Erlotinib: Package Insert and Label Information (Page 2 of 5)

5.7 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 erlotinib tablets 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 erlotinib tablets plus gemcitabine arm and 0% in the control arm.

5.8 Ocular Disorders

Decreased tear production, abnormal eyelash growth, keratoconjunctivitis sicca or keratitis can occur with erlotinib tablets 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 erlotinib tablets arms and 4% in the control arms. The incidence of ocular disorders in the pancreatic cancer study was 12.8% in the erlotinib tablets plus gemcitabine arm and 11.4% in the control arm. Interrupt or discontinue erlotinib tablets therapy if patients present with acute or worsening ocular disorders such as eye pain [see Dosage and Administration (2.4)].

5.9 Hemorrhage in Patients Taking Warfarin

Severe and fatal hemorrhage associated with International Normalized Ratio (INR) elevations can occur when erlotinib tablets and warfarin are administered concurrently. Regularly monitor prothrombin time and INR during erlotinib tablets treatment in patients taking warfarin or other coumarin-derivative anticoagulants [see Adverse Reactions (6.1) and Drug Interactions (7)].

5.10 Embryo-Fetal Toxicity

​ Based on animal data and its mechanism of action, erlotinib tablets 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 exposures approximately 3 times the exposure at the recommended human daily dose of 150 mg. Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during therapy and for one month after the last dose of erlotinib tablets. [see Use in Specific Populations (8.1) and (8.3), Clinical Pharmacology (12.1)].

6. ADVERSE REACTIONS

The following serious adverse reactions, which may include fatalities, are discussed in greater detail in other sections of the labeling:

• 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)]
• Cerebrovascular Accident [see Warnings and Precautions (5.6)]
• Microangiopathic Hemolytic Anemia with Thrombocytopenia [see Warnings and Precautions (5.7)]
• Ocular Disorders [see Warnings and Precautions (5.8)]
• Hemorrhage in Patients Taking Warfarin [see Warnings and Precautions (5.9)]

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 erlotinib tablets is based on more than 1200 cancer patients who received erlotinib tablets as monotherapy, more than 300 patients who received erlotinib tablets 100 or 150 mg plus gemcitabine, and 1228 patients who received erlotinib tablets concurrently with other chemotherapies. The most common adverse reactions with erlotinib tablets are rash and diarrhea usually with onset during the first month of treatment. The incidences of rash and diarrhea from clinical studies of erlotinib tablets 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 erlotinib tablets-treated patients were diarrhea, asthenia, rash, cough, dyspnea, and decreased appetite. In erlotinib tablets-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 erlotinib tablets-treated patients were rash and diarrhea.

Dose interruptions or reductions due to adverse reactions occurred in 37% of erlotinib tablets-treated patients, and 14.3% of erlotinib tablets-treated patients discontinued therapy due to adverse reactions. In erlotinib tablets-treated patients, the most frequently reported adverse reactions leading to dose modification were rash (13%), diarrhea (10%), and asthenia (3.6%).

Common adverse reactions in Study 1, occurring in at least 10% of patients who received erlotinib tablets or chemotherapy and an increase in ≥ 5% in the erlotinib tablets-treated group, are graded by National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0 (NCI-CTCAE v3.0) Grade in Table 1. The median duration of erlotinib tablets treatment was 9.6 months in Study 1.

Table 1: Adverse Reactions with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Erlotinib Tablets Treated Group (Study 1)

	Erlotinib TabletsN = 84		Chemotherapy *N = 83
Adverse Reaction	All Grades%	Grades 3-4%	All Grades%	Grades 3-4%
* Platinum based chemotherapy (cisplatin or carboplatin with gemcitabine or docetaxel). † Rash as a composite term includes rash, acne, folliculitis, erythema, acneiform dermatitis, dermatitis, palmar-plantar erythrodysesthesia syndrome, exfoliative rash, erythematous rash, rash pruritic, skin toxicity, eczema, follicular rash, skin ulcer.
Rash †	85	14	5	0
Diarrhea	62	5	21	1
Cough	48	1	40	0
Dyspnea	45	8	30	4
Dry skin	21	1	2	0
Back pain	19	2	5	0
Chest pain	18	1	12	0
Conjunctivitis	18	0	0	0
Mucosal inflammation	18	1	6	0
Pruritus	16	0	1	0
Paronychia	14	0	0	0
Arthralgia	13	1	6	1
Musculoskeletal pain	11	1	1	0

Hepatic Toxicity: One erlotinib tablets-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4 liver test abnormalities in Study 1 [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 erlotinib tablets 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-CTCAE v3.0 Grade in Table 2.

The most common adverse reactions in patients receiving single-agent erlotinib tablets 150 mg were rash and diarrhea. Grade 3-4 rash and diarrhea occurred in 9% and 2%, respectively, in erlotinib tablets-treated patients. Rash and diarrhea resulted in study discontinuation in 1% and 0.5% of erlotinib tablets-treated patients, respectively. Dose reduction or interruption for rash and diarrhea was needed in 5% and 3% of patients, respectively. In erlotinib tablets-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: Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Single-Agent Erlotinib Tablets Group compared to the Placebo Group (Study 3)

Adverse Reaction	Erlotinib TabletsN = 433			PLACEBON = 445
	Any Grade	Grade 3	Grade 4	Any Grade	Grade 3	Grade 4
	%	%	%	%	%	%
* Rash as a composite term includes: rash, acne, acneiform dermatitis, skin fissures, erythema, papular rash, rash generalized, pruritic rash, skin exfoliation, urticaria, dermatitis, eczema, exfoliative rash, exfoliative dermatitis, furuncle, macular rash, pustular rash, skin hyperpigmentation, skin reaction, skin ulcer
Rash *	60	9	0	9	0	0
Diarrhea	20	2	0	4	0	0

Liver test abnormalities including ALT elevations were observed at Grade 2 or greater severity in 3% of erlotinib tablets-treated patients and 1% of placebo-treated patients. Grade 2 and above bilirubin elevations were observed in 5% of erlotinib tablets-treated patients and in < 1% in the placebo group [see Dosage and Administration (2.4) and Warnings and Precautions (5.3)].

Second/Third Line Treatment

Adverse reactions, regardless of causality, that occurred in at least 10% of patients treated with single-agent erlotinib tablets 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 v2.0 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 erlotinib tablets-treated patients. Rash and diarrhea each resulted in study discontinuation in 1% of erlotinib tablets-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 2^nd /3^rd Line Study: Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Single-Agent Erlotinib Tablets Group Compared to the Placebo Group (Study 4)

Adverse Reaction	Erlotinib Tablets150 mgN=485			PlaceboN=242
	Any Grade	Grade 3	Grade 4	Any Grade	Grade 3	Grade 4
	%	%	%	%	%	%
* Rash as a composite term includes: rash, palmar-plantar erythrodysesthesia syndrome, acne, skin disorder, pigmentation disorder, erythema, skin ulcer, exfoliative dermatitis, papular rash, skin desquamation.
Rash *	75	8	<1	17	0	0
Diarrhea	54	6	<1	18	<1	0
Anorexia	52	8	1	38	5	<1
Fatigue	52	14	4	45	16	4
Dyspnea	41	17	11	35	15	11
Nausea	33	3	0	24	2	0
Infection	24	4	0	15	2	0
Stomatitis	17	<1	0	3	0	0
Pruritus	13	<1	0	5	0	0
Dry skin	12	0	0	4	0	0
Conjunctivitis	12	<1	0	2	<1	0
Keratoconjunctivitis sicca	12	0	0	3	0	0

Liver function test abnormalities [including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin] were observed in patients receiving single-agent erlotinib tablets 150 mg. These elevations were mainly transient or associated with liver metastases. Grade 2 [> 2.5 – 5.0 × upper limit of normal (ULN)] ALT elevations occurred in 4% and < 1% of erlotinib tablets and placebo treated patients, respectively. Grade 3 (> 5.0 – 20.0 × ULN) elevations were not observed in erlotinib tablets-treated patients. Erlotinib tablets dosing should be interrupted or discontinued if changes in liver function are severe [see Dosage and Administration (2.4)].

Pancreatic Cancer — Erlotinib Tablets Administered Concurrently with Gemcitabine

This was a randomized, double-blind placebo-controlled study of erlotinib tablets (150 mg or 100 mg daily) or placebo plus gemcitabine (1000 mg/m ² by intravenous infusion) in patients with locally advanced, unresectable or metastatic pancreatic cancer (Study 5). 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 erlotinib tablets 100 mg plus gemcitabine in the randomized trial of patients with pancreatic cancer (Study 5) were graded according to NCI-CTC v2.0 in Table 4.

The most common adverse reactions in pancreatic cancer patients receiving erlotinib tablets 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. In the erlotinib tablets 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 erlotinib tablets plus gemcitabine. Severe adverse reactions (≥ Grade 3 NCI-CTC) in the erlotinib tablets 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: Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in Erlotinib Tablets -Treated Pancreatic Cancer Patients: 100 mg Cohort (Study 5)

Adverse Reaction	Erlotinib Tablets + Gemcitabine1000 mg/m2 IVN=259			Placebo + Gemcitabine1000 mg/m2 IVN=256
	Any Grade	Grade 3	Grade 4	Any Grade	Grade 3	Grade 4
	%	%	%	%	%	%
* Rash as a composite term includes: rash, palmar-plantar erythrodysesthesia syndrome, pigmentation disorder, acneiform dermatitis, folliculitis, photosensitivity reaction, Stevens-Johnson syndrome, urticaria, erythematous rash, skin disorder, skin ulcer. † Infections as a composite term include infections with unspecified pathogens as well as bacterial (including chlamydial, rickettsial, mycobacterial and mycoplasmal), parasitic (including helminthic, ectoparasitic and protozoal), viral and fungal infectious disorders.
Rash *	70	5	0	30	1	0
Diarrhea	48	5	<1	36	2	0
Decreased weight	39	2	0	29	<1	0
Infection †	39	13	3	30	9	2
Pyrexia	36	3	0	30	4	0
Stomatitis	22	<1	0	12	0	0
Depression	19	2	0	14	<1	0
Cough	16	0	0	11	0	0
Headache	15	<1	0	10	0	0

Ten patients (4%) in the erlotinib tablets/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 erlotinib tablets plus gemcitabine and 9% for placebo plus gemcitabine.

The incidences of liver test abnormalities (≥ Grade 2) in Study 5 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 5)

	Erlotinib Tablets + Gemcitabine1000 mg/m2 IVN=259			Placebo + Gemcitabine1000 mg/m2 IVN=256
	Grade 2	Grade 3	Grade 4	Grade 2	Grade 3	Grade 4
Bilirubin	17%	10%	<1%	11%	10%	3%
ALT	31%	13%	<1%	22%	9%	0%
AST	24%	10%	<1%	19%	9%	0%

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 (5.9) and Drug Interactions (7)]. These adverse reactions were reported as peptic ulcer bleeding (gastritis, gastroduodenal ulcers), hematemesis, hematochezia, melena and hemorrhage from possible colitis.