Getfitinib (Iressa)
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Getfitinib (Iressa)

IRESSA®
(gefitinib) Tablets, 250 mg

DRUG DESCRIPTION

IRESSA® (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, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-4-morpholin) propoxy] and the following structural formula:

IRESSA®  (gefitinib)  Structural Formula Illustration

It has the molecular formula C22H24ClFN4O3, a relative molecular mass of 446.9 and is a white-colored powder. Gefitinib is a free base. The molecule has pKas 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 (getfitinib) tablets are: Tablet core: Lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate and magnesium stearate. Coating: Hypromellose, polyethylene glycol 300, titanium dioxide, red ferric oxide and yellow ferric oxide.

What are the possible side effects of gefitinib (Iressa)?

If you experience any of the following serious side effects from gefitinib, contact your doctor immediately:

  • an allergic reaction (including difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives);
  • lung problems (difficulty breathing, shortness of breath, increased coughing, fever, or chest pain);
  • severe or persistent nausea, vomiting, loss of appetite, or diarrhea; or
  • eye pain or irritation.

Other, less serious side effects may be more likely to occur. Continue taking gefitinib and talk to your doctor if you...

Read All Potential Side Effects and See Pictures of Iressa »

What are the precautions when taking getfitinib (Iressa)?

Before taking this medication, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: lung disease (e.g., pulmonary fibrosis), severe kidney disease, eye problems, stomach/intestinal ulcers, smoking, cancer that has spread to the bowels.

Gefitinib is not recommended for use during pregnancy. It may cause harm to an unborn baby. Consult your doctor for more details.

It is not known whether this drug passes into breast milk. Due to the potential risk to the infant, breast-feeding while using...

Read All Potential Precautions of Iressa »

Last reviewed on RxList: 10/2/2008
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

IRESSA (getfitinib) 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 (getfitinib) .

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 (getfitinib) was initially based on objective response rates (see CLINICAL PHARMACOLOGY - Clinical Studies 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 CLINICAL PHARMACOLOGY - Clinical Studies section).

Results from two large, controlled, randomized trials in first-line treatment of non-small cell lung cancer showed no benefit from adding IRESSA (getfitinib) to doublet, platinum-based chemotherapy.

DOSAGE AND ADMINISTRATION

The recommended daily dose of IRESSA (getfitinib) is one 250 mg tablet with or without food. Higher doses do not give a better response and cause increased toxicity.

For Patients who have Difficulty Swallowing Solids

IRESSA (getfitinib) tablets can also be dispersed in half a glass of drinking water (noncarbonated). No other liquids should be used. Drop the tablet in the water, without crushing it, stir until the tablet is dispersed (approximately 10 minutes) and drink the liquid immediately. Rinse the glass with half a glass of water and drink. The liquid can also be administered through a naso-gastric tube.

Dosage Adjustment

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 (getfitinib) therapy should be interrupted and a prompt investigation of these symptoms should occur and appropriate treatment initiated. If interstitial lung disease is confirmed, IRESSA (getfitinib) should be discontinued and the patient treated appropriately (see WARNINGS - Pulmonary Toxicity, PRECAUTIONS - INFORMATION FOR PATIENTS and ADVERSE REACTIONS sections).

Patients who develop onset of new eye symptoms such as pain should be medically evaluated and managed appropriately, including IRESSA (getfitinib) 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 PRECAUTIONS - INFORMATION FOR PATIENTS and ADVERSE REACTIONS 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 CLINICAL PHARMACOLOGY - Pharmacokinetics-Drug-Drug Interactions and PRECAUTIONS - DRUG INTERACTIONS 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 CLINICAL PHARMACOLOGY - Pharmacokinetics-Special Populations section).

HOW SUPPLIED

IRESSA (getfitinib) tablets are supplied as round, biconvex, brown film-coated tablets intagliated with “IRESSA (getfitinib) 250” on one side and plain on the other side, each containing 250 mg of gefitinib.

Bottles of 30 Tablets (NDC 0310-0482-30)

Storage

Store at controlled room temperature 20-25°C (68-77°F) [see USP].

Manufactured for: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850. By: AstraZeneca UK Limited, Macclesfield, Cheshire, England. Made in the United Kingdom. Rev 06/05. FDA revision date: 6/17/2005

Last reviewed on RxList: 10/2/2008
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

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 (getfitinib) 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 PRECAUTIONS - INFORMATION FOR PATIENTS and DOSAGE AND ADMINISTRATION – Dosage Adjustment 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 (getfitinib) 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.

Table 3 - Drug-Related Adverse Events With an Incidence of ≥ 5% in either 250 mg or 500 mg Dose Group

Drug-related adverse eventa Number (%) of Patients
250 mg/day
(N=102)
%
500 mg/day
(N=114)
%
Diarrhea 49 (48) 76 (67)
Rash 44 (43) 61 (54)
Acne 25 (25) 37 (33)
Dry skin 13 (13) 30 (26)
Nausea 13 (13) 20 (18)
Vomiting 12 (12) 10 (9)
Pruritus 8 (8) 10 (9)
Anorexia 7 (7) 11 (10)
Asthenia 6 (6) 5 (4)
Weight loss 3 (3) 6 (5)
a A patient may have had more than 1 drug-related adverse event.

Table 4 - Drug Related Adverse Events ≥ 5% at 250 mg dose by Worst CTC Grade (n=102)

Adverse Event % of Patients
All
Grades
CTC
Grade 1
CTC
Grade 2
CTC
Grade 3
CTC
Grade 4
Diarrhea 48 41 6 1 0
Rash 43 39 4 0 0
Acne 25 19 6 0 0
Dry Skin 13 12 1 0 0
Nausea 13 7 5 1 0
Vomiting 12 9 2 1 0
Pruritus 8 7 1 0 0
Anorexia 7 3 4 0 0
Asthenia 6 2 2 1 1

Other adverse events reported at an incidence of <5% in patients who received either 250 mg or 500 mg as monotherapy for treatment of NSCLC (along with their frequency at the 250 mg recommended dose) include the following: peripheral edema (2%), amblyopia (2%), dyspnea (2%), conjunctivitis (1%), vesiculobullous rash (1%), and mouth ulceration (1%).

Interstitial Lung Disease

Cases of interstitial lung disease (ILD) have been observed in patients receiving IRESSA (getfitinib) 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 (getfitinib) 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 (getfitinib) 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 (getfitinib) therapy should be interrupted and a prompt investigation of these symptoms should occur. If interstitial lung disease is confirmed, IRESSA (getfitinib) should be discontinued and the patient treated appropriately (see WARNINGS - Pulmonary Toxicity, PRECAUTIONS - INFORMATION FOR PATIENTS and DOSAGE AND ADMINISTRATION - Dosage Adjustment sections).

In patients receiving IRESSA (getfitinib) therapy, there were reports of eye pain and corneal erosion/ulcer, sometimes in association with aberrant eyelash growth (see PRECAUTIONS - INFORMATION FOR PATIENTS section). Hemorrhage, such as epistaxis and hematuria have been reported in patients receiving IRESSA (getfitinib) . There were also rare reports of pancreatitis and very rare reports of corneal membrane sloughing, ocular ischemia/hemorrhage, toxic epidermal necrolysis, erythema multiforme, and allergic reactions, including angioedema and urticaria.

International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin while on IRESSA (getfitinib) therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR (see CLINICAL PHARMACOLOGY - Drug-Drug Interactions and PRECAUTIONS - DRUG INTERACTIONS sections).

Data from non-clinical (in vitro and in vivo) studies indicate that gefitinib has the potential to inhibit the cardiac action potential repolarization process (eg, QT interval). The clinical relevance of these findings is unknown.

Read the Iressa (getfitinib) Side Effects Center for a complete guide to possible side effects »

DRUG 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 (getfitinib) therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR (see CLINICAL PHARMACOLOGY - Pharmacokinetics-Drug-Drug Interactions and ADVERSE REACTIONS 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 (see CLINICAL PHARMACOLOGY - Pharmacokinetics-Drug-Drug Interactions and ADVERSE REACTIONS sections).

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

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

Last reviewed on RxList: 10/2/2008
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Pulmonary Toxicity

Cases of interstitial lung disease (ILD) have been observed in patients receiving IRESSA (getfitinib) 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 (getfitinib) 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 (getfitinib) 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 (getfitinib) therapy should be interrupted and a prompt investigation of these symptoms should occur. If interstitial lung disease is confirmed, IRESSA (getfitinib) should be discontinued and the patient treated appropriately (see PRECAUTIONS - INFORMATION FOR PATIENTS, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION - Dosage Adjustment sections).

Pregnancy Category D

IRESSA (getfitinib) 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 5mg/kg (30 mg/m², about 1/5 the recommended human dose on a mg/m²basis). 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/m², about twice the recommended dose in humans on a mg/m²basis) caused reduced fetal weight.

There are no adequate and well-controlled studies in pregnant women using IRESSA (getfitinib) . If IRESSA (getfitinib) 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.

PRECAUTIONS

Hepatotoxicity

Asymptomatic increases in liver transaminases have been observed in IRESSA (getfitinib) -treated patients; therefore, periodic liver function (transaminases, bilirubin, and alkaline phosphatase) testing should be considered. Discontinuation of IRESSA (getfitinib) should be considered if changes are severe.

Patients with Hepatic Impairment

In vitroand in vivo evidence suggest that gefitinib is cleared primarily by the liver. Therefore, gefitinib exposure may be increased in patients with hepatic dysfunction. In patients with liver metastases and moderately to severely elevated biochemical liver abnormalities, however, gefitinib pharmacokinetics were similar to the pharmacoki-netics of individuals without liver abnormalities (see CLINICAL PHARMACOLOGY - Pharmacokinetics-Special Populations section). The influence of non-cancer related hepatic impairment on the pharmacokinetics of gefitinib has not been evaluated.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Gefitinib has been tested for genotoxicity in a series of in vitro (bacterial mutation, mouse lymphoma, and human lymphocyte) assays and an in vivo rat micronucleus test. Under the conditions of these assays, gefitinib did not cause genetic damage.

Carcinogenicity studies have not been conducted with gefitinib.

Pregnancy

Pregnancy Category D (see WARNINGS and PRECAUTIONS - INFORMATION FOR PATIENTS sections).

Nursing Mothers

It is not known whether IRESSA (getfitinib) is excreted in human milk. Following oral administration of carbon-14 labeled gefitinib to rats 14 days postpartum, concentrations of radioactivity in milk were higher than in blood. 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. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women should be advised against breast-feeding while receiving IRESSA (getfitinib) therapy.

Pediatric Use

IRESSA (getfitinib) is not indicated for use in pediatric patients, as safety and effectiveness have not been established. In clinical trials of IRESSA (getfitinib) alone or with radiation in pediatric patients with primary Central Nervous System (CNS) tumors, cases of CNS hemor-rhageand 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 (getfitinib) .

Geriatric Use

Of the total number of patients participating in trials of second- and third-line IRESSA (getfitinib) treatment of NSCLC, 65% were aged 64 years or less, 30.5% were aged 65 to 74years, and 5% of patients were aged 75 years or older. No differences in safety or efficacy were observed between younger and older patients.

Patients with Severe Renal Impairment

The effect of severe renal impairment on the pharmacokinetics of gefitinib is not known. Patients with severe renal impairment should be treated with caution when given IRESSA (getfitinib) .

Last reviewed on RxList: 10/2/2008
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

The acute toxicity of gefitinib up to 500 mg in clinical studies has been low. In nonclinical studies, a single dose of 12,000 mg/m² (about 80 times the recommended clinical dose on a mg/m²basis) was lethal to rats. Half this dose caused no mortality in mice.

There is no specific treatment for an IRESSA (getfitinib) 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.

CONTRAINDICATIONS

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

Last reviewed on RxList: 10/2/2008
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

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 glyco-protein) 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.

Special Populations

In population based data analyses, no relationships were identified between predicted steady state trough concentration and patient age, body weight, gender, ethnicity or creatinine clearance.

Pediatric: There are no pharmacokinetic data in pediatric patients.

Hepatic Impairment

The influence of hepatic metastases with elevation of serum aspartate aminotrans-ferase (AST/SGOT), alkaline phosphatase, and bilirubin has been evaluated in patients with normal (14 patients), moderately elevated (13 patients) and severely elevated (4 patients) levels of one or more of these biochemical parameters. Patients with moderately and severely elevated biochemical liver abnormalities had gefitinib pharmacokinetics similar to individuals without liver abnormalities (see PRECAUTIONS section).

Renal Impairment

No clinical studies were conducted with IRESSA (getfitinib) in patients with severely compromised renal function (see PRECAUTIONS section). Gefitinib and its metabolites are not significantly excreted via the kidney (<4%).

Drug-Drug Interactions

In human liver microsome studies, gefitinib had no inhibitory effect on CYP1A2, CYP2C9, and CYP3A4 activities at concentrations ranging from 2-5000 ng/mL. At the highest concentration studied (5000 ng/mL), gefitinib inhibited CYP2C19 by 24% and CYP2D6 by 43%. Exposure to metoprolol, a substrate of CYP2D6, was increased by 30% when it was given in combination with gefitinib (500 mg daily for 28 days) in patients with solid tumors.

Rifampicin, an inducer of CYP3A4, reduced mean AUC of gefitinib by 85% in healthy male volunteers (see PRECAUTIONS - DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION -Dosage Adjustment sections).

Concomitant administration of itraconazole (200 mg QD for 12 days), an inhibitor of CYP3A4, with gefitinib (250 mg single dose) to healthy male volunteers, increased mean gefitinib AUC by 88% (see PRECAUTIONS - DRUG INTERACTIONS section).

Co-administration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above pH 5.0) reduced mean gefitinib AUC by 44% (see PRECAUTIONS - DRUG INTERACTIONS section).

International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin while on IRESSA (getfitinib) therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR (see PRECAUTIONS - DRUG INTERACTIONS and ADVERSE REACTIONS sections).

Clinical Studies

Non-Small Cell Lung Cancer (NSCLC): Refractory Disease Tumor Response Study – A multicenter clinical trial in the United States evaluated the tumor response rate of IRESSA (getfitinib) 250 and 500 mg/day in patients with advanced non-small cell lung cancer whose disease had progressed after at least two prior chemotherapy regimens including a platinum drug and docetaxel. IRESSA (getfitinib) was taken once daily at approximately the same time each day.

Two hundred and sixteen patients received IRESSA (getfitinib) , 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 (getfitinib) 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 1: Demographic and Disease Characteristics

Characteristic IRESSA Dose
250 mg/day
N=66 (%)
500 mg/day
N=76 (%)
Age Group
  18-64 years 43 (65) 43 (57)
  64-74 years 19 (29) 30 (39)
  75 years and above 4 (6) 3 (4)
Sex
  Male 38 (58) 41 (54)
  Female 28 (42) 35 (46)
Race
  White 61 (92) 68 (89)
  Black 1 (2) 2 (3)
  Asian/Oriental 1 (2) 2 (3)
  Hispanic 0 (0) 3 (4)
  Other 3 (5) 1 (1)
Smoking History
  Yes (Previous or current smoker) 45 (68) 62 (82)
  No (Never smoked) 21 (32) 14 (18)
Baseline WHO Performance Status
  0 14 (21) 9 (12)
  1 36 (55) 53 (70)
  2 15 (23) 14 (18)
  Not Recorded 1 (2) 0 (0)
Tumor Histology
  Squamous 9 (14) 11 (14)
  Adenocarcinoma 47 (71) 50 (66)
  Undifferentiated 6 (9) 4 (5)
  Large Cell 1 (2) 2 (3)
  Squamous and Adenocarcinoma 3 (5) 7 (9)
  Not Recorded 0 (0) 2 (3)
Current Disease Status
  Locally Advanced 11 (17) 5 (7)
  Metastatic 55 (83) 71 (93)

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 adenocar-cinoma histology, and 6.7% (3/45) with other NSCLC histologies. Similar differences in response 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).

Table 2 - Efficacy Results

  Efficacy Population
250 mg
(N=66)
500 mg
(N=76)
Combined
(N=142)
Objective Tumor Response Rate (%) 13.6 7.9 10.6
95% CI (%) 6.4 - 24.3 3.0 - 16.4 6.0 - 16.8
Median Duration of Objective Response (months) 8.9 4.5 7.0
Range (months) 4.6 - 18.6+ 4.4 - 7.6 4.4 - 18.6+
+ = data are ongoing

Non-Small Cell Lung Cancer (NSCLC): Refractory Disease Survival Study— A double-blind, placebo-controlled parallel-group trial randomized 1692 patients with advanced NSCLC to receive either IRESSA (getfitinib) 250 mg daily plus Best Supportive Care or placebo plus Best Supportive Care. Patients had received 1 or 2 prior chemotherapy regimens and had progressed while receiving or within 90 days of the last dose of chemotherapy or were intolerant to the most recent prior chemotherapy regimen. The two treatment arms were well-balanced for demographic and disease-related patient characteristics. The primary endpoint of the study was survival. IRESSA (getfitinib) did not significantly prolong survival (stratified log rank HR 0.89, P=0.11, Median 5.6 vs 5.1 months for IRESSA (getfitinib) and placebo, respectively).

Non-Small Cell Lung Cancer (NSCLC); Studies of First-line Treatment in Combination with Chemotherapy— Two large trials were conducted in chemotherapy-naïve patients with stage III and IV non-small cell lung cancer. Two thousand one hundred thirty patients were randomized to receive IRESSA (getfitinib) 250 mg daily, IRESSA (getfitinib) 500 mg daily, or placebo in combination with platinum-based chemotherapy regimens. The chemotherapies given in these first-line trials were gemcitabine and cis-platinum (N=1093) or carboplatin and paclitaxel (N=1037). The addition of IRESSA (getfitinib) did not demonstrate any increase, or trend toward such an increase, in tumor response rates, time to progression, or overall survival.

Last reviewed on RxList: 10/2/2008
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

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 WARNINGS - Pulmonary Toxicity, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION - Dosage Adjustment sections).

Women of childbearing potential must be advised to avoid becoming pregnant (see WARNINGS - Pregnancy Category D).

Last reviewed on RxList: 10/2/2008
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

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 WARNINGS - Pulmonary Toxicity, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION - Dosage Adjustment sections).

Women of childbearing potential must be advised to avoid becoming pregnant (see WARNINGS - Pregnancy Category D).

Last reviewed on RxList: 10/2/2008
This monograph has been modified to include the generic and brand name in many instances.

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Iressa Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

GEFITINIB - ORAL

(ge-FI-ti-nib)

COMMON BRAND NAME(S): Iressa

WARNING: Gefitinib has rarely caused very serious (possibly fatal) liver disease. Tell your doctor immediately if you develop symptoms of liver disease, including stomach/abdominal pain, extreme fatigue, dark urine, yellowing eyes/skin.

USES: Gefitinib is used to treat lung cancer. It works by slowing or stopping the growth of cancer cells. Gefitinib blocks a certain protein (an enzyme called tyrosine kinase).

HOW TO USE: Take gefitinib by mouth once daily, with or without food, or as directed.

Medications which reduce or completely block stomach acid (e.g., proton pump inhibitors/PPIs, H2 blockers, antacids) may decrease the absorption of gefitinib. This could decrease the effectiveness of gefitinib. Consult your doctor or pharmacist if you are taking any of these medications.

Avoid eating grapefruit or drinking grapefruit juice while using this medication unless your doctor or pharmacist says you may. Grapefruit may increase the chance of side effects with this medicine. Ask your doctor or pharmacist for more details.

Use this medication regularly in order to get the most benefit from it. To help you remember, use it at the same time each day.

Disclaimer

Iressa Consumer (continued)

SIDE EFFECTS: See also Warning section.

Diarrhea, rash, acne, nausea, vomiting, loss of appetite, nail problems, hair loss, red/sore mouth or throat, or unusual weakness may occur. If any of these effects persist or worsen, notify your doctor or pharmacist immediately.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Persistent nausea, vomiting, diarrhea, or loss of appetite may result in a serious loss of body water (dehydration) and kidney problems. Contact your doctor promptly if you notice any symptoms of dehydration, such as: unusual decreased urination, unusual dry mouth/thirst, fast heartbeat, dizziness/lightheadedness.

Tell your doctor immediately if any of these unlikely but serious side effects occur: unusual bleeding (coughing up blood, blood in urine), bloody or black/tarry stool, eye irritation/pain, swelling of the ankles/feet.

Gefitinib may cause rare (possibly fatal) lung disease (interstitial lung disease-ILD). Tell your doctor immediately if you develop trouble breathing, cough or fever.

If you have persistent diarrhea or skin rashes contact your doctor. Your doctor may temporarily stop gefitinib (for up to 14 days) which may help reverse those side effects. Treatment is then resumed with the same dosage.

An allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of an allergic reaction include: severe rash, itching/swelling (especially of the face/tongue/throat), dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Iressa (getfitinib) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before taking this medication, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: lung disease (e.g., pulmonary fibrosis), severe kidney disease, eye problems, stomach/intestinal ulcers, smoking, cancer that has spread to the bowels.

Gefitinib is not recommended for use during pregnancy. It may cause harm to an unborn baby. Consult your doctor for more details.

It is not known whether this drug passes into breast milk. Due to the potential risk to the infant, breast-feeding while using gefitinib is not recommended.

Disclaimer

Iressa Consumer (continued)

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription products you may use, especially of: "blood thinners" (warfarin), drugs which reduce stomach acid (e.g., ranitidine, cimetidine, famotidine, omeprazole, lansoprazole, rabeprazole), certain liver enzyme inhibitors (CYP 3A4 inhibitors such as ketoconazole, itraconazole, erythromycin, clarithromycin), vinorelbine, NSAIDs (such as ibuprofen, naproxen), corticosteroids (such as prednisone).

Some liver enzyme inducer medications such as rifamycins (e.g., rifampin, rifabutin), St. John's wort or phenytoin will stimulate certain liver enzymes (CYP 3A4). Your dosage of gefitinib may need to be increased if you are using such medications. Consult your doctor or pharmacist for more details.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include: severe/persistent diarrhea, severe skin rash.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (such as kidney/liver function tests) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is less than 12 hours before the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 68 and 77 degrees F (20-25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised June 2011. Copyright(c) 2011 First Databank, Inc.

Iressa Patient Information Including Side Effects

Brand Names: Iressa

Generic Name: gefitinib (Pronunciation: ge FI ti nib)

What is gefitinib (Iressa)?

Gefitinib is a cancer chemotherapy medication. Gefitinib interferes with the growth of cancer cells and slows their growth and spread in the body.

Gefitinib is used in the treatment of non-small cell lung cancer.

Gefitinib may also be used for purposes other than those listed in this medication guide.

Iressa 250 mg

round, brown, imprinted with IRESSA 250

What are the possible side effects of gefitinib (Iressa)?

If you experience any of the following serious side effects from gefitinib, contact your doctor immediately:

  • an allergic reaction (including difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives);
  • lung problems (difficulty breathing, shortness of breath, increased coughing, fever, or chest pain);
  • severe or persistent nausea, vomiting, loss of appetite, or diarrhea; or
  • eye pain or irritation.

Other, less serious side effects may be more likely to occur. Continue taking gefitinib and talk to your doctor if you experience:

  • mild to moderate nausea, vomiting, loss of appetite, or diarrhea;
  • skin rash, dryness, itching, or acne; or
  • weakness.

Other side effects have also been reported. Discuss with your doctor any side effect that occurs during treatment with gefitinib. You may report side effects to FDA at 1-800-FDA-1088.

Read the Iressa (getfitinib) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about gefitinib (Iressa)?

Gefitinib should only be administered under the supervision of a qualified healthcare provider experienced in the use of cancer chemotherapeutic agents.

Serious side effects have been reported with the use of gefitinib including: allergic reactions (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives); lung problems; liver problems; eye problems; severe nausea, vomiting, loss of appetite, or diarrhea; and others. Talk to your doctor about the possible side effects from treatment with gefitinib.

Side Effects Centers

Iressa Patient Information including How Should I Take

What should I discuss with my healthcare provider before taking gefitinib (Iressa)?

Do not use gefitinib without first talking to your doctor if you have

  • liver disease; or
  • lung or breathing problems (other than lung cancer).

You may not be able to take gefitinib, or you may require a dosage adjustment or special monitoring if you have any of the conditions listed above.

Gefitinib is in the FDA pregnancy category D. This means that it is known to be harmful to an unborn baby. Do not use gefitinib without first talking to your doctor if you are pregnant or could become pregnant during treatment. Birth control should be used during treatment with gefitinib.

It is not known whether gefitinib passes into breast milk. Do not take gefitinib without first talking to your doctor if you are breast-feeding a baby.

How should I use gefitinib (Iressa)?

Gefitinib should only be administered under the supervision of a qualified healthcare provider experienced in the use of cancer chemotherapeutic agents.

Take each dose of gefitinib with a full glass of water.

Gefitinib can be taken with or without food.

Your doctor will determine the correct amount and frequency of treatment with gefitinib depending upon the type of cancer being treated and other factors. Talk to your doctor if you have any questions or concerns regarding the treatment schedule.

It is important to take gefitinib regularly to get the most benefit.

Your doctor may want you to have blood tests and other medical evaluations during treatment with gefitinib to monitor progress and side effects.

Your healthcare provider will store gefitinib as directed by the manufacturer. If you are storing gefitinib at home, follow the directions provided by your healthcare provider.

Side Effects Centers

Iressa Patient Information including If I Miss a Dose

What happens if I miss a dose (Iressa)?

Contact your doctor if you miss a dose of gefitinib.

What happens if I overdose (Iressa)?

If an overdose of gefitinib is suspected, seek emergency medical attention or contact your healthcare provider immediately.

Symptoms of a gefitinib overdose tend to be similar to side effects caused by the medication, although often more severe.

What should I avoid while using gefitinib (Iressa)?

There are no restrictions on food, beverages, or activity during treatment with gefitinib unless otherwise directed by your doctor.

What other drugs will affect gefitinib (Iressa)?

Before taking gefitinib, tell your doctor if you are taking any other medicines, especially any of the following:

  • warfarin (Coumadin);
  • rifampin (Rifadin, Rimactane);
  • phenytoin (Dilantin, Phenytek);
  • ketoconazole (Nizoral);
  • itraconazole (Sporanox); or
  • a stomach acid reducer such as cimetidine (Tagamet, Tagamet HB), ranitidine (Zantac, Zantac 75), esomeprazole (Nexium), lansoprazole (Prevacid), omeprazole (Prilosec), and others.

You may not be able to take gefitinib, or you may require a dosage adjustment or special monitoring if you are taking any of the medicines listed above.

Many other drugs may interact with gefitinib. Talk to your doctor and pharmacist before taking any other prescription or over-the-counter medicines, including vitamins, minerals, and herbal products.

Where can I get more information?

Your healthcare provider may have additional information about gefitinib that you may read.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 2.06. Revision date: 12/15/2010.

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