Tabrecta

Treatment with Tabrecta should be initiated by a physician experienced in the use of anticancer therapies. 3 Patients have to be selected for treatment with Tabrecta based on the presence of genetic alterations leading to a METex14 skipping mutation in tumour tissue or plasma specimens using a validated test.

1). Posology The recommended dose of Tabrecta is 400 mg orally twice daily with or without food. Treatment should be continued based on individual safety and tolerability and as long as the patient is deriving clinical benefit from therapy.

If a dose of Tabrecta is missed or vomiting occurs, the patient should not make up for the dose, but take the next dose at the scheduled time. Dose modifications The recommended dose reduction schedule for the management of adverse reactions based on individual safety and tolerability is listed in Table 1.

Table 1 Tabrecta dose reduction schedule Dose level Dose and schedule Number and strength of tablets Starting dose 400 mg twice daily Two 200 mg tablets / twice daily First dose reduction 300 mg twice daily Two 150 mg tablets / twice daily Second dose reduction 200 mg twice daily One 200 mg tablet / twice daily Doses of Tabrecta below 200 mg twice daily have not been investigated in clinical studies.

Recommendations for dose modifications of Tabrecta for adverse reactions are provided in Table 2. Table 2 Tabrecta dose modifications for the management of adverse reactions Adverse reaction Severity Dose modification Interstitial lung disease (ILD)/pneumonitis Any grade treatment- related Permanently discontinue Tabrecta.

0 x ULN) Temporarily withhold Tabrecta until recovery to baseline ALT/AST grade. If recovered to baseline within 7 days, then resume Tabrecta at the same dose, otherwise resume Tabrecta at a reduced dose as per Table 1. 0 x ULN) Permanently discontinue Tabrecta.

Combined elevations in ALT and/or AST with concurrent total bilirubin increase, in the absence of cholestasis or haemolysis If patient develops ALT and/or AST >3 x ULN along with total bilirubin >2 x ULN, irrespective of baseline grade Permanently discontinue Tabrecta.

0 x ULN) Temporarily withhold Tabrecta until recovery to baseline bilirubin grade. If recovered to baseline within 7 days, then resume Tabrecta at the same dose, otherwise resume Tabrecta at a reduced dose as per Table 1. 0 x ULN) Temporarily withhold Tabrecta until recovery to baseline bilirubin grade.

3%). 6%). 8%) who received Tabrecta. 1%). 5%). 1%). 1%). 5%). 8%). 6%). Tabulated list of adverse reactions The safety of Tabrecta was evaluated in patients with locally-advanced or metastatic NSCLC in a pivotal, global, prospective, multi-cohort, non-randomised, open-label Phase II study (GEOMETRY mono-1) across all cohorts (N=373), regardless of prior treatment or MET dysregulation (mutation and/or amplification) status.

03). The safety profile for all GEOMETRY mono-1 patients (N=373) and for patients with METex14 skipping mutations (N=160) is comparable. 6 weeks). 3% were exposed for at least one year. Adverse reactions from clinical studies (Table 3) are listed by MedDRA system organ class.

Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each adverse reaction is based on the following convention: 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).

Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. 6* 1 ILD/pneumonitis includes preferred terms (PTs) of ILD, pneumonitis and organising pneumonia. 2 Rash includes PTs of rash, rash maculopapular and rash vesicular.

3 Oedema peripheral includes PTs of oedema peripheral and peripheral swelling. 4 Pyrexia includes PTs of body temperature increased and pyrexia. 5 Fatigue includes PTs of fatigue and asthenia. 6 Non-cardiac chest pain includes PTs of chest discomfort, musculoskeletal chest pain and non- cardiac chest pain.

* No grade 4 adverse reactions reported in GEOMETRY mono-1 patients with METex14 skipping mutations. † Hypersensitivity has been observed in solid tumour patients treated with Tabrecta monotherapy (N=580). Hypersensitivity has also been observed in the post-marketing setting and in expanded access programmes with Tabrecta.

Assessment of METex14 skipping alterations status When detecting the presence of alterations leading to METex14 skipping using tissue-based or plasma-based specimens, it is important that a well-validated and robust test is chosen to avoid false negative or false positive results.

1. 8). g. dyspnoea, cough, fever). 2). 8). Liver function tests (including ALT, AST and total bilirubin) should be performed prior to the start of treatment, every 2 weeks during the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop transaminase or bilirubin elevations.

2). 8). Amylase and lipase should be monitored at baseline and regularly during treatment with Tabrecta. 2). 6). Pregnant women and women of childbearing potential should be advised of the potential risk to a foetus if Tabrecta is used during pregnancy or if the patient becomes pregnant while taking Tabrecta.

Sexually active women of childbearing potential should use effective contraception during treatment with Tabrecta and for at least 7 days after the last dose. The pregnancy status of women of childbearing potential should be verified prior to starting treatment with Tabrecta.

Male patients with sexual partners who are pregnant, possibly pregnant, or who could become pregnant should use condoms during treatment with Tabrecta and for at least 7 days after the last dose. 3). In Study GEOMETRY mono-1, it was recommended that patients limit direct ultraviolet exposure during treatment with Tabrecta and adopt the following protective measures: use of sunscreen on exposed parts of the body, wearing of protective clothing and sunglasses.

These measures should be continued for at least 7 days after the last dose. 5). Excipients This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

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