TABRECTA: Package Insert and Label Information

TABRECTA- capmatinib tablet, film coated
Novartis Pharmaceuticals Corporation

1 INDICATIONS AND USAGE

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.

This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

Select patients for treatment with TABRECTA based on the presence of a mutation that leads to MET exon 14 skipping in tumor specimens [see Clinical Studies (14)]. Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 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.

2.3 Dosage Modifications for Adverse Reactions

The recommended dose reductions for the management of adverse reactions are listed in Table 1.

Table 1: Recommended TABRECTA Dose Reductions for Adverse Reactions
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.

Table 2: Recommended TABRECTA Dosage Modifications for Adverse Reactions
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ILD, interstitial lung disease; ULN, upper limit of normal.Grading according to CTCAE Version 4.03 (CTCAE = Common Terminology Criteria for Adverse Events).
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.
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.

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

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)].

6 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)]

6.1 Clinical 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=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
a Only includes Grade 3 adverse reactions with exception of dyspnea. Grade 4 dyspnea was reported in 0.6% of patients.b Peripheral edema includes peripheral swelling, peripheral edema, and fluid overload.c Fatigue includes fatigue and asthenia.d Non-cardiac chest pain includes chest discomfort, musculoskeletal chest pain, non-cardiac chest pain, and chest pain.e Pyrexia includes pyrexia and body temperature increased.
Adverse Reactions TABRECTA(N = 334)
Grades 1 to 4(%) Grades 3 to 4a (%)
General disorders and administration-site conditions
Peripheral edemab 52 9
Fatiguec 32 8
Non-cardiac chest paind 15 2.1
Back pain 14 0.9
Pyrexiae 14 0.6
Weight decreased 10 0.6
Gastrointestinal disorders
Nausea 44 2.7
Vomiting 28 2.4
Constipation 18 0.9
Diarrhea 18 0.3
Respiratory, thoracic, and mediastinal disorders
Dyspnea 24 7a
Cough 16 0.6
Metabolism and nutrition disorders
Decreased appetite 21 0.9

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
a The 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.
Laboratory Abnormalities TABRECTAa
Grades 1 to 4(%) Grades 3 to 4(%)
Chemistry
Decreased albumin 68 1.8
Increased creatinine 62 0.3
Increased alanine aminotransferase 37 8
Increased alkaline phosphatase 32 0.3
Increased amylase 31 4.4
Increased gamma-glutamyltransferase 29 7
Increased lipase 26 7
Increased aspartate aminotransferase 25 4.9
Decreased sodium 23 6
Decreased phosphate 23 4.6
Increased potassium 23 3.1
Decreased glucose 21 0.3
Hematology
Decreased lymphocytes 44 14
Decreased hemoglobin 24 2.8
Decreased leukocytes 23 0.9

7 DRUG INTERACTIONS

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