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Tarceva

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Tarceva

SIDE EFFECTS

The following serious adverse reactions, which may include fatalities, are discussed in greater detail in other sections of the labeling:

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Safety evaluation of TARCEVA is based on more than 1200 cancer patients who received TARCEVA as monotherapy, more than 300 patients who received TARCEVA 100 or 150 mg plus gemcitabine, and 1228 patients who received TARCEVA concurrently with other chemotherapies. The most common adverse reactions with TARCEVA are rash and diarrhea usually with onset during the first month of treatment. The incidences of rash and diarrhea from clinical studies of TARCEVA for the treatment of NSCLC and pancreatic cancer were 70% for rash and 42% for diarrhea.

Non-Small Cell Lung Cancer

First-Line Treatment of Patients with EGFR Mutations

The most frequent ( ≥ 30%) adverse reactions in TARCEVA-treated patients were diarrhea, asthenia, rash, cough, dyspnea and decreased appetite. In TARCEVA-treated patients the median time to onset of rash was 15 days and the median time to onset of diarrhea was 32 days.

The most frequent Grade 3-4 adverse reactions in TARCEVA-treated patients were rash and diarrhea.

Dose interruptions or reductions due to adverse reactions occurred in 37% of TARCEVA-treated patients, and 14.3% of TARCEVA-treated patients discontinued therapy due to adverse reactions. In TARCEVA-treated patients, the most frequently reported adverse reactions leading to dose modification were rash (13%), diarrhea (10%), and asthenia (3.6%).

Selected, common adverse reactions in Study 4, occurring in at least 10% of patients who received TARCEVA or chemotherapy and an increase in ≥ 5% in the TARCEVA treated group, are summarized by NCI-CTC (version 3.0) Grade in Table 1. The median duration of TARCEVA treatment was 9.6 months in Study 4.

Table 1: Selected Adverse Reactions with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the TARCEVA-treated Group (Study 4)

MedDRA Preferred Term  TARCEVA
N = 84 
Chemotherapy †
N = 83 
All Grades %  Grades 3-4 %  All Grades %  Grades 3-4 % 
  Rash ‡  85 14 5 0
  Diarrhea  62 5 21 1
  Cough  48 1 40 0
  Dyspnea  45 8 30 4
  Dry skin  21 1 2 0
  Back pain  19 2 5 0
  Chest pain  18 1 12 0
  Conjunctivitis  18 0 0 0
  Mucosal inflammation  18 1 6 0
  Pruritus  16 0 1 0
  Paronychia  14 0 0 0
  Arthralgia  13 1 6 1
  Musculoskeletal pain  11 1 1 0
† Platinum based doublet chemotherapy (cisplatin or carboplatin with gemcitabine or docetaxel)
‡ Rash as a composite term includes: rash, acne, folliculitis, erythema, dermatitis acneiform, dermatitis, palmar-plantar erythrodysaesthesia syndrome, exfoliative rash, rash erythematous, rash pruritic, skin toxicity, eczema, rash follicular, skin ulcer.

Hepatic Toxicity: One TARCEVA-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4 liver test abnormalities in Study 4 [see WARNINGS AND PRECAUTIONS].

Maintenance Treatment

Adverse reactions, regardless of causality, that occurred in at least 3% of patients treated with single-agent TARCEVA at 150 mg and at least 3% more often than in the placebo group in the randomized maintenance trial (Study 3) are summarized by NCI-CTC (version 3.0) Grade in Table 2.

The most common adverse reactions in patients receiving single-agent TARCEVA 150 mg were rash and diarrhea. Grade 3-4 rash and diarrhea occurred in 9% and 2%, respectively, in TARCEVA-treated patients. Rash and diarrhea resulted in study discontinuation in 1% and 0.5% of TARCEVA-treated patients, respectively. Dose reduction or interruption for rash and diarrhea was needed in 5% and 3% of patients, respectively. In TARCEVA-treated patients the median time to onset of rash was 10 days, and the median time to onset of diarrhea was 15 days.

Table 2: NSCLC Maintenance Study: Selected Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Single-Agent TARCEVA Group compared to the Placebo Group (Study 3)

NCI-CTC Grade  TARCEVA
N = 433 
PLACEBO
N = 445 
Any Grade  Grade 3  Grade 4  Any Grade  Grade 3  Grade 4 
MedDRA Preferred Term 
Rash †  60 9 0 9 0 0
Diarrhea  20 2 0 4 0 0
† Rash as a composite term includes: rash, acne, dermatitis acneiform, skin fissures, erythema, rash papular, rash generalized, rash pruritic, skin exfoliation, urticaria, dermatitis, eczema, exfoliative rash, dermatitis exfoliative, furuncle, rash macular, rash pustular, skin hyperpigmentation, skin reaction, skin ulcer.

Liver test abnormalities including ALT elevations were observed at Grade 2 or greater severity in 3% of TARCEVA-treated patients and 1% of placebo-treated patients. Grade 2 and above bilirubin elevations were observed in 5% of TARCEVA-treated patients and in < 1% in the placebo group [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Second/Third Line Treatment

Adverse reactions, regardless of causality, that occurred in at least 10% of patients treated with single-agent TARCEVA at 150 mg and at least 5% more often than in the placebo group in the randomized trial of patients with NSCLC are summarized by NCI-CTC (version 2.0) Grade in Table 3.

The most common adverse reactions in this patient population were rash and diarrhea. Grade 3-4 rash and diarrhea occurred in 9% and 6%, respectively, in TARCEVA-treated patients. Rash and diarrhea each resulted in study discontinuation in 1% of TARCEVA-treated patients. Six percent and 1% of patients needed dose reduction for rash and diarrhea, respectively. The median time to onset of rash was 8 days, and the median time to onset of diarrhea was 12 days.

Table 3: NSCLC 2nd/3rd Line Study: Selected Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Single-Agent TARCEVA Group compared to the Placebo Group (Study 1)

NCI-CTC Grade  TARCEVA 150 mg
N=485 
Placebo
N=242 
Any Grade  Grade 3  Grade 4  Any Grade  Grade 3  Grade 4 
MedDRA Preferred Term 
Rash †  75 8 < 1  17 0 0
Diarrhea  54 6 < 1  18 < 1  0
Anorexia  52 8 1 38 5 < 1 
Fatigue  52 14 4 45 16 4
Dyspnea  41 17 11 35 15 11
Nausea  33 3 0 24 2 0
Infection  24 4 0 15 2 0
Stomatitis  17 < 1  0 3 0 0
Pruritus  13 < 1  0 5 0 0
Dry skin  12 0 0 4 0 0
Conjunctivitis  12 < 1  0 2 < 1  0
Keratoconjunctivitis sicca  12 0 0 3 0 0
† Rash as a composite term includes: rash, palmar-plantar erythrodysaesthesia syndrome, acne, skin disorder, pigmentation disorder, erythema, skin ulcer, dermatitis exfoliative, rash papular, skin desquamation.

Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) were observed in patients receiving single-agent TARCEVA 150 mg. These elevations were mainly transient or associated with liver metastases. Grade 2 ( > 2.5 – 5.0 x ULN) ALT elevations occurred in 4% and < 1% of TARCEVA and placebo treated patients, respectively. Grade 3 ( > 5.0 – 20.0 x ULN) elevations were not observed in TARCEVA-treated patients. TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe [see DOSAGE AND ADMINISTRATION].

Pancreatic Cancer -TARCEVA Administered Concurrently with Gemcitabine

This was a randomized, double blind placebo-controlled study of TARCEVA (150 mg or 100 mg daily) or placebo plus gemcitabine (1000 mg/m² IV) in patients with locally advanced, unresectable or metastatic pancreatic cancer (Study 2). The safety population comprised 282 patients in the erlotinib group (259 in the 100 mg cohort and 23 in the 150 mg cohort) and 280 patients in the placebo group (256 in the 100 mg cohort and 24 in the 150 mg cohort).

Adverse reactions that occurred in at least 10% of patients treated with TARCEVA 100 mg plus gemcitabine in the randomized trial of patients with pancreatic cancer (Study 2) are summarized by NCI-CTC (version 2.0) Grade in Table 4.

The most common adverse reactions in pancreatic cancer patients receiving TARCEVA 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. In the TARCEVA plus gemcitabine arm, Grade 3-4 rash and diarrhea were each reported in 5% of patients. The median time to onset of rash and diarrhea was 10 days and 15 days, respectively. Rash and diarrhea each resulted in dose reductions in 2% of patients, and resulted in study discontinuation in up to 1% of patients receiving TARCEVA plus gemcitabine. Severe adverse reactions ( ≥ Grade 3 NCI-CTC) in the TARCEVA plus gemcitabine group with incidences < 5% included syncope, arrhythmias, ileus, pancreatitis, hemolytic anemia including microangiopathic hemolytic anemia with thrombocytopenia, myocardial infarction/ischemia, cerebrovascular accidents including cerebral hemorrhage, and renal insufficiency [see WARNINGS AND PRECAUTIONS].

The 150 mg cohort was associated with a higher rate of certain class-specific adverse reactions including rash and required more frequent dose reduction or interruption.

Table 4: Selected Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in TARCEVA-treated Pancreatic Cancer Patients: 100 mg cohort (Study 2)

NCI-CTC Grade  TARCEVA + Gemcitabine 1000 mg/m² IV
N=259 
Placebo + Gemcitabine 1000 mg/m² IV
N=256 
Any Grade  Grade 3  Grade 4  Any Grade  Grade 3  Grade 4 
MedDRA Preferred Term 
Rash †  70 5 0 30 1 0
Diarrhea  48 5 < 1  36 2 0
Weight decreased  39 2 0 29 < 1  0
Infection *  39 13 3 30 9 2
Pyrexia  36 3 0 30 4 0
Stomatitis  22 < 1  0 12 0 0
Depression  19 2 0 14 < 1  0
Cough  16 0 0 11 0 0
Headache  15 < 1  0 10 0 0
* Includes all MedDRA preferred terms in the Infections and Infestations System Organ Class
† Rash as a composite term includes: rash, palmar-plantar erythrodysaesthesia syndrome, pigmentation disorder, dermatitis acneiform, folliculitis, photosensitivity reaction, Stevens-Johnson syndrome, urticaria, erythematous rash, skin disorder, skin ulcer.

Ten patients (4%) in the TARCEVA/gemcitabine group and three patients (1%) in the placebo/gemcitabine group developed deep venous thrombosis. The overall incidence of grade 3 or 4 thrombotic events, including deep venous thrombosis was 11% for TARCEVA plus gemcitabine and 9% for placebo plus gemcitabine.

The incidences of liver test abnormalities ( ≥ Grade 2) in Study 2 are provided in Table 5 [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Table 5: Liver Test Abnormalities in Pancreatic Cancer Patients: 100 mg Cohort (Study 2)

NCI-CTC Grade  TARCEVA + Gemcitabine 1000 mg/m² IV
N=259 
Placebo + Gemcitabine 1000 mg/m² IV
N=256 
Grade 2  Grade 3  Grade 4  Grade 2  Grade 3  Grade 4 
Bilirubin  17% 10% < 1%  11% 10% 3%
ALT  31% 13% < 1%  22% 9% 0%
AST  24% 10% < 1%  19% 9% 0%

NSCLC and Pancreatic Indications: Selected Low Frequency Adverse Reactions

Gastrointestinal Disorders

Cases of gastrointestinal bleeding (including fatalities) have been reported, some associated with concomitant warfarin or NSAID administration [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]. These adverse reactions were reported as peptic ulcer bleeding (gastritis, gastroduodenal ulcers), hematemesis, hematochezia, melena and hemorrhage from possible colitis.

Post-Marketing Experience

The following adverse reactions have been identified during post approval use of TARCEVA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis, in combination with statin therapy

Eye Disorders: ocular inflammation including uveitis

Read the Tarceva (erlotinib) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

CYP3A4 Inhibitors

Erlotinib is metabolized predominantly by CYP3A4. Co-treatment with the potent CYP3A4 inhibitor ketoconazole increased erlotinib AUC by 67%. When TARCEVA was co-administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2, the erlotinib exposure [AUC] and maximum concentration [Cmax] increased by 39% and 17%, respectively. Dose modifications are recommended [see DOSAGE AND ADMINISTRATION].

CYP3A4 Inducers

Pre-treatment with the CYP3A4 inducer rifampicin for 7-11 days prior to TARCEVA decreased erlotinib AUC by 58% to 80%. Dose modifications are recommended [see DOSAGE AND ADMINISTRATION].

Drugs Affecting Gastric pH

Co-administration of TARCEVA with omeprazole decreased erlotinib AUC by 46% and co-administration of TARCEVA with ranitidine 300 mg decreased erlotinib AUC by 33%. When TARCEVA was administered with ranitidine 150 mg twice daily (at least 10 h after the previous ranitidine evening dose and 2 h before the ranitidine morning dose), erlotinib AUC decreased by 15%. Increasing the dose of TARCEVA when co-administered with such agents is not likely to compensate for the loss of exposure. Scheduling modifications are recommended [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Cigarette Smoking

Cigarette smoking results in reductions in erlotinib AUC. Dose modifications are recommended [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Anticoagulants

Interaction with coumarin-derived anticoagulants, including warfarin, leading to increased International Normalized Ratio (INR) and bleeding adverse reactions, which in some cases were fatal, have been reported in patients receiving TARCEVA. Regularly monitor prothrombin time or INR in patients taking coumarin-derived anticoagulants. Dose modifications of TARCEVA are not recommended [see WARNINGS AND PRECAUTIONSand ADVERSE REACTIONS].

Read the Tarceva Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 4/28/2014
This monograph has been modified to include the generic and brand name in many instances.

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