Prescribing Information | Important Safety Information | For Patients and Caregivers

Adverse events


The safety of TYKERB has been evaluated in more than 3,500 patients in clinical trials. The efficacy and safety of TYKERB in combination with capecitabine in breast cancer was evaluated in 198 patients in a randomized, phase III clinical trial. Adverse reactions that occurred in at least 10% of patients in either treatment arm are shown in the table below.

  • Among 198 patients who received the TYKERB-capecitabine combination treatment, three experienced an asymptomatic (grade 2) decrease in LVEF and one experienced a symptomatic (grade 3) decrease in LVEF
  • Hepatotoxicity, an ALT or AST that is more than 3 times the upper limit of normal and total bilirubin that is less than 1.5 times the upper limit of normal, has been observed in clinical trials in less than 1% of patients and in postmarketing experience. Hepatotoxicity may be severe and deaths have been reported. The cause of those deaths is uncertain
  • Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis and if symptoms are ≥ Grade 3 (NCI CTCAE), TYKERB should be discontinued
  • The most common adverse reactions (>20%) during therapy with TYKERB plus capecitabine were gastrointestinal (diarrhea, nausea, and vomiting), dermatologic (palmar-plantar erythrodysesthesia and rash), and fatigue. Diarrhea was the most common adverse reaction resulting in discontinuation of study medication1

Table 1. Adverse Reactions Occurring in ≥10% of Patients

  TYKERB 1,250 mg/day +
Capecitabine
2,000 mg/m2/day		 Capecitabine
2,500 mg/m2/day
  (N = 198) (N = 191)
  All Grades* Grade
3		 Grade
4		 All Grades* Grade
3		 Grade
4
Reactions % % % % % %
Gastrointestinal disorders
Diarrhea 65 13 1 40 10 0
Nausea 44 2 0 43 2 0
Vomiting 26 2 0 21 2 0
Stomatitis 14 0 0 11 <1 0
Dyspepsia 11 <1 0 3 0 0
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia 53 12 0 51 14 0
Rash† 28 2 0 14 1 0
Dry skin 10 0 0 6 0 0
General disorders and administrative site conditions
Mucosal inflammation 15 0 0 12 2 0
Musculoskeletal and connective tissue disorders
Pain in extremity 12 1 0 7 <1 0
Back pain 11 1 0 6 <1 0
Respiratory, thoracic, and mediastinal disorders
Dyspnea 12 3 0 8 2 0
Psychiatric disorders
Insomnia 10 <1 0 6 0 0


*National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.
†Grade 3 dermatitis acneiform was reported in <1% of patients in TYKERB plus capecitabine group.1

Diarrhea events
In 9 clinical trials of 1,419 TYKERB-treated patients, 52% of patients taking TYKERB reported diarrhea.2

• Grade

  • 42% had grade 1 or 2 (mild or moderate)
  • 9% had grade 3 (severe)
  • <1% had grade 4 (life threatening)
• Onset and Duration

  • 42% of patients with diarrhea developed it within the first
    6 days
  • 20% of patients had a first diarrhea event between days
    6-14
  • 14% of patients had a first diarrhea event between days
    15-28
  • 23% of patients with diarrhea had it >28 days after treatment initiation
• Management and Resolution

  • Most patients who required intervention responded to standard antidiarrheal medications (eg, loperamide and Lomotil®). In more severe cases, management included hydration, octreotide, and antibiotics
  • 85% of patients with diarrhea did not require dose adjustment or interruption; 2% discontinued treatment2
Lomotil is a registered trademark of Pfizer Inc.

Skin events
In 9 clinical trials of 1,419 TYKERB-treated patients, 59% of patients taking TYKERB experienced skin events.2*

  • Rash was rarely severe; 6% of patients developed grade 3 rash, and no patients developed grade 4 rash
  • 46% of skin events developed early, within the first 14 days of treatment
  • The median duration was 25 days
  • In 87% of events, intervention, dose adjustment, or treatment interruption was not required
  • 1% of patients discontinued treatment because of skin events2
See Managing treatment effects for information on helping your patients who may experience adverse events during treatment with TYKERB.

*Excludes PPE.

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Indication
TYKERB is indicated in combination with Xeloda® (capecitabine) for the 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 Herceptin® (trastuzumab).

Dose Modification Guidelines
For dose modification guidelines, please see complete Prescribing Information.

BOXED WARNING and Additional Important Safety Information

Hepatotoxicity
TYKERB has been associated with hepatotoxicity. Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >1.5 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with TYKERB should be discontinued and patients should not be re-treated with TYKERB.

Decreased Left Ventricular Ejection Fraction
TYKERB has been reported to decrease LVEF. Caution should be taken if TYKERB is to be administered to patients with preexisting cardiac conditions, including uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure. Confirm normal LVEF before starting TYKERB, and continue evaluations during treatment.

Patients with Severe Hepatic Impairment
If TYKERB is to be administered to patients with severe hepatic impairment, dose reduction should be considered.

Diarrhea
Diarrhea, including severe diarrhea, has been reported during treatment with TYKERB and was the most common adverse reaction resulting in discontinuation of TYKERB therapy. Proactive management of diarrhea with anti-diarrheal agents is important, and severe cases of diarrhea may require administration of oral or intravenous electrolytes and fluids, and interruption or discontinuation of therapy with TYKERB.

Interstitial Lung Disease/Pneumonitis
TYKERB has been associated with interstitial lung disease and pneumonitis. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis and if symptoms are ≥ Grade 3 (NCI CTCAE), TYKERB should be discontinued.

QT Prolongation
TYKERB prolongs the QT interval in some patients. TYKERB should be administered with caution to patients who have or may develop prolongation of QTc. Hypokalemia or hypomagnesemia should be corrected prior to TYKERB administration. Baseline and on-treatment electrocardiograms with QT measurement should be considered.

Pregnancy
Pregnancy D
TYKERB can cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant when taking TYKERB. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions
The most common adverse reactions (>20%) during therapy with TYKERB plus capecitabine compared to capecitabine alone were diarrhea (65%, 40%), nausea (44%, 43%), vomiting (26%, 21%), palmar-plantar erythrodysesthesia (53%, 51%), rash (28%, 14%), and fatigue (46%, 47%).

The most common grade 3 and 4 adverse reactions (NCI CTC v3) with TYKERB plus capecitabine compared to capecitabine alone were diarrhea (14%, 10%) and palmar-plantar erythrodysesthesia (12%, 14%).

Please see full prescribing information, including BOXED WARNING.

Xeloda is a registered trademark of Roche Laboratories Inc.

Herceptin is a registered trademark of Genentech, Inc.

References:

  1. TYKERB [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2008
  2. Data on file. GlaxoSmithKline.

     

               

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