Kadcyla Special Precautions

General: Patients treated with Kadcyla must have confirmed HER2-positive tumor status as assessed by either HER2 protein over-expression or gene amplification.
In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded (or stated) in the patient file.
Pulmonary Toxicity: Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or a fatal outcome, have been reported in clinical trials with Kadcyla (see Adverse Reactions). Signs and symptoms include dyspnea, cough, fatigue, and pulmonary infiltrates.
It is recommended that treatment with Kadcyla be permanently discontinued in patients who are diagnosed with ILD or pneumonitis, except for radiation pneumonitis in the adjuvant setting, where KADCYLA should be permanently discontinued for ≥Grade 3 or for Grade 2 not responding to standard treatment (see Dose Modifications under Dosage & Administration).
Patients with dyspnea at rest due to complications of advanced malignancy, co-morbidities, and receiving concurrent pulmonary radiation therapy may be at increased risk of pulmonary events.
Hepatotoxicity: Hepatotoxicity, predominantly in the form of asymptomatic increases in the concentrations of serum transaminases (Grade 1-4 transaminitis), has been observed while on treatment with Kadcyla in clinical trials (see Adverse Reactions). Transaminase elevations were generally transient with peak elevation at day 8 after therapy and subsequent recovery to Grade 1 or less prior to the next cycle. A cumulative effect of Kadcyla on transaminases has also been observed. Patients with elevated transaminases improved to Grade 1 or normal within 30 days of the last dose of Kadcyla in the majority of the cases. Serious hepatobiliary disorders, including nodular regenerative hyperplasia (NRH) of the liver and some with a fatal outcome due to drug-induced liver injury have been observed in patients treated with Kadcyla in clinical trials. Observed cases may have been confounded by comorbidities and/or concomitant medications with known hepatotoxic potential.
Liver function should be monitored prior to initiation of treatment and each Kadcyla dose. Dose reductions or discontinuation for increased serum transaminases and total bilirubin are specified in Dose Modifications under Dosage & Administration.
Kadcyla has not been studied in patients with serum transaminases >2.5x ULN or total bilirubin >1.5x ULN prior to initiation of treatment. Kadcyla treatment in patients with serum transaminases >3x ULN and concomitant total bilirubin >2x ULN should be permanently discontinued.
Cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies in patients treated with Kadcyla. NRH is a rare liver condition characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to non-cirrhotic portal hypertension. Diagnosis of NRH can be confirmed only by histopathology. NRH should be considered in all patients with clinical symptoms of portal hypertension and/or cirrhosis-like pattern seen on the computed tomography (CT) scan of the liver but with normal transaminases and no other manifestations of cirrhosis. Upon diagnosis of NRH, Kadcyla treatment must be permanently discontinued.
Left Ventricular Dysfunction: Patients treated with Kadcyla are at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) < 40% has been observed in patients treated with Kadcyla, and therefore symptomatic congestive heart failure (CHF) is a potential risk. Standard cardiac function testing (echocardiogram or multigated acquisition (MUGA) scanning) should be performed prior to initiation and at regular intervals (e.g. every three months) during treatment with Kadcyla. Treatment with Kadcyla has not been studied in patients with LVEF <50% prior to initiation of treatment. Specific guidelines regarding dose modifications and discontinuation are provided in Dose Modifications under Dosage & Administration.
Infusion-Related Reactions: Treatment with Kadcyla has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRR); 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 general, these symptoms were not severe (see Adverse Reactions). 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. Kadcyla treatment should be permanently discontinued in the event of a life threatening infusion-related reaction (see Dose Modifications under Dosage & Administration).
Hypersensitivity Reactions: Patients should be observed closely for hypersensitivity reactions, especially during the first infusion. Hypersensitivity, including serious anaphylactic-like reactions, has been observed in clinical trials with treatment of 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 with Kadcyla. Some of these bleeding events resulted in fatal outcomes. In some of the observed cases the patients were also receiving anti-coagulation therapy, 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, or decreased platelet counts, was reported in patients in clinical trials of Kadcyla. The majority of these patients had Grade 1 or 2 events (≥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, the incidence and severity of thrombocytopenia were higher in Asian patients.
Patients with thrombocytopenia (<100,000/mm³) and patients on anti-coagulant treatment should be monitored closely while on Kadcyla treatment. It is recommended that platelet counts are monitored 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 or greater (<50,000/mm³), do not administer Kadcyla until platelet counts recover to Grade 1 (≥75,000/mm³). Please see Dose Modifications under Dosage & Administrations.
Neurotoxicity: Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has been reported in clinical trials of Kadcyla. Treatment with Kadcyla should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until symptoms resolve or improve to ≤Grade 2. Patients should be clinically monitored on an ongoing basis for signs/symptoms of neurotoxicity.
Extravasation: In Kadcyla clinical studies, reactions secondary to extravasation have been observed. These reactions were usually mild and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. These reactions have been observed more frequently within 24 hours of infusion. Specific treatment for Kadcyla extravasation is unknown at this time. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration.
Drug Abuse and Dependence: No data to report.
Ability to Drive and Use Machines: Kadcyla has no or negligible influence on the ability to drive and use machines. The significance of reported adverse reactions such as fatigue, headache, dizziness and blurred vision on the ability to drive or use machines is unknown. Patients experiencing symptoms of infusion related reactions (flushing, shivering fits, fever, trouble breathing, low blood pressure or a rapid heartbeat) should be advised not to drive and use machines until symptoms abate.
Renal Impairment: See Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetic in Special Populations under Actions.
Hepatic Impairment: See Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetic in Special Populations under Actions.
Females and Males of Reproductive Potential: Contraception: Women of child bearing potential and female partners of male patients of child bearing potential should use effective contraception while receiving Kadcyla and for at least 7 months following the last dose of Kadcyla.
Use in Children: Safety and efficacy in pediatric patients below the age of 18 have not been established.
Use in the Elderly: There are insufficient data to establish the safety and efficacy of Kadcyla in patients 75 years of age or older.