Iressa

Iressa - General Information

Iressa (originally coded ZD1839) is a drug used in the treatment of certain types of cancer. Acting in a similar manner to erlotinib (marketed as Tarceva), gefitinib selectively targets the mutant proteins in malignant cells. It is marketed by AstraZeneca under the trade name Iressa. [Wikipedia]

Pharmacology of Iressa

Iressa 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.

Iressa for patients

Patients should be advised to seek medical advice promptly if they develop 1) severe or persistent diarrhea, nausea, anorexia, or vomiting, as these have sometimes been associated with dehydration; 2) an onset or worsening of pulmonary symptoms, ie, shortness of breath or cough; 3) an eye irritation; or, 4) any other new symptom.

Women of childbearing potential must be advised to avoid becoming pregnant.

Iressa Interactions

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 (see CLINICAL PHARMACOLOGY-Pharmacokinetics-Drug-Drug Interactions and DOSAGE AND ADMINISTRATION-Dosage Adjustment sections).

International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin while on IRESSA 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 IRESSA.

Drugs that cause significant sustained elevation in gastric pH (histamine H₂-receptor antagonists such as ranitidine or cimetidine) may reduce plasma concentrations of IRESSA and therefore potentially may reduce efficacy.

Phase II clinical trial data, where IRESSA and vinorelbine have been used concomitantly, indicate that IRESSA may exacerbate the neutropenic effect of vinorelbine.

Iressa Contraindications

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

Additional information about Iressa

Iressa Indication: For the continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of either platinum-based or docetaxel chemotherapies.
Mechanism Of Action: Iressa inhibits the epidermal growth factor receptor (EGFR) tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme. Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited; and malignant cells are inhibited. Iressa is the first selective inhibitor of the EGFR tyrosine kinase which is also referred to as Her1 or ErbB-1. EGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers. Overexpression leads to inappropriate activation of the apoptotic Ras signal transduction cascade, eventually leading to uncontrolled cell proliferation.
Drug Interactions: Amobarbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Aprobarbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Butabarbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Butalbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Butethal This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Carbamazepine This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Dihydroquinidine barbiturate This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Ethotoin This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Fosphenytoin This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Mephenytoin This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Phenytoin This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Heptabarbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Hexobarbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Methohexital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Methylphenobarbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Pentobarbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Phenobarbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Primidone This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Quinidine barbiturate This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Secobarbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
St. John's Wort This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Talbutal This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
Warfarin Iressa increases the anticoagulant effect
Acenocoumarol Iressa increases the anticoagulant effect
Dicumarol Iressa increases the anticoagulant effect
Anisindione Iressa increases the anticoagulant effect
Clarithromycin This CYP3A4 inhibitor increases levels/toxicity of gefitinib
Erythromycin This CYP3A4 inhibitor increases levels/toxicity of gefitinib
Itraconazole This CYP3A4 inhibitor increases levels/toxicity of gefitinib
Ketoconazole This CYP3A4 inhibitor increases levels/toxicity of gefitinib
Ritonavir This CYP3A4 inhibitor increases levels/toxicity of gefitinib
Rifampin Rifampin reduces levels and efficacy of gefitinib
Food Interactions: Take without regard to meals.
Avoid fresh grapefruit and its juice during therapy as grapefruit may increase serum product levels.
Generic Name: Gefitinib
Synonyms: ZD1839; ZD-1839
Drug Category: Antineoplastic Agents; Protein Kinase Inhibitors
Drug Type: Small Molecule; Approved; Investigational

Other Brand Names containing Gefitinib: Iressa; Irressat; Tarceva;
Absorption: Absorbed slowly after oral administration with mean bioavailability of 60%.
Toxicity (Overdose): The acute toxicity of gefitinib up to 500 mg in clinical studies has been low. In non-clinical studies, a single dose of 12,000 mg/m² (about 80 times the recommended clinical dose on a mg/m² basis) was lethal to rats. Half this dose caused no mortality in mice. Symptoms of overdose include diarrhea and skin rash.
Protein Binding: 90% primarily to serum albumin and alpha 1-acid glycoproteins.
Biotransformation: Primarily hepatic via 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.
Half Life: 48 hours
Dosage Forms of Iressa: Tablet Oral
Chemical IUPAC Name: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine
Chemical Formula: C22H24ClFN4O3
Gefitinib on Wikipedia: https://en.wikipedia.org/wiki/Gefitinib
Organisms Affected: Humans and other mammals