IRESSA (Page 2 of 6)

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)]

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
*
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
Includes Ingrowing nail, Nail bed infection, Nail disorder, Nail infection, Onychoclasis, Onycholysis, Paronychia
Includes Diarrhea, Feces soft, Frequent bowel movements
§
Includes Aphthous stomatitis, Cheilitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral mucosal blistering, Stomatitis, Tongue disorder, Tongue ulceration
Includes Blepharitis, Conjunctival hyperemia, Conjunctivitis, Dry eye, Eye irritation, Eye pruritus, Eye swelling, Eyelid irritation, Eyelid edema, Eyelids pruritus

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 *

47%

2%

17%

0.4%

Nail disorders

5%

0.1%

0.7%

0%

Gastrointestinal disorders

Diarrhea

29%

3%

10%

1%

Vomiting

14%

1.2%

10%

0.4%

Stomatitis §

7%

0.3%

4%

0.2%

Metabolism and nutrition disorders

Decreased appetite

17%

2.3%

14%

2.0%

Eye disorders

Conjunctivitis/blepharitis/dry eye

6%

0%

3.2%

0%

Table 2 — Treatment Emergent Laboratory Abnormalities Occurring More Frequently in IRESSA-Treated Patients in Study 3
*
Patients were allowed to enter the clinical study with lab values of ALT or AST CTCAE grade 1 or 2
14% gefitinib patients and 10% placebo patients were CTC grade 1 or 2 ALT at baseline
0.2% of placebo patients were CTC grade 3 at baseline
§
15% gefitinib patients and 12% placebo patients were CTC grade 1 or 2 AST at baseline
0.4% of placebo patients were CTC grade 3 at baseline

Adverse Reaction

IRESSA

Placebo

All Grades

%

Grade 3 and 4

%

All Grades

%

Grade 3 and 4

%

Alanine aminotransferase increased *

38%

2.4%

23%

1.4%

Aspartate aminotransferase increased *

40%§

2.0%

25%§

1.3%

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%).

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