Erlotinib (Page 3 of 8)

6. ADVERSE REACTIONS

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

6.1 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 erlotinib tablets is based on more than 1200 cancer patients who received erlotinib tablets as monotherapy, more than 300 patients who received erlotinib tablets 100 or 150 mg plus gemcitabine, and 1228 patients who received erlotinib tablets concurrently with other chemotherapies. The most common adverse reactions with erlotinib tablets are rash and diarrhea usually with onset during the first month of treatment. The incidences of rash and diarrhea from clinical studies of erlotinib tablets 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 erlotinib tablets-treated patients were diarrhea, asthenia, rash, cough, dyspnea, and decreased appetite. In erlotinib tablets-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 erlotinib tablets-treated patients were rash and diarrhea.

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

Common adverse reactions in Study 1, occurring in at least 10% of patients who received erlotinib tablets or chemotherapy and an increase in ≥ 5% in the erlotinib tablets-treated group, are graded by National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0 (NCI-CTCAE v3.0) Grade in Table 1. The median duration of erlotinib tablets treatment was 9.6 months in Study 1.

Table 1: Adverse Reactions with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Erlotinib Tablets Treated Group (Study 1)
Erlotinib TabletsN = 84 Chemotherapy *N = 83
Adverse Reaction All Grades% Grades 3-4% All Grades% Grades 3-4%
*
Platinum based chemotherapy (cisplatin or carboplatin with gemcitabine or docetaxel).
Rash as a composite term includes rash, acne, folliculitis, erythema, acneiform dermatitis, dermatitis, palmar-plantar erythrodysesthesia syndrome, exfoliative rash, erythematous rash, rash pruritic, skin toxicity, eczema, follicular rash, skin ulcer.
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

Hepatic Toxicity: One erlotinib tablets-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4 liver test abnormalities in Study 1 [see Warnings and Precautions (5.3)].

Maintenance Treatment

Adverse reactions, regardless of causality, that occurred in at least 3% of patients treated with single-agent erlotinib tablets 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-CTCAE v3.0 Grade in Table 2.

The most common adverse reactions in patients receiving single-agent erlotinib tablets 150 mg were rash and diarrhea. Grade 3-4 rash and diarrhea occurred in 9% and 2%, respectively, in erlotinib tablets-treated patients. Rash and diarrhea resulted in study discontinuation in 1% and 0.5% of erlotinib tablets-treated patients, respectively. Dose reduction or interruption for rash and diarrhea was needed in 5% and 3% of patients, respectively. In erlotinib tablets-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: Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Single-Agent Erlotinib Tablets Group compared to the Placebo Group (Study 3)
Adverse Reaction Erlotinib TabletsN = 433 PLACEBON = 445
Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
% % % % % %
*
Rash as a composite term includes: rash, acne, acneiform dermatitis, skin fissures, erythema, papular rash, rash generalized, pruritic rash, skin exfoliation, urticaria, dermatitis, eczema, exfoliative rash, exfoliative dermatitis, furuncle, macular rash, pustular rash, skin hyperpigmentation, skin reaction, skin ulcer
Rash * 60 9 0 9 0 0
Diarrhea 20 2 0 4 0 0

Liver test abnormalities including ALT elevations were observed at Grade 2 or greater severity in 3% of erlotinib tablets-treated patients and 1% of placebo-treated patients. Grade 2 and above bilirubin elevations were observed in 5% of erlotinib tablets-treated patients and in < 1% in the placebo group [see Dosage and Administration (2.4) and Warnings and Precautions (5.3)].

Second/Third Line Treatment

Adverse reactions, regardless of causality, that occurred in at least 10% of patients treated with single-agent erlotinib tablets 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 v2.0 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 erlotinib tablets-treated patients. Rash and diarrhea each resulted in study discontinuation in 1% of erlotinib tablets-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: Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Single-Agent Erlotinib Tablets Group Compared to the Placebo Group (Study 4)
Adverse Reaction Erlotinib Tablets150 mgN=485 PlaceboN=242
Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
% % % % % %
*
Rash as a composite term includes: rash, palmar-plantar erythrodysesthesia syndrome, acne, skin disorder, pigmentation disorder, erythema, skin ulcer, exfoliative dermatitis, papular rash, skin desquamation.
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

Liver function test abnormalities [including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin] were observed in patients receiving single-agent erlotinib tablets 150 mg. These elevations were mainly transient or associated with liver metastases. Grade 2 [> 2.5 – 5.0 × upper limit of normal (ULN)] ALT elevations occurred in 4% and < 1% of erlotinib tablets and placebo treated patients, respectively. Grade 3 (> 5.0 – 20.0 × ULN) elevations were not observed in erlotinib tablets-treated patients. Erlotinib tablets dosing should be interrupted or discontinued if changes in liver function are severe [see Dosage and Administration (2.4)].

Pancreatic Cancer — Erlotinib Tablets Administered Concurrently with Gemcitabine

This was a randomized, double-blind placebo-controlled study of erlotinib tablets (150 mg or 100 mg daily) or placebo plus gemcitabine (1000 mg/m 2 by intravenous infusion) in patients with locally advanced, unresectable or metastatic pancreatic cancer (Study 5). 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 erlotinib tablets 100 mg plus gemcitabine in the randomized trial of patients with pancreatic cancer (Study 5) were graded according to NCI-CTC v2.0 in Table 4.

The most common adverse reactions in pancreatic cancer patients receiving erlotinib tablets 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. In the erlotinib tablets 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 erlotinib tablets plus gemcitabine. Severe adverse reactions (≥ Grade 3 NCI-CTC) in the erlotinib tablets 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 (5)].

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: Adverse Reactions Occurring with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in Erlotinib Tablets -Treated Pancreatic Cancer Patients: 100 mg Cohort (Study 5)
Adverse Reaction Erlotinib Tablets + Gemcitabine1000 mg/m2 IVN=259 Placebo + Gemcitabine1000 mg/m2 IVN=256
Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
% % % % % %
*
Rash as a composite term includes: rash, palmar-plantar erythrodysesthesia syndrome, pigmentation disorder, acneiform dermatitis, folliculitis, photosensitivity reaction, Stevens-Johnson syndrome, urticaria, erythematous rash, skin disorder, skin ulcer.
Infections as a composite term include infections with unspecified pathogens as well as bacterial (including chlamydial, rickettsial, mycobacterial and mycoplasmal), parasitic (including helminthic, ectoparasitic and protozoal), viral and fungal infectious disorders.
Rash * 70 5 0 30 1 0
Diarrhea 48 5 <1 36 2 0
Decreased weight 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

Ten patients (4%) in the erlotinib tablets/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 erlotinib tablets plus gemcitabine and 9% for placebo plus gemcitabine.

The incidences of liver test abnormalities (≥ Grade 2) in Study 5 are provided in Table 5 [see Dosage and Administration (2.4) and Warnings and Precautions (5.3)].

Table 5: Liver Test Abnormalities in Pancreatic Cancer Patients: 100 mg Cohort (Study 5)
Erlotinib Tablets + Gemcitabine1000 mg/m2 IVN=259 Placebo + Gemcitabine1000 mg/m2 IVN=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 (5.9) and Drug Interactions (7)]. These adverse reactions were reported as peptic ulcer bleeding (gastritis, gastroduodenal ulcers), hematemesis, hematochezia, melena and hemorrhage from possible colitis.

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