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Cellular-mesenchymal-epithelial transition factor (c-MET) kinase inhibitors

Tabrecta

Approved 6 May 2020OralTablet

The FDA lists this product in 2 strengths and forms.

Indications

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. TABRECTA is a kinase inhibitor 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.

Contraindications

None. None.

Warnings and precautions

Interstitial Lung Disease (ILD)/Pneumonitis : Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Permanently discontinue TABRECTA in patients with ILD/pneumonitis. ( 2.3 , 5.1 ) Hepatotoxicity : Monitor liver function tests. Withhold, dose reduce, or permanently discontinue TABRECTA based on severity. ( 2.3 , 5.2 ) Pancreatic Toxicity : Monitor amylase and lipase levels. Withhold, dose reduce, or permanently discontinue TABRECTA based on severity.

( 2.3 , 5.3 ) Hypersensitivity Reactions : Withhold or permanently discontinue TABRECTA based on severity. ( 2.3 , 5.4 ) Risk of Photosensitivity : May cause photosensitivity reactions. Advise patients to limit direct ultraviolet exposure. ( 5.5 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 )

5.1Interstitial 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).

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Interactions

Strong and Moderate CYP3A Inducers : Avoid concomitant use. ( 7.1 )

7.1Effect 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.

7.2Effect 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.

Pregnancy and breastfeeding

8.1Pregnancy 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.

Adverse reactions

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)] Pancreatic Toxicity [see Warnings and Precautions (5.3)] Hypersensitivity reactions [see Warnings and Precautions (5.4)] The most common adverse reactions (≥ 20%) are edema, nausea, musculoskeletal pain, fatigue, vomiting, dyspnea, cough, and decreased appetite.

( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience

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 = 373).

Among patients who received TABRECTA, 37% were exposed for at least 6 months and 22% were exposed for at least one year. Serious adverse reactions occurred in 53% of patients who received TABRECTA. Serious adverse reactions in ≥ 2% of patients included dyspnea (7%), pneumonia (7%), pleural effusion (4.3%), musculoskeletal pain (3.8%), general physical health deterioration (2.9%), ILD/pneumonitis (2.7%), edema (2.4%), and vomiting (2.4%).

Fatal adverse reactions occurred in 0.5% of patients who received TABRECTA, including pneumonitis (0.3%) and death, not otherwise specified (0.3%). Permanent discontinuation of TABRECTA due to an adverse reaction occurred in 17% of patients. The most frequent adverse reactions (≥ 1%) leading to permanent discontinuation of TABRECTA were ILD/pneumonitis (2.4%), edema (2.4%), fatigue (1.3%), and pneumonia (1.1%). Dose interruptions due to an adverse reaction occurred in 57% of patients who received TABRECTA.

Adverse reactions requiring dosage interruption in > 2% of patients who received TABRECTA included edema, increased blood creatinine, nausea, increased lipase, vomiting, increased ALT, dyspnea, pneumonia, fatigue, increased amylase, increased AST, musculoskeletal pain, abdominal pain, and increased blood bilirubin. Dose reductions due to an adverse reaction occurred in 26% of patients who received TABRECTA. Adverse reactions requiring dosage reductions in > 2% of patients who received TABRECTA included edema, increased ALT and increased blood creatinine.

The most common adverse reactions (≥ 20%) in patients who received TABRECTA were edema, nausea, musculoskeletal pain, fatigue, vomiting, dyspnea, cough, 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 a Edema includes edema peripheral, generalized edema, face edema, edema, localized edema, edema genital, eyelid edema, peripheral swelling, scrotal edema, and penile edema. b Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, pain in jaw, spinal pain. c Fatigue includes fatigue and asthenia. d Pyrexia includes pyrexia and body temperature increased. e Cough includes cough, upper airway cough syndrome, and productive cough. f Pneumonia includes pneumonia aspiration, pneumonia, pneumonia influenzal, pneumonia bacterial, lower respiratory tract infection, and lung abscess. g Rash includes rash, dermatitis acneiform, rash maculo-papular, eczema, erythema multiforme, rash macular, dermatitis, rash erythematous, rash pustular, dermatitis bullous, and rash vesicular. h Dizziness includes dizziness, vertigo, and vertigo positional.

Adverse reactions TABRECTA (N = 373) Grades 1 to 4 (%) Grades 3 to 4 (%) General disorders and administration-site conditions Edema a 59 13 Musculoskeletal pain b 40

4.3 Fatigue c 34 8 Pyrexia d 14

0.8 Weight decreased 11

0.5 Gastrointestinal disorders Nausea 46

2.4 Vomiting 28

2.4 Constipation 19

0.8 Diarrhea 19

0.5 Respiratory, thoracic, and mediastinal disorders Dyspnea 25 7 Cough e 21

0.5 Pneumonia f 13 6 Metabolism and nutrition disorders Decreased appetite 21

1.1Skin

and subcutaneous tissue disorders Rash g 13

0.5 Nervous system disorders Dizziness h 13

0.5 Clinically relevant adverse reactions occurring in < 10% of patients treated with TABRECTA included pruritus (including allergic pruritus), 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 a The denominator used to calculate the rate varied from 359 to 364 based on the number of patients with a baseline value and at least one post-treatment value.

Laboratory abnormalities TABRECTA a Grades 1 to 4 (%) Grades 3 to 4 (%) Chemistry Decreased albumin 72

1.9 Increased creatinine 65

0.5 Increased alanine aminotransferase 39 9 Increased amylase 34

4.7 Increased alkaline phosphatase 32

0.6 Increased gamma-glutamyltransferase 30 6 Increased lipase 29 9 Increased aspartate aminotransferase 28 6 Decreased phosphate 26

4.4 Increased potassium 25

4.1 Decreased sodium 24 6 Decreased glucose 23

0.3Hematology

Decreased lymphocytes 45 14 Decreased leukocytes 25

1.7 Decreased hemoglobin 24

2.8Other Clinical Trials Experience

The following adverse reactions have been reported following administration of TABRECTA: hypersensitivity and thrombocytopenia.

Tabrecta

Indications

Contraindications

Warnings and precautions

5.1Interstitial Lung Disease (ILD)/Pneumonitis

Two medicines in one question?

5.2Hepatotoxicity

5.3Pancreatic Toxicity Elevations

5.4Hypersensitivity Reactions

5.5Risk of Photosensitivity Based

5.6Embryo-Fetal Toxicity Based

Interactions

7.1Effect of Other Drugs on

7.2Effect of

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary Based

Adverse reactions

6.1Clinical Trials Experience

1.1Skin

0.3Hematology

2.8Other Clinical Trials Experience

Composition

Strengths and forms

Official product information

At a glance

Guidelines