Lumykras^® (Tablets) Instructions for Use

Marketing Authorization Holder

Amgen Europe, B.V. (Netherlands)

Manufactured By

Patheon Inc. (Canada)

Labeled By

PATHEON Inc. (Canada)

Or

DOBROLEK, LLC (Russia)

Quality Control Release

AMGEN EUROPE, B.V. (Netherlands)

Or

DOBROLEK, LLC (Russia)

ATC Code

L01XX73 (Sotorasib)

Active Substance

Sotorasib (Rec.INN registered by WHO)

Dosage Form

Lumykras®

Tablets, film-coated, 120 mg: 240 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets yellow, oblong, with the inscription “AMG” on one side and “120” on the other, without visible physical defects.

Excipients: microcrystalline cellulose (102), lactose monohydrate, croscarmellose sodium, magnesium stearate; film coating: polyvinyl alcohol, titanium dioxide (E171), macrogol 4000, talc, yellow iron oxide (E172).

8 pcs. – blisters (30) – cardboard packs with a divider and first-opening control.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agents; other antineoplastic agents

Pharmacological Action

Selective inhibitor of KRAS G12C (Kirsten rat sarcoma viral oncogene homolog), which covalently and irreversibly binds to a unique cysteine in the KRAS G12C gene.

Inactivation of KRAS G12C by sotorasib blocks tumor cell signaling and survival, suppresses cell growth, and promotes selective apoptosis in tumors containing the KRAS G12C oncogene that contributes to carcinogenesis.

Pharmacokinetics

After oral administration of a single dose, Sotorasib was absorbed with a median T_max of 1 hour.

The geometric mean apparent V_d after oral administration of sotorasib at a dose of 960 mg once daily for 8 consecutive days was 211 L (based on non-compartmental analysis).

Sotorasib plasma protein binding, primarily to alpha-1-acid glycoprotein, is 89%.

The main metabolic pathways of sotorasib are non-enzymatic conjugation and oxidative metabolism.

In vitro studies indicate that Sotorasib is metabolized by cytochromes CYP2C8, CYP3A4, and CYP3A5 and is a substrate of P-glycoprotein.

After a single oral dose of radioactive sotorasib 720 mg, the cysteine adduct (formed by hydrolysis of the glutathione adduct) and an oxidative metabolite resulting from CYP3A-mediated cleavage of the piperazineacrylamide group were the major circulating metabolites.

None of these metabolites were pharmacologically active.

The geometric mean apparent clearance after oral administration of sotorasib at a dose of 960 mg once daily for 8 consecutive days was 26.2 L/h (based on non-compartmental analysis).

The mean T_1/2 is 5 hours.

Steady-state was reached by day 22 and remained stable.

Sotorasib is primarily eliminated via the intestine: approximately 74% of the dose via the intestine, 6% (at least 1%) via the kidneys.

Nonlinear pharmacokinetics were observed after single and multiple oral doses of sotorasib once daily at doses ranging from 180 to 960 mg, as C_max and AUC_0-24h values were less than dose-proportional.

Mean C_max and AUC_0-24h values after multiple doses were similar across all dose levels from 180 to 960 mg once daily.

After administration of sotorasib 960 mg once daily, its blood concentration decreased over time until steady-state was reached.

Indications

As monotherapy for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with a KRAS G12C mutation who have progressed after at least one prior line of systemic therapy.

ICD codes

Dosage Regimen

Treatment with sotorasib should be prescribed by a physician experienced in the use of antineoplastic drugs.

Before starting treatment, the presence of a KRAS G12C mutation must be confirmed using an approved test method.

Take orally at the same time each day.

The recommended dose is 960 mg once daily.

Treatment is recommended to be continued until disease progression or unacceptable toxicity occurs.

Adverse Reactions

Blood and lymphatic system disorders very common – anemia.

Nervous system disorders very common – headache.

Respiratory system disorders: very common – cough, dyspnea; uncommon – interstitial lung disease/pneumonitis.

Gastrointestinal disorders very common – diarrhea, nausea, vomiting, constipation, abdominal pain.

Hepatobiliary disorders very common – increased AST, ALT; common – drug-induced liver injury, increased alkaline phosphatase, GGT, blood bilirubin concentration.

Musculoskeletal and connective tissue disorders very common – arthralgia, back pain.

General disorders and administration site conditions very common – fatigue, pyrexia.

Contraindications

Hypersensitivity to sotorasib, pregnancy, breastfeeding, children and adolescents under 18 years of age.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

There are no specific recommendations for dose adjustment in patients with mild hepatic impairment (AST or ALT < 2.5 × ULN or total bilirubin < 1.5 × ULN). Use of sotorasib is not recommended in patients with moderate or severe hepatic impairment.

Use in Renal Impairment

Dose adjustment is not recommended for patients with mild renal impairment (CrCl ≥ 60 ml/min). The effect of sotorasib in patients with moderate or severe renal impairment (CrCl < 60 ml/min) has not been studied. Therefore, treatment of patients with moderate and severe renal impairment or end-stage renal disease should be carried out with particular caution.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Limited safety and efficacy data for sotorasib in patients aged 75 years and older do not indicate a need for dose adjustment in elderly patients.

Special Precautions

Increased liver enzyme levels may be asymptomatic.

Liver function (ALT, AST and total bilirubin) should be monitored in patients before starting treatment with sotorasib every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated.

Patients with elevated transaminases and/or bilirubin levels should be tested more frequently.

Depending on the severity of the laboratory abnormalities, treatment should be withheld until the values recover to Grade ≤1 or baseline, followed by dose modification or permanently discontinued according to recommendations.

Interstitial lung disease (ILD)/pneumonitis occurred in patients treated with Sotorasib, who had previously received immunotherapy or radiation therapy.

Patients should be monitored for the development of new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever).

If ILD/pneumonitis is suspected, treatment with sotorasib should be immediately withheld and, in the absence of other potential causes of ILD/pneumonitis, permanently discontinued.

Drug Interactions

Concomitant administration of sotorasib with omeprazole or famotidine led to a decrease in sotorasib concentration.

Concomitant administration of multiple doses of omeprazole and a single dose of sotorasib 960 mg after a meal (with standard calories and moderate fat content) resulted in a 65% decrease in C_max and a 57% decrease in AUC.

Administration of a single dose of famotidine 10 hours before and 2 hours after a single dose of sotorasib 960 mg resulted in a 35% decrease in sotorasib C_max and a 38% decrease in AUC.

Concomitant administration of multiple doses of omeprazole and a single dose of sotorasib 960 mg on an empty stomach resulted in a 57% decrease in sotorasib C_max and a 42% decrease in AUC.

Sotorasib is not recommended to be taken concomitantly with proton pump inhibitors and histamine H₂-receptor blockers, as the effect of these drugs on the efficacy of sotorasib has not been established.

If antacid use is necessary, Sotorasib should be taken 4 hours before or 10 hours after administration of a local antacid.

Concomitant administration of sotorasib and multiple doses of a strong CYP3A4 inducer (rifampicin) resulted in a 35% decrease in sotorasib C_max and a 51% decrease in AUC.

Sotorasib is not recommended to be taken concomitantly with strong CYP3A4 inducers (such as rifampicin, carbamazepine, enzalutamide, mitotane, phenytoin and St. John’s wort), as they may lead to a decrease in sotorasib blood concentration.

Sotorasib is a moderate inducer of CYP3A4.

Concomitant administration of sotorasib and CYP3A4 substrates led to a decrease in their plasma concentration, which may also reduce the efficacy of these substrates.

Concomitant administration of sotorasib and midazolam (a sensitive CYP3A4 substrate) resulted in a 48% decrease in midazolam C_max and a 53% decrease in AUC.

Concomitant use of sotorasib and CYP3A4 substrates with a narrow therapeutic index, including drugs such as alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus and tacrolimus, should be avoided.

If concomitant use is necessary, the dose of the CYP3A4 substrate should be adjusted according to the current prescribing information/summary of product characteristics.

According to in vitro data, Sotorasib is capable of inducing CYP2B6, CYP2C8, CYP2C9 and CYP2C19 isoenzymes, but the clinical significance of these data has not been established.

When sotorasib is co-administered with drugs that are metabolized by these enzymes, appropriate monitoring is recommended.

According to in vitro data, Sotorasib is capable of inhibiting the CYP2D6 isoenzyme, but the clinical significance of these data has not been established.

When sotorasib is co-administered with CYP2D6 substrates (such as flecainide, propafenone, metoprolol), appropriate monitoring is recommended.

Sotorasib is a weak inhibitor of BCRP.

Concomitant administration of sotorasib with BCRP substrates led to an increase in the plasma concentration of BCRP substrates, which may enhance the effect of the substrates.

Concomitant administration of sotorasib and rosuvastatin (a BCRP substrate) resulted in a 70% increase in rosuvastatin C_max and a 34% increase in AUC.

When sotorasib is co-administered with BCRP substrates (such as methotrexate, mitoxantrone, topotecan and lapatinib), appropriate monitoring is recommended.

When sotorasib is co-administered with BCRP substrates (including lapatinib, methotrexate, mitoxantrone, rosuvastatin and topotecan), patients should be monitored for the occurrence of adverse reactions associated with the BCRP substrate, and the dose of the BCRP substrate should be reduced in accordance with the current summary of product characteristics.

Concomitant administration of sotorasib and digoxin (a P-glycoprotein substrate) resulted in a 1.9-fold increase in digoxin C_max and a 1.2-fold increase in AUC_inf compared to digoxin alone.

Concomitant use of sotorasib and P-glycoprotein substrates with a narrow therapeutic index is not recommended.

If concomitant use is necessary, the dose of the P-glycoprotein substrate should be adjusted according to the current prescribing information/summary of product characteristics.

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.