Pulmonary Toxicity

There have been infrequent reports of serious Interstitial Lung Disease (ILD)-like events, including fatalities, in patients receiving TARCEVA for treatment of NSCLC, pancreatic cancer or other advanced solid tumors. In the randomized single-agent NSCLC study (see Clinical Studies section), the incidence of ILD-like events (0.8%) was the same in both the placebo and TARCEVA groups. In the pancreatic cancer study - in combination with gemcitabine - (see Clinical Studies section), the incidence of ILD-like events was 2.5% in the TARCEVA plus gemcitabine group vs. 0.4% in the placebo plus gemcitabine group.

The overall incidence of ILD-like events in approximately 4900 TARCEVA-treated patients from all studies (including uncontrolled studies and studies with concurrent chemotherapy) was approximately 0.7%. Reported diagnoses in patients suspected of having ILD-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, 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. In the lung cancer trials most of the cases were associated with confounding or contributing factors such as concomitant/prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, or pulmonary infections.

In the event of an acute onset of new or progressive, unexplained pulmonary symptoms such as dyspnea, cough, and fever, TARCEVA therapy should be interrupted pending diagnostic evaluation. If ILD is diagnosed, TARCEVA should be discontinued and appropriate treatment instituted as needed (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION - Dose Modifications sections).

Myocardial infarction/ischemia

In the pancreatic carcinoma trial, six patients (incidence of 2.3%) in the TARCEVA/gemcitabine group developed myocardial infarction/ischemia. One of these patients died due to myocardial infarction. In comparison, 3 patients in the placebo/gemcitabine group developed myocardial infarction (incidence 1.2%) and one died due to myocardial infarction.

Cerebrovascular accident

In the pancreatic carcinoma trial, six patients in the TARCEVA/gemcitabine group developed cerebrovascular accidents (incidence: 2.3%) One of these was hemorrhagic and was the only fatal event. In comparison, in the placebo/gemcitabine group there were no cerebrovascular accidents.

Microangiopathic Hemolytic Anemia with Thrombocytopenia

In the pancreatic carcinoma trial, two patients in the TARCEVA/gemcitabine group developed microangiopathic hemolytic anemia with thrombocytopenia (incidence: 0.8%). Both patients received TARCEVA and gemcitabine concurrently. In comparison, in the placebo/gemcitabine group there were no cases of microangiopathic hemolytic anemia with thrombocytopenia.

Pregnancy Category D

Erlotinib has been shown to cause maternal toxicity with associated embryo/fetal lethality and abortion in rabbits when given at doses that result in plasma drug concentrations of approximately 3 times those in humans (AUCs at 150 mg daily dose). When given during the period of organogenesis to achieve plasma drug concentrations approximately equal to those in humans, based on AUC, there was no increased incidence of embryo/fetal lethality or abortion in rabbits or rats. However, female rats treated with 30 mg/m²/day or 60 mg/m²/day (0.3 or 0.7 times the clinical dose, on a mg/m² basis) of erlotinib prior to mating through the first week of pregnancy had an increase in early resorptions that resulted in a decrease in the number of live fetuses.

There are no adequate and well-controlled studies in pregnant women using TARCEVA. Women of childbearing potential should be advised to avoid pregnancy while on TARCEVA. Adequate contraceptive methods should be used during therapy, and for at least 2 weeks after completing therapy. Treatment should only be continued in pregnant women if the potential benefit to the mother outweighs the risk to the fetus. If TARCEVA is used during pregnancy, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy.

Renal Failure

Cases of acute renal failure or renal insufficiency (including fatalities) with or without hypokalemia have been reported. Some were secondary to severe dehydration due to diarrhea, vomiting, and/or anorexia while others were confounded by concurrent chemotherapy use. In the event of dehydration, particularly in patients with contributing risk factors for renal failure (eg, preexisting 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 (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION - Dose Modifications sections).

Hepatotoxicity

Asymptomatic increases in liver transaminases have been observed in TARCEVA treated patients; therefore, periodic liver function testing (transaminases, bilirubin, and alkaline phosphatase) should be considered. Dose reduction or interruption of TARCEVA should be considered if changes in liver function are severe (see ADVERSE REACTIONS section).

Patients with Hepatic Impairment

In vitro and in vivo evidence suggest that erlotinib is cleared primarily by the liver. Therefore, erlotinib exposure may be increased in patients with hepatic dysfunction (see CLINICAL PHARMACOLOGY - Special Populations - Patients with Hepatic Impairment and DOSAGE AND ADMINISTRATION - Dose Modificationsections).

Elevated International Normalized Ratio and Potential Bleeding

International Normalized Ratio (INR) elevations and infrequent reports of bleeding events including gastrointestinal and non-gastrointestinal bleedings 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 (see ADVERSE REACTIONS section).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Erlotinib has not been tested for carcinogenicity.

Erlotinib has been tested for genotoxicity in a series of in vitro assays (bacterial mutation, human lymphocyte chromosome aberration, and mammalian cell mutation) and an in vivo mouse bone marrow micronucleus test and did not cause genetic damage. Erlotinib did not impair fertility in either male or female rats.

Pregnancy

Pregnancy Category D (see WARNINGS and PRECAUTIONS - INFORMATION FOR PATIENTS sections).

Nursing Mothers

It is not known whether erlotinib is excreted in human milk. Because many drugs are excreted in human milk and because the effects of TARCEVA on infants have not been studied, women should be advised against breast-feeding while receiving TARCEVA therapy.

Pediatric Use

The safety and effectiveness of TARCEVA in pediatric patients have not been studied.

Geriatric Use

Of the total number of patients participating in the randomized NSCLC trial, 62% were less than 65 years of age, and 38% of patients were aged 65 years or older. The survival benefit was maintained across both age groups (see Clinical Studies section). In the pancreatic cancer study, 53% of patients were younger than 65 years of age and 47% were 65 years of age or older. No meaningful differences in safety or pharmacokinetics were observed between younger and older patients in either study. Therefore, no dosage adjustments are recommended in elderly patients.

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