Tabrecta
(capmatinib)Dosage & Administration
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Tabrecta Prescribing Information
TABRECTA is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test.
Patient Selection
Select patients for treatment with TABRECTA based on the presence of a mutation that leads to MET exon 14 skipping in tumor or plasma specimens [see Clinical Studies (14)]. If a mutation that leads to MET exon 14 skipping is not detected in a plasma specimen, test tumor tissue if feasible. Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics.
Recommended Dosage
The recommended dosage of TABRECTA is 400 mg orally twice daily with or without food.
Swallow TABRECTA tablets whole. Do not break, crush or chew the tablets.
If a patient misses or vomits a dose, instruct the patient not to make up the dose, but to take the next dose at its scheduled time.
Dosage Modifications for Adverse Reactions
The recommended dose reductions for the management of adverse reactions are listed in Table 1.
| Dose reduction | Dose and schedule |
| First | 300 mg orally twice daily |
| Second | 200 mg orally twice daily |
Permanently discontinue TABRECTA in patients who are unable to tolerate 200 mg orally twice daily.
The recommended dosage modifications of TABRECTA for adverse reactions are provided in Table 2.
| Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ILD, interstitial lung disease; ULN, upper limit of normal. Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. | ||
| Adverse reaction | Severity | Dosage modification |
| Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.1)] | Any grade | Permanently discontinue TABRECTA. |
| Increased ALT and/or AST without increased total bilirubin [see Warnings and Precautions (5.2)] | Grade 3 | Withhold TABRECTA until recovery to baseline ALT/AST. If recovered to baseline within 7 days, then resume TABRECTA at the same dose; otherwise resume TABRECTA at a reduced dose. |
| Grade 4 | Permanently discontinue TABRECTA. | |
| Increased ALT and/or AST with increased total bilirubin in the absence of cholestasis or hemolysis [see Warnings and Precautions (5.2)] | ALT and/or AST greater than 3 times ULN with total bilirubin greater than 2 times ULN | Permanently discontinue TABRECTA. |
| Increased total bilirubin without concurrent increased ALT and/or AST [see Warnings and Precautions (5.2)] | Grade 2 | Withhold TABRECTA until recovery to baseline bilirubin. If recovered to baseline within 7 days, then resume TABRECTA at the same dose; otherwise resume TABRECTA at a reduced dose. |
| Grade 3 | Withhold TABRECTA until recovery to baseline bilirubin. If recovered to baseline within 7 days, then resume TABRECTA at a reduced dose; otherwise permanently discontinue TABRECTA. | |
| Grade 4 | Permanently discontinue TABRECTA. | |
| Increased lipase or amylase [see Warnings and Precautions (5.3)] | Grade 3 | Withhold TABRECTA until ≤ Grade 2 or baseline. If recovered to baseline or ≤ Grade 2 within 14 days, resume TABRECTA at a reduced dose; otherwise permanently discontinue TABRECTA. |
| Grade 4 | Permanently discontinue TABRECTA. | |
| Pancreatitis [see Warnings and Precautions (5.3)] | Grade 3 or Grade 4 | Permanently discontinue TABRECTA. |
| Hypersensitivity [see Warnings and Precautions (5.4)] | All Grades | If hypersensitivity is suspected based on clinical judgment, withhold TABRECTA until resolution of the event. Permanently discontinue TABRECTA in patients who develop serious hypersensitivity reactions. |
| Other adverse reactions [see Adverse Reactions (6.1)] | Grade 2 | Maintain dose level. If intolerable, consider withholding TABRECTA until resolved, then resume TABRECTA at a reduced dose. |
| Grade 3 | Withhold TABRECTA until resolved, then resume TABRECTA at a reduced dose. | |
| Grade 4 | Permanently discontinue TABRECTA. | |
Tablets:
- 150 mg: pale orange brown, ovaloid, curved film-coated with beveled edges, unscored, debossed with ‘DU’ on one side and ‘NVR’ on the other side
- 200 mg: yellow, ovaloid, curved film-coated with beveled edges, unscored, debossed with ‘LO’ on one side and ‘NVR’ on the other side
Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], TABRECTA can cause fetal harm when administered to a pregnant woman. There are no available data on TABRECTA use in pregnant women. Oral administration of capmatinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at maternal exposures less than the human exposure based on AUC at the 400 mg twice daily clinical dose (see Data). Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
In rats, maternal toxicity (reduced body weight gain and food consumption) occurred at 30 mg/kg/day (approximately 1.4 times the human exposure based on AUC at the 400 mg twice daily clinical dose). Fetal effects included reduced fetal weights, irregular/incomplete ossification, and increased incidences of fetal malformations (e.g., abnormal flexure/inward malrotation of hindpaws/forepaws, thinness of forelimbs, lack of/reduced flexion at the humerus/ulna joints, and narrowed or small tongue) at doses of ≥ 10 mg/kg/day (approximately 0.6 times the human exposure based on AUC at the 400 mg twice daily clinical dose).
In rabbits, no maternal effects were detected at doses up to 60 mg/kg/day (approximately 1.5 times the human exposure based on AUC at the 400 mg twice daily clinical dose). Fetal effects included small lung lobe at ≥ 5 mg/kg/day (approximately 0.016 times the human exposure based on AUC at the 400 mg twice daily clinical dose), and reduced fetal weights, irregular/incomplete ossification and increased incidences of fetal malformations (e.g., abnormal flexure/malrotation of hindpaws/forepaws, thinness of forelimbs/hindlimbs, lack of/reduced flexion at the humerus/ulna joints, small lung lobes, narrowed or small tongue) at the dose of 60 mg/kg/day.
Lactation
Risk Summary
There are no data on the presence of capmatinib or its metabolites in either human or animal milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with TABRECTA and for 1 week after the last dose.
Females and Males of Reproductive Potential
Based on animal data, TABRECTA can cause malformations at doses less than the human exposure based on AUC at the 400 mg twice daily clinical dose [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify pregnancy status for females of reproductive potential prior to starting treatment with TABRECTA.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with TABRECTA and for 1 week after the last dose.
Males
Advise males with female partners of reproductive potential to use effective contraception during treatment with TABRECTA and for 1 week after the last dose.
Pediatric Use
Safety and effectiveness of TABRECTA in pediatric patients have not been established.
Geriatric Use
In GEOMETRY mono-1, 61% of the 373 patients were 65 years or older and 18% were 75 years or older. No overall differences in the safety or effectiveness were observed between these patients and younger patients.
Renal Impairment
No dosage adjustment is recommended in patients with mild (baseline creatinine clearance [CLcr] 60 to 89 mL/min by Cockcroft-Gault) or moderate renal impairment (CLcr 30 to 59 mL/min) [see Clinical Pharmacology (12.3)]. TABRECTA has not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min).
None.
Interstitial Lung Disease (ILD)/Pneumonitis
ILD/pneumonitis, which can be fatal, occurred in patients treated with TABRECTA [see Adverse Reactions (6.1)]. ILD/pneumonitis occurred in 4.8% of patients treated with TABRECTA 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 TABRECTA 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 TABRECTA in patients with suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified [see Dosage and Administration (2.3)].
Hepatotoxicity
Hepatotoxicity occurred in patients treated with TABRECTA [see Adverse Reactions (6.1)]. Increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST) occurred in 15% of patients treated with TABRECTA in GEOMETRY mono-1. Grade 3 or 4 increased ALT/AST occurred in 7% of patients. Three patients (0.8%) discontinued TABRECTA 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 TABRECTA, 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 TABRECTA [see Dosage and Administration (2.3)].
Pancreatic Toxicity
Elevations in amylase and lipase levels occurred in patients treated with TABRECTA [see Adverse Reactions (6.1)]. Increased amylase/lipase occurred in 14% of patients treated with TABRECTA 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 TABRECTA 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%); TABRECTA was permanently discontinued for this event.
Monitor amylase and lipase at baseline and regularly during treatment with TABRECTA. Based on the severity of the adverse reaction, temporarily withhold, dose reduce, or permanently discontinue TABRECTA [see Dosage and Administration (2.3)].
Hypersensitivity Reactions
Serious hypersensitivity reactions occurred in patients treated with TABRECTA in clinical trials other than GEOMETRY mono-1 [see Adverse Reactions (6.1)]. 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 TABRECTA [see Dosage and Administration (2.3)].
Risk of Photosensitivity
Based on findings from animal studies, there is a potential risk of photosensitivity reactions with TABRECTA [see Nonclinical Toxicology (13.2)]. 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 TABRECTA. Advise patients to limit direct ultraviolet exposure during treatment with TABRECTA.
Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, TABRECTA 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 TABRECTA and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TABRECTA and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)].