IRESSA SIDE EFFECTS
SIDE EFFECTS
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.
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 reactions1 | 47% | 2% | 17% | 0.4% |
| Nail disorders2 | 5% | 0.1% | 0.7% | 0% |
| Gastrointestinal disorders | ||||
| Diarrhea3 | 29% | 3% | 10% | 1% |
| Vomiting | 14% | 1.2% | 10% | 0.4% |
| Stomatitis4 | 7% | 0.3% | 4% | 0.2% |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 17% | 2.3% | 14% | 2.0% |
| Eye disorders | ||||
| Conjunctivitis/blepharitis/dry eye5 | 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, Rash maculo-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 |
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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 increased1 | 38%2 | 2.4% | 23%2 | 1.4%4 |
| Aspartate aminotransferase increased1 | 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 0.4% of placebo patients were CTC grade 3 at baseline |
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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%).
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.
SRC: NLM .