Gefitinib Sandoz Adverse Reactions

Summary of the safety profile: In the pooled dataset from the ISEL, INTEREST and IPASS phase III clinical trials (2462 gefitinib-treated patients), the most frequently reported adverse drug reactions (ADRs), occurring in more than 20% of the patients, are diarrhoea and skin reactions (including rash, acne, dry skin and pruritus). ADRs usually occur within the first month of therapy and are generally reversible. Approximately 8% of patients had a severe ADR (common toxicity criteria (CTC) grade 3 or 4).
Approximately 3% of patients stopped therapy due to an ADR.
Interstitial lung disease (ILD) has occurred in 1.3% of patients, often severe (CTC grade 3-4). Cases with fatal outcomes have been reported.
List of adverse reactions: The safety profile presented as follows is based on the gefitinib clinical development programme and postmarketed experience. Adverse reactions have been assigned to the frequency categories as follows where possible based on the incidence of comparable adverse event reports in a pooled dataset from the ISEL, INTEREST and IPASS phase III clinical trials (2462 gefitinib­-treated patients).
Frequencies of occurrence of undesirable effects are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Metabolism and nutrition disorders: Very common: Anorexia mild or moderate (CTC grade 1 or 2).
Eye disorders: Common: Conjunctivitis, blepharitis, and dry eye*, mainly mild (CTC grade 1).
Uncommon: Corneal erosion, reversible and sometimes in association with aberrant eyelash growth, keratitis (0.12%).
Vascular disorders: Common: Haemorrhage, such as epistaxis and haematuria.
Respiratory, thoracic and mediastinal disorders: Common: Interstitial lung disease (1.3%), often severe (CTC grade 3-4). Cases with fatal outcomes have been reported.
Gastrointestinal disorders: Very common: Diarrhoea, mainly mild or moderate (CTC grade 1 or 2), vomiting, mainly mild or moderate (CTC grade 1 or 2), nausea, mainly mild (CTC grade 1), stomatitis, predominantly mild in nature (CTC grade 1).
Common: Dehydration, secondary to diarrhoea, nausea, vomiting or anorexia, dry mouth*, predominantly mild (CTC grade 1).
Uncommon: Pancreatitis, gastrointestinal perforation.
Hepatobiliary disorders: Very common: Elevations in alanine aminotransferase, mainly mild to moderate.
Common: Elevations in aspartate aminotransferase, mainly mild to moderate, elevations in total bilirubin, mainly mild to moderate.
Uncommon: Hepatitis**.
Skin and subcutaneous tissue disorders: Very common: Skin reactions, mainly a mild or moderate (CTC grade 1 or 2) pustular rash, sometimes itchy with dry skin, including skin fissures, on an erythematous base.
Common: Nail disorder, alopecia, allergic reactions (1.1%), including angioedema and urticaria.
Rare: Bullous conditions including toxic epidermal necrolysis, Stevens Johnson syndrome and erythema multiforme, cutaneous vasculitis.
Renal and urinary disorders: Common: Asymptomatic laboratory elevations in blood creatinine, proteinuria, cystitis.
Rare: Haemorrhagic cystitis.
General disorders and administration site conditions: Very common: Asthenia, predominantly mild (CTC grade 1).
Common: Pyrexia.
The frequency of adverse drug reactions relating to abnormal laboratory values is based on patients with a change from baseline of 2 or more CTC grades in the relevant laboratory parameters.
*This adverse reaction can occur in association with other dry conditions (mainly skin reactions) seen with gefitinib.
**This includes isolated reports of hepatic failure which in some cases led to fatal outcomes.
Interstitial lung disease (ILD): In the INTEREST trial, the incidence of ILD type events was 1.4% (10) patients in the gefitinib group versus 1.1% (8) patients in the docetaxel group. One ILD-type event was fatal, and this occurred in a patient receiving gefitinib.
In the ISEL trial, the incidence of ILD-type events in the overall population was approximately 1% in both treatment arms. The majority of ILD-type events reported was from patients of Asian ethnicity and the ILD incidence among patients of Asian ethnicity receiving gefitinib therapy and placebo was approximately 3% and 4% respectively. One ILD-type event was fatal, and this occurred in a patient receiving placebo.
In a post-marketing surveillance study in Japan (3350 patients) the reported rate of ILD-type events in patients receiving gefitinib was 5.8%. The proportion of ILD-type events with a fatal outcome was 38.6%.
In a phase III open-label clinical trial (IPASS) in 1217 patients comparing gefitinib to carboplatin/paclitaxel doublet chemotherapy as first-line treatment in selected patients with advanced NSCLC in Asia, the incidence of ILD-type events was 2.6% on the gefitinib treatment arm versus 1.4% on the carboplatin/paclitaxel treatment arm.