Trileksa^® (Tablet kit) Instructions for Use

Marketing Authorization Holder

Tuteur S.A.C.I.F.I.A. (Argentina)

ATC Code

R07AX32 (Ivacaftor, Tezacaftor and Elexacaftor)

Active Substances

Ivacaftor (Rec.INN registered by WHO)

Tezacaftor (Rec.INN registered by WHO)

Elexacaftor (Rec.INN registered by WHO)

Dosage Forms

	Trileksa®	Tablet kit, film-coated tablets 37.5 mg+25 mg+50 mg + 75 mg
		Tablet kit, film-coated tablets 75 mg+50 mg+100 mg + 150 mg

Dosage Form, Packaging, and Composition

Tablet kit

Film-coated tablets orange-pink in color, round, biconvex.

Film-coated tablets light blue in color, round, cylindrical, with biconvex upper and lower surfaces.

– blisters (72 pcs.) – cardboard packs /tablet kit: Ivacaftor+Tezacaftor+Elexacaftor tablets (10 tablets per blister – 6 blisters); Ivacaftor tablets (5 tablets per blister – 6 blisters); 6 kits per cardboard pack/ – By prescription

Tablet kit

Film-coated tablets orange-pink in color, round, biconvex.

Film-coated tablets light blue in color, round, cylindrical, with biconvex upper and lower surfaces, with a score line.

– blisters (72 pcs.) – cardboard packs /tablet kit: Ivacaftor+Tezacaftor+Elexacaftor tablets (10 tablets per blister – 6 blisters); Ivacaftor tablets (5 tablets per blister – 6 blisters); 6 kits per cardboard pack/ – By prescription

Clinical-Pharmacological Group

Combined CFTR protein potentiator. Drug for the treatment of cystic fibrosis

Pharmacotherapeutic Group

Other drugs for the treatment of respiratory system diseases

Pharmacological Action

Tezacaftor and Elexacaftor bind to different sites of the CFTR protein and have an additive effect, improving cellular processing and trafficking of certain mutant forms of CFTR (including F508del-CFTR), thereby increasing the amount of CFTR protein delivered to the cell surface compared to either molecule alone.

Ivacaftor increases the probability of channel opening (or gating) of the CFTR protein on the cell surface.

The combined action of ivacaftor, tezacaftor, and elexacaftor results in an increased amount and enhanced functionality of CFTR on the cell surface, leading to increased CFTR activity, which is measured based on CFTR-mediated chloride ion transport.

Pharmacokinetics

Ivacaftor: AUC_ss (CV) – 11.7 (4.01) µg×h/ml, C_max (CV) – 1.2 (0.3) µg/ml, time to reach C_ss – within 3-5 days, accumulation factor 2.4, absolute bioavailability – not determined, median T_max (range) – 4 h (3-6h), mean V_d– 293 (89.8) L, plasma protein binding – about 99%, T_1/2 – 15.0 (3.92) h, mean apparent clearance – 10.2 (3.13%),

Tezacaftor: AUC_ss (CV) – 89.3 (23.2) µg×h/ml, C_max (CV) – 7.7 (1.7) µg/ml, time to reach C_ss – within 8 days, accumulation factor 2.07, absolute bioavailability – not determined, median T_max (range) – 3 h (2-4 h), mean V_d– 82.0 (22.3), plasma protein binding – about 99%, T_1/2 – 25.1 (4.93) h, mean apparent clearance – 0.79 (0.10),

Elexacaftor: AUC_ss (CV) – 162 (47.5) µg×h/ml, C_max (CV) – 9.2 (2.1) µg/ml, time to reach C_ss – within 7 days, accumulation factor 2.2, absolute bioavailability – 80%, median T_max (range) – 6 h (4-12 h), mean V_d– 53.7(17.7), plasma protein binding > 99%, T_1/2 – 27.4 (9.31) h, mean apparent clearance – 1.18 (0.29).

The primary metabolic pathway for all components is CYP3A4/5, active metabolites Ivacaftor M1, Tezacaftor M1, Elexacaftor M23 are formed.

Ivacaftor – elimination via intestine – 87.8%, via kidneys – 6.6%; Tezacaftor – elimination via intestine – 72% (unchanged or as the pharmacologically less active metabolite M2-TEZ); Elexacaftor – elimination via intestine – 87.3% (mainly as metabolites), renal elimination – 0.23%.

Indications

Treatment of cystic fibrosis (CF) in patients aged 6 years and older, who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or a mutation in the CFTR gene that is responsive to the drug based on in vitro data.

If the patient’s genotype is unknown, an approved genetic test should be used to detect at least one F508del mutation or a mutation that is responsive to the drug based on in vitro data.

ICD codes

Dosage Regimen

Take orally. Swallow tablets whole with fat-containing food to enhance absorption. Examples of appropriate fat-containing foods include eggs, butter, peanut butter, cheese pizza, or whole-milk dairy products.

Select the kit strength based on patient age and weight. For patients aged 6 to 11 years weighing less than 30 kg, use the Trileksa^® tablet kit containing Ivacaftor+Tezacaftor+Elexacaftor 37.5 mg/25 mg/50 mg and Ivacaftor 75 mg. For patients aged 12 years and older, and for patients aged 6 to 11 years weighing 30 kg or more, use the Trileksa^® tablet kit containing Ivacaftor+Tezacaftor+Elexacaftor 75 mg/50 mg/100 mg and Ivacaftor 150 mg.

Follow a specific daily dosing schedule. On days 1 to 7, take two orange-pink tablets (Ivacaftor+Tezacaftor+Elexacaftor) in the morning. From day 8 onwards, take two orange-pink tablets (Ivacaftor+Tezacaftor+Elexacaftor) in the morning and one light blue tablet (Ivacaftor) in the evening, approximately 12 hours apart.

Administer a reduced dose when co-administered with potent CYP3A inhibitors. For patients aged 12 years and older (and patients 6 to 11 years weighing ≥30 kg), take two orange-pink tablets (Ivacaftor+Tezacaftor+Elexacaftor 75 mg/50 mg/100 mg) only twice per week, approximately 3 to 4 days apart, in the morning. Omit the evening Ivacaftor 150 mg dose. For patients aged 6 to 11 years weighing less than 30 kg, take two orange-pink tablets (Ivacaftor+Tezacaftor+Elexacaftor 37.5 mg/25 mg/50 mg) only twice per week, approximately 3 to 4 days apart, in the morning. Omit the evening Ivacaftor 75 mg dose.

Administer a reduced dose when co-administered with moderate CYP3A inhibitors. For patients aged 12 years and older (and patients 6 to 11 years weighing ≥30 kg), take two orange-pink tablets (Ivacaftor+Tezacaftor+Elexacaftor 75 mg/50 mg/100 mg) in the morning every other day and take one light blue tablet (Ivacaftor 150 mg) in the evening on alternate days. For patients aged 6 to 11 years weighing less than 30 kg, take two orange-pink tablets (Ivacaftor+Tezacaftor+Elexacaftor 37.5 mg/25 mg/50 mg) in the morning every other day and take one light blue tablet (Ivacaftor 75 mg) in the evening on alternate days.

Adjust the dosage for patients with hepatic impairment. For patients with moderate hepatic impairment (Child-Pugh Class B), use the same reduced dosing schedule as for concomitant use with moderate CYP3A inhibitors. The combination is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C). No dose adjustment is required for patients with mild hepatic impairment (Child-Pugh Class A).

If a morning dose is missed within 6 hours of the scheduled time, take the dose immediately with food. If more than 6 hours have passed, skip the missed morning dose and resume the normal schedule the next morning. If an evening dose is missed within 6 hours of the scheduled time, take the dose immediately. If more than 6 hours have passed, skip the missed evening dose and resume the normal schedule the next evening. Do not take a double dose to make up for a missed dose.

Adverse Reactions

Infections and infestations: very common – upper respiratory tract infection (common cold), including nasal congestion; common – rhinitis, influenza, sinusitis.

Nervous system disorders very common – headache.

Respiratory system disorders common – nasal congestion, rhinorrhea.

Gastrointestinal disorders very common – abdominal pain, diarrhea.

Skin and subcutaneous tissue disorders very common – rash.

Laboratory and instrumental data common – increased ALT, AST, CPK activity, increased bilirubin concentration.

Contraindications

Hypersensitivity to ivacaftor, tezacaftor, elexacaftor; severe hepatic impairment (Child-Pugh class C); children under 6 years of age.

Use in Pregnancy and Lactation

This combination should be used during pregnancy only if clearly needed, when the expected benefit outweighs the possible risk of use.

Information on the presence of ivacaftor, tezacaftor, or elexacaftor in breast milk, their effect on the breastfed child, or on milk production in the mother is not available. Ivacaftor, Tezacaftor, and Elexacaftor are excreted in the milk of lactating rats. The benefits of breastfeeding for the development and health of the child, as well as the mother’s clinical need for this medication and any potential adverse reactions for the breastfed child from taking this combination or the mother’s underlying condition should be considered.

This combination should be used during breastfeeding only if the potential benefit to the mother outweighs the potential risk to the breastfed child.

Use in Hepatic Impairment

In patients with mild and moderate hepatic impairment, dosage adjustment is required.

Contraindicated in severe hepatic impairment.

Use in Renal Impairment

No dose adjustment is required in patients with mild (eGFR from 60 to <90 ml/min/1.73 m²) or moderate (eGFR from 30 to <60 ml/min/1.73 m²) renal impairment. Use with caution in patients with severe renal impairment (eGFR <30 ml/min/1.73 m²) or end-stage renal disease.

Pediatric Use

Contraindicated in children under 6 years of age.

Geriatric Use

Clinical studies of the drug containing the fixed combination Ivacaftor + Tezacaftor + Elexacaftor and Ivacaftor in patients aged 65 years and older have not been conducted.

Special Precautions

Use of this combination should be avoided in patients with pre-existing progressive liver disease (e.g., cirrhosis, portal hypertension, ascites, hepatic encephalopathy) except in cases where the expected benefit outweighs the risks. If this combination is used in such patients, they should be carefully monitored after initiation of therapy.

Isolated elevations of liver transaminases and bilirubin have been observed in CF patients taking this combination. In some cases, the elevation of liver transaminases was associated with a concurrent increase in total bilirubin and/or INR and led to hospitalization of patients for interventions, including patients with no history of pre-existing liver disease.

It is recommended to assess liver function biochemically (ALT, AST, and bilirubin) in all patients prior to initiating therapy, every 3 months during the first year of treatment, and then annually. In case of a significant increase in liver function tests, for example, ALT/AST activity more than 5 times the upper limit of normal (ULN), or ALT/AST more than 3 times ULN in combination with bilirubin exceeding 2 times ULN, the drug should be discontinued and laboratory results should be closely monitored until the parameters normalize. After normalization of liver function biochemical parameters, the benefit-risk ratio of resuming therapy with this combination should be assessed. For patients with a history of hepatobiliary disease or elevated liver function tests, more frequent monitoring should be considered.

The use of this medication in CF patients who have undergone organ transplantation has not been studied. Therefore, this medication is not recommended for patients who have undergone organ transplantation.

Cases of acquired lens opacities have been reported in pediatric patients receiving therapy with drugs containing Ivacaftor. Although other risk factors were present in some cases (such as corticosteroid use, radiation exposure), a potential risk associated with ivacaftor cannot be excluded. In pediatric patients initiating therapy with this medication, baseline and follow-up ophthalmological examinations are recommended.

Effect on ability to drive and operate machinery

In some cases, this combination causes dizziness. Patients experiencing dizziness should refrain from driving vehicles, operating machinery, or any activity requiring increased concentration until the symptoms resolve.

Drug Interactions

Concomitant use of CYP3A4 isoenzyme inducers significantly reduces the exposure of ivacaftor and may also reduce the exposure of tezacaftor and elexacaftor and lead to reduced therapeutic efficacy of this medication. Concomitant administration of ivacaftor with rifampicin, a potent CYP3A isoenzyme inducer, significantly reduced ivacaftor exposure (AUC) by 89%. It is anticipated that the exposures of tezacaftor and elexacaftor will be reduced when co-administered with potent CYP3A4 isoenzyme inducers. Therefore, concomitant use of this combination with potent CYP3A4 isoenzyme inducers is not recommended. Examples of potent CYP3A4 isoenzyme inducers: rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort (Hypericum perforatum).

Concomitant administration with itraconazole, a potent CYP3A4 isoenzyme inhibitor, increased the AUC of elexacaftor by 2.8 times, and the AUC of tezacaftor by 4.0-4.5 times. When co-administered with itraconazole and ketoconazole, the AUC of ivacaftor increased by 15.6 times and 8.5 times, respectively. When co-administered with potent CYP3A4 isoenzyme inhibitors, the dose of this combination should be reduced. Examples of potent CYP3A4 isoenzyme inhibitors: ketoconazole, itraconazole, posaconazole, and voriconazole; telithromycin and clarithromycin.

Concomitant use with moderate CYP3A isoenzyme inhibitors may increase the AUC of tezacaftor and elexacaftor by approximately 1.9-2.3 times and 2.1 times, respectively. Concomitant use with fluconazole increased the AUC of ivacaftor by 2.9 times. When co-administered with moderate CYP3A isoenzyme inhibitors, the dose of this combination should be reduced: fluconazole, erythromycin.

Concomitant intake of this combination with grapefruit juice, which contains one or more components that moderately inhibit the CYP3A isoenzyme, may increase the exposure of ivacaftor, tezacaftor, and elexacaftor; therefore, consumption of food or beverages containing grapefruit should be avoided during treatment with this combination.

Exposure to M2-TEZ (a metabolite of tezacaftor) may be increased when used with P-glycoprotein inhibitors, so caution should be exercised when using P-glycoprotein inhibitors (e.g., cyclosporine) with the combination Ivacaftor + Tezacaftor + Elexacaftor.

Ivacaftor may inhibit the CYP2C9 isoenzyme, so proper monitoring of INR is recommended when this combination is co-administered with warfarin. Other medicinal products whose exposure may be increased when taking this combination include glimepiride and glipizide. Caution is required during concomitant use.

Concomitant administration of ivacaftor or the combination Ivacaftor + Tezacaftor with digoxin, a sensitive P-glycoprotein substrate, increased the AUC of digoxin by 1.3 times, which is consistent with weak inhibition of P-glycoprotein by ivacaftor.

Taking this combination may increase the systemic exposure of medicinal products that are sensitive P-glycoprotein substrates, which may increase the intensity and duration of their therapeutic effect and the occurrence of adverse reactions. Caution should be exercised and proper monitoring should be conducted when taken concomitantly with digoxin or other P-glycoprotein substrates with a narrow therapeutic range, such as cyclosporine, everolimus, sirolimus, and tacrolimus.

Elexacaftor and M23-ELX inhibit the uptake of OATP1B1 and OATP1B3 based on in vitro studies. Concomitant use of this medication may increase the exposure of medicinal products that are substrates of these transporters, such as statins, glyburide, nateglinide, and repaglinide. Caution should be exercised and proper monitoring should be conducted when used concomitantly with substrates of OATP1B1 or OATP1B3.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.