[Web]

Introduction

Antineoplastic agent; a mesenchymal-epithelial transition (MET) tyrosine kinase inhibitor.

Uses for Capmatinib (Systemic)

Non-small Cell Lung Cancer (NSCLC)

Treatment of metastatic NSCLC in adults whose tumors harbor a MET exon 14 skipping mutation as detected by an FDA-approved companion diagnostic test (designated an orphan drug by FDA for this use). Information on FDA-approved companion diagnostic tests for the detection of MET mutations in NSCLC is available at FDA's website ([Web]). Current indication is based on objective response rate and duration of response; continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory studies.

Capmatinib (Systemic) Dosage and Administration

General

Pretreatment Screening

• Confirmation of MET exon 14 skipping mutation in tumor or plasma specimens from patients with metastatic NSCLC is necessary prior to initiating therapy.

• Liver function tests, including ALT, AST, and total bilirubin concentrations, prior to initiation of therapy.

• Pregnancy test in females of reproductive potential.

• Monitor amylase and lipase at baseline.

Patient Monitoring

• Monitor patients for pulmonary symptoms indicative of interstitial lung disease or pneumonitis.

• Monitor liver function tests, including ALT, AST, and total bilirubin concentrations, every 2 weeks during the first 3 months of therapy, monthly thereafter, and as clinically indicated. More frequent testing necessary if increased aminotransferase or total bilirubin concentrations occur.

• Monitor amylase and lipase regularly during treatment.

• Monitor patients for signs and symptoms of hypersensitivity reactions (e.g., pyrexia, chills, pruritus, rash, decreased blood pressure, nausea, vomiting) during treatment.

Dispensing and Administration Precautions

Based on the Institute for Safe Medication Practices (ISMP), capmatinib is a high-alert mediation that has a heightened risk of causing significant patient harm when used in error.

Other General Considerations

• Avoid unnecessary or excessive exposure to sunlight or artificial UV light (e.g., tanning beds, UVA/UVB treatment) during capmatinib therapy. Protective measures (e.g., sunscreen, protective clothing) recommended.

Administration

Oral Administration

Administer orally twice daily without regard to meals. Swallow tablets whole; do not break, crush, or chew.

If a dose is missed or vomited, do not double the dose or administer extra doses. Administer the next dose at the regularly scheduled time.

Dosage

Available as capmatinib hydrochloride; dosage expressed in terms of capmatinib.

Adults

NSCLC

Oral

400 mg twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Oral

Temporary interruption of therapy, dosage reduction, and/or discontinuance of the drug may be necessary for adverse reactions.

If dosage reduction is required, reduce dosage as described in Table 1.

Pulmonary Effects

If interstitial lung disease or pneumonitis occurs, permanently discontinue capmatinib.

Hepatic Toxicity

If grade 3 elevations in ALT or AST concentrations (without elevated total bilirubin concentrations) occur, interrupt therapy until recovery to baseline values. If recovery occurs within 7 days, may resume capmatinib at the same dosage. If recovery is delayed beyond 7 days, may resume capmatinib at next lower dosage.

If grade 4 elevations in ALT or AST concentrations (without elevated total bilirubin concentrations) occur, permanently discontinue capmatinib.

If ALT or AST concentrations >3 times the ULN with total bilirubin concentrations >2 times the ULN (without cholestasis or hemolysis) occur, permanently discontinue capmatinib.

If grade 2 elevations in total bilirubin concentrations (without elevated ALT and/or AST concentrations) occur, interrupt therapy until recovery to baseline values. If recovery occurs within 7 days, may resume capmatinib at the same dosage. If recovery is delayed beyond 7 days, may resume capmatinib at next lower dosage.

If grade 3 elevations in total bilirubin concentrations (without elevated ALT and/or AST concentrations) occur, interrupt therapy until recovery to baseline values. If recovery occurs within 7 days, may resume capmatinib at next lower dosage. Otherwise, permanently discontinue capmatinib.

If grade 4 elevations in total bilirubin concentrations (without elevated ALT and/or AST concentrations) occur, permanently discontinue capmatinib.

Pancreatic Toxicity

Permanently discontinue if grade 3 or 4 pancreatitis occur.

If grade 4 elevations of lipase or amylase occur, permanently discontinue capmatinib therapy. If grade 3 elevations of lipase or amylase occur, withhold capmatinib until lipase and/or amylase elevations return to ≤ grade 2 or baseline. If recovered to baseline or ≤ grade 2 within 14 days, may resume capmatinib at a reduced dose; otherwise permanently discontinue.

Hypersensitivity

If any grade of hypersensitivity is suspected based on clinical judgment, withhold until resolution of the event. Permanently discontinue in patients who develop serious hypersensitivity reactions.

Other Toxicity

If any other grade 2 adverse reaction occurs, may continue capmatinib at the same dosage. If grade 2 adverse reaction is intolerable, consider interrupting therapy. When the toxicity resolves, may resume capmatinib at next lower dosage.

If any other grade 3 adverse reaction occurs, interrupt therapy. When the toxicity resolves, may resume capmatinib at next lower dosage.

If any other grade 4 adverse reaction occurs, permanently discontinue capmatinib.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

Mild to moderate renal impairment (Cl_cr 30–89 mL/minute): No dosage adjustment required.

Severe renal impairment (Cl_cr <30 mL/minute): No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Sensitivity Reactions

Photosensitivity Reactions

Risk of photosensitivity reactions.

Patient should avoid unnecessary or excessive exposure to sunlight or artificial UV light (e.g., tanning beds, UVA/UVB treatment) during capmatinib therapy. Protective measures (e.g., sunscreen, protective clothing) recommended.

Pulmonary Effects

Interstitial lung disease (ILD)/pneumonitis reported in 4.8% of patients in the principal efficacy trial; ILD/pneumonitis was grade 3 in 1.9% of patients and fatal in one patient. Permanent discontinuance required because of ILD/pneumonitis in 2.4% of patients. Onset of grade 3 or greater ILD/pneumonitis occurred at a median of 1.8 months (range: approximately 6 days to 1.7 years) after therapy initiation.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. If ILD/pneumonitis suspected, immediately withhold therapy; permanently discontinue capmatinib if no other potential etiology identified.

Hepatic Toxicity

Hepatotoxicity reported. ALT or AST elevations reported in 15% of patients in the principal efficacy trial; grade 3 or 4 ALT or AST elevations reported in 7% of patients, and permanent discontinuance of therapy required because of ALT or AST elevations in 0.8% of patients. Median time to onset of grade 3 or greater ALT or AST elevations was 1.8 months (range: 0.5–46.4 months).

Monitor liver function tests, including ALT, AST, and total bilirubin, prior to initiating capmatinib, every 2 weeks during the first 3 months of therapy, monthly thereafter, and as clinically indicated. More frequent testing necessary in patients who develop aminotransferase or total bilirubin elevations.

If hepatic toxicity occurs, temporary interruption, dosage reduction, or discontinuance of capmatinib may be necessary.

Pancreatic Toxicity

Elevations in amylase and lipase levels occurred in patients treated with capmatinib. In the principal efficacy trial, increased amylase/lipase occurred in 14% of patients; grade 3 and 4 increased amylase/lipase occurred in 7% and 1.9% of patients, respectively, and 3 patients (0.8%) discontinued the drug due to increased amylase/lipase. Grade 3 pancreatitis occurred in one patient (0.3%) and capmatinib was permanently discontinued for this event.

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

Hypersensitivity Reactions

Serious hypersensitivity reactions reported. 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.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryofetal toxicity (i.e., decreased fetal body weight, incomplete ossification) and teratogenicity (i.e., visceral and skeletal malformations) demonstrated in animals.

Avoid pregnancy during therapy. Perform pregnancy test prior to initiation of capmatinib in women of reproductive potential. Women of reproductive potential and men who are partners of such women should use effective contraceptive methods while receiving the drug and for 1 week after the last dose. If used during pregnancy or if the patient or their partner becomes pregnant during therapy, apprise of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm.

Perform pregnancy test prior to initiation of capmatinib in women of reproductive potential. Women of reproductive potential and men who are partners of such women should use effective contraceptive methods while receiving the drug and for 1 week after the last dose. If used during pregnancy or if the patient or their partner becomes pregnant during therapy, apprise of potential fetal hazard.

Lactation

Not known whether capmatinib is distributed into milk, affects nursing infants, or affects milk production. Women should not breast-feed during therapy and for 1 week after the last dose.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

In the principal efficacy study evaluating capmatinib in patients with metastatic NSCLC, 57% of patients were ≥65 years of age and 16% were ≥75 years of age. No overall differences in safety or efficacy in patients ≥65 years of age compared with younger adults.

Hepatic Impairment

Pharmacokinetics not substantially altered by hepatic impairment.

Renal Impairment

Pharmacokinetics not substantially altered by mild to moderate renal impairment; no dosage adjustment required. Not studied in patients with severe renal impairment.

Common Adverse Effects

Most common adverse reactions (≥20%): edema, nausea, musculoskeletal pain, fatigue, vomiting, dyspnea, cough, decreased appetite.

General

Pretreatment Screening

• Confirmation of MET exon 14 skipping mutation in tumor or plasma specimens from patients with metastatic NSCLC is necessary prior to initiating therapy.

• Liver function tests, including ALT, AST, and total bilirubin concentrations, prior to initiation of therapy.

• Pregnancy test in females of reproductive potential.

• Monitor amylase and lipase at baseline.

Patient Monitoring

• Monitor patients for pulmonary symptoms indicative of interstitial lung disease or pneumonitis.

• Monitor liver function tests, including ALT, AST, and total bilirubin concentrations, every 2 weeks during the first 3 months of therapy, monthly thereafter, and as clinically indicated. More frequent testing necessary if increased aminotransferase or total bilirubin concentrations occur.

• Monitor amylase and lipase regularly during treatment.

• Monitor patients for signs and symptoms of hypersensitivity reactions (e.g., pyrexia, chills, pruritus, rash, decreased blood pressure, nausea, vomiting) during treatment.

Dispensing and Administration Precautions

Based on the Institute for Safe Medication Practices (ISMP), capmatinib is a high-alert mediation that has a heightened risk of causing significant patient harm when used in error.

Other General Considerations

• Avoid unnecessary or excessive exposure to sunlight or artificial UV light (e.g., tanning beds, UVA/UVB treatment) during capmatinib therapy. Protective measures (e.g., sunscreen, protective clothing) recommended.

Administration

Oral Administration

Administer orally twice daily without regard to meals. Swallow tablets whole; do not break, crush, or chew.

If a dose is missed or vomited, do not double the dose or administer extra doses. Administer the next dose at the regularly scheduled time.

Dosage

Available as capmatinib hydrochloride; dosage expressed in terms of capmatinib.

Adults

NSCLC

Oral

400 mg twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Oral

Temporary interruption of therapy, dosage reduction, and/or discontinuance of the drug may be necessary for adverse reactions.

If dosage reduction is required, reduce dosage as described in Table 1.

Pulmonary Effects

If interstitial lung disease or pneumonitis occurs, permanently discontinue capmatinib.

Hepatic Toxicity

If grade 3 elevations in ALT or AST concentrations (without elevated total bilirubin concentrations) occur, interrupt therapy until recovery to baseline values. If recovery occurs within 7 days, may resume capmatinib at the same dosage. If recovery is delayed beyond 7 days, may resume capmatinib at next lower dosage.

If grade 4 elevations in ALT or AST concentrations (without elevated total bilirubin concentrations) occur, permanently discontinue capmatinib.

If ALT or AST concentrations >3 times the ULN with total bilirubin concentrations >2 times the ULN (without cholestasis or hemolysis) occur, permanently discontinue capmatinib.

If grade 2 elevations in total bilirubin concentrations (without elevated ALT and/or AST concentrations) occur, interrupt therapy until recovery to baseline values. If recovery occurs within 7 days, may resume capmatinib at the same dosage. If recovery is delayed beyond 7 days, may resume capmatinib at next lower dosage.

If grade 3 elevations in total bilirubin concentrations (without elevated ALT and/or AST concentrations) occur, interrupt therapy until recovery to baseline values. If recovery occurs within 7 days, may resume capmatinib at next lower dosage. Otherwise, permanently discontinue capmatinib.

If grade 4 elevations in total bilirubin concentrations (without elevated ALT and/or AST concentrations) occur, permanently discontinue capmatinib.

Pancreatic Toxicity

Permanently discontinue if grade 3 or 4 pancreatitis occur.

If grade 4 elevations of lipase or amylase occur, permanently discontinue capmatinib therapy. If grade 3 elevations of lipase or amylase occur, withhold capmatinib until lipase and/or amylase elevations return to ≤ grade 2 or baseline. If recovered to baseline or ≤ grade 2 within 14 days, may resume capmatinib at a reduced dose; otherwise permanently discontinue.

Hypersensitivity

If any grade of hypersensitivity is suspected based on clinical judgment, withhold until resolution of the event. Permanently discontinue in patients who develop serious hypersensitivity reactions.

Other Toxicity

If any other grade 2 adverse reaction occurs, may continue capmatinib at the same dosage. If grade 2 adverse reaction is intolerable, consider interrupting therapy. When the toxicity resolves, may resume capmatinib at next lower dosage.

If any other grade 3 adverse reaction occurs, interrupt therapy. When the toxicity resolves, may resume capmatinib at next lower dosage.

If any other grade 4 adverse reaction occurs, permanently discontinue capmatinib.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

Mild to moderate renal impairment (Cl_cr 30–89 mL/minute): No dosage adjustment required.

Severe renal impairment (Cl_cr <30 mL/minute): No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Metabolized mainly by CYP3A4 and aldehyde oxidase.

In vitro, reversibly inhibits multidrug and toxin extrusion protein (MATE) 1 and 2K, but does not inhibit organic anion transport protein (OATP) 1B1 or 1B3, organic cation transporter (OCT) 1, organic anion transporter (OAT) 1 or 3, or multidrug resistance-associated protein 2 (MRP2). In vitro, a substrate of P-glycoprotein (P-gp); not a substrate of breast cancer resistance protein (BCRP) or MRP2.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible increased systemic exposure to and increased adverse effects of capmatinib. Monitor closely for adverse effects.

Moderate or potent CYP3A inducers: Possible decreased plasma concentrations and decreased efficacy of capmatinib. Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP1A2: Possible increased plasma concentrations of the CYP1A2 substrate and possible adverse effects. Avoid concomitant use of capmatinib and CYP1A2 substrates with narrow therapeutic indices. If such concomitant use cannot be avoided, reduce dosage of substrate drug.

Substrates of CYP3A: No clinically important changes in pharmacokinetics of a sensitive CYP3A substrate.

Substrates of Drug Transport Systems

Substrates of P-gp: Possible increased plasma concentrations of the P-gp substrate and possible adverse effects. Avoid concomitant use of capmatinib and P-gp substrates with narrow therapeutic indices. If such concomitant use cannot be avoided, reduce dosage of substrate drug.

Substrates of BCRP: Possible increased plasma concentrations of the BCRP substrate and possible adverse effects. Avoid concomitant use of capmatinib and BCRP substrates with narrow therapeutic indices. If such concomitant use cannot be avoided, reduce dosage of substrate drug.

Substrates of MATE1 or MATE2K: Possible increased plasma concentrations of the MATE1 or MATE2K substrate and possible adverse effects. Avoid concomitant use of capmatinib and MATE1 or MATE2K substrates with narrow therapeutic indices. If such concomitant use cannot be avoided, reduce dosage of substrate drug.

Specific Drugs