Erlotinib (Page 2 of 8)

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

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)]