WARNINGS AND PRECAUTIONS
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 ], 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], 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 Dosage and Administration ].
Patients with Hepatic Impairment
In a pharmacokinetic study in patients with moderate hepatic impairment (Child-Pugh B) associated with significant liver tumor burden, 10 out of 15 patients died on treatment or within 30 days of the last TARCEVA 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 suggesting severe hepatic impairment. 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 [see Clinical Pharmacology and Dosage and Administration].
Hepatotoxicity
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 [see Adverse Reactions and Dosage and Administration (2.3 )].
Renal Failure
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 [see Adverse Reactions and Dosage and Administration].
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.
Use in Pregnancy
Pregnancy Category D
Women of childbearing potential should avoid becoming pregnant while being treated with TARCEVA. Erlotinib administered to rabbits during organogenesis at doses that result in plasma drug concentrations of approximately 3 times those in humans (AUCs at 150 mg daily dose) was associated with embryo/fetal lethality and abortion. When erlotinib was administered to female rats prior to mating and through the first week of pregnancy, at doses 0.3 or 0.7 times the clinical dose of 150 mg, on a mg/m2 basis, there was an increase in early resorptions that resulted in a decrease in the number of live fetuses. [ see Use in Specific Populations (8.1)]
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 ].
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category D [See Warnings and Precautions (5.8) ]
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.
No teratogenic effects were observed in rabbits or rats dosed with erlotinib during organogenesis at doses up to 600 mg/m2/day in the rabbit (3 times the plasma drug concentration seen in humans at 150 mg/day) and up to 60 mg/m2/day in the rat (0.7 times the clinical dose of 150 mg/day on a mg/m2 basis).
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 [see Warnings and Precautions (5.8) ].
Nursing Mothers
It is not known whether erlotinib is excreted in human milk. Because many drugs are excreted in human milk and 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, taking into account the importance of the drug to the mother.
Pediatric Use
The safety and effectiveness of TARCEVA in pediatric patients have not been established.
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 [HR = 0.75 (95% CI: 0.6, 0.9) in patients less than 65 years of age, and HR = 0.79 (95% CI: 0.6, 1.0) in patients who were 65 years or older] .
In the pancreatic cancer study, 53% of patients were younger than 65 years of age and 47% were 65 years of age or older. There were no clinically relevant differences between the age groups [HR = 0.78 (95% CI: 0.6, 1.0) in patients less than 65 years of age, and HR = 0.94 (95% CI: 0.7, 1.2) in patients who were 65 years 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.
Gender
Of the total number of patients participating in the randomized NSCLC trial, 65% were males and 35% females. There were no clinically relevant differences in safety and efficacy based on gender [HR = 0.76 (95% CI: 0.6, 0.9) in males and HR = 0.80 (95% CI: 0.6, 1.1) in females].
In the pancreatic cancer study, 52% of patients were males and 48% females. There were no clinically relevant differences in safety and efficacy based on gender [HR = 0.74 (95% CI: 0.6, 0.9) in males and HR = 1.0 (95% CI: 0.8, 1.3) in females].
Race
In the randomized NSCLC trial, 78% of all patients were Caucasian and 12% were Asian. There were no clinically relevant differences in safety and efficacy based on race [HR = 0.79 (95% CI: 0.6, 1.0) in Caucasians and HR = 0.61 (95% CI: 0.4, 1.0) in Asians].
In the pancreatic cancer study, 88% of all patients were Caucasian and 7% were Asian. There were no clinically relevant differences in safety and efficacy based on race [HR = 0.88 (95% CI: 0.7, 1.1) in Caucasians and HR = 0.61 (95% CI: 0.3, 1.3) in Asians].
Patients with Hepatic Impairment
Patients with hepatic impairment (total bilirubin > ULN or Child Pugh A, B and C) should be closely monitored during therapy with TARCEVA. Treatment with TARCEVA should be used with extra caution in patients with total bilirubin > 3 x ULN [ see Warnings (5.2 ), Adverse Reactions (6.3), and Dosage and Administration (2.3) ].
In vitro and in vivo evidence suggest that erlotinib is cleared primarily by the liver. However, erlotinib exposure was similar in patients with moderately impaired hepatic function (Child-Pugh B) compared with patients with adequate hepatic function including patients with primary liver cancer or hepatic metastases [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ].
Patients with Renal Impairment
Less than 9% of a single dose is excreted in the urine. No clinical studies have been conducted in patients with compromised renal function.
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