Because clinical trials are conducted under widely varying conditions, adverse reactions 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 (erlotinib) is based on more than 1200 cancer patients who received TARCEVA (erlotinib) as monotherapy, more than 300 patients who received TARCEVA (erlotinib) 100 or 150 mg plus gemcitabine, and 1228 patients who received TARCEVA (erlotinib) concurrently with other chemotherapies.

There have been reports of serious events, including fatalities, in patients receiving TARCEVA (erlotinib) for treatment of NSCLC, pancreatic cancer or other advanced solid tumors [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION].

Clinical Trial Experience

Non-Small Cell Lung Cancer

Maintenance Study

Adverse reactions, regardless of causality, that occurred in at least 3% of patients treated with single-agent TARCEVA (erlotinib) at 150 mg and at least 3% more often than in the placebo group in the randomized maintenance trial are summarized by NCI-CTC (version 3.0) Grade in Table 1.

The most common adverse reactions in patients receiving single-agent TARCEVA (erlotinib) 150 mg were rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 6.0% and 1.8%, respectively, in TARCEVA (erlotinib) -treated patients. Rash and diarrhea resulted in study discontinuation in 1.2% and 0.5% of TARCEVA (erlotinib) -treated patients, respectively. Dose reduction or interruption for rash and diarrhea was needed in 5.1% and 2.8% of patients, respectively. In TARCEVA (erlotinib) -treated patients who developed rash, the onset was within two weeks in 66% and within one month in 81%.

Table 1: NSCLC Maintenance Study: Adverse Reactions Occurring More Frequently ( ≥ 3%) in the Single-Agent TARCEVA (erlotinib) Group than in the Placebo Group and in ≥ 3% of Patients in the TARCEVA (erlotinib) Group.

Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) were observed in patients receiving single-agent TARCEVA (erlotinib) 150 mg in the Maintenance study. Grade 2 ( > 2.5 – 5.0 x ULN) ALT elevations occurred in 2% and 1%, and Grade 3 ( > 5.0 – 20.0 x ULN) ALT elevations were observed in 1% and 0% of TARCEVA (erlotinib) and placebo treated patients, respectively. The TARCEVA (erlotinib) treatment group had Grade 2 ( > 1.5-3.0 x ULN) bilirubin elevations in 4% and Grade 3 ( > 3.0-10.0 x ULN) in < 1% compared with < 1% for both Grades 2 and 3 in the placebo group. TARCEVA (erlotinib) dosing should be interrupted or discontinued if changes in liver function are severe [see DOSAGE AND ADMINISTRATION].

Second/Third Line Study

Adverse reactions, regardless of causality, that occurred in at least 10% of patients treated with single-agent TARCEVA (erlotinib) 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 2.

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 (erlotinib) -treated patients. Rash and diarrhea each resulted in study discontinuation in 1% of TARCEVA (erlotinib) -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 2: NSCLC 2nd/3rd Line Study: Adverse Reactions Occurring More Frequently ( ≥ 3%) in the Single-agent TARCEVA (erlotinib) 150 mg Group than in the Placebo Group and in ≥ 10% of Patients in the TARCEVA (erlotinib) Group.

Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) were observed in patients receiving single-agent TARCEVA (erlotinib) 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 (erlotinib) and placebo treated patients, respectively. Grade 3 ( > 5.0 – 20.0 x ULN) elevations were not observed in TARCEVA (erlotinib) -treated patients. TARCEVA (erlotinib) dosing should be interrupted or discontinued if changes in liver function are severe [see DOSAGE AND ADMINISTRATION].

Pancreatic Cancer

Adverse reactions, regardless of causality, that occurred in at least 10% of patients treated with TARCEVA (erlotinib) 100 mg plus gemcitabine in the randomized trial of patients with pancreatic cancer are summarized by NCI-CTC (version 2.0) Grade in Table 3.

The most common adverse reactions in pancreatic cancer patients receiving TARCEVA (erlotinib) 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. In the TARCEVA (erlotinib) plus gemcitabine arm, Grade 3/4 rash and diarrhea were each reported in 5% of TARCEVA (erlotinib) 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 (erlotinib) 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 3: Adverse Reactions Occurring in ≥ 10% of TARCEVA (erlotinib) -treated Pancreatic Cancer Patients: 100 mg cohort

In the pancreatic carcinoma trial, 10 patients in the TARCEVA (erlotinib) /gemcitabine group developed deep venous thrombosis (incidence: 3.9%). In comparison, 3 patients in the placebo/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 (erlotinib) plus gemcitabine and 9% for placebo plus gemcitabine.

No differences in Grade 3 or Grade 4 hematologic laboratory toxicities were detected between the TARCEVA (erlotinib) plus gemcitabine group compared to the placebo plus gemcitabine group.

Severe adverse reactions ( ≥ grade 3 NCI-CTC) in the TARCEVA (erlotinib) 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].

Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) have been observed following the administration of TARCEVA (erlotinib) plus gemcitabine in patients with pancreatic cancer. Table 4 displays the most severe NCI-CTC grade of liver function abnormalities that developed. TARCEVA (erlotinib) dosing should be interrupted or discontinued if changes in liver function are severe [see DOSAGE AND ADMINISTRATION].

Table 4 :Liver Function Test Abnormalities (most severe NCI-CTC grade) in Pancreatic Cancer Patients: 100 mg Cohort

NSCLC and Pancreatic Indications: Low Frequency Adverse Reactions

Gastrointestinal Disorders

Gastrointestinal perforations have been reported [see WARNINGS AND PRECAUTIONS].

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 WARNINGS AND PRECAUTIONS]. These adverse reactions were reported as peptic ulcer bleeding (gastritis, gastroduodenal ulcers), hematemesis, hematochezia, melena and hemorrhage from possible colitis.

Renal Disorders

Cases of acute renal failure or renal insufficiency, including fatalities, with or without hypokalemia have been reported [see WARNINGS AND PRECAUTIONS].

Hepatic Disorders

Hepatic failure has been reported in patients treated with single-agent TARCEVA (erlotinib) or TARCEVA (erlotinib) combined with chemotherapy [see WARNINGS AND PRECAUTIONS].

Ocular Disorders

Corneal ulcerations or perforations have been reported in patients receiving TARCEVA (erlotinib) treatment. Abnormal eyelash growth including in-growing eyelashes, excessive growth and thickening of the eyelashes have been reported [see WARNINGS AND PRECAUTIONS] and are risk factors for corneal ulceration/perforation.

NCI-CTC Grade 3 conjunctivitis and keratitis have been reported infrequently in patients receiving TARCEVA (erlotinib) therapy in the NSCLC and pancreatic cancer clinical trials. [see PATIENT INFORMATION].

Skin, Hair, and Nail Disorders

Bullous, blistering and exfoliative skin conditions have been reported including cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis [seeWARNINGS AND PRECAUTIONS].

In patients who develop skin rash, the appearance of the rash is typically erythematous and maculopapular and it may resemble acne with follicular pustules, but is histopathologically different. This skin reaction commonly occurs on the face, upper chest and back, but may be more generalized or severe (NCI-CTC Grade 3 or 4) with desquamation. Skin reactions may occur or worsen in sun exposed areas; therefore, the use of sunscreen or avoidance of sun exposure is recommended. Associated symptoms may include itching, tenderness and/or burning. Also, hyperpigmentation or dry skin with or without digital skin fissures may occur.

Hair and nail disorders including alopecia, hirsutism, eyelash/eyebrow (see above) changes, paronychia and brittle and loose nails have been reported.

Other Disorders

Epistaxis was also reported in both the single-agent NSCLC and the pancreatic cancer clinical trials.

In general, no notable differences in the safety of TARCEVA (erlotinib) 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 [see Use in Specific Populations]. The safety of TARCEVA (erlotinib) appears similar in Caucasian and Asian patients.

Post-marketing Experience

The following adverse reactions have been identified during post approval use of TARCEVA (erlotinib) . 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.

Skin and subcutaneous tissue disorders

Hair and nail changes, mostly non-serious e.g. hirsutism, eyelash/eyebrow changes, paronychia and brittle and loose nails. Bullous, blistering and exfoliative skin conditions have been reported including cases suggested of Stevens-Johnson syndrome/Toxic epidermal necrolysis [seeWARNINGS AND PRECAUTIONS].

Gastrointestinal Disorders

Gastrointestinal perforations [seeWARNINGS AND PRECAUTIONS].

Hepatic Disorders

Hepatic failure has been reported in patients treated with single-agent TARCEVA (erlotinib) or TARCEVA (erlotinib) combined with chemotherapy [seeWARNINGS AND PRECAUTIONS].

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

Erlotinib is metabolized predominantly by CYP3A4, and inhibitors of CYP3A4 would be expected to increase exposure. Co-treatment with the potent CYP3A4 inhibitor ketoconazole increases erlotinib AUC by 2/3. When TARCEVA (erlotinib) 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. Caution should be used when administering or taking TARCEVA (erlotinib) with ketoconazole and other strong CYP3A4 inhibitors such as, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole and grapefruit or grapefruit juice [see DOSAGE AND ADMINISTRATION].

Pre-treatment with the CYP3A4 inducer rifampicin for 7 days prior to TARCEVA decreased erlotinib AUC by about 2/3 to 4/5, which is equivalent to a dose of about 30 to 50 mg in NSCLC patients. In a separate study, treatment with rifampicin for 11 days, with co-administration of a single 450 mg dose of TARCEVA on day 8 resulted in a mean erlotinib exposure (AUC) that was 57.6% of that observed following a single 150 mg TARCEVA (erlotinib) dose in the absence of rifampicin treatment [see Dose Modifications]. Use of alternative treatments lacking CYP3A4 inducing activity is strongly recommended. If an alternative treatment is unavailable, adjusting the starting dose should be considered. If the TARCEVA (erlotinib) dose is adjusted upward, the dose will need to be reduced immediately to the indicated starting dose upon discontinuation of rifampicin or other inducers. Other CYP3A4 inducers include, but are not limited to, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital and St. John's Wort [see DOSAGE AND ADMINISTRATION].

Cigarette smoking has been shown to reduce erlotinib AUC. Patients should be advised to stop smoking; however, if they continue to smoke, a cautious increase in the dose of TARCEVA (erlotinib) may be considered, while monitoring the patient's safety. If the TARCEVA (erlotinib) dose is adjusted upward, the dose should be reduced immediately to the indicated starting dose upon cessation of smoking [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Pretreatment and co-administration of TARCEVA (erlotinib) decreased the AUC of CYP3A4 substrate, midazolam, by 24%. The mechanism is not clear.

In a study, there were no significant effects of gemcitabine on the pharmacokinetics of erlotinib nor were there significant effects of erlotinib on the pharmacokinetics of gemcitabine.

Drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and reduce its bioavailability. Increasing the dose of TARCEVA (erlotinib) when coadministered with such agents is not likely to compensate for the loss of exposure. Co-administration of TARCEVA (erlotinib) with omeprazole, a proton pump inhibitor, decreased the erlotinib AUC by 46%. Since proton pump inhibitors affect pH of the upper GI tract for an extended period, separation of doses may not eliminate the interaction. The concomitant use of proton pump inhibitors with TARCEVA (erlotinib) should be avoided if possible. Co-administration of TARCEVA (erlotinib) with 300 mg ranitidine, an H2 receptor antagonist, decreased erlotinib AUC by 33%. When TARCEVA (erlotinib) 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), the erlotinib AUC decreased by 15%. If patients need to be treated with an H2-receptor antagonist such as ranitidine, it should be used in a staggered manner. TARCEVA (erlotinib) must be taken once a day, 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of H2-receptor antagonist. Although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the TARCEVA (erlotinib) dose should be separated by several hours, if an antacid is necessary. [see CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 5/7/2010
This monograph has been modified to include the generic and brand name in many instances.