TABRECTA Film-coated tablet Ref.[50200] Active ingredients: Capmatinib

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. For the characteristics of tests used in clinical studies see section 5.1.

Interstitial lung disease (ILD)/pneumonitis

ILD/pneumonitis, which can be fatal, has occurred in patients treated with Tabrecta (see section 4.8). Prompt investigation should be performed in any patient with new or worsening of pulmonary symptoms indicative of ILD/pneumonitis (e.g. dyspnoea, cough, fever). Tabrecta should be immediately withheld in patients with suspected ILD/pneumonitis and permanently discontinued if no other potential causes of ILD/pneumonitis are identified (see section 4.2).

Hepatic effects

Transaminase elevations have occurred in patients treated with Tabrecta (see section 4.8). 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. Based on the severity of the adverse reaction, temporarily withhold, dose reduce, or permanently discontinue Tabrecta (see section 4.2).

Elevations of pancreatic enzymes

Elevations in amylase and lipase levels have occurred in patients treated with Tabrecta (see section 4.8). Amylase and lipase should be monitored at baseline and regularly during treatment with Tabrecta. Based on the severity of the adverse reaction, temporarily withhold, dose reduce, or permanently discontinue Tabrecta (see section 4.2).

Embryo-foetal toxicity

Based on findings from animal studies and its mechanism of action, Tabrecta can cause foetal harm when administered to a pregnant woman due to its foetotoxicity and teratogenicity (see section 4.6). 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.

Risk of photosensitivity

Based on findings from animal studies, there is a potential risk of photosensitivity reactions with Tabrecta (see section 5.3). 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.

Interaction with other medicinal products

There is a potential for drug-drug interactions with Tabrecta as victim or perpetrator (see section 4.5).

Excipients

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

Capmatinib undergoes metabolism through CYP3A4 enzyme and aldehyde oxidase. The risk of a drug-drug interaction via aldehyde oxidase has not been evaluated as there are no confirmed clinically relevant inhibitors.

Effect of other medicinal products on Tabrecta

Strong CYP3A inhibitors

In healthy subjects, co-administration of a single 200 mg capmatinib dose with the strong CYP3A inhibitor itraconazole (200 mg once daily for 10 days) increased capmatinib AUC_inf by 42% with no change in capmatinib C_max compared to administration of capmatinib alone. Patients should be closely monitored for adverse reactions during co-administration of Tabrecta with strong CYP3A inhibitors, including but not limited to, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole.

Strong CYP3A inducers

In healthy subjects, co-administration of a single 400 mg capmatinib dose with the strong CYP3A inducer rifampicin (600 mg once daily for 9 days) decreased capmatinib AUC_inf by 67% and decreased C_max by 56% compared to administration of capmatinib alone. Decreases in capmatinib exposure may decrease Tabrecta anti-tumour activity. Co-administration of Tabrecta with strong CYP3A inducers, including but not limited to, carbamazepine, phenobarbital, phenytoin, rifampicin and St. John’s wort (Hypericum perforatum), should be avoided. An alternative medicinal product with no or minimal potential to induce CYP3A should be considered.

Moderate CYP3A inducers

Simulations using physiologically-based pharmacokinetic (PBPK) models predicted that co-administration of a 400 mg capmatinib dose with the moderate CYP3A inducer efavirenz (600 mg daily for 20 days) would result in a 44% decrease in capmatinib AUC_0-12h and 34% decrease in C_max at steady-state compared to administration of capmatinib alone. Decreases in capmatinib exposure may decrease Tabrecta anti-tumour activity. Caution should be exercised during co-administration of Tabrecta with moderate CYP3A inducers.

Agents that raise gastric pH

Capmatinib demonstrates pH-dependent solubility and becomes poorly soluble as pH increases in vitro. In healthy subjects, co-administration of a single 600 mg capmatinib dose with the proton pump inhibitor rabeprazole (20 mg once daily for 4 days) decreased capmatinib AUC_inf by 25% and decreased C_max by 38% compared to administration of capmatinib alone. Clinically relevant drug-drug interactions between capmatinib and gastric-acid-reducing agents are unlikely to occur as co-administration of rabeprazole had no clinically meaningful effect on exposure of capmatinib.

Effect of Tabrecta on other medicinal products

Substrates of CYP enyzmes

Moderate inhibition of CYP1A2 was observed when capmatinib was co-administered with the sensitive CYP1A2 substrate caffeine. Co-administration of capmatinib (400 mg twice daily) with caffeine increased caffeine AUC_inf by 134%. If capmatinib is co-administered with narrow therapeutic index CYP1A2 substrates, such as theophylline and tizanidine, dose reduction of the co-administered medicinal product may be required.

Clinically relevant drug-drug interactions between capmatinib and CYP3A substrates are unlikely to occur as co-administration of capmatinib had no clinically meaningful effect on exposure of midazolam (a CYP3A substrate).

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrates

In cancer patients, co-administration of digoxin (P-gp substrate) with multiple doses of capmatinib (400 mg twice daily) increased digoxin AUC_inf by 47% and increased C_max by 74% compared to administration of digoxin alone. In cancer patients, co-administration of rosuvastatin (BCRP substrate) with multiple doses of capmatinib (400 mg twice daily) increased rosuvastatin AUC_inf by 108% and increased C_max by 204% compared to administration of rosuvastatin alone.

Co-administration of Tabrecta with a P-gp or BCRP substrate may increase the incidence and severity of adverse reactions of these substrates. Caution should be exercised during co-administration of Tabrecta with P-gp (digoxin, dabigatran etexilate, colchicine, sitagliptin, saxagliptin and posaconazole) or BCRP (methotrexate, rosuvastatin, pravastatin, mitoxantrone and sulphasalazine) substrates. If capmatinib is co-administered with narrow therapeutic index P-gp or BCRP substrates, dose reduction of the co-administered medicinal product may be required.

Women of childbearing potential/Contraception in males and females

Sexually-active women of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with Tabrecta and for at least 7 days after the last dose.

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.

Pregnancy

There are no data from the use of capmatinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Based on findings from animal studies and its mechanism of action, capmatinib is suspected to cause congenital malformations when administered during pregnancy. Tabrecta should not be used during pregnancy unless the clinical condition of the woman requires treatment with capmatinib.

The pregnancy status of women of childbearing potential should be verified prior to starting treatment with Tabrecta.

Breast-feeding

It is unknown whether capmatinib or its metabolites are excreted in human milk after administration of Tabrecta. There is insufficient information on the excretion of capmatinib or its metabolites in animal milk. A risk to the breast-fed infant cannot be excluded. Because of the potential for serious adverse reactions in breast-fed infants, breast-feeding should be discontinued during treatment with Tabrecta and for at least 7 days after the last dose.

Fertility

No human fertility data on capmatinib are available. Fertility studies with capmatinib were not conducted in animals.

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

Summary of the safety profile

The most common adverse reactions are peripheral oedema (67.5%), nausea (44.4%), fatigue (34.4%), blood creatinine increased (33.8%), vomiting (25.0%), dyspnoea (22.5%), decreased appetite (21.3%) and back pain (20.6%). The most common grade 3 or 4 adverse reactions are peripheral oedema (14.4%), lipase increased (9.4%), ALT increased (8.1%), fatigue (8.1%), dyspnoea (6.9%) and amylase increased (5.6%).

Serious adverse reactions were reported in 35 of 160 patients (21.9%) who received Tabrecta. Serious adverse reactions in >2% of patients included dyspnoea (5.6%), ILD/pneumonitis (5.0%), cellulitis (3.1%) and peripheral oedema (2.5%).

Dose interruptions were reported in 81 of 160 patients (50.6%). Adverse reactions requiring dose interruption included peripheral oedema (15.0%), blood creatinine increased (11.3%), lipase increased (8.1%), nausea (8.1%), ALT increased (6.3%), fatigue (5.6%), amylase increased (5.0%), vomiting (5.0%), dyspnoea (3.8%), blood bilirubin increased (3.1%) and AST increased (3.1%).

Dose reductions were reported in 49 of 160 patients (30.6%). Adverse reactions requiring dose reductions included peripheral oedema (16.3%), ALT increased (5.0%), blood creatinine increased (3.8%), fatigue (3.1%) and nausea (2.5%).

Permanent discontinuation was reported in 19 of 160 patients (11.9%). The most frequent adverse reactions leading to permanent discontinuation of Tabrecta were ILD/pneumonitis (3.8%), peripheral oedema (2.5%), ALT increased (1.3%), AST increased (1.3%), blood bilirubin increased (1.3%), blood creatinine increased (1.3%), lipase increased (1.3%), amylase increased (0.6%), fatigue (0.6%) and urticaria (0.6%).

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. The frequencies of adverse reactions are based on all-cause adverse event frequencies identified in 160 patients with METex14 skipping mutations exposed to capmatinib at the recommended dose, whereas frequencies for changes in laboratory parameters are based on worsening from baseline shifts by at least 1 grade (grading according to CTCAE version 4.03). The safety profile for all GEOMETRY mono-1 patients (N=373) and for patients with METex14 skipping mutations (N=160) is comparable. The median duration of exposure to capmatinib across MET-mutated cohorts was 34.9 weeks (range: 0.4 to 195.7 weeks). Among patients who received capmatinib, 55.0% were exposed for at least 6 months and 36.3% 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.

Table 3. Adverse reactions in patients (N=160) harbouring METex14 skipping mutations in study GEOMETRY mono-1 (Data cut-off: 30-Aug-2021):

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 Fatigue includes PTs of fatigue and asthenia.
⁵ 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.
Cases of acute kidney injury (n=1), renal failure (n=4) and acute pancreatitis (n=1) were reported in GEOMETRY mono-1 MET-amplified patients.

Description of selected adverse reactions

ILD/pneumonitis

Any grade ILD/pneumonitis was reported in 12 of 160 patients (7.5%). Grade 3 ILD/pneumonitis was reported in 7 patients (4.4%), with one fatal event of treatment-related pneumonitis (0.6%) and one fatal event of organising pneumonia (0.6%). ILD/pneumonitis occurred in 6 of 63 patients (9.5%) with a history of prior radiotherapy and 6 of 97 patients (6.2%) who did not receive prior radiotherapy. Six patients (3.8%) discontinued Tabrecta due to ILD/pneumonitis. ILD/pneumonitis mostly occurred within approximately the first 3 months of treatment. The median time-to-onset of grade 3 or higher ILD/pneumonitis was 7.0 weeks (range: 0.7 to 88.4 weeks).

Hepatic effects

Any grade ALT/AST elevations were reported in 24 of 160 patients (15.0%). Grade 3 or 4 ALT/AST elevations were observed in 13 of 160 patients (8.1%) treated with Tabrecta. Two patients (1.3%) discontinued Tabrecta due to ALT/AST elevations. ALT/AST elevations mostly occurred within approximately the first 3 months of treatment. The median time-to-onset of grade 3 or higher ALT/AST elevations was 6.4 weeks (range: 2.1 to 17.9 weeks).

Elevations of pancreatic enzymes

Any grade amylase/lipase elevations were reported in 27 of 160 patients (16.9%). Grade 3 or 4 amylase/lipase elevations were reported in 18 of 160 patients (11.3%) treated with Tabrecta. Three patients (1.9%) discontinued Tabrecta due to amylase/lipase elevations. The median time to onset of grade 3 or higher amylase/lipase elevations was 10.1 weeks (range: 2.3 to 68.0 weeks).

Peripheral oedema

Any grade peripheral oedema was reported in 108 of 160 patients (67.5%). This adverse reaction includes the PTs of peripheral oedema, which was the most frequent at 65.0% and peripheral swelling which occurred in 4.4% of patients. Grade 3 or 4 peripheral oedema was reported in 23 of 160 patients (14.4%) treated with Tabrecta. Four patients (2.5%) discontinued Tabrecta due to peripheral oedema. The median time to onset of grade 3 or higher peripheral oedema was 24.3 weeks (range: 1.4 to 86.9 weeks).

Special populations

Elderly

Of the 160 patients with METex14 skipping mutations in the GEOMETRY mono-1 study who received 400 mg capmatinib twice daily, 85% were 65 years or older, and 4.4% were 85 years or older. The occurrence of grade ≥3 events increased with age. Treatment-related serious events were more frequent in patients aged ≥65 to <75 years (22%) and those aged ≥85 years (28.6%) when compared to those patients aged ≥75 to <85 years (8.5%) and patients younger than 65 years (8.3%), although this comparison is limited by the small sample size in patients aged ≥85 years.

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.

Not applicable.