Dosing for Tarceva in advanced pancreatic cancer

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Dosing and administration

TARCEVA® Dosage Recommendation for Pancreatic Cancer Treatment

  • The recommended daily dose of Tarceva for advanced pancreatic cancer is 100 mg taken once daily in combination with gemcitabine.1 

Tarceva should be taken on an empty stomach (ie, at least one hour before or two hours after the ingestion of food.) Treatment should continue until disease progression or unacceptable toxicity occurs.

 

Discontinue Tarceva for1:

  • Interstitial lung disease (ILD)
  • Severe hepatic toxicity that does not improve significantly or resolve within 3 weeks 
  • Gastrointestinal perforation
  • Severe bullous, blistering, or exfoliating skin conditions
  • Corneal perforation or severe ulceration 

Withhold Tarceva1:

  • During diagnostic evaluation for possible ILD.
  • For severe (Common Terminology Criteria for Adverse Events [CTCAE] grade 3/4) renal toxicity, and consider discontinuation of Tarceva.
  • In patients without pre-existing hepatic impairment for total bilirubin levels >3 x upper limit of normal (ULN) or transaminases >5 x ULN, and consider discontinuation of Tarceva.
  • In patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline and consider discontinuation of Tarceva. 
  • For persistent severe diarrhea not responsive to medical management (eg, loperamide).
  • For severe rash not responsive to medical management.
  • For keratitis of (National Cancer Institute Common Toxicity Criteria [NCI-CTC] version 4.0) grade 3/4 or for grade 2 lasting more than 2 weeks.
  • For acute/worsening ocular disorders such as eye pain, and consider discontinuation of Tarceva.

Dose modifications

  • Reduce Tarceva by 50-mg decrements:
    • If severe reactions occur with concomitant use of strong CYP3A4 inhibitors [such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole, or grapefruit or grapefruit juice] or when using concomitantly with an inhibitor of both CYP3A4 and CYP1A2 (eg, ciprofloxacin). Avoid concomitant use if possible.
    • When restarting therapy following withholding treatment for a dose-limiting toxicity that has resolved to baseline or grade ≤1.
  • Increase Tarceva by 50-mg increments as tolerated for: 
    • Concomitant use with CYP3A4 inducers (such as rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, or St. John’s wort). Increase dose by 50-mg increments at 2-week intervals to a maximum of 450 mg. Avoid concomitant use if possible.
    • Concurrent cigarette smoking. Increase by 50-mg increments at 2-week intervals to a maximum of 300 mg. Immediately reduce the dose of Tarceva to the recommended dose (100 mg) upon cessation of smoking.
  • For drugs affecting gastric pH:
    • Avoid concomitant use of Tarceva with proton pump inhibitors if possible. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period.  
    • If treatment with an H2-receptor antagonist is required, Tarceva must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist. 
    • Although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the Tarceva dose should be separated by several hours, if an antacid is necessary.

Patient counseling information1

Advise patients to contact their healthcare provider for:

  • Severe or persistent diarrhea, nausea, anorexia, or vomiting
  • Onset or worsening of unexplained shortness of breath or cough
  • Eye irritation
  • Onset or worsening of skin rash or development of bullous lesions or desquamation
  • Any changes in smoking status

Advise patients on the presentation of skin, hair, and nail disorders.

  • 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 3/4) with desquamation. Skin reactions may occur or worsen in areas exposed to the sun. Symptoms associated with rash may include itching, tenderness, and/or burning.
  • Hyperpigmentation and dry skin, with or without digital skin fissures, have been reported and in the majority of cases were associated with rash.
  • Hair and nail disorders, including hirsutism and brittle and loose nails, have been reported.

Instruct patients on initial management of rash or diarrhea.

  • Given that skin reactions are anticipated when taking Tarceva, proactive intervention may include alcohol-free emollient cream and use of sunscreen or avoidance of exposure to the sun.
  • Management of rash may include topical corticosteroids or antibiotics with anti-inflammatory properties. These approaches were used in the advanced NSCLC and advanced pancreatic pivotal clinical trials. Acne preparations with drying properties may aggravate the dry skin and erythema. Treatment of rash has not been formally studied and should be based on rash severity.
  • Diarrhea can usually be managed with loperamide.

Counsel patients on pregnancy planning and prevention.

  • Advise females of reproductive potential to use highly effective contraception during treatment with Tarceva and for at least 2 weeks after the last dose of Tarceva.
  • Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with Tarceva.
  • Advise breast-feeding mothers to discontinue nursing while receiving Tarceva.

Advise patients to stop smoking. Advise patients that the dose of Tarceva may need to be adjusted if they smoke.

Advanced Pancreatic Cancer Indication

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

Important Safety Information

CONTRAINDICATIONS

None

WARNINGS AND PRECAUTIONS

  • Interstitial Lung Disease (ILD): 
    • Cases of serious ILD, including fatal cases, can occur with Tarceva treatment. The overall incidence of ILD in approximately 32,000 Tarceva-treated patients in uncontrolled studies and studies with concurrent chemotherapy was approximately 1.1%. In patients with ILD, the onset of symptoms was between 5 days to more than 9 months (median 39 days) after initiating Tarceva therapy.
    • Withhold Tarceva for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever pending diagnostic evaluation. If ILD is confirmed, permanently discontinue Tarceva.
  • Renal Failure: 
    • Hepatorenal syndrome, severe acute renal failure including fatal cases, and renal insufficiency can occur with Tarceva treatment. Renal failure may arise from exacerbation of underlying baseline hepatic impairment or severe dehydration.
    • The pooled incidence of severe renal impairment in the 3 monotherapy lung cancer studies was 0.5% in the Tarceva arms and 0.8% in the control arms. The incidence of renal impairment in the pancreatic cancer study was 1.4% in the Tarceva plus gemcitabine arm and 0.4% in the control arm.
    • Withhold Tarceva in patients developing severe renal impairment until renal toxicity is resolved. Perform periodic monitoring of renal function and serum electrolytes during Tarceva treatment.
  • Hepatotoxicity With or Without Hepatic Impairment:
    • Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with Tarceva treatment in patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline hepatic impairment.
      • Hepatic Toxicity: One Tarceva-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4 liver test abnormalities. 
    • In clinical studies where patients with moderate to severe hepatic impairment were excluded, the pooled incidence of hepatic failure in the 3 monotherapy lung cancer studies was 0.4% in the Tarceva arms and 0% in the control arms. The incidence of hepatic failure in the pancreatic cancer study was 0.4% in the Tarceva plus gemcitabine arm and 0.4% in the control arm.
    • Perform periodic liver testing (transaminases, bilirubin, and alkaline phosphatase) during treatment with Tarceva. Increased frequency of monitoring of liver function is required for patients with pre-existing hepatic impairment or biliary obstruction.
    • Withhold Tarceva in patients without pre-existing hepatic impairment for total bilirubin >3 x ULN and/or transaminases >5 x ULN. Withhold Tarceva in patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases value over baseline.
    • Discontinue Tarceva in patients whose abnormal liver tests meeting the above criteria do not improve significantly or resolve within 3 weeks.
  • Gastrointestinal Perforation:
    • Gastrointestinal perforation, including fatal cases, can occur with Tarceva treatment. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease may be at increased risk of perforation.
    • The pooled incidence of gastrointestinal perforation in the 3 monotherapy lung cancer studies was 0.2% in the Tarceva arms and 0.1% in the control arms. The incidence of gastrointestinal perforation in the pancreatic cancer study was 0.4% in the Tarceva plus gemcitabine arm and 0% in the control arm.
    • Permanently discontinue Tarceva in patients who develop gastrointestinal perforation.
  • Bullous and Exfoliative Skin Disorders:
    • Bullous, blistering and exfoliative skin conditions, including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, which in some cases were fatal, can occur with Tarceva treatment.
    • The pooled incidence of bullous and exfoliative skin disorders in the 3 monotherapy lung cancer studies was 1.2% in the Tarceva arms and 0% in the control arms. The incidence of bullous and exfoliative skin disorders in the pancreatic cancer study was 0.4% in the Tarceva plus gemcitabine arm and 0% in the control arm.
    • Discontinue Tarceva treatment if the patient develops severe bullous, blistering or exfoliating conditions.
  • Myocardial Infarction (MI)/Ischemia:
    • In the pancreatic carcinoma trial, 6 patients (incidence 2.1%) in the Tarceva plus gemcitabine group developed myocardial infarction/ischemia. One of these patients died due to myocardial infarction. In comparison, 3 patients in the placebo/gemcitabine group developed myocardial infarction (incidence 1.1%), and one died due to myocardial infarction. The pooled incidence of myocardial infarction/ischemia in the 3 monotherapy lung cancer studies was 0.2% in the Tarceva arms and 0.4% in the control arms.
  • Cerebrovascular Accident:
    • In the pancreatic carcinoma trial, 7 patients in the Tarceva plus gemcitabine group developed cerebrovascular accident (incidence 2.5%). One of these was hemorrhagic and was the only fatal event. In comparison, in the placebo/gemcitabine group there were no cerebrovascular accidents. The pooled incidence of cerebrovascular accident in the 3 monotherapy lung cancer studies was 0.6% in the Tarceva arms and 0.9% in the control arms.
  • Microangiopathic Hemolytic Anemia With Thrombocytopenia:
    • The pooled incidence of microangiopathic hemolytic anemia with thrombocytopenia in the 3 monotherapy lung cancer studies was 0% in the Tarceva arms and 0.1% in the control arms. The incidence of microangiopathic hemolytic anemia with thrombocytopenia in the pancreatic cancer study was 1.4% in the Tarceva plus gemcitabine arm and 0% in the control arm.
  • Ocular Disorders:
    • Decreased tear production, abnormal eyelash growth, keratoconjunctivitis sicca or keratitis can occur with Tarceva treatment and can lead to corneal perforation or ulceration.
    • The pooled incidence of ocular disorders in the 3 monotherapy lung cancer studies was 17.8% in the Tarceva arms and 4% in the control arms. The incidence of ocular disorders in the pancreatic cancer study was 12.8% in the Tarceva plus gemcitabine arm and 11.4% in the control arm.
    • Interrupt or discontinue Tarceva therapy if patients present with acute or worsening ocular disorders such as eye pain.
  • Hemorrhage in Patients Taking Warfarin:
    • Severe and fatal hemorrhage associated with International Normalized Ratio (INR) elevations can occur when Tarceva and warfarin are administered concurrently.
    • Regularly monitor prothrombin time and INR during Tarceva treatment in patients taking warfarin or other coumarin-derivative anticoagulants.
  • Embryo-Fetal Toxicity:
    • Tarceva is pregnancy category D. Based on its mechanism of action, Tarceva can cause fetal harm when administered to a pregnant woman. If Tarceva is used during pregnancy, or if the patient becomes pregnant while taking Tarceva, the patient should be apprised of the potential hazard to a fetus.
    • Advise females of reproductive potential to use highly effective contraception during therapy and for at least 2 weeks after the last dose of Tarceva. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Tarceva.

MOST COMMON ADVERSE REACTIONS

  • Advanced Pancreatic Cancer – Tarceva Administered Concurrently with Gemcitabine:
    • Fatigue, rash, nausea, anorexia, and diarrhea.
    • Grade 3/4 (NCI-CTC Version 2.0) adverse reactions were rash (5%) and diarrhea (5%). Rash and diarrhea each resulted in dose reductions in 2% of patients and discontinuation in up to 1% of patients receiving Tarceva plus gemcitabine.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.

Please see the Tarceva full Prescribing Information for additional Important Safety Information.

Reference

  1. Tarceva [package insert]. Northbrook, IL: OSI Pharmaceuticals, LLC, an affiliate of Astellas Pharma US, Inc.; 2015.