Erlotinib

ERLOTINIB- erlotinib hydrochloride tablet, film coated
Areva Pharmaceuticals

1. INDICATIONS AND USAGE

1.1 Non-Small Cell Lung Cancer (NSCLC)

Erlotinib Tablets was indicated for:

• The 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 receiving first-line, maintenance, or second or greater line treatment after progression following at least one prior chemotherapy regimen [see Clinical Studies (14.1, 14.3)].

Limitations of use:

• Safety and efficacy of erlotinib have not been established in patients with NSCLC whose tumors have other EGFR mutations [see Clinical Studies (14.1, 14.2)].
• Erlotinib tablet is not recommended for use in combination with platinum-based chemotherapy [see Clinical Studies (14.4)].

1.2 Pancreatic Cancer

Erlotinib tablet 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 Selection of Patients with Metastatic NSCLC

Select patients for the treatment of metastatic NSCLC with erlotinib tablets based on the presence of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations in tumor or plasma specimens [See Clinical Studies (14.1, 14.2)]. If these mutations are not detected in a plasma specimen, test tumor tissue if available. 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 erlotinib tablets 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 erlotinib tablets for pancreatic cancer is 100 mg taken once daily in combination with gemcitabine. Take erlotinib tablet 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

Adverse Reactions
Pulmonary†	Interstitial Lung Disease (ILD)	Discontinue Erlotinib tablet
	During diagnostic evaluation for possible ILD	Withhold Erlotinib tablet *
Hepatic†	Severe hepatic toxicity that does not improve significantly or resolve within three weeks	Discontinue Erlotinib tablets
	In patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline	Withhold Erlotinib tablet* 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 Erlotinib tablet* and consider discontinuation
Renal†	For severe (CTCAE grade 3 to 4) renal toxicity	Withhold Erlotinib tablet* and consider discontinuation
Gastrointestinal†	Gastrointestinal perforation	Discontinue Erlotinib tablet
	For persistent severe diarrhea not responsive to medical management (e.g., loperamide)	Withhold Erlotinib tablet*
Skin†	Severe bullous, blistering or exfoliating skin conditions	Discontinue Erlotinib tablet
	For severe rash not responsive to medical management	Withhold Erlotinib tablet*
Ocular†	Corneal perforation or severe ulceration	Discontinue Erlotinib tablet
	For keratitis of (NCI-CTC version 4.0) grade 3-4 or for grade 2 lasting more than 2 weeks	Withhold Erlotinib tablet*
	For acute/worsening ocular disorders such as eye pain	Withhold Erlotinib tablet* and consider discontinuation
Drug Interactions
CYP3A4 inhibitors‡	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 erlotinib 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 erlotinib by 50 mg increments at 2-week intervals to a maximum of 450 mg as tolerated. Avoid concomitant use if possible
Concurrent Cigarette Smoking ‡§	Concurrent cigarette smoking	Increase erlotinib by 50 mg increments at 2-week intervals to a maximum of 300 mg. Immediately reduce the dose of erlotinib tablet 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
H 2 -receptor antagonists	If treatment with an H2-receptor antagonist such as ranitidine is required, separate dosing.	Erlotinib tablet must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H 2 receptor antagonist
Antacids	The effect of antacids on erlotinib pharmacokinetics has not been evaluated.	The antacid dose and the erlotinib dose should be separated by several hours, if an antacid is necessary

† For additional information see Warnings and Precautions (5).

* Reduce erlotinib by 50 mg decrements when restarting therapy following withholding treatment for a dose-limiting toxicity that has resolved to baseline or grade ≤ 1.

‡ For additional information see Drug Interactions (7).

§ For additional information see Clinical Pharmacology (12.3).

3 DOSAGE FORMS AND STRENGTHS

25 mg Tablets: White to off white round, biconvex film-coated tablets, debossed with “S13” on one side and plain on other side.

100 mg Tablets: White to off white round, biconvex film-coated tablets, debossed with “S12” on one side and plain on other side.

150 mg Tablets: White to off white round, biconvex film-coated tablets, debossed with “S11” on one side and plain on other side.