Capmatinib (Monograph)

Brand name: Tabrecta
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Aug 25, 2023. Written by ASHP.

[Web]

Introduction

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

Uses for Capmatinib

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 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

Oral

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

Hepatic Toxicity

Oral

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

Oral

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

Oral

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

Oral

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.

Cautions for Capmatinib

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.

Drug Interactions

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

Capmatinib Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations are attained in approximately 1–2 hours.

Steady-state concentrations are achieved within 3 days; median accumulation ratio is 1.5.

Estimated absorption of a single 400-mg oral dose is >70%.

Systemic exposure increases in a dose-proportional manner over dosage range of 200–400 mg twice daily.

Food

High-fat meal increased capmatinib AUC by 46% but did not affect peak plasma concentration; low-fat meal did not substantially alter exposure. In cancer patients receiving capmatinib 400 mg twice daily, exposure was similar whether administered in fed or fasted state.

Distribution

Extent

Crosses the blood-brain barrier.

Not known whether distributed into human milk.

Plasma Protein Binding

96%; independent of drug concentration.

Elimination

Metabolism

Metabolized mainly by CYP3A4 and aldehyde oxidase.

Elimination Route

Eliminated in feces (78%) and urine (22%); unchanged drug accounted for 42% of dose recovered in feces and negligible amount in urine.

Half-life

Elimination half-life: 6.5 hours.

Special Populations

Mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C) does not affect pharmacokinetics.

Mild or moderate renal impairment (Cl_cr 30–89 mL/minute) does not affect pharmacokinetics.

Severe renal impairment (Cl_cr <30 mL/minute): Pharmacokinetics not studied.

Age, sex, race, and body weight do not affect pharmacokinetics.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C). Protect from moisture; dispense in original package with desiccant. Discard any unused tablets 6 weeks after first opening the bottle.

Actions

• Potent and selective inhibitor of mesenchymal-epithelial transition (MET) receptor tyrosine kinase.

• Activation of MET tyrosine kinase, occurring through overexpression, MET amplification, or MET exon 14 skipping mutation, is thought to initiate a cascade of intracellular signaling events leading to cell proliferation and influencing processes critical to cell survival and tumor progression (e.g., angiogenesis, apoptosis, metastasis).

• MET exon 14 skipping mutations identified in approximately 2–4% of patients with NSCLC.

• Inhibits MET phosphorylation caused by binding of hepatocyte growth factor or by MET amplification, resulting in downregulation of downstream MET signaling proteins and inhibition of proliferation and survival of MET-dependent tumor cells.

Advice to Patients

• Importance of advising patients to take capmatinib exactly as prescribed and of not altering the dosage or discontinuing the therapy unless advised to do so by their clinician.

• Importance of advising patients to swallow capmatinib tablets whole and not to chew, crush, or split the tablets. If a dose is missed or if vomiting occurs after a dose is administered, the next dose should be taken at the regularly scheduled time; the missed dose should not be taken, and an additional dose should not be administered to replace the vomited dose.

• Risk of ILD/pneumonitis. Importance of immediately informing clinician if new or worsening respiratory symptoms (e.g., dyspnea, cough) or fever occurs.

• Risk of hepatotoxicity; importance of liver function test monitoring. Importance of advising patients to immediately report possible symptoms of hepatotoxicity (e.g., jaundice, dark or “tea-colored” urine, right upper quadrant pain, light-colored stool, decreased appetite, nausea, vomiting, weakness, fatigue, confusion) to their clinician.

• Risk of pancreatic toxicity; inform patients of the need for lab testing to monitor pancreatic function. Advise patients to immediately inform their clinician if signs and symptoms of pancreatitis occur.

• Risk of hypersensitivity reactions. Advise patients to stop taking capmatinib and immediately contact their clinician if signs and symptoms (e.g., pyrexia, chills, pruritus, rash, decreased blood pressure, nausea and vomiting) of hypersensitivity occur.

• Possibility of photosensitivity reactions; importance of using protective measures (e.g., wearing protective clothing, using sunscreen) and limiting direct exposure to UV light during capmatinib therapy.

• Risk of fetal harm. Necessity of advising women of reproductive potential and men who are partners with such women that they should use effective contraceptive methods while receiving the drug and for 1 week after the last dose. Importance of patients informing their clinicians if they or their partners are pregnant or think they may be pregnant. If pregnancy occurs, advise patient of potential risk to fetus.

• Importance of advising women to avoid breast-feeding while receiving capmatinib therapy and for 1 week after the last dose.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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Frequently asked questions

• How effective is Tabrecta?

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