TABRECTA Film-coated tablet Ref.[10096] Active ingredients: Capmatinib

5.1 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 4.5% of patients treated with TABRECTA in GEOMETRY mono-1, with 1.8% of patients experiencing Grade 3 ILD/pneumonitis and one patient experiencing death (0.3%). Eight patients (2.4%) discontinued TABRECTA due to ILD/pneumonitis. The median time-to-onset of Grade 3 or higher ILD/pneumonitis was 1.4 months (range: 0.2 months to 1.2 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)].

5.2 Hepatotoxicity

Hepatotoxicity occurred in patients treated with TABRECTA [see Adverse Reactions (6.1)]. Increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST) occurred in 13% of patients treated with TABRECTA in GEOMETRY mono-1. Grade 3 or 4 increased ALT/AST occurred in 6% of patients. Three patients (0.9%) discontinued TABRECTA due to increased ALT/AST. The median time-to-onset of Grade 3 or higher increased ALT/AST was 1.4 months (range: 0.5 to 4.1 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)].

5.3 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.

5.4 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)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• ILD/Pneumonitis [see Warnings and Precautions (5.1)]
• Hepatotoxicity [see Warnings and Precautions (5.2)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Metastatic Non-Small Cell Lung Cancer

The safety of TABRECTA was evaluated in GEOMETRY mono-1 [see Clinical Studies (14)]. Patients received TABRECTA 400 mg orally twice daily until disease progression or unacceptable toxicity (N=334). Among patients who received TABRECTA, 31% were exposed for at least 6 months and 16% were exposed for at least one year.

Serious adverse reactions occurred in 51% of patients who received TABRECTA. Serious adverse reactions in ≥2% of patients included dyspnea (7%), pneumonia (4.8%), pleural effusion (3.6%), general physical health deterioration (3%), vomiting (2.4%), and nausea (2.1%). A fatal adverse reaction occurred in one patient (0.3%) due to pneumonitis.

Permanent discontinuation of TABRECTA due to an adverse reaction occurred in 16% of patients. The most frequent adverse reactions (≥1%) leading to permanent discontinuation of TABRECTA were peripheral edema (1.8%), pneumonitis (1.8%), and fatigue (1.5%).

Dose interruptions due to an adverse reaction occurred in 54% of patients who received TABRECTA. Adverse reactions requiring dosage interruption in >2% of patients who received TABRECTA included peripheral edema, increased blood creatinine, nausea, vomiting, increased lipase, increased ALT, dyspnea, increased amylase, increased AST, increased blood bilirubin, fatigue, and pneumonia.

Dose reductions due to an adverse reaction occurred in 23% of patients who received TABRECTA. Adverse reactions requiring dosage reductions in >2% of patients who received TABRECTA included peripheral edema, increased ALT, increased blood creatinine, and nausea.

The most common adverse reactions (≥20%) in patients who received TABRECTA were peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite.

Table 3 summarizes the adverse reactions in GEOMETRY mono-1.

Table 3. Adverse Reactions (≥10%) in Patients Who Received TABRECTA in GEOMETRY mono-1:

^aOnly includes Grade 3 adverse reactions with exception of dyspnea. Grade 4 dyspnea was reported in 0.6% of patients.
^bPeripheral edema includes peripheral swelling, peripheral edema, and fluid overload.
^cFatigue includes fatigue and asthenia.
^dNon-cardiac chest pain includes chest discomfort, musculoskeletal chest pain, non-cardiac chest pain, and chest pain.
^ePyrexia includes pyrexia and body temperature increased.

Clinically relevant adverse reactions occurring in <10% of patients treated with TABRECTA included pruritus (allergic and generalized), ILD/pneumonitis, cellulitis, acute kidney injury (including renal failure), urticaria, and acute pancreatitis.

Table 4 summarizes the laboratory abnormalities in GEOMETRY mono-1.

Table 4. Select Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients Who Received TABRECTA in GEOMETRY mono-1:

^aThe denominator used to calculate the rate varied from 320 to 325 based on the number of patients with a baseline value and at least one post-treatment value.

7.1 Effect of Other Drugs on TABRECTA

Strong CYP3A Inhibitors

Coadministration of TABRECTA with a strong CYP3A inhibitor increased capmatinib exposure, which may increase the incidence and severity of adverse reactions of TABRECTA [see Clinical Pharmacology (12.3)]. Closely monitor patients for adverse reactions during coadministration of TABRECTA with strong CYP3A inhibitors.

Strong and Moderate CYP3A Inducers

Coadministration of TABRECTA with a strong CYP3A inducer decreased capmatinib exposure. Coadministration of TABRECTA with a moderate CYP3A inducer may also decrease capmatinib exposure. Decreases in capmatinib exposure may decrease TABRECTA anti-tumor activity [see Clinical Pharmacology (12.3)]. Avoid coadministration of TABRECTA with strong and moderate CYP3A inducers.

7.2 Effect of TABRECTA on Other Drugs

CYP1A2 Substrates

Coadministration of TABRECTA increased the exposure of a CYP1A2 substrate, which may increase the adverse reactions of these substrates [see Clinical Pharmacology (12.3)]. If coadministration is unavoidable between TABRECTA and CYP1A2 substrates where minimal concentration changes may lead to serious adverse reactions, decrease the CYP1A2 substrate dosage in accordance with the approved prescribing information.

P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) Substrates

Coadministration of TABRECTA increased the exposure of a P-gp substrate and a BCRP substrate, which may increase the adverse reactions of these substrates [see Clinical Pharmacology (12.3)]. If coadministration is unavoidable between TABRECTA and P-gp or BCRP substrates where minimal concentration changes may lead to serious adverse reactions, decrease the P-gp or BCRP substrate dosage in accordance with the approved prescribing information.

MATE1 and MATE2K Substrates

Coadministration of TABRECTA may increase the exposure of MATE1 and MATE2K substrates, which may increase the adverse reactions of these substrates [see Clinical Pharmacology (12.3)]. If coadministration is unavoidable between TABRECTA and MATE1 or MATE2K substrates where minimal concentration changes may lead to serious adverse reactions, decrease the MATE1 or MATE2K substrate dosage in accordance with the approved prescribing information.

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.

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.

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.

Safety and effectiveness of TABRECTA in pediatric patients have not been established.

In GEOMETRY mono-1, 57% of the 334 patients were 65 years or older and 16% were 75 years or older. No overall differences in the safety or effectiveness were observed between these patients and younger patients.

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).