Gefitinib (patient information)

Gefitinib (patient information)
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]

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Overview

Gefitinib (patient information) is a tyrosine kinase inhibitor that is FDA approved for the {{{indicationType}}} of patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Common adverse reactions include {{{adverseReactions}}}.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

There is limited information regarding Gefitinib (patient information) FDA-Labeled Indications and Dosage (Adult) in the drug label.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Gefitinib (patient information) in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Gefitinib (patient information) in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Gefitinib (patient information) FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Gefitinib (patient information) in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Gefitinib (patient information) in pediatric patients.

Contraindications

Is contraindicated in patients with severe hypersensitivity to gefitinib or to any other component of it.

Warnings

Pulmonary Toxicity

Cases of interstitial lung disease (ILD) have been observed in patients receiving IRESSA 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 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 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 therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, IRESSA should be discontinued and the patient treated appropriately.

Hepatotoxicity

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

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Gefitinib (patient information) Clinical Trials Experience in the drug label.

Postmarketing Experience

There is limited information regarding Gefitinib (patient information) Postmarketing Experience in the drug label.

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.
• 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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): D 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/m2, about 1/5 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 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/m2 basis) caused reduced fetal weight.

There are no adequate and well-controlled studies in pregnant women using IRESSA. If IRESSA 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.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gefitinib (patient information) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Gefitinib (patient information) during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Gefitinib (patient information) in women who are nursing.

Pediatric Use

There are no pharmacokinetic data in pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Gefitinib (patient information) in geriatric settings.

Gender

There is no FDA guidance on the use of Gefitinib (patient information) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Gefitinib (patient information) with respect to specific racial populations.

Renal Impairment

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

Hepatic Impairment

In vitro and 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 pharmacokinetics of individuals without liver abnormalities. The influence of non-cancer related hepatic impairment on the pharmacokinetics of gefitinib has not been evaluated.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Gefitinib (patient information) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Gefitinib (patient information) in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Gefitinib (patient information) Administration in the drug label.

Monitoring

There is limited information regarding Gefitinib (patient information) Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Gefitinib (patient information) and IV administrations.

Overdosage

There is limited information regarding Gefitinib (patient information) overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Gefitinib (patient information) Pharmacology in the drug label.

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.

Structure

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:

Pharmacodynamics

There is limited information regarding Gefitinib (patient information) Pharmacodynamics in the drug label.

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 glycoprotein) 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.

Nonclinical Toxicology

Carcinogenesis and Mutagenesis

• 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.

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 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 was taken once daily at approximately the same time each day.

Two hundred and sixteen patients received IRESSA, 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 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

A double-blind, placebo-controlled parallel-group trial randomized 1692 patients with advanced NSCLC to receive either IRESSA 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 did not significantly prolong survival (stratified log rank HR 0.89, P=0.11, Median 5.6 vs 5.1 months for IRESSA 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 250 mg daily, IRESSA 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 did not demonstrate any increase, or trend toward such an increase, in tumor response rates, time to progression, or overall survival.

How Supplied

There is limited information regarding Gefitinib (patient information) How Supplied in the drug label.

Storage

There is limited information regarding Gefitinib (patient information) Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

• Patients should be advised to seek medical advice promptly if they develop:

• severe or persistent diarrhea, nausea, anorexia, or vomiting, as these have sometimes been associated with dehydration;
• an onset or worsening of pulmonary symptoms, ie, shortness of breath or cough;
• an eye irritation; or,
• any other new symptom.

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

Precautions with Alcohol

Alcohol-Gefitinib (patient information) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Gefitinib (patient information) Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Gefitinib (patient information) Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

Why this medication is prescribed

Gefitinib is used to treat non-small cell lung cancer in people who have already been treated with certain other chemotherapy medications and have not improved or whose condition has worsened. Gefitinib has not been shown to help people who have non-small cell lung cancer live longer. There are other medications that may help people who have non-small cell lung cancer live longer. Therefore, only people who have already taken gefitinib and benefited from the medication should continue to take it. People who have never taken gefitinib should start their treatment with a medication that is known to help patients with lung cancer live longer. Gefitinib is in a class of anti-cancer medications called epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. It works by blocking the action of a certain naturally occurring substance that may be needed to help cancer cells multiply.

How this medication should be used

Gefitinib comes as a tablet to take by mouth. It is usually taken with or without food once a day. Take gefitinib at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take gefitinib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

If you are unable to swallow the tablets, you may dissolve them in water. Place one tablet in a half a glass of plain, non-carbonated drinking water. Stir with a spoon for about 10 minutes until the tablet is dissolved. Do not use the spoon to crush the tablet. Drink the mixture right away. Rinse the glass with another half glass of water and drink the rinse water to be sure that you swallow all of the medication.

Gefitinib is not available in pharmacies. You can only get gefitinib through a distribution program that has been set up by the manufacturer for people who have taken gefitinib in the past. You will need to sign a consent form before you receive any medication. You will receive your medication by mail from a specific mail order pharmacy. Ask your doctor if you have any questions about receiving your medication.

Other uses for this medicine

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Special precautions

Before taking gefitinib:

• tell your doctor and pharmacist if you are allergic to gefitinib or any other medications.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take. Be sure to mention any of the following: anticoagulants ('blood thinners') such as warfarin (Coumadin); antifungals such as itraconazole (Sporanox), ketoconazole (Nizoral), and voriconazole (Vfend); carbamazepine (Carbatrol, Equetro, Tegretol); amiodarone (Cordarone, Pacerone); clarithromycin (Biaxin); diltiazem (Cardizem, Dilacor, Tiazac); erythromycin (E.E.S, E-Mycin, Erythrocin); fluvoxamine (Luvox); medications for heartburn and ulcers such as cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), and ranitidine (Zantac); metoprolol (Lopressor, Toprol XL); rifabutin (Mycobutin); rifampin (Rifadin, Rimactane); medications for human immunodeficiency virus (HIV) such as indinavir (Crixivan), nelfinavir (Viracept), and ritonavir (Norvir, in Kaletra); nefazodone; phenobarbital; phenytoin (Dilantin); verapamil (Calan, Covera, Isoptin, Verelan); and vinorelbine (Navelbine). Many other medications may interact with gefitinib, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor what herbal products you are taking, especially St. John's wort.
• tell your doctor if you have or have ever had pulmonary fibrosis (scarring of the lungs), or liver or kidney disease.
• tell your doctor if you are pregnant or plan to become pregnant. You should use birth control to prevent pregnancy during your treatment with gefitinib and for some time after you stop using the medication. If you become pregnant while taking gefitinib, call your doctor. *Gefitinib may harm the fetus and increase the risk of pregnancy loss.
• tell your doctor if you are breast-feeding. You should not breast-feed while you are taking gefitinib.

Special dietary instructions

Talk to your doctor about eating grapefruit and drinking grapefruit juice while you are taking this medicine.

What to do if you forget a dose

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Side effects

Minor side effects

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
• weight loss
• weakness

Severe side effects

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

• new or worsening shortness of breath, cough, or fever
• diarrhea
• nausea
• vomiting
• loss of appetite
• eye pain, redness, or irritation
• change in vision
• growth of eyelashes on the inside of the eyelid
• hives
• swelling of the eyes, face, lips, tongue, throat, hands, arms, feet, ankles or lower legs

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

Storage conditions needed for this medication

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication.

In case of emergency/overdose

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include:

• diarrhea
• rash

Other information

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your body's response to gefitinib.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

Brand names

• Iressa®