Usual Adult Dose for Breast Cancer

HER2-Positive Metastatic Breast Cancer (in combination with capecitabine):
1250 mg orally once a day on Days 1 to 21 continuously in repeating 21-day cycles in combination with capecitabine 2000 mg/m2/day (administered orally in 2 doses approximately 12 hours apart) on Days 1 to 14 in a repeating 21-day cycle

Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer (in combination with letrozole):
1500 mg orally once a day continuously in combination with letrozole 2.5 mg orally once a day

Comments:

• The dose of this drug should be once daily (5 tablets administered all at once); do not divide the daily dose.

is not recommended [see Clinical Pharmacology (12.3)]. Capecitabine should be taken with food or within 30 minutes after food. If a day's dose is missed, the patient should not double the dose the next day. Treatment should be continued until disease progression or unacceptable toxicity occurs.

• HER2-positive metastatic breast cancer patients should have disease progression on trastuzumab prior to initiation of therapy with this drug in combination with capecitabine.

Uses:

• In combination with capecitabine for treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.
• In combination with letrozole for treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated.

Renal Dose Adjustments

Data not available regarding dosage adjustments; however, the pharmacokinetics of this drug are unlikely to be affected given that less than 2% of an administered dose is eliminated by the kidneys.

Liver Dose Adjustments

Preexisting severe hepatic impairment (Child-Pugh C):

• HER2-positive metastatic breast cancer (in combination with capecitabine): Reduce dose to 750 mg/day
• Hormone receptor-positive, HER2-positive metastatic breast cancer (in combination with letrozole): Reduce dose to 1000 mg/day

Severe hepatic impairment that develops during therapy (Child-Pugh C):

• Permanently discontinue therapy.

Dose Adjustments

CONCOMITANT USE WITH STRONG CYP450 3A4 INHIBITORS AND/OR STRONG CYP450 3A4 INDUCERS: Avoid concomitant use if possible. Dose adjustment recommendations are based on pharmacokinetic studies; there are no clinical data available.
CONCOMITANT USE WITH STRONG CYP450 3A4 INHIBITOR: Reduce dose to 500 mg/day; allow washout period of approximately 1 week before upward adjustment of this drug to the usual recommended dose if inhibitor discontinued.
CONCOMITANT USE WITH STRONG CYP450 3A4 INDUCER: Gradually up-titrate dose based on tolerability; decrease dose back to the usual recommended dose if inducer discontinued.

• HER2-Positive Metastatic Breast Cancer (in combination with capecitabine): Increase dose up to 4500 mg/day.
• Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer (in combination with letrozole): Increase dose up to 5500 mg/day.

GRADE 2 or GREATER DECREASED LEFT VENTRICULAR EJECTION FRACTION (LVEF) OR LVEF THAT DROPS BELOW INSTITUTION'S LOWER LIMIT OF NORMAL: Discontinue treatment; may restart at reduced dose after a minimum of 2 weeks if LVEF recovers to normal and patient is asymptomatic.
Reduced Doses:

• HER2-Positive Metastatic Breast Cancer (in combination with capecitabine): 1000 mg/day
• Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer (in combination with letrozole): 1250 mg/day

GRADE 3 OR GRADE 1 or 2 DIARRHEA WITH COMPLICATING FEATURES (moderate to severe abdominal cramping, Grade 2 or greater nausea or vomiting, decreased performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration): May reintroduce at lower dose when diarrhea resolves to Grade 1 or less.
Reduced Doses:

• HER2-Positive Metastatic Breast Cancer Patients (in combination with capecitabine): 1000 mg/day
• Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer Patients: 1250 mg/day

GRADE 4 DIARRHEA: Permanently discontinue treatment.

OTHER TOXICITIES, GRADE 2 or GREATER: May consider discontinuation or interruption of dosing; may restart at the usual recommended dose when toxicity improves to Grade 1 or less.
IF TOXICITY RECURS: Reduce dose:

• HER2-Positive Metastatic Breast Cancer (in combination with capecitabine): 1000 mg/day
• Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer Patients: 1250 mg/day

Precautions

US BOXED WARNINGS:
Hepatotoxicity:

• Hepatotoxicity, sometimes fatal, has been observed in clinical trials and postmarketing experience.
• Causality of the deaths is uncertain.

CONTRAINDICATIONS:

• Hypersensitivity to the active component or any of the ingredients

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available; however, hemodialysis would not be expected to be an effective method to enhance drug elimination because this drug is not significantly renally excreted (less than 2%) and is highly bound to plasma proteins (more than 99%)

Other Comments

Administration Advice:

• Administer this drug at least 1 hour before or 1 hour after food, and at the same time in relation to food intake (e.g., 1 hour before a meal every day) to minimize variability in the individual patient.
• Capecitabine should be taken with food or within 30 minutes after food.
• Administer the daily dose all at once; do not divide the dose.
• In the event of a missed dose, advise patients to skip those doses and to resume dosing with the next scheduled daily dose.

Storage Requirements:

• Do not store above 30 degrees Celsius.

General:

• The maximum oral dose administered in clinical trials is 1800 mg once a day.
• This drug is not indicated in the adjuvant setting.
• Overdosage: No known antidote; hemodialysis is not expected to be an effective method to enhance drug elimination.
• HER2 (ErbB2) overexpressing tumors are defined by a score of 3+ using an immunohistochemistry-based assessment (IHC3+), IHC2+ with gene amplification, or gene amplification alone.

Monitoring:

• Cardiovascular: Cardiac function, including left ventricular ejection fraction (prior to treatment initiation and approximately every 8 to 12 weeks during treatment); QTc prolongation (prior to and during treatment)
• Gastrointestinal: Change in bowel patterns and diarrhea (regularly during treatment)
• Hematological: Complete blood count (regularly during treatment when this drug is administered in combination with paclitaxel)
• Hepatic: Liver function/transaminases, bilirubin, alkaline phosphatase (prior to treatment initiation, every 4 to 6 weeks during treatment, and as clinically indicated)
• Respiratory: Pulmonary symptoms indicative of interstitial lung disease or pneumonitis (regularly during treatment)

Patient Advice:

• Avoid drinking grapefruit juice and taking any grapefruit products during treatment with this drug.
• Avoid potentially dangerous activities such as driving and operating machinery until you know how this drug affects you.

Frequently asked questions

• Does Tykerb have a good response?
• How does Tykerb work?