TARCEVA SIDE EFFECTS
SIDE EFFECTS
The following serious adverse reactions, which may include fatalities, are discussed in greater detail in other sections of the labeling:
- Interstitial Lung Disease (ILD).
- Renal Failure.
- Hepatotoxicity with or without Hepatic Impairment.
- Gastrointestinal Perforation.
- Bullous and Exfoliative Skin Disorders.
- Cerebrovascular Accident.
- Microangiopathic Hemolytic Anemia with Thrombocytopenia.
- Ocular Disorders.
- Hemorrhage in Patients Taking Warfarin.
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%).
Common adverse reactions in Study 1, occurring in at least 10% of patients who received TARCEVA or chemotherapy and an increase in ≥ 5% in the TARCEVA-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 TARCEVA treatment was 9.6 months in Study 1.
Table 1: Adverse Reactions with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the TARCEVA-Treated Group (Study 1)
| Adverse Reaction | TARCEVA N = 84 |
Chemotherapy† N = 83 |
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| 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 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. |
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Hepatic Toxicity: One TARCEVA-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4 liver test abnormalities in Study 1.
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-CTCAE v3.0 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: 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)
| Adverse Reaction | TARCEVA N = 433 |
PLACEBO N = 445 |
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| Any Grade % | Grade 3 % | Grade 4 % | Any Grade % | Grade 3 % | Grade 4 % | |
| Rash † | 60 | 9 | 0 | 9 | 0 | 0 |
| Diarrhea | 20 | 2 | 0 | 4 | 0 | 0 |
| † 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. | ||||||
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.
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 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 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: 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 4)
| Adverse Reaction | TARCEVA 150 mg N=485 |
Placebo N=242 |
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| Any Grade % | Grade 3 % | Grade 4 % | Any Grade % | Grade 3 % | Grade 4 % | |
| 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 erythrodysesthesia syndrome, acne, skin disorder, pigmentation disorder, erythema, skin ulcer, exfoliative dermatitis, papular rash, 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 upper limit of normal (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.
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 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 TARCEVA 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 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.
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 TARCEVA-Treated Pancreatic Cancer Patients: 100 mg Cohort (Study 5)
| Adverse Reaction | TARCEVA + Gemcitabine 1000 mg/m² IV N=259 |
Placebo + Gemcitabine 1000 mg/m² IV N=256 |
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| Any Grade% | Grade 3% | Grade 4% | Any Grade% | Grade 3% | Grade 4% | |
| 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 |
| * 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 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. |
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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 5 are provided in Table 5.
Table 5: Liver Test Abnormalities in Pancreatic Cancer Patients: 100 mg Cohort (Study 5)
| TARCEVA + Gemcitabine 1000 mg/m² IV N=259 |
Placebo + Gemcitabine 1000 mg/m² IV N=256 |
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| 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. 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.
SRC: NLM .