Dosing and Administration

Indication and use in advanced pancreatic cancer

Tarceva (erlotinib) in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.

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Recommended dosing for advanced pancreatic cancer

• The recommended once-daily dose of Tarceva for the treatment of pancreatic cancer is 100 mg taken orally in combination with gemcitabine.^{* 1}
• Tarceva is indicated for use in advanced pancreatic cancer in combination with gemcitabine 1,000 mg/m2 IV. In the Phase III trial, patients received the approved gemcitabine dose and schedule for pancreatic cancer:¹
  • Cycle 1 of gemcitabine: Days 1, 8, 15, 22, 29, 36 and 43 of an 8-week cycle
  • Cycle 2 and subsequent cycles of gemcitabine: Days 1, 8 and 15 of a 4-week cycle

Do not take with food

• Patients should be instructed to take Tarceva at least one hour before or two hours after the ingestion of food, since food substantially alters the bioavailability of erlotinib and may increase the risk of adverse events.^{1, 2, 5} Tarceva tablets should be taken on an empty stomach to help ensure that patients obtain consistent plasma levels of the drug.^{1, 2}
• If a dose is missed, Tarceva can be taken at any time during the same day between meals. If the daily dose is missed entirely, the regularly prescribed dose should be taken the next day, one hour before or two hours after a meal.^{1, 2}
• Caution your patients not to double the daily prescribed dose of Tarceva. Administering Tarceva above the recommended daily dose may result in an unacceptable incidence of severe adverse events, such as diarrhea, rash, and liver transaminase elevation.¹

Treatment should continue until disease progression or unacceptable toxicity occurs; there is no evidence that treatment beyond disease progression is beneficial.

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Dose adjustment

• If patients experience intolerable adverse events, such as intolerable skin reactions, intolerable diarrhea that is unresponsive to loperamide or that causes dehydration, or severe liver function test abnormalities, consider dose reduction or interruption of Tarceva.¹
  • two percent of pancreatic cancer patients who received the 100mg dose required dose reduction for both rash and diarrhea in the combination Phase III trial

Multiple tablet strengths allow for dose adjustment when appropriate

• To allow for reduction when appropriate, Tarceva is also available 25-mg strength.¹
• When dose reduction is necessary, the Tarceva dose should be reduced by 50-mg decrements.¹
• Tarceva therapy should be discontinued if ILD is diagnosedýdose reduction is not appropriate in this situation.¹
• For the treatment of advanced pancreatic cancer, gemcitabine dose administration could be withheld or reduced for toxicities following the recommendations in the manufacturerýs package insert.¹

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Most common adverse events in patients with advanced pancreatic cancer taking Tarceva

• The most common side effects in patients with pancreatic cancer receiving Tarceva 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. Severe rash and diarrhea (5% and 5% NCI-CTC Grades 3–4, respectively) were reported. Rash and diarrhea each resulted in dose reductions in 2% of patients, and discontinuation in up to 1% of patients receiving Tarceva plus gemcitabine.

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How Supplied

Tarceva is appropriate for the treatment of pancreatic cancer in 100-mg and 25-mg strengths. Tarceva is supplied as white film-coated tablets for daily oral administration.

Tarceva® (erlotinib) Tablets, 100 mg Round, biconvex face and straight sides, white film-coated, printed in gray with a "T" and "100" on one side and plain on the other side. Supplied in bottles of 30 tablets (NDC 50242-063-01).	Not actual size
Tarceva® (erlotinib) Tablets, 25 mg Round, biconvex face and straight sides, white film-coated, printed in orange with a "T" and "25" on one side and plain on the other side. Supplied in bottles of 30 tablets (NDC 50242-062-01).	Not actual size

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Storage

Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). See USP Controlled Room Temperature.

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Overdosage

• Single oral doses of Tarceva up to 1,000 mg in healthy subjects and up to 1,600 mg in cancer patients have been tolerated. Repeated twice-daily doses of single-agent Tarceva 200 mg in healthy subjects were poorly tolerated after only a few days of dosing. Based on the data from these studies, severe adverse events, such as diarrhea, rash, and possibly liver transaminase elevations, may occur above the recommended dose. In case of suspected overdose, Tarceva should be withheld and symptomatic treatment instituted.

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Dose modifications: concomitant use with CYP3A4 inhibitors and inducers

• 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.
• 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.

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Important Safety Information:

There have been infrequent reports of serious Interstitial Lung Disease (ILD)-like events, including fatalities, in patients receiving Tarceva for treatment of NSCLC, pancreatic cancer or other advanced solid tumors. In the event of an acute onset of new or progressive, unexplained pulmonary symptoms such as dyspnea, cough and fever, Tarceva therapy should be interrupted pending diagnostic evaluation. If ILD is diagnosed, Tarceva should be discontinued and appropriate treatment instituted as needed.

Cases of hepatic failure, hepatorenal syndrome, acute renal failure (all including fatalities), and renal insufficiency have been reported during use of Tarceva. Treatment with Tarceva should be used with extra caution in patients with total bilirubin > 3 x ULN. Tarceva dosing should be interrupted or discontinued if changes in liver function are severe. Patients should be closely monitored during therapy with Tarceva.

In the pancreatic cancer trial, other serious adverse reactions associated with Tarceva plus gemcitabine and which may have included fatalities, were myocardial infarction/ischemia, cerebrovascular accident and microangiopathic hemolytic anemia with thrombocytopenia.

When receiving Tarceva therapy, women should be advised against becoming pregnant or breastfeeding. Tarceva is pregnancy category D.

The most common adverse reactions in patients with pancreatic cancer receiving Tarceva 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. Severe rash and diarrhea (5% and 5% NCI-CTC Grades 3ý4, respectively) were reported. Rash and diarrhea each resulted in dose reductions in 2% of patients, and discontinuation in up to 1% of patients receiving Tarceva plus gemcitabine.

• Please see the Tarceva full prescribing information for complete safety information.

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• 1. Tarceva® (erlotinib) full prescribing information,OSI Pharmaceuticals,Inc., 2008.
• 2. Data on file, OSI Pharmaceuticals, Inc.
• 4. National Comprehensive Cancer Network. NCCNý Clinical Practice Guidelines in Oncologyýv.2.2005: nonýsmall-cell lung cancer. National Comprehensive Cancer Network. Available at: http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf. Accessed July 28, 2005.
• 5. Hidalgo M, Siu LL, Nemunaitis J, et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol. 2001;19:3267-3279.