Gafvex

A brick red colored round biconvex film-coated tablets.
Each film-coated tablet contains: Gefitinib 250 mg, Excipients q.s.
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 C₂₂H₂₄CIFN₄O & molecular weight 446.90.

Pharmacological Classification: Anti-neoplastic.
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.

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.

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.

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.

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

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 Gefitinib Tablets 250 mg, and some cases have been fatal. If patients experience worsening of respiratory symptoms such as dyspnoea, cough and fever, Gefitinib Tablets 250 mg should be interrupted and the patient should be promptly investigated. If ILD is confirmed, Gefitinib Tablets 250 mg should be discontinued and the patient treated appropriately.
In a Japanese pharmacoepidemiological case control study in 3159 patients with NSCLC receiving Gefitinib Tablets 250 mg or chemotherapy who were followed up for 12 weeks, the following risk factors for developing ILD (irrespective of whether the patient received Gefitinib Tablets 250 mg 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, older age (55 years old) and concurrent cardiac disease. An increased risk of ILD on gefitinib relative to chemotherapy was seen predominantly during the first 4 weeks of treatment (adjusted OR 3.8; 95% CI 1.9 to 7.7); thereafter the relative risk was lower (adjusted OR 2.5; 95% CI 1.1 to 5.8). Risk of mortality among patients who developed ILD on Gefitinib Tablets 250 mg or chemotherapy was higher in patients with the following risk factors: smoking, CT scan evidence of reduced normal lung (50%), pre-existing ILD, older age (65 years old), and extensive areas adherent to pleura (50%).
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. Gefitinib Tablets 250 mg 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 Tablets 250 mg may have a similar effect.
Data from phase II clinical trials, where gefitinib and vinorelbine have been used concomitantly, indicate that gefitinib may exacerbate the neutropenic effect of vinorelbine.
Lactose: Gefitinib Tablets 250 mg contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicinal product.
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 tablets 250 mg should be interrupted, and if symptoms do not resolve, or if symptoms recur on reintroduction of Gefitinib tablets 250 mg, 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 Gefitinib tablets 250 mg. 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.

Frequencies of occurrence of undesirable effects are defined as: Very common (1/10); common (>1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See table.)

Click on icon to see table/diagram/image

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.

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

Targeted Cancer Therapy

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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