Capmatinib Side Effects and Dosage
The recommended dosage of capmatinib is 400 mg orally twice daily with or without food, and the most common side effects include peripheral edema, nausea, vomiting, increased blood creatinine, and fatigue, with serious concerns for hepatotoxicity, pleural effusion, and interstitial lung disease requiring close monitoring. 1
Recommended Dosage
Standard dosing is 400 mg twice daily (BID) taken orally as tablets. 1, 2 The medication can be taken with or without food, as pharmacokinetic studies demonstrate that food intake minimally impacts exposure levels 2, 3. When taken with food, the median time to maximum concentration (Tmax) is 4.0-5.6 hours 2.
Dose Modifications
- For hepatic impairment: Dose reduction is recommended, though capmatinib can be used across all levels of hepatic impairment without absolute contraindication 3
- For intolerance: Consider dose reduction to 300 mg BID if patients experience significant adverse events 2
- Drug interactions: Reduce to lower doses when combined with strong CYP3A4 inhibitors (similar principles apply as with other tyrosine kinase inhibitors) 4
The drug accumulation at steady state is low (geometric mean accumulation ratio 1.29-1.69), minimizing risk of toxicity from drug buildup 2.
Common Side Effects (Occurring in >25% of patients)
The most frequently reported adverse events include:
- Peripheral edema (31-53% of patients) 5, 6, 7
- Nausea (34-42% of patients) 2, 6, 7
- Increased blood creatinine (53% in Japanese cohort) 5
- Fatigue/Asthenia (37%) 2
- Vomiting (31-35%) 2, 6
- Decreased appetite 6
- Diarrhea 6
Most of these events are grade 1-2 severity and manageable with supportive care 5.
Serious and Organ-Specific Adverse Events
Respiratory Complications
Capmatinib demonstrates a distinct respiratory adverse event profile compared to other MET inhibitors:
- Pleural effusion - significant signal identified in post-marketing surveillance 8
- Pulmonary edema 8
- Interstitial lung disease - requires immediate evaluation and potential drug discontinuation 8
This contrasts with tepotinib, which shows more infectious respiratory complications 8. Monitor patients closely for dyspnea, cough, or respiratory deterioration.
Hepatotoxicity
Severe liver injury can occur and may require aggressive intervention. 9 Grade 3-4 hepatotoxicity has been documented, with one case report demonstrating grade 4 liver injury requiring treatment with N-acetylcysteine (NAC) plus ursodeoxycholic acid (ursodiol) when drug discontinuation alone was insufficient 9.
Monitoring strategy:
- Obtain baseline liver function tests
- Monitor liver enzymes regularly during treatment
- If grade 3-4 elevation occurs: hold drug until recovery to grade 1, then consider resuming at reduced dose
- Consider NAC plus ursodiol for severe cases not responding to drug discontinuation 9
Cardiovascular and Thrombotic Events
Novel signals identified beyond the drug label include:
These require baseline cardiovascular assessment and ongoing monitoring, particularly in patients with pre-existing cardiac risk factors.
Neurological Effects
Sensory disturbances represent a newly identified signal not currently in the drug label 8. Monitor patients for:
- Changes in sensation
- Peripheral neuropathy symptoms
- Visual or auditory changes
Gastrointestinal Disorders
Beyond nausea and vomiting, comprehensive gastrointestinal adverse events are common 7. Taking capmatinib with food may reduce gastrointestinal symptoms 2.
Renal Effects
Increased blood creatinine is very common (53% in Japanese patients) 5, though this is typically reversible and does not require dose adjustment in most cases. Unlike some other agents, capmatinib does not require specific renal dose adjustments 3.
Drug Interactions
Capmatinib is an inhibitor of P-glycoprotein (P-gp) and BCRP transporters, creating clinically relevant drug-drug interaction potential. 10
Specific interactions documented:
- Digoxin exposure increased by 47% (AUC) and 74% (Cmax) when co-administered 10
- Rosuvastatin exposure increased by 108% (AUC) and 204% (Cmax) when co-administered 10
Avoid or dose-reduce P-gp and BCRP substrates (including digoxin, rosuvastatin, and other statins) when using capmatinib. If combination is necessary, monitor closely for toxicity of the co-administered drug.
Monitoring Requirements
Establish this monitoring schedule:
- Baseline: Complete blood count, comprehensive metabolic panel including liver function tests, creatinine, cardiovascular assessment
- During treatment:
- Liver function tests monthly initially, then as clinically indicated
- Renal function monitoring (creatinine)
- Assessment for peripheral edema at each visit
- Respiratory symptom evaluation at each visit
- For drug interactions: Monitor levels of co-administered P-gp/BCRP substrates
Clinical Pearls
- Capmatinib has faster absorption and clearance compared to other MET inhibitors, reducing accumulation risk 3
- Brain metastases: Capmatinib demonstrates marked efficacy for CNS disease due to lipophilicity and permeability 3
- No food restrictions: Unlike some targeted therapies, capmatinib can be taken with or without food, improving adherence 2, 3
- Dose-limiting toxicities are rare: In phase I studies, only 2 DLTs occurred (suicidal ideation and depression), both at higher doses 6
When to Discontinue
Permanently discontinue capmatinib for:
- Confirmed interstitial lung disease
- Grade 4 hepatotoxicity not responding to dose interruption and supportive care
- Severe hypersensitivity reactions
- Intolerable grade 3 adverse events despite dose reduction
Temporarily hold for:
- Grade 3 hepatotoxicity (resume at reduced dose when recovered to grade 1)
- Symptomatic pleural effusion requiring intervention
- Grade 3-4 non-hematologic toxicities until improvement