Elptan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ELPTAN (ELPTAN)

Composition:

Active substance: eletriptan;

One film-coated tablet contains 25.17 mg or 50.34 mg of eletriptan hydrobromide monohydrate, equivalent to 20 mg or 40 mg of eletriptan;

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

Film coating: lactose monohydrate, hypromellose, titanium dioxide (E 171), triacetin, yellow azo dye FCF aluminum lake (E 110).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics:

20 mg tablets — orange-colored, round, biconvex film-coated tablets;

40 mg tablets — orange-colored, round, biconvex film-coated tablets with "40" engraved on one side.

Pharmacotherapeutic group. Analgesics. Medicinal products 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 acute treatment of migraine headache were evaluated in 10 placebo-controlled studies involving over 6,000 patients (all treatment groups) at doses ranging from 20 to 80 mg. Headache relief was observed as early as 30 minutes after oral administration. Reduction of moderate or severe headache to mild or no headache at 2 hours was reported in 59–77% of patients at the 80 mg dose, 54–65% at the 40 mg dose, 47–54% at the 20 mg dose, and 19–40% in the placebo group. Eletriptan was also effective in treating associated migraine symptoms such as vomiting, nausea, photophobia, and phonophobia.

The recommendation for dose titration up to 80 mg is based on results from long-term open-label studies and a short-term double-blind study, where only a trend toward statistical significance was observed.

Eletriptan remains effective in menstrually associated migraine. In clinical studies, administration of eletriptan during the aura phase did not prevent migraine headache; therefore, eletriptan should be taken only during the headache phase of migraine.

In a pharmacokinetic study without placebo control in patients with impaired renal function, a higher increase in blood pressure (BP) was observed after an 80 mg dose of eletriptan compared to healthy volunteers (see section "Special Warnings and Precautions for Use"). This cannot be explained by any pharmacokinetic changes and may therefore reflect a specific pharmacodynamic response to eletriptan in patients with impaired renal function.

Pharmacokinetics

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

The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of eletriptan were increased by approximately 20–30% following oral administration with a high-fat meal. Following oral administration during a migraine attack, a reduction of approximately 30% in AUC was observed, and Tmax increased to 2.8 hours.

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

Distribution. The volume of distribution of eletriptan after intravenous administration is 138 L, indicating tissue distribution. Eletriptan is moderately bound to plasma proteins (approximately 85%).

Metabolism. In vitro studies indicate that eletriptan is primarily metabolized by the hepatic enzyme CYP3A4 of the cytochrome P450 system. This conclusion is supported by increased eletriptan plasma concentrations following co-administration with erythromycin and ketoconazole, known selective and potent inhibitors of CYP3A4. In vitro studies also suggest minor involvement of the CYP2D6 enzyme in eletriptan metabolism, although clinical studies do not indicate polymorphism of this enzyme.

Two major circulating metabolites have been identified, which significantly contribute to plasma radioactivity after administration of carbon-14 (14C)-labeled eletriptan. In animal in vitro experiments, the metabolite formed via N-oxidation showed no activity, while the metabolite formed via N-demethylation showed activity similar to eletriptan. A third metabolite of plasma radioactivity has not been formally identified but is likely a mixture of hydroxylated metabolites, which were also detected in excreta (urine and feces). Plasma concentrations of the active N-demethylated metabolite are only 10–20% of eletriptan concentrations; therefore, a significant contribution to the therapeutic effect of eletriptan is not expected.

Elimination. The mean total plasma clearance of eletriptan after intravenous administration is 36 L/h, with a plasma half-life (T1/2) of approximately 4 hours. Mean renal clearance after oral administration is approximately 3.9 L/h. Non-renal clearance accounts for approximately 90% of total clearance, indicating that eletriptan is primarily eliminated via metabolism.

Pharmacokinetics in Specific Patient Populations

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

Elderly patients (65 years and older). Although not statistically significant, a slight decrease (16%) in clearance associated with a statistically significant increase in T1/2 (from approximately 4.4 to 5.7 hours) has been observed in elderly patients (65–93 years) compared to adults under 65 years.

Adolescents (12–17 years). The pharmacokinetics of eletriptan (40 mg and 80 mg) in adolescents with migraine, administered between attacks, were similar to those observed in healthy adults.

Children (6–11 years). Eletriptan clearance in children does not differ from that in adolescents. However, the volume of distribution is lower in children, resulting in higher plasma levels compared to predicted levels after the same dose in adults.

Patients with hepatic impairment. In patients with hepatic impairment (Child-Pugh classes A and B), statistically significant increases in both AUC (34%) and T1/2 have been demonstrated. A slight increase in Cmax (18%) was observed. These minor changes are not considered clinically significant.

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, no statistically significant changes in eletriptan pharmacokinetics or plasma protein binding were observed. An increase in BP was observed in this group.

Clinical Characteristics

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

Contraindications

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Severe impairment of liver or kidney function.
• Moderate to severe arterial hypertension or untreated mild arterial hypertension.
• Confirmed cardiovascular diseases, including ischemic heart disease (IHD) (angina, previous myocardial infarction, or confirmed asymptomatic ischemia). Do not use in patients with coronary artery vasospasm (Prinzmetal’s angina) or with objective or subjective symptoms of IHD.
• Significant arrhythmias or heart failure.
• Peripheral vascular disease.
• Cerebrovascular disorders or history of transient ischemic attack (TIA).
• Do not use ergotamine or ergotamine derivatives (including methysergide) within 24 hours before or after treatment with eletriptan.
• Concomitant use of other 5-HT1 receptor agonists with eletriptan is contraindicated.

Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on eletriptan

Key clinical trials of eletriptan lack data on interactions with β-blockers, tricyclic antidepressants, selective serotonin reuptake inhibitors, and flunarizine; however, formal clinical interaction studies with these drugs are not available (except for propranolol, see below).

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

Eletriptan is not a substrate for monoamine oxidase (MAO); therefore, interaction between eletriptan and MAO inhibitors is not expected, and formal interaction studies have not been conducted.

In clinical studies with propranolol (160 mg), verapamil (480 mg), and fluconazole (100 mg), the Cmax of eletriptan increased by 1.1-fold, 2.2-fold, and 1.4-fold, respectively; the AUC of eletriptan increased by 1.3-fold, 2.7-fold, and 2-fold, respectively. These effects are not considered clinically significant, as there were no associated increases in blood pressure or adverse events compared to eletriptan alone.

In clinical studies with erythromycin (1000 mg) and ketoconazole (400 mg), specific and potent inhibitors of CYP3A4, a significant increase in eletriptan Cmax (by 2-fold and 2.7-fold, respectively) and AUC (by 3.6-fold and 5.9-fold, respectively) was observed. This increased exposure was associated with an increase in eletriptan’s T1/2 from 4.6 to 7.1 hours with erythromycin and from 4.8 to 8.3 hours with ketoconazole (see section "Pharmacokinetics"). Therefore, eletriptan should not be used concomitantly with potent CYP3A4 inhibitors 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 by the pharmacology of both drugs. Therefore, it is recommended not to use medicinal products containing ergotamine or ergotamine-like compounds (e.g., dihydroergotamine) within 24 hours after taking eletriptan. Likewise, eletriptan should not be taken earlier than 24 hours after administration of medicinal products containing ergotamine.

Effect of eletriptan on other medicinal products

There is no evidence in vitro or in vivo that clinical doses (and corresponding plasma concentrations) of eletriptan inhibit or induce cytochrome P450 enzymes or affect the metabolism of drugs that are substrates of these enzymes. Therefore, it is considered unlikely that eletriptan will cause clinically significant interactions mediated by these enzymes.

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

There have been reports of symptoms consistent with serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular abnormalities) following concomitant use of SSRIs or SNRIs and triptans (see section "Special precautions for use").

Special precautions for use

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

Eletriptan should be used only 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., headache that may be associated with a serious condition (e.g., stroke, aneurysm rupture), where cerebral vasoconstriction could be harmful.

After administration of eletriptan, transient symptoms such as chest pain and sensation of tightness may occur, which can be intense and radiate to the throat (see section "Adverse reactions"). If symptoms suggestive of ischemic heart disease (IHD) occur, the drug should be discontinued and appropriate evaluation initiated.

Patients with heart failure

Eletriptan should not be used in patients at risk of IHD or in patients who may have undiagnosed cardiovascular disorders without prior evaluation (e.g., patients with hypertension, diabetes, smokers or those receiving nicotine replacement therapy, men over 40 years of age, postmenopausal women, and those with a family history of IHD).

Rare cases of coronary vasospasm, ischemia, or myocardial infarction have been reported in patients receiving 5-HT1 receptor agonists. Therefore, eletriptan and other 5-HT1 serotonin receptor agonists should not be used in patients with established IHD (see section "Contraindications").

An increased frequency of adverse effects may occur when triptans are used concomitantly with herbal medicinal products containing St. John's wort (Hypericum perforatum).

Within the clinical dose range of eletriptan (60 mg and higher), a slight transient increase in blood pressure (BP) has been observed. However, this increase was not associated with clinical consequences within the clinical trial program. The effect was more pronounced in patients with renal impairment and elderly patients. In patients with renal insufficiency, the range of mean maximum increase in systolic BP was 14–17 mm Hg (vs. 3 mm Hg in controls), and diastolic BP increased by 14–21 mm Hg (vs. 4 mm Hg in controls). In elderly patients, the mean maximum increase in systolic BP was 23 mm Hg compared to 13 mm Hg in younger individuals (placebo group: 8 mm Hg). During the post-marketing period, increased BP has also been observed in patients taking eletriptan doses of 20 and 40 mg, as well as in patients without renal impairment and in elderly patients.

Medication-overuse headache

Prolonged use of any analgesic for headache may lead to worsening of headache. If such a causal relationship is suspected or confirmed, the drug should be discontinued and medical advice sought. This diagnosis should be considered if the patient experiences frequent or daily headaches despite (or because of) regular use of headache medications.

Serotonin syndrome

There have been reports of serotonin syndrome (including mental status changes, autonomic instability, and neuromuscular abnormalities) following concomitant use of triptans and SSRIs or SNRIs. These reactions may be severe. If concomitant treatment with eletriptan and an SSRI or SNRI is clinically justified, appropriate patient monitoring is recommended, particularly at the beginning of treatment, during dose escalation, or when adding another serotonergic medicinal product (see section "Interaction with other medicinal products and other forms of interaction").

Important information on excipients

The medicinal product contains lactose; therefore, it is contraindicated in patients with rare hereditary conditions of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

The medicinal product contains sodium; therefore, patients on a sodium-restricted diet should exercise caution when using this product.

The medicinal product contains the dye "Tartrazine" (Yellow West), which may cause allergic reactions.

Use during pregnancy or breastfeeding

Pregnancy

There is no clinical experience with the use of eletriptan in pregnant women. Animal studies have not shown any direct or indirect harmful effects on pregnancy, embryonal or fetal development, parturition, or postnatal development. Eletriptan should be used during pregnancy only in the absence of a safe alternative and when the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding

Eletriptan passes into breast milk. In a study involving 8 women who received a single 80 mg dose, the average total amount of eletriptan in breast milk over 24 hours was 0.02% of the dose. Therefore, caution should be exercised when considering the use of eletriptan in breastfeeding women. The risk to the infant can be minimized by avoiding breastfeeding for 24 hours after administration of eletriptan.

Ability to affect reaction speed when driving or operating machinery

Eletriptan has a moderate influence on the ability to drive and operate machinery. Migraine itself or treatment with eletriptan may cause drowsiness or dizziness in some patients. Caution should be exercised when performing tasks requiring heightened attention, such as driving or operating complex machinery, during migraine attacks and after administration of eletriptan.

Method of Administration and Dosage

Method of Administration

Tablets should be swallowed whole with water.

Dosage

The medicinal product should be used as early as possible after the onset of migraine headache; however, it is also effective at later stages during a migraine attack.

Administration of eletriptan during the aura phase has not demonstrated prevention of migraine headache; therefore, this medicinal product should be used in migraine only during the headache phase.

The medicinal product should not be used for prophylactic purposes.

Adults (aged 18 to 65 years)

The recommended initial dose is 40 mg.

Recurrent headache within 24 hours: If migraine headache resolves but then recurs within 24 hours, eletriptan may be re-administered at the same effective dose to treat recurrences. The second dose should not be taken within 2 hours of the initial dose.

Absence of response to treatment: If the first dose does not reduce headache within 2 hours, a second dose should not be used to treat that particular attack (efficacy has not been established in clinical studies).

Clinical trials indicate that in patients who fail to respond to treatment during one attack, eletriptan is likely to be effective in treating subsequent attacks.

If patients receiving the 40 mg dose do not achieve satisfactory effect (e.g., good tolerability but failure to abort 2 out of 3 attacks), a dose of 80 mg may be effective in subsequent migraine attacks (see section "Pharmacodynamics"). A second 80 mg dose 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 limited data from clinical trials. Therefore, use of eletriptan in elderly patients is not recommended.

Patients with Hepatic Impairment

Dose adjustment is not required in patients with mild or moderate hepatic impairment. Since eletriptan levels have not been studied in patients with severe hepatic impairment, its use in these patients is contraindicated.

Patients with Renal Impairment

Since the effects of eletriptan on blood pressure are enhanced in patients with renal impairment (see section "Special Warnings and Precautions for Use"), the recommended initial dose for patients with mild or moderate renal impairment is 20 mg. The daily dose should not exceed 40 mg. The medicinal product is contraindicated in patients with severe renal impairment.

Children. Use of eletriptan in patients under 18 years of age is not indicated due to lack of experience with its use in pediatric populations.

Overdose

No significant adverse effects were observed following a single 120 mg dose. However, overdose with selective serotonin 5-HT₁ receptor agonists may result in arterial hypertension or other more serious cardiovascular reactions.

In case of overdose, symptomatic and supportive therapy should be administered as needed. The elimination half-life of eletriptan is approximately 4 hours; therefore, patients should be observed and provided with symptomatic and supportive therapy for at least 20 hours after overdose, or until signs and symptoms have resolved.

It is unknown whether hemodialysis or peritoneal dialysis affect eletriptan plasma concentrations.

Adverse Reactions

The most commonly reported adverse reactions from clinical trials (5000 patients receiving doses of 20 mg, 40 mg, and 80 mg of eletriptan) were asthenia, somnolence, nausea, and dizziness. A dose-dependent frequency of adverse events was also observed.

The table below lists adverse reactions (with a frequency ≥ 1% and higher compared to placebo) observed in patients receiving therapeutic doses in clinical trials. Frequency is defined using the following categories: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), and rare (≥ 1/10000 to < 1/1000).

Common adverse reactions observed during the use of eletriptan are generally typical for the class of 5-HT₁ receptor agonists.

Adverse reactions reported during post-marketing surveillance

Gastrointestinal disorders: rare cases of ischemic colitis and vomiting.

Nervous system disorders: serotonin syndrome, rare cases of syncope, cerebral circulation disorders.

Vascular disorders: hypertension.

Cardiac disorders: myocardial ischemia or infarction, coronary artery spasm.

Immune system disorders: allergic reactions, sometimes serious, including angioneurotic edema.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is of great importance. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and/or lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions

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

Packaging. 3 tablets in a blister; 1 blister per carton.

Prescription status. Prescription only.

Manufacturer. Raffarm S.A.

Manufacturer’s address and location of its business operations. Tesi Pousi Agiou Louka, Paiania, 190 02, Greece.

Marketing Authorization Holder. JSC "Pharmaceutical Company "Darnytsia".

Address of the Marketing Authorization Holder. 13, Boryspilska Street, Kyiv, 02093, Ukraine.