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`PACKAGE INSERT
`
`TARCEVATM
`(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 which 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.
`
`OSI 2026
`APOTEX V. OSI
`IPR2016-01284
`
`Page 1
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`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.
`
`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 patient age, body weight or gender were observed. Smokers had a 24%
`higher rate of erlotinib clearance.
`
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`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).
`
`CLINICAL STUDIES
`
`TARCEVA as Monotherapy in Non-Small Cell Lung Cancer
`(NSCLC)
`
`The efficacy and safety of 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 end points 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
`
`
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`87
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`91
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`96
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`17 countries. About 1/3 of the patients (238) 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
`
`TARCEVA
`(N = 488)
`N
`(%)
`
`Placebo
`(N = 243)
`(%)
`
`N
`
`
`Characteristics
`Gender
` Female
` Male
`Age (Years)
` <65
` (cid:116)65
`Race
` Caucasian
` Black
` Asian
` Other
`ECOG Performance Status at
`Baseline*
` 0
` 1
` 2
` 3
`Weight Loss in Previous 6
`Months
` < 5%
` 5 – 10%
`
`
`
`
`(34)
`(66)
`
`(63)
`(37)
`
`(77)
`(5)
`(12)
`(6)
`
`
`(14)
`(54)
`(23)
`(9)
`
`
`(68)
`(15)
`
`173
`315
`
`299
`189
`
`379
`18
`63
`28
`
`
`64
`256
`126
`42
`
`
`320
`96
`
`83
`160
`
`153
`90
`
`188
`12
`28
`15
`
`
`34
`132
`56
`21
`
`
`166
`36
`
`(35)
`(65)
`
`(61)
`(39)
`
`(78)
`(4)
`(13)
`(6)
`
`
`(13)
`(52)
`(26)
`(9)
`
`
`(66)
`(20)
`
`Page 4
`
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`

`

`
`
`
`Characteristics
` > 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
` 3
`Exposure to Prior Platinum at
`Baseline*
` Yes
` No
`
`TARCEVA
`(N = 488)
`N
`(%)
`52
`(11)
`20
`(4)
`
`
`104
`(21)
`358
`(73)
`26
`(5)
`
`
`246
`(50)
`144
`(30)
`41
`(8)
`11
`(2)
`46
`(9)
`
`
`
`Placebo
`(N = 243)
`(%)
`(12)
`(5)
`
`(17)
`(77)
`(6)
`
`(49)
`(32)
`(9)
`(<1)
`(9)
`
`
`N
`29
`12
`
`42
`187
`14
`
`119
`78
`23
`2
`21
`
`
`63
`157
`268
`
`
`196
`101
`191
`
`
`243
`238
`7
`
`
`454
`34
`
`(13)
`(32)
`(55)
`
`
`(40)
`(21)
`(39)
`
`
`(50)
`(49)
`(1)
`
`
`(93)
`(7)
`
`34
`85
`124
`
`
`96
`51
`96
`
`
`121
`119
`3
`
`
`224
`19
`
`(14)
`(35)
`(51)
`
`
`(40)
`(21)
`(40)
`
`
`(50)
`(49)
`(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.
`
`
`
`
`Page 5
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`98
`99
`100
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`Table 2: Efficacy Results
`
`
`
`Hazard
`Ratio (1)
`
`95% CI
`
`p-value
`
`Tarceva
` Median
`6.7 mo
`31.2%
` Median
`9.9 wk
`
`Placebo
`Median
`4.7 mo
`21.5%
`Median
`7.9 wk
`
`8.9%
`Median
`34.3 wk
`
`0.9%
`Median
`15.9 wk
`
`103
`104
`105
`106
`107
`108
`109
`110
`111
`112
`113
`114
`
`0.73
`
`
`0.59
`
`
`
`
`
`0.61 – 0.86
`
`
`<0.001 (2)
`
`
`0.50 – 0.70
`
`<0.001 (2)
`
`
`
`
`
`<0.001 (3)
`
`
`
`Survival
`1-year Survival
`Progression-
`Free Survival
`Tumor
`Response
`(CR+PR)
`Response
`Duration
`
`(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.
`
`
`
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`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 = 0.65) and patients who
`never smoked (HR = 0.42). These subsets are considered further below.
`
`
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`Figure 2: Survival Hazard Ratio (HR) (Tarceva : Placebo) in Subgroups
`According to Pretreatment Characteristics
`
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`130
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`
`
`
`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
`
`
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`Page 8
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`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 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 238 study patients (33%).
`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
`effect of 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 DAKO EGFR pharmDxTM kit instructions.
`The use of the pharmDx kit has not been validated for use in non-small cell lung
`cancer.
`
`TARCEVA prolonged survival in the EGFR positive subgroup (N = 127; HR = 0.65;
`95% CI = 0.43 – 0.97)(Figure 3) and the subgroup whose EGFR status was
`unmeasured (N = 493; HR = 0.76; 95% CI = 0.61 – 0.93)(Figure 5), but did not
`appear to have an effect on survival in the EGFR negative subgroup (N = 111; HR =
`1.01; 95% CI = 0.65 – 1.57)(Figure 4). However, the confidence intervals for the
`EGFR positive, negative and unmeasured subgroups are wide and overlap, so that a
`survival benefit due to TARCEVA in the EGFR negative subgroup cannot be
`excluded.
`
`For the subgroup of 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 = 30; HR = 0.27; 95% CI
`= 0.11 – 0.67). There were too few EGFR negative patients who never smoked to
`reach a conclusion.
`
`Tumor responses were observed in all EGFR subgroups: 11.6% in the EGFR positive
`subgroup, 9.5% in the EGFR unmeasured subgroup and 3.2% in the EGFR negative
`
`
`
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`166
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`subgroup. An improvement in progression free survival was demonstrated in the
`EGFR positive subgroup (HR = 0.49; 95% CI = 0.33 – 0.72), the EGFR unmeasured
`subgroup (HR = 0.56; 95% CI = 0.46 – 0.70), and less certain in the EGFR negative
`subgroup (HR = 0.91; 95% CI = 0.59 – 1.39).
`
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`
`
`TARCEVA Administered Concurrently with Chemotherapy in NSCLC
`
`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)].
`
`INDICATIONS AND USAGE
`
`TARCEVA 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.
`
`
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`CONTRAINDICATIONS
`
`None.
`
`189
`
`WARNINGS
`
`190
`
`191
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`196
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`203
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`218
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`Pulmonary Toxicity
`
`There have been infrequent reports of serious Interstitial Lung Disease (ILD),
`including fatalities, in patients receiving TARCEVA for treatment of NSCLC or
`other advanced solid tumors. In the randomized single-agent study (see CLINICAL
`STUDIES section), the incidence of ILD (0.8%) was the same in both the placebo
`and TARCEVA groups. The overall incidence in TARCEVA-treated patients from
`all studies (including uncontrolled studies and studies with concurrent
`chemotherapy) was approximately 0.6%. Reported diagnoses in patients suspected of
`having ILD included 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
`47 days) after initiating TARCEVA therapy. 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 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 necessary (see ADVERSE
`REACTIONS and DOSAGE AND ADMINISTRATION - Dose Modifications
`sections).
`
`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
`
`
`
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`226
`227
`228
`229
`
`dose, on a mg/m2 basis) of erlotinib prior to mating through the first week of
`pregnancy had an increase in early resorptions which resulted in a decrease in the
`number of live fetuses.
`
`No teratogenic effects were observed in rabbits or rats.
`
`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.
`
`230
`
`PRECAUTIONS
`
`231
`
`232
`233
`234
`235
`236
`237
`
`238
`239
`240
`241
`242
`243
`244
`245
`
`246
`
`247
`248
`249
`
`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 atanazavir,
`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. 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 rifabutin, rifapentin, 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
`
`
`
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`261
`262
`263
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`264
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`265
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`267
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`277
`
`TARCEVA should be considered if changes in liver function are severe (see
`ADVERSE REACTIONS section).
`
`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 bleeding 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.
`
`
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`288
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`289
`290
`291
`292
`293
`294
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`295
`296
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`297
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`298
`299
`300
`301
`302
`303
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`304
`305
`306
`307
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`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 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).
`No meaningful differences in safety or pharmacokinetics were observed between
`younger and older patients. 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).
`(cid:120) Severe or persistent diarrhea, nausea, anorexia, or vomiting
`(cid:120) Onset or worsening of unexplained shortness of breath or cough
`(cid:120) Eye irritation
`
`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 and 1228 patients who received TARCEVA
`concurrently with chemotherapy. Adverse events, regardless of causality, that
`occurred in at least 10% of patients treated with TARCEVA and at least 3% more
`often than in the placebo group in the randomized trial are summarized by NCI-CTC
`(version 2.0) Grade in Table 3.
`
`There have been reports of serious ILD, including fatalities, in patients receiving
`TARCEVA for treatment of NSCLC or other advanced solid tumors (see
`WARNINGS - Pulmonary Toxicity, and DOSAGE AND ADMINISTRATION -
`Dose Modifications sections).
`
`
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`315
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`The most common adverse reactions in patients receiving TARCEVA 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 3:
`
`Adverse Events Occurring in (cid:149)10% of TARCEVA-treated Patients
`(2:1 Randomization of TARCEVA to Placebo)
`
`
`
`NCI CTC Grade
`MedDRA Preferred
`Term
`Rash
`Diarrhea
`Anorexia
`Fatigue
`Dyspnea
`Cough
`Nausea
`Infection
`Vomiting
`Stomatitis
`Pruritus
`Dry skin
`Conjunctivitis
`Keratoconjunctivitis
`sicca
`Abdominal pain
`
`TARCEVA
`N = 485
`Grade
`3
`
`Any
`Grade
`
`Grade
`4
`
`Any
`Grade
`
`Placebo
`N = 242
`Grade
`3
`
`Grade
`4
`
`%
`75
`54
`52
`52
`41
`33
`33
`24
`23
`17
`13
`12
`12
`12
`
`11
`
`%
`8
`6
`8
`14
`17
`4
`3
`4
`2
`<1
`<1
`0
`<1
`0
`
`2
`
`%
`<1
`<1
`1
`4
`11
`0
`0
`0
`<1
`0
`0
`0
`0
`0
`
`<1
`
`%
`17
`18
`38
`45
`35
`29
`24
`15
`19
`3
`5
`4
`2
`3
`
`7
`
`%
`0
`<1
`5
`16
`15
`2
`2
`2
`2
`0
`0
`0
`<1
`0
`
`1
`
`%
`0
`0
`<1
`4
`11
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`<1
`
`316
`317
`318
`319
`320
`321
`
`Liver function test abnormalities (including elevated alanine aminotransferase
`(ALT), aspartate aminotransferase (AST) and bilirubin) have been observed. These
`elevations were mainly transient or associated with liver metastases. Grade 2 (>2.5 –
`5.0 x ULN) ALT elevations occurred in 4% and <1% of TARCEVA and placebo
`treated patients, respectively. Grade 3 (> 5.0 – 20.0 x ULN) elevations were not
`observed in TARCEVA-treated patients. Dose reduction or interruption of
`
`
`
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`327
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`328
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`330
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`331
`332
`333
`334
`
`335
`
`336
`337
`338
`339
`340
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`342
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`346
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`351
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`TARCEVA should be considered if changes in liver function are severe (see
`DOSAGE AND ADMINISTRATION - Dose Modification section).
`
`Infrequent cases of gastrointestinal bleeding have been reported in clinical studies,
`some associated with concomitant warfarin administration (see PRECAUTIONS -
`Elevated International Normalized Ratio and Potential Bleeding section) and
`some with concomitant NSAID administration.
`
`NCI CTC grade 3 conjunctivitis and keratitis have been reported infrequently in
`patients receiving TARCEVA therapy. Corneal ulcerations may also occur (see
`PRECAUTIONS - Information for Patients section).
`
`In general, no notable differences in the safety of TARCEVA could be discerned
`between females or males and between patients younger or older than the age of 65
`years. The safety of TARCEVA appears similar in Caucasian and Asian patients (see
`PRECAUTIONS - Geriatric Use section).
`
`OVERDOSAGE
`
`Single oral doses of TARCEVA up to 1,000 mg in healthy subjects, and up to 1,600
`mg in cancer patients have been tolerated. Repeated twice-daily doses of 200 mg in
`healthy subjects were poorly tolerated after only a few days of dosing. Based on the
`data from these studies, an unacceptable incidence of severe adverse events, such as
`diarrhea, rash, and liver transaminase elevation, may occur above the recommended
`dose of 150 mg daily. In case of suspected overdose, TARCEVA should be withheld
`and symptomatic treatment instituted.
`
`DOSAGE AND ADMINISTRATION
`
`The recommended daily dose of TARCEVA is 150 mg taken at least one hour before
`or two hours after the ingestion of food. Treatment should continue until disease
`progression or unacceptable toxicity occurs. There is no evidence that treatment
`beyond progression is beneficial.
`
`Dose Modifications
`
`In patients who develop an acute onset of new or progressive pulmonary symptoms,
`such as dyspnea, cough or fever, treatment with TARCEVA should be interrupted
`pending diagnostic evaluation. If ILD is diagnosed, TARCEVA should be
`
`
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`358
`359
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`360
`361
`362
`363
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`365
`366
`367
`368
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`379
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`380
`381
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`discontinued and appropriate treatment instituted as necessary (see WARNINGS –
`Pulmonary Toxicity section).
`
`Diarrhea can usually be managed with loperamide. Patients with severe diarrhea who
`are unresponsive to loperamide or who become dehydrated may require dose
`reduction or temporary interruption of therapy. Patients with severe skin reactions
`may also require dose reduction or temporary interruption of therapy.
`
`When dose reduction is necessary, the TARCEVA dose should be reduced in 50 mg
`decrements.
`
`In patients who are being concomitantly treated with a strong CYP3A4 inhibitor
`such as atanazavir, clarithromycin, indinavir, itraconazole, ketoconazole,
`nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO),
`or voriconazole, a dose reduction should be considered should severe adverse
`reactions occur.
`
`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. 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 rifabutin, rifapentin, phenytoin, carbamazepine,
`phenobarbital and St. John's Wort. These too should be avoided if possible (see
`PRECAUTIONS - Drug Interactions section).
`
`Erlotinib is eliminated by hepatic metabolism and biliary excretion. Therefore,
`caution should be used when administering TARCEVA to patients with hepatic
`impairment. Dose reduction or interruption of TARCEVA should be considered
`should severe adverse reactions occur (see CLINICAL PHARMACOLOGY -
`Special Populations – Patients With Hepatic Impairment, PRECAUTIONS -
`Patients With Hepatic Impairment, and ADVERSE REACTIONS sections).
`
`HOW SUPPLIED
`
`The 25 mg, 100 mg and 150 mg strengths are supplied as white film-coated tablets
`for daily oral administration.
`
`
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`388
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`390
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`391
`
`392
`393
`
`TARCEVATM (erlotinib) Tablets, 25 mg: Round, biconvex face and straight sides,
`white film-coated, printed in orange with a “T” and “25” on one side and plain on the
`other side. Supplied in bottles of 30 tablets (NDC 50242-062-01).
`
`TARCEVATM (erlotinib) Tablets, 100 mg: Round, biconvex face and straight sides,
`white film-coated, printed in gray with “T” and “100” on one side and plain on the
`other side. Supplied in bottles of 30 tablets (NDC 50242-063-01).
`
`TARCEVATM (erlotinib) Tablets, 150 mg: Round, biconvex face and straight sides,
`white film-coated, printed in maroon with “T” and “150” on one side and plain on
`the other side. Supplied in bottles of 30 tablets (NDC 50242-064-01).
`
`STORAGE
`
`Store at 25°C (77°F); excursions permitted to 15° – 30°C (59° – 86°F). See USP
`Controlled Room Temperature.
`
`
`
`
`Page 19
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`

`

`Manufactured for:
`OSI Pharmaceuticals Inc., Melville, NY 11747
`Manufactured by:
`Schwarz Pharma Manufacturing, Seymour, IN 47274
`Distributed by:
`Genentech Inc., 1 DNA Way, South San Francisco, CA 94080-4990
`
`For further information please call 1-877-TARCEVA (1-877-827-2382).
`
`TARCEVA and
`are trademarks of OSI Pharmaceuticals, Inc., Melville, NY, 11747, USA.
`©2004 OSI Pharmaceuticals, Inc., and Genentech, Inc. All rights reserved.
`
`Page 20
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`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Robert Temple
`11/18/04 06:47:27 PM
`
`Page 21
`
`