Adverse reactions : תופעות לוואי

4.8 Undesirable effects

Summary of the safety profile
In the pooled dataset from the ISEL, INTEREST and IPASS phase III clinical trials (2462 IRESSA-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

Tabulated list of adverse reactions
The safety profile presented in Table 1 is based on the gefitinib clinical development programme and postmarketed experience. Adverse reactions have been assigned to the frequency categories in Table 1 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 IRESSA-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.

Table 1 Adverse reactions
Adverse reactions by system organ class and frequency
Metabolism and nutrition      Very Common                          Anorexia mild or moderate disorders                                                          (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        Common                            Interstitial lung disease (1.3 mediastinal disorders                                              %), 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).
Pancreatitis,
Uncommon 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                                Hepatits **
Skin and subcutaneous tissue            Very Common                             Skin reactions, mainly a mild disorders                                                                       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
Uncommon                                Palmar-plantar erythrodysaesthesia syndrome
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                   Very Common                             Asthenia, predominantly mild administration site conditions                                                  (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 IRESSA 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 IRESSA treatment arm versus 1.4% on the carboplatin/paclitaxel treatment arm.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il