Instructions Zolmigren spray nasal spray dosed 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 physicochemical properties:
5 mg/dose: yellow liquid. Slight opalescence is allowed.
Pharmacotherapeutic group
Drugs used for migraine. Selective 5-HT1 serotonin 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, a1-, a2-, b1-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 affects 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 of the trigeminal nerve supported by orthodromic fibers 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.
Pharmacokinetics
Absorption. Zolmitriptan is rapidly absorbed in the nasopharynx after nasal administration, as confirmed by positron emission tomography studies using radioactive [carbonyl-11C] zolmitriptan. The average relative bioavailability of Zolmigren® spray is 102% compared to oral administration of zolmitriptan in tablet form. Zolmitriptan is detected in plasma after 5 minutes, and the time to reach its maximum concentration is 3 hours. After administration of the drug, its therapeutic concentration in plasma is maintained for 4-6 hours. With repeated administration, cumulation of the drug is not observed.
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 N-demethylated metabolite is detected in plasma after 15 minutes, and the time to peak concentration is 3 hours.
Excretion: The mean elimination 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 indole acetic acid metabolite) and about 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, one sixth 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) who did not suffer from migraine headaches, the same pharmacokinetic parameters of the drug were observed as in healthy young volunteers (18-39 years) who also did not suffer from migraine headaches.
Female and male patients.
Mean plasma concentrations of oral zolmitriptan were 1.5 times higher in women than in men.
Patients of different races.
Patients with renal failure.
When zolmitriptan was administered orally, renal clearance was reduced by 25% in patients with severe renal impairment (CLCr ≥ 5 ≤ 25 mL/min) compared to that in healthy subjects (CLCr ≥ 70 mL/min). There was no significant change in clearance in patients with moderate renal impairment (CLCr ≥ 26 ≤ 50 mL/min).
Patients with liver failure.
When zolmitriptan was administered orally to patients with severe hepatic impairment, the mean Cmax, Tmax and AUC were increased 1.5-fold, 2-fold (2 hours vs. 4 hours) and 3-fold, respectively, compared to the corresponding values in subjects with normal hepatic 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 subjects with normal blood pressure.
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, including a history of myocardial infarction; angiospastic angina (Prinzmetal's angina); ischemic stroke or transient ischemic attack and migraine attacks accompanied by hemiplegia and basilar disorders in history; simultaneous use of ergotamine, ergotamine derivatives or other 5HT1B/1D receptor agonists; peripheral arterial disease; simultaneous use of MAO-A inhibitors and within 14 days after their withdrawal; Wolff-Parkinson-White syndrome or arrhythmias associated with other additional cardiac conduction pathways.
Interaction with other medicinal products and other types of interactions
In studies of 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 detected.
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.
MAO-A inhibitors increase the systemic exposure of zolmitriptan, therefore the use of Zolmigren® spray in patients receiving MAO-A inhibitors is contraindicated.
It is contraindicated to take Zolmigren® spray with other 5HT1B/1D receptor agonists due to the risk of vasospastic reactions.
After taking cimetidine, the half-life and AUC of zolmitriptan and its active N-dimethylated metabolite are doubled. Therefore, for patients taking Zolmigren® spray simultaneously with cimetidine, the maximum single dose of Zolmigren® spray should be limited to 2.5 mg, but not more than 5.0 mg within 24 hours.
Based on the general interaction profile, the possibility of interactions with specific CYP 1A2 inhibitors cannot be excluded. Therefore, when using similar compounds such as fluvoxamine and quinolones (e.g. ciprofloxacin), a dose reduction is also recommended.
From a pharmacokinetic perspective, selegiline (an MAO-B inhibitor) and fluoxetine (an SSRI) do not interact with zolmitriptan. However, serotonin syndrome (including altered mental status, autonomic lability, neuromuscular abnormalities) has been reported following concomitant use of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs).
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).
Like other 5HT1B/1D receptor agonists, zolmitriptan may slow the absorption of other drugs.
Application features
Zolmigren® spray should only be used when a diagnosis of migraine is clearly established. Before starting treatment of headaches in patients who have not previously been diagnosed with migraine or in patients prone to migraine who have atypical symptoms, other neurological conditions should be excluded. Zolmigren® spray should not be prescribed for hemiplegic, basilar and ophthalmoplegic migraine. Cerebrovascular disorders (hemorrhagic stroke, subarachnoid hemorrhage and ischemic stroke) have been reported with 5HT1B/1D agonists. However, it is assumed that in most cases, cerebrovascular disorders occurred first and 5HT1B/1D agonists were prescribed subsequently due to the mistaken interpretation of symptoms of cerebrovascular disorders as migraine attacks. Therefore, when prescribing 5HT1B/1D agonists to patients with acute headache accompanied by atypical symptoms, it is necessary to exclude possible serious neurological conditions. The use of Zolmigren® spray is contraindicated in patients with a history of stroke, transient ischemic attacks and migraine attacks accompanied by hemiplegia and basilar disorders. In people prone to migraine, certain symptoms associated with cerebrovascular insufficiency may occur. In the event of cerebrovascular disorders, the use of Zolmigren® spray should be immediately discontinued.
Zolmigren® spray should not be prescribed to patients suffering from symptomatic Wolff-Parkinson-White syndrome or arrhythmias associated with other additional cardiac conduction pathways.
Zolmitriptan is contraindicated in patients with coronary artery disease and vasospastic angina. Serious cardiac adverse reactions, including acute myocardial infarction, have been reported rarely. In the presence of factors predisposing to the development of coronary artery disease (such as smoking, high blood pressure, hyperlipidemia, diabetes mellitus, heredity), Zolmigren® spray should be prescribed only after examination of the patient's cardiovascular system. Particular attention should be paid to postmenopausal women and men over 40 years of age with such risk factors. However, examination does not allow to identify every patient with heart disease, therefore, there have been isolated cases of serious cardiac events in patients without a history of cardiovascular disorders.
Some patients have experienced heaviness, pressure or squeezing in the heart area after administration. If chest pain or symptoms characteristic of coronary heart disease occur, the use of Zolmigren® spray should be discontinued until an appropriate medical examination 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.
Zolmigren® spray should be used in a dose that does not exceed the recommended dose.
5HT1B/1D agonists, including Zolmigren® spray, can cause non-coronary vasospastic reactions, such as gastrointestinal ischemia and infarction (clinical manifestations are abdominal pain and bloody diarrhea), splenic infarction and Raynaud's phenomenon. Patients who have had a history of symptoms or signs suggestive of vasospastic reactions after use of any 5HT1B/1D agonist should be excluded from receiving additional doses of Zolmigren® spray.
Temporary and permanent blindness, as well as cases of partial loss of vision, have been reported with the use of 5HT1B/1D agonists, but these symptoms may have been caused by a migraine attack, i.e. a causal relationship between these events and the use of 5HT1B/1D agonists has not been clearly established.
With the simultaneous use of triptans and herbal preparations containing St. John's wort, the frequency of adverse reactions may increase (see section "Interaction with other medicinal products and other types of interactions").
Serotonin syndrome has been reported with the concomitant use of triptans and selective serotonin and noradrenaline reuptake inhibitors (SSRIs). Serotonin syndrome can be life-threatening and may be manifested by the following signs and symptoms: changes in mental status (agitation, hallucinations, coma), autonomic symptoms (tachycardia, blood pressure lability, hyperthermia), neuromuscular symptoms (hyperreflexia, incoordination), and gastrointestinal symptoms (nausea, vomiting, diarrhea). Close monitoring of patients is recommended when Zolmigren® spray is co-administered with SSRIs or SSRIs, especially when initiating therapy, increasing the dose, or adding another drug that affects serotonin metabolism to the therapy (see section "Interaction with other medicinal products and other forms of interaction").
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.
Cardiovascular system examinations should be performed periodically in patients who use Zolmigren® spray for a long time.
Zolmigren® spray is not recommended for patients with moderate or severe hepatic impairment.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies have shown that oral administration of zolmitriptan at a dose of 20 mg does not affect the results of psychomotor tests. However, patients whose activities require rapid psychomotor reactions are advised to take into account the possible development of drowsiness and other symptoms of migraine.
Use during pregnancy or breastfeeding
The safety of zolmitriptan during pregnancy has not been studied. Therefore, the use of Zolmigren® spray in pregnant women is possible only if the expected therapeutic effect for the woman outweighs the potential risk to the fetus/child.
There are no data on the penetration of zolmitriptan into breast milk. Therefore, women who are breastfeeding should use the drug only if the expected therapeutic effect for the woman outweighs the potential risk to the child. Animal studies have shown that when zolmitriptan is taken orally, its concentration in milk is 4 times higher than in blood plasma.
Method of administration and doses
Zolmigren® spray is not intended for use in the prevention of migraine attacks. It is recommended to use the drug as soon as possible after the onset of a migraine attack. 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.
No dose adjustment is required for patients with mild hepatic impairment. The drug is not recommended for patients with moderate and severe hepatic impairment.
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 in 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 the bottle, hold it with the spray tip 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: Sedation was observed in volunteers given a single oral dose of zolmitriptan 50 mg. Patients should be monitored for at least 15 hours or until symptoms or signs resolve.
Treatment: symptomatic and supportive therapy.
Adverse reactions
From the cardiovascular system: palpitations; arrhythmia; tachycardia; lability of blood pressure; myocardial infarction; angina pectoris; coronary spasm.
From the side of the central and peripheral nervous system: impaired sensitivity, dizziness, headache, hyperesthesia, paresthesia, drowsiness, feeling of heat, loss of consciousness, depression, insomnia, convulsions, nervous excitement, anxiety, amnesia, tinnitus, hallucinations, coma, hyperthermia, Raynaud's syndrome, cerebrovascular disorders, including stroke.
On the part of the digestive system: abdominal pain, nausea, vomiting, dry mouth; ischemia and infarction of gastrointestinal vessels (clinical manifestations are represented by abdominal pain and diarrhea with blood or pain in the abdominal cavity), splenic infarction, dyspepsia, dysphagia.
From the genitourinary system: polyuria, frequent urination; urgent urination.
Musculoskeletal system: muscle weakness, muscle pain.
Immune system disorders: Hypersensitivity reactions including urticaria, angioedema and anaphylactic/anaphylactoid reactions.
From the respiratory system: bronchitis, increased cough, shortness of breath, nosebleeds, laryngeal edema, pharyngitis, rhinitis, sinusitis.
From the organs of vision: conjunctivitis, dry eyes, visual field defect.
General disorders: asthenia, feeling of heaviness, tightness, pain or pressure in the throat, neck, chest and extremities, increased sweating.
Certain symptoms may be due to the migraine itself.
Expiration date
2 years.
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
Location of the manufacturer and its business address
Ukraine, 04080, Kyiv, Kyrylivska St., 74.
