Relpax pills 40mg №2

Mechanism of action

Antifungal drug. Eletriptan is a representative group of serotonin vascular 5-HT selective agonists._1B- and neuronal 5-HT_1D-receptors. Eletriptan also has a high affinity for serotonin 5-HT_1F-receptors, which may be related to its anti-migraine mechanism of action, and has a moderate effect on serotonin 5-HT_1A-, 5-HT_2b-, 5-HT_1E- and 5-HT₇receptors.

Compared to Sumatriptan, eletriptan is significantly more selective for serotonin receptors located in the carotid arteries than 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

Suction

After ingestion, 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%. T_max after oral administration in blood plasma averaged 1.5 hours. In the range of therapeutic doses (20-80 mg), eletriptan's pharmacokinetics is characterized by a linear dependence.

C_max eletriptan in blood plasma and AUC increased by about 20-30% when taking the drug after eating fatty foods. When administered during a migraine attack, the AUC decreased by approximately 30%, T_max in blood plasma increased to 2.8 h.

With regular use (20 mg 3 times / day) for 5-7 days, eletriptan's pharmacokinetics remained linear with predictable cumulation. When administered at higher doses (40 mg 3 times / day and 80 mg 2 times / day), eletriptan cumulation exceeded the expected (about 40%) for 7 days.

Distribution

V_d eletriptan with the on / in the introduction is 138 liters, which indicates a good distribution in the tissue. Eletriptan binds moderately to proteins (approximately 85%).

Metabolism

In vitro studies indicate that eletriptan's primary metabolism occurs under the action of 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 a slight involvement of CYP2D6 in eletriptan metabolism, although clinical studies have not revealed a clinical effect of this enzyme polymorphism on the pharmacokinetic parameters of eletriptan.

Two major circulating metabolites have been identified, the proportion of which constitutes a significant part of the total radioactivity of blood plasma after administration of eletriptan, 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 in the urine and feces.

The concentration of the active N-demethylated metabolite in the blood plasma is only 10–20% of the concentration of eletriptan and, accordingly, does not make a significant contribution to its therapeutic effect.

Removal

The total clearance of eletriptan from the blood plasma after the on / in the introduction is an average of 36 l / h, and T_1/2 - about 4 h. The average renal clearance after oral administration is 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 in urine and feces.

Pharmacokinetics in special clinical situations

Floor

The results of a meta-analysis of clinical and pharmacological studies and population pharmacokinetic analysis suggest that sex does not have a clinically significant effect on plasma concentration of eletriptan.

Elderly patients (over 65)

In elderly people (65-93 years), a small and statistically insignificant decrease (16%) in eletriptan clearance and a statistically significant increase in T_1/2 (approximately from 4.4 to 5.7 h) compared with those in young adults.The effect of eletriptan on blood pressure in older people may be more pronounced compared with younger patients.

Teens 12-17 years old

The pharmacokinetics of eletriptan (40 mg and 80 mg) in adolescents aged 12-17 years with migraine who took the drug during the interictal period was similar to that in healthy adults.

Children 7-11 years old

In children aged 7-11 years, eletriptan's clearance does not differ from that of adolescents, while they have less than V_d. Plasma concentrations of the drug exceed its expected levels after taking eletriptan at the same dose in adults.

In patients with impaired liver function (grades A and B on the Child-Pugh scale) a statistically significant increase in AUC (by 34%) and T_1/2as well as a slight increase in C_max (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 <30 ml / min) impaired renal function, no statistically significant changes in the pharmacokinetics of eletriptan or its binding to plasma proteins were detected blood.

Indications for use of the drug

- relief of migraine attacks with and without aura.

Dosage and administration

The drug is prescribed inside. pills should be swallowed whole with water.

When migraine headache Relpax ^® should be taken as early as possible after the onset of pain, but the drug is effective in the later stage of a migraine attack.

For adult patients (aged 18-65 years) The recommended starting dose is 40 mg.

If migraine headache is relieved, but then resumes within 24 hours, then Relpax^® You can reappoint in the same dose. If a second dose is needed, it should be taken no earlier than 2 hours after the first dose.

If the first dose of Relpax^® does not lead to a reduction in headache for 2 hours, then for the relief of the same attack should not take a second dose, because in clinical studies, the effectiveness of such treatment has not been proven. At the same time, patients who failed to stop an attack can give an effective clinical response in the next attack.

If taking the drug at a dose of 40 mg does not allow to achieve an adequate effect, then at subsequent migraine attacks a dose of 80 mg may be effective.

The maximum daily dose is 160 mg.

Have patients with mild or moderate liver dysfunction dose adjustment is not required.

Side effect

In general, Relpax^® well tolerated. Usually, the side effects are transient, mild or moderate, and go away on their own without additional treatment. The frequency and severity of adverse reactions in patients taking the drug 2 times in the same dose to relieve an attack are similar to those in patients taking the drug once. The main side effects recorded during treatment with the drug Relpaksom^®typical for an entire class of 5-HT agonists₁-receptors.In patients taking Relpax^® at therapeutic doses, the following adverse reactions were observed (with a frequency of ≥1%, compared with placebo). Determination of the frequency of adverse reactions: often (≥1 / 100 to <1/10), sometimes (≥1 / 1000 to 1/100), rarely (≥1 / 10 000 to 1/1000).

On the part of the respiratory system: often - pharyngitis, rhinitis, feeling of "tightness" in the throat; sometimes - dyspnea, yawning; rarely - respiratory tract infections, bronchial asthma, changes in the tone of the voice.

Violations of the lymphatic system: rarely lymphadenopathy.

Metabolism: sometimes anorexia.

From the side of the central nervous system and peripheral nervous system: often - drowsiness, headache, dizziness, tingling sensation or other sensory disturbances, muscle hypertonia, hypesthesia, myasthenia; sometimes - tremor, hyperesthesia, ataxia, hypokinesia, impaired speech, stuporous state, impaired taste, impaired thinking, agitation, confusion, depersonalization, euphoria, depression, insomnia; rarely - emotional lability.

Violations of the senses: often vertigo; sometimes - blurred vision, pain in the eyes, photophobia and impaired tearing, ear pain, ringing in the ears; rarely - conjunctivitis.

Since the cardiovascular system: often - palpitations, tachycardia; rarely - angina, increased blood pressure, bradycardia, shock.

From the digestive system: often - abdominal pain, nausea, dry mouth, dyspepsia ; sometimes - diarrhea, glossitis; rarely - constipation, esophagitis, edema of the tongue, belching, hyperbilirubinemia, increased ACT activity.

Dermatological reactions: often - increased sweating; sometimes - rash, itching; rarely - skin diseases, urticaria.

From the musculoskeletal system: often - back pain, muscle pain; sometimes - pain in the joints, arthrosis and pain in the bones; rarely - arthritis, myopathy, myalgia, convulsions.

From the urinary system: sometimes - frequent urination, polyuria.

Reproductive system disorders: rarely - pain in the mammary glands, menorrhagia.

General violations: often - a feeling of warmth or "hot flashes" of heat to the face, chills, asthenia, chest symptoms (pain, feeling of tightness, pressure); sometimes - general weakness, swelling of the face, thirst, peripheral edema.

Side Effects Reported in Post-Marketing Studies

On the part of the nervous system: rarely - fainting.

Since the cardiovascular system: arterial hypertension.

From the digestive system: rarely - ischemic colitis, vomiting.

Other: allergic reactions.

Contraindications to the use of the drug

- severe abnormal liver function;

- uncontrolled arterial hypertension;

- IHD (angina pectoris, Prinzmetal angina pectoris, myocardial infarction, confirmed asymptomatic myocardial ischemia) or suspicion of its presence;

- occlusive diseases of peripheral vessels;

- violation of cerebral circulation or tranzitorny ischemic attack in the anamnesis;

- simultaneous administration of the drug Relpax^® with other serotonin 5-HT agonists₁-receptors;

- concomitant use with CYP3A4 inhibitors (ketoconazole, itraconazole, erythromycin, Clarithromycin, josamycin) and protease inhibitors (ritonavir, indinavir and nelfinavir);

- within 24 hours before or after taking the drug Relpax^® do not use ergotamine or ergotamine derivatives (including methysergide);

- children and adolescents under 18 years of age (data on the efficacy and safety of the use of the drug in this age group are limited);

- in order to relieve hemiplegic, ophthalmoplegic or basilar migraine;

- rare hereditary diseases - lactose intolerance, lactase deficiency or glucose / lactose malabsorption;

- hypersensitivity to the drug.

WITH caution apply Relpax^® simultaneously with other drugs with serotonergic activity, such as selective serotonin reuptake inhibitors and selective serotonin and noradrenaline reuptake inhibitors (since in some cases the development of serotonin syndrome was observed while eletriptan and other serotonergic drugs were developed); at a dose of more than 40 mg in patients with impaired renal function (since in such patients the effect of eletriptan on blood pressure increases).

Use of the drug 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 the drug Relpax^® at a dose of 80 mg, excretion in breast milk during 24 hours averaged 0.02% of the dose taken. The risk of eletriptan's exposure to the newborn can be minimized if not breastfed for 24 hours after taking Relpax^®.

Application for violations of the liver

Contraindication: severe abnormal liver function

In patients with impaired liver function (grades A and B on the Child-Pugh scale) a statistically significant increase in AUC (by 34%) and T_1/2as well as a slight increase in C_max (18%), however, these small changes are not considered clinically insignificant.

In patients with mild or moderate hepatic impairment, a dose change is not required. In patients with severely impaired liver function, the efficacy and safety of Relpax have not been studied, therefore, in such cases, the drug is contraindicated.

Application for violations of kidney function

In patients with lung (CK 61-89 ml / min), moderate (CK 31-60 ml / min) and severe (CK <30 ml / min) impaired renal function, no statistically significant changes in the pharmacokinetics of eletriptan or its binding to plasma proteins were detected blood.

In patients with impaired renal function, the hypertensive effect of Relpax is enhanced, therefore, it is necessary to prescribe the drug with caution in doses exceeding 40 mg. When using Relpax at doses of 60 mg or more (in the range of therapeutic doses), a small and transient increase in blood pressure was recorded, which increased to a greater extent in renal dysfunction and in elderly patients (such changes were not accompanied by clinical consequences).

special instructions

The use of the drug Relpax is not recommended.^® in combination with potent inhibitors of CYP3A4 isoenzyme, in particular, with Ketoconazole, itraconazole, erythromycin, clarithromycin, josamycin, and protease inhibitors, such as ritonavir, indinavir and nelfinavir.

Like other serotonin 5-HT agonists₁-receptors, Relpax^® should be used only in cases where the diagnosis of migraine is not in doubt.

Relpax^® effective in treating migraine with and without aura and migraine accompanying the menstrual cycle. Relpax^®, taken during the appearance of the aura, does not prevent the development of headache, so it should be taken only during the headache phase.

Relpax^®as other serotonin 5-HT agonists₁-receptors should not be prescribed for the treatment of "atypical" headaches, which can be associated with serious diseases (stroke, rupture of the aneurysm), when the narrowing of cerebral vessels can be harmful.

Relpax^® should not be taken prophylactically.

Relpax^® It should not be prescribed without a preliminary examination in patients who are likely to have or are at increased risk of cardiovascular diseases. Systemic study of eletriptan in patients with heart failure was not conducted. The use of eletriptan, as well as other serotonin 5-HT agonists₁-receptors in these patients are not recommended.

In clinical studies, it is established that Relpax^® It is also effective in relieving symptoms accompanying migraines, such as nausea, vomiting, photophobia, phonophobia, and in the treatment of recurring headaches during an attack.

When using the drug Relpax^® at doses of 60 mg or more (in the range of therapeutic doses) a small and transient increase in blood pressure was recorded, which increased to a greater extent in renal dysfunction and in elderly patients.

Influence on ability to manage motor transport and work with mechanisms

In some cases, the migraine itself or taking serotonin 5-HT agonists₁receptors, including Relpax^®may be accompanied by drowsiness or dizziness. Patients when performing work that requires increased attention, such as driving vehicles and working with complex mechanisms, should be careful during migraine attacks and after taking the drug Relpax^®.

Overdose

Symptoms: possible development of arterial hypertension or other disorders of the cardiovascular system.

Treatment: conducting maintenance therapy. T_1/2 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 disappear. The effect of hemodialysis and peritoneal dialysis on serum concentrations of eletriptan is unknown.

Drug interaction

Effect of other drugs on eletriptan

With the simultaneous appointment of erythromycin (1 g) and ketoconazole (400 mg), which are potent specific inhibitors of the CYP3A4 isoenzyme, a significant increase in C was detected_max (2 and 2.7 times respectively) and AUC (3.6 and 5.9 times respectively) of eleptriptan. These effects were accompanied by an increase in T_1/2 eletriptan from 4.6 to 7.1 h with the use of erythromycin and from 4.8 to 8.3 h with the use of ketoconazole. Therefore Relpax^® should not be used in combination with powerful inhibitors of the isoenzyme CYP3A4, in particular with ketoconazole, itraconazole, erythromycin, clarithromycin, josamycin and protease inhibitors (ritonavir, indinavir and nelfinavir).

The interaction of the drug Relpax^® no beta-blockers, tricyclic antidepressants, selective serotonin reuptake inhibitors and flunarizine have been identified, but the results of special clinical studies on the interaction with these drugs are currently absent (except for propranolol).

A population pharmacokinetic analysis of clinical studies has shown that the effect of the following drugs on the pharmacokinetics of the drug Relpax^® unlikely: beta-blockers, tricyclic antidepressants, selective serotonin reuptake inhibitors, estrogen-containing drugs for hormone replacement therapy and estrogen-containing oral contraceptives, Calcium channel blockers.

Eletriptan is not a substrate of MAO. In this regard, it is not expected interaction drug Relpax^® and MAO inhibitors, special studies of their interaction has been conducted.

With simultaneous use of propranolol (160 mg), Verapamil (480 mg) or Fluconazole (100 mg) C_max eletriptan increases by 1.1, 2.2, and 1.4 times, respectively, and its AUC increases by 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.

Intake of 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 the 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 the drug Relpax^®.

Conversely, Relpax^® You can appoint no earlier than 24 hours after taking ergotamine-containing drugs.

Effect of eletriptan on other drugs

At therapeutic doses, no effect (inhibition or induction) of the drug on the cytochrome P450 system was detected.

Interaction with serotonergic drugs

The simultaneous use of serotonin 5-HT receptor agonists, incl. 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.