Contents

Gefitinib

Indication

Gefitinib Tablets 250 mg 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.

Dosage / Direction For Use

The recommended posology of Gefitinib Tablets 250 mg is one tablet once a day. If a dose of Gefitinib Tablets 250 mg 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 Gefitinib Tablets 250 mg in children and adolescents aged less than 18 years have not been established. There is no relevant use of Gefitinib Tablets 250 mg 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.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. For patients unable to tolerate treatment after a therapy interruption, it should be discontinued and an alternative treatment should be considered.Method of administration: The tablet may be taken 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 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-gastricor gastrostomy tube.

Overdosage

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 Gefitinib Tablets 250 mg 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 Gefitinib.

Administration

May be taken with or without food: Tab may be dispersed in ½ glass of non-carbonated water. No other liqd should be used. Drop the tab in water & w/o crushing it, stir until dispersed (approx 20 min). Drink the liqd immediately. Rinse the glass w/ another ½ glass of water & drink. Dispersed liqd may also be administered via a nasogastric tube. Take at about the same time each day.

Contraindication

Gefitinib Tablets is contraindicated in patients with severe hypersensitivity to gefitinib or to any other component of Gefitinib Tablets.

Special Precaution

Avoid false -ve or +ve EGFR determinations. Discontinue if interstitial lung disease or ulcerative keratitis occurs. GI perforation. Galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. Avoid concomitant use w/ CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampicin, barbiturates or herbal prep containing St. John’s wort). Hepatoxicity & liver impairment. Childn & adolescent <18 yr

Adverse Reactions

Anorexia; diarrhea, vomiting, nausea, stomatitis; elevation in alanine aminotransferase; skin reactions mainly pustular rash; fissures, asthenia. Conjunctivitis, blepharitis, dry eye; hemorrhage (eg, epistaxis & hematuria); interstitial lung disease; dehydration, dry mouth; elevation in aspartate aminotransferase & total bilirubin; nail disorder, alopecia; asymptomatic lab elevations in blood creatinine, proteinuria, cystitis; pyrexia.

Drug Interaction

Substances that are inducers of CYP3A4 activity increase the metabolism of Gefitinib and decrease its plasma concentrations. In patients receiving a potent CYP3A4 inducer such as rifampicin or phenytoin, a dose increase to 500 mg daily should be considered in the absence of severe adverse drug reaction, and clinical response and adverse events should be carefully monitored.International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin while on Gefitinib therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR.Substances that are potent inhibitors of CYP3A4 activity (eg, ketoconazole and itraconazole) decrease Gefitinib metabolism and increase Gefitinib plasma concentrations. This increase may be clinically relevant as adverse experiences are related to dose and exposure; therefore, caution should be used when administering CYP3A4 inhibitors with Gefitinib.Drugs that cause significant sustained elevation in gastric pH (histamine H2-receptor antagonists such as ranitidine or cimetidine) may reduce plasma concentrations of Gefitinib and therefore potentially may reduce efficacy.

Storage

Store at temperatures not exceeding 30°C. Protect from light & moisture.

Description

Each film-coated tabled contains: Gefitinib 250 mg.Gefitinib is a white to off-white crystalline powder and soluble in dimethyl sulphoxide. Chemically, it is N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy) quinazolin-4-Amine. Its molecular formula is C22H24CIFN40 & molecular weight 446.90.

Action

Pharmacology: Pharmacodynamics: Mechanism of Action: The mechanism of the clinical antitumor action of gefitinib is not fully characterized. Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). EGFR is expressed on the cell surface of many normal cells and cancer cells. No clinical studies have been performed that demonstrate a correlation between EGFR receptor expression and response to Gefitinib.Pharmacokinetics: Gefitinib is absorbed slowly after oral administration with mean bioavailability of 60%. Elimination is by metabolism (primarily CYP3A4) and excretion in feces. The elimination half-life is about 48 hours. Daily oral administration of Gefitinib to cancer patients resulted in a 2-fold accumulation compared to single dose administration. Steady state plasma concentrations are achieved within 10 days.Absorption and Distribution: Gefitinib is slowly absorbed, with peak plasma levels occurring 3-7 hours after dosing and mean oral bioavailability of 60%. Bioavailability is not significantly altered by food. Gefitinib is extensively distributed throughout the body with a mean steady state volume of distribution of 1400 L following intravenous administration. In vitro binding of gefitinib to human plasma proteins (serum albumin and α1-acid glycoprotein) is 90% and is independent of drug concentrations.Metabolism and Elimination: Gefitinib undergoes extensive hepatic metabolism in humans, predominantly by CYP3A4. Three sites of biotransformation have been identified: metabolism of the N-propoxymorpholino-group, demethylation of the methoxy-substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group.Five metabolites were identified in human plasma. Only O-desmethyl gefitinib has exposure comparable to gefitinib.Although this metabolite has similar EGFR-TK activity to gefitinib in the isolated enzyme assay, it had only 1/14 of the potency of gefitinib in one of the cell-based assays.Gefitinib is cleared primarily by the liver, with total plasma clearance and elimination half-life values of 595 mL/min and 48 hours, respectively, after intravenous administration. Excretion is predominantly via the feces (86%), with renal elimination of drug and metabolites accounting for less than 4% of the administered dose.