IRESSA (Page 3 of 6)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of IRESSA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Renal and urinary disorders: cystitis, hemorrhagic cystitis

Skin and subcutaneous tissue disorders: cutaneous vasculitis

7 DRUG INTERACTIONS

7.1 Drugs Affecting Gefitinib Exposure

CYP3A4 Inducer

Drugs that are strong inducers of CYP3A4 increase the metabolism of gefitinib and decrease gefitinib plasma concentrations. Increase IRESSA to 500 mg daily in patients receiving a strong CYP3A4 inducer (e.g., rifampicin, phenytoin, or tricyclic antidepressant) and resume IRESSA at 250 mg 7 days after discontinuation of the strong inducer [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3)].

CYP3A4 Inhibitor

Drugs that are strong inhibitors of CYP3A4 (e.g., ketoconazole and itraconazole) decrease gefitinib metabolism and increase gefitinib plasma concentrations. Monitor adverse reactions when administering strong CYP3A4 inhibitors with IRESSA.

Drugs Affecting Gastric pH

Drugs that elevate gastric pH (e.g., proton pump inhibitors, histamine H2 -receptor antagonists, and antacids) may reduce plasma concentrations of gefitinib. Avoid concomitant use of IRESSA with proton pump inhibitors, if possible. If treatment with a proton-pump inhibitor is required, take IRESSA 12 hours after the last dose or 12 hours before the next dose of the proton-pump inhibitor. Take IRESSA 6 hours after or 6 hours before an H2 -receptor antagonist or an antacid [see Clinical Pharmacology (12.3)].

7.2 Hemorrhage in Patients taking Warfarin

International Normalized Ratio (INR) elevations and/or hemorrhage 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on its mechanism of action and animal data, IRESSA can cause fetal harm when administered to a pregnant woman. In animal reproductive studies, oral administration of gefitinib from organogenesis through weaning resulted in fetotoxicity and neonatal death at doses below the recommended human dose (see Animal Data). Advise pregnant women of the potential hazard to a fetus or potential risk for loss of the pregnancy.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and miscarriage is 15-20% of clinically recognized pregnancies.

Data

Animal Data

A single dose study in rats showed that gefitinib crosses the placenta after an oral dose of 5 mg/kg (30 mg/m2 , about 0.2 times the recommended human dose on a mg/m2 basis). When pregnant rats were treated with 5 mg/kg from the beginning of organogenesis to the end of weaning there was a reduction in the number of offspring born alive. This effect was more severe at 20 mg/kg (approximate the human clinical dose on a mg/m2 basis) and was accompanied by high neonatal mortality soon after parturition. In rabbits, a dose of 20 mg/kg/day (240 mg/m2 , about twice the recommended dose in humans on a mg/m2 basis) caused reduced fetal weight.

8.2 Lactation

Risk Summary

It is not known whether IRESSA is excreted in human milk. Animal studies indicate the gefitinib and its metabolites are present in rat milk at a concentration higher than those in maternal plasma. Because of the potential for serious adverse reactions in nursing infants from IRESSA, advise women to discontinue breast-feeding during treatment with IRESSA.

Data

Animal Data

Levels of gefitinib and its metabolites were 11-to-19-fold higher in milk than in blood, after oral exposure of lactating rats to a dose of 5 mg/kg.

8.3 Females and Males of Reproductive Potential

Contraception

Based on its mechanism of action and animal data, IRESSA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with IRESSA and for at least two weeks following completion of therapy.

Infertility

IRESSA may result in reduced fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of IRESSA in pediatric patients have not been established.

8.5 Geriatric Use

Of the 823 patients enrolled in two randomized, active-controlled clinical trials 374 patients (45%) were 65 years and older, and 93 patients (11%) were 75 years and older. No overall differences in safety were observed between patients 65 years and older and those younger than 65 years. There is insufficient information to assess for differences in efficacy between older and younger patients.

8.6 Renal Impairment

Less than four percent (<4%) of gefitinib and its metabolites are excreted via the kidney. No clinical studies were conducted with IRESSA in patients with severe renal impairment.

8.7 Hepatic Impairment

The systemic exposure of gefitinib was compared in patients with mild, moderate, or severe hepatic impairment due to cirrhosis (according to Child-Pugh classification) and healthy subjects with normal hepatic function (N=10/group). The mean systemic exposure (AUC0-∞ ) was increased by 40% in patients with mild impairment, 263% in patients with moderate impairment, and 166% in patients with severe hepatic impairment. Monitor adverse reactions when IRESSA is administered to patients with moderate and severe hepatic impairment.

In a study comparing 13 patients with liver metastases and moderate hepatic impairment (addition of CTC grade of baseline AST/SGOT, ALP, and bilirubin equals 3 to 5) to 14 patients with liver metastases and normal hepatic function, the systemic exposure of gefitinib was similar [see Warnings and Precautions (5.2)].

10 OVERDOSAGE

Twenty three patients were treated weekly with doses from 1500 mg to 3500 mg, and IRESSA 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 IRESSA. In the event of suspected overdose, interrupt IRESSA, institute supportive care, and observe until clinical stabilization. There are no specific measures/treatments that should be taken following IRESSA overdosing.

11 DESCRIPTION

Gefitinib is a kinase inhibitor.

The chemical name of gefitinib is 4-Quinazolinamine N -(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl) propoxy] and the following structural formula:

structural formula for gefitinib
(click image for full-size original)

Gefitinib has the molecular formula C22 H24 ClFN4 O3 , a relative molecular mass of 446.9 daltons and is a white-colored powder. Gefitinib is a free base. The molecule has pKa s of 5.4 and 7.2. Gefitinib can be defined as sparingly soluble at pH 1, but is practically insoluble above pH 7, with the solubility decreasing sharply between pH 4 and pH 6. In non-aqueous solvents, gefitinib is freely soluble in glacial acetic acid and dimethyl sulfoxide, soluble in pyridine, sparingly soluble in tetrahydrofuran, and slightly soluble in methanol, ethanol (99.5%), ethyl acetate, propan-2-ol and acetonitrile.

IRESSA® (gefitinib) tablets are available as brown film-coated tablets, containing 250 mg of gefitinib, for oral administration. The inactive ingredients of the tablet core of IRESSA tablets are lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate and magnesium stearate. The tablet coating is composed of hypromellose, polyethylene glycol 300, titanium dioxide, red ferric oxide and yellow ferric oxide.

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