LAZCLUZE Film-coated tablet Ref.[114943] Active ingredients: Lazertinib

Source: European Medicines Agency (EU)  Revision Year: 2025  Publisher: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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.

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. Alcohol-free emollient cream is recommended for dry areas. A prophylactic approach to rash prevention should be considered. This includes prophylactic therapy with an oral antibiotic (e.g., doxycycline or minocycline, 100 mg twice daily) starting on Day 1 for the first 12 weeks of treatment and after completion of oral antibiotic therapy, topical antibiotic lotion to the scalp (e.g., clindamycin 1%) for the next 9 months of treatment.

Non-comedogenic skin moisturiser on the face and whole body (except scalp) and chlorhexidine solution to wash hands and feet should be considered beginning on Day 1 and continued for the first 12 months of treatment.

Prescriptions for additional topical and/or oral antibiotics and topical corticosteroids are recommended to be available at the time of initial dosing to minimise any delay in reactive management should rash develop despite prophylactic treatment. If skin or nail reactions develop, topical corticosteroids and topical and/or oral antibiotics should be administered. For Grade 3 or poorly-tolerated Grade 2 events, systemic antibiotics and oral steroids should also be administered and dermatologic consultation should be considered. Lazcluze should be dose reduced, interrupted, or permanently discontinued based on severity (see section 4.2).

Eye disorders

Eye disorders, including keratitis, occurred in patients treated with lazertinib in combination with amivantamab (see section 4.8). Patients presenting with worsening eye symptoms should promptly be referred to an ophthalmologist and should discontinue use of contact lenses until symptoms are evaluated.

Excipients

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

4.5. Interaction with other medicinal products and other forms of interaction

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).

4.6. Fertility, pregnancy and lactation

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.

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).

4.7. Effects on ability to drive and use machines

Lazcluze has minor influence on the ability to drive and use machines. If patients experience treatment-related symptoms (such as fatigue) affecting their ability to concentrate and react, it is recommended that they do not drive or use machines until the effect subsides.

4.8. Undesirable effects

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%).

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
Adverse reaction
Frequency
category
Any grade
(%)
Grade 3-4
(%)
Metabolism and nutrition disorders
Hypoalbuminaemiaa,b Very common 485
Decreased appetite 24 1.0
Hypocalcaemia 21 2.1
Hypokalaemia 14 3.1
Hypomagnesaemia Common 5 0
Nervous system disorders
Paraesthesiaa Very common 34 1.7
Dizzinessa 13 0
Eye disorders
Other eye disordersa Very common 21 0.5
Visual impairmenta Common 4.5 0
Keratitis 2.6 0.5
Growth of eyelashesa 1.9 0
Vascular disorders
Venous thromboembolisma Very common 37 11
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease/pneumonitisa Common 3.11.2
Gastrointestinal disorders
Stomatitisa Very common 43 2.4
Diarrhoea 29 2.1
Constipation 29 0
Nausea 21 1.2
Vomiting 12 0.5
Abdominal paina 11 0
Haemorrhoids Common 10 0.2
Hepatobiliary disorders
Hepatotoxicitya Very common 47 9
Skin and subcutaneous tissue disorders
Rasha Very common 89 27
Nail toxicitya 71 11
Dry skina 26 1.0
Pruritus 24 0.5
Palmar-plantar erythrodysaesthesia syndrome Common 6 0.2
Urticaria 1.2 0
Musculoskeletal and connective tissue disorders
Muscle spasms Very common 17 0.5
Myalgia 13 0.7
General disorders and administration site conditions
Oedemaa,b Very common 47 2.9
Fatiguea 32 3.8
Pyrexia 12 0
Injury, poisoning and procedural complications
Infusion-related reactionb Very common 63 6

a grouped terms
b applicable only to amivantamab.

Description of selected adverse reactions

Venous thromboembolism

Venous thromboembolic (VTE) events, including deep vein thrombosis (14.5%) and pulmonary embolism (PE) (17.3%), were reported in 37% of patients receiving lazertinib in combination with amivantamab. Most cases were Grade 1 or 2, with Grade 3-4 events occurring in 11% and deaths occurring in 0.5% of patients receiving lazertinib in combination with amivantamab. For information on prophylactic anticoagulants and management of VTE events, see sections 4.2 and 4.4.

In patients receiving lazertinib in combination with amivantamab, the median time to first onset of a VTE event was 84 days. VTE events led to any treatment discontinuation in 2.9% of patients.

Interstitial lung disease (ILD)/pneumonitis

Interstitial lung disease or ILD-like adverse reactions (e.g., pneumonitis) have been reported with the use of lazertinib in combination with amivantamab as well as with other EGFR inhibitors. ILD or pneumonitis was reported in 3.1% of patients treated with lazertinib in combination with amivantamab, including 0.2% fatal cases. 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 clinical study (see section 4.4).

Skin and nail reactions

Rash (including dermatitis acneiform), pruritus and dry skin has occurred. Rash occurred in 89% of patients treated with lazertinib in combination with amivantamab. Most cases were Grade 1 or 2, with Grade 3 events occurring in 27% of patients. Rash leading to any treatment discontinuation occurred in 6% of patients. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of 14 days. Nail toxicity occurred in patients treated with lazertinib in combination with amivantamab. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 11% of patients (see section 4.4).

Eye disorders

Eye disorders, including keratitis (2.6%), occurred in patients treated with lazertinib in combination with amivantamab. Other reported adverse reactions included growth of eyelashes, visual impairment, and other eye disorders. Most events were Grade 1-2 (see section 4.4).

Hepatotoxicity

Hepatotoxicity-related reactions occurred in 47% of patients treated with lazertinib in combination with amivantamab. Most events were Grade 1-2, with Grade 3-4 hepatotoxicity occurring in 9% of patients. Most events were related to elevations of serum transaminases (36% alanine aminotransferase increased and 29% aspartate aminotransferase increased). Most patients with elevations of transaminases were able to continue study treatment without modification of study treatment while a small number were managed with a dose interruption or with a dose reduction. There were no cases of liver failure or fatal cases of hepatotoxicity in clinical studies.

Paraesthesia

Paraesthesia occurred in 34% of patients treated with lazertinib in combination with amivantamab. Most events were Grade 1-2, with Grade 3 paraesthesia occurring in 1.7% of patients. Most patients with paraesthesia had resolution with dose interruption or dose reduction.

Stomatitis

Stomatitis occurred in 43% of patients treated with lazertinib in combination with amivantamab. Most events were Grade 1-2, with Grade 3 stomatitis occurring in 2.4% of patients.

Diarrhoea

Diarrhoea occurred in 29% of patients treated with lazertinib in combination with amivantamab. Most events were Grade 1-2, with Grade 3 diarrhoea occurring in 2.1% of patients.

Special populations

Elderly

There are limited clinical data with lazertinib in patients 75 years of age or over (see section 5.1). Older patients (≥65 years of age) reported more Grade 3 or higher adverse events compared to patients <65 years of age (81% vs. 70%). While the rates of drug interruptions and dose reductions were similar, the rate of adverse events leading to any treatment discontinuation was higher in patients ≥65 years of age compared to patients <65 years of age (47% vs. 25%).

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.

6.2. Incompatibilities

Not applicable.

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