ADVERSE REACTIONS
Safety evaluation of TARCEVA is based on 856 cancer patients who received TARCEVA as monotherapy, 308 patients who received TARCEVA 100 or 150 mg plus gemcitabine, and 1228 patients who received TARCEVA concurrently with other chemotherapies.
There have been reports of serious events, including fatalities, in patients receiving TARCEVA for treatment of NSCLC, pancreatic cancer or other advanced solid tumors (see Warnings, Precautions, and DOSAGE AND ADMINISTRATION - Dose Modifications sections).
Non-Small Cell Lung Cancer
Adverse events, regardless of causality, that occurred in at least 10% of patients treated with single-agent TARCEVA at 150 mg and at least 3% 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 5.
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 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 5: Adverse Events Occurring More Frequently (≥ 3%) in the Single Agent TARCEVA Group than in the Placebo Group and in ≥10% of Patients in the TARCEVA Group | TARCEVA 150 mg
N = 485 | Placebo
N = 242 |
| NCI CTC Grade | 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 |
| Cough | 33 | 4 | 0 | 29 | 2 | 0 |
| Nausea | 33 | 3 | 0 | 24 | 2 | 0 |
| Infection | 24 | 4 | 0 | 15 | 2 | 0 |
| Vomiting | 23 | 2 | <1 | 19 | 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 |
| Abdominal pain | 11 | 2 | <1 | 7 | 1 | <1 |
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 if changes in liver function are severe (see DOSAGE AND ADMINISTRATION - Dose Modifications section).
Pancreatic Cancer
Adverse events, regardless of causality, that occurred in at least 10% of patients treated with TARCEVA 100 mg plus gemcitabine in the randomized trial of patients with pancreatic cancer are summarized by NCI-CTC (version 2.0) Grade in Table 6.
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 TARCEVA plus gemcitabine-treated 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. 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 6: Adverse Events Occurring in ≥10% of TARCEVA-treated Pancreatic Cancer Patients: 100 mg cohort | TARCEVA + Gemcitabine
1000 mg/m2 IV
N=259 | Placebo + Gemcitabine
1000 mg/m2 IV
N=256 |
| NCI CTC Grade | Any Grade | Grade 3 | Grade 4 | Any Grade | Grade 3 | Grade 4 |
| MedDRA Preferred Term | % | % | % | % | % | % |
| Fatigue | 73 | 14 | 2 | 70 | 13 | 2 |
| Rash | 69 | 5 | 0 | 30 | 1 | 0 |
| Nausea | 60 | 7 | 0 | 58 | 7 | 0 |
| Anorexia | 52 | 6 | <1 | 52 | 5 | <1 |
| Diarrhea | 48 | 5 | <1 | 36 | 2 | 0 |
| Abdominal pain | 46 | 9 | <1 | 45 | 12 | <1 |
| Vomiting | 42 | 7 | <1 | 41 | 4 | <1 |
| Weight decreased | 39 | 2 | 0 | 29 | <1 | 0 |
| InfectionIncludes all MedDRA preferred terms in the Infections and Infestations System Organ Class | 39 | 13 | 3 | 30 | 9 | 2 |
| Edema | 37 | 3 | <1 | 36 | 2 | <1 |
| Pyrexia | 36 | 3 | 0 | 30 | 4 | 0 |
| Constipation | 31 | 3 | 1 | 34 | 5 | 1 |
| Bone pain | 25 | 4 | <1 | 23 | 2 | 0 |
| Dyspnea | 24 | 5 | <1 | 23 | 5 | 0 |
| Stomatitis | 22 | <1 | 0 | 12 | 0 | 0 |
| Myalgia | 21 | 1 | 0 | 20 | <1 | 0 |
| Depression | 19 | 2 | 0 | 14 | <1 | 0 |
| Dyspepsia | 17 | <1 | 0 | 13 | <1 | 0 |
| Cough | 16 | 0 | 0 | 11 | 0 | 0 |
| Dizziness | 15 | <1 | 0 | 13 | 0 | <1 |
| Headache | 15 | <1 | 0 | 10 | 0 | 0 |
| Insomnia | 15 | <1 | 0 | 16 | <1 | 0 |
| Alopecia | 14 | 0 | 0 | 11 | 0 | 0 |
| Anxiety | 13 | 1 | 0 | 11 | <1 | 0 |
| Neuropathy | 13 | 1 | <1 | 10 | <1 | 0 |
| Flatulence | 13 | 0 | 0 | 9 | <1 | 0 |
| Rigors | 12 | 0 | 0 | 9 | 0 | 0 |
In the pancreatic carcinoma trial, 10 patients in the TARCEVA plus gemcitabine group developed deep venous thrombosis (incidence: 3.9%). In comparison, 3 patients in the placebo plus gemcitabine group developed deep venous thrombosis (incidence 1.2%). The overall incidence of Grade 3 or 4 thrombotic events, including deep venous thrombosis, was similar in the two treatment arms: 11% for TARCEVA plus gemcitabine and 9% for placebo plus gemcitabine.
No differences in Grade 3 or Grade 4 hematologic laboratory toxicities were detected between the TARCEVA plus gemcitabine group compared to the placebo plus gemcitabine group.
Severe adverse events (≥ 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 section).
Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) have been observed following the administration of TARCEVA plus gemcitabine in patients with pancreatic cancer. Table 7 displays the most severe NCI-CTC Grade of liver function abnormalities that developed. TARCEVA dosing should be interrupted if changes in liver function are severe (see DOSAGE AND ADMINISTRATION - Dose Modifications section).
Table 7: Liver Function Test Abnormalities (most severe NCI-CTC Grade) in Pancreatic Cancer Patients: 100 mg Cohort | TARCEVA + Gemcitabine 1000 mg/m2 IV
N = 259 | Placebo + Gemcitabine 1000 mg/m2 IV
N = 256 |
| NCI CTC Grade | 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 Cancer Indications
During the NSCLC and the combination pancreatic cancer trials, infrequent cases of gastrointestinal bleeding have been reported, some associated with concomitant warfarin or NSAID administration (see PRECAUTIONS - Elevated International Normalized Ratio and Potential Bleeding section). These adverse events were reported as peptic ulcer bleeding (gastritis, gastroduodenal ulcers), hematemesis, hematochezia, melena and hemorrhage from possible colitis. Cases of acute renal failure or renal insufficiency, including fatalities, with or without hypokalemia have been reported (see Precautions section). Cases of Grade 1 epistaxis were also reported in both the single-agent NSCLC and the pancreatic cancer clinical trials.
NCI-CTC Grade 3 conjunctivitis and keratitis have been reported infrequently in patients receiving TARCEVA therapy in the NSCLC and pancreatic cancer clinical trials. Corneal ulcerations may also occur (see PRECAUTIONS - Information for Patients section).
Hepatic failure has been reported in patients treated with single-agent TARCEVA or TARCEVA combined with chemotherapy in clinical studies and during post-marketing use of TARCEVA (see Precautions section); it is not possible to reliably estimate the frequency or establish a causal relationship to TARCEVA treatment.
In general, no notable differences in the safety of TARCEVA monotherapy or in combination with gemcitabine could be discerned between females or males and between patients younger or older than the age of 65 years. The safety of TARCEVA appears similar in Caucasian and Asian patients (see PRECAUTIONS - Geriatric Use section).
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