Elet

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ELET (ELET)

Composition:

Active substance: eletriptan;

One film-coated tablet contains eletriptan (as eletriptan hydrobromide) 20 mg or 40 mg;

Excipients: microcrystalline cellulose; lactose monohydrate; sodium croscarmellose; magnesium stearate;

film coating: Opadry Orange 85F530100, containing polyvinyl alcohol (E1203), titanium dioxide (E171), macrogol (E1521), talc (E553b), yellow FCF aluminum lake (E110).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

20 mg tablets: round, convex film-coated tablets, orange in color, smooth on one side and embossed with "20" on the other;

40 mg tablets: round, convex film-coated tablets, orange in color, smooth on one side and embossed with "40" on the other.

Pharmacotherapeutic group. Analgesics. Medicinal products used for migraine treatment. Selective 5-HT1 serotonin receptor agonists. Eletriptan. ATC code N02C C06.

Pharmacological properties.

Pharmacodynamics.

Eletriptan is a selective agonist of vascular 5-HT_1B and neuronal 5-HT<1D receptors. Eletriptan also exhibits high affinity for the 5-HT_1F receptor, which may contribute to its antimigraine mechanism of action. Eletriptan has low affinity for human recombinant 5-HT_1A, 5-HT_2B, 5-HT_1E, and 5-HT₇ receptors.

Clinical efficacy and safety

The efficacy and safety of eletriptan at doses of 20 to 80 mg for the acute treatment of migraine headache pain were evaluated in 10 placebo-controlled studies involving over 6000 patients (all treatment groups). Headache relief was observed as early as 30 minutes after oral administration. Reduction of headache severity from moderate or severe to mild or none at 2 hours was reported in 59–77% of patients receiving the 80 mg dose, 54–65% with the 40 mg dose, 47–54% with the 20 mg dose, and 19–40% after placebo. Eletriptan was also effective in treating migraine-associated symptoms such as vomiting, nausea, photophobia, and phonophobia.

The recommendation for dose titration up to 80 mg is based on 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-related migraine. Administration of eletriptan during the aura phase did not prevent migraine headache, and 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 administration of eletriptan 80 mg compared to healthy volunteers (see section "Special precautions for use"). This cannot be explained by any pharmacokinetic changes and may therefore represent a specific pharmacodynamic response to eletriptan in patients with impaired renal function.

Pharmacokinetics.

Absorption. Eletriptan is rapidly and well absorbed from the gastrointestinal tract (at least 81%) following oral administration. Absolute bioavailability in men and women is approximately 50%. The median time to reach maximum plasma concentration (T_max) 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 (C_max) of eletriptan were increased by approximately 20–30% when administered with a high-fat meal. Following administration during a migraine attack, AUC decreased by approximately 30%, and T_max 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 repeated 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 show 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 indicate minor involvement of the CYP2D6 enzyme in eletriptan metabolism, although clinical studies do not suggest 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 by N-oxidation showed no activity, while the metabolite formed by N-demethylation exhibited activity similar to eletriptan. A third metabolite contributing to plasma radioactivity was not formally identified but is most likely a mixture of hydroxylated metabolites, which were also detected in excreta (urine and feces). Plasma concentrations of the N-demethylated active metabolite are only 10–20% of those of eletriptan, so 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, and the elimination half-life (T_1/2) from plasma is approximately 4 hours. The 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 (aged 65 years and older). Although not statistically significant, a slight decrease (16%) in clearance associated with a statistically significant increase in T_1/2 (from approximately 4.4 to 5.7 hours) was observed in elderly patients (65–93 years) compared to patients under 65 years of age.

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

Children (6–11 years). Eletriptan clearance in children is unchanged compared to adolescents. However, the volume of distribution in children is smaller, resulting in higher plasma levels than predicted 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 T_1/2 were demonstrated. A small increase in C_max (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, there were no statistically significant changes in the pharmacokinetics of eletriptan or in plasma protein binding. An increase in BP was observed in patients in this group.

Clinical characteristics.

Indications.

Acute headache relief during migraine attacks, with or without aura.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Severe hepatic or renal impairment.
• Moderate to severe hypertension or untreated mild hypertension.
• Confirmed cardiovascular diseases, including ischemic heart disease (IHD) (angina, previous myocardial infarction, or confirmed asymptomatic ischemia). Coronary artery vasospasm (Prinzmetal's angina), objective or subjective symptoms of IHD.
• Significant arrhythmias or heart failure.
• Peripheral vascular diseases.
• History of cerebrovascular events (CVA) or transient ischemic attack (TIA).
• Use of 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.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on eletriptan

In pivotal clinical trials of eletriptan, there are no data on interactions with β-blockers, tricyclic antidepressants, selective serotonin reuptake inhibitors, and flunarizine; however, formal clinical interaction studies with these medicinal products are not available (except for propranolol, see below).

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

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 using propranolol (160 mg), verapamil (480 mg), and fluconazole (100 mg), the C_max 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 used alone.

In clinical studies using erythromycin (1000 mg) and ketoconazole (400 mg), specific and potent inhibitors of CYP3A4, a significant increase in eletriptan C_max (by 2-fold and 2.7-fold) and AUC (by 3.6-fold and 5.9-fold, respectively) was observed. This increased exposure was associated with an increase in eletriptan T_1/2 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 slight but additive increase in blood pressure, which was predictable based on the pharmacological properties of both medicinal products. Therefore, it is recommended not to use medicinal products containing ergotamine or ergotamine-like substances (e.g., dihydroergotamine) within 24 hours after taking eletriptan. Conversely, eletriptan may be administered no sooner than 24 hours after the use of medicinal products containing ergotamine.

Effect of eletriptan on other medicinal products

There is no evidence in vitro or in vivo that eletriptan, at clinical doses (and corresponding concentrations), inhibits or induces cytochrome P450 enzymes, including those metabolized by the CYP3A4 enzyme. Therefore, it is considered unlikely that eletriptan will cause clinically significant 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 disturbances) following the use of SSRIs or SNRIs together with triptans (see section "Special precautions for use").

Special precautions for use.

Eletriptan should not be used concomitantly with potent inhibitors of CYP3A4, 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 vasospasm could be harmful.

Use of eletriptan may be associated with transient symptoms, including chest pain and tightness, which may 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 should be performed.

Patients with cardiovascular disease

Eletriptan should not be used in patients at risk of IHD or without prior cardiovascular evaluation in patients who may have undiagnosed cardiovascular disorders (e.g., patients with hypertension, diabetes, smokers or those receiving nicotine replacement therapy, men over 40 years of age, postmenopausal women, and individuals with a strong 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 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, a slight and transient increase in blood pressure has been observed following administration of eletriptan at doses of 60 mg. However, this increase was not associated with clinical consequences in the clinical trial program. The effect was more pronounced in patients with renal impairment and in elderly patients. In patients with renal insufficiency, the mean maximum increase in systolic blood pressure ranged from 14 to 17 mm Hg (normal: 3 mm Hg), and in diastolic blood pressure from 14 to 21 mm Hg (normal: 4 mm Hg). In elderly subjects, the mean maximum increase in systolic blood pressure was 23 mm Hg compared to 13 mm Hg in younger subjects (placebo: 8 mm Hg). Post-marketing reports of increased blood pressure have also been received from patients taking eletriptan doses of 20 mg and 40 mg, including patients without renal impairment and elderly patients.

Medication-overuse headache

Prolonged use of any analgesic for headache may worsen the condition. If such a situation is suspected or occurs, the drug should be discontinued and medical advice should be sought. This diagnosis should be considered in patients who experience frequent or daily headaches despite (or because of) regular use of headache medications.

Serotonin syndrome

Serotonin syndrome (including mental status changes, autonomic instability, and neuromuscular abnormalities) has been reported following concomitant use of triptans and SSRIs or SNRIs. These reactions may be severe. If concomitant treatment with eletriptan and SSRIs or SNRIs is clinically justified, appropriate monitoring of the patient 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 about excipients

The medicinal product contains lactose; therefore, patients with known intolerance to certain sugars should consult their physician before taking this medicinal product.

The medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

This medicinal product also contains the colouring agent Sunset Yellow, which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Pregnancy

There is no clinical experience with the use of eletriptan in pregnant women. Eletriptan should be used during pregnancy only if no safe alternative is available and the expected benefit to the pregnant woman outweighs the potential risk to the fetus.

Breastfeeding

Eletriptan is excreted in breast milk. In one study involving 8 women who received a single 80 mg dose, the mean 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 of exposure 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. During migraine attacks or treatment with eletriptan, somnolence or dizziness may occur in some patients. Caution should be exercised when performing tasks requiring heightened attention, such as driving a car 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 administered as early as possible after the onset of migraine headache, although it is also effective at later stages of a migraine attack.

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

The medicinal product should not be used for prophylactic purposes.

Adults (aged 18 to 65 years)

The recommended initial dose is 40 mg.

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

If no response to treatment: if the first dose does not reduce headache within 2 hours, a second dose should not be administered for that attack, as efficacy of a second dose has not been established in clinical studies.

Clinical trials indicate that although treatment may fail to relieve one attack, it may still be effective for subsequent attacks.

If patients receiving the 40 mg dose do not achieve satisfactory response (e.g., good tolerability but failure to abort 2 out of 3 attacks), a dose of 80 mg may be effective for subsequent migraine attacks (see section "Pharmacodynamics"). A second 80 mg dose should not be administered 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 such patients in clinical trials. Therefore, the 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 effect of eletriptan on blood pressure (BP) is 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 maximum daily dose should not exceed 40 mg. The medicinal product is contraindicated in patients with severe renal impairment.

Children

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

Overdose

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

In case of overdose, symptomatic and supportive therapy should be administered, if necessary. The elimination half-life of eletriptan is approximately 4 hours; therefore, monitoring of the patient and provision of symptomatic and supportive therapy after eletriptan overdose should continue for at least 20 hours or until signs and symptoms of overdose have resolved.

It is unknown whether hemodialysis or peritoneal dialysis has any effect on plasma concentrations of eletriptan.

Adverse reactions.

Summary of safety profile

The most commonly reported adverse reactions known from clinical studies (5000 patients receiving doses of 20 mg, 40 mg, and 80 mg) with eletriptan were asthenia, somnolence, nausea, and dizziness. A tendency towards dose-dependence in the frequency of adverse events was also observed.

Tabulated list of adverse reactions

The table below lists adverse reactions (with frequency ≥ 1% and higher compared to placebo) that were reported in patients receiving therapeutic doses in clinical studies; adverse reactions are classified by frequency: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), or rare (≥ 1/10000 to < 1/1000).

Common adverse reactions observed with eletriptan are typical of those associated with 5-HT₁ receptor agonists as a class.

Adverse reactions reported during post-marketing surveillance include:

Gastrointestinal disorders: rare reports of ischemic colitis and vomiting.

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

Vascular disorders: hypertension.

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

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Information System of Pharmacovigilance at: https://aisf.dec.gov.ua/.

Shelf life. 3 years.

Storage conditions.

No special storage conditions required. Keep out of reach and sight of children.

Packaging.

2 tablets in a blister; 1, 3, or 6 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Chanel Medical Limited Company.

Manufacturer's address and location of operations.

Dublin Road, Loughrea, N62 FH90, Ireland.