Skin rash, bullous and exfoliative skin disorders

•Advise patients that skin reactions can occur or worsen on sun-exposed areas while taking TARCEVA, and proactive intervention may include alcohol-free emollient cream and use of sunscreen or avoidance of sun exposure. Advise patients that hyperpigmentation or dry skin, with or without digital skin fissures, have been reported and in the majority of cases were associated with rash

[see

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)
[seeWarnings and Precautions(5.1)]
•Renal Failure
[seeWarnings and Precautions(5.2)]
•Hepatotoxicity with or without Hepatic Impairment
[seeWarnings and Precautions(5.3)]
•Gastrointestinal Perforation
[seeWarnings and Precautions(5.4)]
•Bullous and Exfoliative Skin Disorders
[seeWarnings and Precautions(5.5)]
•Cerebrovascular Accident
[seeWarnings and Precautions(5.6)]
•Microangiopathic Hemolytic Anemia with Thrombocytopenia
[seeWarnings and Precautions(5.7)]
•Ocular Disorders
[seeWarnings and Precautions(
5.8
)]
•Hemorrhage in Patients Taking Warfarin
[seeWarnings and Precautions(5.9)]

The most common adverse reactions (≥ 20%) with TARCEVA from a pooled analysis in patients with NSCLC across all approved lines of therapy, with and without EGFR mutations, and in patients with pancreatic cancer were rash, diarrhea, anorexia, fatigue, dyspnea, cough, nausea, and vomiting. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact OSI Pharmaceuticals, LLC, at 1-800-572-1932 or FDA at 1-800-FDA-1088 orhttp://www.fda.gov/medwatch

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%).

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

Table 1: Adverse Reactions with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the TARCEVA-Treated Group (Study 1)
	TARCEVA N = 84		Chemotherapy Platinum-based chemotherapy (cisplatin or carboplatin with gemcitabine or docetaxel). N = 83
Adverse Reaction	All Grades %	Grades 3-4 %	All Grades %	Grades 3-4 %
RashRash 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.	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 TARCEVA-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4 liver test abnormalities in Study 1

[seeWarnings 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-CTCAE v3.0 Grade inTable 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: 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)
Adverse Reaction	TARCEVA N = 433			PLACEBO N = 445
	Any Grade	Grade 3	Grade 4	Any Grade	Grade 3	Grade 4
	%	%	%	%	%	%
RashRash 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.	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 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

[seeDosage and Administration(2.4) andWarnings 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 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 v2.0 Grade inTable 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 2^nd/3^rdLine Study: 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 4)
Adverse Reaction	TARCEVA 150 mg N=485			Placebo N=242
	Any Grade	Grade 3	Grade 4	Any Grade	Grade 3	Grade 4
	%	%	%	%	%	%
RashRash as a composite term includes: rash, palmar-plantar erythrodysesthesia syndrome, acne, skin disorder, pigmentation disorder, erythema, skin ulcer, exfoliative dermatitis, papular rash, skin desquamation.	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 TARCEVA 150 mg. These elevations were mainly transient or associated with liver metastases. Grade 2 [> 2.5 – 5.0 x upper limit of normal (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

Adverse Reaction	TARCEVA + Gemcitabine 1000 mg/m²IV N=259			Placebo + Gemcitabine 1000 mg/m²IV N=256
	Any Grade	Grade 3	Grade 4	Any Grade	Grade 3	Grade 4
	%	%	%	%	%	%
RashRash 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.	70	5	0	30	1	0
Diarrhea	48	5	<1	36	2	0
Decreased weight	39	2	0	29	<1	0
InfectionInfections 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.	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

	TARCEVA + Gemcitabine 1000 mg/m²IV N=259			Placebo + Gemcitabine 1000 mg/m²IV N=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%

Adverse Reactions
PulmonaryFor additional information seeWarnings and Precautions(5) .	Interstitial Lung Disease (ILD)	Discontinue TARCEVA
	During diagnostic evaluation for possible ILD	Withhold TARCEVAReduce TARCEVA by 50 mg decrements when restarting therapy following withholding treatment for a dose-limiting toxicity that has resolved to baseline or grade ≤ 1.
Hepatic	Severe hepatic toxicity that does not improve significantly or resolve within three weeks	Discontinue TARCEVA
	In patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline	Withhold TARCEVA and consider discontinuation
	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 and consider discontinuation
Renal	For severe (CTCAE grade 3 to 4) renal toxicity	Withhold TARCEVA and consider discontinuation
Gastrointestinal	Gastrointestinal perforation	Discontinue TARCEVA
Gastrointestinal	For persistent severe diarrhea not responsive to medical management (e.g., loperamide)	Withhold TARCEVA
Skin	Severe bullous, blistering or exfoliating skin conditions	Discontinue TARCEVA
Skin	For severe rash not responsive to medical management	Withhold TARCEVA
Ocular	Corneal perforation or severe ulceration	Discontinue TARCEVA
	For keratitis of (NCI-CTC version 4.0) grade 3-4 or for grade 2 lasting more than 2 weeks	Withhold TARCEVA
	For acute/worsening ocular disorders such as eye pain	Withhold TARCEVA and consider discontinuation
Drug Interactions
CYP3A4 inhibitorsFor additional information seeDrug Interactions(7) .	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)	Reduce TARCEVA by 50 mg decrements; avoid concomitant use if possible
CYP3A4 inducers	Concomitant use with CYP3A4 inducers, such as rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, or St. John’s Wort	Increase TARCEVA by 50 mg increments at 2-week intervals to a maximum of 450 mg as tolerated. Avoid concomitant use if possible
Concurrent Cigarette Smoking For additional information seeClinical Pharmacology(12.3) .	Concurrent cigarette smoking	Increase TARCEVA 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
Proton Pump inhibitors	Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period	Avoid concomitant use if possible
H₂-receptor antagonists	If treatment with an H₂-receptor antagonist such as ranitidine is required, separate dosing.	TARCEVA must be taken 10 hours after the H₂-receptor antagonist dosing and at least 2 hours before the next dose of the H₂-receptor antagonist
Antacids	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

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