Precautions of Capmatinib

Healthcare professionals and patients must carefully read and fully understand the following precautions before initiating treatment, which contain critical safety information and essential clinical management guidelines.

Interstitial Lung Disease/Pneumonitis

Patients treated with capmatinib may develop fatal interstitial lung disease (ILD)/pneumonitis. In the GEOMETRY mono-1 study, ILD/pneumonitis occurred in 4.8% of patients receiving capmatinib, including 1.9% of patients with grade 3 ILD/pneumonitis and 1 patient (0.3%) who died from the condition. Nine patients (2.4%) discontinued capmatinib due to ILD/pneumonitis.

Patients should be monitored for the emergence or worsening of pulmonary symptoms suggestive of ILD/pneumonitis (e.g., dyspnea, cough, fever). Capmatinib should be immediately withheld in patients with suspected ILD/pneumonitis; permanent discontinuation of capmatinib is required if no other underlying cause is identified.

Hepatotoxicity

Hepatotoxicity may occur in patients treated with capmatinib. In the GEOMETRY mono-1 study, elevations in alanine aminotransferase (ALT)/aspartate aminotransferase (AST) were observed in 15% of patients receiving capmatinib. Grade 3 or 4 ALT/AST elevations occurred in 7% of patients. Three patients (0.8%) discontinued capmatinib due to ALT/AST elevations.

Liver function tests (including ALT, AST, and total bilirubin) should be monitored before the initiation of capmatinib, every 2 weeks during the first 3 months of treatment, monthly thereafter, or as clinically indicated. For patients with elevated transaminases or bilirubin, the frequency of monitoring should be increased. Capmatinib should be withheld, dose-reduced, or permanently discontinued based on the severity of the adverse reaction.

Pancreatic Toxicity

Elevations in amylase and lipase levels may occur in patients treated with capmatinib. In the GEOMETRY mono-1 study, amylase/lipase elevations were reported in 14% of patients receiving capmatinib. Grade 3 or 4 amylase elevations and lipase elevations occurred in 7% and 1.9% of patients, respectively. Three patients (0.8%) discontinued capmatinib due to amylase/lipase elevations. One patient (0.3%) developed pancreatitis (grade 3), which resulted in permanent discontinuation of capmatinib.

Amylase and lipase levels should be monitored at baseline and periodically during capmatinib treatment. Capmatinib should be temporarily withheld, dose-reduced, or permanently discontinued based on the severity of the adverse reaction.

Hypersensitivity Reactions

Severe hypersensitivity reactions have been reported in patients treated with capmatinib in clinical trials outside of GEOMETRY mono-1. Signs and symptoms of hypersensitivity reactions include fever, chills, pruritus, rash, hypotension, nausea, and vomiting. Capmatinib should be temporarily withheld or permanently discontinued based on the severity of the adverse reaction.

Risk of Photosensitivity Reaction

Based on animal studies, capmatinib has the potential to cause photosensitivity reactions. In the GEOMETRY mono-1 study, patients were advised to take sun protection measures (e.g., using sunscreen or wearing protective clothing) during capmatinib treatment. Patients are recommended to limit direct exposure to ultraviolet (UV) light while receiving capmatinib.

Embryo-Fetal Toxicity

Based on animal study findings and its mechanism of action, capmatinib may cause fetal harm if administered to pregnant women. Pregnant women should be informed of the potential risk to the fetus. Females of reproductive potential are advised to use effective contraception during capmatinib treatment and for 1 week after the last dose. Males with female partners of reproductive potential are advised to use effective contraception during capmatinib treatment and for 1 week after the last dose.

Most Common Adverse Reactions

The most common adverse reactions (incidence ≥ 20%) were: edema (59%), nausea (46%), musculoskeletal pain (40%), fatigue (34%), vomiting (28%), dyspnea (25%), cough (21%), and decreased appetite (21%). The most common grade 3 adverse reactions (incidence ≥ 2%) were: edema (13%), fatigue (8%), dyspnea (7%), pneumonitis (6%), musculoskeletal pain (4.3%), nausea (2.4%), and vomiting (2.4%). Grade 4 dyspnea and pneumonitis were reported in 0.5% of patients, respectively.

Clinically Relevant Adverse Reactions

Clinically relevant adverse reactions observed in < 10% of patients included: pruritus (including allergic pruritus), interstitial lung disease/pneumonitis, cellulitis, acute kidney injury (including renal failure), urticaria, and acute pancreatitis.

Laboratory Abnormalities

Selected laboratory abnormalities that worsened from baseline (incidence ≥ 20%) in patients receiving capmatinib included: decreased albumin (72%), increased creatinine (65%), decreased lymphocytes (45%), increased ALT (39%), increased amylase (34%), increased alkaline phosphatase (32%), increased gamma-glutamyl transferase (30%), increased lipase (29%), increased AST (28%), decreased phosphate (26%), decreased leukocytes (25%), increased potassium (25%), decreased hemoglobin (24%), decreased sodium (24%), and decreased glucose (23%).

from FDA,2023.03