LUMYKRAS Film-coated tablet Ref.[50027] Active ingredients: Sotorasib

Hepatotoxicity

Sotorasib can cause hepatotoxicity, which may lead to drug-induced liver injury (DILI) and hepatitis. Sotorasib has been associated with transient elevations of serum transaminases (ALT and AST). These elevations improved or resolved with dose modification or permanent discontinuation of treatment and did not result in any cases of liver failure or fatal cases in clinical studies. Among patients who experienced hepatotoxicity, 38% had hepatotoxicity leading to dose interruption or dose reduction. Overall, 26% of patients with hepatotoxicity received concurrent corticosteroids. Cases of liver enzyme increase can be asymptomatic. Patients should be monitored for liver function (ALT, AST, and total bilirubin) prior to the start of LUMYKRAS, every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop transaminase and/or bilirubin elevations. Based on the severity of the laboratory abnormalities, treatment with LUMYKRAS must be stopped until recovered to ≤ grade 1 or to baseline grade, and the dose must either be modified or permanently discontinue treatment as recommended (see section 4.2).

Interstitial Lung Disease (ILD)/pneumonitis

ILD/pneumonitis occurred in patients treated with LUMYKRAS with prior exposure to immunotherapy or radiotherapy (see section 4.8). Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g. dyspnoea, cough, fever). Immediately withhold LUMYKRAS in patients with suspected ILD/pneumonitis and permanently discontinue LUMYKRAS if no other potential causes of ILD/pneumonitis are identified (see section 4.2).

Lactose intolerance

LUMYKRAS contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

In vitro studies indicate that sotorasib is metabolised by cytochrome P450 (CYP) 2C8, CYP3A4, and CYP3A5, and is a substrate of P-glycoprotein (P-gp). Sotorasib was an inducer of CYP3A4, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 in vitro. Sotorasib is an in vitro inhibitor of CYP2C8, CYP2D6, and CYP3A. In vitro studies indicate that sotorasib is an inhibitor of human organic anion transporter (OAT)1/3, OATP1B1, Breast Cancer Resistance Protein (BCRP) and P-gp.

Effects of other medicinal products on sotorasib

Acid-reducing agents

Co-administration of sotorasib with a PPI (omeprazole) or an H₂ receptor antagonist (famotidine) led to a decrease in sotorasib concentrations.

Under fed conditions (standard-calorie moderate-fat meals), co-administration of multiple doses of omeprazole with a single dose of 960 mg sotorasib decreased sotorasib C_max by 65% and AUC by 57%. Co-administration of a single dose of famotidine given 10 hours prior and 2 hours after a single dose of 960 mg sotorasib decreased sotorasib C_max by 35% and AUC by 38%.

Under fasted conditions, co-administration of multiple doses of omeprazole with a single dose of 960 mg sotorasib decreased sotorasib C_max by 57% and AUC by 42%.

Co-administration of PPIs and H₂ receptor antagonists with LUMYKRAS is not recommended because the impact on sotorasib efficacy is unknown. If treatment with an acid-reducing agent is required, LUMYKRAS should be taken 4 hours before or 10 hours after administration of a local antacid (see section 4.2).

Co-administration of multiple-dose itraconazole (a strong CYP3A4 and P-gp inhibitor) did not increase sotorasib exposures to a clinically significant extent. No dose adjustment of LUMYKRAS is recommended when co-administered with CYP3A4 inhibitors.

Strong CYP3A4 inducers

Co-administration of sotorasib with multiple doses of a strong CYP3A4 inducer (rifampicin) decreased sotorasib C_max by 35% and AUC by 51%. Co-administration of strong CYP3A4 inducers (e.g. rifampicin, carbamazepine, enzalutamide, mitotane, phenytoin and St. John’s wort) with LUMYKRAS is not recommended because they may decrease sotorasib exposure.

Effect of sotorasib on other medicinal products

CYP3A4 substrates

Sotorasib is a moderate CYP3A4 inducer. Co-administration of sotorasib with CYP3A4 substrates led to a decrease in their plasma concentrations, which may reduce the efficacy of these substrates.

Co-administration of sotorasib with midazolam (a sensitive CYP3A4 substrate) decreased midazolam C_max by 48% and AUC by 53%.

Avoid co-administration of LUMYKRAS with CYP3A4 substrates with narrow therapeutic indices, including but not limited to alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus and tacrolimus. If co-administration cannot be avoided, adjust the CYP3A4 substrate dose in accordance with the current summary of product characteristics.

CYP2B6, CYP2C8, CYP2C9 and CYP2C19 substrates

In vitro data indicated that sotorasib may have the potential to induce CYP2B6, CYP2C8, CYP2C9 and CYP2C19; the clinical relevance of these findings is unknown. When sotorasib is co-administered with medicinal products metabolised by these enzymes, appropriate monitoring is recommended.

CYP2D6 substrates

In vitro data indicated that sotorasib may have the potential to inhibit CYP2D6, the clinical relevance of these findings is unknown. When LUMYKRAS is co-administered with CYP2D6 substrates (e.g. flecainide, propafenone, metoprolol), appropriate monitoring is recommended.

BCRP substrates

LUMYKRAS is a weak BCRP inhibitor. Co-administration of LUMYKRAS with a BCRP substrate led to an increase in the plasma concentrations of the BCRP substrate, which may increase the effect of the substrate.

Co-administration of LUMYKRAS with rosuvastatin (a BCRP substrate) increased the rosuvastatin C_max by 70% and AUC by 34%.

When LUMYKRAS is co-administered with a BCRP substrate, including but not limited to lapatinib, methotrexate, mitoxantrone, rosuvastatin and topotecan, monitor for adverse reactions of the BCRP substrate and reduce the BCRP substrate dose in accordance with its current summary of product characteristics.

Effect of sotorasib on P-gp substrates

Co-administration of sotorasib with digoxin (a P-glycoprotein [P-gp] substrate) increased digoxin C_max by 1.9-fold and AUC_inf by 1.2-fold of digoxin administered alone. Co-administration of LUMYKRAS with P-gp substrates with narrow therapeutic indices is not recommended. If co-administration cannot be avoided, adjust the P-gp substrate dosage in accordance with the current summary of product characteristics.

Women of childbearing potential/Contraception

Women of childbearing potential must be advised to avoid pregnancy while on LUMYKRAS. Female patients of child-bearing potential receiving LUMYKRAS must use highly effective contraceptive methods during treatment and for at least 7 days following the last dose of LUMYKRAS. LUMYKRAS may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method.

Pregnancy

There are no data from the use of sotorasib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). LUMYKRAS is not recommended during pregnancy and in women of childbearing potential not using contraception. Patients must be informed of the potential hazards to the foetus if LUMYKRAS is used during pregnancy, or if the patient becomes pregnant while taking LUMYKRAS.

Breast-feeding

It is unknown if sotorasib or its metabolites are excreted in human milk. A risk to breast-fed newborns/infants cannot be excluded. LUMYKRAS should not be used during breast-feeding.

Fertility

There are no clinical studies to evaluate the effect of sotorasib on fertility.

LUMYKRAS has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most common adverse reactions were diarrhoea (34%), nausea (25%), and fatigue (21%). The most common severe (grade ≥ 3) adverse reactions were increased ALT (5%), increased AST (4%), and diarrhoea (4%). The most common adverse reactions leading to permanent discontinuation of treatment were increased ALT (1%) and increased AST (1%) and DILI (1%). The most common adverse reactions leading to dose modification were increased ALT (6%), diarrhoea (6%), increased AST (6%), nausea (3%), increased blood alkaline phosphatase (3%) and vomiting (2%).

Tabulated list of adverse reactions

Adverse reactions reported in LUMYKRAS clinical studies are displayed in table 3 below. Frequency categories are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from available data). Within each system organ class, adverse reactions are presented in order of decreasing seriousness.

The safety of LUMYKRAS was evaluated in 359 patients with KRAS G12C mutated solid tumours who received 960 mg orally once daily as monotherapy. The median duration of exposure to LUMYKRAS was 4.1 months (range: 0.02 to 21).

Table 3. Adverse reactions:

^a Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower

Description of selected adverse reactions

Elevated liver enzymes

In clinical studies, transient elevations of serum transaminases were observed (see section 4.4). Elevations of ALT occurred in 14% of subjects and elevations of AST in 16% of subjects, with a median time to onset of 8 weeks (range: 1 to 42) and 8 weeks (range: 0 to 42), respectively. Elevations of ALT resulted in dose interruption and/or reduction in 6.1% of subjects, and elevations of AST resulted in dose interruption and/or reduction in 6.1% of subjects.

ILD/pneumonitis

In clinical studies, among 359 patients who received LUMYKRAS, ILD/pneumonitis occurred in 0.8% of patients, all cases were grade 3 or 4 at onset. The median time to first onset for ILD/pneumonitis was 2 weeks (range: 2 to 18 weeks). LUMYKRAS was discontinued due to ILD/pneumonitis in 0.6% of patients (see section 4.2 and 4.4).

Elderly

In clinical studies, no overall differences in safety or efficacy were observed between elderly patients (≥65 years old) and younger patients (see section 4.2 and 5.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be dispersed with other liquids than that mentioned in section 4.2. Acidic beverages (e.g. fruit juices) should also be excluded.