Retsevmo^® (Capsules) Instructions for Use

Marketing Authorization Holder

Swix Healthcare LLC (Russia)

Manufactured By

Lilly Del Caribe, Inc. (Puerto Rico)

Packaging and Quality Control Release

LILLY, S.A. (Spain)

ATC Code

L01EX22 (Selpercatinib)

Active Substance

Selpercatinib (Rec.INN registered by WHO)

Dosage Forms

	Retsevmo®	Capsules 40 mg: 14, 42, 56 or 168 pcs.
		Capsules 80 mg: 14, 28, 56 or 112 pcs.

Dosage Form, Packaging, and Composition

Capsules are gray, opaque, with black ink inscriptions “Lilly”, “3977” and “40 mg”.

Excipients: colloidal silicon dioxide, microcrystalline cellulose.

Capsule shell composition gelatin, titanium dioxide and iron oxide black.
Black ink composition shellac, ethanol (96%), isopropyl alcohol, butyl alcohol, propylene glycol, purified water, concentrated ammonia solution, potassium hydroxide, black iron oxide.

14 pcs. – blisters (1) – cardboard covers (1) – cardboard packs.
14 pcs. – blisters (1) – cardboard covers (4) – cardboard packs.
21 pcs. – blisters (2) – cardboard covers (1) – cardboard packs.
21 pcs. – blisters (2) – cardboard covers (4) – cardboard packs.

Capsules are gray, opaque, with black ink inscriptions “Lilly”, “2980” and “80 mg”.

Excipients: colloidal silicon dioxide, microcrystalline cellulose.

Capsule shell composition gelatin, titanium dioxide and black iron oxide, brilliant blue FCF.
Black ink composition shellac, ethanol (96%), isopropyl alcohol, butyl alcohol, propylene glycol, purified water, concentrated ammonia solution, potassium hydroxide, black iron oxide.

14 pcs. – blisters (1) – cardboard covers (1) – cardboard packs.
14 pcs. – blisters (1) – cardboard covers (4) – cardboard packs.
14 pcs. – blisters (2) – cardboard covers (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard covers (4) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agents; protein kinase inhibitors; other protein kinase inhibitors

Pharmacological Action

Inhibitor of the tyrosine kinase of the RET receptor. Selpercatinib inhibited wild-type RET receptor and multiple mutated isoforms of RET receptors, as well as vascular endothelial growth factor receptors VEGFR1 and VEGFR3 with IC₅₀ values ranging from 0.92 to 67.8 nM. In other enzyme assays, Selpercatinib also inhibited fibroblast growth factor receptors FGFR 1, 2, and 3 at higher concentrations that were still clinically achievable.

In a binding assay at a selpercatinib concentration of 1 µM, pronounced antagonist-binding activity (> 50%) was observed for the 5-HT (serotonin) transporter (70.2%) and the α_2C-adrenergic receptor (51.7%). A concentration of 1 µM is approximately 7 times the plasma C_max of the unbound form of selpercatinib at its effective dose.

Specific point mutations in the RET gene or chromosomal rearrangements involving in-frame fusions of RET with various partners can lead to the formation of constitutively activated RET rearrangement chimeric proteins that can act as oncogenic drivers, promoting the proliferation of tumor cell lines.

In in vitro and in vivo tumor models, Selpercatinib demonstrated antitumor activity in cells carrying constitutive activation of the RET protein due to gene rearrangements and mutations, including CCDC6-RET, KIF5B-RET, RET V804M, and RET M918T.

Furthermore, Selpercatinib exhibited antitumor activity in mice with intracranially implanted RET fusion-positive tumors derived from a patient.

Cases of QT interval prolongation have been reported in patients treated with Selpercatinib. Therefore, patients may require temporary discontinuation of Selpercatinib therapy.

Pharmacokinetics

After oral administration of a 160 mg dose, absorption is rapid, with a mean time to reach plasma C_max of selpercatinib of 2 hours. The mean absolute bioavailability of selpercatinib is 73.2% (range 60.2-81.5%).

The mean V_d, calculated using population pharmacokinetic analysis, is 191 L (69%) after oral administration in adult patients. Selpercatinib is 96% bound to human plasma proteins in vitro, and the extent of binding is independent of drug concentration. The blood-to-plasma drug concentration ratio is 0.7.

Selpercatinib is predominantly metabolized by the CYP3A4 isoenzyme. After a single oral dose of 160 mg of radiolabeled [¹⁴C]selpercatinib in healthy volunteers, unchanged Selpercatinib accounted for 86% of the measured radioactive components in plasma.

After administration of a 160 mg dose of radiolabeled [¹⁴C]selpercatinib, the clearance is 6 L/h, and T_1/2 is 2 hours, 69% was excreted via the intestine (14% unchanged), 24% – by the kidneys (11.5% unchanged).

Indications

Adults and children aged 12 years and older: advanced or metastatic medullary thyroid cancer (MTC) with an identified RET gene mutation – when systemic therapy is needed; advanced or metastatic thyroid cancer with RET gene fusion, refractory to radioactive iodine therapy (if radioactive iodine therapy was used) – when systemic therapy is needed.

ICD codes

Dosage Regimen

The presence of a RET gene fusion (thyroid cancer) or its mutations (MTC) should be confirmed prior to initiation of therapy.

The dose is set based on body weight: for body weight less than 50 kg – 120 mg twice daily; for body weight 50 kg or more – 160 mg twice daily.

Therapy should be continued until signs of disease progression or unacceptable toxicity develop.

In case of concomitant use with a strong CYP3A isoenzyme inhibitor, the current dose of selpercatinib should be reduced by 50%. If the CYP3A isoenzyme inhibitor is discontinued, the selpercatinib dose should be increased (after 3-5 T_1/2 of the inhibitor) to the dose used before starting the inhibitor.

Contraindications

Hypersensitivity to selpercatinib; concomitant use of strong CYP3A4 isoenzyme inducers due to the risk of reduced efficacy of selpercatinib.

With caution

Congenital or acquired long QT syndrome, as well as other clinical conditions predisposing to the development of arrhythmias.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Women of childbearing potential should use highly effective contraception during treatment with selpercatinib and for at least one week after the last dose of Selpercatinib. Men whose sexual partners are of childbearing potential should use effective contraception during treatment with selpercatinib and for at least one week after the last dose of Selpercatinib.

According to preclinical safety data, treatment with selpercatinib may impair fertility in men and women. Before starting treatment, men and women should consult with specialists about fertility preservation.

Use in Hepatic Impairment

Close monitoring of patients with impaired liver function is necessary. For patients with mild and moderate hepatic insufficiency (Child-Pugh class A and B), no dose adjustment is required. Patients with severe hepatic insufficiency (Child-Pugh class C) should take Selpercatinib at a dose of 80 mg twice daily.

Use in Renal Impairment

No dose adjustment is required in patients with mild, moderate, or severe renal impairment. Data on use in patients with end-stage renal disease or on dialysis are not available.

Pediatric Use

The dosage regimen for children from 12 to 18 years of age does not differ from the dosage regimen for adults.

The safety and efficacy of Selpercatinib in children under 12 years of age have not been established to date. Data are not available.

Geriatric Use

No dose adjustment based on age is required.

Overall, no differences were noted between patients aged 65 years and older and younger patients regarding treatment-emergent adverse events and the efficacy of selpercatinib. Data on the use of selpercatinib in patients aged 75 years and older are limited.

Special Precautions

During treatment, it is necessary to monitor for the appearance of pulmonary symptoms of ILD/pneumonitis in patients. Selpercatinib should be discontinued, and patients should be immediately evaluated for ILD if they experience acute or worsening respiratory symptoms that may indicate ILD (e.g., dyspnea, cough, and fever), and treated as medically indicated.

Depending on the severity of ILD/pneumonitis, selpercatinib should be interrupted, the dose reduced, or permanently discontinued.

ALT and AST values should be monitored before starting selpercatinib therapy, every 2 weeks for the first 3 months of treatment, monthly for the next 3 months of therapy, or as clinically indicated. Depending on the degree of elevation of ALT or AST, adjustment of the selpercatinib dose may be required.

Blood pressure should be monitored before starting selpercatinib treatment, monitored during therapy, and treated with standard antihypertensive therapy if necessary. Depending on the degree of blood pressure elevation, adjustment of the selpercatinib dose may be required. Selpercatinib should be permanently discontinued if clinically significant hypertension is not controlled with antihypertensive therapy.

Hypokalemia, hypomagnesemia, and hypocalcemia should be corrected before starting and during selpercatinib treatment. In patients requiring concomitant medications that prolong the QT interval, more frequent monitoring of the QT interval via ECG should be performed. Temporary discontinuation of selpercatinib therapy or dose adjustment may be required.

Concomitant use of strong CYP3A4 isoenzyme inducers should be avoided due to the risk of reduced efficacy of selpercatinib.

If hypersensitivity develops, selpercatinib should be temporarily discontinued and corticosteroid therapy initiated. Depending on the severity of hypersensitivity reactions, adjustment of the selpercatinib dose may be required. Corticosteroid treatment should be continued until the patient reaches the target dose, after which the corticosteroid dose should be gradually reduced. If hypersensitivity recurs, selpercatinib should be permanently discontinued.

Cases of serious hemorrhagic events, including fatal ones, have been reported in patients receiving Selpercatinib.

If severe or life-threatening hemorrhagic events occur, selpercatinib should be permanently discontinued.

Risk factors for tumor lysis syndrome (TLS) include high tumor burden, history of chronic renal failure, oliguria, dehydration, hypotension, and acidic urine. Such patients should be closely monitored and receive therapy as clinically indicated, and appropriate prophylaxis, including hydration, should be considered.

Effect on ability to drive vehicles and operate machinery

Patients are advised to exercise caution when driving vehicles or operating machinery if fatigue or dizziness occurs during the use of Selpercatinib.

Drug Interactions

Selpercatinib is metabolized by the CYP3A4 isoenzyme. Therefore, drugs that can affect the activity of the CYP3A4 isoenzyme may alter the pharmacokinetics of selpercatinib.

In vitro, Selpercatinib is a substrate of P-glycoprotein and Breast Cancer Resistance Protein (BCRP), however, these transporters do not appear to limit the absorption of selpercatinib upon oral administration, given that the oral bioavailability of selpercatinib is 73%, and the increase in its exposure when co-administered with the P-glycoprotein inhibitor rifampicin is minimal (increase in AUC_0-24 and C_max of selpercatinib by 6.5% and 19%, respectively).

When a single 160 mg dose of selpercatinib was taken concomitantly with itraconazole, a strong CYP3A isoenzyme inhibitor, an increase in C_max and AUC of selpercatinib by 30% and 130%, respectively, was observed compared to selpercatinib monotherapy. If concomitant use of selpercatinib with strong inhibitors of the CYP3A isoenzyme and/or P-glycoprotein is necessary, including ketoconazole, itraconazole, voriconazole, ritonavir, saquinavir, clarithromycin, posaconazole, and nefazodone, the dose of selpercatinib should be reduced.

Concomitant administration of selpercatinib with rifampicin, a strong CYP3A4 isoenzyme inducer, resulted in a decrease in the AUC and C_max of selpercatinib by approximately 87% and 70%, respectively, compared to selpercatinib monotherapy, therefore concomitant use of strong CYP3A4 isoenzyme inducers should be avoided, including carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, and St. John’s wort (Hypericum perforatum).

Selpercatinib increased the C_max and AUC of repaglinide (a CYP2C8 isoenzyme substrate) by approximately 91% and 188%, respectively. Therefore, concomitant use of selpercatinib with sensitive substrates of the CYP2C8 isoenzyme (such as enzalutamide, paclitaxel, repaglinid, torsemide, sorafenib, rosiglitazone, buprenorphine, selexipag, dasabuvir, and montelukast) should be avoided.

Selpercatinib increased the C_max and AUC of midazolam (a CYP3A4 isoenzyme substrate) by approximately 39% and 54%, respectively. Therefore, concomitant use of selpercatinib with sensitive substrates of the CYP3A4 isoenzyme (such as avanafil, buspirone, darifenacin, darunavir, ebastine, lovastatin, midazolam, saquinavir, simvastatin, vardenafil) should be avoided.

Selpercatinib has pH-dependent solubility: as pH increases, the solubility of the drug decreases. No clinically significant differences in the pharmacokinetics of selpercatinib were observed when co-administered with multiple daily doses of ranitidine (an H₂ receptor blocker) taken 2 hours after selpercatinib administration.

Concomitant use of selpercatinib with multiple daily doses of omeprazole (a proton pump inhibitor) reduced the AUC_0-∞ and C_max of selpercatinib when taken on an empty stomach. Concomitant use of selpercatinib with multiple daily doses of omeprazole slightly altered the AUC_0-∞ and C_max of selpercatinib when selpercatinib was taken with food.

Selpercatinib inhibits the renal transporter, multidrug and toxin extrusion protein 1 (MATE1). In vivo, interaction of selpercatinib with clinically significant MATE1 substrates, such as creatinine, may occur.

Selpercatinib is an inhibitor of P-glycoprotein and BCRP in vitro. In vivo, Selpercatinib increased the C_max and AUC of dabigatran, a P-glycoprotein substrate, by 43% and 38%, respectively. Caution should be exercised when using sensitive P-glycoprotein substrates (such as fexofenadine, dabigatran etexilate, colchicine, saxagliptin) and especially drugs with a narrow therapeutic index (such as digoxin).

Selpercatinib may inhibit deiodinase D2 and thereby reduce the conversion of levothyroxine (T4) to triiodothyronine (T3). Thus, patients may have an insufficient response to levothyroxine replacement therapy and may require the addition of liothyronine.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°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.