IRESSA

IRESSA- gefitinib tablet, coated
AstraZeneca Pharmaceuticals LP

1 INDICATIONS AND USAGE

IRESSA is 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 IRESSA 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 IRESSA 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 IRESSA 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 IRESSA 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 IRESSA (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 IRESSA when the adverse reaction fully resolves or improves to NCI CTCAE Grade 1.

Permanently discontinue IRESSA 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 IRESSA to 500 mg daily in the absence of severe adverse drug reaction, and resume IRESSA 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, brown film-coated, debossed with “IRESSA 250” 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 IRESSA across clinical trials; of these, 0.7% were Grade 3 or higher and 3 cases were fatal.

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

5.2 Hepatotoxicity

In patients who received IRESSA 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 IRESSA 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 IRESSA-treated patients across clinical trials [see Adverse Reactions (6.1)]. Permanently discontinue IRESSA 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 IRESSA-treated patients across clinical trials. Withhold IRESSA 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 IRESSA-treated patients across clinical trials. The incidence of Grade 3 ocular disorders was 0.1% [see Adverse Reactions (6.1)]. Interrupt or discontinue IRESSA 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 IRESSA. Erythema multiforme and dermatitis bullous have been reported in two patients (0.08%) across NSCLC trials (Study 2, Study 3 and Study 4). IRESSA 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 IRESSA 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 IRESSA and for at least two weeks following completion of therapy [see Use in Specific Populations (8.1, 8.3)].

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