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Gefitinib

FDA Drug Information • Also known as: Gefitinib, Iressa

Brand Names
Gefitinib, Iressa
Dosage Form
POWDER
Product Type
BULK INGREDIENT

Description

11 DESCRIPTION Gefitinib is a kinase inhibitor. The chemical name of gefitinib is 4-Quinazolinamine N -(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl) propoxy] and the following structural formula: Gefitinib has the molecular formula C 22 H 24 ClFN 4 O 3 , a relative molecular mass of 446.9 daltons and is a white-colored powder. Gefitinib is a free base. The molecule has pK a s of 5.4 and 7.2. Gefitinib can be defined as sparingly soluble at pH 1, but is practically insoluble above pH 7, with the solubility decreasing sharply between pH 4 and pH 6. In non-aqueous solvents, gefitinib is freely soluble in glacial acetic acid and dimethyl sulfoxide, soluble in pyridine, sparingly soluble in tetrahydrofuran, and slightly soluble in methanol, ethanol (99.5%), ethyl acetate, propan-2-ol and acetonitrile. IRESSA ® (gefitinib) tablets are available as brown film-coated tablets, containing 250 mg of gefitinib, for oral administration. The inactive ingredients of the tablet core of IRESSA tablets are lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate and magnesium stearate. The tablet coating is composed of hypromellose, polyethylene glycol 300, titanium dioxide, red ferric oxide and yellow ferric oxide. structural formula for gefitinib

What Is Gefitinib Used For?

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) ] . IRESSA is a tyrosine kinase inhibitor 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. (1) Limitation of Use: Safety and efficacy of IRESSA have not been established in patients whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations. (1)

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Recommended dose is 250 mg orally, once daily with or without food. (2.2) 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) ] .

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following adverse drug reactions are discussed in more detail in other sections of the labeling:

  • Interstitial Lung Disease [see Warnings and Precautions (5.1) ]
  • Hepatotoxicity [see Warnings and Precautions (5.2) ]
  • Gastrointestinal Perforation [see Warnings and Precautions (5.3) ]
  • Severe or Persistent Diarrhea [see Warnings and Precautions (5.4) ]
  • Ocular Disorders including Keratitis [see Warnings and Precautions (5.5) ]
  • Bullous and Exfoliative Skin Disorders [see Warning and Precautions (5.6) ] The most commonly reported adverse drug reactions (ADRs), reported in more than 20% of the patients and greater than placebo were skin reactions and diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. The safety of IRESSA is based on the data from 2462 patients with NSCLC who received IRESSA 250 mg daily monotherapy in three randomized clinical studies (Study 2, Study 3 and Study 4). Patients with a history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis that required steroid treatment or any evidence of clinically active interstitial lung disease were excluded from these studies. Controlled Studies: Study 2 was a randomized, multicenter, open-label trial in which 1217 patients were randomized to receive first-line treatment for metastatic NSCLC; 607 patients received IRESSA 250 mg daily and 589 patients received carboplatin/paclitaxel. The median duration of treatment with IRESSA was 5.9 months. The study population characteristics were: median age 57 years, age less than 65 years (73%), female (79%), Asian (100%), NSCLC adenocarcinoma histology (100%), never smoker (94%), light ex-smoker (6%), ECOG PS 0 or 1 (90%). Study 3 was a randomized, multicenter, double-blind, placebo-controlled trial in which 1692 patients were randomized to receive second- or third-line treatment for metastatic NSCLC; of which 1126 patients received IRESSA 250 mg daily and 562 patients received placebo. The median duration of treatment with IRESSA was 2.9 months. The study population characteristics were: median age 62 years, age less than 65 years (60%), female (33%), Caucasian (75%), Asian (21%), NSCLC adenocarcinoma histology (48%), never smoker (22%), ECOG PS 0 or 1 (65%), PS 2 (29%), PS 3 (5%) and two or more prior therapies (51%). Study 4 was a randomized, multicenter, open-label trial in which 1466 patients were randomized to receive second-line treatment for metastatic NSCLC; 729 patients received IRESSA 250 mg daily and 715 patients received docetaxel. The median duration of treatment with IRESSA was 2.4 months. The study population characteristics were: median age 61 years, age less than 65 years (61%), female (36%), Caucasian (79%), Asian (21%), NSCLC adenocarcinoma histology (54%), never smoker (20%), ECOG PS 0 or 1 (88%) and two or more prior therapies (16%). The pooled safety database from the three randomized trials was used to evaluate for serious and uncommon adverse drug reactions. Common adverse reactions were evaluated in Study 3. The most frequent adverse reactions in Study 3 (incidence of >20% and greater than placebo) reported in IRESSA-treated patients were skin reactions (47%) and diarrhea (29%). The most frequent fatal adverse reactions in IRESSA-treated patients were respiratory failure (0.9%), pneumonia (0.8%), and pulmonary embolism (0.5%). Approximately 5% of IRESSA-treated patients and 2.3% of placebo-treated patients discontinued treatment due to an adverse event. The most frequent adverse reactions that led to discontinuation in patients treated with IRESSA were nausea...

    • Drug Interactions

    7 DRUG INTERACTIONS

  • CYP3A4 Inducer: Increase IRESSA to 500 mg daily in patients receiving a strong CYP3A4 inducer. ( 2.4 , 7.1 )
  • CYP3A4 Inhibitor: Monitor adverse reactions if concomitant use with IRESSA. ( 7.1 )
  • Drugs Affecting Gastric pH: Avoid concomitant use of IRESSA with proton pump inhibitors, if possible. ( 7.1 )
  • Hemorrhage in patients taking warfarin: Monitor changes in prothrombin time or INR. ( 7.2 ) 7.1 Drugs Affecting Gefitinib Exposure CYP3A4 Inducer Drugs that are strong inducers of CYP3A4 increase the metabolism of gefitinib and decrease gefitinib plasma concentrations. Increase IRESSA to 500 mg daily in patients receiving a strong CYP3A4 inducer (e.g., rifampicin, phenytoin, or tricyclic antidepressant) and resume IRESSA at 250 mg 7 days after discontinuation of the strong inducer [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ] . CYP3A4 Inhibitor Drugs that are strong inhibitors of CYP3A4 (e.g., ketoconazole and itraconazole) decrease gefitinib metabolism and increase gefitinib plasma concentrations. Monitor adverse reactions when administering strong CYP3A4 inhibitors with IRESSA. Drugs Affecting Gastric pH Drugs that elevate gastric pH (e.g., proton pump inhibitors, histamine H 2 -receptor antagonists, and antacids) may reduce plasma concentrations of gefitinib. Avoid concomitant use of IRESSA with proton pump inhibitors, if possible. If treatment with a proton-pump inhibitor is required, take IRESSA 12 hours after the last dose or 12 hours before the next dose of the proton-pump inhibitor. Take IRESSA 6 hours after or 6 hours before an H 2 -receptor antagonist or an antacid [see Clinical Pharmacology (12.3) ] . 7.2 Hemorrhage in Patients taking Warfarin International Normalized Ratio (INR) elevations and/or hemorrhage have been reported in some patients taking warfarin while on IRESSA therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR.

    • Contraindications

    4 CONTRAINDICATIONS None. None. (4)

    Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary Based on its mechanism of action and animal data, 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 ( see Animal Data ). Advise pregnant women of the potential hazard to a fetus or potential risk for loss of the pregnancy. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and miscarriage is 15-20% of clinically recognized pregnancies. Data Animal Data A single dose study in rats showed that gefitinib crosses the placenta after an oral dose of 5 mg/kg (30 mg/m 2 , about 0.2 times the recommended human dose on a mg/m 2 basis). When pregnant rats were treated with 5 mg/kg from the beginning of organogenesis to the end of weaning there was a reduction in the number of offspring born alive. This effect was more severe at 20 mg/kg (approximate the human clinical dose on a mg/m 2 basis) and was accompanied by high neonatal mortality soon after parturition. In rabbits, a dose of 20 mg/kg/day (240 mg/m 2 , about twice the recommended dose in humans on a mg/m 2 basis) caused reduced fetal weight.

    Overdosage

    10 OVERDOSAGE Twenty three patients were treated weekly with doses from 1500 mg to 3500 mg, and IRESSA exposure did not increase with increasing dose. Adverse events were mostly mild to moderate in severity, and were consistent with the known safety profile of IRESSA. In the event of suspected overdose, interrupt IRESSA, institute supportive care, and observe until clinical stabilization. There are no specific measures/treatments that should be taken following IRESSA overdosing.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING IRESSA ® (gefitinib) is available as 250 mg tablets. IRESSA 250 mg tablets are round, biconvex, brown film-coated, debossed with "IRESSA 250" on one side and plain on the other side. IRESSA ® (gefitinib) tablets are supplied as: Bottles of 30 Tablets (NDC 0310-0482-30) Store at controlled room temperature 20°C-25°C (68°F-77°F) [see USP Controlled Room Temperature ].

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.