PACKAGE INSERT
`
`TARCEVA®
`(erlotinib)
`Tablets
`
`DESCRIPTION
`
`RX Only
`
`TARCEVA (erlotinib) is a Human Epidermal Growth Factor Receptor Type
`1/Epidermal Growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor.
`Erlotinib is a quinazolinamine with the chemical name N-(3-ethynylphenyl)-6,7-
`bis(2-methoxyethoxy)-4-quinazolinamine. TARCEVA contains erlotinib as the
`hydrochloride salt that has the following structural formula:
`
`O
`O
`
`O
`
`O
`
`HN
`
`N
`
`N
`
`• HCl
`
`Erlotinib hydrochloride has the molecular formula C22H23N3O4.HCl and a molecular
`weight of 429.90. The molecule has a pKa of 5.42 at 25oC. Erlotinib hydrochloride is
`very slightly soluble in water, slightly soluble in methanol and practically insoluble
`in acetonitrile, acetone, ethyl acetate and hexane.
`
`Aqueous solubility of erlotinib hydrochloride is dependent on pH with increased
`solubility at a pH of less than 5 due to protonation of the secondary amine. Over the
`pH range of 1.4 to 9.6, maximal solubility of approximately 0.4 mg/mL occurs at a
`pH of approximately 2.
`
`TARCEVA tablets are available in three dosage strengths containing erlotinib
`hydrochloride (27.3 mg, 109.3 mg and 163.9 mg) equivalent to 25 mg, 100 mg and
`150 mg erlotinib and the following inactive ingredients: lactose monohydrate,
`hypromellose, hydroxypropyl cellulose, magnesium stearate, microcrystalline
`cellulose, sodium starch glycolate, sodium lauryl sulfate and titanium dioxide. The
`tablets also contain trace amounts of color additives, including FD&C Yellow #6 (25
`mg only) for product identification.
`
`1
`
`OSI 2027
`APOTEX V. OSI
`IPR2016-01284
`
`

`

`CLINICAL PHARMACOLOGY
`
`Mechanism of Action and Pharmacodynamics
`
`The mechanism of clinical antitumor action of erlotinib is not fully characterized.
`Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with
`the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to
`other tyrosine kinase receptors has not been fully characterized. EGFR is expressed
`on the cell surface of normal cells and cancer cells.
`
`Pharmacokinetics
`
`Erlotinib is about 60% absorbed after oral administration and its bioavailability is
`substantially increased by food to almost 100%. Its half-life is about 36 hours and it
`is cleared predominantly by CYP3A4 metabolism and to a lesser extent by CYP1A2.
`
`Absorption and Distribution
`
`Bioavailability of erlotinib following a 150 mg oral dose of TARCEVA is about 60%
`and peak plasma levels occur 4 hrs after dosing. Food increases bioavailability
`substantially, to almost 100%.
`
`Following absorption, erlotinib is approximately 93% protein bound to albumin and
`alpha-1 acid glycoprotein (AAG). Erlotinib has an apparent volume of distribution of
`232 liters.
`
`Metabolism and Elimination
`
`In vitro assays of cytochrome P450 metabolism showed that erlotinib is metabolized
`primarily by CYP3A4 and to a lesser extent by CYP1A2, and the extrahepatic
`isoform CYP1A1. Following a 100 mg oral dose, 91% of the dose was recovered:
`83% in feces (1% of the dose as intact parent) and 8% in urine (0.3% of the dose as
`intact parent).
`
`A population pharmacokinetic analysis in 591 patients receiving single-agent
`TARCEVA showed a median half-life of 36.2 hours. Time to reach steady state
`plasma concentration would therefore be 7 – 8 days. No significant relationships of
`clearance to covariates of patient age, body weight or gender were observed.
`Smokers had a 24% higher rate of erlotinib clearance.
`
`2
`
`

`

`A second population pharmacokinetic analysis was conducted that incorporated
`erlotinib data from 204 pancreatic cancer patients who received erlotinib plus
`gemcitabine. This analysis demonstrated that covariates affecting erlotinib clearance
`in patients from the pancreatic study were very similar to those seen in the prior
`single-agent pharmacokinetic analysis. No new covariate effects were identified. Co-
`administration of gemcitabine had no effect on erlotinib plasma clearance.
`
`Special Populations
`
`Patients with Hepatic Impairment
`
`Erlotinib is cleared predominantly by the liver. No data are currently available
`regarding the influence of hepatic dysfunction and/or hepatic metastases on the
`pharmacokinetics of erlotinib (see PRECAUTIONS - Patients with Hepatic
`Impairment, ADVERSE REACTIONS and DOSAGE AND
`ADMINISTRATION - Dose Modifications sections).
`
`Patients with Renal Impairment
`
`Less than 9% of a single dose is excreted in the urine. No clinical studies have been
`conducted in patients with compromised renal function.
`
`Interactions
`
`Erlotinib is metabolized predominantly by CYP3A4, and inhibitors of CYP3A4
`would be expected to increase exposure. Co-treatment with the potent CYP3A4
`inhibitor ketoconazole increased erlotinib AUC by 2/3 (see PRECAUTIONS -
`Drug Interactions and DOSAGE AND ADMINISTRATION - Dose
`Modifications sections).
`
`Pre- or co-treatment with the CYP3A4 inducer rifampicin increased erlotinib
`clearance by 3-fold and reduced AUC by 2/3 (see PRECAUTIONS - Drug
`Interactions and DOSAGE AND ADMINISTRATION - Dose Modifications
`sections).
`
`In a Phase Ib study, there were no significant effects of gemcitabine on the
`pharmacokinetics of erlotinib nor were there significant effects of erlotinib on the
`pharmacokinetics of gemcitabine.
`
`3
`
`

`

`CLINICAL STUDIES
`
`Non-Small Cell Lung Cancer (NSCLC) – TARCEVA
`Administered as a Single Agent
`
`The efficacy and safety of single-agent TARCEVA was assessed in a randomized,
`double blind, placebo-controlled trial in 731 patients with locally advanced or
`metastatic NSCLC after failure of at least one chemotherapy regimen. Patients were
`randomized 2:1 to receive TARCEVA 150 mg or placebo (488 Tarceva, 243
`placebo) orally once daily until disease progression or unacceptable toxicity. Study
`endpoints included overall survival, response rate, and progression-free survival
`(PFS). Duration of response was also examined. The primary endpoint was survival.
`The study was conducted in 17 countries. About half the patients (326) had EGFR
`expression status characterized.
`
`Table 1 summarizes the demographic and disease characteristics of the study
`population. Demographic characteristics were well balanced between the two
`treatment groups. About two-thirds of the patients were male. Approximately one-
`fourth had a baseline ECOG performance status (PS) of 2, and 9% had a baseline
`ECOG PS of 3. Fifty percent of the patients had received only one prior regimen of
`chemotherapy. About three quarters of these patients were known to have smoked at
`some time.
`
`Table 1: Demographic and Disease Characteristics
`
`
`
`Characteristics
`Gender
` Female
` Male
`Age (years)
` < 65
` (cid:116)(cid:3)65
`Race
` Caucasian
` Black
` Asian
`
`TARCEVA
`(N = 488)
`n
`(%)
`
`Placebo
`(N = 243)
`(%)
`
`n
`
`
`
`
`
`
`
`
`
`(35)
`(65)
`
`(61)
`(39)
`
`(78)
`(4)
`(13)
`
`83
`160
`
`153
`90
`
`188
`12
`28
`
`(34)
`(66)
`
`(63)
`(37)
`
`(77)
`(5)
`(12)
`
`173
`315
`
`299
`189
`
`379
`18
`63
`
`4
`
`

`

` Other
`ECOG Performance Status at
`Baseline*
` 0
` 1
` 2
` 3
`Weight Loss in Previous 6
`Months
` < 5%
` 5 – 10%
` > 10%
` Unknown
`Smoking History
` Never Smoked
` Current or Ex-smoker
` Unknown
`Histological Classification
` Adenocarcinoma
` Squamous
` Undifferentiated Large Cell
` Mixed Non-Small Cell
` Other
`Time from Initial Diagnosis to
`Randomization (Months)
` < 6
` 6 – 12
` > 12
`Best Response to Prior Therapy
`at Baseline*
` CR/PR
` PD
` SD
`Number of Prior Regimens at
`Baseline*
` 1
` 2
`
`28
`
`
`64
`256
`126
`42
`
`
`320
`96
`52
`20
`
`104
`358
`26
`
`246
`144
`41
`11
`46
`
`
`63
`157
`268
`
`
`196
`101
`191
`
`
`243
`238
`
`5
`
`(6)
`
`
`(13)
`(52)
`(26)
`(9)
`
`
`(66)
`(20)
`(11)
`(4)
`
`(21)
`(73)
`(5)
`
`(50)
`(30)
`(8)
`(2)
`(9)
`
`
`(13)
`(32)
`(55)
`
`
`(40)
`(21)
`(39)
`
`
`(50)
`(49)
`
`15
`
`
`34
`132
`56
`21
`
`
`166
`36
`29
`12
`
`42
`187
`14
`
`119
`78
`23
`2
`21
`
`
`34
`85
`124
`
`
`96
`51
`96
`
`
`121
`119
`
`(6)
`
`
`(14)
`(54)
`(23)
`(9)
`
`
`(68)
`(15)
`(12)
`(5)
`
`(17)
`(77)
`(6)
`
`(49)
`(32)
`(9)
`(<1)
`(9)
`
`
`(14)
`(35)
`(51)
`
`
`(40)
`(21)
`(40)
`
`
`(50)
`(49)
`
`

`

` 3
`Exposure to Prior Platinum at
`Baseline*
` Yes
` No
`
`7
`
`
`454
`34
`
`(1)
`
`
`(93)
`(7)
`
`3
`
`
`224
`19
`
`(1)
`
`
`(92)
`(8)
`
`* Stratification factor as documented at baseline; distribution differs slightly from
`values reported at time of randomization.
`
`The results of the study are shown in Table 2.
`
`Table 2: Efficacy Results
`
` TARCEVA Placebo
` Median
`Median
`6.7 mo
`4.7 mo
`31.2%
`21.5%
` Median
`Median
`9.9 wk
`7.9 wk
`
`8.9%
`Median
`34.3 wk
`
`0.9%
`Median
`15.9 wk
`
`Survival
`1-year Survival
`Progression-
`Free Survival
`Tumor
`Response
`(CR+PR)
`Response
`Duration
`
`Hazard
`Ratio (1)
`
`95% CI
`
`p-value
`
`0.73
`
`0.61 – 0.86
`
`<0.001 (2)
`
`0.59
`
`0.50 – 0.70
`
`<0.001 (2)
`
`<0.001 (3)
`
`(1) Cox regression model with the following covariates: ECOG performance
`status, number of prior regimens, prior platinum, best response to prior
`chemotherapy.
`(2) Two-sided Log-Rank test stratified by ECOG performance status, number
`of prior regimens, prior platinum, best response to prior chemotherapy.
`(3) Two-sided Fisher’s exact test
`
`Survival was evaluated in the intent-to-treat population. Figure 1 depicts the Kaplan-
`Meier curves for overall survival. The primary survival and PFS analyses were two-
`sided Log-Rank tests stratified by ECOG performance status, number of prior
`regimens, prior platinum, best response to prior chemotherapy.
`
`6
`
`

`

`Note: HR is from Cox regression model with the following
`covariates: ECOG performance status, number of prior regimens,
`prior platinum, best response to prior chemotherapy. P-value is from
`two-sided Log-Rank test stratified by ECOG performance status,
`number of prior regimens, prior platinum, best response to prior
`chemotherapy.
`
`A series of subsets of patients were examined in exploratory univariate analyses. The
`results of these analyses are shown in Figure 2.The effect of TARCEVA on survival
`was similar across most subsets. An apparently larger effect, however, was observed
`in two subsets: patients with EGFR positive tumors (HR = 0.68) and patients who
`never smoked (HR = 0.42). These subsets are considered further below.
`
`7
`
`

`

`Figure 2: Survival Hazard Ratio (HR) (TARCEVA: Placebo) in Subgroups
`According to Pretreatment
`Characteristics
`
`8
`
`

`

`Note: Depicted are the univariate hazard ratio (HR) for death in the TARCEVA
`patients relative to the placebo patients, the 95% confidence interval (CI) for the HR,
`and the sample size (N) in each subgroup. The hash mark on the horizontal bar
`represents the HR, and the length of the horizontal bar represents the 95%
`confidence interval. A hash mark to the left of the vertical line corresponds to a HR
`that is less than 1.00, which indicates that survival is better in the TARCEVA arm
`compared with the placebo arm in that subgroup.
`
`Relation of Single-Agent TARCEVA Results in NSCLC to EGFR
`Protein Expression Status (as Determined by
`Immunohistochemistry)
`
`Analysis of the impact of EGFR expression status on the treatment effect on clinical
`outcome is limited because EGFR status is known for 326 NSCLC study patients
`(45%). EGFR status was ascertained for patients who already had tissue samples
`prior to study enrollment. However, the survival in the EGFR tested population and
`the effects of single-agent TARCEVA were almost identical to that in the entire
`study population, suggesting that the tested population was a representative sample.
`A positive EGFR expression status was defined as having at least 10% of cells
`staining for EGFR in contrast to the 1% cut-off specified in the EGFR pharmDxTM
`kit instructions. The use of the pharmDx kit has not been validated for use in non-
`small cell lung cancer.
`
`Single-agent TARCEVA prolonged survival in the EGFR positive subgroup (N =
`185; HR = 0.68; 95% CI = 0.49 – 0.94) (Figure 3) and the subgroup whose EGFR
`status was unmeasured (N = 405; HR = 0.77; 95% CI = 0.61 – 0.98) (Figure 5), but
`did not appear to have an effect on survival in the EGFR negative subgroup (N =
`141; HR = 0.93; 95% CI = 0.63 – 1.36) (Figure 4). However, the confidence
`intervals for the EGFR positive, negative and unmeasured subgroups of NSCLC
`patients are wide and overlap, so that a survival benefit due to TARCEVA in the
`EGFR negative subgroup cannot be excluded.
`
`For the subgroup of NSCLC patients who never smoked, EGFR status also appeared
`to be predictive of TARCEVA survival benefit. Patients who never smoked and were
`EGFR positive had a large TARCEVA survival benefit (N = 41; HR = 0.28; 95% CI
`= 0.13 – 0.61). There were too few EGFR negative patients who never smoked to
`reach a conclusion.
`
`Tumor responses were observed in all EGFR subgroups: 11.3% in the EGFR positive
`subgroup, 9.5% in the EGFR unmeasured subgroup and 3.8% in the EGFR negative
`subgroup. An improvement in progression free survival was demonstrated in the
`
`9
`
`

`

`EGFR positive subgroup (HR = 0.49; 95% CI = 0.35 – 0.68), the EGFR unmeasured
`subgroup (HR = 0.60; 95% CI = 0.47 – 0.75), and less certain in the EGFR negative
`subgroup (HR = 0.80; 95% CI = 0.55 – 1.16).
`
`10
`
`

`

`NSCLC - TARCEVA Administered Concurrently with Chemotherapy
`
`Results from two, multicenter, placebo-controlled, randomized, trials in over 1000
`patients conducted in first-line patients with locally advanced or metastatic NSCLC
`showed no clinical benefit with the concurrent administration of TARCEVA with
`platinum-based chemotherapy [carboplatin and paclitaxel (TARCEVA, N = 526) or
`gemcitabine and cisplatin (TARCEVA, N = 580)].
`
`Pancreatic Cancer - TARCEVA Administered Concurrently with
`Gemcitabine
`
`The efficacy and safety of TARCEVA in combination with gemcitabine as a first-
`line treatment was assessed in a randomized, double blind, placebo-controlled trial in
`569 patients with locally advanced, unresectable or metastatic pancreatic cancer.
`Patients were randomized 1:1 to receive TARCEVA (100 mg or 150 mg) or placebo
`once daily on a continuous schedule plus gemcitabine IV (1000 mg/m2, Cycle 1 -
`Days 1, 8, 15, 22, 29, 36 and 43 of an 8 week cycle; Cycle 2 and subsequent cycles -
`Days 1, 8 and 15 of a 4 week cycle [the approved dose and schedule for pancreatic
`cancer, see the gemcitabine package insert]). TARCEVA or placebo was taken orally
`once daily until disease progression or unacceptable toxicity. The primary endpoint
`was survival. Secondary endpoints included response rate, and progression-free
`survival (PFS). Duration of response and the role of EGFR tumor expression in
`survival were also examined. The study was conducted in 18 countries. A total of
`
`11
`
`

`

`285 patients were randomized to receive gemcitabine plus TARCEVA (261 patients
`in the 100 mg cohort and 24 patients in the 150 mg cohort) and 284 patients were
`randomized to receive gemcitabine plus placebo (260 patients in the 100 mg cohort
`and 24 patients in the 150 mg cohort). Too few patients were treated in the 150 mg
`cohort to draw conclusions.
`
`Table 3 summarizes the demographic and disease characteristics of the study
`population that was randomized to receive 100 mg of TARCEVA plus gemcitabine
`or placebo plus gemcitabine. Baseline demographic and disease characteristics of the
`patients were similar between the 2 treatment groups, except for a slightly larger
`proportion of females in the TARCEVA arm (51%) compared with the placebo arm
`(44%). The median time from initial diagnosis to randomization was approximately
`1.0 month. Most patients presented with metastatic disease at study entry as the
`initial manifestation of pancreatic cancer. About 1/4 of the patients (136/521) had
`EGFR expression status characterized.
`
`Table 3:
`
`Demographic and Disease Characteristics: 100 mg Cohort
`
`Characteristics
`Gender
` Female
` Male
`Age (Years)
` <65
` (cid:116)65
`Race
` Caucasian
` Black
` Asian
` Other
`ECOG Performance
`Status*
` 0
`
`TARCEVA+
`Gemcitabine
`
`(N=261)
`(%)
`
`n
`
`Placebo +
`Gemcitabine
`
`(N=260)
`(%)
`
`n
`
`134
`127
`
`136
`125
`
`225
`8
`20
`8
`
`(51)
`(49)
`
`(52)
`(48)
`
`(86)
`(3)
`(8)
`(3)
`
`114
`146
`
`138
`122
`
`231
`5
`14
`10
`
`(44)
`(56)
`
`(53)
`(47)
`
`(89)
`(2)
`(5)
`(3)
`
`82
`
`(31)
`
`83
`
`(32)
`
`12
`
`

`

`TARCEVA+
`Gemcitabine
`
`Placebo +
`Gemcitabine
`
`n
`
`(N=261)
`(%)
`(51)
`(17)
`(<1)
`
`134
`44
`1
`
`n
`
`(N=260)
`(%)
`(51)
`(17)
`(0)
`
`132
`45
`0
`
`Characteristics
` 1
` 2
` Unknown*
`Disease Status at
`Baseline**
`(23)
`61
` Locally Advanced
`(77)
`200
` Distant Metastasis
`*Unknown includes responses of 'Unknown' and missing.
`**Stratification factor as documented at baseline; distribution differs slightly from
`values reported at time of randomization.
`
`63
`197
`
`(24)
`(76)
`
`The results of the study are shown in Table 4.
`
`Table 4: Efficacy Results: 100 mg Cohort
`
`Hazard
`Ratio (1)
`
`95% CI
`
`p-value
`
`0.81
`
`
`0.68 – 0.97
`
`
`0.028 (2)
`
`
`
`
`Survival
`1-year
`Survival
`
`TARCEVA +
`Gemcitabine
`Median
`6.4 mo
`250 deaths
`
`Placebo+
`Gemcitabine
`Median
`6.0 mo
`254 deaths
`
`23.8%
`Median
`3.8 mo
`225 events
`
`19.4%
`Median
`3.5 mo
`232 events
`
`Progression-
`Free Survival
`Tumor
`Response
`7.9%
`8.6%
`(CR+PR)
`Median
`Median
`Response
`23.3 wk
`23.9 wk
`Duration
`(1) Cox regression model with the following covariates: ECOG performance status,
`and extent of disease.
`(2) Two-sided Log-Rank test stratified by ECOG performance status and extent of
`disease.
`(3) Two-sided Fisher’s exact test.
`
`0.76
`
`
`0.64 – 0.92
`
`
`
`
`
`
`0.006 (2)
`
`
`0.87 (3)
`
`
`Survival was evaluated in the intent-to-treat population. Figure 6 depicts the Kaplan-
`Meier curves for overall survival in the 100 mg cohort. The primary survival and
`PFS analyses were two-sided Log-Rank tests stratified by ECOG performance status
`and extent of disease.
`
`13
`
`

`

`Note: HR is from Cox regression model with the following covariates: ECOG
`performance status and extent of disease. P-value is from two-sided Log-Rank test
`stratified by ECOG performance status and extent of disease.
`
`In a series of exploratory univariate subset analyses (the stratification factors at
`randomization and at baseline, as well as pain intensity by visual analog score,
`EGFR status, gender, age, race, and any prior chemotherapy), all of the HRs in the
`TARCEVA plus gemcitabine arm relative to the placebo plus gemcitabine arm were
`less than or equal to 1.0 suggesting consistency across all patient subsets. However,
`in patients with pain intensity score >20, female, locally advanced, age (cid:149)65 years, or
`performance status 0 or 1, the benefit of erlotinib was uncertain.
`
`14
`
`

`

`Figure 7: Survival Hazard Ratio (HR) (TARCEVA : Placebo) in Subgroups
`According to Pretreatment Characteristics: 100 mg Cohort
`
`Note: Depicted are the univariate hazard ratio (HR) for death in the patients
`receiving TARCEVA plus gemcitabine relative to the patients receiving placebo plus
`gemcitabine, the 95% confidence interval (CI) for the HR, and the sample size (N) in
`each subgroup. The hash mark on the horizontal bar represents the HR, and the
`length of the horizontal bar represents the 95% confidence interval. A hash mark to
`the left of the vertical line corresponds to a HR that is less than 1.00, which indicates
`that survival is better in the TARCEVA arm compared with the placebo arm in that
`subgroup. Only chemotherapy given concurrently with radiation treatment as a
`radiosensitizer was allowed.
`
`15
`
`

`

`Relation of Pancreatic Cancer Trial Results to EGFR Protein
`Expression Status (as Determined by Immunohistochemistry)
`
`Analysis of the impact of EGFR expression status on the treatment effect on clinical
`outcome is limited because EGFR status is known for only 136 study patients (26%)
`in the 100 mg cohort. There were no significant differences in patient or disease
`characteristics between the patients for whom results were known and the patients
`for whom the results were unknown, suggesting that the tested population was a
`representative sample. EGFR expression was determined using the EGFR
`pharmDxTM kit. In contrast to the 1% cut-off specified in the pharmDx kit
`instructions, a positive EGFR expression status was defined as having at least 10%
`of cells staining for EGFR. The pharmDx kit has not been validated for use in
`pancreatic cancer.
`
`The survival results of TARCEVA plus gemcitabine compared to gemcitabine alone
`by EGFR status were as follows: EGFR positive subgroup (N = 70; HR = 0.82; 95%
`CI = 0.50 –1.32) (Figure 8), EGFR negative subgroup (N = 66; HR = 0.75; 95% CI =
`0.46 – 1.23) (Figure 9), and the subgroup whose EGFR status was unmeasured (N =
`385; HR = 0.86; 95% CI = 0.70 – 1.05) (Figure 10). The confidence intervals for
`each subgroup are wide and overlapping and none of the p-values reached statistical
`significance.
`
`Tumor responses were observed in all EGFR subgroups receiving TARCEVA plus
`gemcitabine: 5.0% in the EGFR positive subgroup, 9.7% in the EGFR negative
`subgroup and 9.2% in the EGFR unmeasured subgroup.
`
`16
`
`

`

`100 mg Cohort
`Figure 8: Survival in EGFR Positive Patients:
` 1.00 |
`
`
`
`
`
`0.75|
`
`0.50 |
`
`HR: 0.82
`
`95% Cl: 0.50 — 1.32
`
`
`Tarceva (N=41)
`
`Placebo (N=29)
`
`0.25; 0.00
`
`
`0.75 | 95% Cl: 0.46 — 1.23
`
`
`
`SurvivalProbability
`
`
`
`SurvivalProbability
`
`Survival Time (Months)
`
`100 mg Cohort
`in EGFR Negative Patients:
`Figure 9: Survival
` 1.00 |
`
`0.50 |
`
`0.25 |
`
`0.00 +,
`0
`
`HR: 0.75
`
`
`
`
`Tarceva (N=34)
`
`Placebo (N=32)
`
`6
`
`12
`
`18
`
`24
`
`Survival Time (Months)
`
`17
`
`

`

`INDICATIONS AND USAGE
`
`Non-Small Cell Lung Cancer
`
`TARCEVA monotherapy is indicated for the treatment of patients with locally
`advanced or metastatic non-small cell lung cancer after failure of at least one prior
`chemotherapy regimen.
`
`Results from two, multicenter, placebo-controlled, randomized, Phase 3 trials
`conducted in first-line patients with locally advanced or metastatic NSCLC showed
`no clinical benefit with the concurrent administration of TARCEVA with platinum-
`based chemotherapy [carboplatin and paclitaxel or gemcitabine and cisplatin] and its
`use is not recommended in that setting.
`
`Pancreatic Cancer
`
`TARCEVA in combination with gemcitabine is indicated for the first-line treatment
`of patients with locally advanced, unresectable or metastatic pancreatic cancer.
`
`18
`
`

`

`CONTRAINDICATIONS
`
`None.
`
`WARNINGS
`
`Pulmonary Toxicity
`
`There have been infrequent reports of serious Interstitial Lung Disease (ILD)-like
`events, including fatalities, in patients receiving TARCEVA for treatment of
`NSCLC, pancreatic cancer or other advanced solid tumors. In the randomized single-
`agent NSCLC study (see CLINICAL STUDIES section), the incidence of ILD-like
`events (0.8%) was the same in both the placebo and TARCEVA groups. In the
`pancreatic cancer study - in combination with gemcitabine - (see CLINICAL
`STUDIES section), the incidence of ILD-like events was 2.5% in the TARCEVA
`plus gemcitabine group vs. 0.4% in the placebo plus gemcitabine group.
`
`The overall incidence of ILD-like events in approximately 4900 TARCEVA-treated
`patients from all studies (including uncontrolled studies and studies with concurrent
`chemotherapy) was approximately 0.7%. Reported diagnoses in patients suspected of
`having ILD-like events included pneumonitis, radiation pneumonitis,
`hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease,
`obliterative bronchiolitis, pulmonary fibrosis, Acute Respiratory Distress Syndrome
`and lung infiltration. Symptoms started from 5 days to more than 9 months (median
`39 days) after initiating TARCEVA therapy. In the lung cancer trials most of the
`cases were associated with confounding or contributing factors such as
`concomitant/prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung
`disease, metastatic lung disease, or pulmonary infections.
`
`In the event of an acute onset of new or progressive, unexplained pulmonary
`symptoms such as dyspnea, cough, and fever, TARCEVA therapy should be
`interrupted pending diagnostic evaluation. If ILD is diagnosed, TARCEVA should
`be discontinued and appropriate treatment instituted as needed (see ADVERSE
`REACTIONS and DOSAGE AND ADMINISTRATION - Dose Modifications
`sections).
`
`19
`
`

`

`Myocardial infarction/ischemia:
`
`In the pancreatic carcinoma trial, six patients (incidence of 2.3%) in the
`TARCEVA/gemcitabine group developed myocardial infarction/ischemia. One of
`these patients died due to myocardial infarction. In comparison, 3 patients in the
`placebo/gemcitabine group developed myocardial infarction (incidence 1.2%) and
`one died due to myocardial infarction.
`
`Cerebrovascular accident:
`
`In the pancreatic carcinoma trial, six patients in the TARCEVA/gemcitabine group
`developed cerebrovascular accidents (incidence: 2.3%) One of these was
`hemorrhagic and was the only fatal event. In comparison, in the
`placebo/gemcitabine group there were no cerebrovascular accidents.
`
`Microangiopathic Hemolytic Anemia with Thrombocytopenia:
`
`In the pancreatic carcinoma trial, two patients in the TARCEVA/gemcitabine group
`developed microangiopathic hemolytic anemia with thrombocytopenia (incidence:
`0.8%). Both patients received TARCEVA and gemcitabine concurrently. In
`comparison, in the placebo/gemcitabine group there were no cases of
`microangiopathic hemolytic anemia with thrombocytopenia.
`
`Pregnancy Category D
`
`Erlotinib has been shown to cause maternal toxicity with associated embryo/fetal
`lethality and abortion in rabbits when given at doses that result in plasma drug
`concentrations of approximately 3 times those in humans (AUCs at 150 mg daily
`dose). When given during the period of organogenesis to achieve plasma drug
`concentrations approximately equal to those in humans, based on AUC, there was no
`increased incidence of embryo/fetal lethality or abortion in rabbits or rats. However,
`female rats treated with 30 mg/m2/day or 60 mg/m2/day (0.3 or 0.7 times the clinical
`dose, on a mg/m2 basis) of erlotinib prior to mating through the first week of
`pregnancy had an increase in early resorptions that resulted in a decrease in the
`number of live fetuses.
`
`No teratogenic effects were observed in rabbits or rats.
`
`20
`
`

`

`There are no adequate and well-controlled studies in pregnant women using
`TARCEVA. Women of childbearing potential should be advised to avoid pregnancy
`while on TARCEVA. Adequate contraceptive methods should be used during
`therapy, and for at least 2 weeks after completing therapy. Treatment should only be
`continued in pregnant women if the potential benefit to the mother outweighs the risk
`to the fetus. If TARCEVA is used during pregnancy, the patient should be apprised
`of the potential hazard to the fetus or potential risk for loss of the pregnancy.
`
`PRECAUTIONS
`
`Drug Interactions
`
`Co-treatment with the potent CYP3A4 inhibitor ketoconazole increases erlotinib
`AUC by 2/3. Caution should be used when administering or taking TARCEVA with
`ketoconazole and other strong CYP3A4 inhibitors such as, but not limited to,
`atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir,
`saquinavir, telithromycin, troleandomycin (TAO), and voriconazole (see DOSAGE
`AND ADMINISTRATION - Dose Modifications section).
`
`Pre-treatment with the CYP3A4 inducer rifampicin decreased erlotinib AUC by
`about 2/3. Alternate treatments lacking CYP3A4 inducing activity should be
`considered. If an alternative treatment is unavailable, a TARCEVA dose greater than
`150 mg should be considered for NSCLC patients, and greater than 100 mg
`considered for pancreatic cancer patients. If the TARCEVA dose is adjusted upward,
`the dose will need to be reduced upon discontinuation of rifampicin or other
`inducers. Other CYP3A4 inducers include, but are not limited to, rifabutin,
`rifapentine, phenytoin, carbamazepine, phenobarbital and St. John's Wort (see
`DOSAGE AND ADMINISTRATION - Dose Modifications section).
`
`Hepatotoxicity
`
`Asymptomatic increases in liver transaminases have been observed in TARCEVA
`treated patients; therefore, periodic liver function testing (transaminases, bilirubin,
`and alkaline phosphatase) should be considered. Dose reduction or interruption of
`TARCEVA should be considered if changes in liver function are severe (see
`ADVERSE REACTIONS section).
`
`21
`
`

`

`Patients with Hepatic Impairment
`
`In vitro and in vivo evidence suggest that erlotinib is cleared primarily by the liver.
`Therefore, erlotinib exposure may be increased in patients with hepatic dysfunction
`(see CLINICAL PHARMACOLOGY - Special Populations - Patients with
`Hepatic Impairment and DOSAGE AND ADMINISTRATION - Dose
`Modification sections).
`
`Elevated International Normalized Ratio and Potential Bleeding
`
`International Normalized Ratio (INR) elevations and infrequent reports of bleeding
`events including gastrointestinal and non-gastrointestinal bleedings have been
`reported in clinical studies, some associated with concomitant warfarin
`administration. Patients taking warfarin or other coumarin-derivative anticoagulants
`should be monitored regularly for changes in prothrombin time or INR (see
`ADVERSE REACTIONS section).
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Erlotinib has not been tested for carcinogenicity.
`
`Erlotinib has been tested for genotoxicity in a series of in vitro assays (bacterial
`mutation, human lymphocyte chromosome aberration, and mammalian cell
`mutation) and an in vivo mouse bone marrow micronucleus test and did not cause
`genetic damage. Erlotinib did not impair fertility in either male or female rats.
`
`Pregnancy
`
`Pregnancy Category D (see WARNINGS and PRECAUTIONS - Information
`for Patients sections).
`
`Nursing Mothers
`
`It is not known whether erlotinib is excreted in human milk. Because many drugs are
`excreted in human milk and because the effects of TARCEVA on infants have not
`been studied, women should be advised against breast-feeding while receiving
`TARCEVA therapy.
`
`22
`
`

`

`Pediatric Use
`
`The safety and effectiveness of TARCEVA in pediatric patients have not been
`studied.
`
`Geriatric Use
`
`Of the total number of patients participating in the randomized NSCLC trial, 62%
`were less than 65 years of age, and 38% of patients were aged 65 years or older. The
`survival benefit was maintained across both age groups (see CLINICAL STUDIES
`section). In the pancreatic cancer study, 53% of patients were younger than 65 years
`of age and 47% were 65 years of age or older. No meaningful differences in safety or
`pharmacokinetics were observed between younger and older patients in either study.
`Therefore, no dosage adjustments are recommended in elderly patients.
`
`Information for Patients
`
`If the following signs or symptoms occur, patients should seek medical advice
`promptly (see WARNINGS, ADVERSE REACTIONS and DOSAGE AND
`ADMINISTRATION - Dose Modification sections).
`Severe or persistent diarrhea, nausea, anorexia, or vomiting
`(cid:120)
`(cid:120) Onset or worsening of unexplained shortness of breath or cough
`Eye irritation
`(cid:120)
`
`Women of childbearing potential should be advised to avoid becoming pregnant
`while taking TARCEVA (see WARNINGS - Pregnancy Category D section).
`
`ADVERSE REACTIONS
`
`Safety evaluation of TARCEVA is based on 856 cancer patients who received
`TARCEVA as monotherapy, 308 patients who received TARCEVA 100 or 150 mg
`plus gemcitabine, and 1228 patients who received TARCEVA concurrently with
`other chemotherapies.
`
`There have been reports of serious events, including fatalities, in patients receiving
`TARCEVA for treatment of NSCLC, pancreatic cancer or other advanced solid
`tumors (see WARNINGS, and DOSAGE AND ADMINISTRATION - Dose
`Modifications sections).
`
`23
`
`

`

`Non-Small Cell Lung Cancer
`
`Adverse events, regardless of causality, that occurred in at least 10% of patients
`treated with single-agent TARCEVA at 150 mg and at least 3% more often than in
`the placebo group in the randomized trial of patients with NSCLC are summarized
`by NCI-CTC (version 2.0) Grade in Table 5.
`
`The most common adverse reactions in patients receiving single-agent TARCEVA
`150 mg were rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 9% and 6%,
`respectively, in TARCEVA-treated patients. Rash and diarrhea each resulted in study
`discontinuation in 1% of TARCEVA-treated patients. Six percent and 1% of patients
`needed dose reduction for rash and diarrhea, respectively. The median time to onset
`of rash was 8 days, and the median time to onset of diarrhea was 12 days.
`
`Table 5:
`
`Adverse Event