Релпакс®

General characteristics. Structure:

Active agent: an eletriptana hydrobromide (20 mg or 40 mg of an eletriptan are equivalent); Excipients: cellulose microcrystallic, lactoses monohydrate, croscarmellose sodium, magnesium stearate; film cover: опадрай orange OY-LS-23016 (a gipromelloza, lactoses monohydrate, titanium dioxide (E171), triacetin, dye a sunset yellow with a varnish aluminum (E110); опадрай transparent YS-2-19114-A (gipromelloz, triacetin).

Pharmacological properties:

Pharmacodynamics. Eletriptan is the representative of group of the selection agonists of serotoninovy vascular 5-HT1B  and  neyronalny 5-HT1D receptors. Eletriptan also has high affinity to 5-HT1F serotoninovy receptors and has moderate effect on 5-HT1A, 5-HT2B, 5-HT1E and 5-Nt7serotoninovy receptors. In comparison with sumatriptany, элетриптан shows considerably big selectivity concerning the serotoninovy receptors located in carotid arteries than concerning the serotoninovy receptors located in coronary and femoral arteries. Ability of an eletriptan to narrow intracranial blood vessels, and also its inhibiting effect concerning a neurogenic inflammation can cause its protivomigrenozny activity.  

Pharmacokinetics. Absorption. After intake элетриптан it is quickly and rather fully soaked up in the digestive tract (DT): (absorption makes about 81%). Absolute bioavailability at intake at men and women makes about 50%. Time of achievement of the maximum concentration in a blood plasma (TCmax) averaged 1,5 h after intake. In the range of therapeutic doses from 20 mg to 80 mg the pharmacokinetics of an eletriptan is characterized by linear dependence. The maximum concentration (Cmax) of an eletriptan and the area under a curve concentration time (AUC) increased approximately by 20-30% at administration of drug after the use of greasy food. At intake during an attack of migraine of AUC decreased approximately by 30%, and  TCmax in a blood plasma increased to 2,8 h. At regular use (20 mg three times a day) within 5-7 days the pharmacokinetics of an eletriptan remained linear with predictable cumulation. At appointment in higher doses (40 mg three times a day and 80 mg two times a day) within more than 7  days  cumulation of an eletriptan exceeded expected (approximately for  40%). Distribution the Volume of distribution of an eletriptan at intravenous administration makes 138 l that indicates good distribution in fabrics. Eletriptan moderately contacts proteins of a blood plasma (approximately for 85%). Metabolism  of the Research in vitro demonstrate that primary metabolism of an eletriptan happens under the influence of a P450 cytochrome CYP3A4 isoenzyme in a liver. This fact is confirmed by increase in concentration of an eletriptan in a blood plasma at a concomitant use of erythromycin which is powerful selection inhibitor of an isoenzyme CYP3A4. The researches in vitrodemonstriruyut also that the isoenzyme of CYP2D6 makes a certain contribution to metabolism of an eletriptan though in clinical trials the effect of polymorphism of this enzyme on pharmacokinetics of an eletriptan is not revealed. It is identified two main circulating a metabolite which share makes a considerable part of the general radioactivity of a blood plasma after introduction of an eletriptan, marked C14 carbon isotope. In in vitro experiments the metabolite which is formed as a result of N-oxidation had no activity while the metabolite which is formed as a result of N-demethylation on activity was comparable with eletriptany. The third component of radioactive plasma is not identified.  Believe that it represents mix of hydroxylated metabolites which are also removed by kidneys and through intestines. Concentration of active N-demetilirovannogo of a metabolite in a blood plasma makes only 10-20% of concentration of an eletriptan and, respectively, does not make the significant contribution to its therapeutic effect.  

Removal. The general clearance of an eletriptan from a blood plasma after intravenous administration averages 36 l/h, and an elimination half-life (T1/2) - about 4 h. The average renal clearance after intake makes about 3,9 l/h. The share of not renal clearance makes about 90% of the general clearance; it demonstrates to what элетриптан is removed, mainly,  in the form of metabolites by kidneys and through intestines. Pharmacokinetics at special groups of patients of Paule Rezoultata of the metaanalysis of kliniko-pharmacological researches and the population pharmacokinetic analysis demonstrate that a floor does not exert clinically significant impact on concentration of an eletriptan in a blood plasma. Elderly people (65 years are more senior) At elderly people (65-93 years) small and statistically doubtful decrease in clearance of an eletriptan by 16% and statistically significant increase in T1/2 (approximately from 4,4 to 5,7 h) in comparison with these indicators at young people is revealed. On arterial pressure elderly people can have more expressed in comparison with patients of younger age effect of an eletriptan. The abnormal liver function At patients with an abnormal liver function (stages And yes In on classification of Chayld-Pyyu) is revealed statistically reliable increase in AUC (for 34%) and T1/2, and also small increase in Cmax (for 18%), however these changes are not clinically significant. A renal failure At patients with the lung (clearance of creatinine of 61-89 ml/min.) moderated (clearance of creatinine of 31-60 ml/min.) or expressed (clearance of creatinine <30 ml/min.) the renal failure did not reveal statistically reliable changes of pharmacokinetics of an eletriptan or extent of its linkng with proteins of a blood plasma.

Indications to use:

Stopping of attacks of migraine with aura or without aura.

Route of administration and doses:

Inside. Tablets should be swallowed entirely, washing down with water. At emergence of a migrenozny headache of Relpaks® it is necessary to accept as soon as possible, however drug is effective also at later stage of an attack of migraine. Adults (18-65 years) the Recommended initial dose makes 40 mg. If the headache renews during the 24th hour: if the migrenozny headache is stopped, however then renews during the 24th hour, then Relpaks® can appoint repeatedly in the same dose. If the second dose is necessary, it should be accepted not earlier than in the 2nd hour after the first dose. In the absence of effect: if the first dose of Relpaksa® does not lead to reduction of a headache during the 2nd hour, then for stopping of an attack it is not necessary to accept the second dose as in clinical trials efficiency of such treatment is not proved. At the same time patients at whom it was not succeeded to stop an attack can give the effective clinical answer at the following attack. If administration of drug in a dose of 40 mg does not allow to achieve adequate effect, then at the subsequent attacks of migraine there can be effective a dose of 80 mg. The daily dose should not exceed 160 mg. With an easy or moderate abnormal liver function change of a dose is not required from patients.

Features of use:

Use of Relpaksa® in combination with powerful inhibitors of isoenzymes CYP3A4, in particular ketokonazoly, itrakonazoly, erythromycin, klaritromitsiny, dzhozamitsiny and protease inhibitors, such as ритонавир, индинавир and нелфинавир is not recommended (see. "Interaction with other medicines"). As well as other agonists of 5-HT1  receptors, Relpaks® should be applied only when the diagnosis of migraine does not raise doubts. Релпакс®, as well as other agonists of 5-HT1  receptors, it is not necessary to appoint for treatment of "atypical" headaches which can be connected with serious diseases (a stroke, a rupture of aneurism) when vasoconstriction of a brain can be harmful. Релпакс® it is not necessary to appoint without preliminary survey by the patient at which existence of cardiovascular diseases is probable or the risk of their development is increased (see  the section "Contraindications"). System studying of an eletriptan at patients with heart failure it was not carried out. Use of an eletriptan, as well as other agonists of 5HT1-receptors, for these patients is not recommended. Релпакс® it is effective in treatment of migraine with aura and without aura and migraine accompanying a menstrual cycle. Релпакс®, accepted during emergence of aura, does not interfere with development of a headache therefore it should be accepted only during  a headache phase. In clinical trials it is established that Relpaks® is effective also for stopping of the symptoms accompanying migraine such as nausea, vomiting, photophobia, phonophobia, and in treatment of return of a headache during an attack. Релпакс® it is not necessary to accept preventively. At use of Relpaksa® in therapeutic doses of 60 mg and more registered small and passing increase in arterial pressure. Arterial pressure increased more at patients with a renal failure and elderly people. Influence on ability to drive the car and to control of mechanisms At some patients migraine or reception of agonists of 5-HT1 receptors, including элетриптан, can be followed by drowsiness or dizziness. When performing the tasks requiring special attention such as driving of the car and work with a difficult technique, it is necessary to show care during attacks of migraine and after reception of Relpaksa®.

Side effects:

In general, Relpaks® is transferred well. Usually side effects have passing character, poorly or are moderately expressed and pass independently without additional treatment. Frequency and weight of side reactions at the patients accepting  drug of one dosage twice for  stopping  of an attack are similar to that at the patients accepting it once. The main side effects registered at treatment of Relpaksom® are typical for all class of agonists of 5-HT1 receptors. At the patients accepting Relpaks® in therapeutic doses the following side reactions were observed (with a frequency ≥ 1% and above in comparison with placebo). These phenomena were distributed on the following categories according to frequency: frequent (> 1/100 to <1/10), infrequent (> 1/1000 to 1/100) or rare (> 1/10000 to 1/1000).  

Infections: Frequent: pharyngitis and rhinitis Rare:  Disturbance respiratory infections from lymphatic system: Rare: limfoadenopatiya  

Disturbances of food and metabolism: Infrequent: anorexia Mental disturbances: Infrequent: disturbance of thinking, agitation, confusion of consciousness, depersonalization, euphoria, depression, sleeplessness Rare: emotional lability  

Disturbances from a nervous system: Frequent: drowsiness, headache, dizziness, feeling of "pricking" or other disturbances of sensitivity, hyper tone of muscles, hypesthesia, myasthenia Infrequent: tremor, hyperesthesia, ataxy, hypokinesia, disturbance of the speech, struporous condition, disturbance of flavoring feelings  

Disturbances from an organ of sight: Infrequent: vision disorder, eye pain, photophobia and disturbance of a slezootdeleniye Rare: conjunctivitis  

Disturbances from acoustic organs and balance: Frequent: вертиго Infrequent: ear pain, ring in ears  

Disturbances from cardiovascular system: Frequent: cardiopalmus and tachycardia Rare: stenocardia, increase in arterial pressure, bradycardia, shock Respiratory, thoracic and mediastinal disturbances: Frequent: feeling of "constraint" in a throat, Infrequent: диспноэ, yawning Rare: asthma and change of a timbre of a voice  

Disturbances from the alimentary system: Frequent: an abdominal pain, nausea, dryness in a mouth and dyspepsia Infrequent: diarrhea, glossitis Rare: lock, esophagitis, paraglossa, eructation  

Disturbances from gepatobiliarny system: Rare: hyperbilirubinemia, increase in activity of nuclear heating plant (aspartate aminotransferase)  

Disturbances from skin and hypodermic cellulose: Frequent: the increased sweating Infrequent: rash, itch Rare: skin diseases, urticaria  

Disturbances from a musculoskeletal system, connecting and bone fabrics: Frequent: dorsodynia, muscle pain Infrequent: joint pain, arthrosis and ostealgia Rare: arthritis, myopathy, mialgiya, spasms

Disturbances from an urinary system: Infrequent: disturbances from an urethral path (the speeded-up urination, a polyuria)

Disturbances from reproductive system and a mammary gland: Rare: mammary gland pain, menorrhagia General disturbances: Frequent: a caumesthesia or "inflows" of heat to the person, a fever, an adynamy, symptoms from a thorax (pain, feeling of compression, pressure) Infrequent: the general weakness, puffiness of the person, thirst, peripheral hypostases In post-market researches it was reported about the following undesirable effects:

Disturbances from immune system: allergic reactions.

Disturbances from a nervous system: exceptional cases of unconscious conditions of Disturbance from vascular system: arterial hypertension

Disturbances from the alimentary system: as at and some other 5-HT1B/1D-agonists, rare messages on ischemic colitis, vomiting were received.

Interaction with other medicines:

Influence of other    medicines on  pharmacokinetics of an eletriptan At erythromycin co-administration (1000 mg) and a ketokonazola (400 mg) which are powerful specific inhibitors of an isoenzyme CYP3A4, Cmax of an eletriptan increased in 2 and 2,7 times, respectively, and Auceletriptana – in 3,6 and 5,9 times, respectively. At this  T1/2    of an eletriptan increased from 4,6 to 7,1 o'clock at use of erythromycin and from 4,8 to 8,3 o'clock - at use of a ketokonazol (see the section "Pharmacokinetics"). Thus, Relpaks® should not be applied in a combination with powerful inhibitors of an isoenzyme CYP3A4, in particular ketokonazoly, itrakonazoly, erythromycin, klaritromitsiny, dzhozamitsiny and protease inhibitors (ritonaviry, indinaviry and nelfinaviry). Interaction of Relpaksa® with beta adrenoblockers, tricyclic antidepressants, selective serotonin reuptake inhibitors and flunariziny is not revealed, however results of special clinical trials of intermedicinal interactions are not available yet (except for propranolol, see below). The population pharmacokinetic analysis of clinical trials showed that the following medicines hardly influence a pharmakokinetikueletriptan: beta adrenoblockers, tricyclic antidepressants, selective serotonin reuptake inhibitors, estrogensoderzhashchy hormonal replaceable drugs, estrogensoderzhashchy peroral contraceptive drugs and blockers of calcium channels. As элетриптан is not MAO substrate, pharmacokinetic interaction of Relpaksa® and MAO inhibitors is improbable, and special researches of their interaction were not conducted. At simultaneous use of propranolol in a dose of 160 mg, verapamil in a dose of 480 mg or the flukonazola in a dose of 100 mg  of Cmax of an eletriptan increased in 1,1, 2,2 and 1,4 times, and AUC – in 1,3, 2,7 and 2,0 times, respectively. These changes are not clinically significant as they were not followed by increase in arterial pressure or increase in frequency of the undesirable phenomena in comparison with use of one eletriptan. Caffeine/ergotamine reception inside in 1 hour and the 2nd hour after reception of Relpaksa®privodit to small, but the additive increase in arterial pressure which could be predicted on the basis of pharmacological properties of these drugs. In this regard it is not necessary to appoint the drugs containing ergotamine or ergotaminopodobny means, in particular, dihydroergotamine during the 24th hour after reception of Relpaksa®. On the contrary, Relpaks® can appoint not earlier than in the 24th hour after reception of ergotaminosoderzhashchy drugs. Influence of an eletriptan on  other medicines In therapeutic doses is not revealed influence (inhibition or induction) of drug on system of P450 cytochrome. Interaction with serotonergic drugs Simultaneous use of agonists of 5-HT receptors, including an eletriptana, with the drugs having serotonergic activity such as SIOZS (selective serotonin reuptake inhibitors) and SIOZSN (selective serotonin reuptake inhibitors and noradrenaline), can increase risk of development of a serotoninovy syndrome. In case of clinical need of simultaneous use of an eletriptan and serotonergic drugs it is necessary to be careful. Such patients should be observed carefully, especially in an initiation of treatment and at increase in a dose of each drug.

Contraindications:

Hypersensitivity to an eletriptan or to any other component of drug. Heavy abnormal liver functions Age up to 18 years (data on efficiency and safety of use of drug in this age group are limited). A concomitant use with CYP3A4 inhibitors (кетоконазол, итраконазол, erythromycin, кларитромицин, джозамицин) and protease inhibitors (ритонавир, индинавир and нелфинавир). As well as at other agonists of receptors of a 5-gidroksitriptamin of the I type (5-HT1) of a contraindication to use of an eletriptan are proved by its pharmakodinamichesky properties: uncontrollable arterial hypertension; coronary heart disease (stenocardia, Printsmetal's stenocardia, the postponed myocardial infarction, the confirmed asymptomatic ischemia of a myocardium) or suspicion on its existence; occlusal diseases of peripheral vessels; disturbance of cerebral circulation or the tranzitorny ischemic attack in the anamnesis; combined use with other agonists of 5-HT1 receptors; During 24 h to or after reception of an eletriptan it is impossible to apply ergotamine or derivatives of ergotamine, including метисергид (see the section "Interaction with Other Medicines"). Релпакс® it is not shown for stopping of hemiplegic, ophthalmoplegic or basilar migraine. Patients with rare hereditary diseases, such as a lactose intolerance, deficit of lactase or glyukozo-lactose malabsorption should not accept drug.

Overdose:

At overdose it is possible to expect development of arterial hypertension and other disturbances, from cardiovascular system. Treatment: gastric lavage, symptomatic therapy. As T1/2eletriptana makes  near the 4th hour in case of overdose of drug it is necessary to observe patients within, at least, 20th hour or before disappearance of clinical symptoms of overdose. Influence of a hemodialysis and peritoneal dialysis on concentration of an eletriptan in a blood plasma is unknown.

Storage conditions:

To store at a temperature not above 30 °C. To store in the places unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated 20 mg or 40 mg. 2, 3, 4, 6 or 10 tablets in the blister from PVC / aluminum foil. 1, 2, 3, 4, 5, 6 or 10 blisters in a cardboard pack together with the application instruction.