Important Safety Information:
There have been infrequent reports of serious Interstitial Lung Disease (ILD)-like events, including fatalities, in patients receiving Tarceva. The overall incidence of ILD-like events in Tarceva-treated patients from all studies was approximately 0.7%. In NSCLC, single agent Phase III study incidence was 0.8%-the same as placebo. In pancreatic cancer, in combination with gemcitabine study incidence was 2.5% in the Tarceva plus gemcitabine arm vs. 0.4% in the placebo plus gemcitabine arm.
Reported diagnoses in patients suspected of having ILD-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, ILD, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress syndrome and lung infiltration. Symptoms started from 5 days to more than 9 months (median 39 days) after the initiation of Tarceva therapy.
Tarceva should be interrupted for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever, and if ILD is diagnosed, Tarceva should be discontinued.
Cases of hepatorenal syndrome, acute renal failure (including fatalities), and renal insufficiency have been reported. Some were secondary to baseline hepatic impairment while others were associated with severe dehydration due to diarrhea, vomiting, and/or anorexia or concurrent chemotherapy use. In the event of dehydration, particularly in patients with contributing risk factors for renal failure (eg, pre-existing renal disease, medical conditions or medications that may lead to renal disease, or other predisposing conditions including advanced age), Tarceva therapy should be interrupted and appropriate measures should be taken to intensively rehydrate the patient. Periodic monitoring of renal function and serum electrolytes is recommended in patients at risk of dehydration.
Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been reported during use of Tarceva, particularly in patients with baseline hepatic impairment. Therefore, periodic liver function testing (transaminases, bilirubin, and alkaline phosphatase) is recommended. In the setting of worsening liver function tests, dose interruption and/or dose reduction with frequent liver function test monitoring should be considered. Tarceva dosing should be interrupted or discontinued if total bilirubin is >3 x ULN and/or transaminases are >5 x ULN in the setting of normal pretreatment values.
Treatment with Tarceva should be used with extra caution in patients with total bilirubin > 3 x ULN. Patients with hepatic impairment (total bilirubin > ULN or Child-Pugh A, B and C) should be closely monitored during therapy with Tarceva. Tarceva dosing should be interrupted or discontinued if changes in liver function are severe such as doubling of total bilirubin and/or tripling of transaminases in the setting of pretreatment values outside normal range.
Gastrointestinal perforation (including fatalities) has been reported in patients receiving Tarceva. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease are at increased risk. Permanently discontinue Tarceva in patients who develop gastrointestinal perforation.
Bullous, blistering and exfoliative skin conditions have been reported including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, which in some cases were fatal. Interrupt or discontinue Tarceva treatment if the patient develops severe bullous, blistering or exfoliating conditions.
Corneal perforation and ulceration have been reported during use of Tarceva. Other ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis have been observed with Tarceva treatment and are known risk factors for corneal ulceration/perforation. Interrupt or discontinue Tarceva therapy if patients present with acute/worsening ocular disorders such as eye pain.
When receiving Tarceva, women of childbearing potential should be advised to avoid pregnancy and pregnant women apprised of the potential risks to the fetus. Tarceva should only be continued in pregnant women if the potential benefit to the mother outweighs the risk to the fetus. Women receiving Tarceva should be advised against breastfeeding. Tarceva is pregnancy category D.
International Normalized Ratio (INR) elevation and infrequent reports of bleeding events, including gastrointestinal bleeding, have been reported in clinical studies, some associated with concomitant warfarin administration. Patients taking warfarin or other coumarin-derivative anticoagulants should be monitored regularly for changes in prothrombin time or INR. Some infrequent cases of gastrointestinal bleeding were also associated with concomitant NSAID administration.
The potent CYP3A4 inhibitor ketoconazole has been shown to increase erlotinib AUC; thus, caution should be used during co-treatment with Tarceva and ketoconazole or other strong CYP3A4 inhibitors such as, but not limited to: atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO) and voriconazole, and grapefruit or grapefruit juice. When Tarceva was co-administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2, the erlotinib AUC increased by 39%.
The CYP3A4 inducer rifampicin has been shown to decrease erlotinib AUC, thus, alternate treatments lacking CYP3A4 inducing activity are strongly recommended. In the absence of an alternative treatment, Tarceva dose modification should be considered. If the Tarceva dose is adjusted upward, the dose will need to be reduced immediately to the indicated starting dose upon discontinuation of rifampicin or other CYP3A4 inducers such as, but not limited to: rifabutin, rifapentine, phenytoin, carbamazepine, Phenobarbital and St. John's Wort.
Drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and reduce its bioavailability. Co-administration of Tarceva with omeprazole, a proton pump inhibitor, decreased the erlotinib AUC by 46%. Increasing the dose of Tarceva when co-administered with such agents is not likely to compensate for the loss of exposure. The concomitant use of proton pump inhibitors with Tarceva should be avoided if possible.
Smokers should be advised to stop smoking while taking Tarceva as plasma concentrations of erlotinib are reduced due to the effect of cigarette smoking. However, if they continue to smoke, cautious increase in the dose of Tarceva, not to exceed 300 mg, may be considered while monitoring the patient's safety. If the Tarceva dose is adjusted upward, the dose should be reduced immediately to the indicated starting dose upon cessation of smoking.
NCI-CTC Grade 3 conjunctivitis and keratitis have been reported infrequently in patients receiving Tarceva therapy. Corneal ulcerations may also occur.
The most common adverse reactions in patients with NSCLC receiving Tarceva monotherapy 150 mg were mild to moderate rash and diarrhea. Severe rash and diarrhea (9% & 6% NCI-CTC Grades 3-4, respectively) were reported. Rash and diarrhea each resulted in dose reductions (6% and 1%, respectively) and discontinuation in 1% of Tarceva-treated patients during the single-agent Phase III trial.
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