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Precautions of Capmatinib

1.Interstitial Lung Disease (ILD)/Pneumonitis

ILD/pneumonitis, which can be fatal, occurred in patients treated with Capmatinib. ILD/pneumonitis occurred in 4.8% of patients treated with Capmatinib in GEOMETRY mono-1, with 1.9% of patients experiencing Grade 3 ILD/pneumonitis and one patient experiencing death (0.3%). Nine patients (2.4%) discontinued Capmatinib due to ILD/pneumonitis. The median time-to-onset of Grade 3 or higher ILD/pneumonitis was 1.8 months (range: 0.2 months to 1.7 years).

Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold Capmatinib in patients with suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified.

2.Hepatotoxicity

Hepatotoxicity occurred in patients treated with Capmatinib. Increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST) occurred in 15% of patients treated with Capmatinib in GEOMETRY mono-1. Grade 3 or 4 increased ALT/AST occurred in 7% of patients. Three patients (0.8%) discontinued Capmatinib due to increased ALT/AST. The median time-to-onset of Grade 3 or higher increased ALT/AST was 1.8 months (range: 0.5 to 46.4 months).

Monitor liver function tests (including ALT, AST, and total bilirubin) prior to the start of Capmatinib, 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 increased transaminases or bilirubin. Based on the severity of the adverse reaction, withhold, dose reduce, or permanently discontinue Capmatinib.

3.Pancreatic Toxicity

Elevations in amylase and lipase levels occurred in patients treated with Capmatinib. Increased amylase/lipase occurred in 14% of patients treated with Capmatinib in GEOMETRY mono-1. Grade 3 and 4 increased amylase/lipase occurred in 7% and 1.9% of patients, respectively. Three patients (0.8%) discontinued Capmatinib due to increased amylase/lipase. The median time-to-onset of Grade 3 or higher increased amylase/lipase was 2 months (range: 0.03 to 31.1 months). Pancreatitis (Grade 3) occurred in one patient (0.3%); Capmatinib was permanently discontinued for this event.

Monitor amylase and lipase at baseline and regularly during treatment with Capmatinib. Based on the severity of the adverse reaction, temporarily withhold, dose reduce, or permanently discontinue Capmatinib.

4.Hypersensitivity Reactions

Serious hypersensitivity reactions occurred in patients treated with Capmatinib in clinical trials other than GEOMETRY mono-1. Signs and symptoms of hypersensitivity included pyrexia, chills, pruritus, rash, decreased blood pressure, nausea and vomiting. Based on the severity of the adverse reaction, temporarily withhold or permanently discontinue Capmatinib.

5.Risk of Photosensitivity

Based on findings from animal studies, there is a potential risk of photosensitivity reactions with Capmatinib. In GEOMETRY mono-1, it was recommended that patients use precautionary measures against ultraviolet exposure such as use of sunscreen or protective clothing during treatment with Capmatinib. Advise patients to limit direct ultraviolet exposure during treatment with Capmatinib.

6.Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, Capmatinib can cause fetal harm when administered to a pregnant woman. Oral administration of capmatinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at exposures less than the human exposure based on area under the curve (AUC) at the 400 mg twice daily clinical dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Capmatinib and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Capmatinib and for 1 week after the last dose.

from FDA,2023.03