Iressa Information
Iressa (Gefitinib) Description
Iressa (Gefitinib) (gefitinib tablets) contain 250 mg of gefitinib and are available as brown film-coated tablets for daily oral administration.
Gefitinib is an anilinoquinazoline with the chemical name 4-Quinazolinamine, -(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-4-morpholin) propoxy] and the following structural formula:
It has the molecular formula CHClFNO, a relative molecular mass of 446.9 and is a white-colored powder. Gefitinib is a free base. The molecule has pKs of 5.4 and 7.2 and therefore ionizes progressively in solution as the pH falls. Gefitinib can be defined as sparingly soluble at pH 1, but is practically insoluble above pH 7, with the solubility dropping sharply between pH 4 and pH 6. In non-aqueous solvents, gefitinib is freely soluble in glacial acetic acid and dimethylsulphoxide, soluble in pyridine, sparingly soluble in tetrahydrofuran, and slightly soluble in methanol, ethanol (99.5%), ethyl acetate, propan-2-ol and acetonitrile.
The inactive ingredients of Iressa (Gefitinib) tablets are: Lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate and magnesium stearate. hypromellose, polyethylene glycol 300, titanium dioxide, red ferric oxide and yellow ferric oxide.
Iressa (Gefitinib) Clinical Pharmacology
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.
Non-Small Cell Lung Cancer (NSCLC): Refractory Disease Tumor Response Study -
Two hundred and sixteen patients received Iressa (Gefitinib) , 102 (47%) and 114 (53%) receiving 250 mg and 500 mg daily doses, respectively. Study patient demographics and disease characteristics are summarized in Table 1. Forty-one percent of the patients had received two prior treatment regimens, 33% three prior treatment regimens, and 25% four or more prior treatment regimens. Effectiveness of Iressa (Gefitinib) as third line therapy was determined in the 142 evaluable patients with documented disease progression on platinum and docetaxel therapies or who had had unacceptable toxicity on these agents.
Table 2 shows tumor response rates and response duration. The overall response rate for the 250 and 500 mg doses combined was 10.6% (95% CI: 6%, 16.8%). Response rates appeared to be highly variable in subgroups of the treated population: 5.1% (4/79) in males, 17.5% (11/63) in females, 4.6% (5/108) in previous or current smokers, 29.4% (10/34) in nonsmokers, 12.4% (12/97) with adenocarcinoma histology, and 6.7% (3/45) with other NSCLC histologies. Similar differences were seen in a multinational study in patients who had received 1 or 2 prior chemotherapy regimens, at least 1 of which was platinum-based. In responders, the median time from diagnosis to study randomization was 16.7 months (range 8 to 34 months).
Non-Small Cell Lung Cancer (NSCLC): Refractory Disease Survival Study -
Non-Small Cell Lung Cancer (NSCLC); Studies of First-line Treatment in Combination with Chemotherapy -
Iressa (Gefitinib) Indications And Usage
Iressa (Gefitinib) is indicated as monotherapy for the continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies who are benefiting or have benefited from Iressa (Gefitinib) .
In light of positive survival data with other agents including another oral EGFR inhibitor, physicians should use other treatment options in advanced non-small cell lung cancer patient populations who have received one or two prior chemotherapy regimens and are refractory or intolerant to their most recent regimen.
The effectiveness of Iressa (Gefitinib) was initially based on objective response rates (see section). Subsequent studies intended to demonstrate an increase in survival have been unsuccessful. Specifically, results from a large placebo-controlled randomized trial in patients with advanced NSCLC who progressed while receiving or within 90 days of the last dose of chemotherapy or were intolerant to the most recent prior chemotherapy regimen, did not show an improvement in survival (see section).
Results from two large, controlled, randomized trials in first-line treatment of non-small cell lung cancer showed no benefit from adding Iressa (Gefitinib) to doublet, platinum-based chemotherapy.
Iressa (Gefitinib) Contraindications
Iressa (Gefitinib) is contraindicated in patients with severe hypersensitivity to gefitinib or to any other component of Iressa (Gefitinib) .
Iressa (Gefitinib) Warnings
Cases of interstitial lung disease (ILD) have been observed in patients receiving Iressa (Gefitinib) at an overall incidence of about 1%. Approximately 1/3 of the cases have been fatal. The reported incidence of ILD was about 2% in the Japanese post-marketing experience, about 0.3% in approximately 23,000 patients treated with Iressa (Gefitinib) in a US expanded access program and about 1% in the studies of first-line use in NSCLC (but with similar rates in both treatment and placebo groups).
Reports have described the adverse event as interstitial pneumonia, pneumonitis and alveolitis. Patients often present with the acute onset of dyspnea, sometimes associated with cough or low-grade fever, often becoming severe within a short time and requiring hospitalization. ILD has occurred in patients who have received prior radiation therapy (31% of reported cases), prior chemotherapy (57% of reported patients), and no previous therapy (12% of reported cases). Patients with concurrent idiopathic pulmonary fibrosis whose condition worsens while receiving Iressa (Gefitinib) have been observed to have an increased mortality compared to those without concurrent idiopathic pulmonary fibrosis.
In the event of acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever), Iressa (Gefitinib) therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, Iressa (Gefitinib) should be discontinued and the patient treated appropriately (see , and sections).
Iressa (Gefitinib) may cause fetal harm when administered to a pregnant woman. A single dose study in rats showed that gefitinib crosses the placenta after an oral dose of 5 mg/kg (30 mg/m, about 1/5 the recommended human dose on a mg/m basis). When pregnant rats were treated with 5 mg/kg from the beginning of organogenesis to the end of weaning gave birth, there was a reduction in the number of offspring born alive. This effect was more severe at 20 mg/kg and was accompanied by high neonatal mortality soon after parturition. In this study a dose of 1 mg/kg caused no adverse effects.
In rabbits, a dose of 20 mg/kg/day (240 mg/m, about twice the recommended dose in humans on a mg/m basis) caused reduced fetal weight.
There are no adequate and well-controlled studies in pregnant women using Iressa (Gefitinib) . If Iressa (Gefitinib) is used during pregnancy or if the patient becomes pregnant while receiving this drug, she should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy.
Iressa (Gefitinib) Precautions
In vitro
in vivo
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 (see , and sections).
Women of childbearing potential must be advised to avoid becoming pregnant (see ).
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 and sections).
International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin while on Iressa (Gefitinib) therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR (see and sections).
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 (Gefitinib) (see and sections).
Drugs that cause significant sustained elevation in gastric pH (histamine H-receptor antagonists such as ranitidine or cimetidine) may reduce plasma concentrations of Iressa (Gefitinib) and therefore potentially may reduce efficacy (see section).
Phase II clinical trial data, where Iressa (Gefitinib) and vinorelbine have been used concomitantly, indicate that Iressa (Gefitinib) may exacerbate the neutropenic effect of vinorelbine.
Gefitinib has been tested for genotoxicity in a series of (bacterial mutation, mouse lymphoma, and human lymphocyte) assays and an rat micronucleus test. Under the conditions of these assays, gefitinib did not cause genetic damage.
Carcinogenicity studies have not been conducted with gefitinib.
Pregnancy Category D
Iressa (Gefitinib) is not indicated for use in pediatric patients as safety and effectiveness have not been established (see CLINICAL PHARMACOLOGY-Special Populations-Pediatric).
In clinical trials of Iressa (Gefitinib) alone or with radiation in pediatric patients with primary Central Nervous System (CNS) tumors, cases of CNS hemorrhage and death have been reported. There are insufficient data in pediatric patients to establish a causal relationship. There is no evidence to suggest increased risk of cerebral hemorrhage in adult patients with NSCLC receiving Iressa (Gefitinib) .
Iressa (Gefitinib) is not indicated for use in pediatric patients as safety and effectiveness have not been established.
Iressa (Gefitinib) Adverse Reactions
The safety database includes 941 patients from clinical trials and approximately 23,000 patients in the Expanded Access Program.
Table 3 includes drug-related adverse events with an incidence of 5% for the 216 patients who received either 250 mg or 500 mg of Iressa (Gefitinib) monotherapy for treatment of NSCLC. The most common adverse events reported at the recommended 250 mg daily dose were diarrhea, rash, acne, dry skin, nausea, and vomiting (see and sections). The 500 mg dose showed a higher rate for most of these adverse events.
Table 4 provides drug-related adverse events with an incidence of 5% by CTC grade for the patients who received the 250 mg/day dose of Iressa (Gefitinib) monotherapy for treatment of NSCLC. Only 2% of patients stopped therapy due to an adverse drug reaction (ADR). The onset of these ADRs occurred within the first month of therapy.
Other adverse events reported at an incidence of
Iressa (Gefitinib) Overdosage
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/m (about 80 times the recommended clinical dose on a mg/m basis) was lethal to rats. Half this dose caused no mortality in mice.
There is no specific treatment for an Iressa (Gefitinib) overdose and possible symptoms of overdose are not established. However, in Phase 1 clinical trials, a limited number of patients were treated with daily doses of up to 1000 mg. An increase in frequency and severity of some adverse reactions was observed, mainly diarrhea and skin rash. Adverse reactions associated with overdose should be treated symptomatically; in particular, severe diarrhea should be managed appropriately.
Iressa (Gefitinib) Dosage And Administration
The recommended daily dose of Iressa (Gefitinib) is one 250 mg tablet with or without food. Higher doses do not give a better response and cause increased toxicity.
Patients with poorly tolerated diarrhea (sometimes associated with dehydration) or skin adverse drug reactions may be successfully managed by providing a brief (up to 14 days) therapy interruption followed by reinstatement of the 250 mg daily dose.
In the event of acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever), Iressa (Gefitinib) therapy should be interrupted and a prompt investigation of these symptoms should occur and appropriate treatment initiated. If interstitial lung disease is confirmed, Iressa (Gefitinib) should be discontinued and the patient treated appropriately (see , and sections).
Patients who develop onset of new eye symptoms such as pain should be medically evaluated and managed appropriately, including Iressa (Gefitinib) therapy interruption and removal of an aberrant eyelash if present. After symptoms and eye changes have resolved, the decision should be made concerning reinstatement of the 250 mg daily dose (see and sections).
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 and sections).
No dosage adjustment is required on the basis of patient age, body weight, gender, ethnicity, or renal function; or in patients with moderate to severe hepatic impairment due to liver metastases (see section).
Iressa (Gefitinib) How Supplied
Iressa (Gefitinib) tablets are supplied as round, biconvex, brown film-coated tablets intagliated with "Iressa (Gefitinib) 250" on one side and plain on the other side,each containing 250 mg of gefitinib.
Bottles of 30 Tablets (NDC 0310-0482-30)
Iressa (Gefitinib) Package Label.principal Display Panel
