Advanced Pancreatic Cancer Indication

Tarceva in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer

Important Safety Information

There have been reports of serious Interstitial Lung Disease (ILD)-like events, including fatalities, in patients receiving Tarceva. In the pancreatic cancer study, the incidence was 2.5% in the Tarceva/gemcitabine group vs. 0.4% in the placebo/gemcitabine group. The overall incidence of ILD-like events in approximately 32,000 Tarceva-treated patients from all studies (including uncontrolled studies and studies with concurrent chemotherapy) was approximately 1.1%.

Reported diagnoses in patients suspected of having ILD-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, ILD, obliterative bronchiolitis, pulmonary fibrosis, Acute Respiratory Distress Syndrome and lung infiltration. Symptoms started from 5 days to more than 9 months (median 39 days) after initiating Tarceva therapy.

Tarceva should be interrupted for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever. If ILD is diagnosed, Tarceva should be discontinued and appropriate treatment instituted as needed.

Cases of hepatorenal syndrome, acute renal failure (including fatalities), and renal insufficiency have been reported. Some were secondary to baseline hepatic impairment while others were associated with severe dehydration due to diarrhea, vomiting, and/or anorexia or concurrent chemotherapy use. In the event of dehydration, particularly in patients with contributing risk factors for renal failure (eg, pre-existing renal disease, medical conditions or medications that may lead to renal disease, or other predisposing conditions including advanced age), Tarceva therapy should be interrupted and appropriate measures should be taken to intensively rehydrate the patient. Periodic monitoring of renal function and serum electrolytes is recommended in patients at risk of dehydration.

Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been reported during use of Tarceva, particularly in patients with baseline hepatic impairment. Therefore, periodic liver function testing (transaminases, bilirubin, and alkaline phosphatase) is recommended. In the setting of worsening liver function tests, dose interruption and/or dose reduction with frequent liver function test monitoring should be considered. Tarceva dosing should be interrupted or discontinued if total bilirubin is >3 x ULN and/or transaminases are >5 x ULN in the setting of normal pretreatment values.

Treatment with Tarceva should be used with extra caution in patients with total bilirubin > 3 x ULN. Patients with hepatic impairment (total bilirubin > ULN or Child-Pugh A, B and C) should be closely monitored during therapy with Tarceva. Tarceva dosing should be interrupted or discontinued if changes in liver function are severe such as doubling of total bilirubin and/or tripling of transaminases in the setting of pretreatment values outside normal range.

Gastrointestinal perforation (including fatalities) has been reported in patients receiving Tarceva. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease are at increased risk. Permanently discontinue Tarceva in patients who develop gastrointestinal perforation.

Bullous, blistering and exfoliative skin conditions have been reported including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, which in some cases were fatal. Interrupt or discontinue Tarceva treatment if the patient develops severe bullous, blistering or exfoliating conditions.

In the pancreatic cancer trial, myocardial infarction/ischemia occurred in 2.3% of patients (6 patients) in the Tarceva/gemcitabine group vs. 1.2% (3 patients) in the placebo/gemcitabine group. One patient in the Tarceva/gemcitabine group and one patient in the placebo/gemcitabine group died due to myocardial infarction.

In the pancreatic cancer trial, 2.3% of patients (6 patients) in the Tarceva /gemcitabine group developed cerebrovascular accidents vs. no cerebrovascular accidents in the placebo/gemcitabine group. One of the cerebrovascular accidents was hemorrhagic and fatal.

In the pancreatic cancer trial, 0.8% of patients (2 patients) developed microangiopathic hemolytic anemia with thrombocytopenia in the Tarceva /gemcitabine group vs. no cases in the placebo/gemcitabine group.

Corneal perforation and ulceration have been reported during use of Tarceva. Other ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis have been observed with Tarceva treatment and are known risk factors for corneal ulceration/perforation. Interrupt or discontinue Tarceva therapy if patients present with acute/worsening ocular disorders such as eye pain.

International Normalized Ratio (INR) elevation and infrequent reports of bleeding events, including gastrointestinal and non-gastrointestinal bleeding, have been reported in clinical studies, some associated with concomitant warfarin administration. Patients taking warfarin or other coumarin-derivative anticoagulants should be monitored regularly for changes in prothrombin time or INR. Some infrequent cases of gastrointestinal bleeding were also associated with concomitant NSAID administration.

Tarceva is pregnancy category D. When receiving Tarceva, women of childbearing potential should be advised to avoid pregnancy and pregnant women apprised of the potential hazard to a fetus. Adequate contraception methods should be used during therapy, and for at least 2 weeks after completing therapy. Because of the potential for serious adverse reactions in nursing infants from Tarceva, a decision should be made whether to discontinue nursing or discontinue the drug.

Erlotinib is metabolized predominantly by CYP3A4, and inhibitors of CYP3A4 would be expected to increase exposure. Caution should be used during co- treatment with Tarceva and ketoconazole or other strong CYP3A4 inhibitors such as, but not limited to: atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO) and voriconazole, and grapefruit or grapefruit juice.

The CYP3A4 inducer rifampicin has been shown to decrease erlotinib AUC, thus, alternate treatments lacking CYP3A4 inducing activity are strongly recommended. In the absence of an alternative treatment, Tarceva dose modification should be considered. If the Tarceva dose is adjusted upward, the dose will need to be reduced immediately to the indicated starting dose upon discontinuation of rifampicin or other CYP3A4 inducers such as, but not limited to: rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital and St. John's Wort.

Drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and reduce its bioavailability. The concomitant use of proton pump inhibitors, such as omeprazole with Tarceva should be avoided if possible. If patients need to be treated with an H2-receptor antagonist such as ranitidine, it should be used in a staggered manner. Although 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.

Patients should be advised to stop smoking while taking Tarceva as cigarette smoking has been shown to reduce erlotinib AUC. However, if patients continue to smoke, a cautious increase in the dose of Tarceva, not to exceed 300 mg, may be considered while monitoring the patient's safety. If the Tarceva dose is adjusted upward, the dose should be reduced immediately to the indicated starting dose upon cessation of smoking.

The most common adverse reactions in patients with pancreatic cancer receiving Tarceva 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. Severe rash and diarrhea (5% and 5% NCI-CTC, Grades 3/4, respectively) were reported. Rash and diarrhea each resulted in dose reductions in 2% of patients, and discontinuation in up to 1% of patients receiving Tarceva/gemcitabine.

• For additional important safety information, please see accompanying full prescribing information.