NDA 21-399/S-008
`Page 3
`
`FOR ONCOLOGY USE ONLY
`
`DESCRIPTION
`IRESSA(cid:163) (gefitinib tablets) contain 250 mg of gefitinib and are available as brown film-coated tablets
`for daily oral administration.
`
`Gefitinib is an anilinoquinazoline with the chemical name 4-Quinazolinamine, N-(3-chloro-4-
`fluorophenyl)-7-methoxy-6-[3-4-morpholin) propoxy] and the following structural formula:
`
`F
`
`Cl
`
`NH
`
`N
`
`N
`
`O O
`
`O
`
`N
`
`It has the molecular formula C22H24ClFN4O3, a relative molecular mass of 446.9 and is a white-
`colored powder. Gefitinib is a free base. The molecule has pKas of 5.4 and 7.2 and therefore ionizes
`progressively in solution as the pH falls. Gefitinib can be defined as sparingly soluble at pH 1, but is
`practically insoluble above pH 7, with the solubility dropping sharply between pH 4 and pH 6. In non-
`aqueous solvents, gefitinib is freely soluble in glacial acetic acid and dimethylsulphoxide, soluble in
`pyridine, sparingly soluble in tetrahydrofuran, and slightly soluble in methanol, ethanol (99.5%), ethyl
`acetate, propan-2-ol and acetonitrile.
`
`The inactive ingredients of IRESSA tablets are: Tablet core: Lactose monohydrate, microcrystalline
`cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate and magnesium stearate. Coating:
`hypromellose, polyethylene glycol 300, titanium dioxide, red ferric oxide and yellow ferric oxide.
`
`OSI 2031
`APOTEX V. OSI
`IPR2016-01284
`
`1
`
`

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`NDA 21-399/S-008
`Page 4
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`The mechanism of the clinical antitumor action of gefitinib is not fully characterized. Gefitinib
`inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane
`cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor
`receptor (EGFR-TK). EGFR is expressed on the cell surface of many normal cells and cancer cells.
`No clinical studies have been performed that demonstrate a correlation between EGFR receptor
`expression and response to gefitinib.
`
`Pharmacokinetics
`Gefitinib is absorbed slowly after oral administration with mean bioavailability of 60%. Elimination is
`by metabolism (primarily CYP3A4) and excretion in feces. The elimination half-life is about 48
`hours. Daily oral administration of gefitinib to cancer patients resulted in a 2-fold accumulation
`compared to single dose administration. Steady state plasma concentrations are achieved within 10
`days.
`
`Absorption and Distribution
`Gefitinib is slowly absorbed, with peak plasma levels occurring 3-7 hours after dosing and mean oral
`bioavailability of 60%. Bioavailability is not significantly altered by food. Gefitinib is extensively
`distributed throughout the body with a mean steady state volume of distribution of 1400 L following
`intravenous administration. In vitro binding of gefitinib to human plasma proteins (serum albumin and
`α1-acid 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.
`
`Special Populations
`In population based data analyses, no relationships were identified between predicted steady state
`trough concentration and patient age, body weight, gender, ethnicity or creatinine clearance.
`
`Pediatric:
`There are no pharmacokinetic data in pediatric patients.
`
`
`2
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`NDA 21-399/S-008
`Page 5
`
`Hepatic Impairment:
`The influence of hepatic metastases with elevation of serum aspartate aminotransferase (AST/SGOT),
`alkaline phosphatase, and bilirubin has been evaluated in patients with normal (14 patients),
`moderately elevated (13 patients) and severely elevated (4 patients) levels of one or more of these
`biochemical parameters. Patients with moderately and severely elevated biochemical liver
`abnormalities had gefitinib pharmacokinetics similar to individuals without liver abnormalities (see
`PRECAUTIONS section).
`
`Renal Impairment:
`No clinical studies were conducted with IRESSA in patients with severely compromised renal function
`(see PRECAUTIONS section). Gefitinib and its metabolites are not significantly excreted via the
`kidney (<4%).
`
`Drug-Drug Interactions:
`In human liver microsome studies, gefitinib had no inhibitory effect on CYP1A2, CYP2C9, and
`CYP3A4 activities at concentrations ranging from 2-5000 ng/mL. At the highest concentration studied
`(5000 ng/mL), gefitinib inhibited CYP2C19 by 24% and CYP2D6 by 43%. Exposure to metoprolol, a
`substrate of CYP2D6, was increased by 30% when it was given in combination with gefitinib (500 mg
`daily for 28 days) in patients with solid tumors.
`
`Rifampicin, an inducer of CYP3A4, reduced mean AUC of gefitinib by 85% in healthy male
`volunteers (see PRECAUTIONS-Drug Interactions and DOSAGE AND ADMINISTRATION-
`Dosage Adjustment sections).
`
`Concomitant administration of itraconazole (200 mg QD for 12 days), an inhibitor of CYP3A4, with
`gefitinib (250 mg single dose) to healthy male volunteers, increased mean gefitinib AUC by 88% (see
`PRECAUTIONS-Drug Interactions section).
`
`Co-administration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH
`above pH 5.0) reduced mean gefitinib AUC by 44% (See PRECAUTIONS-Drug Interactions
`section).
`
`International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some
`patients taking warfarin while on IRESSA therapy. Patients taking warfarin should be monitored
`regularly for changes in prothrombin time or INR (see PRECAUTIONS-Drug Interactions and
`ADVERSE REACTIONS sections).
`
`Clinical Studies
`Non-Small Cell Lung Cancer (NSCLC): Refractory Disease Tumor Response Study - A multicenter
`clinical trial in the United States evaluated the tumor response rate of IRESSA 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
`
`3
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`38 (58)
`28 (42)
`
`61 (92)
`1 (2)
`1 (2)
`0 (0)
`3 (5)
`
`45 (68)
`
`21 (32)
`
`14 (21)
`36 (55)
`15 (23)
`1 (2)
`
`9 (14)
`47 (71)
`6 (9)
`1 (2)
`3 (5)
`
`0 (0)
`
`11 (17)
`55 (83)
`
`
`
`NDA 21-399/S-008
`Page 6
`
`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 1: Demographic and Disease Characteristics
`IRESSA Dose
`
`
`
`
`
`
`250 mg/day
`500 mg/day
`Characteristic
`N = 66 (%)
`N = 76 (%)
`Age Group
`
`
`18 – 64 years
`43 (65)
`43 (57)
`64 – 74 years
`19 (29)
`30 (39)
`75 years and above
`4 (6)
`3 (4)
`Sex
`Male
`Female
`Race
`White
`Black
`Asian/Oriental
`Hispanic
`Other
`Smoking History
` Yes (Previous or current
` Smoker)
`No (Never Smoked)
`Baseline WHO
`Performance Status
`0
`1
`
`2
`Not recorded
`Tumor Histology
`Squamous
`Adenocarcinoma
`Undifferentiated
`Large Cell
`Squamous &
`Adenocarcinoma
`Not Recorded
`Current Disease Status
`Locally Advanced
`Metastatic
`
`
`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).
`
`
`11 (14)
`50 (66)
`4 (5)
`2 (3)
`7 (9)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`41 (54)
`35 (46)
`
`68 (89)
`2 (3)
`2 (3)
`3 (4)
`1 (1)
`
`62 (82)
`
`14 (18)
`
`9 (12)
`53 (70)
`14 (18)
`0 (0)
`
`2 (3)
`
`5 (7)
`71 (93)
`
`4
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`NDA 21-399/S-008
`Page 7
`
`Table 2: Efficacy Results
`
`
`
`
`
`Efficacy Population
`250 mg
`500 mg
`Combined
`(N=66)
`(N=76)
`(N=142)
`13.6
`7.9
`10.6
`
`3.0 – 16.4
`
`
`
`4.5
`4.4 – 7.6
`
`
`
`6.0 – 16.8
`
`
`
`7.0
`4.4 – 18.6+
`
`
`Objective Tumor
`Response Rate (%)
` 95% CI
`Median Duration of
`Objective Response
`(months)
` Range (months)
`+=data are ongoing
`
`Non-Small Cell Lung Cancer (NSCLC): Refractory Disease Survival Study
`
`6.4– 24.3
`
`
`8.9
`4.6 – 18.6+
`
`
` 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.
`
`INDICATIONS AND USAGE
`IRESSA is indicated as monotherapy for the continued treatment of patients with locally advanced or
`metastatic non-small cell
`lung cancer after failure of both platinum-based and docetaxel
`chemotherapies who are benefiting or have benefited from IRESSA.
`
`In light of positive survival data with other agents including another oral EGFR inhibitor, physicians
`should use other treatment options in advanced non-small cell lung cancer patient populations who
`have received one or two prior chemotherapy regimens and are refractory or intolerant to their most
`recent regimen.
`
`
`
`
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`NDA 21-399/S-008
`Page 8
`
`The effectiveness of IRESSA was initially based on objective response rates (see CLINICAL
`PHARMACOLOGY-Clinical Studies section). Subsequent studies intended to demonstrate an
`increase in survival have been unsuccessful. Specifically, results from a large placebo-controlled
`randomized trial in patients with advanced NSCLC who progressed while receiving or within 90 days
`of the last dose of chemotherapy or were intolerant to the most recent prior chemotherapy regimen, did
`not show an improvement in survival (see CLINICAL PHARMACOLOGY- Clinical Studies
`section).
`
`Results from two large, controlled, randomized trials in first-line treatment of non-small cell lung
`cancer showed no benefit from adding IRESSA to doublet, platinum-based chemotherapy.
`
`
`CONTRAINDICATIONS
`IRESSA is contraindicated in patients with severe hypersensitivity to gefitinib or to any other
`component of IRESSA.
`
`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
`interstitial lung disease is confirmed, IRESSA should be discontinued and the patient treated
`appropriately (see PRECAUTIONS-Information for Patients, ADVERSE REACTIONS and
`DOSAGE AND ADMINISTRATION-Dosage Adjustment sections).
`
`Pregnancy Category D
`IRESSA 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.
`
`
`6
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`

`NDA 21-399/S-008
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`
`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.
`
`
`
`PRECAUTIONS
`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.
`
`
`Patients with 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 (see
`CLINICAL PHARMACOLOGY-Pharmacokinetics- Special Populations section). The influence
`of non-cancer related hepatic impairment on the pharmacokinetics of gefitinib has not been evaluated.
`
`Information for Patients
`Patients should be advised to seek medical advice promptly if they develop 1) severe or persistent
`diarrhea, nausea, anorexia, or vomiting, as these have sometimes been associated with dehydration; 2)
`an onset or worsening of pulmonary symptoms, ie, shortness of breath or cough; 3) an eye irritation;
`or, 4) any other new symptom (see WARNINGS-Pulmonary Toxicity, ADVERSE REACTIONS
`and DOSAGE AND ADMINISTRATION-Dosage Adjustment sections).
`
`Women of childbearing potential must be advised to avoid becoming pregnant (see WARNINGS-
`Pregnancy Category D).
`
`Drug Interactions
`Substances that are inducers of CYP3A4 activity increase the metabolism of gefitinib and decrease its
`plasma concentrations. In patients receiving a potent CYP3A4 inducer such as rifampicin or phenytoin,
`a dose increase to 500 mg daily should be considered in the absence of severe adverse drug reaction,
`and clinical response and adverse events should be carefully monitored (see CLINICAL
`PHARMACOLOGY-Pharmacokinetics-Drug-Drug
`Interactions and DOSAGE AND ADMINISTRATION-Dosage Adjustment sections).
`
`International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some
`patients taking warfarin while on IRESSA therapy. Patients taking warfarin should be monitored
`regularly for changes in prothrombin time or INR (see CLINICAL PHARMACOLOGY-
`Pharmacokinetics-Drug-Drug Interactions and ADVERSE
`REACTIONS sections).
`
`Substances that are potent inhibitors of CYP3A4 activity (eg, ketoconazole and itraconazole) decrease
`gefitinib metabolism and increase gefitinib plasma concentrations. This increase may be clinically
`relevant as adverse experiences are related to dose and exposure; therefore, caution should be used
`
`7
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`

`NDA 21-399/S-008
`Page 10
`
`when administering CYP3A4 inhibitors with IRESSA (see CLINICAL PHARMACOLOGY-
`Pharmacokinetics-Drug-Drug Interactions and ADVERSE REACTIONS sections).
`
`Drugs that cause significant sustained elevation in gastric pH (histamine H2-receptor antagonists such
`as ranitidine or cimetidine) may reduce plasma concentrations of IRESSA and therefore potentially
`may reduce efficacy (see CLINICAL PHARMACOLOGY-Drug-Drug Interactions section).
`
`Phase II clinical trial data, where IRESSA and vinorelbine have been used concomitantly, indicate that
`IRESSA may exacerbate the neutropenic effect of vinorelbine.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`Gefitinib has been tested for genotoxicity in a series of in vitro (bacterial mutation, mouse lymphoma,
`and human lymphocyte) assays and an in vivo rat micronucleus test. Under the conditions of these
`assays, gefitinib did not cause genetic damage.
`
`Carcinogenicity studies have not been conducted with gefitinib.
`
`Pregnancy
`Pregnancy Category D (see WARNINGS and PRECAUTIONS-Information for Patients
`sections).
`
`Nursing Mothers
`It is not known whether IRESSA is excreted in human milk. Following oral administration of carbon-
`14 labeled gefitinib to rats 14 days postpartum, concentrations of radioactivity in milk were higher than
`in blood. Levels of gefitinib and its metabolites were 11-to-19-fold higher in milk than in blood, after
`oral exposure of lactating rats to a dose of 5 mg/kg. Because many drugs are excreted in human milk
`and because of the potential for serious adverse reactions in nursing infants, women should be advised
`against breast-feeding while receiving IRESSA therapy.
`
`Pediatric Use
`IRESSA is not indicated for use in pediatric patients as safety and effectiveness have not been
`established. In clinical trials of IRESSA 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 IRESSA.
`
`Geriatric Use
`Of the total number of patients participating in trials of second- and third-line IRESSA 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.
`
`Patients with Severe Renal Impairment
`The effect of severe renal impairment on the pharmacokinetics of gefitinib is not known. Patients with
`severe renal impairment should be treated with caution when given IRESSA.
`
`8
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`NDA 21-399/S-008
`Page 11
`
`ADVERSE REACTIONS
`The safety database includes 941 patients from clinical trials and approximately 23,000 patients in the
`Expanded Access Program.
`
`Table 3 includes drug-related adverse events with an incidence of >5% for the 216 patients who
`received either 250 mg or 500 mg of IRESSA monotherapy for treatment of NSCLC. The most
`common adverse events reported at the recommended 250 mg daily dose were diarrhea, rash, acne, dry
`skin, nausea, and vomiting (see PRECAUTIONS-Information for Patients and DOSAGE AND
`ADMINISTRATION–Dosage Adjustment sections). The 500 mg dose showed a higher rate for
`most of these adverse events.
`
`Table 4 provides drug-related adverse events with an incidence of >5% by CTC grade for the patients
`who received the 250 mg/day dose of IRESSA monotherapy for treatment of NSCLC. Only 2% of
`patients stopped therapy due to an adverse drug reaction (ADR). The onset of these ADRs occurred
`within the first month of therapy.
`
`
`Table 3: Drug-Related Adverse Events with an Incidence of > 5% in either 250 mg or 500 mg
`Dose Group
`
`Drug-related adverse eventa
`
`
`
`
`
`
`
`Number (%) of Patients
`250 mg/day
`(N=102)
`%
`49 (48)
`44 (43)
`25 (25)
`13 (13)
`13 (13)
`12 (12)
`8 (8)
`7 (7)
`6 (6)
`3 (3)
`
`500 mg/day
`(N=114)
`%
`76 (67)
`61 (54)
`37 (33)
`30 (26)
`20 (18)
`10 (9)
`10 (9)
`11 (10)
`5 (4)
`6 (5)
`
`Diarrhea
`Rash
`Acne
`Dry skin
`Nausea
`Vomiting
`Pruritus
`Anorexia
`Asthenia
`Weight loss
`a A patient may have had more than 1 drug-related adverse event.
`
`Table 4: Drug Related Adverse Events >5% at 250 mg dose by Worst CTC Grade (n=102)
`
`
`
`Adverse Event
`Diarrhea
`Rash
`
`All
`Grades
`48
`43
`
`% of Patients
`CTC
`Grade 2
`6
`4
`
`CTC
`Grade 3
`1
`0
`
`CTC
`Grade 1
`41
`39
`
`CTC
`Grade 4
`0
`0
`
`9
`
`

`

`0
`0
`1
`1
`0
`0
`1
`
`0
`0
`0
`0
`0
`0
`1
`
`19
`12
`7
`9
`7
`3
`2
`
`6
`1
`5
`2
`1
`4
`2
`
`25
`13
`13
`12
`8
`7
`6
`
`NDA 21-399/S-008
`Page 12
`
`Acne
`Dry Skin
`Nausea
`Vomiting
`Pruritus
`Anorexia
`Asthenia
`
`Other adverse events reported at an incidence of <5% in patients who received either 250 mg or 500
`mg as monotherapy for treatment of NSCLC (along with their frequency at the 250 mg recommended
`dose) include the following: peripheral edema (2%), amblyopia (2%), dyspnea (2%), conjunctivitis
`(1%), vesiculobullous rash (1%), and mouth ulceration (1%).
`
`Interstitial Lung Disease
`Cases of interstitial lung disease (ILD) have been observed in patients receiving IRESSA 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
`interstitial lung disease is confirmed, IRESSA should be discontinued and the patient treated
`appropriately (see WARNINGS-Pulmonary Toxicity, PRECAUTIONS-Information for Patients
`and DOSAGE AND ADMINISTRATION-Dosage Adjustment sections).
`
`In patients receiving IRESSA therapy, there were reports of eye pain and corneal erosion/ulcer,
`sometimes in association with aberrant eyelash growth (see PRECAUTIONS-Information for
`Patients section). Hemorrhage, such as epistaxis and hematuria have been reported in patients
`receiving IRESSA. There were also rare reports of pancreatitis and very rare reports of corneal
`membrane sloughing, ocular ischemia/hemorrhage, toxic epidermal necrolysis, erythema multiforme,
`and allergic reactions, including angioedema and urticaria.
`
`International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some
`patients taking warfarin while on IRESSA therapy. Patients taking warfarin should be monitored
`regularly for changes in prothrombin time or INR (see CLINICAL PHARMACOLOGY-Drug-Drug
`Interactions and PRECAUTIONS-Drug Interactions sections).
`
`
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`NDA 21-399/S-008
`Page 13
`
`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.
`
`
`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 IRESSA 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.
`
`
`DOSAGE AND ADMINISTRATION
`The recommended daily dose of IRESSA is one 250 mg tablet with or without food. Higher doses do
`not give a better response and cause increased toxicity.
`
`For Patients who have Difficulty Swallowing Solids
`IRESSA tablets can also be dispersed in half a glass of drinking water (non-carbonated). No other
`liquids should be used. Drop the tablet in the water, without crushing it, stir until the tablet is dispersed
`(approximately 10 minutes) and drink the liquid immediately. Rinse the glass with half a glass of water
`and drink. The liquid can also be administered through a naso-gastric tube.
`
`Dosage Adjustment
`Patients with poorly tolerated diarrhea (sometimes associated with dehydration) or skin adverse drug
`reactions may be successfully managed by providing a brief (up to 14 days) therapy interruption
`followed by reinstatement of the 250 mg daily dose.
`
`In the event of acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever), IRESSA
`therapy should be interrupted and a prompt investigation of these symptoms should occur and
`appropriate treatment initiated. If interstitial lung disease is confirmed, IRESSA should be
`treated appropriately (see WARNINGS-Pulmonary Toxicity,
`discontinued and
`the patient
`PRECAUTIONS-Information for Patients and ADVERSE REACTIONS sections).
`
`Patients who develop onset of new eye symptoms such as pain should be medically evaluated and
`managed appropriately, including IRESSA therapy interruption and removal of an aberrant eyelash if
`present. After symptoms and eye changes have resolved, the decision should be made concerning
`reinstatement of the 250 mg daily dose (see PRECAUTIONS-Information for Patients and
`ADVERSE REACTIONS sections).
`
`In patients receiving a potent CYP3A4 inducer such as rifampicin or phenytoin, a dose increase to 500
`mg daily should be considered in the absence of severe adverse drug reaction, and clinical response
`and adverse events should be carefully monitored (see CLINICAL PHARMACOLOGY-
`Pharmacokinetics-Drug-Drug Interactions and PRECAUTIONS-Drug Interactions sections).
`11
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`NDA 21-399/S-008
`Page 14
`
`No dosage adjustment is required on the basis of patient age, body weight, gender, ethnicity, or renal
`function; or in patients with moderate to severe hepatic impairment due to liver metastases (see
`CLINICAL PHARMACOLOGY-Pharmacokinetics-Special Populations section).
`
`HOW SUPPLIED
`IRESSA tablets are supplied as round, biconvex, brown film-coated tablets intagliated with "IRESSA
`250" on one side and plain on the other side, each containing 250 mg of gefitinib.
`
`Bottles of 30 Tablets (NDC 0310-0482-30)
`
`Storage
`Store at controlled room temperature 20-25°C (68-77°F) [see USP].
`
`All trademarks are the property of the AstraZeneca group
`©AstraZeneca 2003, 2004
`
`Manufactured for:
`AstraZeneca Pharmaceuticals LP
`Wilmington, DE 19850
`By: AstraZeneca UK Limited
`Macclesfield, Cheshire, England
`Made in the United Kingdom
`
`Rev 04-07-04
`
`12
`
`