Pharmacological properties
Pharmacodynamics. Zolmitriptan is a selective agonist of recombinant 5-HT1B/1D human vascular serotonin receptors. It has moderate affinity for serotonin 5-HT1A receptors, and does not exhibit high affinity or pharmacological activity for 5HT2, 5HT3, 5HT4 serotonin receptors, α1, α2, β1 adrenoreceptors, H1, H2 histamine receptors, m-cholinoreceptors, d1, d2 dopaminergic receptors.
The drug causes vasoconstriction, mainly of cranial vessels, blocks the release of neuropeptides, in particular vasoactive intestinal peptide, which is the main effector transmitter of reflex excitation, causing vasodilation, which is the basis of the pathogenesis of migraine. Stops the development of a migraine attack without direct analgesic action. Along with the elimination of a migraine attack, it reduces nausea, vomiting (especially in left-sided attacks), photo- and phonophobia. It affects the brain stem centers associated with migraine, which explains the persistent repeated effect in the treatment of a series of several migraine attacks in one patient. Highly effective in the complex treatment of status migraine (a series of several severe, repeatedly recurring migraine attacks lasting 2-5 days). Eliminates migraine associated with menstruation.
The drug's effect develops within 15-20 minutes and reaches a maximum one hour after administration. The maximum effect is observed when taken during the development of an attack.
Pharmacokinetics. When administered orally, it is well absorbed in the gastrointestinal tract. Absorption of the drug does not depend on food intake. The average absolute bioavailability is about 40%. Binding to blood plasma proteins is 25%. The time to reach C max is 1 hour, the therapeutic concentration in blood plasma is maintained for the next 4-6 hours. With repeated administration, cumulation of the drug is not observed.
The drug is subject to intensive biotransformation in the liver with the formation of an N-desmethyl metabolite, which has 2-6 times greater pharmacological activity than the parent compound. 85% C max in blood plasma is achieved within an hour.
The elimination of zolmitriptan is mainly due to biotransformation processes in the liver, after which the metabolites are excreted in the urine. There are three main metabolites: indoleacetic acid (the main metabolite in blood plasma and urine), N-oxide and N-dimethylanalogues. Only the N-dimethyl metabolite is active. Plasma concentrations of the N-dimethyl metabolite are approximately 2 times lower than those of the parent drug; it may enhance the therapeutic effect of zolmitriptan. After a single oral dose, more than 60% is excreted in the urine (mainly in the form of the metabolite - indoleacetic acid), and almost 30% - with feces in the form of the parent compound. After intravenous administration, the total plasma clearance averages about 10 ml/min/kg body weight, of which a third is renal clearance. Renal clearance exceeds glomerular filtration rate, indicating secretion in the renal tubules. The volume of distribution after IV administration is 2.4 l/kg. The binding of zolmitriptan and its N-dimethylated metabolite to plasma proteins is low (about 25%). The T½ of zolmitriptan is on average 2.5-3 hours. The T½ of its metabolites is similar, indicating that their elimination is limited by the rate of formation. The renal clearance of zolmitriptan and all its metabolites in patients with moderate and severe renal failure is reduced (7-8 times) compared with healthy volunteers, although the AUC of the parent compound and the active metabolite increased only slightly (by 16 and 35%, respectively), and T½ increased by 1 hour to 3-3.5 hours. These figures are within the range determined with the participation of healthy volunteers. The pharmacokinetics of zolmitriptan in healthy elderly subjects and in healthy young volunteers were similar.
Indication
Relief of migraine attacks with and without aura.
Application
The drug is not intended for use in the prevention of migraine attacks. Rapimig is recommended to be used as early as possible after the onset of a migraine attack, although its effectiveness does not depend on how long after the onset of the attack the tablet was taken.
The tablet can be taken without liquid. The tablet is placed on the tongue, where it dissolves, and swallowed with saliva. This dosage form can be used in situations where liquid is not available or to avoid nausea and vomiting that may occur when taking the tablet with liquid.
This dosage form dissolves quickly in the mouth, but sometimes there may be a delay in the absorption of zolmitriptan and a delay in the onset of the drug's action.
Exclusive cakes should be opened by peeling them from the foil, not by pushing through the foil with a tablet.
The recommended dose of Rapimiga for the relief of migraine attacks is 1 tablet (2.5 mg). If symptoms do not disappear or recur within 24 hours, a second dose may be effective. If a second dose is necessary, it should be taken no earlier than 2 hours after the first. If the 2.5 mg dose is not effective, a single dose may be increased to 5 mg (maximum single dose).
Hepatic impairment: No dose adjustment is required in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the daily dose should not exceed 5 mg.
Renal insufficiency: No dose adjustment is required for creatinine clearance of 15 ml/min.
Interactions requiring dose adjustment. See Interactions with other drugs.
Contraindication
Hypersensitivity to the components of the drug. severe or moderate hypertension, as well as mild uncontrolled hypertension, coronary artery disease, including a history of myocardial infarction. angiospastic angina (Prinzmetal's angina). cerebrovascular disorders and transient ischemic attack in history. creatinine clearance 15 ml / min. simultaneous administration of ergotamine, ergotamine derivatives, sumatriptan, naratriptan or other 5HT1B / 1D receptor agonists. peripheral vascular disease. advanced age (65 years).
Side effects
Usually mild, usually self-limiting, appear within 4 hours after taking the drug, do not increase in frequency after repeated use, and disappear spontaneously without additional treatment.
By frequency of occurrence, side effects are classified as follows: very common: ≥1/10; common: ≥1/100, 1/10; uncommon: ≥1/1000, 1/100; rare: ≥1/10,000, 1/1000:
From the cardiovascular system: often - palpitations; sometimes - tachycardia, slight increase in blood pressure; rarely - myocardial infarction, angina pectoris, coronary spasm;
from the side of the central nervous system and autonomic nervous system: often - disturbances in the sensory organs, dizziness, headache, hyperesthesia, paresthesia, drowsiness, feeling of heat;
From the digestive system: often - abdominal pain, nausea, vomiting, dry mouth; rarely - ischemia or infarction (for example, intestinal ischemia, intestinal infarction, splenic infarction), which may manifest as diarrhea with blood or abdominal pain;
From the genitourinary system: infrequently - polyuria, frequent urination; rarely - urgent urination.
Musculoskeletal system: often - muscle weakness, muscle pain;
general disorders: often - asthenia, feeling of heaviness, tightness, pain or tightness in the throat, neck, limbs or chest;
Immune system: sometimes - hypersensitivity reactions, including urticaria, angioedema and anaphylactic reactions.
Certain symptoms may relate to the migraine itself.
Special instructions
Rapimig should only be used in cases where a diagnosis of migraine is clearly established. Before starting treatment for headache in patients with no previous diagnosis of migraine or in patients prone to migraine who present with atypical symptoms, other neurological conditions should be excluded. Rapimig should not be used in hemiplegic, basilar or ophthalmoplegic migraine. Stroke and other cerebrovascular adverse events may occur in patients taking 5HT1B/1D agonists. Certain symptoms associated with cerebrovascular insufficiency may occur in individuals prone to migraine.
Rapimig is not prescribed to patients with symptomatic WPW syndrome or arrhythmias associated with other accessory pathways.
In isolated cases, similar to the use of other 5HT 1B / 1D receptor agonists, coronary spasm, angina pectoris and myocardial infarction have been reported. In the presence of factors predisposing to the development of coronary heart disease (e.g. smoking, high blood pressure, hyperlipidemia, diabetes mellitus, heredity), Rapimig should be prescribed only after examination of the cardiovascular system. Particular attention should be paid to postmenopausal women and men aged 40 years and older with such risk factors. However, the examination does not allow to identify all patients with cardiovascular disease, therefore, there have been isolated cases of serious cardiac events in patients without a history of cardiovascular disorders.
Some patients have experienced a feeling of heaviness in the heart area after taking zolmitriptan. If chest pain or symptoms suggestive of coronary artery disease occur, Rapimiga should be discontinued until appropriate medical evaluation is performed.
In patients with a history of high blood pressure, as well as in patients with normal blood pressure, a temporary increase in blood pressure is possible. Very rarely, such an increase in blood pressure is associated with serious clinical manifestations. Rapimig should be used in a dose that does not exceed the recommended dose.
With the simultaneous use of triptans and herbal preparations containing St. John's wort, the frequency of adverse reactions may increase.
Prolonged use of any painkiller for headaches may worsen the pain. In such a situation, it is necessary to stop treatment and consult a doctor. Headache caused by overmedication should be suspected in patients with frequent or daily occurrences of such pain, which does not decrease with regular use of medications.
Use during pregnancy and breastfeeding. During pregnancy, Rapimig is used only if the possible therapeutic effect for the mother outweighs the potential risk to the fetus. There is no data on the penetration of zolmitriptan into breast milk. Therefore, Rapimig should be used with caution during breastfeeding. The effect on the infant should be minimized, so breastfeeding should be resumed no earlier than 24 hours after taking the drug.
Children. The drug is not used in children under 18 years of age.
Effect on the ability to drive and use machines. When taking the drug by a small group of healthy volunteers at a dosage of up to 20 mg, no significant effect on the results of psychomotor tests was noted.
But drivers of vehicles and people whose work requires increased concentration of attention should be warned that in the event of a migraine attack, drowsiness and other symptoms may develop.
Interactions
The drug can be used with caffeine, paracetamol, metoclopramide, pizotifen, fluoxetine, rifampicin and propranolol.
Based on data obtained with the participation of healthy volunteers, no pharmacokinetic or other interactions of clinical significance have been observed between zolmitriptan and ergotamine. Since the risk of coronary spasm may theoretically be increased, it is recommended to take Rapimig at least 24 hours after taking a drug containing ergotamine. Conversely, it is recommended to take a drug containing ergotamine at least 6 hours after taking Rapimig.
After the use of moclobemide, a specific MAO-A inhibitor, a slight increase (26%) in the AUC of zolmitriptan and a threefold increase in the AUC of the active metabolite were observed. Therefore, patients taking an MAO-A inhibitor should not take zolmitriptan at a dose exceeding 5 mg/day. The drugs should not be prescribed simultaneously with moclobemide at a dose of 150 mg 2 times a day.
After administration of cimetidine, a general P450 inhibitor, the T½ of zolmitriptan increased by 44% and the AUC by 48%. In addition, cimetidine doubled the T½ and AUC of the active, N-dimethylated metabolite (183C91). Patients taking cimetidine are recommended to take zolmitriptan at a dose not exceeding 5 mg/day. Based on the general interaction profile, the possibility of interaction with specific CYP 1A2 inhibitors cannot be excluded. Therefore, when using drugs such as fluvoxamine and ciprofloxacin, a dose reduction is also recommended.
From a pharmacokinetic perspective, selegiline (MAO-B inhibitor) and fluoxetine (selective serotonin reuptake inhibitor) do not interact with zolmitriptan.
Serotonin syndrome (including altered mental status, autonomic lability, neuromuscular abnormalities) has been reported following concomitant use of triptans and selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors. These reactions may be severe. If concomitant use of zolmitriptan, a selective serotonin-norepinephrine reuptake inhibitor is clinically warranted, appropriate patient monitoring is recommended, particularly at the start of treatment, with dose increases or with the introduction of another serotonergic agent.
Like other 5HT 1B/1D receptor agonists, zolmitriptan may slow the absorption of other drugs.
Overdose
Symptoms: Sedation was observed in volunteers who took a single dose of zolmitriptan 50 mg. Observation of patients in case of overdose should last at least 15 hours or until symptoms disappear.
Treatment: gastric lavage, administration of activated charcoal, symptomatic therapy, including ensuring airway patency, monitoring and maintaining cardiovascular function. There is no specific antidote.
It is not known how hemodialysis and peritoneal dialysis affect the plasma concentration of zolmitriptan.
Storage conditions
Store in original packaging. Does not require special storage conditions.
