Lazcluze · 4.6 Fertility, pregnancy and lactation · 1

HOS-100542 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The most frequent adverse reactions in all grades were rash (89%), nail toxicity (71%), infusion-related reaction (amivantamab) (63%), hypoalbuminaemia (amivantamab) (48%), hepatotoxicity (47%), oedema (amivantamab) (47%), stomatitis (43%), venous thromboembolism (37%), paraesthesia (34%), fatigue (32%), constipation (29%), diarrhoea (29%), dry skin (26%), decreased appetite (24%), pruritus (24%), hypocalcaemia (21%), other eye disorders (21%) and nausea (21%). The most frequent serious adverse reactions included venous thromboembolism (11%), pneumonia (4.0%), rash (3.1%), interstitial lung disease/pneumonitis (2.9%), COVID-19 (2.4%), hepatotoxicity (2.4%), pleural effusion (2.1%), infusion-related reaction (amivantamab) (2.1%), respiratory failure (1.4%), fatigue (1.2%), oedema (amivantamab) (1.2%), hypoalbuminaemia (amivantamab) (1.2%), and hyponatraemia (1.2%). The most frequent adverse reactions leading to any treatment discontinuation in patients receiving Lazcluze in combination with amivantamab were rash (6%), infusion-related reaction (amivantamab) (4.5%), nail toxicity (3.6%), interstitial lung disease/pneumonitis (2.9%), venous thromboembolism (2.9%), pneumonia (1.9%) and oedema (amivantamab) (1.7%). 9 Tabulated list of adverse reactions Table 3 summarises the adverse reactions that occurred in patients receiving lazertinib in combination with amivantamab. The data reflects exposure to lazertinib in 421 patients who received lazertinib in combination with amivantamab in MARIPOSA. The median exposure to lazertinib was 18.5 months (range: 0.2 to 31.4 months). Adverse reactions observed during clinical studies are listed below by frequency category. 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 (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Table 3: Adverse reactions in patients receiving lazertinib in combination with amivantamab System organ class Frequency Any grade Grade 3-4 Adverse reaction category (%) (%) Metabolism and nutrition disorders Hypoalbuminaemiaa, b

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HOS-100538 · has-contraindication-information · PDF-Seite 6

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

HOS-100537 · has-indication-information · PDF-Seite 2

Lazcluze in combination with amivantamab is indicated for the first-line treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R substitution mutations.

HOS-100540 · has-interaction-information · PDF-Seite 8

Strong CYP3A4 inducers can decrease lazertinib plasma concentrations. Lazertinib may increase the plasma concentrations of CYP3A4 and BCRP substrates. Agents that may alter lazertinib plasma concentrations CYP3A4 inducers The co-administration of multiple doses of rifampicin (strong CYP3A4 inducer) decreased lazertinib Cmax by 72% and AUC by 83% in healthy subjects. The co-administration of Lazcluze with strong CYP3A4 inducers (e.g. carbamazepine, phenytoin, rifampicin, St. John’s wort) should be avoided. The co-administration of Lazcluze with moderate CYP3A4 inducers may also decrease lazertinib plasma concentrations and hence moderate CYP3A4 inducers (e.g. bosentan, efavirenz, modafinil) should be used with caution. CYP3A4 inhibitors The co-administration of multiple doses of itraconazole (strong CYP3A4 inhibitor) increased lazertinib Cmax by 1.19-fold and AUC by 1.46-fold in healthy subjects. No initial dose adjustment is required when Lazcluze is co-administered with CYP3A4 inhibitors. Gastric acid reducing agents No clinically relevant differences in lazertinib pharmacokinetics were observed when co-administered with gastric acid reducing agents (proton pump inhibitors and H2-receptor antagonists). No dose adjustments are required when Lazcluze is used with gastric acid reducing agents. Agents that may have their plasma concentrations altered by Lazcluze CYP3A4 substrates The co-administration of multiple doses of 160 mg Lazcluze once daily increased midazolam (CYP3A4 substrate) Cmax by 1.39-fold and AUC by 1.47-fold. Narrow therapeutic index medicinal products that are CYP3A4 substrates (e.g., cyclosporine, everolimus, pimozide, quinidine, sirolimus, tacrolimus) should be used with caution, as lazertinib may increase the plasma concentrations of these medicinal products. BCRP substrates The co-administration of multiple doses of 160 mg Lazcluze once daily increased rosuvastatin (BCRP substrate) Cmax by 2.24-fold and AUC by 2.02-fold. Narrow therapeutic index medicinal products that are BCRP substrates (e.g., sunitinib) should be used with caution, as lazertinib may increase the plasma concentrations of these medicinal products. CYP1A2 substrates Induction of CYP1A2 cannot be excluded. Therefore, caution is advised when co-administering with substrates of CYP1A2 (e.g., tizanidine).

HOS-100541 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential/Contraception in males and females Women of childbearing potential should be advised to use effective contraception during treatment and up to 3 weeks after treatment. 8 Male patients with female partners of reproductive potential should be advised to use effective contraception (e.g., condom) and not donate or store semen during treatment and for 3 weeks after the last dose of lazertinib. Pregnancy There are no data from the use of lazertinib in pregnant women. Studies in animals have shown reproductive toxicity (reduced embryo-foetal survival and foetal body weight) (see section 5.3). Based on its mechanism of action and animal data, lazertinib may cause foetal harm when administered to a pregnant woman. Lazertinib should not be used during pregnancy unless the benefit of treatment of the woman is considered to outweigh potential risks to the foetus. If the patient becomes pregnant while taking this medicinal product the patient should be informed of the potential risk to the foetus. Breast-feeding It is unknown whether lazertinib or its metabolites are excreted in human milk or affects milk production. Because the risk to the breast-feeding child cannot be excluded, female patients should be advised not to breast-feed during treatment and for 3 weeks after the last dose of lazertinib. Fertility There are no data on the effect of Lazcluze on human fertility. Studies in animals have shown that lazertinib has effects on reproductive organs in females (decreased numbers of oestrus cycles and corpora lutea) and males (degenerative changes in the testis) and may impair female and male fertility (see section 5.3).

HOS-100539 · has-warning-information · PDF-Seite 6

Interstitial lung disease/pneumonitis Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g., pneumonitis), including fatal events, have been reported in patients treated with lazertinib and amivantamab (see section 4.8). Patients with a medical history of ILD, drug‑induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD were excluded from the pivotal clinical study. 6 Patients should be monitored for symptoms indicative of ILD/pneumonitis (e.g., dyspnoea, cough, fever). If symptoms develop, treatment with Lazcluze should be interrupted pending investigation of these symptoms. Suspected ILD or ILD-like adverse reactions should be evaluated and appropriate treatment should be initiated as necessary. Lazcluze should be permanently discontinued in patients with confirmed ILD or ILD-like adverse reactions (see section 4.2). Venous thromboembolic (VTE) events In patients receiving Lazcluze in combination with amivantamab, venous thromboembolic (VTE) events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), including fatal events, were reported (see section 4.8). Consistent with clinical guidelines, patients should receive prophylactic dosing of either a direct acting oral anticoagulant (DOAC) or a low-molecular weight heparin (LMWH). Use of Vitamin K antagonists is not recommended. Signs and symptoms of VTE events should be monitored. Patients with VTE events should be treated with anticoagulation as clinically indicated. For VTE events associated with clinical instability, treatment should be withheld until the patient is clinically stable. Thereafter, both medicinal products can be resumed at the same dose. In the event of recurrence despite appropriate anticoagulation, amivantamab should be discontinued. Treatment can continue with Lazcluze at the same dose (see section 4.2). Skin and nail reactions Rash (including dermatitis acneiform), pruritus and dry skin occurred in patients treated with lazertinib in combination with amivantamab (see section 4.8). Patients should be instructed to limit sun exposure during and for 2 months after Lazcluze combination therapy. Protective clothing and use of broad-spectrum UVA/UVB sunscreen are advisable. A prophylactic approach to rash prevention is recommended. This includes prophylactic therapy, at treatment initiation, with an oral antibiotic (e.g., doxycycline or minocyclin

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