Iressa

Gefitinib may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• dry skin
• itching
• rash
• acne
• mouth sores
• weakness

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately or get emergency medical treatment:

• new or worsening shortness of breath, cough, or fever
• severe or ongoing diarrhea
• severe abdominal pain
• loss of appetite
• eye pain, redness, or irritation
• vision changes
• watery eyes
• eye sensitivity to light
• hives
• blisters or peeling skin
• swelling of the eyes, face, lips, tongue, throat, hands, arms, feet, ankles or lower legs
• nausea
• vomiting
• yellowing of the skin or eyes
• dark urine
• pale stools
• pain or discomfort in the right upper stomach area

Gefitinib may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

Gefitinib is taken by mouth. The dose is 250 mg once daily. The dose is the same for men or women of any age or weight, and gefitinib can be taken with or without food.

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

Gefitinib is used to treat non-small cell lung cancer.

Gefitinib is sometimes used to treat cancer that has spread to other parts of the body.

Gefitinib may also be used for purposes not listed in this medication guide.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

You should not use gefitinib if you are allergic to it.

To make sure gefitinib is safe for you, tell your doctor if you have:

• liver disease;
• kidney disease;
• vision problems;
• breathing problems, lung disease other than lung cancer; or
• if you take a blood thinner (warfarin, Coumadin, Jantoven).

Do not use gefitinib if you are pregnant. It could harm the unborn baby. Use effective birth control to prevent pregnancy while you are using this medicine and for at least 2 weeks after your treatment ends.

This medicine may affect fertility (the ability to have children) in women. Tell your doctor if you plan to become pregnant.

It is not known whether gefitinib passes into breast milk or if it could harm a nursing baby. Do not breast-feed while taking gefitinib.

Instructions

May take with or without food

Missed dose: Do not take a missed dose within 12 hr of the next scheduled dose

Difficulty swallowing

• Immerse tablet in 4-8 ounces of water and stir for approximately 15 minutes
• Immediately drink the liquid or administer through a NG tube
• Rinse the container with an additional 4-8 ounces of water and immediately drink or administer through the NG tube to assure complete dose

The most common side effects of Iressa therapy include:

• diarrhea
• rash
• acne
• dry skin
• nausea
• vomiting

Also eye pain, redness, and irritation have occurred in people taking Iressa .

This is not a complete list of possible side effects. Talk to your doctor for more information.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Iressa falls into category D. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans, though. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Take Iressa exactly as prescribed by your doctor. Follow the directions carefully. Your doctor will determine the best dose for you. If you forget a dose, take it as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose. Do not take two doses at once.

The recommended daily dose of Iressa is one 250 mg tablet with or without food.

Other drugs may interact with gefitinib, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Non-small Cell Lung Cancer (NSCLC)

Monotherapy for continued treatment of locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel regimens due to disease progression or unacceptable toxicity in patients who are benefiting or have benefited from gefitinib.1

No survival benefit demonstrated.1 Therefore, consider other agents that have been shown to prolong survival (e.g., erlotinib, docetaxel) for management of advanced NSCLC in patients who have received 1 or 2 previous chemotherapy regimens and have refractory disease or unacceptable toxicity.1 12

Use of gefitinib currently is limited to patients already receiving and benefiting from the drug or who are enrolled in a clinical trial.11 12 13 (See Restricted Distribution Program under Dosage and Administration.)

No benefit from adding gefitinib to initial standard platinum-based chemotherapy in patients with NSCLC or as a component in combination chemotherapy in patients with advanced disease.1 3

Contraindications

• Known severe hypersensitivity to gefitinib or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Interstitial lung disease, sometimes fatal, reported; described as interstitial pneumonia, pneumonitis, or alveolitis.1 7 Manifestations often include acute onset of dyspnea, sometimes associated with cough or low-grade fever, usually becoming severe within a short time and requiring hospitalization.1 8

Risk of increased mortality in patients with concurrent idiopathic pulmonary fibrosis whose condition worsens while receiving gefitinib.1

If acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever) occurs, interrupt therapy, promptly evaluate patient, and institute appropriate therapy.1 If diagnosis of interstitial lung disease is confirmed, discontinue gefitinib and provide appropriate treatment.1

May cause fetal harm; neonatal mortality soon after parturition, reduction in number of offspring born alive, and reduced fetal weight demonstrated in animals.1

Avoid pregnancy during therapy; if pregnancy occurs, apprise of potential fetal hazard or risk of pregnancy loss.1

Sensitivity Reactions

Allergic reactions, including angioedema and urticaria, reported.1

Major Toxicities

Diarrhea, nausea, vomiting, anorexia, and weight loss reported.1

Rash, acne, and dry skin reported.1 Toxic epidermal necrolysis and erythema multiforme reported rarely.1

Ocular pain and corneal erosion or ulcer, sometimes in association with aberrant eyelash growth, reported.1 Corneal membrane sloughing, ocular ischemia, or ocular hemorrhage reported rarely.1

Hemorrhage (e.g., epistaxis, hematuria) reported.1 Pancreatitis reported rarely.1

General Precautions

Asymptomatic elevations of hepatic aminotransferase concentrations reported.1

Consider periodic monitoring of liver function (aminotransferase, bilirubin, alkaline phosphatase concentrations); if severe elevations of test results occur, consider discontinuance.1

Specific Populations

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Gefitinib and its metabolites are distributed into milk in rats; not known whether distributed into human milk.1 Women receiving gefitinib should not breast-feed.1

Safety and efficacy not established in children <18 years of age; therefore, not indicated for use in pediatric patients.1 9 CNS hemorrhage and death reported in pediatric patients receiving gefitinib alone or with radiation for primary CNS tumors.1

No substantial differences in safety and efficacy relative to younger adults.1

Possible increased exposure.1 (See Special Populations under Pharmacokinetics.)

Not studied in patients with severe renal impairment; use with caution.1

Common Adverse Effects

Diarrhea, rash, acne, dry skin, nausea, vomiting, pruritus, anorexia, asthenia.1

Metabolized principally by CYP3A4.1 Does not inhibit CYP isoenzymes 1A2, 2C9, or 3A4 in vitro, but may inhibit 2C19 and 2D6 at high drug concentrations.1

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential pharmacokinetic interaction (decreased gefitinib metabolism, increased plasma gefitinib concentrations).1 2 3 Possible increased risk of adverse effects.1 Use with caution.1

CYP3A4 inducers: Potential pharmacokinetic interaction (increased gefitinib metabolism, decreased plasma gefitinib concentrations).1 If used concomitantly with potent CYP3A4 inducer, consider increasing gefitinib dosage to 500 mg daily in the absence of severe adverse effects.1

Drugs Affecting Gastric Acidity

Possible pharmacokinetic interaction (decreased plasma gefitinib concentrations, possible reduction in gefitinib efficacy) with drugs that cause substantial, sustained gastric pH elevation.1 10

Specific Drugs

• Importance of promptly reporting any conditions that can be associated with dehydration (e.g., severe or persistent diarrhea, nausea, anorexia, vomiting), new onset or worsening of pulmonary symptoms (e.g., shortness of breath, cough), ocular irritation, or other new symptoms.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity of advising women to avoid pregnancy and nursing during therapy.1 Advise pregnant women of risk to the fetus.1

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

• If you have an allergy to gefitinib or any other part of Iressa (gefitinib).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

The following adverse drug reactions are discussed in more detail in other sections of the labeling:

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Iressa is based on the data from 2462 patients with NSCLC who received Iressa 250 mg daily monotherapy in three randomized clinical studies (Study 2, Study 3 and Study 4). Patients with a history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis that required steroid treatment or any evidence of clinically active interstitial lung disease were excluded from these studies.

Controlled Studies:

Study 2 was a randomized, multicenter, open-label trial in which 1217 patients were randomized to receive first-line treatment for metastatic NSCLC; 607 patients received Iressa 250 mg daily and 589 patients received carboplatin/paclitaxel. The median duration of treatment with Iressa was 5.9 months. The study population characteristics were: median age 57 years, age less than 65 years (73%), female (79%), Asian (100%), NSCLC adenocarcinoma histology (100%), never smoker (94%), light ex-smoker (6%), ECOG PS 0 or 1 (90%).

Study 3 was a randomized, multicenter, double-blind, placebo-controlled trial in which 1692 patients were randomized to receive second- or third-line treatment for metastatic NSCLC; of which 1126 patients received Iressa 250 mg daily and 562 patients received placebo. The median duration of treatment with Iressa was 2.9 months. The study population characteristics were: median age 62 years, age less than 65 years (60%), female (33%), Caucasian (75%), Asian (21%), NSCLC adenocarcinoma histology (48%), never smoker (22%), ECOG PS 0 or 1 (65%), PS 2 (29%), PS 3 (5%) and two or more prior therapies (51%).

Study 4 was a randomized, multicenter, open-label trial in which 1466 patients were randomized to receive second-line treatment for metastatic NSCLC; 729 patients received Iressa 250 mg daily and 715 patients received docetaxel. The median duration of treatment with Iressa was 2.4 months. The study population characteristics were: median age 61 years, age less than 65 years (61%), female (36%), Caucasian (79%), Asian (21%), NSCLC adenocarcinoma histology (54%), never smoker (20%), ECOG PS 0 or 1 (88%) and two or more prior therapies (16%).

The pooled safety database from the three randomized trials was used to evaluate for serious and uncommon adverse drug reactions. Common adverse reactions were evaluated in Study 3. The most frequent adverse reactions in Study 3 (incidence of >20% and greater than placebo) reported in Iressa-treated patients were skin reactions (47%)and diarrhea (29%). The most frequent fatal adverse reactions in Iressa-treated patients were respiratory failure (0.9%), pneumonia (0.8%), and pulmonary embolism (0.5%).

Approximately 5% of Iressa-treated patients and 2.3% of placebo-treated patients discontinued treatment due to an adverse event. The most frequent adverse reactions that led to discontinuation in patients treated with Iressa were nausea (0.5%), vomiting (0.5%) and diarrhea (0.4%).

The following adverse reactions have been reported with Iressa across NSCLC trials (Study 2, Study 3 and Study 4) and are not listed elsewhere in Section 6: nausea (18%), asthenia (17%), pyrexia (9%), alopecia (4.7%), hemorrhage (including epistaxis and hematuria) (4.3%), dry mouth (2%), dehydration (1.8%), allergic reactions including angioedema and urticaria (1.1%), elevations in blood creatinine (1.5%), and pancreatitis (0.1%).

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

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)].

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.

Applies to gefitinib: oral tablet

Along with its needed effects, gefitinib (the active ingredient contained in Iressa) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking gefitinib:

• Abdominal or stomach pain or tenderness
• clay colored stools
• dark urine
• decreased appetite
• diarrhea, severe
• fever
• headache
• itching or skin rash
• loss of appetite
• nausea and vomiting
• swelling of the feet or lower legs
• unusual tiredness or weakness
• yellow eyes or skin

• Burning, dry, or itching eyes
• chest pain
• chills
• cough
• difficult breathing
• discharge or excessive tearing
• dry eyes
• general feeling of discomfort or illness
• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
• thickening of bronchial secretions
• troubled breathing
• troubled or quick, shallow breathing

• Blistering, peeling, or loosening of the skin
• bloody, black, or tarry stools
• eye redness, irritation, or pain
• heartburn
• indigestion
• joint or muscle pain
• red skin lesions, often with a purple center
• severe abdominal or stomach pain, cramping, or burning
• sore throat
• sores, ulcers, or white spots in the mouth or on the lips
• vomiting of material that looks like coffee grounds, severe and continuing

Some side effects of gefitinib may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Redness or soreness around fingernails or loosening of the fingernails

Applies to gefitinib: oral tablet

Respiratory

Common (1% to 10%): Interstitial lung disease or ILD-like adverse reactions[Ref]

Hepatic

Very common (10% or more): Increased AST (up to 40%), increased ALT (up to 38%)
Common (1% to 10%): Increased bilirubin
Uncommon (0.1% to 1%): Hepatitis/hepatic failure
Rare (less than 0.1%): Fatal hepatotoxicity[Ref]

Gastrointestinal

Very common (10% or more): Diarrhea (up to 29%), nausea (up to 18%), vomiting (up to 14%)
Common (1% to 10%): Stomatitis, dry mouth, pancreatitis, dehydration (secondary to diarrhea, nausea, vomiting, or anorexia)
Uncommon (0.1% to 1%): GI perforation[Ref]

Ocular

Common (1% to 10%): Keratitis, conjunctivitis, blepharitis, dry eye
Uncommon (0.1% to 1%): Corneal erosion/aberrant eyelash growth[Ref]

Nervous system

Rare (less than 0.1%): CNS hemorrhage
Frequency not reported: Cerebrovascular events[Ref]

Dermatologic

Reported skin reactions: acne/acne pustular, dermatitis (acneiform and exfoliative), drug eruption, dry skin, erythema, folliculitis, pruritus, rash (erythematous, exfoliative, generalized, macular, maculo-papular, papular, pruritic, pustular, vesicular), skin exfoliation, skin toxicity, and xeroderma.[Ref]

Very common (10% or more): Skin reactions (up to 47%)
Common (1% to 10%): Nail disorder, alopecia
Rare (less than 0.1%): Bullous conditions (including toxic epidermal necrolysis, Stevens Johnson syndrome, erythema multiforme), cutaneous vasculitis[Ref]

Renal

Very common (10% or more): Proteinuria (up to 35%)
Common (1% to 10%): Elevated blood creatinine, cystitis
Rare (less than 0.1%): Hemorrhagic cystitis
Frequency not reported: Renal failure[Ref]

Metabolic

Very common (10% or more): Decreased appetite (up to 17%), anorexia (10%)[Ref]

Other

Very common (10% or more): Asthenia (up to 17%)
Common (1% to 10%): Pyrexia[Ref]

Hematologic

Common (1% to 10%): Hemorrhage (including epistaxis and hematuria)[Ref]

Immunologic

Common (1% to 10%): Allergic reactions (including angioedema and urticaria)[Ref]

Some side effects of Iressa may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.