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Active ingredients
Eletriptan
Release form
Pills
Composition
Active ingredient: eletriptan (eletriptan) Active ingredient concentration (mg): 40
Pharmacological effect
Antifungal drug. Eletriptan is a representative group of serotonin vascular 5-HT1B- and neuronal 5-HT1D receptor agonists. Eletriptan also has a high affinity for serotonin 5-HT1F receptors and has a moderate effect on serotonin 5-НТ1A-, 5-НТ2B-, 5-НТ1E- and 5-НТ7-receptors. Compared to sumatriptan, eletriptan shows a significantly greater selectivity in in relation to serotonin receptors located in the carotid arteries than in relation to serotonin receptors located in the coronary and femoral arteries. The ability of eletriptan to constrict intracranial blood vessels, as well as its inhibitory action against neurogenic inflammation, may determine its anti-migrainous activity.
Pharmacokinetics
AbsorptionAfter oral administration, eletriptan is rapidly and completely absorbed from the gastrointestinal tract (absorption is about 81%). In men and women, the absolute bioavailability when administered is about 50%. Tmax after oral administration in blood plasma averaged 1.5 hours. At therapeutic doses (20–80 mg), eletriptan's pharmacokinetics is characterized by a linear relationship. Cmax of eletriptan in blood plasma and AUC increased by about 20–30% when the drug was taken after ingesting fatty foods . When administered during a migraine attack, the AUC decreased by approximately 30%, Tmax in the blood plasma increased to 2.8 hours. With regular use (20 mg 3 times / day) for 5-7 days, the pharmacokinetics of eletriptan remained linear with predictable cumulation. When administered in higher doses (40 mg 3 times / day and 80 mg 2 times / day), the accumulation of eletriptan for 7 days exceeded the expected (by about 40%). The distribution of eletriptan Vd with i / v is 138 l, which indicates good distribution in the fabric. Eletriptan binds moderately to proteins (approximately 85%). Metabolism In vitro studies indicate that eletriptan's primary metabolism occurs under the action of the CYP3A4 isoenzyme in the liver. This fact is confirmed by an increase in plasma concentrations of eletriptan with simultaneous use of erythromycin, which is a potent selective CYP3A4 inhibitor.In vitro studies also show little involvement of CYP2D6 in eletriptan metabolism, although clinical studies have not revealed a clinical effect of polymorphism of this enzyme on the pharmacokinetic parameters of eletriptan. Two major circulating metabolites have been identified, which account for a significant portion of the total plasma radioactivity after eletriptan administration labeled 14C. The metabolite resulting from N-oxidation was not active in animal experiments in vitro. The metabolite resulting from N-demethylation was comparable in activity to eletriptan in in vitro animal studies. The third component of radioactive plasma is not identified, it is believed to be a mixture of hydroxylated metabolites, which are also excreted by the kidneys and through the intestine. The concentration of the active N-demethylated metabolite in the blood plasma is only 10-20% of the concentration of eletriptan and therefore does not make a significant contribution to its therapeutic effect. Withdrawal The total clearance of eletriptan from the blood plasma after i / v administration is on average 36 l / h, and T1 / 2 - approximately 4 h. The mean renal clearance after oral administration aven approximately 3.9 l / h. The share of extrarenal clearance is approximately 90% of the total clearance; This indicates that eletriptan is excreted mainly as metabolites by the kidneys and through the intestines. Pharmacokinetics in special clinical cases The results of a meta-analysis of clinical and pharmacological studies and population pharmacokinetic analysis indicate that sex does not have a clinically significant effect on eleptriptan concentration in the blood plasma. In elderly people (65-93 years) a slight and statistically insignificant decrease (16%) in eletriptan clearance and a statistically significant increase were found ie T1 / 2 (approximately 4.4 to 5.7 hours) compared with those in young adults. The effect of eletriptan on blood pressure in the elderly may be more pronounced compared with younger patients. Patients with impaired liver function (grades A and B on the Child-Pugh scale) showed a statistically significant increase in AUC (by 34%) and T1 / 2 , as well as a slight increase in Cmax (by 18%), however, these small changes are not considered clinically insignificant. In patients with lung (CK 61-89 ml / min),moderate (CK 31-60 ml / min) and severe (CK less than 30 ml / min) impaired renal function did not reveal statistically significant changes in the pharmacokinetics of eletriptan or its binding to plasma proteins.
Indications
relief of migraine attacks with and without aura.
Contraindications
Hypersensitivity to eletriptan or to any other component of the drug. Severe abnormal liver function, age up to 18 years. Contraindications common to all serotonton receptor agonists: uncontrolled arterial hypertension, coronary disease, incl. ischemic heart disease (angina pectoris, Prinzmetal angina pectoris, myocardial infarction, confirmed asymptomatic myocardial ischemia) or suspicion of its presence, occlusive peripheral vascular disease, impaired cerebral circulation or transient ischemic attack in history.
Precautionary measures
It should be borne in mind that the unrestricted use of antifungal drugs can lead to chronic daily headaches. Cases of excessive use of any triptans are most often observed in patients with daily headaches.
Use during pregnancy and lactation
Clinical experience with the drug Relpax during pregnancy is absent. The use of the drug is possible only in cases where the intended benefit of therapy for the mother outweighs the potential risk to the fetus. Eletriptan is excreted in breast milk in women. With a single dose of Relpax at a dose of 80 mg, excretion in breast milk over 24 hours averaged 0.02% of the dose taken. The risk of eletriptan's exposure to the newborn can be minimized if you do not breastfeed it within 24 hours after taking the drug Relpax. In experimental animal studies, Relpax had no teratogenic effect.
Dosage and administration
Relpax should be taken as early as possible, but the drug is effective at a later stage of a migraine attack. The recommended starting dose is 40 mg. If migraine headache resumes within 24 hours, then Relpax can be reappointed in the same dose. If a second dose is needed, it should be taken no earlier than 2 hours after the first dose. The daily dose should not exceed 160 mg.
Side effects
In general, Relpax is well tolerated. Usually, the side effects are transient, mild or moderate, and go away on their own without additional treatment. The main side effects registered with the treatment with Relpax are typical for the whole class of 5-HT1 receptor agonists. The most frequent: asthenia, back pain, pain and tightness in the chest, heartbeat, tachycardia, increased blood pressure, drowsiness, dizziness, paresthesia, abdominal pain, dry mouth, nausea, vomiting, dyspepsia, myalgia, pharyngitis, rash, itching , urticaria.
Overdose
Symptoms: possible development of arterial hypertension or other disorders of the cardiovascular system. Treatment: gastric lavage, conducting symptomatic therapy. T1 / 2 eletriptan is about 4 hours, so in case of overdose, the patient’s condition should be monitored for at least 20 hours or until the clinical symptoms of the overdose disappear. The effect of hemodialysis and peritoneal dialysis on plasma plasma concentration of eletriptan is unknown.
Interaction with other drugs
The effect of other drugs on eletriptanIn the simultaneous appointment of erythromycin (1 g) and ketoconazole (400 mg), which are powerful specific inhibitors of the CYP3A4 isoenzyme, a significant increase in Cmax (2 and 2.7 times, respectively) and AUC (3.6 and 5.9 times, respectively) eleriptan . These effects were accompanied by an increase in T1 / 2 of eletriptan from 4.6 to 7.1 hours with the use of erythromycin and from 4.8 to 8.3 hours with the use of ketoconazole. Therefore, the subjects of Relpax should not be used in combination with potent inhibitors of the CYP3A4 isoenzyme, in particular with ketoconazole ap, itraconazole, erythromycin, clarithromycin, josamycin, and protease inhibitors (ritonavir, indinavir, and nelfinavirom). capture of serotonin and flunarizine has not been identified, but the results of special clinical studies on the interaction with these drugs are currently about t are present (except for propranolol). Population pharmacokinetic analysis of clinical studies has shownthat the effect of the following drugs on the pharmacokinetics of the drug Relpax is unlikely: beta-blockers, tricyclic antidepressants, selective serotonin reuptake inhibitors, estrogen-containing drugs for hormonal hormone therapy and estrogen-containing oral contraceptives, calcium channel blockers. In this regard, the interaction of the drug Relpax and the MAO inhibitors is not expected, special studies of their interaction were not conducted. With simultaneous use of propranolol (160 mg), verapamil (480 mg) or fluconazole (100 mg), Cmax of eleptriptan rises respectively in 1.1, 2.2 and 1.4 times, and its AUC - 1.3, 2.7 and 2 times. These changes are considered clinically insignificant, since they were not accompanied by an increase in blood pressure or an increase in the frequency of adverse events, compared with that when using eletriptan alone. Taking caffeine / ergotamine orally after 1 and 2 hours after taking the drug Relpax leads to a small but additive increase in blood pressure, which could be predicted on the basis of pharmacological properties of these drugs. In this regard, drugs containing ergotamine, or ergotamine derivatives (including dihydroergotamine) should not be administered within 24 hours after taking Relpax. On the contrary, Relpax can be prescribed no earlier than 24 hours after taking ergotamine-containing drugs. Effect eletriptan on other drugs At therapeutic doses, no effect (inhibition or induction) of the drug on the cytochrome P450 system has been detected. Interaction with serotonergic drugs Simultaneous use of serotonin 5-HT agonists -receptors, including eletriptan, with drugs that have serotonergic activity, such as selective serotonin reuptake inhibitors and selective serotonin reuptake inhibitors and norepinephrine, may increase the risk of developing serotonin syndrome. In the case of the clinical need for the simultaneous use of eletriptan and serotonergic drugs, caution is required. Such patients should be carefully monitored, especially at the beginning of treatment and with an increase in the dose of each drug.
special instructions
The use of the drug Relpax in combination with powerful inhibitors of the isoenzyme CYP3A4, in particular, with ketoconazole, itraconazole, erythromycin, clarithromycin, josamycin and protease inhibitors such as ritonavir, indinavir and nelfinavir is not recommended. In addition, Relpax should not be taken for 72 hours after completing the intake of CYP3A4 isoenzyme inhibitors. Like other serotonin 5-HT1 receptor agonists, Relpax should be used only in cases where the diagnosis of migraine is beyond doubt. Relpax, like other agonists serotonin 5-HT1 receptors should not be prescribed for the treatment of atypical headaches, which can be associated with serious diseases (stroke, aneurysm rupture), when vasoconstriction of the brain can be harmful. Against the background of sero-agonists otonin 5-HT1 receptors have been reported cases of hemorrhage in the brain, subarachnoid hemorrhage, stroke or other cerebrovascular disorders, in some cases with a fatal outcome. In several cases, cerebrovascular impairment was the main disease and serotonin 5-HT1 receptor agonists were used incorrectly, interpreting the symptoms as signs of migraine. It should be noted that patients with migraine may be at increased risk of cerebrovascular events (eg, stroke, hemorrhage and transient ischemic attack) .If the simultaneous use of eletriptan and an SSRI (eg, fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) and SNRIs ( for example, venlafaxine, duloxetine) a potentially life-threatening serotonin syndrome may develop. This syndrome may manifest itself with the following symptoms: impaired mental status (eg, agitation, hallucinations, coma), instability of the autonomic nervous system (eg, tachycardia, fluctuations in blood pressure, hyperthermia), impaired neuromuscular function (eg, hyperreflexia, impaired coordination) and / or symptoms of dysfunction of the digestive system (for example, nausea, vomiting, diarrhea). It is not recommended to use Relpax in patients with risk factors for developing IHD (for example, arterial hypertension, hypercholesterolemia , smoking, obesity, diabetes mellitus, burdened family history,women in a state of surgical or physiological menopause or men over the age of 40 years) until a thorough examination of the circulatory system is carried out and cardiovascular disease is excluded. Sensitivity of methods for assessing the state of the cardiovascular system is rather small. In this regard, if patient history, ECG or other diagnostic procedures show signs characteristic of arterial vasospasm or myocardial ischemia, eletriptan is not recommended. Patients with cardiovascular risk factors, but who have a cardiovascular risk assessment -vascular system showed a satisfactory result, it is recommended to take the first dose of eletriptan under the supervision of a physician, except for patients who have previously received eletriptan. Since myocardial ischemia may occur in the absence of clinical symptoms, the possibility of an ECG immediately after taking the drug Relpax should be considered. Patients with risk factors for cardiovascular diseases, as described above, receiving eletriptan for a long time, but with interruptions, should periodically be examined by the cardiovascular system, as they continue therapy with eletriptan. Systematic following the above recommendations leads to a decrease in the number of cases where patients with heart failure o-vascular diseases receive therapy eletriptanom.Pri agonists of serotonin 5-HT1 receptors reported cases of severe disorders of cardiac function, including myocardial infarction, life-threatening cardiac arrhythmias and deaths that developed in the first few hours after taking the drug. Given the widespread use of serotonin 5-HT1 receptors in patients with migraine, the incidence of these reactions is extremely low. The following messages were received during the clinical studies. Among patients who underwent diagnostic coronary angiography, in one patient receiving eletriptan IV (Cmax 127 ng / ml, equivalent to 60 mg eletriptan for oral administration) with angina, arterial hypertension and hypercholesterolemia, there was a feeling of tightness in the chest cell, and coronary angiospasm (confirmed by angiography) was detected without changes on the ECG characteristic of ischemia.In addition, one case of atrial fibrillation was reported in a patient with a history of such a rhythm disorder. During the post-marketing period, there were reported cases of severe cardiovascular complications, some of which were fatal. In very rare cases, these complications occurred in the absence of any signs of cardiovascular disease. However, given the difficulty of monitoring messages received in the post-marketing period, it is impossible to definitively determine the relationship of these cases with eletriptan. Relpax should not be prescribed without prior examination in patients who are likely to have cardiovascular diseases or have an increased risk of their development. Systemic study of eletriptan in patients with heart failure was not conducted. The use of eletriptan, as well as other serotonin 5-HT1 receptor agonists, is not recommended in these patients. Relpax is effective in treating migraines with and without aura and migraines accompanying the menstrual cycle. Relpax taken during the onset of aura does not prevent the development of headache, so it should be taken only during the headache phase. In clinical studies, Relpax has been found to be effective also for relief of migraine symptoms, such as nausea, vomiting, photophobia, phonophobia, and for the treatment of the return of headaches during an attack. Relpax should not be taken prophylactically. When using the drug Relpax in therapeutic doses of 60 mg or more, a small and transient condition was recorded Increased blood pressure in patients with impaired renal function and the elderly increased. Impact on ability to drive and work with mechanisms. In some cases, migraine itself or taking serotonin 5-HT1 receptor agonists, including Relpax, may be accompanied by drowsiness or dizziness . Patients when performing work requiring increased attention, such as driving vehicles and working with complex mechanisms, should be careful during migraine attacks and after taking the drug Relpax.