Gefitinib

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)

250 mg tablets: round, biconvex, brown film-coated, debossed with "IRESSA 250" on one side and plain on the other side. Tablets: 250 mg. (3)

None. None. (4)

• Interstitial lung disease (ILD): ILD occurred in patients taking IRESSA. Withhold IRESSA for worsening of respiratory symptoms. Discontinue IRESSA if ILD is confirmed. ( 2.4 , 5.1 )
• Hepatotoxicity: Obtain periodic liver function testing. Withhold IRESSA for Grade 2 or higher for ALT and/or AST elevations. Discontinue for severe hepatic impairment. ( 2.4 , 5.2 )
• Gastrointestinal perforation: Discontinue IRESSA for gastrointestinal perforation. ( 2.4 , 5.3 )
• Diarrhea: Withhold IRESSA for Grade 3 or higher diarrhea. ( 2.4 , 5.4 )
• Ocular Disorders including Keratitis: Withhold IRESSA 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 IRESSA 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 )

5.1 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, blepharitis 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 )] .

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 (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 IRESSA-treated Patients in Study 3 Adverse Reaction Percentage (%) of patients IRESSA (N=1126) Placebo (N=562) 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 IRESSA-Treated Patients in Study 3 Adverse Reaction IRESSA Placebo 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 IRESSA 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 IRESSA. 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 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.

Lactation: Discontinue breast-feeding. (8.2)

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.

8.2 Lactation Risk Summary It is not known whether IRESSA is excreted in human milk. Animal studies indicate the gefitinib and its metabolites are present in rat milk at a concentration higher than those in maternal plasma. Because of the potential for serious adverse reactions in nursing infants from IRESSA, advise women to discontinue breast-feeding during treatment with IRESSA. Data Animal Data Levels of gefitinib and its metabolites were 11-to-19-fold higher in milk than in blood, after oral exposure of lactating rats to a dose of 5 mg/kg.

8.3 Females and Males of Reproductive Potential Contraception Based on its mechanism of action and animal data, IRESSA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with IRESSA and for at least two weeks following completion of therapy. Infertility IRESSA may result in reduced fertility in females of reproductive potential [see Nonclinical Toxicology (13.1) ] .

8.4 Pediatric Use The safety and effectiveness of IRESSA in pediatric patients have not been established.

8.5 Geriatric Use Of the 823 patients enrolled in two randomized, active-controlled clinical trials 374 patients (45%) were 65 years and older, and 93 patients (11%) were 75 years and older. No overall differences in safety were observed between patients 65 years and older and those younger than 65 years. There is insufficient information to assess for differences in efficacy between older and younger patients.

8.6 Renal Impairment Less than four percent (<4%) of gefitinib and its metabolites are excreted via the kidney. No clinical studies were conducted with IRESSA in patients with severe renal impairment.

8.7 Hepatic Impairment The systemic exposure of gefitinib was compared in patients with mild, moderate, or severe hepatic impairment due to cirrhosis (according to Child-Pugh classification) and healthy subjects with normal hepatic function (N=10/group). The mean systemic exposure (AUC 0-∞ ) was increased by 40% in patients with mild impairment, 263% in patients with moderate impairment, and 166% in patients with severe hepatic impairment. Monitor adverse reactions when IRESSA is administered to patients with moderate and severe hepatic impairment. In a study comparing 13 patients with liver metastases and moderate hepatic impairment (addition of CTC grade of baseline AST/SGOT, ALP, and bilirubin equals 3 to 5) to 14 patients with liver metastases and normal hepatic function, the systemic exposure of gefitinib was similar [see Warnings and Precautions (5.2) ] .

The epidermal growth factor receptor (EGFR) is expressed on the cell surface of both normal and cancer cells and plays a role in the processes of cell growth and proliferation. Some EGFR activating mutations (exon 19 deletion or exon 21 point mutation L858R) within NSCLC cells have been identified as contributing to the promotion of tumor cell growth, blocking of apoptosis, increasing the production of angiogenic factors and facilitating the processes of metastasis. Gefitinib reversibly inhibits the kinase activity of wild-type and certain activating mutations of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor, thereby inhibiting further downstream signaling and blocking EGFR-dependent proliferation. Gefitinib binding affinity for EGFR exon 19 deletion or exon 21 point mutation L858R mutations is higher than its affinity for the wild-type EGFR. Gefitinib also inhibits IGF and PDGF-mediated signaling at clinically relevant concentrations; inhibition of other tyrosine kinase receptors has not been fully characterized.