Left Ventricular Dysfunction

Patients treated with KADCYLA are at increased risk of developing left ventricular dysfunction. A decrease of LVEF to <40% has been observed in patients treated with KADCYLA. Serious cases of heart failure, with no fatal cases, have been observed in clinical trials with KADCYLA.

In EMILIA, left ventricular dysfunction occurred in 1.8% of patients in the KADCYLA group and 3.3% of patients in the lapatinib + capecitabine group. In KATHERINE, left ventricular dysfunction occurred in 0.4% of patients in the KADCYLA group and 0.6% of patients in the trastuzumab group.

Based on limited data from a retrospective observational study, 22% (7 of 32) of patients with HER2-positive MBC with a baseline LVEF of 40-49% treated with KADCYLA developed congestive heart failure (CHF) or a >10% reduction in LVEF.

Assess LVEF prior to initiation of KADCYLA and at regular intervals (e.g. every 3 months) during treatment to ensure the LVEF is within the institution’s normal limits. KADCYLA has not been studied in an adequately controlled study in patients with LVEF <50%.

For patients with MBC, if at routine monitoring LVEF is <40%, or is 40% to 45% with a ≥10% absolute decrease below the pretreatment value, withhold KADCYLA and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue KADCYLA if the LVEF has not improved or has declined further.

For patients with EBC, if at routine monitoring LVEF is <45%, or is 45% to 49% with a ≥10% absolute decrease below the pretreatment value, withhold KADCYLA and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue KADCYLA if the LVEF has not improved or has declined further.

Embryo-Fetal Toxicity

KADCYLA can cause fetal harm when administered to a pregnant woman. Cases of oligohydramnios, and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities and neonatal death were observed in the post-marketing setting in patients treated with trastuzumab, the antibody component of KADCYLA. DM1, the cytotoxic component of KADCYLA, can cause embryo-fetal toxicity, based on its mechanism of action.

Verify the pregnancy status of females 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. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with KADCYLA and for 4 months following the last dose.

If KADCYLA is administered during pregnancy, or if a patient becomes pregnant while receiving KADCYLA or within 7 months of the last dose of KADCYLA, immediately report exposure to Genentech at 1-888-835-2555.

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. Signs and symptoms include dyspnea, cough, fatigue, and pulmonary infiltrates.

In patients with MBC, pneumonitis was reported at an incidence of 0.8% (7 out of 884 treated patients), with one case of Grade 3 pneumonitis. The overall incidence of pneumonitis was 1.2% in EMILIA.

In KATHERINE, pneumonitis was reported at an incidence of 1.1% (8 out of 740 patients treated with KADCYLA), with one case of Grade 3 pneumonitis. Radiation pneumonitis was reported at an incidence of 1.8% (11 out of 623 patients treated with adjuvant radiotherapy and KADCYLA), with 2 cases of Grade 3 radiation pneumonitis.

Permanently discontinue treatment with KADCYLA in patients diagnosed with ILD or pneumonitis. For patients with radiation pneumonitis in the adjuvant setting, KADCYLA should be permanently discontinued for Grade ≥ 3 or for Grade 2 not responding to standard treatment.

Patients with dyspnea at rest due to complications of advanced malignancy and comorbidities and receiving concurrent pulmonary radiation therapy may be at increased risk of pulmonary toxicity.

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; treatment with KADCYLA is not recommended for these patients.

Infusion-related reactions, characterized by one or more of the following symptoms—flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, and tachycardia—have been reported in clinical trials of KADCYLA. In EMILIA, the overall incidence of IRR in patients treated with KADCYLA was 1.4%. In KATHERINE, the overall incidence of IRR in patients treated with KADCYLA was 1.6%. In most patients, these reactions resolved over the course of several hours to a day after the infusion was terminated.

KADCYLA treatment should be interrupted in patients with severe IRR and permanently discontinued in the event of a life-threatening IRR. Patients should be observed closely for IRR, especially during the first infusion.

One case of a serious, allergic/anaphylactic-like reaction has been observed in clinical trials of single-agent KADCYLA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use.

Hemorrhage

Cases of hemorrhagic events, including central nervous system, respiratory, and gastrointestinal hemorrhage, have been reported in clinical trials with KADCYLA. Some of these bleeding events resulted in fatal outcomes. In EMILIA, the overall incidence of hemorrhage was 32% in the KADCYLA group and 16% in the lapatinib + capecitabine group. The incidence of Grade ≥ 3 hemorrhage was 1.8% in the KADCYLA group and 0.8% in the lapatinib + capecitabine group. In KATHERINE, the overall incidence of hemorrhage was 29% in the KADCYLA group and 10% in the trastuzumab group. The incidence of Grade ≥ 3 hemorrhage was 0.4% in the KADCYLA group, with one fatal case of intracranial hemorrhage, and 0.3% in the trastuzumab group.

Although 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

Thrombocytopenia was reported in clinical trials of KADCYLA. The majority of these patients had Grade 1 or 2 events (< LLN to ≥50,000/mm³) with the nadir occurring by day 8 and generally improving to Grade 0 or 1 (≥75,000/mm³) by the next scheduled dose. In clinical trials of KADCYLA, the incidence and severity of thrombocytopenia were higher in Asian patients.

In EMILIA, the overall incidence of thrombocytopenia was 31% in the KADCYLA group and 3.3% in the lapatinib + capecitabine group. The incidence of Grade ≥ 3 thrombocytopenia was 15% in the KADCYLA group and 0.4% in the lapatinib + capecitabine group. In Asian patients, the incidence of Grade ≥ 3 thrombocytopenia was 45% and 1.3%, respectively.

In KATHERINE, the overall incidence of thrombocytopenia was 29% in the KADCYLA group and 2.4% in the trastuzumab group. The incidence of Grade ≥ 3 thrombocytopenia was 6% in the KADCYLA group and 0.3% in the trastuzumab group. In Asian patients, the incidence of Grade ≥ 3 thrombocytopenia was 19% and 0%, respectively. The overall incidence of thrombocytopenia in the KADCYLA group for Asian patients was 50%.

Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose. KADCYLA has not been studied in patients with platelet counts <100,000/mm³ prior to initiation of treatment. In the event of decreased platelet count to Grade ≥ 3 (<50,000/mm³), do not administer KADCYLA until platelet counts recover to Grade 1 (≥75,000/mm³). Closely monitor patients with thrombocytopenia (< 100,000/mm³) and patients on anti-coagulant treatment during treatment with KADCYLA.

Neurotoxicity

Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of KADCYLA. In EMILIA, the overall incidence of peripheral neuropathy was 21% in the KADCYLA group and 14% in the lapatinib + capecitabine group. The incidence of Grade ≥ 3 peripheral neuropathy was 2.2% and 0.2%, respectively.

In KATHERINE, the overall incidence of peripheral neuropathy was 32% in the KADCYLA group and 17% in the trastuzumab group. Peripheral neuropathy, including sensory and motor peripheral neuropathy, was not resolved in 30% of cases for KADCYLA treated patients at the time of the primary IDFS analysis for KATHERINE. The incidence of Grade ≥ 3 peripheral neuropathy was 1.6% in the KADCYLA group and 0.1% in the trastuzumab group.

KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to Grade ≤ 2. Monitor patients on an ongoing basis for signs/symptoms of neurotoxicity.

Extravasation

In KADCYLA clinical studies, reactions secondary to extravasation have been observed. These reactions, observed more frequently within 24 hours of infusion, were usually mild and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. Specific treatment for KADCYLA extravasation is unknown. Closely monitor the infusion site for possible subcutaneous infiltration during drug administration.

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