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Tarceva

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Tarceva

Tarceva

WARNINGS

Included as part of the PRECAUTIONS section.

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 [see DOSAGE AND ADMINISTRATION].

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 [see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION].

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. 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. 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 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.

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 levels greater than 3 times the upper limit of normal or transaminases greater than 5 times the upper limit of normal. 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 three weeks [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

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 [see ADVERSE REACTIONS]. 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 [see DOSAGE AND ADMINISTRATION].

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 [see ADVERSE REACTIONS]. 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 [see DOSAGE AND ADMINISTRATION].

Myocardial Infarction/Ischemia

In the pancreatic carcinoma trial, six patients (incidence of 2.1%) 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 1.1%), and one died due to myocardial infarction. The pooled incidence of myocardial infarction/ischemia in the 3 monotherapy lung cancer studies was 0.2% in the TARCEVA arms and 0.4% in the control arms.

Cerebrovascular Accident

In the pancreatic carcinoma trial, seven patients in the TARCEVA/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 TARCEVA arms and 0.9% 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

Corneal perforation or ulceration can occur with TARCEVA treatment. 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 [see ADVERSE REACTIONS]. 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/worsening ocular disorders such as eye pain [see DOSAGE AND ADMINISTRATION].

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 [see ADVERSE REACTIONS and DRUG INTERACTIONS].

Embryo-Fetal Toxicity

Based on its mechanism of action, TARCEVA 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 doses approximately 3 times the recommended human daily dose of 150 mg. If TARCEVA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use In Specific Populations].

Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 2 weeks after the last dose of TARCEVA. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TARCEVA [see Use in Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies were conducted in mice and rats with erlotinib at oral doses of up to 60 mg/kg/day in mice, 5 mg/kg/day in female rats, and 10 mg/kg/day in male rats. The studies were negative for carcinogenic findings. Exposure in mice at the highest dose tested was approximately 10 times the exposure in humans at the erlotinib dose of 150 mg/day. The highest dose evaluated in male rats resulted in exposures that were twice those in humans and exposures at the highest tested dose in female rats were slightly lower than those in humans.

Erlotinib did not cause genetic damage in a series of in vitro assays (bacterial mutation, human lymphocyte chromosome aberration and mammalian cell mutation) and in the in vivo mouse bone marrow micronucleus test.

Erlotinib did not impair fertility in either male or female rats.

Use In Specific Populations

Pregnancy

Pregnancy Category D - Risk Summary

Based on its mechanism of action, TARCEVA 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 doses approximately 3 times the recommended human daily dose of 150 mg. If TARCEVA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see WARNINGS AND PRECAUTIONS].

Animal Data

Erlotinib has been shown to cause maternal toxicity resulting in embryo-fetal lethality and abortion in rabbits when given during the period of organogenesis at doses that result in plasma drug concentrations approximately 3 times those achieved at the recommended dose in humans (AUCs at 150 mg daily dose). During the same period, there was no increase in the incidence of embryo-fetal lethality or abortion in rabbits or rats at doses resulting in exposures approximately equal to those in humans at the recommended daily dose. In an independent fertility study female rats treated with 30 mg/m² /day or 60 mg/m² /day (0.3 or 0.7 times the recommended daily dose, on a mg/m² basis) of erlotinib 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 recommended dose of 150 mg/day on a mg/m² basis).

Nursing Mothers

It is not known whether erlotinib is present in human milk. Because many drugs are present 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 1297 subjects in clinical studies of TARCEVA for the treatment of NSCLC and pancreatic cancer 40% were 65 and older while 10% were 75 and older. No overall differences in safety or efficacy were observed between subjects 65 years and older and those younger than 65.

Females and Males of Reproductive Potential

Contraception

Females

Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive potential to use highly effective contraception during treatment with TARCEVA, and for at least 2 weeks after the last dose of TARCEVA. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TARCEVA [see Use in Specific Populations]

Patients with Hepatic Impairment

Patients with hepatic impairment (total bilirubin > upper limit of normal (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 AND PRECAUTIONS, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION].

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 and CLINICAL PHARMACOLOGY].

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.

Last reviewed on RxList: 5/23/2013
This monograph has been modified to include the generic and brand name in many instances.

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