Elptan tablets 40 mg No. 3

Instructions for Elptan tablets 40 mg No. 3

Composition

active ingredient: eletriptan;

1 film-coated tablet contains eletriptan hydrobromide monohydrate 25.17 mg, 50.34 mg or 100.68 mg, equivalent to eletriptan 20 mg, 40 mg or 80 mg, respectively;

excipients: microcrystalline cellulose pH 102, lactose monohydrate (Tablettose 80), croscarmellose sodium, magnesium stearate;

film coating: lactose monohydrate, hypromellose, titanium dioxide (E 171), triacetin, sunset yellow FCF aluminum lake (E 110).

Dosage form

Film-coated tablets.

Main physicochemical properties:

20 mg tablets – orange film-coated tablets, round in shape, with a biconvex surface.

40 mg tablets – orange film-coated tablets, round in shape, with a biconvex surface, engraved with “40” on one side.

80 mg tablets – orange film-coated tablets, round in shape, with a biconvex surface.

Pharmacotherapeutic group

Analgesics. Drugs used in the treatment of migraine. Selective serotonin 5-HT1 receptor agonists. Eletriptan. ATC code N02C C06.

Pharmacological properties

Pharmacodynamics.

Eletriptan is a selective agonist of vascular 5-HT1B and neuronal 5-HT1D receptors. Eletriptan also exhibits high affinity for the 5-HT1F receptor, which may contribute to its antimigraine mechanism of action. Eletriptan has low affinity for human recombinant 5-HT1A, 5-HT2B, 5-HT1E, and 5-HT7 receptors.

Clinical efficacy and safety.

The efficacy and safety of eletriptan in the treatment of acute migraine pain were evaluated in 10 placebo-controlled trials involving over 6000 patients (all treatment groups) at doses ranging from 20 to 80 mg. Headache relief occurred as early as 30 minutes after oral administration. Reduction of moderate or severe headache to mild or absent pain was observed after 2 hours and was 59–77% for the 80 mg dose, 54–65% for the 40 mg dose, 47–54% for the 20 mg dose, and 19–40% after placebo. Eletriptan was also effective in the treatment of associated migraine symptoms such as vomiting, nausea, photophobia, and phonophobia.

The recommendation to titrate the dose to 80 mg comes from long-term open-label studies and a short-term double-blind study where only a trend towards statistical significance was observed.

Eletriptan remains effective in menstrually associated migraine. Eletriptan has not been shown to prevent migraine headaches if taken during the aura phase, and therefore eletriptan should only be taken during the headache phase of migraine.

In a pharmacokinetic study, which was not placebo-controlled, patients with renal impairment showed a greater increase in blood pressure (BP) after a dose of 80 mg eletriptan than in healthy volunteers (see section 4.4). This cannot be explained by any pharmacokinetic changes and therefore may represent a specific pharmacodynamic response to eletriptan in patients with renal impairment.

Pharmacokinetics.

Absorption. Eletriptan is rapidly and well absorbed from the gastrointestinal tract (at least 81%) after oral administration. Absolute bioavailability in men and women is approximately 50%. The median time to maximum concentration (Tmax) is 1.5 hours after oral dosing. Linear pharmacokinetics have been demonstrated over the clinical dose range (20–80 mg).

The area under the pharmacokinetic concentration-time curve (AUC) and maximum plasma concentration (Cmax) of eletriptan were increased by approximately 20-30% after oral administration with a high-fat meal. After oral administration during a migraine attack, there was an approximately 30% decrease in AUC and an increase in Tmax to 2.8 hours.

After repeated doses (20 mg 3 times a day) for 5–7 days, the pharmacokinetics of eletriptan remained linear and accumulation was predictable. With multiple dosing of higher doses (40 mg 3 times a day and 80 mg 2 times a day), accumulation of eletriptan over 7 days was greater than predicted (approximately 40%).

Distribution: The volume of distribution of eletriptan after 4 doses is 138 L, indicating distribution into tissues. Eletriptan is moderately bound to plasma proteins (approximately 85%).

Two major circulating metabolites have been identified that contribute significantly to plasma radioactivity following administration of eletriptan labeled with the isotope carbon-14 (14C). In in vitro animal experiments, the metabolite formed as a result of N-oxidation did not show activity, and the metabolite formed as a result of N-demethylation showed activity similar to eletriptan. A third metabolite of radioactivity in plasma has not been formally identified, but is most likely a mixture of hydroxylated metabolites that have also been observed in excretions (in urine and feces). Plasma concentrations of the N-demethylated active metabolite are only 10-20% of those of eletriptan, so it is not expected to have a significant effect on the therapeutic effect of eletriptan.

Elimination: The mean total plasma clearance of eletriptan after 4 doses is 36 L/hour, resulting in a plasma elimination half-life (T1/2) of approximately 4 hours. The mean renal clearance after oral administration is approximately 3.9 L/hour. Non-renal clearance accounts for approximately 90% of total clearance, indicating that eletriptan is eliminated primarily by metabolism.

Pharmacokinetics in special patient groups.

Gender: Results from a meta-analysis of clinical pharmacology studies and population pharmacokinetic analysis suggest that gender has no clinically significant effect on eletriptan plasma concentrations.

Elderly patients (65 years and older): Although not statistically significant, there was a small decrease (16%) in clearance associated with a statistically significant increase in T1/2 (from approximately 4.4 hours to 5.7 hours) between elderly patients (65–93 years) and adults (<65 years).

Adolescents (12–17 years): The pharmacokinetics of eletriptan (40 mg and 80 mg) in adolescent migraineurs dosed between attacks were similar to those observed in healthy adults.

Children (6–11 years): The clearance of eletriptan is not altered in children compared to adolescents. However, the volume of distribution in children is lower, resulting in higher plasma levels than predicted after the same dose in adults.

Patients with hepatic impairment: In patients with hepatic impairment (Child-Pugh class A and B), a statistically significant increase in both AUC (34%) and T1/2 was demonstrated. A small increase in Cmax (18%) was observed. These small changes are not considered clinically important.

Patients with renal impairment: In patients with mild (creatinine clearance 61–89 mL/min), moderate (creatinine clearance 31–60 mL/min), or severe (creatinine clearance < 30 mL/min) renal impairment, there were no statistically significant changes in their eletriptan pharmacokinetics or plasma protein binding. An increase in blood pressure was observed in this group.

Indication

Treatment of acute headache during migraine attacks, with or without aura.

Contraindication

Hypersensitivity to the active substance or to any of the excipients of the medicinal product;

Severe liver or kidney dysfunction;

Moderate or severe hypertension or untreated mild hypertension;

Confirmed cardiovascular disease, including ischemic heart disease (CHD) (angina pectoris, previous myocardial infarction or confirmed asymptomatic ischemia). Patients with coronary artery vasospasm (Prinzmetal's angina), objective or subjective symptoms of CHD;

Significant arrhythmias or heart failure;

Peripheral vascular disease;

History of cerebrovascular accident (CVA) or transient ischemic attack (TIA);

Use of ergotamine or ergot derivatives (including methysergide) within 24 hours before or after treatment with eletriptan;

Concomitant use of other 5-HT1 receptor agonists with eletriptan.

Interaction with other medicinal products and other types of interactions

Effects of other drugs on eletriptan.

Key clinical trials of eletriptan showed no interaction data with β-blockers, tricyclic antidepressants, selective serotonin reuptake inhibitors, and flunarizine, but formal clinical interaction studies with these drugs are not available (except for propranolol, see below).

Population pharmacokinetic analysis of clinical trials showed that the following drugs: β-blockers, tricyclic antidepressants, selective serotonin reuptake inhibitors, estrogen-based hormone replacement therapy, oral contraceptives, and calcium channel blockers are unlikely to affect the pharmacokinetics of eletriptan.

Eletriptan is not a substrate for monoamine oxidase (MAO), therefore no interaction between eletriptan and MAO inhibitors is expected, and formal interaction studies have not been conducted.

In clinical studies with erythromycin (1000 mg) and ketoconazole (400 mg), specific and potent inhibitors of CYP3A4, a significant increase in eletriptan Cmax (2- and 2.7-fold) and AUC (3.6- and 5.9-fold), respectively, was observed. This increased exposure was associated with an increase in eletriptan T1/2 from 4.6 to 7.1 hours for erythromycin and from 4.8 to 8.3 hours for ketoconazole (see section 5.2). Therefore, eletriptan should not be used together with potent inhibitors of CYP3A4, such as ketoconazole, itraconazole, erythromycin, clarithromycin, josamycin and protease inhibitors (ritonavir, indinavir and nelfinavir).

In clinical studies, oral administration of caffeine/ergotamine 1 and 2 hours after eletriptan resulted in a small but additive increase in blood pressure, as predicted based on the pharmacology of the two drugs. Therefore, it is recommended that ergotamine-containing or ergotamine-like drugs (e.g., dihydroergotamine) should not be used within 24 hours of eletriptan administration. Conversely, eletriptan should not be used until 24 hours after ergotamine-containing drugs.

The effect of eletriptan on other drugs.

There is no in vitro or in vivo evidence that clinical doses (and associated concentrations) of eletriptan will inhibit or induce cytochrome P450 enzymes, including drugs metabolized by the CYP3A4 enzyme. Therefore, eletriptan is unlikely to cause clinically important drug interactions mediated by these enzymes.

Selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) and serotonin syndrome.

There have been reports describing patients with symptoms consistent with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular disorders) following the use of SSRIs or SNRIs, as well as triptans (see section 4.4).

Application features

Eletriptan should not be used with potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, erythromycin, clarithromycin, josamycin and protease inhibitors (ritonavir, indinavir and nelfinavir).

Eletriptan should only be used when a clear diagnosis of migraine has been established. Eletriptan is not indicated for the treatment of hemiplegic, ophthalmoplegic or basilar migraine.

Eletriptan should not be prescribed for the treatment of "atypical" headache, i.e., one that may be associated with a possible serious condition (stroke, ruptured aneurysm) where cerebrovascular vasoconstriction could be harmful.

Eletriptan may be associated with transient symptoms, including chest pain and tightness, which may be intense and may radiate to the throat (see section 4.8). If symptoms suggestive of CHD occur, the drug should be discontinued and appropriate evaluation should be performed.

Patients with heart failure.

Eletriptan should not be used in patients at risk of CHD or without prior evaluation in patients who may have undiagnosed cardiovascular disease (e.g., patients with elevated blood pressure, diabetes, smokers or users of nicotine replacement therapy, men over 40 years of age, postmenopausal women, and those with a strong family history of CHD).

Coronary vasospasm, ischemia, or myocardial infarction have been reported rarely in patients receiving 5-HT1 receptor agonists. Therefore, eletriptan and other serotonin 5-HT1 receptor agonists should not be used in patients with established coronary artery disease (see section 4.3).

There may be an increased incidence of undesirable effects with the simultaneous use of triptans and herbal medicines containing St. John's wort (Hypericum perforatum).

Within the clinical dose range, small and transient increases in blood pressure were observed with eletriptan doses of 60 mg or more. However, these increases were not associated with the clinical outcomes of the clinical trial program. The effect was more pronounced in patients with impaired renal function and in the elderly. In patients with renal insufficiency, the range of mean maximum increases in systolic blood pressure was 14–17 mmHg (normal 3 mmHg) and for diastolic blood pressure was 14–21 mmHg (normal 4 mmHg). In the elderly, the mean maximum increase in systolic blood pressure was 23 mmHg compared with 13 mmHg in young subjects (placebo 8 mmHg). Postmarketing reports of increases in blood pressure have also been received from patients taking eletriptan doses of 20 and 40 mg, as well as patients without renal insufficiency and from elderly patients.

Headache from excessive use of medications.

Prolonged use of any painkiller for a headache may worsen it. If this situation is suspected or occurs, the drug should be discontinued and a doctor should be consulted. This diagnosis should be suspected in patients who have frequent or daily headaches despite (or because of) regular use of headache medications.

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular abnormalities) has been reported following concomitant treatment with triptans and SSRIs or SNRIs. These reactions may be severe. If concomitant treatment with eletriptan and SSRIs or SNRIs is clinically warranted, appropriate monitoring of the patient is recommended, particularly at the start of treatment, when the dose is increased, or when another serotonergic medicinal product is added (see section 4.5).

Important information about excipients.

This medicinal product contains lactose and is therefore not recommended for patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose/galactose malabsorption.

The medicine contains sodium, so patients on a controlled sodium diet should be careful when using it.

This medicine also contains a yellow dye, which may cause allergic reactions.

Use during pregnancy or breastfeeding

Pregnancy.

There is no clinical experience with eletriptan in pregnant women. Eletriptan should be used during pregnancy only if there is no safer alternative and the expected benefit to the mother outweighs the potential risk to the fetus.

Breast-feeding.

Eletriptan is excreted in breast milk. In one study of 8 women receiving a single 80 mg dose, the mean total amount of eletriptan in breast milk over 24 hours in this group was 0.02% of the dose. Therefore, caution should be exercised when considering the use of eletriptan in a nursing woman. The risk of exposure to the infant can be minimized by avoiding breastfeeding for 24 hours after taking eletriptan.

Ability to influence reaction speed when driving vehicles or other mechanisms

Eletriptan has a moderate influence on the ability to drive and use machines. Some patients may experience drowsiness or dizziness during migraine or treatment with eletriptan. Caution should be exercised when performing tasks requiring alertness, such as driving a car or operating complex machinery, during migraine attacks and after taking eletriptan.

Method of administration and doses

Method of application.

The tablets should be swallowed whole with water.

Dosage.

The medication should be used as early as possible after the onset of a migraine headache, but it is also effective at a later stage during a migraine attack.

Eletriptan has not been shown to prevent migraine headaches if used during the aura phase, and therefore this medicine should only be used during the migraine phase of the headache.

The drug should not be used for prophylactic purposes.

Adults (aged 18 to 65).

The recommended starting dose is 40 mg.

If the headache returns within 24 hours: If a migraine headache resolves but then recurs within 24 hours, eletriptan may be re-administered at the same dose that is effective for treating the recurrence. If a second dose is required, it should not be taken within 2 hours of the initial dose.

If no response to treatment is obtained: If the first dose does not reduce the headache within 2 hours, a second dose should not be used to relieve the attack, because the effectiveness of a second dose has not been established in clinical studies.

Clinical trials show that in patients who have failed to relieve a headache attack, treatment for a subsequent attack may still be effective.

If patients taking the 40 mg dose do not experience satisfactory relief (e.g., good tolerability but failure to control 2 out of 3 attacks), a dose of 80 mg may be effective for subsequent migraine attacks (see section 5.1). A second dose of 80 mg should not be taken within 24 hours.

The maximum daily dose should not exceed 80 mg (see section "Adverse reactions").

Elderly patients.

The safety and efficacy of eletriptan in patients aged 65 years and older have not been systematically evaluated due to the small number of patients in clinical trials. Therefore, the use of eletriptan in elderly patients is not recommended.

Patients with liver dysfunction.

No dose adjustment is required in patients with mild or moderate hepatic impairment. Since eletriptan levels have not been studied in patients with severe hepatic impairment, its use is contraindicated in these patients.

Patients with renal impairment.

Since the effects of eletriptan on blood pressure are increased in renal impairment (see section 4.4), a starting dose of 20 mg is recommended for patients with mild to moderate renal impairment. The maximum daily dose should not exceed 40 mg. The drug is contraindicated in patients with severe renal impairment.

Children

The use of eletriptan in patients under 18 years of age is not indicated due to the lack of experience with its use in pediatrics.

Overdose

No significant side effects have been reported with a single dose of 120 mg. However, overdose with selective serotonin 5-HT1 receptor agonists may result in hypertension or other more serious cardiovascular reactions.

In case of overdose, symptomatic and supportive therapy is indicated as needed. The half-life of eletriptan is approximately 4 hours, therefore, patients should be monitored and symptomatic and supportive therapy should be provided after an overdose of eletriptan for at least 20 hours or as long as signs and symptoms persist.

It is unknown what effect hemodialysis or peritoneal dialysis has on serum concentrations of eletriptan.

Adverse reactions

Summary of the safety profile.

The most common adverse reactions known from clinical trials (5000 patients treated with 20 mg, 40 mg and 80 mg doses) of eletriptan were asthenia, somnolence, nausea and dizziness. A dose-dependent trend in the incidence of adverse events was also observed.

Tabulated list of adverse reactions.

The following table lists adverse reactions (incidence ≥ 1% or greater compared to placebo) that have been reported in patients receiving therapeutic doses in clinical trials and are classified by frequency: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000).

The common adverse reactions observed with eletriptan are typical of the adverse reactions characteristic of 5-HT1 receptor agonists as a class as a whole.

The following adverse reactions have been reported during post-marketing surveillance.

Gastrointestinal: rare reports of ischemic colitis and vomiting.

From the nervous system: serotonin syndrome, rare cases of syncope, cerebrovascular accident.

Vascular: hypertension.

Cardiac: ischemia or myocardial infarction, coronary arteriospasm.

Immune system disorders: allergic reactions, some of which may be serious, including angioedema.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after the marketing authorisation of a medicinal product is an important procedure. It allows for continued monitoring of the benefit-risk balance of the medicinal product in question. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Expiration date

3 years.

Storage conditions

Store in original packaging at a temperature not exceeding 25 ° C. Keep out of the reach of children.

Packaging

3 tablets in a blister; 1 blister in a pack.

Side effects

The most common adverse reactions known from clinical trials (5000 patients treated with 20 mg, 40 mg and 80 mg doses) of eletriptan were asthenia, somnolence, nausea and dizziness. A dose-dependent trend in the incidence of adverse events was also observed.

Tabulated list of adverse reactions.

The following table lists adverse reactions (incidence ≥ 1% or greater compared to placebo) that have been reported in patients receiving therapeutic doses in clinical trials and are classified by frequency: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000).

The common adverse reactions observed with eletriptan are typical of the adverse reactions characteristic of 5-HT1 receptor agonists as a class as a whole.

The following adverse reactions have been reported during post-marketing surveillance.

Gastrointestinal: rare reports of ischemic colitis and vomiting.

From the nervous system: serotonin syndrome, rare cases of syncope, cerebrovascular accident.

Vascular: hypertension.

Cardiac: ischemia or myocardial infarction, coronary arteriospasm.

Immune system disorders: allergic reactions, some of which may be serious, including angioedema.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after the marketing authorisation of a medicinal product is an important procedure. It allows for continued monitoring of the benefit-risk balance of the medicinal product in question. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Vacation category

According to the recipe.

Producer

Rafarm S. A.

Location of the manufacturer and address of its place of business.

Tesi Pusi Hatzi Agiou Louka, Paiania, 19002, Greece.

Applicant

PrJSC "Pharmaceutical Company "Darnitsa".

Location of the applicant.

Ukraine, 02093, Kyiv, Boryspilska St., 13.

Address

Ukraine, 02093, Kyiv, Boryspilska St., 13.