PRODUCT MONOGRAPH

Pr (r)

IRESSA

(gefitinib) 250 mg Tablets Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor NO NEW PATIENTS SHOULD START IRESSA. Under the Notice of Compliance with Conditions (NOC/c) policy, Health Canada has issued a conditional marketing authorization for IRESSA(r) 250 mg tablets. IRESSA, as monotherapy, is indicated for patients with locally advanced or metastatic non-small cell lung cancer after failure of two prior chemotherapy regimens (platinum-based and docetaxel). This indication is restricted to patients who are currently benefiting from IRESSA and whose tumours are EGFR expression status positive or unknown. The efficacy of IRESSA was originally based on objective responses. A subsequent study failed to demonstrate improved survival with IRESSA use. IRESSA remains available to benefiting patients through pharmacies, however for continued supply of the drug, patients will have to be registered by a pharmacist into the IRESSA Patient Registry by contacting 1-866-473-7720. IRESSA is contraindicated in patients with EGFR expression negative tumours. IRESSA appears unlikely to benefit patients whose tumours have been tested and are shown to be EGFR-negative. Furthermore, survival disadvantage in patients with EGFR expression negative tumours cannot be ruled out. EGFR-negative expression status was defined as having less than 10% of cells staining for EGFR using the DAKO EGFR pharmDX(tm) kit. Conditional market authorization is maintained while existing patients continue to benefit from IRESSA.

AstraZeneca Canada Inc. 1004 Middlegate Road Mississauga, Ontario L4Y 1M4

www.astrazeneca.ca

DATE OF REVISION:

January 30, 2008

Control Number: 117685

IRESSA(r) is a trade-mark of the AstraZeneca group of companies. PRODUCT MONOGRAPH

NAME OF DRUG

Pr (r)

IRESSA

(gefitinib) 250 mg Tablets

THERAPEUTIC CLASSIFICATION

(Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor) NO NEW PATIENTS SHOULD START IRESSA. Under the Notice of Compliance with Conditions (NOC/c) policy, Health Canada has issued a conditional marketing authorization for IRESSA(r) 250 mg tablets. IRESSA, as monotherapy, is indicated for patients with locally advanced or metastatic non-small cell lung cancer after failure of two prior chemotherapy regimens (platinum based and docetaxel). This indication is restricted to patients who are currently benefiting from IRESSA and whose tumours are EGFR expression status positive or unknown. The efficacy of IRESSA was originally based on objective responses. A subsequent study failed to demonstrate improved survival with IRESSA use. IRESSA remains available to benefiting patients through pharmacies, however for continued supply of the drug, patients will have to be registered by a pharmacist into the IRESSA Patient Registry by contacting 1-866-473-7720. IRESSA is contraindicated in patients with EGFR expression negative tumours. IRESSA appears unlikely to benefit patients whose tumours have been tested and are shown to be EGFR-negative. Furthermore, survival disadvantage in patients with EGFR expression negative tumours cannot be ruled out. EGFR-negative expression status was defined as having less than 10% of cells staining for EGFR using the DAKO EGFR pharmDX(tm) kit. Conditional market authorization is maintained while existing patients continue to benefit from IRESSA.

CLINICAL PHARMACOLOGY

The mechanism of the clinical anti-tumour action of gefitinib is not yet fully characterized. Gefitinib has been shown to inhibit the intracellular phosphorylation of the epidermal growth factor receptor (EGFR), as well as other receptor tyrosine kinases, although with less affinity. EGFR is expressed on the cell surface of many normal cells as well as cancer cells. In vitro and in vivo pre-clinical models show inhibition of human tumour-derived cell line growth. Evidence to date suggests relationship between EGFR expression and efficacy of Gefitinib (See CLINICAL EXPERIENCE).

Pharmacokinetics

The pharmacokinetics of gefitinib have been evaluated in healthy volunteers and in cancer patients following both single and multiple dosing.

Absorption

Following single oral administration to volunteers or to cancer patients, absorption was moderately slow and the mean terminal half-life was 30.5 and 41.0 hours, respectively. In volunteers, gefitinib AUC showed up to a 20-fold range at the same dose level and increased proportionally with dose over the dose range 50 to 250 mg. Between 250 and 500 mg, there was a slightly greater than dose proportional increase in exposure but the maximum degree of non-proportionality observed was only 2-fold. In cancer patients, gefitinib AUC increased with dose over the dose range 50 to 700 mg and showed up to an 8-fold range of values within a dose level. Daily administration of gefitinib to patients resulted in a 2-to 8-fold accumulation with steady state plasma concentrations achieved within 7-10 days. At steady state, plasma concentrations were typically maintained within a 2-to 3-fold range across the 24-hour dosing interval. Population pharmacokinetic data from Trial 0016 showed a mean steady state trough concentration following a 250 mg oral dose of 264 ng/mL (95% CI: 92.2 to 755 ng/mL) with inter-and intra-patient variability of 54 and 21%, respectively. Mean oral bioavailability of gefitinib was approximately 60% in both healthy volunteers and cancer patients, indicating that it was well absorbed. Cmax was typically achieved within 3 to 7 hours after dosing in both groups. Relative bioavailability of gefitinib in volunteers was not altered by food to an extent likely to be of clinical significance. In a trial in volunteers where gastric pH was maintained above pH 5 by co-administration of high doses of ranitidine with sodium bicarbonate, relative bioavailability was reduced by 47%.

Distribution

Mean volume of distribution at steady state of gefitinib is 1600 L in volunteers and 1400 L in cancer patients indicating extensive distribution into tissue. At clinically relevant concentrations of gefitinib, binding (in vitro) to human plasma proteins is approximately 90% with the binding proteins involved being serum albumin and a1-acid glycoprotein.

Metabolism

In vitro

data indicate that CYP3A4 is the major P450 isozyme involved in the oxidative metabolism of gefitinib. Three sites of biotransformation have been identified: metabolism of the propoxylmorpholino group, demethylation of the methoxy substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group.

Of the five circulating metabolites identified, the major one identified in human plasma was O-desmethyl gefitinib. Although it is present at concentrations similar to those of unchanged gefitinib, it was14-fold less potent than gefitinib at inhibiting EGF-stimulated cell growth and it is therefore unlikely that it contributes significantly to IRESSA clinical activity.

Elimination

Gefitinib total plasma clearance is approximately 500 mL/min. Excretion is predominantly via the faeces with renal elimination of drug and metabolites accounting for less than 4% of the administered dose.

Special Populations Pediatric:

There are no pharmacokinetic data in pediatric patients.

Hepatic Impairment:

In a phase I open-label study of single dose gefitinib 250 mg in patients with mild, moderate or severe hepatic impairment due to cirrhosis (according to Child-Pugh classification), there was an increase in exposure in all groups compared with healthy controls. An average 3.1- fold increase in exposure to gefitinib in patients with moderate and severe hepatic impairment was observed. None of the patients had cancer, all had cirrhosis and some had hepatitis. This increase in exposure may be of clinical relevance since adverse experiences are related to dose and exposure to gefitinib (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Gefitinib has been evaluated in a clinical trial conducted in 41 patients with solid tumours and normal hepatic function or, moderate or severe hepatic dysfunction due to liver metastases. It was shown that following daily dosing of IRESSA 250 mg, time to steady state, total plasma clearance and steady state exposure (Cmaxss, AUC24ss) were similar for the groups with normal and moderately impaired hepatic function. Data from 4 patients with severe hepatic dysfunction due to liver metastases suggested that steady state exposures in these patients are also similar to those in patients with normal hepatic function.

Renal Impairment:

No clinical studies were conducted with IRESSA in patients with severely compromised renal function. Gefitinib and its metabolites are not significantly excreted via the kidney (<4%). A limited number of patients with moderate renal insufficiency (calculated creatinine clearance of 30-50 mL/min) participated in the clinical trials.

Drug Interactions

(See PRECAUTIONS - Drug Interactions) Gefitinib showed no enzyme induction effects in animal studies. Human liver microsome studies demonstrated that in vitro gefitinib was not a potent inhibitor of any human CYP enzyme activities. At the highest concentration studied, it produced approximately 50% inhibition of CYP2D6. In a clinical trial in cancer patients, gefitinib was co-administered with metoprolol (a CYP2D6 substrate). This resulted in a small (35%) increase in exposure to metoprolol, which is not considered to be clinically relevant. Co-administration with rifampicin (a known potent CYP3A4 inducer) in healthy volunteers reduced mean gefitinib AUC by 83% of that without rifampicin. Co-administration with itraconazole (a potent CYP3A4 inhibitor) resulted in an 80% increase in the mean AUC of gefitinib in healthy volunteers.

Clinical Experience

Non-Small Cell Lung Cancer (NSCLC)

- Two randomized, double-blind, parallel group, Phase II multicenter clinical trials of similar design (Trial 0039 [IDEAL 2], a trial conducted in the United States and Trial 0016 [IDEAL 1], a supportive trial conducted in Japan, Europe, Australia, and South Africa) were conducted to assess the efficacy of IRESSA 250 and 500 mg/day in patients with advanced non-small cell lung cancer. IRESSA was taken once daily at approximately the same time each day.

Two hundred and sixteen patients received IRESSA therapy in Trial 0039; 102 (47%) and 114 (53%) received 250 mg and 500 mg daily doses, respectively. Patients had previously received at least two prior chemotherapy regimens that contained platinum and docetaxel given concurrently or sequentially. These prior regimens must have failed the patient because of disease progression or unacceptable toxicity. Forty-one percent of the patients received two prior treatment regimens, 33% received three prior treatment regimens and 25% received four or more prior treatment regimens. Patients entering Trial 0039 due to disease progression on therapy had received their most recent dose of chemotherapy within 90 days of disease progression. The endpoints of Trial 0039 were objective tumour response rate (SWOG modified WHO) and disease-related symptom improvement rate (as measured weekly using the Lung Cancer Subscale [LCS]). The LCS is an independently validated part of the Functional Assessment of Cancer Therapy- Lung (FACT-L) quality of life questionnaire. The LCS consists of seven symptoms, each of which is scored by the patient on a scale of 0 to 4. These seven symptoms were: shortness of breath, coughing, chest tightness, ease of breathing, weight loss, clarity of thinking and poor appetite. A total LCS score of 28 is asymptomatic and a total LCS score of 0 is most symptomatic in all seven symptoms. Patients enrolled in Trial 0039 were required to be symptomatic with an LCS score of 24 or less at entry. Symptom improvement required that the patient's LCS score improve by at least 2 points and be sustained for at least 4 weeks without an interim worsening. Two hundred and nine patients received IRESSA therapy in Trial 0016; 103 received 250 mg once a day and 106 received 500 mg once a day. These patients had received 1 or 2 prior chemotherapy regimens, at least 1 of which was platinum-based. All patients had received 1 previous regimen; 43.8% had received 2 previous regimens. The primary efficacy endpoint of Trial 0016 was objective tumour response rate. Disease- related symptom improvement was a secondary endpoint in Trial 0016; 67% of patients had disease-related symptoms at trial entry with an LCS score of 24 or less. Table 1 provides the efficacy results for Trial 0039 and Trial 0016 by dose. Similar outcomes for tumour response and symptom improvement were observed regardless of performance status and the number of prior therapies.

Table 1 Efficacy Results: Trials 0039 and 0016

(95% confidence interval)

Disease control rate (%) (95% confidence interval)

Median survival (mo)c

(95% confidence interval)

One-year survival rate (%) (95% confidence interval)

42.2

(32.4 to 52.3)

6.5

(4.8 to 8.0)

(19 to 38)

36.0

(27.2 to 45.5)

5.9

(4.6 to 7.2)

(14 to 34)

54.4

(44.3 to 64.2)

7.6

(5.3 to 10.1)

(25 to 44)

51.4

(41.5 to 61.3)

8.0

(6.7 to 9.9)

(20 to 38)

a

Evaluable for symptom improvement population (applicable to symptom improvement rate and median time to symptom improvement) consisted of 140 patients (250 mg, n=67; 500 mg, n=73).

b

As of August 2002.

c

References: Herbst et al. 2002, Schiller et al. 2002.

IRESSA demonstrated clinically significant anti-tumour activity, as evidenced by durable tumour responses in patients with locally advanced or metastatic NSCLC despite a significant proportion of these patients being heavily pre-treated. Objective responses in Trial 0039 were seen in patients with large or bulky tumours, and were generally rapid (i.e., within 4 weeks) and durable, with all responses achieved by 4 months (Table 2); this was notable because approximately 80% of patients had progressed within the previous 90 days. Long-term responses were evident, with 4 responses exceeding 12 months.

Table 2 Qualitative Aspects of Objective Responses: Trials 0039 and 0016

Trial 0039 Trial 0016

Objective response in 22 patients (10.2%)

Size 22 patients with PR

-13 with tumour areas of 10 cm2 to 60 cm2

-5 with tumour areas of <10 cm2

-4 with non-measurable disease

Rapidity 16 patients achieved PR status by Week 4 22 patients achieved PR status by Week 16

Duration Median duration

250 mg - 7.0 months

500 mg - 5.8 months

Quality Responses observed irrespective of multiple prior regimens, performance status, and age, and were documented in both men and women

Objective response in 39 patients (18.6%)

1 patient with CR 38 patients with PR

-26 with tumour areas of 10 cm2 to 85 cm2

-11 with tumour areas of <10 cm2

-1 with non-measurable disease

31 patients achieved PR status by Week 4 39 patients achieved PR status by Week 16

Median duration

250 mg - 13.0 months

500 mg - 10.1 months

Responses observed irrespective of prior regimens, performance status, and age, and were documented in both men and women

Clinically significant improvements in disease-related symptoms were seen in both trials at both doses. The rate of disease-related symptom improvement in Trial 0039 was substantial with 38.9% of patients experiencing improvement for >=1 month. Symptom improvement of the magnitude seen (corresponding to a mean 4.8-point change in LCS score of all improved patient data over time) was extremely rapid (median time to symptom improvement: 9 to 10 days), with the onset of improvement evident within the first 4 weeks of treatment (i.e., prior to the first radiological assessment of response) for approximately 82% of patients receiving 250 mg of IRESSA daily (Table 3). Analyses performed on patients with minimum improvements of 3, 4, or 5 points were consistent and showed a substantial number of patients with symptom improvement. Symptom improvement rates from Trial 0016 were similar despite cultural and racial differences.

Table 3 Qualitative Aspects of Symptom Improvement in Trials 0039 and 0016a

Trial 0039 Trial 0016

Symptom improvement in: 44/102 (43%) patients

27/67 (40%)

patients

Size Mean change in LCS 4.8 5.0

Rapidity % patients with onset of improvement

within 30 days of randomisation

82% 100%

Duration Median time to worsening

% maintained 3 months

% maintained 6 months

Not reached

77% (N at risk=27) 62% (N at risk=2)

Not reached

73% (N at risk=14) This length of

follow-up not

available

Quality % of patients with improvements of at

least 1 point in 6 or 7 items from LCSb

45% 33%

Concomitant medications

% of patients with symptoms improvement also receiving concomitant medications

42 /44 (95.45 %)c 22/27 (81.5%)d

aSymptom improvement was prospectively defined as a >=2-point increase in total LCS score for a minimum of 4 weeks without interim worsening (Cella et. al. 1995, 2002).

b

Baseline or subsequent nadir value

c

Predominantly analgesics, antipyretics, analides, natural opium alkaloids; glucocorticoids; antipropulsives

dPredominantly glucocorticoids, propionic acid derivatives, natural opium alkaloids, H2-receptor antagonists

LCS Lung Cancer Subscale

There was a strong positive correlation between objective tumour response and disease-related symptom improvement. In Trial 0039, 12 of 12 patients (100%) with an objective response also benefited in terms of symptom improvement. In Trial 0016, 9 of 13 patients (69.2%) with an objective response also benefited in terms of symptom improvement (Figure 1). Improvements in World Health Organization - Performance Status scores were also evident amongst patients with objective response: in Trial 0039, 7 of 12 patients reported an improvement of 1-grade (i.e., from PS 2 to PS 1 or from PS 1 to PS 0), including 2 patients with a 2-grade improvement (from PS 2 to PS 0). In Trial 0016, 5 of 19 patients reported an improvement of 1-grade (i.e., from PS 2 to PS 1 or from PS 1 to PS 0). An association between disease stabilization and symptom improvement was also evident (in Trial 0039, 80.6% of patients [25 of 31] with stable disease reported disease-related symptom improvement; in Trial 0016, 70% of patients [14 of 20] with stable disease reported disease- related symptom improvement); this compares with 11.9% of patients (7 of 59) with progressive disease experiencing symptom improvement in Trial 0039 and 11.8% of patients (4 of 34) with progressive disease experiencing symptom improvement in Trial 0016.

Figure 1 Association Between Tumour Response and Symptom Improvement in Trials 0039 and 0016, 250 mg dose

An additional secondary endpoint for patients enrolled in Trials 0039 and 0016, quality of life, was measured monthly using the FACT-L instrument. In Trial 0039, all patients receiving 250 mg/day were evaluable and in Trial 0016, sixty-seven of one hundred and three patients receiving 250-mg/day were evaluable for FACT-L derived endpoints. For Trial 0039, FACT- L improvement rate in patients receiving 250-mg/day was (34.3%; 95% CI: 25.2%, 44.4%). Median time to FACT-L improvement was 30 days for the 250 mg/day group. For Trial 0016, FACT-L improvement rate was 23.9% (95% CI: 14.3%, 35.9%) for the 250 mg/day group. The median time to FACT-L improvement was 29 days.

IRESSA Survival Evaluation in Lung Cancer (ISEL, Trial 709)

ISEL was a 1692-patient, randomised, Phase III study comparing IRESSA to placebo in association with best supportive care (BSC) for patients with advanced NSCLC who were refractory to (i.e. with clinical or radiological evidence of disease progression while receiving, or within 3 months of their last dose), or intolerant of their most recent chemotherapy. The 2 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 (HR 0.89, 95% confidence interval 0.77 to 1.02, p = 0.087). Median survival was 5.6 vs. 5.1 months, IRESSA vs. placebo.

Relationship between EGFR Protein Expression Status (as Determined by Immunohistochemistry) and Efficacy

Determination of EGFR protein expression status was not an entry criterion in ISEL. Using the DAKO EGFR pharmDX(tm) kit, 379 of 1692 patients (22.4%) were tested for EGFR protein expression status. A negative EGFR expression status was defined as having less than 10% of cells staining for EGFR. Table 4 provides the results of an analysis of overall survival by EGFR protein expression status. Based on this data, patients with EGFR expression status positive or unknown tumours had a better survival outcome with IRESSA than with placebo, although when all patients are included in the analysis, this trial failed to demonstrate statistical significance for the primary endpoint of overall survival (HR 0.89, 95% confidence interval 0.77 - 1.02, p = 0.087). In patients with EGFR expression negative tumours, IRESSA appears unlikely to offer benefit, and in fact, survival disadvantage cannot be ruled out (HR 1.57, 95% confidence interval 0.86 - 2.87, p = 0.1402).

Table 4 Analysis of overall survival by EGFR expression status, ISEL

Hazard ratioa

p-value

From Cox regression analysis with stratification factors (smoking history, gender, reason for prior chemotherapy failure, histology, performance status, and number of prior chemotherapy regimens) included as covariates; Hazard ratios<1.00 indicate that treatment with gefitinib 250 mg is associated with a longer survival time than placebo.

EGFR- positive was defined as having at least 10% of cell staining for EGFR.

Response rates for patients with EGFR-positive or -unknown tumours treated with IRESSA were similar to the overall study population, whereas response rates for patients with EGFR- negative tumours were similar to response rates on the placebo arm.

Table 5 Objective tumour response rates by EGFR expression status, ISEL

n/N(%) of patients with objective tumour response Gefitinib 250 mg Placebo

n Number of patients with objective tumour response (CR+PR). N Number of evaluable patients

NOC/c

Non-small Cell Lung Cancer (NSCLC) - Studies of First-line Treatment in Combination with Chemotherapy.

Controlled trials (INTACT I and II) with first-line treatment of NSCLC indicated no benefit from the addition of IRESSA to platinum based combined chemotherapies.

CONTRAINDICATIONS

IRESSA is contraindicated in patients with severe hypersensitivity to gefitinib or to any other component of IRESSA.

Patients with EGFR negative tumours

NOC/c

IRESSA appears unlikely to benefit patients whose tumours have been tested and are shown to be EGFR-negative. Furthermore, survival disadvantage in patients with EGFR expression negative tumours cannot be ruled out. EGFR-negative expression status was defined as having less than 10% of cells staining for EGFR using the DAKO EGFR pharmDX(tm) kit.

WARNINGS

A possible survival disadvantage of gefitinib therapy in patients with EGFR expression negative tumours cannot be ruled out by the data from ISEL (See CLINICAL EXPERIENCE section). Interstitial Lung Disease (ILD), which may be acute in onset, has been observed in patients receiving IRESSA at an overall incidence of about 1%, and approximately 1/3 of the cases have been fatal (See ADVERSE REACTIONS - Interstitial Lung Disease). The incidence of ILD-type events was 5.8% in patients receiving IRESSA in a post-marketing surveillance study in Japan (3350 patients) (see ADVERSE REACTIONS - Interstitial Lung Disease). In a Japanese Pharmacoepidemiological case-control study (see ADVERSE REACTIONS - Interstitial Lung Disease) in 3159 patients with NSCLC who were followed up for 12 weeks when receiving IRESSA or chemotherapy, the cumulative incidence of ILD at 12 weeks' follow-up was 4.0% in patients receiving IRESSA and 2.1% in those receiving chemotherapy. The adjusted odds ratio (OR) of developing ILD was 3.2 (95% confidence interval (CI) 1.9 to 5.4) for IRESSA versus chemotherapy. This trial identified the following risk factors for developing ILD (irrespective of whether the patient received IRESSA or chemotherapy): smoking, poor performance status (PS >= 2), normal lung coverage on CT scan <= 50%, short duration of NSCLC from diagnosis (< 6 months), pre-existing interstitial pneumonia, older age (>= 55 years old) and concurrent cardiac disease. Based on data from worldwide clinical studies , expanded access/compassionate use and post- marketing use, the estimated reporting rate of ILD-type events overall is approximately 0.3% outside of Japan and approximately 3% in Japan. Patients with concurrent Idiopathic Pulmonary Fibrosis/Interstitial Pneumonitis/Pneumoconiosis/ radiation Pneumonitis/drug- induced Pneumonitis have been observed to have an increased rate of mortality from this condition. If patients present with worsening of respiratory symptoms such as dyspnoea, cough and fever, IRESSA should be interrupted and prompt investigation initiated. If Interstitial Lung Disease is confirmed, IRESSA should be discontinued and the patient treated appropriately. The estimated patient exposure to IRESSA from worldwide clinical trials, Expanded Access Program and post-marketing use is >230,000. A total of 995 haemorrhagic events have been reported, irrespective of reported causality and any reported confounding factors. Of these events, 141 had a fatal outcome. These haemorrhagic events were predominantly reported in six specific System Organ Classes (SOCs): gastrointestinal disorders (32.7%); respiratory, thoracic and mediastinal disorders (28.2%); renal and urinary disorders (12.8%); vascular disorders (4.8%); skin and subcutaneous tissue disorders (4.6%) and nervous system disorders (4.5%). Increases in liver transaminases have been observed, rarely presenting as hepatitis. Therefore, periodic liver function testing is recommended. IRESSA should be used cautiously in the presence of mild to moderate increases of liver transaminases. Discontinuation should be considered if changes are severe. Substances that are inducers of CYP3A4 activity may increase metabolism and decrease IRESSA plasma concentrations. Therefore, co-medication with CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampicin, barbiturates or St. John's Wort) may reduce efficacy. Substances that are inhibitors of cytochrome CYP3A4 activity may decrease IRESSA metabolism and increase its plasma concentration. Therefore, co-medication with CYP3A4 inhibitors (e.g. azole antimycotics such as ketoconazole and itraconazole, macrolide antibiotics such as erythromycin and clarithromycin, protease inhibitors, grapefruit juice etc.) may increase toxicity. International Normalised Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin. Patients taking warfarin should be monitored regularly for changes in Prothrombin Time (PT) or INR. Two Phase II trials using the combination IRESSA/vinorelbine have been discontinued due to a high incidence of CTC grade 3 and 4 neutropenia. When used in combination, IRESSA aggravated the neutropenic effect of vinorelbine. Drugs that cause significant sustained elevation in gastric pH may reduce plasma concentrations of IRESSA and therefore may reduce efficacy. Patients should be advised to seek medical advice promptly in the event of developing:

• Any eye symptoms

• Severe or persistent diarrhea, nausea, vomiting or anorexia These symptoms should be managed as clinically indicated.

NOC/c

PRECAUTIONS

Limited Experience in Pediatric Population

In a Phase I/II trial of IRESSA and radiation in pediatric patients, newly diagnosed with brain stem glioma or incompletely resected supratentorial malignant glioma, 4 cases (1 fatal) of CNS haemorrhages were reported from 45 patients enrolled. A further case of CNS haemorrhage has been reported in a child with an ependymoma from a trial with IRESSA alone. The frequency of CNS haemorrhage in >230,000 adult patients estimated to have received IRESSA is 0.02%. However, there is no confirmed evidence of an increased risk of cerebral haemorrhage in adult patients with NSCLC receiving IRESSA. IRESSA is not indicated for use in pediatric patients, as safety and effectiveness have not been established.

Pregnancy and Lactation

There are no adequate and well-controlled studies in pregnant women using IRESSA. Women of childbearing potential must be advised to avoid becoming pregnant. 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. IRESSA may cause fetal harm when administered to a pregnant woman. Gefitinib has been found to cross the placenta following oral administration at 5 mg/kg (30 mg/m2) in rats (about 1/5 the recommended human dose on a mg/m2 basis). The recommended 250 mg daily dose in humans is approximately 4 mg/kg or 160 mg/m2. When pregnant rats that were treated with 5 mg/kg/day from the beginning of organogenesis to the end of weaning gave birth, there was a reduction in the number of offspring born alive. In pregnant rats treated with 20 mg/kg/day, the effects were more severe and included high neonatal mortality. The no observed adverse effect dose level in this study was 1 mg/kg/day. In rabbits, a dose of 20 mg/kg/day (240 mg/m2, or about twice the recommended dose in humans on a mg/m2 basis) caused reduced fetal weight. It is not known whether IRESSA is excreted in human milk. Following oral administration of carbon-14 labelled 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.

Geriatric Use

Of the total number of patients participating in trials 0039 and 0016 with IRESSA, 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.

Effects on Ability to Drive and Use Machinery

IRESSA is not expected to impair a patient's ability to drive or use machines. However, some patients may occasionally feel weak. If this happens, patients should not drive or operate machinery.

Drug Interactions

Gefitinib showed no enzyme induction effects in animal studies. Human liver microsome studies demonstrated that in vitro gefitinib was not a potent inhibitor of any human CYP enzyme activities. At the highest concentration studied, it produced approximately 50% inhibition of CYP2D6. In a clinical trial in cancer patients, gefitinib was co-administered with metoprolol (a CYP2D6 substrate). This resulted in a small (35%) increase in exposure to metoprolol, which is not considered to be clinically relevant. Co-administration with rifampicin (a known potent CYP3A4 inducer) in healthy volunteers reduced mean gefitinib AUC by 83% of that without rifampicin. Co-administration with itraconazole (a potent CYP3A4 inhibitor) resulted in an 80% increase in the mean AUC of gefitinib in healthy volunteers. Substances that are inducers of CYP3A4 activity may increase metabolism and decrease gefitinib plasma concentrations. Therefore, co-medication with CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampicin, barbiturates, or St. John's Wort) may potentially reduce efficacy. Substances that are inhibitors of CYP3A4 activity (e.g., azole antifungals such as ketoconazole and itraconazole, macrolide antibiotics such as erythromycin and clarithromycin, protease inhibitors, grapefruit juice etc.) may decrease metabolism and increase gefitinib plasma concentrations. This increase may be clinically relevant as adverse experiences are related to dose and exposure. Therefore, caution should be used when administering CYP3A4 inhibitors with IRESSA. Drugs that cause significant sustained elevation in gastric pH (histamine H2-receptor antagonists such as ranitidine or cimetidine; proton-pump inhibitors) may reduce plasma concentrations of gefitinib and therefore potentially may reduce efficacy. Co-administration of ranitidine (gastric pH above 5) reduced by 47% the mean gefitinib AUC in healthy volunteers.

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.

Hepatic Impairment

An average 3.1-fold increase in exposure to gefitinib in patients with moderate and severe hepatic impairment was observed in a phase I hepatic impairment study (see CLINICAL PHARMACOLOGY and DOSAGE and ADMINISTRATION). None of the patients had cancer, all had cirrhosis and some had hepatitis. This increase in exposure may be of clinical relevance since adverse experiences are related to dose and exposure to gefitinib.

Hepatotoxicity

Increases in liver transaminases have been observed, rarely presenting as hepatitis. Therefore, periodic liver function (transaminases, bilirubin, and alkaline phosphatase) testing is recommended. IRESSA should be used cautiously in the presence of mild to moderate increases in liver transaminases. Discontinuation should be considered if changes are severe.

Cardiovascular

Study D4200C00003 was a phase II study in patients with locally advanced or metastatic (IIIB/IV) NSCLC. Data from patients that received IRESSA 250 mg as their first treatment in the study were evaluated to determine the effect of IRESSA administration on QT prolongation. Following an analysis of the ECG recordings (scheduled for 4-8 hours post- dose), the mean change from baseline in QTcF (Friderica's corrected QT) for 85 patients who received IRESSA as their first treatment was 1.41 ms (range -88.1 to 87.2 ms). Limitations of this study include the absence of a placebo or positive control arm, such that background changes in the QTc interval and the sensitivity for detection of drug-related changes are unknown.

NOC/c

SYMPTOMS AND TREATMENT OF OVERDOSAGE

In non-clinical studies, the median lethal oral dose in rats was 2000 mg/kg (approximately 400 times the clinically recommended daily dose in humans on a mg/kg basis). The median lethal oral dose in mice was found to be in excess of 2000 mg/kg. There is no specific treatment in the event of overdose of IRESSA and possible symptoms of overdose are not established. However, in Phase I 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 diarrhoea and skin rash. Adverse reactions associated with overdose should be treated symptomatically; in particular, severe diarrhoea should be managed appropriately.

NOC/c

DOSAGE AND ADMINISTRATION

The recommended daily dose of IRESSA is one 250 mg tablet with or without food. Higher doses do not produce a better response and lead to increased toxicity.

Dosage Adjustment

Patients with poorly tolerated diarrhoea (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 once toxicity has resolved. Patients who develop eye symptoms should be evaluated and managed, including interruption of therapy with IRESSA. Reinstatement of the 250 mg/day IRESSA dose should be considered when symptoms and eye changes have resolved. If patients present with acute onset or worsening of respiratory symptoms such as dyspnoea, cough and fever, IRESSA should be interrupted and prompt investigation initiated. If Interstitial Lung Disease (ILD) is confirmed, IRESSA should be discontinued and the patient treated appropriately (see WARNINGS and ADVERSE REACTIONS). No dosage adjustment is required on the basis of patient age, body weight, gender, or ethnicity. An average 3.1-fold increase in exposure to gefitinib in patients with moderate and severe hepatic impairment was observed in a phase I hepatic impairment study (see CLINICAL PHARMACOLOGY and PRECAUTIONS). Since no efficacy studies have been conducted at doses of less than 250 mg daily, no specific advice concerning dose adjustments can be given for patients with hepatic dysfunction. This increase in exposure may be of clinical relevance since adverse experiences are related to dose and exposure to gefitinib. Since renal clearance is negligible, a decrease in clearance is not expected in patients with renal insufficiency. However, in severe renal insufficiency (e.g. Crcl < 30 mL/min) caution is recommended because common adverse events in patients with severe renal insufficiency did show increased incidence in ISEL.

Drug Substance

PHARMACEUTICAL INFORMATION

Proper Name

gefitinib

Lab Code

ZD1839

Chemical Name

N-(3-chloro-4-fluorophenyl-7-methoxy-6-[3-(morpholin-4-yl) propoxy] quinazolin-4-amine)

Structural Formula

O HN Cl

N O

O N

Molecular Formula C22H24ClFN4O3

Molecular Weight

446.9

Description

Gefitinib is a white-colored powder. Gefitinib is a free base.

The molecule has pKa's 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.

Composition

In addition to the active ingredient gefitinib 250 mg, each tablet contains the following non- medicinal ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulphate, magnesium stearate, hypromellose, macrogol 300, titanium dioxide, yellow iron oxide and red iron oxide.

Storage Recommendations

IRESSA should be stored at room temperature, 15 to 30 degC.

AVAILABILITY OF DOSAGE FORMS

IRESSA (gefitinib) is a 250 mg brown, round, biconvex, film-coated tablet impressed with "IRESSA 250" on one side and plain on the other. Available in blister packs of 30 tablets.

INFORMATION FOR THE PATIENT

NO NEW PATIENTS SHOULD START IRESSA.

Under the Notice of Compliance with Conditions (NOC/c) policy, Health Canada has issued a conditional marketing authorization for IRESSA(r) 250 mg tablets. IRESSA, as monotherapy, is for use in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of two chemotherapy regimens (platinum-based and docetaxel). The efficacy of IRESSA was originally based on objective responses. A

subsequent study failed to demonstrate improved survival with IRESSA. IRESSA use is restricted to patients who are currently benefiting from IRESSA and whose tumours are EGFR positive or unknown. IRESSA remains available to benefiting patients through pharmacies, however for continued supply of the drug, patients will have to be registered by a pharmacist into the IRESSA Patient Registry by contacting 1-866-473-7720.

IRESSA is contraindicated in patients with EGFR negative tumours. IRESSA appears unlikely to benefit patients whose tumours have been tested and are shown to be EGFR- negative. Furthermore, survival disadvantage in patients with EGFR negative tumours cannot be ruled out. EGFR-negative expression status was defined as having less than 10% of cells staining for EGFR using the DAKO EGFR pharmDX(tm) kit.

Conditional market authorization is maintained while existing patients continue to benefit from IRESSA.

Read all of this leaflet carefully before you start taking IRESSA. Keep this leaflet. You may need to read it again.

If you have further questions, please ask your doctor or your pharmacist.

This medicine has been prescribed for you personally and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours.

Pr (r)

IRESSA

(gefitinib) The other ingredients are lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulphate, magnesium stearate, hypromellose, macrogol 300, titanium dioxide, yellow iron oxide and red iron oxide.

WHAT IS IRESSA AND WHAT IS IT USED FOR?

IRESSA is a tablet and each tablet contains 250 mg gefitinib. IRESSA comes in blister packs. Each blister pack contains 30 tablets. IRESSA is used for the treatment of NSCLC in patients having failed two or more different chemotherapy regimens. NSCLC is one type of lung cancer. IRESSA targets a protein called Epidermal Growth Factor Receptor (EGFR) and a laboratory test can measure the level of this protein. In patients whose tumours were tested, those with low levels of EGFR appear unlikely to benefit from IRESSA treatment.

BEFORE YOU TAKE IRESSA

Do not take IRESSA

If you are allergic to gefitinib or any of the other ingredients of IRESSA, listed at the beginning of this leaflet. If you think you may be allergic, ask your doctor for advice. If your tumour has been tested for EGFR expression status and shown to produce low levels of this protein.

Previous illness

Before taking IRESSA, tell your doctor if you have, or have had, serious illness: Particularly lung diseases other than lung cancer. Some of them may worsen during treatment with IRESSA.

Pregnancy

Before taking IRESSA, tell your doctor if you are pregnant or trying to become pregnant. You should avoid becoming pregnant during treatment with IRESSA.

Breast-feeding

Before taking IRESSA, tell your doctor if you are breast-feeding. For the safety of your baby, you should discontinue breast-feeding during treatment with IRESSA.

Driving and operating machinery

IRESSA is not expected to impair your ability to drive or use machines. However, some patients may occasionally feel weak. If this happens, you should not drive or operate machinery.

Taking other medicines

Please inform your doctor if

you are taking or have taken any medicines, even those available over the counter.

Your doctor especially needs to know: If you take any of the following medicines: phenytoin, carbamazepine, rifampicin, barbiturates, St John's Wort, itraconazole or grapefruit juice. These medicines may affect the way IRESSA works. If you take warfarin (to prevent blood-clots), as IRESSA may affect it. Your doctor may need to check your blood more often.

HOW TO TAKE IRESSA

Take one 250 mg tablet, once a day, every day about the same time. You can take IRESSA with or without food.

If you take more IRESSA than you should

Talk to your doctor immediately. If you forget to take a dose Take the last missed dose as soon as you remember, as long as it is at least 12 hours before the next dose is due. If it is less than 12 hours to the next dose, do not take the dose you have missed.

POSSIBLE SIDE EFFECTS

Like all medicines, IRESSA can have side effects. These are usually mild to moderate in intensity. Do not be alarmed by the list of side effects. You may not have any of them. Contact your doctor promptly if any of the following happens to you, as you may need further examinations or treatment: Serious breathlessness, or sudden worsening breathlessness, possibly with a cough or fever. Some patients taking IRESSA get an inflammation of the lungs called interstitial lung disease. This side-effect is uncommon (less than 1 in every 100 patients), and some of the patients have died from this. Persistent or severe diarrhoea, vomiting, nausea (feeling sick), or loss of appetite. Some patients have suffered from dehydration following these side effects. These side effects are common ( 1 to 10 of every 100 patients). New eye problems, such as pain, redness or change in vision. Some patients have suffered from ulcer on the surface of the eye (cornea), sometimes with in-growing eyelashes; this side effect is uncommon (less than 1 in every 100 patients). Severe skin reactions affecting large portions of your body including redness, pain, ulcers, blisters, skin sloughing or involvement of lips and mucous membranes (toxic epidermal necrolysis, Stevens Johnson syndrome, erythema multiforme). This type of skin reaction is very rare (less than 1 in every 10,000 patients is likely to have them). Tarry dark stool, blood in stool, urine, or sputum, or sudden, severe headache. Tell your doctor if any of the following side effects bother you: Side effects that are very common:Diarrhoea Nausea (feeling sick) Skin reactions such as acne-like rash, sometimes itchy with dry skin Side effects that are common:Vomiting Loss of appetite Dehydration Dry mouth Red and sore mouth Nail problems Loss of hair Weakness Dry eye Red and itchy eye Red and sore eyelid Nosebleeds Blood in urine Fever Bleeding events (for example stomach ulcers or coughing up blood) have been reported at an incidence of 0.4% in patients taking IRESSA therapy. Patients with tarry dark stool, blood in stool, urine or sputum, or sudden severe headache should contact their physician immediately. Side effects that are rare:Inflammation of the pancreas, with symptoms such as very severe pain in the upper part of the stomach area and severe nausea (feeling sick) and vomiting. Inflammation of the liver. Symptoms may include a general feeling of being unwell, with or without possible jaundice (yellowing of the skin and eyes). Side effects that are very rare:Allergic reactions, including swelling of lips and hives or nettle-rash. Toxic epidermal necrolysis, Stevens Johnson syndrome and erythema multiforme. The following side effects can also occur with IRESSA, and they are seen when a blood test is taken: Changes of the levels of liver enzymes. If these levels become very high, your doctor may need to stop the treatment. This side effect is common (1 to 10 of every 100 patients). Changes to the level of creatinine in your blood, which show how well your kidneys are working. This side effect is common (1 to 10 of every 100 patients). Changes to the way your blood clots, if you are taking warfarin (medicine to prevent blood-clotting). This side effect is uncommon (less than 1 in every 100 patients). If you notice any side effects not mentioned in this leaflet, please inform your doctor or pharmacist as soon as possible.

STORING IRESSA

Keep out of the reach and sight of children. Store at room temperature, 15 to 30 degC. Keep IRESSA in the original container in order to protect from moisture. Do not use IRESSA after the expiry date on the blister pack. This Information for the Patient Leaflet provides you with the most current information at the time of printing. Please refer to the Information for the Patient located at www.astrazeneca.ca, under the heading "Patients with Prescriptions," to see if more up-to- date information has been posted. Customer Inquiries: 1 800 668 6000 IRESSA(r) is a trade-mark of the AstraZeneca group of companies. AstraZeneca Canada Inc. Mississauga, Ontario L4Y 1M4 www.astrazeneca.ca January 30, 2008

PHARMACOLOGY

Animal Pharmacology Pharmacodynamics

ZD1839 has been administered orally at 5, 50 and 500 mg/kg to rats in studies designed to evaluate its effect on the major functional systems. These included the gastrointestinal (rat, GI transit), respiratory (rat, plethysmography), central nervous (rat, Functional Observation Battery and locomotor activity) and cardiovascular (dog, telemetry, only at 5 and 50 mg/kg) systems. No effects were seen on intestinal transit. Minimal effects were noted at 50 and 500 mg/kg on the respiratory system (decreases in peak inspiratory and expiratory flows, tidal volume and minute volume); on the central nervous system (slight reduction in motor activity); and on the cardiovascular system (dog telemetry at doses of 50 mg/kg showed slight hypotension). Because the doses studied are higher than the clinically recommended dose, the effects seen in these studies are not likely to be clinically relevant, but caution is advised. ZD1839 was tested using a cloned potassium channel assay (hERG assay) to evaluate its effect upon the Ikr potassium current and was shown to be active in this hERG assay, with an IC50 of 1 mM. Dog Purkinje fibre studies were undertaken to investigate the potential for ZD1839 to affect the cardiac action potential. The results indicate a modest potential to affect re-polarisation at high plasma concentrations. There is some evidence for in vivo effects, in the conscious telemetered dog, however these were not clear even at the highest dose tested.

Pharmacokinetics

ZD1839 is well absorbed in rat, dog and man based on measured bioavailabilities of >40% in all species. There is evidence of first pass metabolism and prolonged absorption at high doses in animals. ZD1839 related radioactivity was well distributed into rat tissues and showed an association with melanin containing tissues; however, levels in the CNS were low. Plasma protein binding ranged from 86 to 94% across the species and is not concentration dependent. ZD1839 binds to both human serum albumin and a-1 acid glycoprotein. ZD1839 was extensively metabolised with three sites of biotransformation. Circulating metabolite patterns in dog and man were similar and all metabolites measured in human plasma were present in the rat. ZD1839 showed no enzyme induction potential in animals and no appreciable inhibition of human P450 isozymes. In vitro, ZD1839 was predominantly metabolised by CYP3A4. In all species, ZD1839 related material was primarily excreted in the faeces with <6.5% recovered in urine. Biliary elimination was demonstrated in the rat and enterohepatic recirculation of ZD1839 may occur. In rat and dog, ZD1839 showed rapid clearance and a high volume of distribution. In man, the volume of distribution was greater than in animals and the half-life consequently longer leading to accumulation. When dose normalised, exposure in humans was greater than in rat and dog, but at chronically tolerated doses the exposures were comparable. The pharmacokinetic parameters for ZD1839 in animals and man are summarised below:

Table 11 Comparison of Pharmacokinetic Parameters in Rat, Dog and Man

a

Values for study KKR008 and KPR055 respectively

b

Values from study KKD009 and KPD050 respectively

c

Mean data from IL/0035 normalised using a 50 kg body weight

TOXICOLOGY

A standard programme of non-clinical safety evaluation studies of up to 6 months in duration has formed the basis of the support for the clinical development of once daily oral therapy to patients. The no-effect dose level, after administration of ZD1839 for up to 1 month, is 2 mg/kg/day and over a 6 month period is 1 mg/kg/day. In the 1-month studies, a dose of 40 mg/kg/day produced pathological changes in the ovaries of rats and in the eyes, kidneys and skin of both rats and dogs. Loose faeces were recorded in dogs, with no associated histopathological correlate. Similar changes were detected in the 6-month studies and, in addition in rats, minimal/mild hepatocellular necrosis was also detected, together with increased levels of circulating plasma liver enzymes. These effects showed signs of partial or full reversibility after drug withdrawal. There was evidence of reduced fertility in the female rat at 20 mg/kg/day, as well as slight maternal and fetotoxicity in the rabbit. These changes were all attributed to the pharmacological effects of ZD1839 on EGF-dependent tissues. Reversible abnormalities of atrio-ventricular conduction were also seen in the dog, at 40 mg/kg/day in the 1-month study and at 15 mg/kg/day in the 6-month study.

Acute Toxicity

Following a single oral dose of ZD1839 at 2000 mg/kg to rats, there was a 5-day interval prior to the onset of abnormal signs. All animals showed adverse signs, leading to 4 premature deaths in females. The cause of death of 1 of these 4 decedents was a perforated duodenal ulcer. Other compound-related findings were present in tissues of these animals, including the kidneys, liver, skin and upper gastro-intestinal tract. No abnormalities were seen in mice given the same oral dose nor in rats and mice at the maximum achievable dose of 20 mg/kg by the intravenous route. Single oral doses of up to 1000 mg/kg to dogs produced no deaths, but caused adverse effects that had a rapid onset, but were reversible. These effects comprised emesis, diarrhoea, loss of skin tone, reduced blood pressure, reduced appetite, loss of body weight and increased plasma ALT, AST and ALP activities.

Multiple Dose Toxicity Studies

The no effect dose level after administration of ZD1839 to rats and dogs for up to 1 month was 2 mg/kg/day. A dose of 10 mg/kg/day showed only minor changes in red blood cell parameters, plasma protein, and albumin in the 1-month dog study and no adverse effects in the 1-month rat study. A dose of 40 mg/kg/day in the rat for a month produced reversible increases in plasma ALT and AST levels, but with no pathological correlate. There were histopathological changes in the ovaries of rats (reduced corpora lutea) and in the eyes (corneal epithelial atrophy), kidneys (papillary necrosis), and skin of both rats and dogs, all of which showed signs of partial or full reversibility, 4 weeks after drug withdrawal. Loose faeces were recorded in dogs, with no associated histopathological correlate. These changes were attributed to the pharmacological effects of ZD1839. Reversible prolonged PR intervals, with large variations between individual measurements were recorded for 2 out of 12 dogs at 40 mg/kg/day. In addition, one of these two dogs also showed second-degree heart block. The findings in the 6-month studies were consistent with those detected in the 1-month studies and were similarly attributed to the pharmacological effects of ZD1839. These studies commenced with a high dose of 25 mg/kg/day, however this was not tolerated and the dose level was reduced to 15 mg/kg/day from day 11 in dogs and from week 9 in rats. The no adverse effect dose level, after administration of ZD1839 to rats and dogs for up to 6 months was 1 mg/kg/day. At 5 mg/kg/day, rats and dogs showed skin lesions and the rats had reversible corneal atrophy of the eyes. These eye effects were more evident in both species at 15 mg/kg/day, but still showed signs of recovery. However, at this dose level in dogs, some areas of opacity developed that did not fully recover during the 12 week withdrawal period. Evidence of an effect on liver function was detected in the rat at 5 mg/kg/day; this was more pronounced in both species at 15 mg/kg/day. In addition, in the rat at this dose, there was hepatocellular necrosis, associated with the increases in plasma liver enzyme levels. A single female dog showed evidence of a reversible effect on P-R interval, similar to that seen in the 1 month study, at the 15 mg/kg/day dose level.

Carcinogenicity & Mutagenicity

ZD1839 has been tested for genotoxic activity (mutagenicity) in a series of in vitro (bacterial mutation, mouse lymphoma, and human lymphocyte) assays and an in vivo rat micronucleus test. Under the experimental conditions adopted, there was no evidence demonstrated of genotoxic activity for ZD1839. Carcinogenicity studies have not been performed with ZD1839.

Reproduction & Teratology

There was, as expected from the pharmacological activity of ZD1839, a reduction in female fertility in the rat at a dose of 20 mg/kg/day. When administered during organogenesis, there were no effects on rat embryofetal development at the highest dose (30 mg/kg/day); however in the rabbit, there were reduced fetal weights at 20 mg/kg/day and above. There were no compound induced malformations in either species. When dosed to the rat throughout gestation and parturition, there was a reduction in pup survival at a dose of 20 mg/kg/day. There was evidence that ZD1839 was present in the milk of lactating rats. These data suggest that there is the potential for adverse effects if ZD1839 was administered to patients who are pregnant or are breast-feeding.

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