Gefitinib

GEFITINIB- gefitinib tablet, coated
Qilu Pharmaceutical Co., Ltd.

1 INDICATIONS AND USAGE

Gefitinib tablets are indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test [see Clinical Studies (14) ].

Limitation of Use: Safety and efficacy of gefitinib tablets have not been established in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations [see Clinical Studies (14) ].

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

Select patients for the first-line treatment of metastatic NSCLC with gefitinib tablets based on the presence of EGFR exon 19 deletions or exon 21 L858R mutations in their tumor or plasma specimens[see Indications and Usage (1) , Clinical Studies (14)​]. If these mutations are not detected in a plasma specimen, test tumor tissue if feasible.

Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics ​.

2.2 Recommended Dose

The recommended dose of gefitinib tablets is 250 mg orally once daily with or without food until disease progression or unacceptable toxicity.

Do not take a missed dose within 12 hours of the next dose.

2.3 Administration to Patients Who Have Difficulty Swallowing Solids

Immerse gefitinib tablets in 4 to 8 ounces of water by dropping the tablet in water, and stir for approximately 15 minutes. Immediately drink the liquid or administer through a naso-gastric tube. Rinse the container with 4 to 8 ounces of water and immediately drink or administer through the naso-gastric tube.

2.4 Dose Modification

Dose Modifications for Adverse Drug Reactions

Withhold gefitinib tablets (for up to 14 days) for any of the following:

•Acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever) [see Warnings and Precautions (5.1) ]

•NCI CTCAE Grade 2 or higher in ALT and/or AST elevations [see Warnings and Precautions (5.2) ]

•NCI CTCAE Grade 3 or higher diarrhea [see Warnings and Precautions (5.4) ]

•Signs and symptoms of severe or worsening ocular disorders including keratitis [see Warnings and Precautions (5.5) ]

•NCI CTCAE Grade 3 or higher skin reactions [see Warnings and Precautions (5.6) ]

Resume treatment with gefitinib tablets when the adverse reaction fully resolves or improves to NCI CTCAE Grade 1.

Permanently discontinue gefitinib tablets for:

•Confirmed interstitial lung disease (ILD) [see Warnings and Precautions (5.1) ]

•Severe hepatic impairment [see Warnings and Precautions (5.2) ]

•Gastrointestinal perforation [see Warnings and Precautions (5.3) ]

•Persistent ulcerative keratitis [see Warnings and Precautions (5.5) ]

Dose Modifications for Drug Interactions

Strong CYP3A4 Inducers

Increase gefitinib tablets to 500 mg daily in the absence of severe adverse drug reaction, and resume gefitinib tablets at 250 mg seven days after discontinuation of the strong CYP3A4 inducer [see Drug Interactions (7) ,Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

250 mg tablets: round, biconvex face, brown film-coated, debossed with “QL” on one side and plain on the other side.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Interstitial Lung Disease (ILD)

ILD or ILD-like adverse drug reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or pulmonary fibrosis) occurred in 1.3% of the 2462 patients who received gefitinib tablets across clinical trials; of these, 0.7% were Grade 3 or higher and 3 cases were fatal.

Withhold gefitinib tablets and promptly investigate for ILD in any patient who presents with worsening of respiratory symptoms such as dyspnea, cough and fever. Permanently discontinue gefitinib tablets if ILD is confirmed [see Dosage and Administration (2.4), Adverse Reactions (6.1)].

5.2 Hepatotoxicity

In patients who received gefitinib tablets across clinical trials, 11.4% of patients had increased alanine aminotransferase (ALT), 7.9% of patients had increased aspartate aminotransferase (AST), and 2.7% of patients had increased bilirubin. Grade 3 or higher liver test abnormalities occurred in 5.1% (ALT), 3.0% (AST), and 0.7% (bilirubin) of patients. The incidence of fatal hepatotoxicity was 0.04%.

Obtain periodic liver function testing. Withhold gefitinib tablets in patients with worsening liver function and discontinue in patients with severe hepatic impairment [see Dosage and Administration (2.4) , Adverse Reactions (6.1), Use in Specific Populations (8.7)].

5.3 Gastrointestinal Perforation

Gastrointestinal perforation occurred in three (0.1%) of the 2462 gefitinib tablets-treated patients across clinical trials [see Adverse Reactions (6.1) ]. Permanently discontinue gefitinib tablets in patients who develop gastrointestinal perforation [see Dosage and Administration (2.4) ].

5.4 Severe or Persistent Diarrhea

Grade 3 or 4 diarrhea occurred in 3% of 2462 gefitinib tablets-treated patients across clinical trials. Withhold gefitinib tablets for severe or persistent (up to 14 days) diarrhea [see Dosage and Administration (2.4) , Adverse Reactions (6.1)].

5.5 Ocular Disorders including Keratitis

Ocular disorders [keratitis (0.1%), corneal erosion and aberrant eyelash growth (0.2%), conjunctivitis, blephritis and dry eye (6.7%)] occurred in the 2462 gefitinib tablets-treated patients across clinical trials. The incidence of Grade 3 ocular disorders was 0.1% [see Adverse Reactions (6.1) ]. Interrupt or discontinue gefitinib tablets for severe, or worsening ocular disorders [see Dosage and Administration (2.4) ].

5.6 Bullous and Exfoliative Skin Disorders

Bullous conditions including toxic epidermal necrolysis, Stevens Johnson syndrome and erythema multiforme have been reported from treatment with gefitinib tablets. Erythema multiforme and dermatitis bullous have been reported in two patients (0.08%) across NSCLC trials (Study 2, Study 3 and Study 4). Gefitinib tablets treatment should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions.

5.7 Embryo-fetal Toxicity

Based on its mechanism of action and data from animal reproduction studies gefitinib tablets can cause fetal harm when administered to a pregnant woman. In animal reproductive studies, oral administration of gefitinib from organogenesis through weaning resulted in fetotoxicity and neonatal death at doses below the recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with gefitinib tablets and for at least two weeks following completion of therapy [see Use in Specific Population (8.1, 8.3)].