Gefitinib Drug Information

• 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 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) ].

• 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 QILU PHARMA, INC. at 484-838-0633 / 484-875-3013 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 gefitinib tablets is based on the data from 2462 patients with NSCLC who received gefitinib tablets 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 gefitinib tablets 250 mg daily and 589 patients received carboplatin/paclitaxel. The median duration of treatment with gefitinib tablets 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 gefitinib tablets 250 mg daily and 562 patients received placebo. The median duration of treatment with gefitinib tablets 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 gefitinib tablets 250 mg daily and 715 patients received docetaxel. The median duration of treatment with gefitinib tablets 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 gefitinib tablets-treated patients were skin reactions (47%)and diarrhea (29%). The most frequent fatal adverse reactions in gefitinib tablets-treated patients were respiratory failure (0.9%), pneumonia (0.8%), and pulmonary embolism (0.5%). Approximately 5% of gefitinib tablets-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 gefitinib tablets were nausea (0.5%), vomiting (0.5%) and diarrhea (0.4%). Table 1 - Selected Adverse Drug Reactions Occurring with an Incidence Rate ≥ 5% and an Increase of >2% of Gefitinib Tablets-treated Patients in Study 3 Percentage (%) of patients Gefitinib Tablets (N=1126) Placebo (N=562) Adverse Reaction All Grades Grade 3 and 4 All Grades Grade 3 and 4 Skin and subcutaneous tissue disorders Skin reactions Includes Acne, Acne pustular, Dermatitis, Dermatitis acneiform, Dermatitis exfoliative, Drug eruption, Dry skin, Erythema, Exfoliative rash, Folliculitis, Pruritus, Pruritus generalized, Rash, Rash erythematous, Rash generalized, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Rash pustular, Rash vesicular, Skin exfoliation, Skin toxicity, Xeroderma 47% 2% 17% 0.4% Nail disorders Includes Ingrowing nail, Nail bed infection, Nail disorder, Nail infection, Onychoclasis, Onycholysis, Paronychia 5% 0.1% 0.7% 0% Gastrointestinal disorders Diarrhea Includes Diarrhea, Feces soft, Frequent bowel movements 29% 3% 10% 1% Vomiting 14% 1.2% 10% 0.4% Stomatitis Includes Aphthous stomatitis, Cheilitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral mucosal blistering, Stomatitis, Tongue disorder, Tongue ulceration 7% 0.3% 4% 0.2% Metabolism and nutrition disorders Decreased appetite 17% 2.3% 14% 2.0% Eye disorders Conjunctivitis/blepharitis/dry eye Includes Blepharitis, Conjunctival hyperemia, Conjunctivitis, Dry eye, Eye irritation, Eye pruritus, Eye swelling, Eyelid irritation, Eyelid edema, Eyelids pruritus 6% 0% 3.2% 0% Table 2 - Treatment Emergent Laboratory Abnormalities Occurring More Frequently in Gefitinib Tablets-Treated Patients in Study 3 Gefitinib Tablets Placebo Adverse Reaction All Grades % Grade 3 and 4 % All Grades % Grade 3 and 4 % Alanine aminotransferase increased Patients were allowed to enter the clinical study with lab values of ALT or AST CTCAE grade 1 or 2 38% 14% gefitinib patients and 10% placebo patients were CTC grade 1 or 2 ALT at baseline 2.4% 23% 1.4% 0.2% of placebo patients were CTC grade 3 at baseline Aspartate aminotransferase increased 40% 15% gefitinib patients and 12% placebo patients were CTC grade 1 or 2 AST at baseline 2.0% 25% 1.3% 0.4% of placebo patients were CTC grade 3 at baseline Proteinuria 35% 4.7% 31% 3.3% The following adverse reactions have been reported with gefitinib tablets across NSCLC trials (Study 2, Study 3 and Study 4) and are not listed elsewhere in Section 6: nausea (18%), asthenia (17%), pyrexia (9%), alopecia (4.7%), hemorrhage (including epistaxis and hematuria) (4.3%), dry mouth (2%), dehydration (1.8%), elevations in blood creatinine (1.5%), allergic reactions including angioedema and urticaria (1.1%), palmar-plantar erythrodysesthesia syndrome (0.2%) and pancreatitis (0.1%). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of gefitinib tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Renal and urinary disorders : cystitis, hemorrhagic cystitis Skin and subcutaneous tissue disorders : cutaneous vasculitis

• CYP3A4 Inducer: Increase gefitinib tablets to 500 mg daily in patients receiving a strong CYP3A4 inducer. ( 2.4 , 7.1 )
• CYP3A4 Inhibitor: Monitor adverse reactions if concomitant use with gefitinib tablets. ( 7.1 )
• Drugs Affecting Gastric pH: Avoid concomitant use of gefitinib tablets 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 gefitinib tablets to 500 mg daily in patients receiving a strong CYP3A4 inducer (e.g., rifampicin, phenytoin, or tricyclic antidepressant) and resume gefitinib tablets 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 gefitinib tablets. 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 gefitinib tablets with proton pump inhibitors, if possible. If treatment with a proton-pump inhibitor is required, take gefitinib tablets 12 hours after the last dose or 12 hours before the next dose of the proton-pump inhibitor. Take gefitinib tablets 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 gefitinib tablets therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR.

Pregnancy Risk Summary Based on its mechanism of action and animal data, 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 ( 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.

Pediatric Use The safety and effectiveness of gefitinib tablets in pediatric patients have not been established.

Twenty three patients were treated weekly with doses from 1500 mg to 3500 mg, and gefitinib tablets 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 gefitinib tablets. In the event of suspected overdose, interrupt gefitinib tablets, institute supportive care, and observe until clinical stabilization.

There are no specific measures/treatments that should be taken following gefitinib tablets overdosing.