Zomig Rapimelt

General characteristics. Structure:

Active ingredient: золмитриптан 2,5 mg.
Auxiliary ingredients: fragrance of orange SN027512 0,4 mg, aspartame of 5,0 mg, silicon dioxide of colloid 0,3 mg, кросповидон 10,0 mg, citric acid of anhydrous 1,5 mg, magnesium stearate of 2,0 mg, Mannitolum of 60,8 mg, Natrii hydrocarbonas of 2,5 mg, cellulose of microcrystallic 15,0 mg.
Description
Round ploskotsilindrichesky tablets of white color with a facet, with a light orange smell; on one party of a tablet Z engraving.

Pharmacological properties:

Pharmacodynamics. Zolmitriptan is the selection agonist of 5HT1B/1D-serotoninovy receptors which stimulation leads to vasoconstriction. Has high affinity to recombinant 5HT1B/1D-serotoninovy receptors of the person and moderate affinity to 5HT1A-serotoninovy receptors. Zolmitriptan has no affinity and does not show essential pharmacological activity in relation to 5NT2-, 5NT3-, to 5HT4-serotoninovy, adrenergic, histamine, muskarinovy and dofaminergichesky receptors.
Introduction of a zolmitriptan a laboratory animal led to vasoconstriction in the pool of a carotid artery. Besides, results of researches on laboratory animals demonstrate to what золмитриптан blocks the central and peripheral activity of a trifacial at the expense of inhibition of release of the peptide connected with a gene of a calcitonin, vasoactive intestinal peptide and substance P.
In clinical trials the effect of a zolmitriptan concerning a headache and other symptoms of migraine (such as nausea, photophobia, phonophobia) was noted in 1 hour and increased during from 2 to 4 hours after administration of drug.
Zolmitriptan is equally effective concerning migraine with aura, migraines without aura and migraine associated with periods. Reception of a zolmitriptan during aura did not prevent migrenozny-headed pain therefore drug should be accepted after the beginning of a painful attack.

Pharmacokinetics. After intake золмитриптан it is quickly and fully absorbed (at least 64%).
Absorption of a zolmitriptan does not depend on meal. Average absolute bioavailability about 40%. The average volume of distribution makes 7,0 l/kg. Communication with proteins of plasma low (about 25%). The active metabolite of a zolmitriptan (N-dezmetilmetabolit) is also an agonist of 5HT1B/1D-serotoninovy receptors, by 2-6 times stronger, than золмитриптан. At reception by healthy volunteers of a single dose in the range from 2,5 to 50 mg золмитриптан and its active metabolite have dozozavisimy the area under a curve "concentration time" (AUC) and the maximum concentration (Cmax). At reception of multiple doses of cumulation of drug it was not observed.
Within 4 hours after administration of drug inside during a migraine attack concentration of a zolmitriptan and its metabolites in plasma was lower, than in case of administration of drug during the mezhpristupny period. Possibly, it is explained by the delay of absorption of a zolmitriptan connected with delay of gastric emptying during a migraine attack. Bioequivalence of the drugs Zomig® and Зомиг® of Rapimelt was confirmed concerning indicators of AUC and Cmax of a zolmitriptan and its active metabolite. Tmax of a zolmitriptan at administration of drug of Zomig® Rapimelt is more, than at administration of drug of Zomig® (from 0,3 to 15 hours, a median – 3 hours). Drug Cmax in plasma is supported within the next 4 - 6 hours. Tmax of an active metabolite does not differ for the drugs Zomig® and Зомиг® of Rapimelt (a median – 3 hours). Zolmitriptan eliminirutsya preferential by hepatic biotransformation with the subsequent removal of metabolites with urine. Three main metabolites are established: indolacetic acid (the main metabolite revealed in plasma and urine), N-oksid-and N-дезметил-derivatives. N-dezmetilirovanny a metabolite is active, and two other metabolites do not show pharmacological activity. Concentration of N-dezmetilmetabolita in plasma about 2 times is less than concentration of a zolmitriptan. Therefore, it is possible to assume that this metabolite makes the contribution to therapeutic effect of the drug Zomig® of Rapimelt. More than 60% of the drug administered in the form of a single peroral dose are removed with urine (preferential in the form of an indolacetic metabolite) and about 30% are removed with excrements, is preferential in not changed look.
The average general plasma clearance of a zolmitriptan is equal to 31,5 ml/min. which one sixth sizes are made by renal clearance. The renal clearance is higher, than the size of glomerular filtering that assumes existence of canalicular secretion.
The average elimination half-life of a zolmitriptan and N-dezmetilirovannogo of a metabolite makes 4,7 h and 5,7 h at healthy volunteers, patients have 7,3 h and 7,5 h with a moderate abnormal liver function and patients have 12 h and 7,8 h with the expressed abnormal liver function, respectively.
The renal clearance of a zolmitriptan and its metabolites is 7 - 8 times lower at patients with the moderated and expressed renal failure in comparison with healthy faces though AUC of a zolmitriptan and an active metabolite increases slightly (by 16% and 35%, respectively) with increase in an elimination half-life for 1 hour (till 3 - 3,5 o'clock). Values of these pharmacokinetic parameters did not go beyond the values noted at healthy volunteers.
At patients with an abnormal liver function the delay of metabolism of a zolmitriptan proportional to weight of an abnormal liver function was noted. At patients with the expressed abnormal liver function in comparison with healthy volunteers increase in AUC by 226%, Cmax – for 47%, an elimination half-life – was shown till 12 o'clock. At the same time decrease in concentration of metabolites of a zolmitriptan, including, an active metabolite was noted.
Pharmacokinetic parameters at healthy faces of advanced age are similar to that at young healthy volunteers.

Indications to use:

Stopping of attacks of migraine with aura or without aura.

Route of administration and doses:

The recommended dose of the drug Zomig® of Rapimelt for removal of an attack of migraine – 2,5 mg. Zomig® Rapimelt is recommended to be accepted as soon as possible from the moment of the beginning of a headache, however drug is effective also at inclusion in later terms after the beginning of an attack.
The tablet should be put on language. Within several seconds it is dissolved on a language surface, and it can be swallowed with saliva, without washing down with water. Zomig® Rapimelt can be applied to avoid nausea and the vomiting accompanying reception of liquid during a migraine attack and also in situations, when there is no an opportunity to wash down a tablet with water.
The blister with the tablets Zomig® of Rapimelt should be opened according to the scheme given on aluminum foil of the blister (it is not necessary to press through a tablet through a foil).
If symptoms of migraine arise within 24 hours again, it is possible to accept a repeated dose of the drug Zomig® of Rapimelt. It is not necessary to accept a repeated dose earlier, than in 2 hours after reception of the first dose of the drug Zomig® of Rapimelt. If after reception of the first dose the clinical effect is noted, the advantage of repeated administration of drug is improbable during the same attack.
If at the patient the therapeutic effect after reception of a dose of 2,5 mg was not reached, it is possible to apply Zomig® Rapimelt in a dose of 5 mg to removal of the subsequent attacks of migraine. It is not necessary to accept more than 2 doses of the drug Zomig® of Rapimelt a day. The total dose of a zolmitriptan accepted within a day should not exceed 10 mg.
Zomig® Rapimelt is not shown for prevention of migraine.
Use for special groups of patients
Children's and teenage age
Efficiency and safety of a zolmitriptan at children up to 12 years was not studied. Efficiency of a zolmitriptan in platsebokontroliruyemy clinical trial at patients aged from 12 up to 17 years is not established. Use of the drug Zomig® of Rapimelt for children and teenagers is not recommended.
Advanced age
Efficiency and safety of a zolmitriptan at patients are more senior than 65 years is not established. Therefore use of the drug Zomig® of Rapimelt for patients of advanced age is not recommended.
Abnormal liver function
Dose adjustment at an easy and moderate abnormal liver function is not required. For patients with a heavy abnormal liver function the total dose of a zolmitriptan accepted within a day should not exceed 5 mg.
Renal failure
Dose adjustment is not required if the clearance of creatinine is higher than 15 ml/min. (see sections of "Contraindication" and "Pharmacokinetics").
The interaction with other medicines demanding dose adjustment
For the patients accepting Cimetidinum or the selection inhibitors of an isoenzyme CYP1A2 (for example, флувоксамин, ciprofloxacin and other hinolona) the total dose of a zolmitriptan accepted within a day should not exceed 5 mg.

Features of use:

Zomig® Rapimelt can be applied only in cases of accurately diagnosed migraine. Before purpose of a zolmitriptan, as well as other means for stopping of migraine, it is necessary to exclude other possible serious neurologic diseases at patients with earlier not diagnosed migraine, and also patients with the established diagnosis have migraines in the presence of atypical symptoms. Zolmitriptan is not shown for treatment of hemiplegic, basilar and ophthalmoplegic migraine. At the patients accepting agonists of 5HT1B/1D-serotoninovy receptors disturbances of cerebral circulation, a hematencephalon, subarachnoidal hemorrhage, including, strokes were noted. The patients having migraine can be subject to risk of development of certain disturbances of cerebral circulation.
It is not necessary to apply золмитриптан at patients with the WPW-syndrome or arrhythmias associated with other additional ways of carrying out an impulse.
Very seldom at use of this class of drugs (agonists of 5HT1B/1D-serotoninovy receptors) the coronary vasomotor spasm, stenocardia and a myocardial infarction were noted. These phenomena developed within several hours from the moment of administration of drug.
Before purpose of a zolmitriptan patients with risk factors of development of the coronary heart disease (CHD) (for example, smoking, arterial hypertension, a lipidemia, a diabetes mellitus, the burdened family anamnesis concerning an ischemic heart disease) are recommended to conduct examination of cardiovascular system, it is necessary to control the ABP and an ECG (see the section "Contraindications"). Special attention should be paid to women in the post-menopausal period and to men 40 years with the specified risk factors are more senior. Nevertheless, not at all patients at inspection it is possible to reveal cardiovascular diseases, and seldom or never serious cardiovascular complications can develop at the patients who did not have instructions on cardiovascular diseases in the anamnesis.
At the patients for an appreciable length of time receiving intermittent therapy by the drug Zomig® of Rapimelt or with risk factors of development of an ischemic heart disease, it is recommended to conduct examination of cardiovascular system periodically.
Very seldom at use of a zolmitriptan and other agonists of 5HT1-serotoninovy receptors the ischemic phenomena from a GIT were noted, including ischemic colitis, an intestines heart attack, a necrosis which symptoms can be diarrhea with impurity of blood and an abdominal pain.
As well as in case of use of other agonists of 5HT1B/1D-serotoninovy receptors, at use of a zolmitriptan it was reported about heavy feelings, pressure or constraint in heart (see the section "Side effect"). When developing pains in a thorax or symptoms of coronary heart disease it is necessary to stop reception of a zolmitriptan before performing the corresponding medical examination.
As well as in case of other agonists of 5HT1B/1D-serotoninovy receptors, tranzitorny increase in arterial pressure was noted at patients irrespective of existence of arterial hypertension in the anamnesis; such increase in arterial pressure clinically expressed was very rare.
It is not necessary to exceed the recommended doses of a zolmitriptan.
Side effects can be more frequent at joint reception of the triptanes and vegetable drugs containing a St. John's Wort made a hole (Hypericum perforatum).
Development of a serotoninovy syndrome at the combined use of triptanes and selective serotonin reuptake inhibitors (SSRI) or inhibitors of the return serotonin reuptake and noradrenaline (СИОЗСиН) was noted. The Serotoninovy syndrome can pose a threat for life and be shown by the following signs and symptoms: changes of a mental state (excitement, hallucinations, a coma), vegetative symptoms (tachycardia, lability of arterial pressure, a hyperthermia), neuromuscular symptoms (a hyperreflexia, a lack of coordination), and also symptoms from a GIT (nausea, vomiting, diarrhea). Careful observation of patients at the accompanying purpose of the drug Zomig® of Rapimelt and SIOZS or СИОЗСиН, especially in the period of the beginning of therapy, increase in a dose or addition to therapy of other drug influencing serotonin exchange is recommended (see the section "Interaction with Other Medicines and Other Types of Medicinal Interaction").
Excessive use of protivomigrenozny drugs can lead to increase in frequency of developing of a headache that potentially demands treatment cancellation. If at the patient frequent or daily headaches, despite regular administration of drugs for treatment of this state are noted, it is necessary to remember a possibility of development of a headache at the excess use of medicines for therapy of a headache.
INFLUENCE ON ABILITY TO DRIVE THE CAR AND OTHER MECHANISMS
Considerable deterioration in implementation of psychomotor tests at reception of a zolmitriptan in a dose to 20 mg was not observed. Patients whose activity demands the high speed of psychomotor reactions (for example, driving or other mechanisms) are recommended to be careful because of possible development of drowsiness and other symptoms of migraine.

Side effects:

Side effects of a zolmitriptan, as a rule, arise within 4 hours after administration of drug, have tranzitorny character and are resolved spontaneously without treatment. Frequency of side effects does not increase at reception of repeated doses.
Frequency of side reactions is specified in a type of the following gradation: very often (≥1/10); often (≥1/100, <1/10); infrequently (≥1/1000, <1/100); seldom (≥1/10000, <1/1000); very seldom (<1/10000).
Often (≥1/100, <1/10)
From the central nervous system: sensitivity disturbances; dizziness; headache; hyperesthesia; paresthesias; drowsiness; feeling of "heat" or "cold"; вертиго
From cardiovascular system: heart consciousness
From digestive tract: abdominal pain; nausea; vomiting; dryness in a mouth; dyspepsia; dysphagy
From a musculoskeletal system: muscular weakness; mialgiya
General frustration: adynamy; inertness; feeling of constraint of breath; pain or feeling of constraint in a throat, areas of a neck, thorax or extremities; the increased sweating
Infrequently (≥1/1000, <1/100)
From cardiovascular system: tachycardia; slight increase of arterial pressure; tranzitorny increase in arterial pressure; arrhythmia *; syncope *
From an urinary system: polyuria, frequent urination
Seldom (≥1/10000, <1/1000)
From immune system: hypersensitivity reactions, including, small tortoiseshell, Quincke's disease and anaphylactic reactions
From cardiovascular system: bradycardia *, premature ventricular contraction *, postural hypotension *, lengthening of an interval of QT *, thrombophlebitis *
Very seldom (<1/10000)
From cardiovascular system: myocardial infarction **; stenocardia **; coronary vasomotor spasm **
From digestive tract: ischemia or a heart attack (for example, ischemia or a heart attack of a gut, a spleen heart attack) which symptoms can be diarrhea with impurity of blood and an abdominal pain
From an urinary system: imperative desires to an urination
* relationship of cause and effect is authentically not established with administration of drug
** these undesirable phenomena and tranzitorny ischemia of a myocardium, are noted also at post-marketing use of drug. As messages are received spontaneously, from population of the unspecified size, it is impossible to estimate authentically the frequency and relationship of cause and effect with administration of drug.
Some of the listed symptoms can be migraine symptoms.

Interaction with other medicines:

In researches on studying interaction of a zolmitriptan with caffeine, ergotamine, dihydroergotamine, paracetamol, Metoclopramidum, pizotifeny, fluoxetine, rifampicin and propranolol of clinically significant changes of pharmacokinetic parameters of a zolmitriptan and its active metabolite was not revealed.
Results of researches with participation of healthy volunteers testify to lack of pharmacokinetic and clinically significant interaction of a zolmitriptan and ergotamine. However because of theoretical risk of a coronary vasomotor spasm combined use of these drugs is contraindicated. It is recommended to apply золмитриптан not earlier than in 24 hours after administration of drugs of ergotamine or its derivatives.
After use of a moklobemid (MAO A inhibitor) small increase (for 26%) AUC of a zolmitriptan and triple increase in AUC of its active metabolite was noted.
After reception of Cimetidinum, P450 cytochrome inhibitor, increase in T1/2 of a zolmitriptan by 44% and increase in AUC by 48% was noted. T1/2 and AUC of active N-demetilirovannogo of a metabolite increased twice. Therefore for the patients accepting Cimetidinum, the total dose of a zolmitriptan accepted within a day should not exceed 5 mg. Based on the general profile of interaction of the drug Zomig® of Rapimelt, it is impossible to exclude a possibility of its interaction with P450 cytochrome CYP1A2 isoenzyme inhibitors. Therefore for the patients accepting the selection inhibitors of an isoenzyme CYP1A2 (for example, флувоксамин, ciprofloxacin and other hinolona) the total dose of a zolmitriptan accepted within a day should not exceed 5 mg.
Pharmacokinetic interaction of a zolmitriptan with selegiliny (MAO B inhibitor) and fluoxetine (SIOZS) was not confirmed. However at the combined use of triptanes and SIOZS or СИОЗСиН cases of development of a serotoninovy syndrome were described (see the section "Special Instructions").
As well as other agonists of 5HT1B/1D-serotoninovy receptors, золмитриптан can slow down absorption of other medicines.
Side effects can be more frequent at joint reception of the triptanes and vegetable drugs containing a St. John's Wort made a hole (Hypericum perforatum).

Contraindications:

Hypersensitivity to any components of drug.
Children's age – up to 18 years.
Advanced age – is more senior than 65 years (efficiency and safety of use is not studied).
The pregnancy period (safety of use is not studied).
Hemiplegic, basilar and ophthalmoplegic migraine.
Uncontrollable arterial hypertension.
Coronary heart disease.
Coronary vasospasm / stenocardia of Printsmetal.
Diseases of peripheral arteries.
Disturbance of cerebral circulation (including, a stroke or the tranzitorny ischemic attack) in the anamnesis.
The WPW-syndrome or arrhythmias associated with other additional ways of carrying out an impulse.
Heavy renal failure (clearance of creatinine less than 15 ml/min.).
Combined use with other agonists of 5HT1B/1D-serotoninovy receptors (for example, sumatriptany, naratriptany), ergotamine or its derivatives (including, metizergidy), and also within 24 hours after their cancellation.
Combined use with MAO A inhibitors and within 14 days after their cancellation.
Fenilketonuriya (drug contains aspartame).
With care: heavy abnormal liver function.
PREGNANCY AND LACTATION
Pregnancy
Safety of use of a zolmitriptan during pregnancy was not studied. Results of researches on animals did not reveal direct teratogenic effects. However some data of researches of embriotoxity confirm possible decrease in viability of embryos. Use of drug during pregnancy is contraindicated.
Lactation
Zolmitriptan gets into milk of the lactating animals. It is unknown whether gets золмитриптан into breast milk of the feeding women. Therefore it is necessary to approach with care a question of purpose of the drug Zomig® of Rapimelt to the women nursing. The termination of breastfeeding for 24 hours allows to minimize impact of a zolmitriptan on the baby.

Overdose:

Symptoms
At a single dose healthy volunteers of a zolmitriptan in a dose of 50 mg inside usually noted sedation. The elimination half-life of a zolmitriptan makes 2,5 - 3 hours (see the section "Pharmacokinetics") therefore at overdose observation of the patient has to continue, at least, within 15 hours or so far there are overdose symptoms.
Treatment
For a zolmitriptan there is no specific antidote. In case of the expressed intoxication actions of an intensive care, including recovery and maintenance of passability of respiratory tracts, ensuring adequate oxygenation and ventilation of the lungs, and also observation and support of function of cardiovascular system are recommended.
The effect of a hemodialysis and peritoneal dialysis concerning concentration of a zolmitriptan in serum is not established.

Storage conditions:

At a temperature not above 30 °C, in the places unavailable to children. Period of validity 2 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets of 2,5 mg. On 2 tablets in the blister from aluminum foil and PVC; on 1 blister in a cardboard pack with the application instruction.