文案整理： Dr. Jasmine Ding
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
IRESSA® safely and effectively.
See full prescribing information for
IRESSA (gefitinib) tablets for oral use
Initial U.S. Approval: 2015
INDICATIONS AND USAGE ：
IRESSA is a tyrosine kinase inhibitor indicated for the first-line treatment of
patients with metastatic non-small cell lung cancer (NSCLC) whose tumors
have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21
(L858R) substitution mutations as detected by an FDA-approved test. (1)
Limitation of Use: Safety and efficacy of IRESSA have not been established
in patients whose tumors have EGFR mutations other than exon 19 deletions
or exon 21 (L858R) substitution mutations. (1)
DOSAGE AND ADMINISTRATION
Recommended dose is 250 mg orally, once daily with or without food. (2.2)
DOSAGE FORMS AND STRENGTHS
Tablets: 250 mg. (3)
CONTRAINDICATIONS -----------------------------
None.
WARNINGS AND PRECAUTIONS
Interstitial lung disease (ILD):
ILD occurred in patients taking IRESSA.
Withhold IRESSA for worsening of respiratory symptoms. Discontinue
IRESSA if ILD is confirmed. (2.4, 5.1)
Hepatotoxicity: Obtain periodic liver function testing. Withhold
IRESSA for Grade 2 or higher for ALT and/or AST elevations.
Discontinue for severe hepatic impairment. (2.4, 5.2)
Gastrointestinal perforation: Discontinue IRESSA for gastrointestinal
perforation. (2.4, 5.3)
Diarrhea: Withhold IRESSA for Grade 3 or higher diarrhea. (2.4, 5.4)
Ocular Disorders including Keratitis:
Withhold IRESSA for signs and
symptoms of severe or worsening ocular disorders including keratitis.
Discontinue for persistent ulcerative keratitis. (2.4, 5.5)
Bullous and Exfoliative Skin Disorders
Withhold IRESSA for Grade 3
or higher skin reactions or exfoliative conditions. (2.4, 5.6)
Embryo-fetal Toxicity:
Can cause fetal harm. Advise of potential risk
to a fetus and use of effective contraception. (5.7, 8.1, 8.3)
ADVERSE REACTIONS
The most commonly reported adverse drug reactions (ADRs), reported in
more than 20% of the patients and greater than placebo were skin reactions
and diarrhea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/me
DRUG INTERACTIONS
CYP3A4 Inducer:
Increase IRESSA to 500 mg daily in patients
receiving a strong CYP3A4 inducer. (2.4, 7.1)
CYP3A4 Inhibitor:
Monitor adverse reactions if concomitant use with
IRESSA. (7.1)
Drugs Ating Gastric pH: Avoid concomitant use of IRESSA with
proton pump inhibitors, if possible. (7.1)
Hemorrhage in patients taking warfarin: Monitor changes in
prothrombin time or INR. (7.2)
USE IN SPECIFIC POPULATIONS
Lactation: Discontinue breast-feeding. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and FDA
approved patient labeling
Revised: 07/2015
FULL PRESCRIBING INFORMATION:
CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
2.2 Recommended Dose
2.3 Administration to Patients Who Have Difficulty Swallowing Solids
2.4 Dose Modification
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Interstitial Lung Disease (ILD)
5.2 Hepatotoxicity
5.3 Gastrointestinal Perforation
5.4 Severe or Persistent Diarrhea
5.5 Ocular Disorders including Keratitis
5.6 Bullous and Exfoliative Skin Disorders
5.7 Embryo-fetal Toxicity
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.3 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Drugs Affecting Gefitinib Exposure
7.2 Hemorrhage in Patients taking Warfarin
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
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FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
IRESSA is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose
tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as
detected by an FDA-approved test [see Clinical Studies (14)].
Limitation of Use: Safety and efficacy of IRESSA have not been established in patients with metastatic NSCLC whose
tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations [see Clinical
Studies (14)].
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
Select patients for the first-line treatment of metastatic NSCLC with IRESSA based on the presence of EGFR exon 19
deletion or exon 21 (L858R) substitution mutations in their tumor [see Indications and Usage (1), Clinical Studies (14)].
Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at:
http://www.fda.gov/CompanionDiagnostics.
2.2 Recommended Dose
The recommended dose of IRESSA is 250 mg orally once daily with or without food until disease progression or
unacceptable toxicity.
Do not take a missed dose within 12 hours of the next dose.
2.3 Administration to Patients
Who Have Difficulty Swallowing Solids
Immerse IRESSA tablets in 4 to 8 ounces of water by dropping the tablet in water, and stir for approximately 15 minutes.
Immediately drink the liquid or administer through a naso-gastric tube. Rinse the container with 4 to 8 ounces of water
and immediately drink or administer through the naso-gastric tube.
2.4 Dose Modification
Dose Modifications for Adverse Drug Reactions
Withhold IRESSA (for up to 14 days) for any of the following:
Acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever) [see Warnings and Precautions (5.1)]
NCI CTCAE Grade 2 or higher in ALT and/or AST elevations [see Warnings and Precautions (5.2)]
NCI CTCAE Grade 3 or higher diarrhea [see Warnings and Precautions (5.4)]
Signs and symptoms of severe or worsening ocular disorders including keratitis [see Warnings and Precautions (5.5)]
NCI CTCAE Grade 3 or higher skin reactions [see Warnings and Precautions (5.6)]
Resume treatment with IRESSA when the adverse reaction fully resolves or improves to NCI CTCAE Grade 1.
Permanently discontinue IRESSA for:
Confirmed interstitial lung disease (ILD) [see Warnings and Precautions (5.1)]
Severe hepatic impairment [see Warnings and Precautions (5.2)]
Gastrointestinal perforation [see Warnings and Precautions (5.3)]
Persistent ulcerative keratitis [see Warnings and Precautions (5.5)]
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Dose Modifications for Drug Interactions
Strong CYP3A4 Inducers
Increase IRESSA to 500 mg daily in the absence of severe adverse drug reaction, and resume IRESSA at 250 mg seven
days after discontinuation of the strong CYP3A4 inducer [see Drug Interactions (7), Clinical Pharmacology (12.3)].
3 DOSAGE FORMS AND STRENGTHS
250 mg tablets: round, biconvex, brown film-coated, debossed with "IRESSA 250" on one side and plain on the other
side.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Interstitial Lung Disease (ILD)
ILD or ILD-like adverse drug reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or
pulmonary fibrosis) occurred in 1.3% of the 2462 patients who received IRESSA across clinical trials; of these, 0.7%
were Grade 3 or higher and 3 cases were fatal.
Withhold IRESSA and promptly investigate for ILD in any patient who presents with worsening of respiratory symptoms
such as dyspnea, cough and fever. Permanently discontinue IRESSA if ILD is confirmed [see Dosage and Administration
(2.4), Adverse Reactions (6.1)].
5.2 Hepatotoxicity
In patients who received IRESSA across clinical trials, 11.4% of patients had increased alanine aminotransferase (ALT),
7.9% of patients had increased aspartate aminotransferase (AST), and 2.7% of patients had increased bilirubin. Grade 3 or
higher liver test abnormalities occurred in 5.1% (ALT), 3.0% (AST), and 0.7% (bilirubin) of patients. The incidence of
fatal hepatotoxicity was 0.04%.
Obtain periodic liver function testing. Withhold IRESSA in patients with worsening liver function and discontinue in
patients with severe hepatic impairment [see Dosage and Administration (2.4), Adverse Reactions (6.1), Use in Specific
Populations (8.7)].
5.3 Gastrointestinal Perforation
Gastrointestinal perforation occurred in three (0.1%) of the 2462 IRESSA-treated patients across clinical trials [see
Adverse Reactions (6.1)]. Permanently discontinue IRESSA in patients who develop gastrointestinal perforation [see
Dosage and Administration (2.4)].
5.4 Severe or Persistent Diarrhea
Grade 3 or 4 diarrhea occurred in 3% of 2462 IRESSA-treated patients across clinical trials. Withhold IRESSA for severe
or persistent (up to 14 days) diarrhea [see Dosage and Administration (2.4), Adverse Reactions (6.1)].
5.5 Ocular Disorders including Keratitis
Ocular disorders [keratitis (0.1%), corneal erosion and aberrant eyelash growth (0.2%), conjunctivitis, blephritis and dry
eye (6.7%)] occurred in the 2462 IRESSA-treated patients across clinical trials. The incidence of Grade 3 ocular
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disorders was 0.1% [see Adverse Reactions (6.1)]. Interrupt or discontinue IRESSA for severe, or worsening ocular
disorders [see Dosage and Administration (2.4)].
5.6 Bullous and Exfoliative Skin Disorders
Bullous conditions including toxic epidermal necrolysis, Stevens Johnson syndrome and erythema multiforme have been
reported from treatment with IRESSA. Erythema multiforme and dermatitis bullous have been reported in two patients
(0.08%) across NSCLC trials (Study 2, Study 3 and Study 4). IRESSA treatment should be interrupted or discontinued if
the patient develops severe bullous, blistering or exfoliating conditions.
5.7 Embryo-fetal Toxicity
Based on its mechanism of action and data from animal reproduction studies IRESSA can cause fetal harm when
administered to a pregnant woman. In animal reproductive studies, oral administration of gefitinib from organogenesis
through weaning resulted in fetotoxicity and neonatal death at doses below the recommended human dose. Advise
pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception
during treatment with IRESSA and for at least two weeks following completion of therapy [see Use in Specific
Populations (8.1, 8.3)].
6 ADVERSE REACTIONS
The following adverse drug reactions are discussed in more detail in other sections of the labeling:
Interstitial Lung Disease [see Warnings and Precautions (5.1)]
Hepatotoxicity [see Warnings and Precautions (5.2)]
Gastrointestinal Perforation [see Warnings and Precautions (5.3)]
Severe or Persistent Diarrhea [see Warnings and Precautions (5.4)]
Ocular Disorders including Keratitis [see Warnings and Precautions (5.5)]
Bullous and Exfoliative Skin Disorders [see Warning and Precautions (5.6)]
6.1 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%),
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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%).
Table 1- Selected Adverse Drug Reactions Occurring with an Incidence Rate ≥5% and an Increase of
>2% of IRESSA-treated Patients in Study 3
Adverse Reaction
Percentage (%) of patients
IRESSA (N=1126) Placebo (N=562)
All Grades Grade 3 and 4 All Grades Grade 3 and 4
Skin and subcutaneous tissue disorders
Skin reactions1 47% 2% 17% 0.4%
Nail disorders2 5% 0.1% 0.7% 0%
Gastrointestinal disorders
Diarrhea3 29% 3% 10% 1%
Vomiting 14% 1.2% 10% 0.4%
Stomatitis4 7% 0.3% 4% 0.2%
Metabolism and nutrition disorders
Decreased appetite 17% 2.3% 14% 2.0%
Eye disorders
Conjunctivitis/blepharitis/dry
eye5
6% 0% 3.2% 0%
1 Includes Acne, Acne pustular, Dermatitis, Dermatitis acneiform, Dermatitis exfoliative, Drug eruption, Dry skin, Erythema,
Exfoliative rash, Folliculitis, Pruritus, Pruritus generalized, Rash, Rash erythematous, Rash generalized, Rash macular, Rash
maculo-papular, Rash papular, Rash pruritic, Rash pustular, Rash vesicular, Skin exfoliation, Skin toxicity, Xeroderma 2 Includes Ingrowing nail, Nail bed infection, Nail disorder, Nail infection, Onychoclasis, Onycholysis, Paronychia 3 Includes Diarrhea, Feces soft, Frequent bowel movements 4 Includes Aphthous stomatitis, Cheilitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral mucosal blistering,
Stomatitis, Tongue disorder, Tongue ulceration 5 Includes Blepharitis, Conjunctival hyperemia, Conjunctivitis, Dry eye, Eye irritation, Eye pruritus, Eye swelling, Eyelid
irritation, Eyelid edema, Eyelids pruritus
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Table 2 – Treatment Emergent Laboratory Abnormalities Occurring More Frequently in IRESSATreated
Patients in Study 3
Adverse Reaction
IRESSA Placebo
All Grades
%
Grade 3 and 4
%
All Grades
%
Grade 3 and 4
%
Alanine aminotransferase
increased1
38%2 2.4% 23%2 1.4%4
Aspartate aminotransferase
increased1
40%3 2.0% 25%3 1.3%5
Proteinuria 35% 4.7% 31% 3.3%
1 Patients were allowed to enter the clinical study with lab values of ALT or AST CTCAE grade 1 or 2 2 14% gefitinib patients and 10% placebo patients were CTC grade 1 or 2 ALT at baseline 3 15% gefitinib patients and 12% placebo patients were CTC grade 1 or 2 AST at baseline 4 0.2% of placebo patients were CTC grade 3 at baseline 5 0.4% of placebo patients were CTC grade 3 at baseline
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%).
6.3 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
7 DRUG INTERACTIONS
7.1 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
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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)].
7.2 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.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on its mechanism of action and animal data, IRESSA can cause fetal harm when administered to a pregnant
woman. In animal reproductive studies, oral administration of gefitinib from organogenesis through weaning resulted in
fetotoxicity and neonatal death at doses below the recommended human dose (see Animal Data). Advise pregnant women
of the potential hazard to a fetus or potential risk for loss of the pregnancy.
The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the
background risk in the U.S. general population of major birth defects is 2-4% and miscarriage is 15-20% of clinically
recognized pregnancies.
Data
Animal Data
A single dose study in rats showed that gefitinib crosses the placenta after an oral dose of 5 mg/kg (30 mg/m2
, about 0.2
times 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 there was a reduction in the number of offspring born alive. This effect
was more severe at 20 mg/kg (approximate the human clinical dose on a mg/m2 basis) and was accompanied by high
neonatal mortality soon after parturition. 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.
8.2 Lactation
Risk Summary
It is not known whether IRESSA is excreted in human milk. Animal studies indicate the gefitinib and its metabolites are
present in rat milk at a concentration higher than those in maternal plasma. Because of the potential for serious adverse
reactions in nursing infants from IRESSA, advise women to discontinue breast-feeding during treatment with IRESSA.
Data
Animal Data
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.
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8.3 Females and Males of Reproductive Potential
Contraception
Based on its mechanism of action and animal data, IRESSA can cause fetal harm when administered to a pregnant woman
[see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during
treatment with IRESSA and for at least two weeks following completion of therapy.
Infertility
IRESSA may result in reduced fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)].
8.4 Pediatric Use
The safety and effectiveness of IRESSA in pediatric patients have not been established.
8.5 Geriatric Use
Of the 823 patients enrolled in two randomized, active-controlled clinical trials 374 patients (45%) were 65 years and
older, and 93 patients (11%) were 75 years and older. No overall differences in safety were observed between patients 65
years and older and those younger than 65 years. There is insufficient information to assess for differences in efficacy
between older and younger patients.
8.6 Renal Impairment
Less than four percent (<4%) of gefitinib and its metabolites are excreted via the kidney. No clinical studies were
conducted with IRESSA in patients with severe renal impairment.
8.7 Hepatic Impairment
The systemic exposure of gefitinib was compared in patients with mild, moderate, or severe hepatic impairment due to
cirrhosis (according to Child-Pugh classification) and healthy subjects with normal hepatic function (N=10/group). The
mean systemic exposure (AUC0-∞) was increased by 40% in patients with mild impairment, 263% in patients with
moderate impairment, and 166% in patients with severe hepatic impairment. Monitor adverse reactions when IRESSA is
administered to patients with moderate and severe hepatic impairment.
In a study comparing 13 patients with liver metastases and moderate hepatic impairment (addition of CTC grade of
baseline AST/SGOT, ALP, and bilirubin equals 3 to 5) to 14 patients with liver metastases and normal hepatic function,
the systemic exposure of gefitinib was similar [see Warnings and Precautions (5.2)].
10 OVERDOSAGE
Twenty three patients were treated weekly with doses from 1500 mg to 3500 mg, and IRESSA exposure did not increase
with increasing dose. Adverse events were mostly mild to moderate in severity, and were consistent with the known
safety profile of IRESSA. In the event of suspected overdose, interrupt IRESSA, institute supportive care, and observe
until clinical stabilization. There are no specific measures/treatments that should be taken following IRESSA overdosing.
11 DESCRIPTION
Gefitinib is a kinase inhibitor.
The chemical name of gefitinib is 4-Quinazolinamine N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)
propoxy] and the following structural formula:
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Gefitinib has the molecular formula C22H24ClFN4O3, a relative molecular mass of 446.9 daltons and is a white-colored
powder. Gefitinib is a free base. The molecule has pKas of 5.4 and 7.2. Gefitinib can be defined as sparingly soluble at
pH 1, but is practically insoluble above pH 7, with the solubility decreasing sharply between pH 4 and pH 6. In nonaqueous
solvents, gefitinib is freely soluble in glacial acetic acid and dimethyl sulfoxide, soluble in pyridine, sparingly
soluble in tetrahydrofuran, and slightly soluble in methanol, ethanol (99.5%), ethyl acetate, propan-2-ol and acetonitrile.
IRESSA® (gefitinib) tablets are available as brown film-coated tablets, containing 250 mg of gefitinib, for oral
administration. The inactive ingredients of the tablet core of IRESSA tablets are lactose monohydrate, microcrystalline
cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate and magnesium stearate. The tablet coating is
composed of hypromellose, polyethylene glycol 300, titanium dioxide, red ferric oxide and yellow ferric oxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The epidermal growth factor receptor (EGFR) is expressed on the cell surface of both normal and cancer cells and plays a
role in the processes of cell growth and proliferation. Some EGFR activating mutations (exon 19 deletion or exon 21
point mutation L858R) within NSCLC cells have been identified as contributing to the promotion of tumor cell growth,
blocking of apoptosis, increasing the production of angiogenic factors and facilitating the processes of metastasis.
Gefitinib reversibly inhibits the kinase activity of wild-type and certain activating mutations of EGFR, preventing
autophosphorylation of tyrosine residues associated with the receptor, thereby inhibiting further downstream signalling
and blocking EGFR-dependent proliferation.
Gefitinib binding affinity for EGFR exon 19 deletion or exon 21 point mutation L858R mutations is higher than its
affinity for the wild-type EGFR. Gefitinib also inhibits IGF and PDGF-mediated signalling at clinically relevant
concentrations; inhibition of other tyrosine kinase receptors has not been fully characterized.
12.3 Pharmacokinetics
Absorption and Distribution
The mean oral bioavailability of gefitinib is 60%, with peak plasma levels occurring 3-7 hours after dosing. Food does
not alter gefitinib bioavailability to a clinically meaningful extent. IRESSA can be administered with or without 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 1-acid
glycoprotein) is 90%, independent of drug concentrations. Gefitinib is a substrate for the membrane transport Pglycoprotein
(P-gp), but it is unlikely to influence gefitinib absorption as P-gp is saturated at higher concentrations.
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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 methoxysubstituent
on the quinazoline, and oxidative defluorination of the halogenated phenyl group. Five metabolites have been
fully identified in fecal extracts and the major active component was O-desmethyl gefitinib produced by CYP2D6
metabolism and accounted for 14% of the dose.
Eight 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 of 48 hours after
intravenous administration. The inter-subject variability (coefficient of variation) for AUC in healthy subjects was 67%.
Daily oral administration of gefitinib to cancer patients resulted in a two-fold accumulation compared to single dose
administration. Steady state plasma concentrations are achieved within 10 days after daily dosing. Excretion of gefitinib
and its metabolites is predominantly via the feces (86%), with renal elimination accounting for less than 4% of the
administered dose.
Specific Populations
Age, gender, body weight, ethnicity or renal function: Population pharmacokinetic analyses suggest that patient age, body
weight, ethnicity (populations included) or creatinine clearance (above 20 mL/min) has no clinically meaningful effect on
predicted steady state trough concentration of gefitinib. Population pharmacokinetic analyses of Study 1 showed that
women had 27% higher exposure than men; however, this difference was not identified in the analyses of other gefitinib
clinical studies. No dose adjustment based on patient gender is recommended.
Hepatic Impairment: The systemic exposure of gefitinib was compared between patients with mild, moderate, or severe
hepatic impairment due to cirrhosis (according to Child-Pugh classification) and healthy subjects with normal hepatic
function (N=10/group). The mean systemic exposure (AUC0-∞) was increased by 40% in patients with mild impairment,
263% in patients with moderate impairment, and 166% in patients with severe hepatic impairment. In a study comparing
13 patients with liver metastases and moderate hepatic impairment to 14 patients with liver metastases and normal hepatic
function, the systemic exposure of gefitinib was similar [see Warnings and Precautions (5.2), Use in Specific Populations
(8.7)].
CYP2D6 Poor metabolizer: CYP2D6 metabolizes gefitinib to O-desmethyl gefitinib in vitro. In healthy CYP2D6 poor
metabolizers, O-desmethyl gefitinib concentration was not measurable and the mean exposure to gefitinib was 2-fold
higher as compared to the extensive metabolizers. This increase in exposure in CYP2D6 poor metabolizers may be
clinically important because some adverse drug reactions are related to higher exposure of gefitinib. No dose adjustment
is recommended in patients with a known CYP2D6 poor metabolizer genotype, but these patients should be closely
monitored for adverse reactions. The impact of CYP2D6 inhibiting drugs on gefitinib pharmacokinetics has not been
evaluated. However, similar precautions should be used when administering CYP2D6 inhibitors with IRESSA because of
the possibility of increased exposure in these patients.
An exploratory exposure response analysis showed an increase in the incidence of interstitial lung disease (ILD) with a
greater than 2 fold increase in the gefitinib exposure [see Warnings and Precautions (5.1)].
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Drug-Drug Interactions
Strong CYP3A4 Inducer:
Concomitant administration of rifampicin (600 mg QD for 16 days), a strong inducer of CYP3A4, with gefitinib (500 mg
single dose on Day 10 of gefitinib administration) reduced mean AUC of gefitinib by 83% [see Dosage and
Administration (2.4), Drug Interactions (7)].
CYP3A4 Inhibitor:
Concomitant administration of itraconazole (200 mg QD for 12 days), an inhibitor of CYP3A4, with gefitinib (250 mg
single dose on Day 4 of itraconazole administration) to healthy male subjects, increased mean gefitinib AUC by 80% [see
Drug Interactions (7)].
Drugs Affecting Gastric pH:
Co-administration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above pH 5.0) to
healthy subjects decreased mean gefitinib AUC by 47% [see Drug Interactions (7)].
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 on Day 15 of gefitinib dosing
(500 mg daily for 28 days) in patients with solid tumors.
13 NONCLINICAL TOXICOLOGY
13.1 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.
In a two-year carcinogenicity study in mice, administration of gefitinib at a dose of 270 mg/m2
/day (approximately twice
the recommended daily dose of 250 mg on a mg/m2
basis; dose reduced from 375 mg/m2
/day from week 22) caused
hepatocellular adenomas in females. In a two-year carcinogenicity study in rats, administration of gefitinib at 60
mg/m2
/day (approximately 0.4 times the recommended daily clinical dose on a mg/m2
basis) caused hepatocellular
adenomas and hemangiomas/hemagiosarcomas of the mesenteric lymph nodes in female rats. The clinical relevance of
these findings is unknown.
In a dedicated fertility study in rats at doses ≥120 mg/m2 (approximately equal to the recommended human dose of
gefitinib on a mg/m2 basis), animals presented with an increased incidence of irregular estrous, decreased corpora lutea,
and decreases in uterine implants and live embryos per litter.
14 CLINICAL STUDIES
Non-Small Cell Lung Cancer (NSCLC)
Study 1
The efficacy and safety of IRESSA for the first-line treatment of patients with metastatic NSCLC containing EGFR exon
19 deletions or L858R substitution mutations was demonstrated in a multicenter, single-arm, open-label clinical study
(Study 1). A total of 106 treatment-naive patients with metastatic EGFR mutation positive NSCLC received IRESSA at a
Reference ID: 3791123
dose of 250 mg once daily until disease progression or intolerable toxicity. The major efficacy outcome measure was
objective response rate (ORR) according to RECIST v1.1 as evaluated by both a Blinded Independent Central Review
(BICR) and investigators. Duration of response (DOR) was an additional outcome measure. Eligible patients were
required to have a deletion in EGFR exon 19 or L858R, L861Q, or G719X substitution mutation and no T790M or S768I
mutation or exon 20 insertion in tumor specimens as prospectively determined by a clinical trial assay. Tumor samples
from 87 patients were tested retrospectively using the therascreen® EGFR RGQ PCR Kit.
The study population characteristics were: median age 65 years, age 75 years or older (25%), age less than 65 years
(49%), white (100%), female (71%), never smokers (64%), WHO PS 0 (45%), WHO PS 1 (48%), WHO PS 2 (7%), and
adenocarcinoma histology (97%). Sixty patients had exon 19 deletions (65%), 29 patients had L858R substitution (31%),
while two patients each had tumors harboring L861Q or G719X substitution mutation.
The median duration of treatment was 8.0 months. Efficacy results from Study 1 are summarized below.
Table 3 – Efficacy Results in Study 1
Efficacy Parameter BICR1
Assessment
(n=106)2
Investigator Assessment
(n=106)
Objective Response Rate3
(95% CI)
50%
(41, 59)
70%
(61, 78)
Complete Response Rate 0.9% 1.9%
Partial Response Rate 49% 68%
Median Duration of Response (months)
(95% CI)
6.0
(5.6, 11.1)
8.3
(7.6, 11.3)
1 BICR, Blinded Independent Central Review 2 17 patients without target lesion at baseline detected by BICR were deemed non responders 3 Determined by RECIST v 1.1
The response rates were similar in patients whose tumors had EGFR exon 19 deletions and exon 21 L858R substitution
mutations. Two partial responses were observed in both patients whose tumors had G719X substitution mutation with
duration of response of at least 2.8 months and 5.6 months, respectively. One of two patients whose tumors had L861Q
substitution mutation also achieved a partial response with duration of response of at least 2.8 months.
Study 2
The results of Study 1 were supported by an exploratory analysis of a subset of a randomized, multicenter, open-label trial
(Study 2) conducted in patients with metastatic adenocarcinoma histology NSCLC receiving first-line treatment. Patients
were randomized (1:1) to receive IRESSA 250 mg orally once daily or up to 6 cycles of carboplatin/paclitaxel. The
efficacy outcomes included progression-free survival (PFS) and objective response rate (ORR) as assessed by BICR.
The subset population consisted of 186 of 1217 patients (15%) determined to be EGFR positive by the same clinical trial
assay as used in Study 1 and had radiographic scans available for a retrospective assessment by BICR. In this subset,
there were 88 IRESSA-treated patients and 98 carboplatin/paclitaxel-treated patients.
Demographic and baseline characteristics of this subset were a median age of 59 years, age 75 years or older (7%), age
less than 65 (70%), Asian (100%), female (83%), never smokers (96%), adenocarcinoma histology (100%), and PS 0-1
(94%).
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The median duration of treatment for IRESSA-treated patients was 9.8 months. The hazard ratio for PFS favored the
IRESSA-treated patients [HR of 0.54 (95% CI: 0.38, 0.79)] with a median PFS of 10.9 months for the IRESSA-treated
patients and 7.4 months for the carboplatin/paclitaxel-treated patients as assessed by BICR. In addition, the objective
response rate was 67% (95% CI: 56, 77) for IRESSA-treated patients and 41% (95% CI: 31, 51) for
carboplatin/paclitaxel-treated patients based on BICR assessment. The median duration of response was 9.6 months for
IRESSA-treated patients and 5.5 months for carboplatin/paclitaxel-treated patients.
16 HOW SUPPLIED/STORAGE AND HANDLING
IRESSA® (gefitinib) is available as 250 mg tablets.
IRESSA 250 mg tablets are round, biconvex, brown film-coated, debossed with "IRESSA 250" on one side and plain on
the other side.
IRESSA® (gefitinib) tablets are supplied as:
Bottles of 30 Tablets (NDC 0310-0482-30)
Store at controlled room temperature 20C-25C (68F-77F) [see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labelling (Patient Information).
Interstitial Lung Disease: Advise patients to immediately contact their healthcare provider for new onset or worsening of
pulmonary symptoms such as dyspnea, cough and fever [see Warnings and Precautions (5.1)].
Hepatotoxicity: Inform patients that they will need to undergo lab tests to monitor for liver function. Advise patients to
contact their healthcare provider to report any new symptoms indicating hepatic toxicity [see Warnings and Precautions
(5.2)].
Gastrointestinal Perforation: Advise patients that IRESSA can increase the risk of gastrointestinal perforation and to seek
immediate medical attention for severe abdominal pain [see Warnings and Precautions (5.3)].
Severe or Persistent Diarrhea: Advise patients to contact their healthcare provider for severe or persistent diarrhea [see
Warnings and Precautions (5.4)].
Ocular Disorders including Keratitis: Advise patients promptly to contact their healthcare provider if they develop eye
symptoms, lacrimation, light sensitivity, blurred vision, eye pain, red eye or changes in vision [see Warnings and
Precautions (5.5)]
Bullous and Exfoliative Skin Disorders: Advise patients that IRESSA can increase the risk of bullous and exfoliative skin
disorders and to seek immediately medical attention for severe skin reactions [see Warnings and Precautions (5.6)].
Embryo-fetal Toxicity: Advise pregnant women of the potential risk to a fetus or potential risk for loss of the pregnancy
[see Warnings and Precautions (5.7), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use
effective contraception during treatment with IRESSA and for at least two weeks following completion of therapy [see
Use in Specific Populations (8.3)].
Lactation: Advise women to discontinue breast-feeding during treatment with IRESSA [see Use in Specific Populations
(8.2)].
IRESSA is a trademark of the AstraZeneca group of companies.
Reference ID: 3791123
©AstraZeneca 2015
Manufactured for:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
By: AstraZeneca UK Limited
Macclesfield, Cheshire, England
Product of Belgium
Reference ID: 3791123
Patient Information
IRESSA (eye-RES-sah)
(gefitinib) tablets
What is IRESSA?
IRESSA is a prescription medicine used to treat people with non-small cell lung cancer (NSCLC) that has spread to other
parts of the body and:
that have certain types of abnormal epidermal growth factor receptor (EGFR) genes, and
who have not had previous treatment for cancer
Your healthcare provider will perform a test to make sure that IRESSA is right for you.
It is not known if IRESSA is safe and effective in people with NSCLC that have other types of EGFR genes.
It is not known if IRESSA is safe and effective in children.
Before taking IRESSA, tell your healthcare provider about all of your medical conditions, including if you:
have lung or breathing problems
ever had liver problems
have vision or eye problems
are pregnant or plan to become pregnant. IRESSA can harm your unborn baby.
o Females who are able to become pregnant should use an effective method of birth control during treatment with
IRESSA and for at least 2 weeks after the last dose of IRESSA. You should avoid becoming pregnant during
treatment with IRESSA.
o Tell your healthcare provider right away if you become pregnant during treatment with IRESSA.
are breastfeeding or plan to breastfeed. It is not known if IRESSA passes into your breast milk. Do not breastfeed
during treatment with IRESSA. Talk to your healthcare provider about the best way to feed your baby during this time.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines,
vitamins, or herbal supplements.
If you take a proton pump inhibitor (PPI), H2 blocker, or an antacid medicine, talk to your healthcare provider about the
best time to take it during treatment with IRESSA.
If you take a blood thinner called warfarin, your healthcare provider should do blood tests regularly to check how fast your
blood clots, during treatment with IRESSA.
How should I take IRESSA?
Take IRESSA exactly as your healthcare provider tells you to take it.
Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with IRESSA if you
have side effects.
Take IRESSA 1 time each day.
You can take IRESSA with or without food.
If you miss a dose of IRESSA, take it as soon as you remember. If it is less than 12 hours until your next dose, skip
the missed dose. Take your next dose at your regular time.
If you take too much IRESSA, call your healthcare provider or go to the nearest emergency room right away.
If you cannot swallow IRESSA tablets whole:
o place your dose of IRESSA in a container with 4 to 8 ounces of water and stir for about 15 minutes
o drink the mixture right away
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o place another 4 to 8 ounces of water in the same container, and drink it right away
What are the possible side effects of IRESSA?
IRESSA may cause serious side effects, including:
lung or breathing problems. IRESSA may cause inflammation of the lung that may lead to death. Symptoms may
be similar to those symptoms from lung cancer. Tell your healthcare provider right away if you have any new or
worsening lung problems, or any combination of the following symptoms: trouble breathing or shortness of breath,
cough, or fever.
Iiver problems. IRESSA may cause inflammation of the liver that may lead to death. Tell your healthcare provider
right away if you have any symptoms of a liver problem which may include:
o yellowing of your skin or the white part of your eyes (jaundice)
o dark or brown (tea colored) urine
o light-colored bowel movements (stools)
o decreased appetite
o pain on the right side of your stomach (abdomen)
Your healthcare provider will do blood tests to check your liver function during your treatment with IRESSA.
a tear in the wall of your stomach or intestines (perforation). Get emergency medical help right away if you have
severe stomach (abdomen) pain.
diarrhea. Diarrhea is common with IRESSA and can sometimes be severe. Tell your healthcare provider right away if
you have severe diarrhea or diarrhea that will not go away.
eye problems. Tell your healthcare provider if you get watery eyes, sensitivity to light, blurred vision, eye pain, eye
redness, or vision changes.
skin reactions. Skin redness, rash, itching, and acne are common with IRESSA. This may occur on any part of your
body. Get medical help right away if you develop severe skin reactions such as peeling or blistering of your skin.
IRESSA may cause fertility problems in females. Talk to your healthcare provider if you plan to become pregnant.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of IRESSA. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088.
How should I store IRESSA?
Store IRESSA at room temperature between 68˚F to 77˚F (20˚C to 25˚C)
Keep IRESSA and all medicines out of the reach of children.
General information about the safe and effective use IRESSA.
Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use
IRESSA for a condition for which it was not prescribed. Do not give IRESSA to other people, even if they have the same
symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about
IRESSA that is written for health professionals.
What are the ingredients in IRESSA?
Active ingredient: gefitinib
Inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl
sulfate, magnesium stearate
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Tablet coating contains: hypromellose, polyethylene glycol 300, titanium dioxide, yellow iron oxide and red iron oxide.
IRESSA is a trademark of the AstraZeneca group of companies.
©AstraZeneca 2015
Manufactured for: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850
Manufacture by: AstraZeneca UK Limited Macclesfield, Cheshire, England Product of Belgium
For more information, go to www.iressa.com or call 1-800-236-9933
This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: July 2015
Reference ID: 3791123
