When considering the use of IRESSA as first-line treatment for locally advanced or metastatic NSCLC, it is recommended that EGFR mutation assessment of the tumour tissue is attempted for all patients. When assessing the mutation status of a patient it is important that a well-validated and robust methodology is chosen to minimise the possibility of false negative or false positive determinations. Tumour samples which are used for the diagnosis of advanced NSCLC are the preferred sample type for EGFR mutation testing. A tumour sample should be collected and tested where possible. If a tumour sample is not available or evaluable, then circulating tumour DNA (ctDNA) obtained from a blood (plasma) sample may be used. Only robust, reliable, sensitive test(s) with demonstrated utility on ctDNA should be used for the determination of EGFR mutation status of ctDNA. EGFR mutations identified in ctDNA are highly predictive of EGFR mutation positive tumours. However it is not always possible to detect EGFR mutations using this sample type (0.2% false positives, 34.3% false negatives), (see Pharmacology: Pharmacodynamics under Actions).
Interstitial Lung Disease (ILD), which may be acute in onset, has been observed in patients receiving IRESSA, and some cases have been fatal (see Adverse Reactions). If patients present with worsening of respiratory symptoms such as dyspnoea, cough and fever, IRESSA should be interrupted and prompt investigation initiated. If ILD is confirmed, IRESSA should be discontinued and the patient treated appropriately.
In a Japanese Pharmacoepidemiological case control study (see Adverse Reactions) in 3159 patients with NSCLC who were followed up for 12 weeks when receiving IRESSA or chemotherapy, the following risk factors for developing ILD (irrespective of whether the patient received IRESSA or chemotherapy) were identified: smoking, poor performance status (PS ≥ 2), CT scan evidence of reduced normal lung (≤ 50%), recent diagnosis of NSCLC (< 6 months), pre-existing ILD, increasing age (≥ 55 years old) and concurrent cardiac disease. Risk of mortality among patients who developed ILD on both treatments was higher in patients with the following risk factors: smoking, CT scan evidence of reduced normal lung (≤ 50%), pre-existing ILD, increasing age (≥ 65 years old), and extensive areas adherent to pleura (≥ 50%).
Liver function test abnormalities (including increase in alanine aminotransferase, aspartate aminotransferase, bilirubin) have been observed (see Adverse Reactions), uncommonly presenting as hepatitis. There have been isolated reports of hepatic failure which in some cases led to fatal outcomes. Therefore, periodic liver function testing is recommended. IRESSA should be used cautiously in the presence of mild to moderate change in liver function. Discontinuation should be considered if changes are severe.
Cerebrovascular events have been reported in clinical studies of IRESSA. A relationship with IRESSA has not been established.
Substances that are inducers of CYP3A4 activity may increase metabolism and decrease gefitinib plasma concentrations. Therefore, co-medication with CYP3A4 inducers (e.g. phenytoin, carbamazepine, rifampicin, barbiturates or St John's Wort) may reduce efficacy (see Interactions).
International Normalised Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin (see Interactions). Patients taking warfarin should be monitored regularly for changes in Prothrombin Time (PT) or INR.
Drugs that cause significant sustained elevation in gastric pH may reduce plasma concentrations of gefitinib and therefore may reduce efficacy (see Interactions and Pharmacology: Pharmacokinetics under Actions).
Patients should be advised to seek medical advice promptly in the event of developing: severe or persistent diarrhoea, nausea, vomiting or anorexia.
These symptoms should be managed as clinically indicated (see Adverse Reactions).
Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist.
If a diagnosis of ulcerative keratitis is confirmed, treatment with IRESSA should be interrupted, and if symptoms do not resolve, or recur on reintroduction of IRESSA, permanent discontinuation should be considered.
In a phase I/II trial of IRESSA and radiation in paediatric patients, newly diagnosed with brain stem glioma or incompletely resected supratentorial malignant glioma, 4 cases (1 fatal) of CNS haemorrhages were reported from 45 patients enrolled. A further case of CNS haemorrhage has been reported in a child with an ependymoma from a trial with IRESSA alone. An increased risk of cerebral haemorrhage in adult patients with NSCLC receiving IRESSA has not been established.
Phase II clinical trials, where IRESSA and vinorelbine have been used concomitantly, indicate that IRESSA may exacerbate the neutropenic effect of vinorelbine.
Gastrointestinal perforation has been reported in patients taking IRESSA. In most cases this is associated with other known risk factors, including increasing age, concomitant medications such as steroids or NSAIDS, underlying history of GI ulceration, smoking or bowel metastases at sites of perforation.
Also see Use in Pregnancy & Lactation and Effects on Ability to Drive and Use Machines as follows.
Effects on Ability to Drive and Use Machines: During treatment with IRESSA, asthenia has been reported and those patients who experience this symptom should observe caution when driving or using machines.