Erlotinib: Package Insert and Label Information

ERLOTINIB- erlotinib hydrochloride tablet, film coated
Breckenridge Pharmaceutical, Inc.

1. INDICATIONS AND USAGE

1.1 Non-Small Cell Lung Cancer (NSCLC)

​ Erlotinib tablets are 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 tablets have not been established in patients with NSCLC whose tumors have other EGFR mutations [see Clinical Studies (14.1, 14.2)].
• Erlotinib tablets are not recommended for use in combination with platinum-based chemotherapy [see Clinical Studies (14.4)].

1.2 Pancreatic Cancer

Erlotinib tablets in combination with gemcitabine are 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 tablets 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

* For additional information see Warnings and Precautions (5). † Reduce erlotinib tablets 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).
​ Adverse Reactions
Pulmonary *	Interstitial Lung Disease (ILD)	Discontinue erlotinib tablets
	During diagnostic evaluation for possible ILD	Withhold erlotinib tablets †
​ 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 tablets † 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 tablets † and consider discontinuation
​ Renal *	For severe (CTCAE grade 3 to 4) renal toxicity	Withhold erlotinib tablets † and consider discontinuation
​ Gastrointestinal *	Gastrointestinal perforation	Discontinue erlotinib tablets
	For persistent severe diarrhea not responsive to medical management (e.g., loperamide)	Withhold erlotinib tablets †
​ Skin *	Severe bullous, blistering or exfoliating skin conditions	Discontinue erlotinib tablets
	For severe rash not responsive to medical management	Withhold erlotinib tablets †
​ Ocular *	Corneal perforation or severe ulceration	Discontinue erlotinib tablets
	For keratitis of (NCI-CTC version 4.0) grade 3-4 or for grade 2 lasting more than 2 weeks	Withhold erlotinib tablets †
	For acute/worsening ocular disorders such as eye pain	Withhold erlotinib tablets † 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 tablets 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 tablets 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 tablets by 50 mg increments at 2-week intervals to a maximum of 300 mg. Immediately reduce the dose of erlotinib tablets 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.	Erlotinib tablets 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 erlotinib tablets dose should be separated by several hours, if an antacid is necessary

3. DOSAGE FORMS AND STRENGTHS

25 mg tablets: round, biconvex, white film-coated tablets debossed with “N 25” on one side and plain on other side.

100 mg tablets: round, biconvex, white film-coated tablets debossed with “N 100” on one side and plain on other side.

150 mg tablets: round, biconvex, white film-coated tablets debossed with “N 150” on one side and plain on other side.

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

5.1 Interstitial Lung Disease (ILD)

Cases of serious ILD, including fatal cases, can occur with erlotinib tablets treatment. The overall incidence of ILD in approximately 32,000 erlotinib tablets-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 erlotinib tablets therapy.

Withhold erlotinib tablets 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 erlotinib tablets [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 erlotinib tablets 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 erlotinib tablets arms and 0.8% in the control arms. The incidence of renal impairment in the pancreatic cancer study was 1.4% in the erlotinib tablets plus gemcitabine arm and 0.4% in the control arm. Withhold erlotinib tablets in patients developing severe renal impairment until renal toxicity is resolved. Perform periodic monitoring of renal function and serum electrolytes during erlotinib tablets 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 erlotinib tablets 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 erlotinib tablets arms and 0% in the control arms. The incidence of hepatic failure in the pancreatic cancer study was 0.4% in the erlotinib tablets 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 erlotinib tablets 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 × ULN.

Perform periodic liver testing (transaminases, bilirubin, and alkaline phosphatase) during treatment with erlotinib tablets. Increased frequency of monitoring of liver function is required for patients with pre-existing hepatic impairment or biliary obstruction. Withhold erlotinib tablets 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 tablets in patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline. Discontinue erlotinib tablets 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 erlotinib tablets 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 erlotinib tablets arms and 0.1% in the control arms. The incidence of gastrointestinal perforation in the pancreatic cancer study was 0.4% in the erlotinib tablets plus gemcitabine arm and 0% in the control arm. Permanently discontinue erlotinib tablets 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 erlotinib tablets 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 erlotinib tablets 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 erlotinib tablets plus gemcitabine arm and 0% in the control arm. Discontinue erlotinib tablets treatment if the patient develops severe bullous, blistering or exfoliating conditions [see Dosage and Administration (2.4)].

5.6 Cerebrovascular Accident

​ In the pancreatic carcinoma trial, seven patients in the erlotinib tablets/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 erlotinib tablets arms and not higher than that observed in the control arms.