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Cardiac: No thorough QT/QTc study was performed to rule out the effect of gefitinib on QT prolongation. Routine ECG assessments during clinical trials did not identify any concerns regarding QT prolongation (see Pharmacology: Detailed Pharmacology: Pharmacodynamics under Actions).
Carcinogenicity: Pre-clinical studies have identified a statistically significant increase in hepatocellular adenomas in rats and mice and in mesenteric lymph node hemangiosarcomas in rats. The clinical relevance of these findings is unknown (see Pharmacology: Toxicology: Carcinogenicity & Mutagenicity under Actions).
Drug Interactions: Drugs that cause significant sustained elevation in gastric pH may reduce plasma concentrations of gefitinib and therefore may reduce efficacy (see Interactions).
CYP3A4: Gefitinib is primarily metabolized by CYP3A4.
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 potentially reduce efficacy (see Interactions).
Substances that are inhibitors of CYP3A4 activity (e.g. ketoconazole, macrolides, grapefruit juice) may decrease metabolism and increase gefitinib plasma concentrations. This may be clinically relevant and caution is advised as adverse experiences are related to dose and exposure (see Interactions).
CYP2D6: In vitro studies demonstrate gefitinib has potential to inhibit CYP2D6. In a clinical trial in cancer patients, gefitinib was co-administered with metoprolol (a CYP2D6 substrate). This resulted in a 35% increase in metoprolol exposure. 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 (see Interactions).
Gastrointestinal: Diarrhea, Dehydration and Renal Dysfunction: APO-GEFITINIB use is very commonly associated with diarrhea, nausea, vomiting, stomatitis, and anorexia. 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 as any subsequent dehydration may lead to renal dysfunction if left untreated (see Recommended Dose and Dosage Adjustment under Dosage & Administration).
Gastrointestinal perforation: Gastrointestinal (GI) perforation has been reported uncommonly (0.2%) in patients taking gefitinib, and some cases have been fatal. 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, bowel metastases at sites of perforation, diverticulitis, GI obstructions, or advanced bowel disease. If a diagnosis of GI perforation is confirmed, treatment with APO-GEFITINIB should be interrupted or discontinued.
Haematologic: International Normalised Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin. Patients taking warfarin should be monitored regularly for changes in Prothrombin Time (PT) or INR (see Interactions).
Two Phase II trials using the combination gefitinib/vinorelbine have been discontinued due to a high incidence of CTC grade 3 and 4 neutropenia. When used in combination, gefitinib aggravated the neutropenic effect of vinorelbine.
Cerebrovascular events have been reported in clinical studies of gefitinib. A relationship with gefitinib has not been established.
Haemorrhage: Throughout the gefitinib lung cancer clinical trials, the incidence of haemoptysis/pulmonary haemorrhage reported on the gefitinib arm has consistently been higher than that reported on the comparator arm (e.g. on IPASS 3.5% vs. 3.1%, gefitinib vs. carboplatin/paclitaxel. Pooled incidence: gefitinib 5.3% vs. placebo 4.4%; gefitinib 5.0% vs. docetaxel 3.5%; gefitinib 3.7% vs. other chemotherapy 2.8%; overall pooled gefitinib incidence: 4.8%). This may in part be explained by the longer duration of treatment on the gefitinib arm.
Epistaxis and haematuria are commonly associated with gefitinib therapy (4.3%).
Hepatic/Biliary/Pancreatic: Hepatotoxicity: Liver function test abnormalities (including increases in alanine aminotransferase, aspartate aminotransferase, bilirubin) have been observed, uncommonly presenting as hepatitis. Isolated cases of hepatic failure and fulminant hepatitis, including fatalities, have been reported with gefitinib use. Therefore, periodic liver function testing is recommended. Gefitinib should be used cautiously in the presence of mild to moderate changes in liver function. Discontinuation should be considered if changes are severe.
Ophthalmologic: Conjunctivitis, blepharitis, and dry eye are commonly seen in patients treated with gefitinib (6.7%) and are generally mild in nature (CTC grade 1). Corneal erosion occurs uncommonly (0.3%), is reversible and sometimes is associated with aberrant eyelash growth. The safety of wearing contact lenses during gefitinib therapy has not been adequately studied.
Patients should be advised to seek medical advice promptly in the event of developing any eye symptoms. 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 (see Adverse Reactions). If a diagnosis of ulcerative keratitis is confirmed, treatment with gefitinib should be interrupted, and if symptoms do not resolve, or recur on reintroduction of gefitinib, permanent discontinuation should be considered.
Cases of corneal erosion have been reported during use of gefitinib tablets. Other ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis have been observed with gefitinib treatment. Recent corneal surgery and contact lens wearing are known to be independent risk factors for ocular toxicity including corneal erosion.
These symptoms should be managed as clinically indicated (see Recommended Dose and Dosage Adjustment under Dosage & Administration).
Renal: There have been reports of renal failure secondary to dehydration due to diarrhea, nausea, vomiting and/or anorexia, or associated with pre-renal factors such as concurrent infections or concomitant medications including chemotherapy. In more severe or persistent cases of diarrhea, or cases leading to dehydration, particularly in patients with known risk factors (e.g. renal disease, concurrent vomiting, concomitant medications that impair ability to tolerate dehydration such as NSAIDs and diuretics), gefitinib therapy should be interrupted and appropriate measures taken to intensively rehydrate the patient.
In addition, urea, creatinine and electrolytes should be monitored in patients at high risk of dehydration.
Respiratory: Interstitial Lung Disease (ILD), which may be acute in onset, has been observed in patients receiving gefitinib at an overall incidence of about 1%, and approximately 1/3 of the cases have been fatal (see Clinical Trial Adverse Drug Reactions: Interstitial Lung Disease under Adverse Reactions).
If patients present with worsening of respiratory symptoms such as dyspnoea, cough and fever, gefitinib should be interrupted and prompt investigation initiated. If ILD is confirmed, APO-GEFITINIB should be discontinued and the patient treated appropriately.
The incidence of ILD-type events was 5.8% in patients receiving gefitinib tablets in a post-marketing surveillance study in Japan (3350 patients) (see Clinical Trial Adverse Drug Reactions: Interstitial Lung Disease under Adverse Reactions). In a Japanese Pharmacoepidemiological case-control study (see Clinical Trial Adverse Drug Reactions: Interstitial Lung Disease under Adverse Reactions) in 3159 patients with NSCLC who were followed up for 12 weeks when receiving gefitinib tablets or chemotherapy, the cumulative incidence of ILD (unadjusted for imbalances in patient characteristics) at 12 weeks' follow-up was 4.0% in patients receiving gefitinib tablets and 2.1% in those receiving chemotherapy. The adjusted odds ratio (OR) of developing ILD was 3.2 (95% confidence interval (CI) 1.9 to 5.4) for gefitinib versus chemotherapy. This trial identified the following risk factors for developing ILD (irrespective of whether the patient received gefitinib or chemotherapy): 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%).
Skin: Rash is very common with gefitinib use (57.9%), mainly mild to moderate (CTC grade 1 or 2). Toxic epidermal necrolysis, Stevens Johnson syndrome and erythema multiforme occur rarely (0.04%), and some cases have been fatal (see Recommended Dose and Dosage Adjustment under Dosage & Administration). Cutaneous vasculitis, skin fissures (including rhagades) have been reported. Preclinical work in guinea pigs indicates that gefitinib may be a potential skin (contact) sensitiser. Results of an in vitro phototoxicity study demonstrated that gefitinib may have phototoxicity potential.
Monitoring and Laboratory Tests: Assessment of EGFR Mutation Status: EGFR mutation status must be known prior to starting gefitinib therapy because only patients with an activating mutation of EGFR TK should be treated with gefitinib tablets (see Indications/Uses; Pharmacology: Clinical Trials under Actions). When assessing the EGFR mutation status of a patient, it is important that a well-validated and robust methodology is chosen to minimize the possibility of false negative or false positive determinations.
Clinical characteristics of never smoker, adenocarcinoma histology, and female gender have been shown to be independent predictors of positive EGFR mutation status for both non-Asian and Asian patients. Asian patients also have a higher incidence of EGFR mutation positive tumours (approximately 40% positive rate) than non-Asian patients (approximately 10% positive rate). These clinical characteristics should not be used to guide treatment choice, however they may be helpful in guiding mutation testing. A patient must be defined as EGFR mutation positive before starting gefitinib therapy.
Hematology and Chemistry Assessment: Electrolytes, BUN, creatinine, liver function tests (alanine aminotransferase, aspartate aminotransferase, bilirubin) should be performed at baseline and periodically during gefitinib therapy.
Patients taking warfarin should be monitored regularly for changes in Prothrombin Time (PT) or INR (see Interactions).
Effects on Ability to Drive and Use Machinery: APO-GEFITINIB is not expected to impair a patient's ability to drive or use machines. However, some patients may occasionally feel weak. If this happens, patients should not drive or operate machinery.
Hepatic Impairment: Patients with moderate to severe hepatic impairment (Child Pugh B or C) due to cirrhosis have increased plasma concentrations of gefitinib (see Pharmacology under Actions; Dosage & Administration). An average 3.1-fold increase in exposure to gefitinib in patients with moderate and severe hepatic impairment was observed in a phase I hepatic impairment study. None of the patients had cancer, all had cirrhosis and some had hepatitis. This increase in exposure may be of clinical relevance since adverse experiences are related to dose and exposure to gefitinib.
In the pivotal trial IPASS, patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 2.5 times upper limit of normal (ULN) with no demonstrable liver metastases or greater than 5 times ULN in the presence of liver metastases were excluded due to potential hepatic concerns associated with the carboplatin/paclitaxel doublet. Consequently, the IPASS study does not contribute any data in this patient population.
CYP2D6 Poor Metabolisers: In a clinical trial of healthy volunteers, CYP2D6 poor metabolisers achieved a 2-fold higher mean exposure to gefitinib than in extensive metabolisers. The higher average gefitinib exposures achieved by individuals with no active CYP2D6 may be clinically relevant since adverse experiences are related to dose and exposure.
Use in Pregnancy: There are no adequate and well-controlled studies in pregnant women using gefitinib tablets. Women of childbearing potential must be advised to avoid becoming pregnant. If gefitinib tablets are used during pregnancy or if the patient becomes pregnant while receiving this drug, she should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy. Gefitinib tablets may cause fetal harm when administered to a pregnant woman (see Pharmacology: Toxicology: Reproduction & Teratology under Actions).
Use in Lactation: It is not known whether gefitinib is excreted in human milk, however this is documented to occur in pre-clinical testing (see Pharmacology: Toxicology: Reproduction & Teratology under Actions). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women should be advised against breast-feeding while receiving gefitinib therapy.
Use in Children: In a Phase I/II trial of gefitinib and radiation in paediatric patients, newly diagnosed with brain stem glioma or incompletely resected supratentorial malignant glioma, 4 cases (1 fatal) of CNS haemorrhages have been reported in 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. Gefitinib is not indicated for use in paediatric patients (≤16 years of age), as safety and effectiveness have not been established.
Use in the Elderly: Of the total number of patients participating in the INTEREST and ISEL trials, 37% were aged 65 or older. No differences in gefitinib safety or efficacy effect relative to the comparator were observed between younger and older patients.
