Zolmitriptan

Pharmacological properties

zolmitriptan is a selective agonist of recombinant 5-nt1v / 1d receptors for human vascular serotonin. has a moderate affinity for serotonin 5-nt1a receptors, does not show great affinity or pharmacological activity for 5nt2-, 5nt3-, 5nt4-serotonin receptors, α1-, α2-, β1-adrenergic receptors, n1-, H2-histamine receptors, m- cholinergic receptors, d1-, d2-dopaminergic receptors.

The drug causes vasoconstriction, mainly of the cranial vessels, blocks the release of neuropeptides, in particular the vasoactive intestinal peptide, which is the main effector transmitter of reflex excitation causing vasodilation, which underlies the pathogenesis of migraine. Stops the development of a migraine attack without a direct analgesic effect. Together with the relief of a migraine attack, it reduces nausea, vomiting (especially with left-side attacks), photo and phonophobia. It affects the centers of the brain stem 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 migraine status (a series of several severe, repeatedly recurring migraine attacks lasting 2-5 days). Eliminates migraine associated with menstruation.

The action of the drug develops after 15-20 minutes and reaches a maximum one hour after administration. The maximum effect is noted when taken during the development of an attack.

Pharmacokinetics When administered orally, it is well absorbed in the digestive tract. The absorption of the drug is independent of food intake. The average absolute bioavailability is about 40%. Linking blood plasma proteins - 25%. Time to reach C_max is 1 hour, the therapeutic concentration in the blood plasma is maintained for the next 4-6 hours. With repeated administration of cumulation of the drug is not observed.

The drug is subject to intensive biotransformation in the liver with the formation of N-desmethylmetabolite, which has 2-6 times greater pharmacological activity than the primary compound. 85% C_max in blood plasma is reached within an hour.

The excretion of zolmitriptan is mainly determined by the processes of biotransformation in the liver, after which the excretion of metabolites in the urine occurs. There are three main metabolites: indole acetic acid (the main metabolite in blood plasma and urine), N-oxide and N-dimethyl analogs. Only the N-dimethylated metabolite is active. Plasma concentrations of N-dimethylated metabolite are approximately 2 times lower than the concentration of the starting drug; it can enhance the therapeutic effect of zolmitriptan. With single oral administration, over 60% is excreted in the urine (mainly in the form of a metabolite - indoleacetic acid), and almost 30% with feces in the form of the starting compound. After iv administration, the total plasma clearance averages about 10 ml / min / kg body weight, of which one third is renal clearance. The renal clearance exceeds the glomerular filtration rate, which indicates secretion in the renal tubules. The volume of distribution after iv administration is 2.4 l / kg. The binding of zolmitriptan and N-dimethylated metabolite with plasma proteins is low (about 25%). T_½ zolmitriptan averages 2.5–3 hours. T_½ its metabolites are similar, which indicates that their excretion 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 active metabolite increased only slightly (by 16 and 35%, respectively), and T_½ increased by 1 hour and reached 3–3.5 hours. These indicators are within the framework defined with the participation of healthy volunteers.The pharmacokinetics of zolmitriptan in healthy elderly people and in healthy young volunteers was similar.

Indications

Relieving migraine attacks accompanied by an aura and without an aura.

Application

The drug is not intended for use to prevent a migraine attack. Rapimig is recommended to be used as soon 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 pill was taken.

The tablet can not be washed down with liquid. The tablet is placed on the tongue, where it dissolves, and swallowed with saliva. This dosage form can be used in situations where there is no liquid at hand or in order to avoid nausea and vomiting that may occur when washing the tablet with liquid.

This dosage form quickly dissolves in the oral cavity, but sometimes it is still possible to delay the absorption of zolmitriptan and delay the onset of the drug.

The blister pack should be opened by cleaning it from the foil, and not by pushing the foil with a tablet.

The recommended dose of Rapimig to eliminate a migraine attack is 1 tablet (2.5 mg). If symptoms persist or reappear within 24 hours, a second dose may be effective. If the use of the second dose is necessary, it should be taken no earlier than 2 hours after the first. With a lack of efficacy of a dose of 2.5 mg, a single dose may be increased to 5 mg (maximum single dose).

The maximum daily dose should not exceed 10 mg. Within a 24-hour period, more than 2 doses of zolmitriptan should not be used.

Liver failure. In patients with mild to moderate hepatic impairment, dose adjustment is not required. In patients with severely impaired liver function, the daily dose should not exceed 5 mg.

Renal failure. With creatinine clearance of 15 ml / min, the dose does not need to be adjusted.

Interactions requiring dose adjustment. See INTERACTIONS.

Contraindications

Hypersensitivity to the drug. severe or moderate arterial hypertension, as well as a slight uncontrolled increase in hell, coronary heart disease, including a history of myocardial infarction. angiospastic angina pectoris (prinzmetal angina). a cerebrovascular disorder and a history of transient ischemic attack. creatinine clearance 15 ml / min. simultaneous administration of ergotamine, derivatives of ergotamine, sumatriptan, naratriptan or other 5ht1b / 1d receptor agonists. peripheral vascular disease. advanced age (65 years).

Side effects

Usually a little pronounced, usually passing, appear within 4 hours after taking the drug, do not become more frequent after its repeated use and disappear spontaneously without additional treatment.

By the frequency of occurrence, side effects are classified as follows: very often: ≥1 / 10; often: ≥1 / 100, 1/10; sometimes: ≥1 / 1000, 1/100; rarely: ≥1 / 10,000, 1/1000:

from the cardiovascular system: often - a feeling of palpitations; sometimes - tachycardia, a slight increase in blood pressure, rarely - myocardial infarction, angina pectoris, coronary spasm;

from the central nervous system and autonomic nervous system: often - disorders of the sensory organs, dizziness, headache, hyperesthesia, paresthesia, drowsiness, sensation of heat;

from the digestive system: often - abdominal pain, nausea, vomiting, dry mouth; rarely, ischemia or myocardial infarction (e.g. intestinal ischemia, intestinal infarction, spleen infarction), which may result in diarrhea with an admixture of blood or abdominal pain;

from the genitourinary system: infrequently - polyuria, frequent urination; rarely - peremptory urination.

from the musculoskeletal system: often - muscle weakness, muscle pain;

general disorders: often - asthenia, a feeling of heaviness, constriction, pain or compression in the throat, neck, limbs or chest;

from the immune system: sometimes - hypersensitivity reactions, including urticaria, Quinckes edema and anaphylactic reactions.

Individual symptoms may relate to the migraine itself.

special instructions

Rapimig should only be used in cases where the diagnosis of migraine has been accurately established. Before starting treatment for headache in patients who have not previously been diagnosed with migraine, or patients predisposed to migraine who have atypical symptoms, other neurological conditions should be excluded. rapimig should not be prescribed for hemiplegic, basilar and ophthalmoplegic migraines. in patients taking 5ht1b / 1d agonists, stroke and other adverse cerebrovascular disorders may occur. persons prone to migraines may have certain symptoms associated with cerebrovascular insufficiency.

Rapimig is not prescribed for patients with symptomatic WPW syndrome or arrhythmia associated with other additional conduction pathways.

In some cases, similar to the use of other 5HT agonists_{1B / 1D}receptors, reported coronary spasm, angina pectoris and myocardial infarction. If there are factors contributing to the development of IHD (for example, smoking, increased blood pressure, hyperlipidemia, diabetes mellitus, heredity), Rapimig is prescribed only after examination of the cardiovascular system. Particular attention should be given to postmenopausal women and men over the age of 40 with these risk factors. However, the examination does not reveal all patients with cardiovascular diseases, therefore there have been isolated cases of serious cardiac events in patients without a history of cardiovascular disorders.

In some patients, after taking zolmitriptan, a feeling of heaviness in the region of the heart was noted. If chest pain or symptoms characteristic of IHD appear, Rapimig should be discontinued before an appropriate medical examination is performed.

In patients with a history of elevated blood pressure or normal blood pressure, a transient 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.

With the simultaneous use of triptans and collections of medicinal plants containing St. Johns wort, the frequency of adverse reactions may increase.

Prolonged use of any pain medication for headaches can aggravate the pain. In such a situation, it is necessary to stop treatment and consult a doctor. Headache caused by over-treatment should be suspected in patients with frequent or daily cases of such pain that does not decrease with regular use of drugs.

Rapimig contains aspartame (a source of phenylalanine), which can cause side effects in patients with phenylketonuria. Each 2.5 mg tablet contains 4 mg of aspartame, each 5 mg tablet contains 8 mg of aspartame.

Use during pregnancy and lactation. 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, during breastfeeding, Rapimig should be used with caution. The effect on the infant must be minimized, so breastfeeding is resumed no earlier than 24 hours after taking the drug.

Children. The drug is not used in children under the age of 18 years.

Influence on the ability to drive vehicles and work with complex mechanisms. While taking the drug, a small group of healthy volunteers in a dosage of up to 20 mg did not significantly affect the results of psychomotor tests.

But drivers of vehicles and persons whose work is associated with increased concentration of attention, it must be warned that in the event of a migraine attack, drowsiness and other symptoms may develop.

Interactions

It is acceptable to use the drug with caffeine, paracetamol, metoclopramide, pizotifen, fluoxetine, rifampicin and propranolol.

Based on the data obtained with the participation of healthy volunteers, no pharmacokinetic or other interaction of clinical significance was observed between zolmitriptan and ergotamine. Since theoretically, the risk of coronary spasm may increase, Rapimig is recommended to be taken no less than 24 hours after taking the drug containing ergotamine. Conversely, a drug containing ergotamine is recommended to be taken no less than 6 hours after the use of Rapimig.

After the use of moclobemide, a specific MAO-A inhibitor, a slight increase (26%) in AUC for zolmitriptan and a three-fold increase in AUC for the active metabolite were detected. Therefore, patients who use an MAO-A inhibitor are advised to take zolmitriptan at a dose of no more than 5 mg / day. Drugs should not be prescribed at the same time when taking moclobemide in a dose of 150 mg 2 times a day.

After taking cimetidine, a common inhibitor of P450, T_½ zolmitriptan increased by 44%, and AUC - by 48%. In addition, cimetidine doubled T_½ and AUC of an active, N-dimethylated metabolite (183C91). Patients who use cimetidine, it is recommended to take zolmitriptan in a dose of not more than 5 mg / day. Based on the general interaction profile, the possibility of interaction with specific CYP 1A2 inhibitors cannot be ruled out. Therefore, when using drugs such as fluvoxamine and ciprofloxacin, the dose is also recommended to be reduced.

From a pharmacokinetic point of view, selegiline (an MAO-B inhibitor) and fluoxetine (a selective serotonin reuptake inhibitor) do not interact with zolmitriptan.

After the simultaneous use of triptans and selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors, the appearance of serotonin syndrome (including a change in mental state, autonomic lability, neuromuscular anomalies) is reported. These reactions can be severe. If the simultaneous use of zolmitriptan, a selective serotonin reuptake inhibitor and norepinephrine is clinically feasible, it is recommended to conduct an appropriate examination of the patient, especially at the beginning of treatment, with an increase in dose or the use of another serotonergic agent.

Like other 5HT receptor agonists_{1B / 1D}zolmitriptan may slow the absorption of other drugs.

Overdose

Symptoms: in volunteers who took a single dose of zolmitriptan at a dose of 50 mg, a sedative effect was noted. monitoring patients in case of overdose should last at least 15 hours or until symptoms disappear.

Treatment: gastric lavage, intake of activated carbon, symptomatic therapy, including ensuring airway patency, monitoring and maintaining the function of the cardiovascular system. There is no specific antidote.

It is not known how hemodialysis and peritoneal dialysis affect the plasma concentration of zolmitriptan.

Storage conditions

Store in the original packaging. does not require special storage conditions.