Lumykras · 4.6 Fertility, pregnancy and lactation · 1

HOS-099781 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile Adverse drug reactions (ADRs) described in table 3 reflect exposure to sotorasib 960 mg once daily as monotherapy in 740 patients with KRAS G12C-mutated solid tumours across multiple clinical studies, including CodeBreaK 200, CodeBreaK 100 phase 2 part A, and CodeBreaK 100 phase 2 part B (dose comparison sub-study) and three phase 1 studies. The most common adverse reactions in patients treated with LUMYKRAS 960 mg once daily were diarrhoea (36.6%), nausea (24.7%), fatigue (19.1%), vomiting (16.1%), arthralgia (15.3%), and decreased appetite (15.1%). The most common severe (grade ≥ 3) adverse reactions were diarrhoea (6.9%), increased ALT (5.9%) and increased AST (4.6%). The most common adverse reactions leading to permanent discontinuation of treatment were increased ALT (1.5%) and increased AST (1.1%) and DILI (1%). The most common adverse reactions leading to dose modification were diarrhoea (11.4%), increased ALT (5.9%), increased AST (5.7%), nausea (3.8%), increased blood alkaline phosphatase (2.4%) and vomiting (2%). 8 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 740 patients with KRAS G12C-mutated solid tumours who received 960 mg orally once daily as monotherapy. The median duration of exposure to LUMYKRAS was 4.2 months (range: 0 to 41). Table 3. Adverse reactions MedDRA system Very common Common Uncommon organ class (≥ 1/10) (≥ 1/100 to (≥ 1/1 000 to < 1/10) < 1/100) Blood and lymphatic Anaemia system disorders Nervous system Headache disorders Respiratory, thoracic Cough ILD/pneumonitis and mediastinal Dyspnoea disorders Gastrointestinal Diarrhoea disorders

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HOS-099777 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-099776 · has-indication-information · PDF-Seite 2

LUMYKRAS as monotherapy is indicated for the treatment of adults with advanced non-small cell lung cancer (NSCLC) with KRAS G12C-mutation and who have progressed after at least one prior line of systemic therapy.

HOS-099779 · has-interaction-information · PDF-Seite 6

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 Cmax by 65% and area under the curve (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 Cmax 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 Cmax by 57% and AUC by 42%. Under fasted conditions, co-administration of repeat doses of omeprazole with a single dose of 960 mg sotorasib and 240 mL of 6 an acidic beverage (non-diet cola) decreased sotorasib Cmax by 32% and AUC by 23%. The clinical relevance of the decreased sotorasib exposure when co-administered with omeprazole and cola is unclear and efficacy might be reduced. If co-administration of LUMYKRAS with an acid-reducing agent (such as a PPI or an H2 receptor antagonist) is required, LUMYKRAS should be taken with an acidic beverage (such as cola). Alternatively, LUMYKRAS should be taken 4 hours before or 10 hours after administration of a local antacid. CYP3A4 inhibitors 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 Cmax 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

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HOS-099780 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential/Contraception Women of childbearing potential must be advised to avoid pregnancy while on LUMYKRAS. Female patients of childbearing 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.

HOS-099778 · has-warning-information · PDF-Seite 5

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), alkaline phosphatase and total bilirubin in 960 mg monotherapy clinical trials. In a total of 740 patients with KRAS G12C-mutated solid tumours who received LUMYKRAS 960 mg monotherapy daily, the incidence for hepatotoxicity is highest in the sub-group of patients with recent (≤ 3 months) immunotherapy (38%) prior to starting LUMYKRAS, as compared to those who started LUMYKRAS either more than 3 months after last dose of immunotherapy (17%) or those who never received immunotherapy (22%). Regardless of time from prior immunotherapy, 87% of elevations improved or resolved with interruption of LUMYKRAS treatment and treatment with corticosteroids. Elevated liver enzymes led to discontinuation of treatment in 10%, 2% and 0% of patients with prior immunotherapy within ≤ 3 months, with prior immunotherapy within > 3 months and no prior immunotherapy, respectively. Among 740 patients with KRAS G12C-mutated solid tumours who received 960 mg orally once daily, 26% experienced hepatotoxicity and 13% had hepatotoxicity leading to dose interruption and/or dose reduction. Overall, 41% of patients with hepatotoxicity 5 received concurrent corticosteroids. Cases of liver enzyme increase can be asymptomatic. Patients should be monitored for liver function (ALT, AST, alkaline phosphatase 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 with recent immunotherapy and in patients with serious hepatotoxicity events. Based on the severity of the laboratory abnormalities, treatment with LUMYKRAS must be interrupted until recovered to ≤ 3 × ULN or to ≤ 3 baseline (if baseline abnormal) and treatment with corticosteroids considered, and the dose of LUMYKRAS must be either modified or permanently discontinued (see section 4.2). Interstitial Lung Disease (ILD)/pneumonitis LUMYKRAS can cause ILD/pneumonitis that can be fatal. ILD/pneumonitis occurred in patients treated with LUMYKRAS with prior exposure to immunotherapy or radiotherapy (see section 4.8). Recent (≤ 3 months) immunotherapy prior to starting LUMYKRAS may be considered a risk factor for ILD/pneumonitis. Monitor patient

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