Important Safety Information

Boxed WARNINGS: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO­-FETAL TOXICITY

• Do not substitute KADCYLA for or with trastuzumab
• Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin
• Cardiac toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function
• Embryo-fetal toxicity: Exposure to KADCYLA during pregnancy can result in embryo-fetal harm. Advise patients of these risks and the need for effective contraception

Additional Important Safety Information:

Left Ventricular Dysfunction (LVD)

• Patients treated with KADCYLA are at increased risk of developing LVD. In EMILIA, LVD occurred in 1.8% of patients in the KADCYLA-treated group and in 3.3% in the comparator group. Permanently discontinue KADCYLA if LVEF has not improved or has declined further

Embryo-Fetal Toxicity

• Verify the pregnancy status of women of reproductive potential prior to the initiation of KADCYLA
• Advise pregnant women and females of reproductive potential that exposure to KADCYLA during pregnancy or within 7 months prior to conception can result in fetal harm
• Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of KADCYLA
• If KADCYLA is administered during pregnancy or if a patient becomes pregnant while receiving KADCYLA or within 7 months following the last dose of KADCYLA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555
• Encourage women who may be exposed to KADCYLA during pregnancy or within 7 months prior to conception, to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 or visiting http://www.motherpregnancyregistry.com/

Pulmonary Toxicity

• Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or fatal outcome, have been reported in clinical trials with KADCYLA. In EMILIA, the overall frequency of pneumonitis was 1.2%
• Treatment with KADCYLA should be permanently discontinued in patients diagnosed with ILD or pneumonitis

Infusion-Related Reactions, Hypersensitivity Reactions

• Treatment with KADCYLA has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRR) and/or hypersensitivity reactions; treatment with KADCYLA is not recommended for these patients. In EMILIA, the overall frequency of IRRs in patients treated with KADCYLA was 1.4%
• KADCYLA treatment should be interrupted in patients with severe IRRs and permanently discontinued in the event of a life-threatening IRR. Patients should be closely monitored for IRRs, especially during the first infusion

Hemorrhage

• Hemorrhagic events, sometimes fatal, have been reported in clinical trials. In EMILIA, the incidence of ≥Grade 3 hemorrhage was 1.8% in the KADCYLA-treated group and 0.8% in the comparator group (overall incidence 32.2% and 16.4%, respectively)
• In some of the observed cases, the patients were also receiving anticoagulation therapy or antiplatelet therapy, or had thrombocytopenia; in others, there were no known additional risk factors. Use caution with these agents and consider additional monitoring when concomitant use is medically necessary

Thrombocytopenia

• In EMILIA, the incidence of ≥Grade 3 thrombocytopenia was 14.5% in the KADCYLA-treated group and 0.4% in the comparator group (overall incidence 31.2% and 3.3%, respectively)
• Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose. Institute dose modifications as appropriate

Neurotoxicity

• In EMILIA, the incidence of ≥Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the comparator group (overall incidence 21.2% and 13.5%, respectively)
• Monitor for signs or symptoms of neurotoxicity. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or four peripheral neuropathy until resolution to ≤Grade 2

HER2 Testing

• Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA. Perform using FDA-approved tests by laboratories with demonstrated proficiency

Extravasation

• In KADCYLA clinical studies, reactions secondary to extravasation have been observed and were generally mild. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration. Specific treatment for KADCYLA extravasation is unknown

Nursing Mothers

• Discontinue nursing or discontinue KADCYLA, taking into consideration the importance of the drug to the mother

Adverse Reactions

• The most common (frequency >25%) adverse drug reactions (ADR) across clinical trials with KADCYLA were nausea, fatigue, musculoskeletal pain, hemorrhage, thrombocytopenia, increased transaminases, headache, constipation, and epistaxis. In EMILIA, the most common severe adverse reactions Grades ≥3 (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue according to NCI-CTCAE (version 3)

You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.

Please see full Prescribing Information for additional Important Safety Information, including Boxed WARNINGS.