Tablets are brown coloured, round shaped, film coated tablets debossed with "N" on one side and "250" on the other.
Each film-coated tablet contains 250 mg of Gefitinib.
Pharmacology: Pharmacodynamics: Gefitinib belongs to drug class antineoplastic agents or protein kinase inhibitors. The epidermal growth factor (EGF) and its receptor (EGFR [HER1; ErbB1]) have been identified as key drivers in the process of cell growth and proliferation for normal and cancer cells. EGFR activating mutation within a cancer cell is an important factor in the promotion of tumour cell growth, blocking of apoptosis, increasing the production of angiogenic factors and facilitating the processes of metastasis. Gefitinib is a selective small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase and is an effective treatment for patients with tumours with activating mutations of the EGFR tyrosine kinase domain regardless of line of therapy. No clinically relevant activity has been shown in patients with known EGFR mutation-negative tumours. Most NSCLC tumours with sensitising EGFR kinase mutations eventually develop resistance to Gefitinib treatment, with a median time to disease progression of 1 year.
Pharmacokinetics: Absorption: Following oral administration of Gefitinib, absorption is moderately slow and peak plasma concentrations of Gefitinib typically occur at 3 to 7 hours after administration. Exposure to Gefitinib is not significantly altered by food.
Distribution: Gefitinib has a mean steady-state volume of distribution of 1400 l indicating extensive distribution into tissue. Plasma protein binding is approximately 90%. Gefitinib binds to serum albumin and alpha 1-acid glycoprotein.
Biotransformation: Gefitinib is extensively metabolised in humans. Five metabolites have been fully identified in excreta and 8 metabolites in plasma where the major metabolite identified was O-desmethyl Gefitinib.
Elimination: Gefitinib is excreted mainly as metabolites via the faeces, with renal elimination of Gefitinib and metabolites accounting for less than 4% of the administered dose. Gefitinib total plasma clearance is approximately 500 ml/min and the mean terminal half-life is 41 hours in cancer patients. Administration of Gefitinib once daily results in 2- to 8-fold accumulation, with steady-state exposures achieved after 7 to 10 doses. At steady-state, circulating plasma concentrations are typically maintained within a 2- to 3-fold range over the 24-hour dosing interval.
Hepatic impairment: 3-fold increase in exposure to Gefitinib in patients with moderate and severe hepatic impairment was observed.
Gefitinib is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of EGFR-TK.
Recommended Dosage: Dosage and Administration: The recommended dose of Gefitinib is one 250 mg tablet once a day, taken with or without food. If a dose of Gefitinib 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. Where dosing of whole tablets is not possible, such as patients who are only able to swallow liquids, tablets may be administered as a dispersion in water. The tablet should be dropped into half a glass of drinking water (non-carbonated), without crushing, and the glass stirred until the tablet has dispersed (approximately 15 minutes) and the contents subsequently drunk immediately. The glass should be rinsed with a further half glass of water and the contents drunk. The liquid can also be administered via a nasogastric tube.
Gefitinib is not recommended for use in children or adolescents as safety and effectiveness in these patient populations has not been studied.
No dosage adjustment is required on the basis of patient age, body weight, gender, ethnicity or renal function or in patients with moderate to severe hepatic impairment due to liver metastases.
Dosage adjustment: Patients with poorly tolerated diarrhoea or skin adverse drug reactions may be successfully managed by providing a brief (up to 14 days) therapy interruption followed by reinstatement of the 250 mg dose.
Route of Administration: Oral.
Symptoms and Treatment of Overdose: There is no specific treatment in the event of overdose of Gefitinib. Adverse reactions associated with overdose should be treated symptomatically; in particular severe diarrhoea should be managed as clinically indicated.
Hypersensitivity to the active substance or to any of the excipients of this product.
Breast-feeding (see Use in Pregnancy & Lactation).
When considering the use of Gefitinib as a treatment for locally advanced or metastatic NSCLC, it is important that EGFR mutation assessment of the tumour tissue is attempted for all patients. If a tumour sample is not evaluable, then circulating tumour DNA (ctDNA) obtained from a blood (plasma) sample may be used.
Only robust, reliable and sensitive test(s) with demonstrated utility for the determination of EGFR mutation status of tumours or ctDNA should be used to avoid false negative or false positive determinations.
Interstitial lung disease (ILD): Interstitial lung disease (ILD), which may be acute in onset, has been observed in 1.3% of patients receiving Gefitinib, and some cases have been fatal. If patients experience worsening of respiratory symptoms such as dyspnoea, cough and fever, Gefitinib should be interrupted and the patient should be promptly investigated. If ILD is confirmed, Gefitinib should be discontinued and the patient treated appropriately.
Hepatotoxicity and liver impairment: Liver function test abnormalities (including increases in alanine aminotransferase, aspartate aminotransferase, and 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. Gefitinib 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.
Interactions with other medicinal products: CYP3A4 inducers may increase metabolism of Gefitinib and decrease Gefitinib plasma concentrations. Therefore, concomitant administration of CYP3A4 inducers (e.g. phenytoin, carbamazepine, rifampicin, barbiturates or herbal preparations containing St John's wort/Hypericum perforatum) may reduce efficacy of the treatment and should be avoided. In individual patients with CYP2D6 poor metaboliser genotype, treatment with a potent CYP3A4 inhibitor might lead to increased plasma levels of Gefitinib. At initiation of treatment with a CYP3A4 inhibitor, patients should be closely monitored for Gefitinib adverse reactions.
International normalised ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin together with Gefitinib. Patients taking warfarin and Gefitinib concomitantly should be monitored regularly for changes in prothrombin time (PT) or INR. Medicinal products that cause significant sustained elevation in gastric pH, such as proton-pump inhibitors and h2-antagonists may reduce bioavailability and plasma concentrations of Gefitinib and, therefore, may reduce efficacy. Antacids if taken regularly close in time to administration of Gefitinib may have a similar effect.
Lactose: Gefitinib contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Sodium: Gefitinib 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 Gefitinib should be interrupted, and if symptoms do not resolve, or if symptoms recur on reintroduction of Gefitinib, permanent discontinuation should be considered.
Gastrointestinal perforation has been reported in patients taking Gefitinib. 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.
Effects on ability to drive and use machines: During treatment with Gefitinib, asthenia has been reported. Therefore, patients who experience this symptom should be cautious when driving or using machines.
Women of childbearing potential: Women of childbearing potential must be advised not to get pregnant during therapy.
Pregnancy: There are no data from the use of Gefitinib in pregnant women. The potential risk for humans is unknown. Gefitinib should not be used during pregnancy unless clearly necessary.
Breast-feeding: It is not known whether Gefitinib is secreted in human milk. Gefitinib is contraindicated during breast-feeding and therefore breast-feeding must be discontinued while receiving Gefitinib therapy.
Summary of the safety profile: The most frequently reported adverse drug reactions (ADRs) 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. (See table.)
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The metabolism of Gefitinib is via the cytochrome P450 isoenzyme CYP3A4 (predominantly) and via CYP2D6.
Active substances that may increase Gefitinib plasma concentrations: 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. In situations of concomitant treatment with potent inhibitors of CYP3A4 the patient should be closely monitored for Gefitinib adverse reactions. Concomitant treatment with an inhibitor of CYP2D6 might cause increased plasma concentrations of Gefitinib in CYP2D6 extensive metabolisers. 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. Substances that cause significant sustained elevation in gastric pH may reduce Gefitinib plasma concentrations and thereby reduce the efficacy of Gefitinib. High doses of short-acting antacids may have a similar effect if taken regularly close in time to administration of Gefitinib
Active substances that may have their plasma concentrations altered by Gefitinib: 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.
Incompatibilities: Not Applicable.
Store in the original package in order to protect from moisture. Do not store above 30°C.
L01EB01 - gefitinib ; Belongs to the class of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Used in the treatment of cancer.
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