Gefitinib

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 . 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 . Gefitinib tablets are 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. Limitation of Use: Safety and efficacy of gefitinib tablets have not been established in patients whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations.

Recommended dose is 250 mg orally, once daily with or without food.

2.1Patient Selection Select

patients for the first-line treatment of metastatic NSCLC with gefitinib tablets are based on the presence of EGFR exon 19 deletions or exon 21 (L858R) mutations in their tumor or plasma specimens . 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/Companion Diagnostics.

2.2Recommended 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.

2.3Administration to Patients Who Have Difficulty

Swallowing Solids Immerse gefitinib tablet 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.

2.4Dose 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) NCI CTCAE Grade 2 or higher in ALT and/or AST elevations NCI CTCAE Grade 3 or higher diarrhea Signs and symptoms of severe or worsening ocular disorders including keratitis NCI CTCAE Grade 3 or higher skin reactions 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) Severe hepatic impairment Gastrointestinal perforation Persistent ulcerative keratitis 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 .

Interstitial lung disease (ILD): ILD occurred in patients taking gefitinib tablets Withhold gefitinib tablets for worsening of respiratory symptoms. Discontinue gefitinib tablets if ILD is confirmed. ( 2.4 , 5.1 ) Hepatotoxicity: Obtain periodic liver function testing. Withhold gefitinib tablets for Grade 2 or higher for ALT and/or AST elevations. Discontinue for severe hepatic impairment. ( 2.4 , 5.2 ) Gastrointestinal perforation: Discontinue gefitinib tablets for gastrointestinal perforation. ( 2.4 , 5.3 ) Diarrhea: Withhold gefitinib tablets for Grade 3 or higher diarrhea. ( 2.4 , 5.4 ) Ocular Disorders including Keratitis: Withhold gefitinib tablets for signs and symptoms of severe or worsening ocular disorders including keratitis. Discontinue for persistent ulcerative keratitis. ( 2.4 , 5.5 ) Bullous and Exfoliative Skin Disorders: Withhold gefitinib tablets for Grade 3 or higher skin reactions or exfoliative conditions. ( 2.4 , 5.6 ) Embryo-fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. ( 5.7 , 8.1 , 8.3 )

5.1Interstitial 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 .

5.2Hepatotoxicity 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 .

5.3Gastrointestinal Perforation Gastrointestinal

perforation occurred in three (0.1%) of the 2462 gefitinib tablets-treated patients across clinical trials . Permanently discontinue gefitinib tablets in patients who develop gastrointestinal perforation .

5.4Severe 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 .

5.5Ocular 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% . Interrupt or discontinue gefitinib tablets for severe, or worsening ocular disorders .

5.6Bullous 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.

5.7Embryo-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 .

None. None.

8.1Pregnancy 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 . 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.

8.3Females and Males of Reproductive Potential Contraception

Based on its mechanism of action and animal data, gefitinib tablets can cause fetal harm when administered to a pregnant woman . Advise females of reproductive potential to use effective contraception during treatment with gefitinib tablets and for at least two weeks following completion of therapy. Infertility Gefitinib tablets may result in reduced fertility in females of reproductive potential .

The following adverse drug reactions are discussed in more detail in other sections of the labeling: Interstitial Lung Disease Hepatotoxicity Gastrointestinal Perforation Severe or Persistent Diarrhea Ocular Disorders including Keratitis Bullous and Exfoliative Skin Disorders 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. To report SUSPECTED ADVERSE REACTIONS, contact Natco Pharma USA LLC at 201-786-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 gefitinib tablets of 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 and 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 Adverse Reaction Percentage (%) of patients Gefitinib Tablets (N=1126) Placebo (N=562) All Grades Grade 3 and 4 All Grades Grade 3 and 4 Skin and subcutaneous tissue disorders Skin reactions 1 47% 2% 17% 0.4% Nail disorders 2 5% 0.1% 0.7% 0% Gastrointestinal disorders Diarrhea 3 29% 3% 10% 1% Vomiting 14% 1.2% 10% 0.4% Stomatitis 4 7% 0.3% 4% 0.2% Metabolism and nutrition disorders Decreased appetite 17% 2.3% 14% 2.0% Eye disorders Conjunctivitis/blepharitis/dry eye 5 6% 0% 3.2% 0% 1 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, Rashmaculo-papular, Rash papular, Rash pruritic, Rash pustular, Rash vesicular, Skin exfoliation, Skin toxicity, Xeroderma 2 Includes Ingrowing nail, Nail bed infection, Nail disorder, Nail infection, Onychoclasis, Onycholysis, Paronychia 3 Includes Diarrhea, Feces soft, Frequent bowel movements 4 Includes Aphthous stomatitis, Cheilitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral mucosal blistering, Stomatitis, Tongue disorder, Tongue ulceration 5 Includes Blepharitis, Conjunctival hyperemia, Conjunctivitis, Dry eye, Eye irritation, Eye pruritus, Eye swelling, Eyelid irritation, Eyelid edema, Eyelids pruritus Table 2 – Treatment Emergent Laboratory Abnormalities Occurring More Frequently in Gefitinib tablets - Treated Patients in Study 3 Gefitinib Tablets Placebo Adverse Reaction All Grades % Grades 3 and 4 % All Grades % Grade 3 and 4 % Alanine aminotransferase Increase 1 38% 2 2.4% 23% 2 1.4% 4 Aspartate aminotransferase Increased 1 40% 3 2.0% 25% 3 1.3% 5 Proteinuria 35% 4.7% 31% 3.3% 1 Patients were allowed to enter the clinical study with lab values of ALT or AST CTCAE grade 1 or 2 2 14% gefitinib patients and 10% placebo patients were CTC grade 1 or 2 ALT at baseline 3 15% gefitinib patients and 12% placebo patients were CTC grade 1 or 2 AST at baseline 4 0.2% of placebo patients were CTC grade 3 at baseline 5 .4% of placebo patients were CTC grade 3 at baseline 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%).

6.3Postmarketing 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