Gefitinib

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Gefitinib
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 is a tyrosine kinase inhibitor that is FDA approved for the treatment 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 diarrhea, rash, acne and dry skin.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

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 gefitinib.

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

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 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 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 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 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), gefitinib therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, gefitinib should be discontinued and the patient treated appropriately.

Hepatotoxicity

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

Adverse Reactions

Clinical Trials Experience

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 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. 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 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.

Gefitinib adverse reactions.png

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 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 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 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), gefitinib therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, gefitinib should be discontinued and the patient treated appropriately.

In patients receiving gefitinib therapy, there were reports of eye pain and corneal erosion/ulcer, sometimes in association with aberrant eyelash growth. Hemorrhage, such as epistaxis and hematuria have been reported in patients receiving gefitinib. 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 gefitinib therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR.

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.

Postmarketing Experience

There is limited information regarding Gefitinib 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 gefitinib 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 gefitinib.
  • Drugs that cause significant sustained elevation in gastric pH (histamine H2-receptor antagonists such as ranitidine or cimetidine) may reduce plasma concentrations of gefitinib and therefore potentially may reduce efficacy.
  • Phase II clinical trial data, where gefitinib and vinorelbine have been used concomitantly, indicate that gefitinib 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 gefitinib. If 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.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gefitinib in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Gefitinib during labor and delivery.

Nursing Mothers

It is not known whether gefitinib 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 gefitinib therapy.

Pediatric Use

Gefitinib is not indicated for use in pediatric patients as safety and effectiveness have not been established.

In clinical trials of 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 gefitinib.

Gefitinib is not indicated for use in pediatric patients as safety and effectiveness have not been established.

Geriatic Use

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

Gender

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

Race

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

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 gefitinib.

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 in women of reproductive potentials and males.

Immunocompromised Patients

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

Administration and Monitoring

Administration

Oral

Monitoring

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

IV Compatibility

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

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/m2 (about 80 times the recommended clinical dose on a mg/m2 basis) was lethal to rats. Half this dose caused no mortality in mice.

There is no specific treatment for an 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.

Pharmacology

Gefitinib structure.png
Gefitinib
Systematic (IUPAC) name
N-(3-chloro-4-fluoro-phenyl)-7-methoxy-
6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine
Identifiers
CAS number 184475-35-2
ATC code L01XE02
PubChem 123631
DrugBank DB00317
Chemical data
Formula C22H24ClFN4O3 
Mol. mass 446.902 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 59% (oral)
Protein binding 90%
Metabolism Hepatic (mainly CYP3A4)
Half life 6–49 hours
Excretion Faecal
Therapeutic considerations
Pregnancy cat.

C (Au), D (U.S.)

Legal status

S4 (Au), POM (UK), ℞-only (U.S.)

Routes Oral

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:

Gefitinib structural formula.jpg

Pharmacodynamics

There is limited information regarding Gefitinib 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 gefitinib 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. gefitinib was taken once daily at approximately the same time each day.

Two hundred and sixteen patients received 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 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.

Gefitinib demographic and disease characteristics.png

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).

Gefitinib efficacy results.png
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 gefitinib 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. Gefitinib did not significantly prolong survival (stratified log rank HR 0.89, P=0.11, Median 5.6 vs 5.1 months for gefitinib 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 gefitinib 250 mg daily, gefitinib 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 gefitinib did not demonstrate any increase, or trend toward such an increase, in tumor response rates, time to progression, or overall survival.

How Supplied

Supplied in tablets of 250 mg

  • Bottles of 30 Tablets
  • NDC 0310-0482-30

Storage

Store at 20-25°C (68-77°F)

Images

Drug Images

Package and Label Display Panel

Gefitinib FDA package label.png

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

Look-Alike Drug Names

There is limited information regarding Gefitinib 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.



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