex excitation and release of vasoactive intestinal peptide, stops the development of a migraine attack without direct analgesic action.
Along with stopping a migraine attack, it reduces nausea, vomiting (especially in left-sided attacks), photo- and phonophobia. Highly effective in the complex treatment of status migraine (a series of several severe, successive migraine attacks lasting 2-5 days). Eliminates migraine associated with menstruation.
Clinical efficacy and safety
One controlled clinical trial in 696 adolescents with migraine did not demonstrate superiority of zolmitriptan tablets at doses of 2.5 mg, 5 mg, and 10 mg over placebo. Efficacy was not demonstrated.
Pharmacokinetics
Absorption. Zolmitriptan is rapidly absorbed from the nasopharynx after nasal administration, as demonstrated by positron emission tomography studies using radioactive [carbonyl-11C] zolmitriptan. The mean relative bioavailability of Zolmigren® spray is 102% compared to oral zolmitriptan tablet. In healthy volunteers, after single and multiple intranasal doses, zolmitriptan and its active metabolite N-desmethyl-zolmitriptan have dose-proportional area under the pharmacokinetic curve (AUC) and maximum concentration (Cmax) in the dose range of 1 to 5 mg. On average, 40% of the Cmax of the parent zolmitriptan is achieved within 15 minutes. The appearance of the active metabolite N-desmethyl-zolmitriptan in the blood plasma, which is formed partly by first-pass metabolism, is delayed for 15-60 minutes after taking the dose. Zolmitriptan is detected in the blood plasma after 5 minutes, and the time to reach its maximum concentration (Tmax) is 3 hours. After using the drug, its therapeutic concentration in the blood plasma is maintained for 4-6 hours. With repeated use, cumulation of the drug is not observed.
The plasma concentration and elimination pharmacokinetics of zolmitriptan and the three major metabolites are similar for the nasal spray and conventional tablet formulations.
The absorption of zolmitriptan nasal spray in healthy volunteers was found to be unchanged when co-administered with the sympathomimetic nasal decongestant xylometazoline.
Distribution: The mean apparent volume of distribution for Zolmigren® nasal spray is 8.4 l/kg. Plasma protein binding is 25%.
Metabolism. Three major metabolites of zolmitriptan have been identified: indoleacetic acid (the major metabolite in plasma and urine), N-oxide and N-desmethyl analogues. The N-desmethyl metabolite (183C91) is active, while the other two metabolites are inactive. The N-desmethyl metabolite also has vascular serotonin 5-HT1B/1D receptor agonist activity, but is 2-6 times higher than zolmitriptan.
The pharmacokinetics of the N-desmethyl metabolite are similar to those of zolmitriptan. After single and multiple dosing of the drug in the dose range of 0.1-10 mg, zolmitriptan and its N-desmethyl metabolite demonstrate linear kinetics.
The metabolism of zolmitriptan is dependent on CYP1A2, and the metabolism of the active metabolite N-desmethyl-zolmitriptan occurs via the monoamine oxidase A (MAO-A) enzyme system.
Excretion: The elimination of zolmitriptan and the active metabolite N-desmethyl-zolmitriptan is similar after oral and intranasal administration. The mean half-life of zolmitriptan and the N-desmethyl metabolite is approximately 3 hours.
In a study with oral administration of zolmitriptan, it was found that 65% of the administered dose was excreted in the urine (mainly as the indoleacetic metabolite) and approximately 30% of the administered dose was excreted in the feces, mainly as unchanged substance.
The mean total plasma clearance of Zolmigren® spray is 25.9 ml/min/kg, 1/6 of which is renal clearance. Renal clearance is greater than glomerular filtration rate, suggesting the presence of tubular secretion.
Pharmacokinetics in certain patient groups.
Elderly patients
When zolmitriptan was administered orally to healthy elderly volunteers (65-76 years old) who did not suffer from migraine headache, the same pharmacokinetic parameters of the drug were observed as in healthy young volunteers (18-39 years old) who also did not suffer from migraine headache.
Patients with renal insufficiency
Renal clearance of zolmitriptan and all its metabolites in patients with moderate and severe renal insufficiency is reduced by 7-8 times, although the AUC of the parent compound and the active metabolite is only slightly increased (by 16 and 35%, respectively), and the half-life is increased by 1 hour and reaches 3-3.5 hours. The values of these pharmacokinetic parameters do not exceed the values in healthy volunteers. These data are obtained from studies of the use of zolmitriptan in tablet form.
Patients with hepatic insufficiency
A study of the effect of liver disease on the pharmacokinetics of zolmitriptan administered orally has shown that in patients with severe liver disease, AUC and Cmax are increased by 94% and 50%, respectively, in patients with moderate liver disease and by 226% and 47%, respectively, in patients with severe liver disease compared to healthy volunteers. The residence time of metabolites, including the active metabolite, is reduced. For the metabolite N-desmethyl-zolmitriptan, AUC and Cmax were reduced by 33% and 44%, respectively, in patients with moderate liver disease and by 82% and 90%, respectively, in patients with severe liver disease.
The T1/2 of zolmitriptan was 4.7 hours in healthy volunteers, 7.3 hours in patients with moderate liver disease and 12 hours in patients with severe liver disease. The corresponding T1/2 values for the metabolite N-desmethyl-zolmitriptan were 5.7 hours, 7.5 hours and 7.8 hours, respectively. No studies have been conducted to characterize the pharmacokinetics of intranasal zolmitriptan in patients with impaired liver function.
Patients with hypertensive heart disease
Oral administration of zolmitriptan to patients with mild to moderate hypertension had no effect on pharmacokinetics or blood pressure parameters compared to volunteers with normal blood pressure.
Pharmacokinetic interactions
No pharmacokinetic interaction with ergotamine was observed in a small group of healthy volunteers. Co-administration of zolmitriptan with ergotamine/caffeine was well tolerated and did not result in an increase in adverse events or changes in blood pressure compared with zolmitriptan alone. These data are from studies of zolmitriptan in tablet form.
From a pharmacokinetic perspective, selegiline (an MAO-B inhibitor) and fluoxetine (a selective serotonin reuptake inhibitor (SSRI)) do not interact with zolmitriptan. These data are derived from studies of zolmitriptan in tablet form.
No clinically significant differences in the pharmacokinetics of zolmitriptan or its active metabolite were observed after administration of rifampicin. These data are derived from studies of zolmitriptan in tablet form.
Indication
Relief of migraine attacks with and without aura.
Contraindication
Increased individual sensitivity to the components of the drug; uncontrolled arterial hypertension; ischemic heart disease; angiospastic angina (Prinzmetal's angina); cerebrovascular disorders and transient ischemic attack (TIA) in history; simultaneous use of ergotamine, ergotamine derivatives or other 5HT1 receptor agonists.
Interaction with other medicinal products and other types of interactions
In studies of the interaction of zolmitriptan in the form of oral tablets with ergotamine, paracetamol, and metoclopramide, no clinically significant changes in the pharmacokinetic parameters and tolerability of zolmitriptan were found.
Based on data obtained in healthy volunteers, no pharmacokinetic interaction or any interaction of clinical significance has been observed between zolmitriptan and ergotamine. Since the risk of coronary spasm may be increased, it is recommended that Zolmigren® spray be taken no earlier than 24 hours after taking ergotamine-containing drugs. Conversely, it is recommended that ergotamine-containing drugs be taken no earlier than 6 hours after taking Zolmigren® spray.
After concomitant administration of moclobemide, a specific MAO-A inhibitor, and zolmitriptan in the form of oral tablets, a small increase (26%) in the AUC of zolmitriptan and a three-fold increase in the AUC of the active metabolite were observed. Therefore, in patients taking an MAO-A inhibitor, the use of zolmitriptan in the form of nasal spray is recommended at a dose not exceeding 5 mg per day.
It is contraindicated to take Zolmigren® spray with other 5HT1B/1D receptor agonists due to the risk of vasospastic reactions within 24 hours.
After administration of cimetidine, a general P450 inhibitor, and zolmitriptan in the form of oral tablets, the half-life increases by 44% and the AUC by 48%. In addition, cimetidine doubled the half-life and AUC of the active, N-desmethylated metabolite. Therefore, for patients using Zolmigren® spray simultaneously with cimetidine, the maximum daily dose of Zolmigren® spray should be limited to no more than 5.0 mg.
Based on the general interaction profile, the possibility of interaction with specific inhibitors of cytochrome P450 CYP1A2 cannot be excluded. Therefore, when using similar compounds, such as fluvoxamine and quinolones (e.g. ciprofloxacin), a dose reduction is also recommended.
Fluoxetine did not affect the pharmacokinetics of zolmitriptan in a study using zolmitriptan tablets. Therapeutic doses of the specific serotonin reuptake inhibitors fluoxetine, sertraline, paroxetine and citalopram do not inhibit CYP1A2. However, serotonin syndrome has been reported following concomitant use of triptans and SSRIs, such as fluoxetine, paroxetine, sertraline, or selective serotonin and norepinephrine reuptake inhibitors (SSRIs), such as venlafaxine, duloxetine.
When zolmitriptan is taken simultaneously with St. John's wort (Hypericum perforatum) preparations, an interaction is possible that may increase the risk of developing undesirable effects (as with other 5HT1B/1D serotonin receptor agonists).
The absorption and pharmacokinetics of the drug are not changed if a vasoconstrictor, the sympathomimetic xylometazoline, is used before its use.
Application features
Zolmigren® spray should only be used when a diagnosis of migraine is clearly established. Before starting treatment for headache, patients should be excluded from other potentially serious neurological conditions. The drug should not be prescribed for hemiplegic, basilar migraine.
An increased risk of cerebrovascular events (hemorrhagic stroke, subarachnoid hemorrhage, ischemic stroke) has been reported with the use of 5HT1B/1D agonists.
Zolmigren® spray should not be prescribed to patients suffering from symptomatic Wolff-Parkinson-White syndrome or arrhythmia associated with other additional cardiac conduction pathways.
In isolated cases, as with other 5HT1B/1D agonists, coronary spasm, angina pectoris and myocardial infarction may occur. Zolmitriptan should not be used in patients with risk factors for coronary heart disease without prior examination for cardiovascular disease. However, examination does not identify every patient with cardiac disease and there have been isolated cases of serious cardiac events in patients without a history of cardiovascular disease.
Some patients have experienced a feeling of heaviness, pressure or squeezing in the heart area after taking zolmitriptan, as with other 5HT1B/1D agonists. If chest pain or symptoms suggestive of coronary artery disease occur, zolmitriptan should be discontinued until appropriate medical evaluation has been performed.
In patients with a history of hypertension, as well as in patients with normal blood pressure, a transient increase in blood pressure may occur. Very rarely, such an increase in blood pressure is associated with serious clinical manifestations.
Serotonin syndrome has been reported with concomitant use of triptans and SSRIs or SNRIs. Serotonin syndrome can be life-threatening and may present with the following signs and symptoms (when used with a serotonergic medicinal product):
spontaneous clonus; induced or ocular clonus with agitation or diaphoresis; tremor and hyperreflexia; hypertonicity and fever >38°C and induced or ocular clonus.
Withdrawal of serotonergic drugs usually results in rapid improvement. Treatment depends on the type and severity of symptoms.
Prolonged use of any painkiller for headaches may worsen the pain. In such a situation, treatment should be discontinued and a doctor should be consulted. The diagnosis of overmedication headache should be suspected in patients with frequent or daily headaches that do not improve with regular medication.
As with other 5HT1B/1D agonists, anaphylaxis/anaphylactoid reactions have been reported rarely in patients using Zolmigren® spray.
The medicine contains benzalkonium chloride. When applied externally, it causes irritation and may cause skin reactions.
Ability to influence reaction speed when driving vehicles or other mechanisms
In studies, it was found that oral administration of zolmitriptan at a dose of 20 mg does not affect the results of psychomotor tests. Zolmigren® spray has no or negligible influence on the ability to drive and use machines. However, patients whose activities require rapid psychomotor reactions should be warned that in the event of a migraine attack, drowsiness and other migraine symptoms may develop.
Use during pregnancy or breastfeeding
The safety of zolmitriptan during pregnancy has not been studied, therefore the drug should be used in pregnant women only if the expected therapeutic effect for the woman outweighs the potential risk to the fetus/child. The results of animal studies have not revealed direct teratogenic effects.
There are no data on the excretion of zolmitriptan in human milk, so caution should be exercised when administering the drug to nursing mothers. Animal studies have shown that zolmitriptan is excreted in the milk of lactating animals.
Method of administration and doses
Zolmigren® spray is not intended for use in the prevention of migraine attacks. After the onset of a migraine attack, it is recommended to use the drug as soon as possible. The initial recommended dose is 2.5 mg, which corresponds to one spray of Zolmigren® spray at a dosage of 2.5 mg/dose. The maximum recommended dose is 5 mg, which corresponds to one spray of Zolmigren® spray at a dosage of 5 mg/dose or two sprays at a dosage of 2.5 mg/dose. In the absence of effect or in case of recurrence of pain, repeated administration is possible, but not earlier than 2 hours after the first dose. The maximum daily dose is 10 mg.
Elderly patients
The safety and efficacy of Zolmigren® spray in patients aged 65 years and older have not been systematically studied.
Liver dysfunction
The effect of hepatic impairment on the pharmacokinetics of zolmitriptan nasal spray has not been studied. In patients with moderate or severe hepatic impairment, the clearance of zolmitriptan is reduced after oral administration. In patients with moderate or severe hepatic impairment, a maximum dose of 5 mg/day is recommended.
Kidney dysfunction
There is no need for dose adjustment.
For interactions requiring dosage adjustment, see section “Interaction with other medicinal products and other types of interactions”.
Instructions for use
For greater effectiveness of Zolmigren® spray, you should clear your nostrils (gently blow your nose) before using it.
Before using the product for the first time, press the sprayer several times, directing the spray into the air, until a uniform cloud of spray is formed. The product is now ready for use.
If more than four weeks have passed since the last use of the drug, the first spray should be done into the air to prevent the use of an incomplete dose. Between uses, the bottle with the drug should be stored with the cap tightly closed.
When using, hold the bottle with the sprayer facing upwards.
Tilt your head slightly forward, insert the spray into your nostril, slightly tilting the tip of the spray away from the center of your nose, and press once. If necessary, repeat the same with the other nostril.
Children
The efficacy and safety of the drug in children have not been established, therefore it is not recommended for use in this age group.
Overdose
Symptoms: No cases of overdose with zolmitriptan, nasal spray have been reported. Sedation was observed in volunteers given a single oral dose of 50 mg zolmitriptan. The elimination half-life of zolmitriptan after intranasal administration is 3 hours. Patients in case of overdose should be monitored for at least 15 hours or until symptoms or signs resolve.
Treatment. There is no specific antidote for zolmitriptan. In case of severe intoxication, intensive care procedures are recommended, including ensuring a patent airway, adequate oxygenation and ventilation, and monitoring and maintaining cardiovascular function.
Adverse reactions
Zolmitriptan is well tolerated. Adverse reactions are usually mild to moderate, are usually transient, non-serious, occur within 4 hours of taking the drug, do not occur more frequently after repeated use, and resolve spontaneously without additional treatment.
Adverse reactions are classified according to their frequency and effect on organs or organ systems. The following adverse reactions have been reported and are classified according to frequency: very common (≥1/10); common (≥1/100 - <1/10); uncommon (≥1/1000 - <1/100); rare (≥10,000 - <1/1,000); very rare (<1/10,000).
Heart disease:
often - feeling of palpitations;
infrequently – tachycardia;
very rarely - myocardial infarction, angina pectoris, coronary spasm.
Vascular disorders:
infrequently - temporary increase in blood pressure.
From the nervous system:
very often - change in taste;
often – pathologies or disorders of sensitivity, dizziness, headache, hyperesthesia, paresthesia, drowsiness, feeling of heat.
From the digestive system:
often - abdominal pain, dry mouth, dysphagia, nausea, vomiting;
very rarely - diarrhea with blood, intestinal infarction or necrosis, ischemic phenomena from the gastrointestinal tract, ischemic colitis, splenic infarction.
From the genitourinary system:
infrequently - polyuria, increased frequency of urination;
very rarely - urgent urge to urinate.
Musculoskeletal and connective tissue disorders:
often - muscle weakness, muscle pain.
On the part of the immune system:
rarely - hypersensitivity reactions, anaphylactic/anaphylactoid reactions.
Skin and subcutaneous tissue disorders:
rarely - angioedema, urticaria.
Respiratory, thoracic and mediastinal disorders:
often - nosebleeds, nasal discomfort.
General disorders and administration site conditions:
often - asthenia, feeling of heaviness, tightness, pain or pressure in the throat, neck, chest and extremities.
Expiration date
2 years.
Do not use the drug after the expiration date indicated on the package.
Storage conditions
Store at a temperature not exceeding 30 °C in the original packaging. Do not freeze.
Keep out of reach of children.
Packaging
2 ml (20 doses) in a light-resistant glass bottle in a cardboard box.
Vacation category
According to the recipe.
Producer
JSC "Farmak".
Location of the manufacturer and its business address
Ukraine, 04080, Kyiv, Kyrylivska St., 74.
