TARCEVA erlotinib hydrochloride tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
ERLOTINIB HYDROCHLORIDE (UNII: DA87705X9K) (ERLOTINIB - UNII:J4T82NDH7E)
Available from:
Avera McKennan Hospital
INN (International Name):
ERLOTINIB HYDROCHLORIDE
Composition:
ERLOTINIB 100 mg
Prescription type:
PRESCRIPTION DRUG
Authorization status:
New Drug Application

TARCEVA- erlotinib hydrochloride tablet

Avera McKennan Hospital

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use TARCEVA safely and effectively. See full

prescribing information for TARCEVA.

TARCEVA (erlotinib) tablets, for oral use

Initial U.S. Approval: 2004

INDICATIONS AND USAGE

TARCEVA is a kinase inhibitor indicated for:

Limitations of Use:

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

®

First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal

growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-

approved test. (1.1)

Maintenance treatment of patients with locally advanced or metastatic NSCLC whose disease has not progressed

after four cycles of platinum-based first-line chemotherapy. (1.1)

Treatment of locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. (1.1)

First-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer, in combination

with gemcitabine. (1.2)

TARCEVA is not recommended for use in combination with platinum-based chemotherapy.

Safety and efficacy of TARCEVA have not been evaluated as first-line treatment in patients with metastatic NSCLC

whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution.

NSCLC: 150 mg orally, on an empty stomach, once daily (2.2)

Pancreatic cancer: 100 mg orally, on an empty stomach, once daily (2.3)

Tablets: 25 mg, 100 mg, and 150 mg. (3)

None. (4)

Interstitial Lung Disease (ILD): Occurs in 1.1% of patients. Withhold TARCEVA for acute onset of new or

progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever. Discontinue TARCEVA if ILD is

diagnosed. (5.1)

Renal Failure: Monitor renal function and electrolytes, particularly in patients at risk of dehydration. Withhold

TARCEVA for severe renal toxicity. (5.2)

Hepatotoxicity with or without hepatic impairment including hepatic failure and hepatorenal syndrome: Monitor

periodic liver testing. Withhold or discontinue TARCEVA for severe or worsening liver tests. (5.3)

Gastrointestinal perforations: Discontinue TARCEVA. (5.4)

Bullous and exfoliative skin disorders: Discontinue TARCEVA. (5.5)

Myocardial infarction (MI)/ischemia: The risk of MI is increased in patients with pancreatic cancer. (5.6)

Cerebrovascular accident (CVA): The risk of CVA is increased in patients with pancreatic cancer. (5.7)

Microangiopathic hemolytic anemia (MAHA): The risk of MAHA is increased in patients with pancreatic cancer. (5.8)

Ocular disorders: Discontinue TARCEVA for corneal perforation, ulceration or persistent severe keratitis. (5.9)

Hemorrhage in patients taking warfarin: Regularly monitor INR in patients taking warfarin or other coumarin-

derivative anticoagulants. (5.10)

Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to the fetus

ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact OSI Pharmaceuticals, LLC, at 1-800-572-1932 or FDA

at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

USE IN SPECIFIC POPULATIONS

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 11/2015

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Non-Small Cell Lung Cancer (NSCLC)

1.2 Pancreatic Cancer

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

2.2 Recommended Dose – NSCLC

2.3 Recommended Dose – Pancreatic Cancer

2.4 Dose Modifications

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Interstitial Lung Disease (ILD)

5.2 Renal Failure

5.3 Hepatotoxicity with or without Hepatic Impairment

5.4 Gastrointestinal Perforation

5.5 Bullous and Exfoliative Skin Disorders

5.6 Myocardial Infarction/Ischemia

5.7 Cerebrovascular Accident

5.8 Microangiopathic Hemolytic Anemia with Thrombocytopenia

5.9 Ocular Disorders

5.10 Hemorrhage in Patients Taking Warfarin

5.11 Embryo-Fetal Toxicity

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

6.2 Post-Marketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

and to use highly effective contraception (5.11, 8.6)

The most common adverse reactions (≥ 20%) with TARCEVA from a pooled analysis of Studies 1-4 were rash,

diarrhea, anorexia, fatigue, dyspnea, cough, nausea, and vomiting. (6.1)

CYP3A4 inhibitors increase erlotinib plasma concentrations. (7)

CYP3A4 inducers decrease erlotinib plasma concentrations. (7)

Drugs affecting gastric pH decrease erlotinib plasma concentrations. (7)

Cigarette smoking decreases erlotinib plasma concentrations. (7)

Nursing Mothers: Discontinue drug or nursing. (8.3)

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Females and Males of Reproductive Potential

8.7 Patients with Hepatic Impairment

8.8 Patients with Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Non-Small Cell Lung Cancer (NSCLC) – First-Line Treatment of Patients with EGFR

Mutations

14.2 NSCLC - Maintenance Treatment

14.3 NSCLC –Second/Third Line Treatment

14.4 NSCLC – Lack of Efficacy of TARCEVA Administered Concurrently with Chemotherapy

14.5 Pancreatic Cancer - TARCEVA Administered Concurrently with Gemcitabine

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Non-Small Cell Lung Cancer (NSCLC)

TARCEVA is indicated for:

Limitations of use:

1.2 Pancreatic Cancer

Sections or subsections omitted from the full prescribing information are not listed.

The first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose

tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R)

substitution mutations as detected by an FDA-approved test [see Clinical Studies (14.1)].

The maintenance treatment of patients with locally advanced or metastatic non-small cell lung

cancer whose disease has not progressed after four cycles of platinum-based first-line

chemotherapy [see Clinical Studies (14.2)].

The treatment of patients with locally advanced or metastatic non-small cell lung cancer after

failure of at least one prior chemotherapy regimen [see Clinical Studies (14.3)].

TARCEVA is not recommended for use in combination with platinum-based chemotherapy [see

Clinical Studies (14.4)].

Safety and efficacy of TARCEVA have not been evaluated as first-line treatment in patients with

metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21

(L858R) substitution [see Clinical Studies (14.1)].

TARCEVA in combination with gemcitabine is indicated for the first-line treatment of patients with

locally advanced, unresectable or metastatic pancreatic cancer [see Clinical Studies (14.5)].

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

Select patients for the first-line treatment of metastatic NSCLC with TARCEVA based on the presence

of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations in tumor specimens [See Clinical

Studies (14.1)]. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is

available at: http://www.fda.gov/CompanionDiagnostics

2.2 Recommended Dose – NSCLC

The recommended daily dose of TARCEVA for NSCLC is 150 mg taken on an empty stomach, i.e., at

least one hour before or two hours after the ingestion of food. Treatment should continue until disease

progression or unacceptable toxicity occurs.

2.3 Recommended Dose – Pancreatic Cancer

The recommended daily dose of TARCEVA for pancreatic cancer is 100 mg taken once daily in

combination with gemcitabine. Take TARCEVA on an empty stomach, i.e., at least one hour before or

two hours after the ingestion of food. Treatment should continue until disease progression or

unacceptable toxicity occurs [see Clinical Studies (14.5)].

2.4 Dose Modifications

Discontinue TARCEVA for:

Withhold TARCEVA:

Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.1)].

Severe hepatic toxicity that does not improve significantly or resolve within three weeks [see

Warnings and Precautions (5.3)].

Gastrointestinal perforation [see Warnings and Precautions (5.4)].

Severe bullous, blistering or exfoliating skin conditions [see Warnings and Precautions (5.5)].

Corneal perforation or severe ulceration [see Warnings and Precautions (5.9)].

During diagnostic evaluation for possible ILD.

For severe (CTCAE grade 3 to 4) renal toxicity, and consider discontinuation of TARCEVA [see

Warnings and Precautions (5.2)].

In patients without pre-existing hepatic impairment for total bilirubin levels greater than 3 times

the upper limit of normal or transaminases greater than 5 times the upper limit of normal, and

consider discontinuation of TARCEVA [see Warnings and Precautions (5.3)].

In patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or

tripling of transaminases values over baseline and consider discontinuation of TARCEVA [see

Warnings and Precautions (5.3)].

For persistent severe diarrhea not responsive to medical management (e.g., loperamide).

For severe rash not responsive to medical management.

For keratitis of (NCI-CTC version 4.0) grade 3-4 or for grade 2 lasting more than 2 weeks [see

Warnings and Precautions (5.9)].

For acute/worsening ocular disorders such as eye pain, and consider discontinuation of

TARCEVA [see Warnings and Precautions (5.9)].

Reduce TARCEVA by 50 mg decrements:

Increase TARCEVA by 50 mg increments as tolerated for:

Drugs Affecting Gastric pH

3 DOSAGE FORMS AND STRENGTHS

25 mg tablets

White film-coated tablets for daily oral administration. 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.

100 mg tablets

White film-coated tablets for daily oral administration. 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.

150 mg tablets

White film-coated tablets for daily oral administration. 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.

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Interstitial Lung Disease (ILD)

If severe reactions occur with concomitant use of strong CYP3A4 inhibitors [such as atazanavir,

clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir,

telithromycin, troleandomycin (TAO), voriconazole, or grapefruit or grapefruit juice] or when

using concomitantly with an inhibitor of both CYP3A4 and CYP1A2 (e.g., ciprofloxacin). Avoid

concomitant use if possible [see Drug Interactions (7)].

When restarting therapy following withholding treatment for a dose-limiting toxicity that has

resolved to baseline or grade ≤ 1.

Concomitant use with CYP3A4 inducers, such as rifampin, rifabutin, rifapentine, phenytoin,

carbamazepine, phenobarbital, or St. John’s Wort. Increase doses by 50 mg increments at 2 week

intervals to a maximum of 450 mg. Avoid concomitant use, if possible [see Drug Interactions (7)].

Concurrent cigarette smoking. Increase by 50 mg increments at 2 week intervals to a maximum of

300 mg. Immediately reduce the dose of TARCEVA to the recommended dose (150 mg or

100 mg daily) upon cessation of smoking [see Drug Interactions (7) and Clinical Pharmacology

(12.3)].

Avoid concomitant use of TARCEVA with proton pump inhibitors if possible. Separation of

doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI

tract for an extended period.

If treatment with an H -receptor antagonist such as ranitidine is required, TARCEVA must be

taken 10 hours after the H -receptor antagonist dosing and at least 2 hours before the next dose of

the H -receptor antagonist.

Although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid

dose and the TARCEVA dose should be separated by several hours, if an antacid is necessary.

Cases of serious ILD, including fatal cases, can occur with TARCEVA treatment. The overall

incidence of ILD in approximately 32,000 TARCEVA-treated patients in uncontrolled studies and

studies with concurrent chemotherapy was approximately 1.1%. In patients with ILD, the onset of

symptoms was between 5 days to more than 9 months (median 39 days) after initiating TARCEVA

therapy.

Withhold TARCEVA for acute onset of new or progressive unexplained pulmonary symptoms such as

dyspnea, cough, and fever pending diagnostic evaluation. If ILD is confirmed, permanently discontinue

TARCEVA [see Dosage and Administration (2.4)].

5.2 Renal Failure

Hepatorenal syndrome, severe acute renal failure including fatal cases, and renal insufficiency can

occur with TARCEVA treatment. Renal failure may arise from exacerbation of underlying baseline

hepatic impairment or severe dehydration. The pooled incidence of severe renal impairment in the 3

monotherapy lung cancer studies was 0.5% in the TARCEVA arms and 0.8% in the control arms. The

incidence of renal impairment in the pancreatic cancer study was 1.4% in the TARCEVA plus

gemcitabine arm and 0.4% in the control arm. Withhold TARCEVA in patients developing severe renal

impairment until renal toxicity is resolved. Perform periodic monitoring of renal function and serum

electrolytes during TARCEVA treatment [see Adverse Reactions (6.1) and Dosage and Administration

(2.4)].

5.3 Hepatotoxicity with or without Hepatic Impairment

Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with TARCEVA treatment in

patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline

hepatic impairment. In clinical studies where patients with moderate to severe hepatic impairment were

excluded, the pooled incidence of hepatic failure in the 3 monotherapy lung cancer studies was 0.4% in

the TARCEVA arms and 0% in the control arms. The incidence of hepatic failure in the pancreatic

cancer study was 0.4% in the TARCEVA plus gemcitabine arm and 0.4% in the control arm. In a

pharmacokinetic study in 15 patients with moderate hepatic impairment (Child-Pugh B) associated with

significant liver tumor burden, 10 of these 15 patients died within 30 days of the last TARCEVA dose.

One patient died from hepatorenal syndrome, 1 patient died from rapidly progressing liver failure and

the remaining 8 patients died from progressive disease. Six out of the 10 patients who died had baseline

total bilirubin > 3 x ULN.

Perform periodic liver testing (transaminases, bilirubin, and alkaline phosphatase) during treatment with

TARCEVA. Increased frequency of monitoring of liver function is required for patients with pre-

existing hepatic impairment or biliary obstruction. Withhold TARCEVA in patients without pre-existing

hepatic impairment for total bilirubin levels greater than 3 times the upper limit of normal or

transaminases greater than 5 times the upper limit of normal. Withhold TARCEVA in patients with pre-

existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases

values over baseline. Discontinue TARCEVA in patients whose abnormal liver tests meeting the above

criteria do not improve significantly or resolve within three weeks [see Dosage and Administration (2.4)

and Clinical Pharmacology (12.3)].

5.4 Gastrointestinal Perforation

Gastrointestinal perforation, including fatal cases, can occur with TARCEVA treatment. Patients

receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, or taxane-based chemotherapy,

or who have prior history of peptic ulceration or diverticular disease may be at increased risk of

perforation [see Adverse Reactions (6.1, 6.2)]. The pooled incidence of gastrointestinal perforation in the

3 monotherapy lung cancer studies was 0.2% in the TARCEVA arms and 0.1% in the control arms. The

incidence of gastrointestinal perforation in the pancreatic cancer study was 0.4% in the TARCEVA plus

gemcitabine arm and 0% in the control arm. Permanently discontinue TARCEVA in patients who

develop gastrointestinal perforation [see Dosage and Administration (2.4)].

5.5 Bullous and Exfoliative Skin Disorders

Bullous, blistering and exfoliative skin conditions, including cases suggestive of Stevens-Johnson

syndrome/Toxic epidermal necrolysis, which in some cases were fatal, can occur with TARCEVA

treatment [see Adverse Reactions (6.1, 6.2)]. The pooled incidence of bullous and exfoliative skin

disorders in the 3 monotherapy lung cancer studies was 1.2% in the TARCEVA arms and 0% in the

control arms. The incidence of bullous and exfoliative skin disorders in the pancreatic cancer study was

0.4% in the TARCEVA plus gemcitabine arm and 0% in the control arm. Discontinue TARCEVA

treatment if the patient develops severe bullous, blistering or exfoliating conditions [see Dosage and

Administration (2.4)].

5.6 Myocardial Infarction/Ischemia

In the pancreatic carcinoma trial, six patients (incidence of 2.1%) 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

1.1%), and one died due to myocardial infarction. The pooled incidence of myocardial

infarction/ischemia in the 3 monotherapy lung cancer studies was 0.2% in the TARCEVA arms and

0.4% in the control arms.

5.7 Cerebrovascular Accident

In the pancreatic carcinoma trial, seven patients in the TARCEVA/gemcitabine group developed

cerebrovascular accidents (incidence: 2.5%). One of these was hemorrhagic and was the only fatal

event. In comparison, in the placebo/gemcitabine group there were no cerebrovascular accidents. The

pooled incidence of cerebrovascular accident in the 3 monotherapy lung cancer studies was 0.6% in the

TARCEVA arms and 0.9% in the control arms.

5.8 Microangiopathic Hemolytic Anemia with Thrombocytopenia

The pooled incidence of microangiopathic hemolytic anemia with thrombocytopenia in the 3

monotherapy lung cancer studies was 0% in the TARCEVA arms and 0.1% in the control arms. The

incidence of microangiopathic hemolytic anemia with thrombocytopenia in the pancreatic cancer study

was 1.4% in the TARCEVA plus gemcitabine arm and 0% in the control arm.

5.9 Ocular Disorders

Decreased tear production, abnormal eyelash growth, keratoconjunctivitis sicca or keratitis can occur

with TARCEVA treatment and can lead to corneal perforation or ulceration [see Adverse Reactions (6.1)

and (6.2)]. The pooled incidence of ocular disorders in the 3 monotherapy lung cancer studies was

17.8% in the TARCEVA arms and 4% in the control arms. The incidence of ocular disorders in the

pancreatic cancer study was 12.8% in the TARCEVA plus gemcitabine arm and 11.4% in the control

arm. Interrupt or discontinue TARCEVA therapy if patients present with acute or worsening ocular

disorders such as eye pain [see Dosage and Administration (2.4)].

5.10 Hemorrhage in Patients Taking Warfarin

Severe and fatal hemorrhage associated with International Normalized Ratio (INR) elevations can occur

when TARCEVA and warfarin are administered concurrently. Regularly monitor prothrombin time and

INR during TARCEVA treatment in patients taking warfarin or other coumarin-derivative anticoagulants

[see Adverse Reactions (6.1) and Drug Interactions (7)].

5.11 Embryo-Fetal Toxicity

Based on its mechanism of action, TARCEVA can cause fetal harm when administered to a pregnant

woman. When given during organogenesis, erlotinib administration resulted in embryo-fetal lethality and

abortion in rabbits at doses approximately 3 times the recommended human daily dose of 150 mg. If

TARCEVA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the

patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

Advise females of reproductive potential to use highly effective contraception during therapy, and for

at least 2 weeks after the last dose of TARCEVA. Advise patients to contact their healthcare provider if

they become pregnant, or if pregnancy is suspected, while taking TARCEVA [see Use in Specific

Populations (8.1) and (8.6)].

6 ADVERSE REACTIONS

The following serious adverse reactions, which may include fatalities, are discussed in greater detail in

other sections of the labeling:

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug

and may not reflect the rates observed in practice.

Safety evaluation of TARCEVA is based on more than 1200 cancer patients who received TARCEVA

as monotherapy, more than 300 patients who received TARCEVA 100 or 150 mg plus gemcitabine, and

1228 patients who received TARCEVA concurrently with other chemotherapies. The most common

adverse reactions with TARCEVA are rash and diarrhea usually with onset during the first month of

treatment. The incidences of rash and diarrhea from clinical studies of TARCEVA for the treatment of

NSCLC and pancreatic cancer were 70% for rash and 42% for diarrhea.

Non-Small Cell Lung Cancer

First-Line Treatment of Patients with EGFR Mutations

The most frequent (≥ 30%) adverse reactions in TARCEVA-treated patients were diarrhea, asthenia,

rash, cough, dyspnea and decreased appetite. In TARCEVA-treated patients the median time to onset of

rash was 15 days and the median time to onset of diarrhea was 32 days.

The most frequent Grade 3-4 adverse reactions in TARCEVA-treated patients were rash and diarrhea.

Dose interruptions or reductions due to adverse reactions occurred in 37% of TARCEVA-treated

patients, and 14.3% of TARCEVA-treated patients discontinued therapy due to adverse reactions. In

TARCEVA-treated patients, the most frequently reported adverse reactions leading to dose

modification were rash (13%), diarrhea (10%), and asthenia (3.6%).

Selected, common adverse reactions in Study 4, occurring in at least 10% of patients who received

TARCEVA or chemotherapy and an increase in ≥ 5% in the TARCEVA treated group, are summarized

by NCI-CTC (version 3.0) Grade in Table 1. The median duration of TARCEVA treatment was 9.6

months in Study 4.

Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.1)]

Renal Failure [see Warnings and Precautions (5.2)]

Hepatotoxicity with or without Hepatic Impairment [see Warnings and Precautions (5.3)]

Gastrointestinal Perforation [see Warnings and Precautions (5.4)]

Bullous and Exfoliative Skin Disorders [see Warnings and Precautions (5.5)]

Myocardial Infarction/Ischemia [see Warnings and Precautions (5.6)]

Cerebrovascular Accident [see Warnings and Precautions (5.7)]

Microangiopathic Hemolytic Anemia with Thrombocytopenia [see Warnings and Precautions (5.8)]

Ocular Disorders [see Warnings and Precautions (5.9)]

Hemorrhage in Patients Taking Warfarin [see Warnings and Precautions (5.10)]

Table 1: Selected Adverse Reactions with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in

the TARCEVA-treated Group (Study 4)

TARCEVA

N = 84

Chemotherapy

N = 83

MedDRA Preferred

Term

All Grades

%

Grades 3-4

%

All Grades

%

Grades 3-4

%

Rash

Diarrhea

Cough

Dyspnea

Dry skin

Back pain

Chest pain

Conjunctivitis

Mucosal inflammation

Pruritus

Paronychia

Arthralgia

Musculoskeletal pain

Hepatic Toxicity: One TARCEVA-treated patient experienced fatal hepatic failure and four additional

patients experienced grade 3-4 liver test abnormalities in Study 4 [see Warnings and Precautions (5.3)].

Maintenance Treatment

Adverse reactions, regardless of causality, that occurred in at least 3% of patients treated with single-

agent TARCEVA at 150 mg and at least 3% more often than in the placebo group in the randomized

maintenance trial (Study 3) are summarized by NCI-CTC (version 3.0) Grade in Table 2.

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 2%, respectively, in TARCEVA-treated

patients. Rash and diarrhea resulted in study discontinuation in 1% and 0.5% of TARCEVA-treated

patients, respectively. Dose reduction or interruption for rash and diarrhea was needed in 5% and 3% of

patients, respectively. In TARCEVA-treated patients the median time to onset of rash was 10 days, and

the median time to onset of diarrhea was 15 days.

Table 2: NSCLC Maintenance Study: Selected Adverse Reactions Occurring with an Incidence

Rate ≥ 10% and an Increase of ≥ 5% in the Single-Agent TARCEVA Group compared to the

Placebo Group (Study 3)

TARCEVA

N = 433

PLACEBO

N = 445

NCI-CTC Grade

Any Grade

Grade 3

Grade 4

Any Grade

Grade 3

Grade 4

MedDRA Preferred Term

%

%

%

%

%

%

Rash

Diarrhea

Platinum based doublet chemotherapy (cisplatin or carboplatin with gemcitabine or docetaxel)

Rash as a composite term includes: rash, acne, folliculitis, erythema, dermatitis acneiform, dermatitis, palmar-

plantar erythrodysaesthesia syndrome, exfoliative rash, rash erythematous, rash pruritic, skin toxicity, eczema,

rash follicular, skin ulcer.

Rash as a composite term includes: rash, acne, dermatitis acneiform, skin fissures, erythema, rash papular, rash

Liver test abnormalities including ALT elevations were observed at Grade 2 or greater severity in 3%

of TARCEVA-treated patients and 1% of placebo-treated patients. Grade 2 and above bilirubin

elevations were observed in 5% of TARCEVA-treated patients and in < 1% in the placebo group [see

Dosage and Administration (2.4) and Warnings and Precaution (5.3)].

Second/Third Line Treatment

Adverse reactions, regardless of causality, that occurred in at least 10% of patients treated with single-

agent TARCEVA at 150 mg and at least 5% 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 3.

The most common adverse reactions in this patient population 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: NSCLC 2nd/3rd Line Study: Selected Adverse Reactions Occurring with an Incidence

Rate ≥ 10% and an Increase of ≥ 5% in the Single-Agent TARCEVA Group compared to the

Placebo Group (Study 1)

TARCEVA 150 mg

N=485

Placebo

N=242

NCI-CTC Grade

Any Grade

Grade 3

Grade 4

Any Grade

Grade 3

Grade 4

MedDRA Preferred Term

%

%

%

%

%

%

Rash

<1

Diarrhea

<1

<1

Anorexia

<1

Fatigue

Dyspnea

Nausea

Infection

Stomatitis

<1

Pruritus

<1

Dry skin

Conjunctivitis

<1

<1

Keratoconjunctivitis sicca

Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate

aminotransferase (AST) and bilirubin) were observed in patients receiving single-agent TARCEVA

150 mg. 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. TARCEVA dosing should be interrupted or discontinued if changes in liver function are

severe [see Dosage and Administration (2.4)].

Pancreatic Cancer - TARCEVA Administered Concurrently with Gemcitabine

This was a randomized, double blind placebo-controlled study of TARCEVA (150 mg or 100 mg daily)

generalized, rash pruritic, skin exfoliation, urticaria, dermatitis, eczema, exfoliative rash, dermatitis exfoliative,

furuncle, rash macular, rash pustular, skin hyperpigmentation, skin reaction, skin ulcer.

Rash as a composite term includes: rash, palmar-plantar erythrodysaesthesia syndrome, acne, skin disorder,

pigmentation disorder, erythema, skin ulcer, dermatitis exfoliative, rash papular, skin desquamation.

or placebo plus gemcitabine (1000 mg/m IV) in patients with locally advanced, unresectable or

metastatic pancreatic cancer (Study 2). The safety population comprised 282 patients in the erlotinib

group (259 in the 100 mg cohort and 23 in the 150 mg cohort) and 280 patients in the placebo group

(256 in the 100 mg cohort and 24 in the 150 mg cohort).

Adverse reactions that occurred in at least 10% of patients treated with TARCEVA 100 mg plus

gemcitabine in the randomized trial of patients with pancreatic cancer (Study 2) are summarized by NCI-

CTC (version 2.0) Grade in Table 4.

The most common adverse reactions in pancreatic cancer patients receiving TARCEVA 100 mg plus

gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. In the TARCEVA plus gemcitabine arm,

Grade 3-4 rash and diarrhea were each reported in 5% of patients. The median time to onset of rash and

diarrhea was 10 days and 15 days, respectively. Rash and diarrhea each resulted in dose reductions in

2% of patients, and resulted in study discontinuation in up to 1% of patients receiving TARCEVA plus

gemcitabine. Severe adverse reactions (≥ Grade 3 NCI-CTC) in the TARCEVA plus gemcitabine group

with incidences < 5% included syncope, arrhythmias, ileus, pancreatitis, hemolytic anemia including

microangiopathic hemolytic anemia with thrombocytopenia, myocardial infarction/ischemia,

cerebrovascular accidents including cerebral hemorrhage, and renal insufficiency [see Warnings and

Precautions (5)].

The 150 mg cohort was associated with a higher rate of certain class-specific adverse reactions

including rash and required more frequent dose reduction or interruption.

Table 4: Selected Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of

≥ 5% in TARCEVA-treated Pancreatic Cancer Patients: 100 mg cohort (Study 2)

* Includes all MedDRA preferred terms in the Infections and Infestations System Organ Class

Rash as a composite term includes: rash, palmar-plantar erythrodysaesthesia syndrome, pigmentation

disorder, dermatitis acneiform, folliculitis, photosensitivity reaction, Stevens-Johnson syndrome,

urticaria, erythematous rash, skin disorder, skin ulcer.

TARCEVA + Gemcitabine

1000 mg/m IV

N=259

Placebo + Gemcitabine

1000 mg/m IV

N=256

NCI-CTC Grade

Any Grade

Grade 3

Grade 4

Any Grade

Grade 3

Grade 4

MedDRA Preferred Term

%

%

%

%

%

%

Rash

Diarrhea

<1

Weight decreased

<1

Infection*

Pyrexia

Stomatitis

<1

Depression

<1

Cough

Headache

<1

Ten patients (4%) in the TARCEVA/gemcitabine group and three patients (1%) in the

placebo/gemcitabine group developed deep venous thrombosis. The overall incidence of grade 3 or 4

thrombotic events, including deep venous thrombosis was 11% for TARCEVA plus gemcitabine and

9% for placebo plus gemcitabine.

The incidences of liver test abnormalities (≥ Grade 2) in Study 2 are provided in Table 5[see Dosage

and Administration (2.4) and Warnings and Precautions (5.3)].

Table 5: Liver Test Abnormalities in Pancreatic Cancer Patients: 100 mg Cohort (Study 2)

2

2

Table 5: Liver Test Abnormalities in Pancreatic Cancer Patients: 100 mg Cohort (Study 2)

TARCEVA + Gemcitabine

1000 mg/m IV

N=259

Placebo + Gemcitabine

1000 mg/m IV

N=256

NCI-CTC

Grade

Grade 2

Grade 3

Grade 4

Grade 2

Grade 3

Grade 4

Bilirubin

<1%

<1%

<1%

NSCLC and Pancreatic Indications: Selected Low Frequency Adverse Reactions

Gastrointestinal Disorders

Cases of gastrointestinal bleeding (including fatalities) have been reported, some associated with

concomitant warfarin or NSAID administration [see Warnings and Precautions (5.10) and Drug

Interactions (7)]. These adverse reactions were reported as peptic ulcer bleeding (gastritis,

gastroduodenal ulcers), hematemesis, hematochezia, melena and hemorrhage from possible colitis.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post approval use of TARCEVA.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always

possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis, in combination

with statin therapy

Eye Disorders: ocular inflammation including uveitis

7 DRUG INTERACTIONS

CYP3A4 Inhibitors

Erlotinib is metabolized predominantly by CYP3A4. Co-treatment with the potent CYP3A4 inhibitor

ketoconazole increased erlotinib AUC by 67%. When TARCEVA was co-administered with

ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2, the erlotinib exposure [AUC] and maximum

concentration [C

] increased by 39% and 17%, respectively. Dose modifications are recommended

[see Dosage and Administration (2.4)].

CYP3A4 Inducers

Pre-treatment with the CYP3A4 inducer rifampicin for 7-11 days prior to TARCEVA decreased

erlotinib AUC by 58% to 80%. Dose modifications are recommended [see Dosage and Administration

(2.4)].

Drugs Affecting Gastric pH

Co-administration of TARCEVA with omeprazole decreased erlotinib AUC by 46% and co-

administration of TARCEVA with ranitidine 300 mg decreased erlotinib AUC by 33%. When

TARCEVA was administered with ranitidine 150 mg twice daily (at least 10 h after the previous

ranitidine evening dose and 2 h before the ranitidine morning dose), erlotinib AUC decreased by 15%.

Increasing the dose of TARCEVA when co-administered with such agents is not likely to compensate

for the loss of exposure. Scheduling modifications are recommended [see Dosage and Administration

(2.4) and Clinical Pharmacology (12.3)].

Cigarette Smoking

Cigarette smoking results in reductions in erlotinib AUC. Dose modifications are recommended [see

Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Anticoagulants

2

2

Interaction with coumarin-derived anticoagulants, including warfarin, leading to increased International

Normalized Ratio (INR) and bleeding adverse reactions, which in some cases were fatal, have been

reported in patients receiving TARCEVA. Regularly monitor prothrombin time or INR in patients taking

coumarin-derived anticoagulants. Dose modifications of TARCEVA are not recommended [see

Warnings and Precautions (5.10) and Adverse Reactions (6.1)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D

Risk Summary

Based on its mechanism of action, TARCEVA can cause fetal harm when administered to a pregnant

woman. When given during organogenesis, erlotinib administration resulted in embryo-fetal lethality and

abortion in rabbits at doses approximately 3 times the recommended human daily dose of 150 mg. If

TARCEVA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the

patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.11)].

Animal Data

Erlotinib has been shown to cause maternal toxicity resulting in embryo-fetal lethality and abortion in

rabbits when given during the period of organogenesis at doses that result in plasma drug

concentrations approximately 3 times those achieved at the recommended dose in humans (AUCs at

150 mg daily dose). During the same period, there was no increase in the incidence of embryo-fetal

lethality or abortion in rabbits or rats at doses resulting in exposures approximately equal to those in

humans at the recommended daily dose. In an independent fertility study female rats treated with 30

mg/m /day or 60 mg/m /day (0.3 or 0.7 times the recommended daily dose, on a mg/m basis) of

erlotinib 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 dosed with erlotinib during organogenesis at

doses up to 600 mg/m /day in the rabbit (3 times the plasma drug concentration seen in humans at

150 mg/day) and up to 60 mg/m /day in the rat (0.7 times the recommended dose of 150 mg/day on a

mg/m basis).

8.3 Nursing Mothers

It is not known whether erlotinib is present in human milk. Because many drugs are present in human milk

and because of the potential for serious adverse reactions in nursing infants from TARCEVA, a

decision should be made whether to discontinue nursing or discontinue the drug, taking into account the

importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of TARCEVA in pediatric patients have not been established.

In an open-label, multi-center trial, 25 pediatric patients (median age 14 years, range 3-20 years) with

recurrent or refractory ependymoma were randomized (1:1) to TARCEVA or etoposide. Thirteen

patients received TARCEVA at a dose of 85 mg/m /day orally until disease progression, death, patient

request or investigator decision to discontinue study drug or intolerable toxicity. Four patients

randomized to etoposide also received TARCEVA following disease progression. The trial was

terminated prematurely for lack of efficacy; there were no objective responses observed in these 17

TARCEVA-treated patients.

No new adverse events were identified in the pediatric population.

Based on the population pharmacokinetics analysis conducted in 105 pediatric patients (2 to 21 years

old) with cancer, the geometric mean estimates of CL/F/BSA (apparent clearance normalized to body

surface area) were comparable across the three age groups: 2-6 years (n=29), 7-16 years (n=59), and

17-21 years (n=17).

8.5 Geriatric Use

Of the 1297 subjects in clinical studies of TARCEVA for the treatment of NSCLC and pancreatic

cancer 40% were 65 and older while 10% were 75 and older. No overall differences in safety or

efficacy were observed between subjects 65 years and older and those younger than 65.

8.6 Females and Males of Reproductive Potential

Contraception

Females

Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive potential

to use highly effective contraception during treatment with TARCEVA, and for at least 2 weeks after

the last dose of TARCEVA. Advise patients to contact their healthcare provider if they become

pregnant, or if pregnancy is suspected, while taking TARCEVA [see Use in Specific Populations (8.1)].

8.7 Patients with Hepatic Impairment

Patients with hepatic impairment (total bilirubin > upper limit of normal (ULN) or Child-Pugh A, B and

C) should be closely monitored during therapy with TARCEVA. Treatment with TARCEVA should be

used with extra caution in patients with total bilirubin > 3 x ULN [see Warnings and Precautions (5.3),

Adverse Reactions (6.1, 6.2), and Dosage and Administration (2.4)].

In vitro and in vivo evidence suggest that erlotinib is cleared primarily by the liver. However, erlotinib

exposure was similar in patients with moderately impaired hepatic function (Child-Pugh B) compared

with patients with adequate hepatic function including patients with primary liver cancer or hepatic

metastases [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

8.8 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.

10 OVERDOSAGE

Single oral doses of TARCEVA up to 1,000 mg in healthy subjects and weekly doses up to 1,600 mg in

cancer patients have been tolerated. Repeated twice-daily doses of 200 mg single-agent TARCEVA 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 reactions, such as diarrhea, rash, and liver

transaminase elevation, may occur above the recommended dose [see Dosage and Administration (2)]. In

case of suspected overdose, TARCEVA should be withheld and symptomatic treatment instituted.

11 DESCRIPTION

TARCEVA (erlotinib), a kinase inhibitor, 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:

Erlotinib hydrochloride has the molecular formula C

H N O .HCl and a molecular weight of

429.90. The molecule has a pK of 5.42 at 25 C. 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 for oral administration 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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Epidermal growth factor receptor (EGFR) is expressed on the cell surface of both normal and cancer

cells. In some tumor cells signaling through this receptor plays a role in tumor cell survival and

proliferation irrespective of EGFR mutation status. Erlotinib reversibly inhibits the kinase activity of

EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor and thereby

inhibiting further downstream signaling. Erlotinib binding affinity for EGFR exon 19 deletion or exon

21 (L858R) mutations is higher than its affinity for the wild type receptor. Erlotinib inhibition of other

tyrosine kinase receptors has not been fully characterized.

12.3 Pharmacokinetics

Absorption and Distribution:

Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially

increased by food to almost 100%. Peak plasma levels occur 4 hours after dosing. The solubility of

erlotinib is pH dependent. Erlotinib solubility decreases as pH increases. Co-administration of

TARCEVA with omeprazole, a proton pump inhibitor, decreased the erlotinib exposure [AUC] and

maximum concentration [C

] by 46% and 61%, respectively. When TARCEVA was administered 2

hours following a 300 mg dose of ranitidine, an H receptor antagonist, the erlotinib AUC was reduced

by 33% and C

by 54%. When TARCEVA was administered with ranitidine 150 mg twice daily (at

least 10 h after the previous ranitidine evening dose and 2 h before the ranitidine morning dose), the

erlotinib AUC and C

decreased by 15% and 17%, respectively [see Drug Interactions (7)].

Following absorption, erlotinib is approximately 93% protein bound to plasma albumin and alpha-1 acid

glycoprotein (AAG). Erlotinib has an apparent volume of distribution of 232 liters.

Metabolism and Excretion:

A population pharmacokinetic analysis in 591 patients receiving the single-agent TARCEVA 2

line regimen 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.

An additional population pharmacokinetic analysis was conducted in 291 NSCLC patients administered

single-agent erlotinib as maintenance treatment. This analysis demonstrated that covariates affecting

erlotinib clearance in this patient population were similar to those seen in the prior single-agent

pharmacokinetic analysis. No new covariate effects were identified.

A third population pharmacokinetic analysis was conducted that incorporated erlotinib data from 204

pancreatic cancer patients who received erlotinib plus gemcitabine. Similar results were observed 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.

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).

Cigarette smoking reduces erlotinib exposure. In the Phase 3 NSCLC trial, current smokers achieved

erlotinib steady-state trough plasma concentrations which were approximately 2-fold less than the

former smokers or patients who had never smoked. This effect was accompanied by a 24% increase in

apparent erlotinib plasma clearance. In a separate study which evaluated the single-dose

pharmacokinetics of erlotinib in healthy volunteers, current smokers cleared the drug faster than former

smokers or volunteers who had never smoked. The AUC

in smokers was about 1/3 to 1/2 of that

in never/former smokers. In another study which was conducted in NSCLC patients (N=35) who were

current smokers, pharmacokinetic analyses at steady-state indicated a dose-proportional increase in

erlotinib exposure when the TARCEVA dose was increased from 150 mg to 300 mg. However, the

exact dose to be recommended for patients who currently smoke is unknown [see Drug Interactions (7)

and Patient Counseling Information (17)].

Special Populations:

Patients with Hepatic Impairment

Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with TARCEVA treatment in

patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline

hepatic impairment. [see Warnings and Precautions (5.3), Adverse Reactions (6.1, 6.2), and Dosage and

Administration (2.4)].

In vitro and in vivo evidence suggest that erlotinib is cleared primarily by the liver. However, erlotinib

exposure was similar in patients with moderately impaired hepatic function (Child-Pugh B) compared

with patients with adequate hepatic function including patients with primary liver cancer or hepatic

metastases.

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies were conducted in mice and rats with erlotinib at oral doses of up to

60 mg/kg/day in mice, 5 mg/kg/day in female rats, and 10 mg/kg/day in male rats. The studies were

negative for carcinogenic findings. Exposure in mice at the highest dose tested was approximately 10

times the exposure in humans at the erlotinib dose of 150 mg/day. The highest dose evaluated in male

0-infinity

rats resulted in exposures that were twice those in humans and exposures at the highest tested dose in

female rats were slightly lower than those in humans.

Erlotinib did not cause genetic damage in a series of in vitro assays (bacterial mutation, human

lymphocyte chromosome aberration and mammalian cell mutation) and in the in vivo mouse bone marrow

micronucleus test.

Erlotinib did not impair fertility in either male or female rats.

14 CLINICAL STUDIES

14.1 Non-Small Cell Lung Cancer (NSCLC) – First-Line Treatment of Patients with EGFR

Mutations

The safety and efficacy of TARCEVA as monotherapy for the first-line treatment of patients with

metastatic NSCLC containing EGFR exon 19 deletions or exon 21 (L858R) substitution mutations was

demonstrated in a randomized, open-label, clinical trial conducted in Europe (Study 4). One hundred

seventy-four (174) White patients were randomized 1:1 to receive erlotinib 150 mg once daily until

disease progression (n=86) or four cycles of a standard platinum-based doublet chemotherapy (n=88);

standard chemotherapy regimens were cisplatin plus gemcitabine, cisplatin plus docetaxel, carboplatin

plus gemcitabine, and carboplatin plus docetaxel. The main efficacy outcome measure was progression-

free survival (PFS) as assessed by the investigator. Randomization was stratified by EGFR mutation

(exon 19 deletion or exon 21 (L858R) substitution) and ECOG PS (0 vs. 1 vs. 2). EGFR mutation status

for screening and enrollment of patients was determined by a clinical trials assay (CTA). Tumor samples

from 134 patients (69 patients from the erlotinib arm and 65 patients from the chemotherapy arm) were

tested retrospectively by the FDA-approved companion diagnostic, the cobas® EGFR Mutation Test.

The baseline demographics of the overall study population were as follows: female (72%), white

(99%), age ≥ 65 years (51%), ECOG PS 1 (53%), with ECOG PS 0 (33%), and ECOG PS 2 (14%),

current smoker (11%), past-smoker (20%), and never smoker (69%). The disease characteristics were

93% stage IV and 7% Stage IIIb with pleural effusion as classified by the American Joint Commission

on Cancer (AJCC, 6

edition), 93% adenocarcinoma histology, 66% exon 19 mutation deletions and

34% exon 21 (L858R) point mutation by a CTA.

A statistically significant improvement in investigator-determined PFS was demonstrated for patients

randomized to erlotinib compared to those randomized chemotherapy (see Table 6 and Figure 1).

Similar results for PFS were observed for the subgroup evaluated by an independent-review committee

(approximately 75% of patients in Study 4 evaluated) and in the subgroup of 134 patients (77% of the

Study 4 population) with EGFR mutations confirmed by the cobas® EGFR Mutation Test.

A protocol-specified analysis of overall survival conducted at the time of the final analysis of PFS

showed no statistically significant difference between the TARCEVA and chemotherapy arms. At the

time of the data cut-off, 84% of patients in the chemotherapy arm had received at least one subsequent

treatment, of whom 97% received an EGFR tyrosine kinase inhibitor. In the TARCEVA arm, 66% of

patients had received at least one subsequent treatment.

Table 6: Efficacy Results (Study 4):

Erlotinib

(N = 86)

Chemotherapy

(N = 88)

Progression-free Survival

Number of Progressions or Deaths

71 (83%)

63 (72%)

Median PFS in Months (95% CI)

10.4 (8.7, 12.9)

5.2 (4.6, 6.0)

Hazard Ratio (95% CI)

0.34 (0.23, 0.49)

P-value (unstratified log-rank test)

<0.001

Overall Survival

Number of Deaths (%)

55 (64%)

54 (61%)

Median OS in Months (95% CI)

22.9 (17.0, 26.8)

19.5 (17.3, 28.4)

Hazard Ratio (95% CI)

0.93 (0.64, 1.35)

Objective Response

Objective Response Rate (95% CI)

65% (54.1%, 75.1%)

16% (9.0%, 25.3%)

Fig ure 1: Kaplan-Meier Plot of Investig ator-Assessed PFS in Study 4

Fig ure 1: Kaplan-Meier Plot of Investig ator-Assessed PFS in Study 4

In exploratory subgroup analyses based on EGFR mutation subtype, the hazard ratio (HR) for PFS was

0.27 (95% CI 0.17 to 0.43) in patients with exon 19 deletions and 0.52 (95% CI 0.29 to 0.95) in patients

with exon 21 (L858R) substitution. The HR for OS was 0.94 (95% CI 0.57 to 1.54) in the exon 19

deletion subgroup and 0.99 (95% CI 0.56 to 1.76) in the exon 21 (L858R) substitution subgroup.

14.2 NSCLC - Maintenance Treatment

The efficacy and safety of TARCEVA as maintenance treatment of NSCLC were demonstrated in a

randomized, double-blind, placebo-controlled trial conducted in 26 countries, in 889 patients with

locally advanced or metastatic NSCLC whose disease did not progress during first-line platinum-based

chemotherapy (Study 3). Patients were randomized 1:1 to receive TARCEVA 150 mg or placebo orally

once daily (438 TARCEVA, 451 placebo) until disease progression or unacceptable toxicity. The

primary objective of the study was to determine if the administration of TARCEVA after standard

platinum-based chemotherapy in the treatment of NSCLC resulted in improved progression free survival

(PFS) when compared with placebo, in all patients or in patients with EGFR immunohistochemistry

(IHC) positive tumors.

Demographic characteristics were balanced between the two treatment groups.

Baseline demographics of the overall study population were as follows: male (74%), age < 65 years

(66%), ECOG PS 1 (69%), ECOG PS 0 (31%), white (84%), Asian (15%), current smoker (55%), past-

Unstratified Cox regression model.

smoker (27%), and never smoker (17%). Disease characteristics were as follows: Stage IV (75%), Stage

IIIb with effusion (25%) as classified by AJCC (6

edition) with histologic subtypes of

adenocarcinoma including bronchioalveolar (45%), squamous (40%) and large cell (5%); and EGFR

IHC positive (70%), negative (14%), indeterminate (4%), and missing (12%).

Table 7: Efficacy Results (Study 3): (ITT Population)

Median in Months

(95% CI)

Hazard Ratio

(95% CI)

p-value

TARCEVA 150

mg

N = 438

Placebo

N = 451

Progres s ion-Free

Survival based on

inves tigator's

as s es s ment

2.8 (2.8, 3.1)

2.6 (1.9, 2.7)

0.71 (0.62, 0.82)

p < 0.0001

Overall Survival

12.0 (10.6, 13.9)

11.0 (9.9, 12.1)

0.81 (0.70, 0.95)

0.0088

Figure 2 depicts the Kaplan-Meier Curves for Overall Survival (ITT Population).

Fig ure 2: Kaplan - Meier Curve for Overall Survival of Patients by Treatment Group in Study 3

Fig ure 2: Kaplan - Meier Curve for Overall Survival of Patients by Treatment Group in Study 3

Note: HR is from a univariate Cox regression model.

The PFS and OS Hazard Ratios, respectively, in patients with EGFR IHC-positive tumors were 0.69

(95% CI: 0.58, 0.82) and 0.77 (95% CI: 0.64, 0.93). The PFS and OS Hazard Ratios in patients with

IHC-negative tumors were 0.77 (95% CI: 0.51, 1.14) and 0.91 (95% CI: 0.59, 1.38), respectively.

Univariate Cox regression model

Unstratified log-rank test.

Patients with adenocarcinoma had an OS Hazard Ratio of 0.77 (95% CI: 0.61, 0.97) and patients with

squamous histology had an OS Hazard Ratio of 0.86 (95% CI: 0.68, 1.10).

14.3 NSCLC –Second/Third Line Treatment

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 (Study 1). 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.

Baseline demographics of the overall study population were as follows: male (65%), white (78%),

Asian (12%), black (4%), age < 65 years (62%), ECOG PS 1 (53%), ECOG PS 0 (13%), ECOG PS 2

(25%), ECOG PS 3 (9%), current or ex-smoker (75%), never smoker (20%), and exposure to prior

platinum therapy (93%). Tumor characteristics were as follows: adenocarcinoma (50%), squamous

(30%), undifferentiated large cell (9%), and mixed non-small cell (2%).

The results of the study are shown in Table 8.

Table 8: Efficacy Results (Study 1): (ITT Population)

TARCEVA

Placebo

Hazard

Ratio

95% CI

p-value

Survival

Median

6.7 mo

Median

4.7 mo

0.73

0.61 - 0.86

<0.001

1-year Survival

31.2%

21.5%

Progression-

Free Survival

Median

9.9 wk

Median

7.9 wk

0.59

0.50 - 0.70

<0.001

Tumor Response

(CR+PR)

8.9%

0.9%

<0.001

Response

Duration

Median

34.3 wk

Median

15.9 wk

Survival was evaluated in the intent-to-treat population. Figure 3 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.

Cox regression model with the following covariates: ECOG performance status, number of prior regimens, prior

platinum, best response to prior chemotherapy.

Two-sided Log-Rank test stratified by ECOG performance status, number of prior regimens, prior platinum, best

response to prior chemotherapy.

Two-sided Fisher's exact test.

Fig ure 3: Kaplan - Meier Curve for Overall Survival of Patients by Treatment Group in Study 1

Fig ure 3: Kaplan - Meier Curve for Overall Survival of Patients by Treatment Group in Study 1

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.

14.4 NSCLC – Lack of Efficacy of 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)].

14.5 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 (Study 2). 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/m , 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 was also examined. The study

was conducted in 18 countries. A total of 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.

In the 100 mg cohort, baseline demographics of the overall study population were as follows: male

(52%), white (88%), Asian (7%), black (2%), age < 65 years (53%), ECOG PS 1 (51%), ECOG PS 0

(32%), and ECOG PS 2 (17%). There was 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. The majority of the patients (76%) had distant metastases at baseline and

24% had locally advanced disease.

The results of the study are shown in Table 9.

Table 9: Efficacy Results: 100 mg Cohort (Study 2)

TARCEVA +

Gemcitabine

Placebo +

Gemcitabine

Hazard

Ratio

95% CI

p-value

Survival

Median

6.4 mo

250 deaths

Median

6.0 mo

254 deaths

0.81

0.68 - 0.97

0.028

1-year Survival

23.8%

19.4%

Progression-Free

Survival

Median

3.8 mo

225 events

Median

3.5 mo

232 events

0.76

0.64 - 0.92

0.006

Tumor Response

(CR+PR)

8.6%

7.9%

0.87

Response Duration

Median

23.9 wk

Median

23.3 wk

Survival was evaluated in the intent-to-treat population. Figure 4 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.

Cox regression model with the following covariates: ECOG performance status, and extent of disease.

Two-sided Log-Rank test stratified by ECOG performance status and extent of disease.

Two-sided Fisher's exact test.

Fig ure 4 : Kaplan - Meier Curve for Overall Survival: 100 mg Cohort in Study 2

Fig ure 4 : Kaplan - Meier Curve for Overall Survival: 100 mg Cohort in Study 2

Note: HR is from Cox regression model with the following covariates: ECOG performance status and

extent of disease. The p-value is from two-sided Log-Rank test stratified by ECOG performance status

and extent of disease.

16 HOW SUPPLIED/STORAGE AND HANDLING

100 mg Tablets

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: NDC 50242-063-01

NDC 69189-0063-1 single dose pack with one tablet as repackaged by Avera McKennan Hospital

Store at 25°C (77°F); excursions permitted to 15°C - 30°C (59°F - 86°F). See USP Controlled Room

Temperature.

17 PATIENT COUNSELING INFORMATION

Advise patients to contact their health care provider for:

Severe or persistent diarrhea, nausea, anorexia, or vomiting [see Adverse Reactions (6.1)]Onset or

worsening of unexplained shortness of breath or cough [see Warnings and Precautions (5.1)]Eye

irritation [see Warnings and Precautions (5.9)]Onset or worsening of skin rash or development of

bullous lesions or desquamation [see Warnings and Precautions (5.5)]Any changes in smoking status

[see Clinical Pharmacology (12.3)]

Advise patients on the presentation of skin, hair and nail disorders.

In patients who develop skin rash, the appearance of the rash is typically erythematous and

maculopapular and it may resemble acne with follicular pustules, but is histopathologically different.

This skin reaction commonly occurs on the face, upper chest and back, but may be more generalized or

severe (NCI-CTC Grade 3 or 4) with desquamation. Skin reactions may occur or worsen in sun exposed

areas. Symptoms associated with rash may include itching, tenderness and/or

burning.Hyperpigmentation or dry skin, with or without digital skin fissures, have been reported and in

the majority of cases were associated with rash.Hair and nail disorders, including hirsutism and brittle

and loose nails, have been reported.

Instruct patients on initial management of rash or diarrhea.

Given that skin reactions are anticipated when taking TARCEVA, proactive intervention may include

alcohol-free emollient cream and use of sunscreen or avoidance of sun exposure [see Adverse Reactions

(6.1)].Management of rash may include topical corticosteroids or antibiotics with anti-inflammatory

properties. These approaches were used in the NSCLC and pancreatic pivotal clinical trials. Acne

preparations with drying properties may aggravate the dry skin and erythema. Treatment of rash has not

been formally studied and should be based on rash severity.Diarrhea can usually be managed with

loperamide.

Counsel patients on pregnancy planning and prevention.

Advise females of reproductive potential to use highly effective contraception during treatment with

TARCEVA, and for at least 2 weeks after the last dose of TARCEVA.Advise patients to contact their

healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with

TARCEVA [see Use in Specific Populations (8.1), (8.6)].Advise breast-feeding mothers to discontinue

nursing while receiving TARCEVA [see Use in Specific Populations (8.3)].

Advise patients to stop smoking. Advise patients that the dose of TARCEVA may need to be adjusted if

they smoke. [see Clinical Pharmacology (12.3)].

Manufactured for:

OSI Pharmaceuticals, LLC, Northbrook, IL 60062

an affiliate of Astellas Pharma US, Inc.

Product of Japan or Italy – See bottle label for origin

Manufactured by:

Kremers Urban Pharmaceuticals, Inc., Seymour, IN 47274

Distributed by:

Genentech USA, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-

4990

For further information please call 1-877-TARCEVA (1-877-827-2382).

TARCEVA is a trademark of OSI Pharmaceuticals, LLC, Northbrook, IL, 60062, USA, an affiliate of

Astellas Pharma US, Inc.

©2015 Astellas Pharma US, Inc., and Genentech, Inc. All rights reserved.

14A002-TAR-SPL

Principal Display Panel

TARCEVA

erlotinib hydrochloride tablet

Product Information

Product T ype

HUMAN PRESCRIPTION

DRUG

Ite m Code (Source )

NDC:6 9 18 9 -0 0 6 3(NDC:50 242-0 6 3)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

ERLO TINIB HYDRO CHLO RIDE (UNII: DA8 770 5X9 K) (ERLOTINIB - UNII:J4T8 2NDH7E)

ERLOTINIB

10 0 mg

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

ROUND

S iz e

9 mm

Flavor

Imprint Code

T;10 0

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 9 18 9 -0 0 6 3-1

1 in 1 DOSE PACK; Type 0 : No t a Co mbinatio n Pro duct

Avera McKennan Hospital

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 21743

0 4/0 1/20 15

Labeler -

Avera McKennan Hospital (068647668)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Avera McKennan Ho spital

0 6 8 6 476 6 8

relabel(6 9 18 9 -0 0 6 3) , repack(6 9 18 9 -0 0 6 3)

Revised: 11/2015

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