Presentation and Status in Health Basket
Film Coated Tablets
30 X 250 mg
The recommended posology of IRESSA is one 250 mg tablet once a day. If a dose is missed, it should be taken as soon as the patient remembers. If it is less than 12 hours to the next dose, the patient should not take the missed dose. Patients should not take a double dose (two doses at the same time) to make up for a forgotten dose.
Paediatric population: The safety and efficacy of IRESSA in children and adolescents aged less than 18 years have not been established. There is no relevant use of gefitinib in the paediatric population in the indication of NSCLC.
Hepatic impairment: Patients with moderate to severe hepatic impairment (Child Pugh B or C) due to cirrhosis have increased plasma concentrations of gefitinib. These patients should be closely monitored for adverse events. Plasma concentrations were not increased in patients with elevated aspartate
transaminase (AST), alkaline phosphatase or bilirubin due to liver metastases.
Renal impairment: No dose adjustment is required in patients with impaired renal function at creatinine clearance >20 ml/min. Only limited data are available in patients with creatinine clearance ≤ 20 ml/min and caution is advised in these patients.
Elderly: No dose adjustment is required on the basis of patient age.
CYP2D6 poor metabolisers: No specific dose adjustment is recommended in patients with known CYP2D6 poor metaboliser genotype, but these patients should be closely monitored for adverse events.
Dose adjustment due to toxicity: Patients with poorly tolerated diarrhoea or skin adverse reactions may be successfully managed by providing a brief (up to 14 days) therapy interruption followed by reinstatement of the 250 mg dose (see section 4.8). For patients unable to tolerate treatment after a therapy interruption, gefitinib should be discontinued and an alternative treatment should be considered.
Method of administration: The tablet may be taken orally with or without food, at about the same time each day. The tablet can be swallowed whole with some water or if dosing of whole tablets is not possible, tablets may be administered as a dispersion in water (non-carbonated). No other liquids should be used.
Without crushing it, the tablet should be dropped in half a glass of drinking water. The glass should be swirled occasionally, until the tablet is dispersed (this may take up to 20 minutes). The dispersion should be drunk immediately after dispersion is complete (i.e. within 60 minutes). The glass should be rinsed with half a glass of water, which should also be drunk. The dispersion can also be administered through a naso-gastric or gastrostomy tube.
For the treatment of adult patients with locally advanced or metastatic nonsmall cell lung cancer (NSCLC) with activating mutations of EGFR-TK.
Known severe hypersensitivity to the active substance or to any of the excipients of the product. Breast-feeding.
Assessment of EGFR mutation status: When assessing the EGFR mutation status of a patient, it is important that a well-validated and robust methodology is chosen to avoid false negative or false positive determinations.
Interstitial lung disease (ILD): ILD, which may be acute in onset, has been observed in 1.3 % of patients receiving IRESSA, and some cases have been fatal. If patients experience worsening of respiratory symptoms such as dyspnoea, cough and fever, IRESSA should be interrupted and the patient should be promptly investigated. If ILD is confirmed, IRESSA should be discontinued and the patient treated appropriately.
Hepatotoxicity and liver impairment: Liver function test abnormalities (including increases in alanine aminotransferase, aspartate aminotransferase, bilirubin) have been observed, 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 changes in liver function. Discontinuation should be considered if changes are severe. Impaired liver function due to cirrhosis has been shown to lead to increased plasma concentrations of gefitinib.
Lactose: IRESSA contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicinal product.
Sodium: IRESSA contains less than 1 mmol (23 mg) of sodium per tablet, that is to say it is essentially ‘sodium-free.’
Further precautions for use: Patients should be advised to seek medical advice immediately if they experience severe or persistent diarrhoea, nausea, vomiting or anorexia as these may indirectly lead to dehydration. These symptoms should be managed as clinically indicated.
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 studying the use of gefitinib and radiation in paediatric patients, with newly diagnosed brain stem glioma or incompletely resected supratentorial malignant glioma, 4 cases (1 fatal) of Central Nervous System (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 gefitinib alone. An increased risk of cerebral haemorrhage in adult patients with NSCLC receiving gefitinib has not been established.
Gastrointestinal perforation has been reported in patients taking IRESSA. In most cases this is associated with other known risk factors, including concomitant medications such as steroids or NSAIDS, underlying history of GI ulceration, age, smoking or bowel metastases at sites of perforation.
See prescribing information for full details.
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.
See prescribing information for full details.
The metabolism of gefitinib is via the cytochrome P450 isoenzyme CYP3A4 (predominantly) and via CYP2D6.
Active substances that may increase gefitinib plasma concentrations: In vitro studies have shown that gefitinib is a substrate of p-glycoprotein (Pgp). Available data do not suggest any clinical consequences to this in vitro finding.
Substances that inhibit CYP3A4 may decrease the clearance of gefitinib. Concomitant administration with potent inhibitors of CYP3A4 activity (e.g. ketoconazole, posaconazole, voriconazole, protease inhibitors, clarithromycin, telithromycin) may increase gefitinib plasma concentrations. The increase may be clinically relevant since adverse reactions are related to dose and exposure. The increase might be higher in individual patients with CYP2D6 poor metaboliser genotype. Pre-treatment with itraconazole (a potent CYP3A4 inhibitor) resulted in an 80 % increase in the mean AUC of gefitinib in healthy volunteers. In situations of concomitant treatment with potent inhibitors of CYP3A4 the patient should be closely monitored for gefitinib adverse reactions.
There are no data on concomitant treatment with an inhibitor of CYP2D6 but potent inhibitors of this enzyme might cause increased plasma concentrations of gefitinib in CYP2D6 extensive metabolisers by about 2-fold. If concomitant treatment with a potent CYP2D6 inhibitor is initiated, the patient should be closely monitored for adverse reactions.
Active substances that may reduce gefitinib plasma concentrations:
Substances that are inducers of CYP3A4 activity may increase metabolism and decrease gefitinib plasma concentrations and thereby reduce the efficacy of gefitinib. Concomitant medicinal products that induce CYP3A4 (e.g. phenytoin, carbamazepine, rifampicin, barbiturates or St John’s wort /Hypericum perforatum, should be avoided. Pre-treatment with rifampicin (a potent CYP3A4 inducer) in healthy volunteers reduced mean gefitinib AUC by 83%.
Substances that cause significant sustained elevation in gastric pH may reduce gefitinib plasma concentrations and thereby reduce the efficacy of gefitinib IRESSA. High doses of short-acting antacids may have a similar effect if taken regularly close in time to administration of gefitinib.
Concomitant administration of gefitinib with ranitidine at a dose that caused sustained elevations in gastric pH ≥5, resulted in a reduced mean gefitinib AUC by 47 % in healthy volunteers.
Active substances that may have their plasma concentrations altered by gefitinib: In vitro studies have shown that gefitinib has limited potential to inhibit CYP2D6. In a clinical trial in patients, gefitinib was co-administered with metoprolol (a CYP2D6 substrate). This resulted in a 35% increase in exposure to metoprolol. Such an increase might potentially be relevant for CYP2D6 substrates with narrow therapeutic index. When the use of CYP2D6 substrates are considered in combination with gefitinib, a dose modification of the CYP2D6
substrate should be considered especially for products with a narrow therapeutic window.
Gefitinib inhibits the transporter protein BCRP in vitro, but the clinical relevance of this finding is unknown.
Other potential interactions: INR elevations and/or bleeding events have been reported in some patients concomitantly taking warfarin.
Pregnancy and Lactation
Pregnancy: There are no data from the use of gefitinib in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. IRESSA should not be used during pregnancy unless clearly necessary.
Breastfeeding: Gefitinib is contraindicated during breastfeeding and therefore breast-feeding must be discontinued while receiving IRESSA therapy.
See prescribing information for full details.
There is no specific treatment in the event of overdose of gefitinib. However, in phase I clinical trials, a limited number of patients were treated with daily doses of up to 1000 mg. An increase of frequency and severity of some adverse reactions was observed, mainly diarrhoea and skin rash. Adverse reactions associated with overdose should be treated symptomatically; in particular severe diarrhoea should be managed as clinically indicated. In one study a limited number of patients were treated weekly with doses from 1500 mg to 3500 mg. In this study IRESSA exposure did not increase with increasing dose, adverse events were mostly mild to moderate in severity, and were consistent with the known safety profile of IRESSA.