Gefitinib

Oral
EGFR positive locally advanced non-small cell lung cancer, EGFR positive metastatic non-small cell lung cancer

Patients taking potent CYP3A4 inducers (e.g. rifampicin, phenytoin, TCAs): 500 mg once daily, if tolerated. May reduce dose to 250 mg once daily after 7 days of discontinuing the potent CYP3A4 inducer.

Pharmacogenomics:

Gefitinib is predominantly metabolised by CYP3A4 isoenzyme, and by CYP2D6 isoenzyme to form O-desmethyl gefitinib metabolite. Individuals with reduced CYP2D6 enzyme activity, known as CYP2D6 poor metabolisers, may experience increased gefitinib exposure.

CYP2D6 ultrarapid metabolisers
Patients may experience decreased gefitinib plasma concentrations; however, no dosage adjustment is needed.

CYP2D6 intermediate metabolisers
Patients may experience higher gefitinib plasma levels resulting in increased risk of adverse effects. However, the adverse effects are manageable and reversible; thus, no dosage adjustment is needed.

CYP2D6 poor metabolisers
Patients may experience increased exposure which may be clinically important since some adverse effects are related to higher gefitinib exposure (e.g. increased risk of severe hepatotoxicity and rash). Although no specific dosage adjustment is recommended in CYP2D6 poor metabolisers, these individuals should be closely monitored for adverse events.

CYP2D6 genetic testing prior to gefitinib treatment initiation has not been addressed by currently available references.

Some mutations of EGFR may lead to enhanced activation of EGFR tyrosine kinase in patients with non-small cell lung carcinoma (NSCLC). Various somatic exons 18, 19 and 21 corresponding to tyrosine kinase domain of EGFR have been associated with clinical response. The exon 19 leucine-arginine-glutamate-alanine (LREA) deletion and L858R in exon 21 comprise approx 45 and 40%, respectively, of EGFR mutations identified in patients with NSCLC. The prevalence of these genomic variants is approx 10% in Caucasians and up to 50% in Asian populations with NSCLC.

EGFR mutation testing is recommended prior to gefitinib NSCLC treatment initiation. If tumour specimen is not evaluable, the circulating tumour DNA (ctDNA) from a plasma specimen may be used.

The safety and efficacy of gefitinib have not been established in patients whose tumours have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations.

film-coated tab: May be taken with or without food. May also be dispersed in ½ glass of plain, non-carbonated water. No other liqd should be used. Drop the tab in water & stir w/o crushing until it disperses (approx 10 min). Drink immediately. Rinse glass w/ another ½ glass of water & drink. Dispersed liqd may also be administered via NG tube.

Lactation.

Patient with history of keratitis, ulcerative keratitis or severe dry eyes; recent corneal surgery, wearing of contact lenses; risk factors for gastrointestinal perforation (e.g. history of gastrointestinal ulceration, age, smoking, bowel metastases). Renal CrCl ≤20 mL/min and moderate to severe hepatic impairment. Pregnancy. Patients taking potent CYP3A4 inducers. CYP2D6 poor metabolisers.

Significant: Gastrointestinal effects (e.g. severe or persistent diarrhoea, nausea, vomiting, anorexia, gastrointestinal perforation), dermatologic toxicity (e.g. toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, dermatitis bullous), ocular toxicity (e.g. keratitis, corneal erosion, abnormal eyelash growth, conjunctivitis, blepharitis, dry eyes); elevated ALT/AST and bilirubin.
Gastrointestinal disorders: Nausea, vomiting, stomatitis, dry mouth, pancreatitis.
General disorders and admin site conditions: Asthenia, pyrexia.
Immune system disorders: Urticaria, angioedema.
Investigations: Increased blood creatinine.
Metabolism and nutrition disorders: Anorexia, dehydration.
Renal and urinary disorders: Proteinuria, cystitis.
Skin and subcutaneous tissue disorders: Pustular rash, pruritus, dry skin, skin fissures, erythema, nail disorder, alopecia.
Vascular disorders: Epistaxis, haematuria.
Potentially Fatal: Interstitial lung disease (ILD) or ILD-like reactions (e.g. acute respiratory distress syndrome, lung infiltration, pneumonitis, pulmonary fibrosis), CNS haemorrhage. Rarely, hepatic failure.

This drug may cause asthenia, if affected, do not drive or operate machinery.

Establish EGFR mutation status prior to treatment initiation. Monitor LFTs (e.g. ALT, AST, bilirubin), renal function tests, and serum electrolytes at baseline and periodically thereafter; INR or prothrombin time in patients receiving warfarin. Assess for symptoms of gastrointestinal perforation, dermatologic, ocular, or pulmonary toxicity especially in CYP2D6 poor metabolisers and patients with hepatic impairment.

Symptoms: Diarrhoea, skin rash. Management: Symptomatic and supportive treatment.

Decreased plasma concentrations and efficacy with CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, barbiturates). Increased plasma levels and risk of adverse effects with potent CYP3A4 inhibitors (e.g. ketoconazole, protease inhibitors, clarithromycin). Increased risk of elevated INR and bleeding events with warfarin. Reduced plasma concentrations, bioavailability and efficacy with drugs that elevate gastric pH (e.g. PPIs, H₂-receptor antagonists, antacids). May exacerbate neutropenic effects of vinorelbine. May increase exposure of metoprolol. Increased risk of gastrointestinal perforation with NSAIDs or steroids.

Increased plasma concentrations and risk of toxicity with grapefruit or grapefruit juice. Decreased plasma levels and efficacy with St. John’s wort.

Description:
Mechanism of Action: Gefitinib is a tyrosine kinase inhibitor that reversibly blocks the kinase activity of wild-type and certain activating mutations of epidermal growth factor receptor (EGFR), which is responsible for cell growth and proliferation expressed on cell surfaces of normal and cancer cells. It prevents the autophosphorylation of tyrosine residues associated with EGFR receptor, thereby inhibiting further downstream signaling and EGFR-dependent proliferation. It has a higher binding affinity for EGFR exon 19 deletion and exon 21 (L858R) substitution mutation as compared with the wild-type EGFR.
Pharmacokinetics:
Absorption: Slowly absorbed from the gastrointestinal tract. Bioavailability: Approx 60%. Time to peak plasma concentration: 3-7 hours.
Distribution: Extensively distributed throughout the body. Volume of distribution: 1,400 L. Plasma protein binding: Approx 90%, mainly to albumin and α₁-acid glycoprotein.
Metabolism: Extensively metabolised in the liver primarily by CYP3A4 isoenzyme, and to a lesser extent by CYP2D6 isoenzyme into metabolite, O-desmethyl gefitinib.
Excretion: Mainly via faeces (86% as metabolites); urine (<4%). Elimination half-life: Approx 41-48 hours.

Source: National Center for Biotechnology Information. PubChem Database. Gefitinib, CID=123631, https://pubchem.ncbi.nlm.nih.gov/compound/Gefitinib (accessed on Jan. 22, 2020)

Store between 20-25°C. Protect from moisture. This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.

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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