Dosing for Tarceva in metastatic NSCLC

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Dosing and administration

TARCEVA® Dosage Recommendation for mNSCLC Treatment

  • The recommended daily dose of Tarceva for metastatic NSCLC is 150 mg.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.1

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 or when using concomitantly with an inhibitor of both CYP3A4 and CYP1A2. Avoid concomitant use if possible.
      • Examples include atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole, grapefruit, grapefruit juice, or ciprofloxacin.
    • 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. Increase doses by 50 mg increments at 2-week intervals to a maximum of 450 mg. Avoid concomitant use, if possible.
      • Examples include rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, and St John’s wort.
    • 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 (150 mg or 100 mg daily) upon cessation of smoking.
  • Drugs that Increase 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 such as ranitidine 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

Skin rash, bullous and exfoliative skin disorders

  • Advise patients that skin reactions can occur or worsen on sun-exposed areas while taking Tarceva, and proactive intervention may include alcohol-free emollient cream and use of sunscreen or avoidance of sun exposure. Advise patients that hyperpigmentation or dry skin, with or without digital skin fissures, have been reported and in the majority of cases were associated with rash.
  • Advise patients that Tarceva can increase the risk of bullous and exfoliative skin disorders and to seek immediately medical attention for severe skin reactions.

Diarrhea

  • Advise patients that diarrhea can usually be managed with loperamide and to contact their healthcare provider for severe or persistent diarrhea.

Interstitial lung disease (ILD)

  • Advise patients of the risk of severe or fatal ILD, including pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening unexplained shortness of breath or coughing.

Renal failure

  • Advise patients of the risk of developing renal failure. Inform patients of the need for the healthcare provider to monitor kidney function and electrolytes.

Hepatotoxicity

  • Advise patients to immediately report signs or symptoms of hepatotoxicity.

Gastrointestinal perforations

  • Advise patients that Tarceva can increase the risk of gastrointestinal perforation or fistula and to seek immediate medical attention for severe abdominal pain.

Cerebrovascular accident

  • Advise patients of the risk of cerebrovascular accident and see immediate medical attention.

Ocular disorders

  • Advise patients promptly to contact their healthcare provider if they develop eye signs or symptoms, lacrimation, light sensitivity, blurred vision, eye pain, red eye, or changes in vision.

Hemorrhage in patients taking warfarin

  • Advise patients who are receiving warfarin of the need to monitor International Normalized Ration (INR) or other coumarin-derivative anticoagulants.

Hair and nail disorders

  • Advise patients that hair and nail disorders, including hirsutism and brittle and loose nails, have been reported.

Embryo-fetal toxicity

  • Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.
  • Advise females of reproductive potential to use effective contraception during treatment with Tarceva, and for at least 1 month after the last dose.

Lactation

  • Advise women not to breastfeed during treatment with Tarceva and for 2 weeks after the final dose.

Smoking

  • Advise patients to contact their health care provider for any changes in smoking status and that the dose of Tarceva may need to be adjusted if they smoke.
  • Advise patients to stop smoking.

 

Contact a representative

Indication

Metastatic NSCLC

Tarceva is indicated for:

  • The treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test receiving first-line, maintenance, or second or greater line treatment after progression following at least one prior chemotherapy regimen.

Limitations of use:

  • Safety and efficacy of Tarceva have not been established in patients with NSCLC whose tumors have other EGFR mutations.
  • Tarceva is not recommended for use in combination with platinum-based chemotherapy.

Important Safety Information

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 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 values 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.
  • Cerebrovascular Accident:
    • In the pancreatic carcinoma trial, 7 patients in the Tarceva plus gemcitabine group developed cerebrovascular accidents (incidence: 2.5%). One of these was hemorrhagic and was the only fatal event. In comparison, in the placebo plus 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 not higher than that observed 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:
    • Based on animal data and its mechanism of action, Tarceva can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus.
    • Advise females of reproductive potential to use effective contraception during therapy and for one month after the last dose of Tarceva.

MOST COMMON ADVERSE REACTIONS

  • Metastatic NSCLC – First-Line Treatment of Patients With EGFR Mutations:
    • Most frequent (≥30%) adverse reactions were diarrhea, asthenia, rash, cough, dyspnea, and decreased appetite. 
    • Most frequent Grade 3/4 (NCI-CTC Version 3.0) adverse reactions were rash (14%) and diarrhea (5%). In Tarceva-treated patients, the most frequently reported adverse reactions leading to dose modification were rash (13%), diarrhea (10%), and asthenia (3.6%). 

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.; 2016.