Important Safety Information

WARNINGS AND PRECAUTIONS

• Interstitial Lung Disease (ILD):
  • Cases of serious ILD, including fatal cases, can occur with Tarceva treatment. The overall incidence of ILD in approximately 32,000 Tarceva-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 Tarceva therapy.
  • Withhold Tarceva 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 Tarceva.
• Renal Failure:
  • Hepatorenal syndrome, severe acute renal failure including fatal cases, and renal insufficiency can occur with Tarceva 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 Tarceva arms and 0.8% in the control arms. The incidence of renal impairment in the pancreatic cancer study was 1.4% in the Tarceva plus gemcitabine arm and 0.4% in the control arm.
  • Withhold Tarceva in patients developing severe renal impairment until renal toxicity is resolved. Perform periodic monitoring of renal function and serum electrolytes during Tarceva treatment.
• Hepatotoxicity With or Without Hepatic Impairment:
  • Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with Tarceva treatment in patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline hepatic impairment.
    • Hepatic Toxicity: One Tarceva-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4 liver test abnormalities.
  • 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 Tarceva arms and 0% in the control arms. The incidence of hepatic failure in the pancreatic cancer study was 0.4% in the Tarceva plus gemcitabine arm and 0.4% in the control arm.
  • Perform periodic liver testing (transaminases, bilirubin, and alkaline phosphatase) during treatment with Tarceva. Increased frequency of monitoring of liver function is required for patients with pre-existing hepatic impairment or biliary obstruction.
  • Withhold Tarceva in patients without pre-existing hepatic impairment for total bilirubin >3 x ULN or transaminases >5 x ULN. Withhold Tarceva in patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline.
  • Discontinue Tarceva in patients whose abnormal liver tests meeting the above criteria do not improve significantly or resolve within 3 weeks.
• Gastrointestinal Perforation:
  • Gastrointestinal perforation, including fatal cases, can occur with Tarceva 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.
  • The pooled incidence of gastrointestinal perforation in the 3 monotherapy lung cancer studies was 0.2% in the Tarceva arms and 0.1% in the control arms. The incidence of gastrointestinal perforation in the pancreatic cancer study was 0.4% in the Tarceva plus gemcitabine arm and 0% in the control arm.
  • Permanently discontinue Tarceva in patients who develop gastrointestinal perforation.
• 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 Tarceva treatment.
  • The pooled incidence of bullous and exfoliative skin disorders in the 3 monotherapy lung cancer studies was 1.2% in the Tarceva 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 Tarceva plus gemcitabine arm and 0% in the control arm.
  • Discontinue Tarceva treatment if the patient develops severe bullous, blistering or exfoliating conditions.
• Cerebrovascular Accident:
  • In the pancreatic carcinoma trial, 7 patients in the Tarceva plus gemcitabine group developed cerebrovascular accident (incidence 2.5%). One of these was hemorrhagic and was the only fatal event. In comparison, in the placebo plus 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 Tarceva arms and not higher than that observed in the control arms.
• 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 Tarceva 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 Tarceva plus gemcitabine arm and 0% in the control arm.
• Ocular Disorders:
  • Decreased tear production, abnormal eyelash growth, keratoconjunctivitis sicca or keratitis can occur with Tarceva treatment and can lead to corneal perforation or ulceration.
  • The pooled incidence of ocular disorders in the 3 monotherapy lung cancer studies was 17.8% in the Tarceva arms and 4% in the control arms. The incidence of ocular disorders in the pancreatic cancer study was 12.8% in the Tarceva plus gemcitabine arm and 11.4% in the control arm.
  • Interrupt or discontinue Tarceva therapy if patients present with acute or worsening ocular disorders such as eye pain.
• Hemorrhage in Patients Taking Warfarin:
  • Severe and fatal hemorrhage associated with International Normalized Ratio (INR) elevations can occur when Tarceva and warfarin are administered concurrently.
  • Regularly monitor prothrombin time and INR during Tarceva treatment in patients taking warfarin or other coumarin-derivative anticoagulants.
• Embryo-Fetal Toxicity:
  • Based on animal data and its mechanism of action, Tarceva can cause fetal harm when administered to a pregnant woman. 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 Tarceva.

MOST COMMON ADVERSE REACTIONS

• Metastatic NSCLC – First-Line Treatment of Patients With EGFR Mutations:
  • Most frequent (≥30%) adverse reactions were diarrhea, asthenia, rash, cough, dyspnea, and decreased appetite.
  • Most frequent Grade 3/4 (NCI-CTC Version 3.0) adverse reactions were rash (14%) and diarrhea (5%). In Tarceva-treated patients, the most frequently reported adverse reactions leading to dose modification were rash (13%), diarrhea (10%), and asthenia (3.6%).
• Metastatic NSCLC – Maintenance Treatment:
  • Rash and diarrhea.
  • Grade 3/4 (NCI-CTC Version 3.0) rash and diarrhea occurred in 9% and 2%, respectively. Rash and diarrhea resulted in dose reductions or interruption (5% and 3%, respectively) and discontinuation (1% and 0.5%, respectively) of Tarceva-treated patients.
• Metastatic NSCLC – Second/Third-line Treatment:
  • Rash and diarrhea.
  • Grade 3/4 (NCI-CTC Version 2.0) rash and diarrhea occurred in 9% and 6%, respectively. Rash and diarrhea each resulted in dose reductions (6% and 1%, respectively) and discontinuation in 1% of Tarceva-treated patients.
• Advanced Pancreatic Cancer – Tarceva Administered Concurrently with Gemcitabine:
  • Fatigue, rash, nausea, anorexia, and diarrhea.
  • Grade 3/4 (NCI-CTC version 2.0) rash and diarrhea were each reported in 5% of patients. Rash and diarrhea each resulted in dose reductions in 2% of patients and discontinuation in up to 1% of patients receiving Tarceva plus gemcitabine.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.

For additional Important Safety Information, please see full Prescribing Information at www.tarceva.com.