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Kadcyla

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Kadcyla

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hepatotoxicity

Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the concentrations of serum transaminases, has been observed in clinical trials with KADCYLA [see ADVERSE REACTIONS]. Serious hepatobiliary disorders, including at least two fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy, have been reported in clinical trials with KADCYLA. Some of the observed cases may have been confounded by comorbidities and/or concomitant medications with known hepatotoxic potential.

Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Patients with known active hepatitis B virus or hepatitis C virus were excluded from Study 1 [see Clinical Studies]. Reduce the dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases and/or total bilirubin [see DOSAGE AND ADMINISTRATION]. Permanently discontinue KADCYLA treatment in patients with serum transaminases > 3 x ULN and concomitant total bilirubin > 2 x ULN. KADCYLA has not been studied in patients with serum transaminases > 2.5 x ULN or bilirubin > 1.5 x ULN prior to the initiation of treatment.

In clinical trials of KADCYLA, cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies (3 cases out of 884 treated patients, one of which was fatal). Two of these three cases of NRH were observed in the randomized trial (Study 1) [see ADVERSE REACTIONS]. 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. The 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. A decrease of LVEF to < 40% has been observed in patients treated with KADCYLA. In the randomized trial (Study 1), left ventricular dysfunction occurred in 1.8% of patients in the KADCYLA-treated group and 3.3% of patients in the lapatinib plus capecitabine-treated group [see ADVERSE REACTIONS].

Assess LVEF prior to initiation of KADCYLA and at regular intervals (e.g. every three months) during treatment to ensure the LVEF is within the institution's normal limits. Treatment with KADCYLA has not been studied in patients with LVEF < 50% prior to initiation of treatment. If, at routine monitoring, LVEF is < 40%, or is 40% to 45% with a 10% or greater 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 [see DOSAGE AND ADMINISTRATION]. Patients with a history of symptomatic congestive heart failure (CHF), serious cardiac arrhythmia, or history of myocardial infarction or unstable angina within 6 months were excluded from Study 1 [see Clinical Studies].

Embryo-Fetal Toxicity

KADCYLA can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of KADCYLA in pregnant women and no reproductive and developmental toxicology studies have been conducted with ado-trastuzumab emtansine. Nevertheless, treatment with trastuzumab, the antibody component of KADCYLA, during pregnancy in the postmarketing setting has resulted in oligohydramnios, some associated with fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. DM1, the cytotoxic component of KADCYLA, can be expected to cause embryo-fetal toxicity based on its mechanism of action.

If KADCYLA is used during pregnancy, or if the patient becomes pregnant while receiving KADCYLA, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations].

Verify pregnancy status prior to the initiation of KADCYLA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If KADCYLA is administered during pregnancy or if a patient becomes pregnant while receiving KADCYLA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see PATIENT INFORMATION].

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. Pneumonitis at an incidence of 0.8% (7 out of 884 treated patients) has been reported, with one case of grade 3 pneumonitis. Signs and symptoms include dyspnea, cough, fatigue, and pulmonary infiltrates. These events may or may not occur as sequelae of infusion reactions. In the randomized trial (Study 1), the overall frequency of pneumonitis was 1.2% [see ADVERSE REACTIONS].

Permanently discontinue treatment with KADCYLA in patients diagnosed with ILD or pneumonitis.

Patients with dyspnea at rest due to complications of advanced malignancy and co-morbidities 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 the randomized trial (Study 1), the overall frequency of IRRs in patients treated with KADCYLA was 1.4% [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 IRR [see DOSAGE AND ADMINISTRATION]. Patients should be observed closely for IRR reactions, 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 the randomized trial (Study 1), the overall frequency of hemorrhage was 32.2% in the KADCYLA-treated group and 16.4% in the lapatinib plus capecitabine-treated group. The incidence of ≥ Grade 3 hemorrhage was 1.8% in the KADCYLA-treated group and 0.8% in the lapatinib plus capecitabine-treated group [see ADVERSE REACTIONS]. Although, 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 count, was reported in clinical trials of KADCYLA (103 of 884 treated patients with ≥ Grade 3; 283 of 884 treated patients with any Grade). 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 the randomized trial (Study 1), the overall frequency of thrombocytopenia was 31.2% in the KADCYLA-treated group and 3.3% in the lapatinib plus capecitabine-treated group [see ADVERSE REACTIONS]. The incidence of ≥ Grade 3 thrombocytopenia was 14.5% in the KADCYLA-treated group and 0.4% in the lapatinib plus capecitabine-treated group. In Asian patients, the incidence of > Grade 3 thrombocytopenia was 45.1% in the KADCYLA-treated group and 1.3% in the lapatinib plus capecitabine-treated group.

Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose [see DOSAGE AND ADMINISTRATION]. 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) [see DOSAGE AND ADMINISTRATION]. Patients with thrombocytopenia ( < 100,000/mm³) and patients on anti-coagulant treatment should be closely monitored during treatment with KADCYLA.

Neurotoxicity

Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of KADCYLA (14 of 884 treated patients with ≥ Grade 3; 196 of 884 treated patients with any Grade). In the randomized trial (Study 1), the overall frequency of peripheral neuropathy was 21.2% in the KADCYLA-treated group and 13.5% in the lapatinib plus capecitabine-treated group [see ADVERSE REACTIONS]. The incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the lapatinib plus capecitabine-treated group.

KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2. Patients should be clinically monitored on an ongoing basis for signs or symptoms of neurotoxicity [see Nonclinical Toxicology].

HER2 Testing

Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA therapy because these are the only patients studied for whom benefit has been shown [see INDICATIONS AND USAGE, Clinical Studies]. In the randomized study (Study 1), patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by Dako Herceptest™ or evidence of overexpression defined as FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH and 0 or 1+ by IHC.

Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of sub-optimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.

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. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies have not been conducted with ado-trastuzumab emtansine.

DM1 was aneugenic or clastogenic in an in vivo single-dose rat bone marrow micronucleus assay at exposures that were comparable to mean maximum concentrations of DM1 measured in humans administered KADCYLA. DM1 was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay.

Based on results from animal toxicity studies, KADCYLA may impair fertility in humans. In a single-dose toxicity study of ado-trastuzumab emtansine in rats, degeneration of seminiferous tubules with hemorrhage in the testes associated with increased weights of testes and epididymides at a severely toxic dose level (60 mg/kg; about 4 times the clinical exposure based on AUC) were observed. The same dose in female rats resulted in signs of hemorrhage and necrosis of the corpus luteum in ovaries. In monkeys dosed with ado-trastuzumab emtansine once every three weeks for 12 weeks (four doses), at up to 30 mg/kg (about 7 times the clinical exposure based on AUC), there were decreases in the weights of epididymides, prostate, testes, seminal vesicles and uterus, although the interpretation of these effects is unclear due to the varied sexual maturity of enrolled animals.

Use In Specific Populations

Pregnancy

Pregnancy Category D

[see WARNINGS AND PRECAUTIONS]

Risk Summary

KADCYLA can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of KADCYLA in pregnant women. No reproductive and developmental toxicology studies have been conducted with ado-trastuzumab emtansine. Nevertheless, two components of KADCYLA (trastuzumab and DM1) are known or suspected to cause fetal harm or death when administered to a pregnant woman. If KADCYLA is administered during pregnancy, or if a patient becomes pregnant while receiving KADCYLA, apprise the patient of the potential hazard to the fetus. Patients should be advised to use effective contraception during treatment with KADCYLA and for 6 months following the last dose of KADCYLA.

If KADCYLA is administered during pregnancy or if a patient becomes pregnant while receiving KADCYLA, immediately report exposure to the Genentech Adverse Event Line at 1-888-8352555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see PATIENT INFORMATION].

Human Data

In the post-marketing setting, treatment with trastuzumab during pregnancy has resulted in cases of oligohydramnios, some associated with fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. These case reports described oligohydramnios in pregnant women who received trastuzumab either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after trastuzumab was stopped. In one case, trastuzumab therapy resumed after the amniotic fluid index improved, and oligohydramnios recurred.

Animal Data

There were no reproductive and developmental toxicology studies conducted with adotrastuzumab emtansine. DM1, the cytotoxic component of KADCYLA, disrupts microtubule function. DM1 is toxic to rapidly dividing cells in animals and is genotoxic, suggesting it has the potential to cause embryotoxicity and teratogenicity. In studies where trastuzumab was administered to pregnant monkeys at doses up to 25 mg/kg (about 7 times the clinical dose), trastuzumab crossed the placental barrier during the early and late phases of gestation. The resulting concentrations of trastuzumab in fetal blood and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse findings.

Nursing Mothers

It is not known whether KADCYLA, specifically, is excreted in human milk, but IgG is known to be excreted in human milk. In lactating monkeys, trastuzumab was excreted in small amounts (about 0.3% of maternal serum concentrations) in breast milk after post-partum doses of 25 mg/kg (about 7 times the clinical dose of KADCYLA). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from KADCYLA, a decision should be made whether to discontinue nursing or discontinue KADCYLA, taking into account the importance of the drug to the mother [see WARNINGS AND PRECAUTIONS].

Pediatric Use

Safety and effectiveness of KADCYLA have not been established in pediatric patients.

Geriatric Use

Of 495 patients who were randomized to KADCYLA in the randomized trial (Study 1) [see Clinical Studies], 65 patients (13%) were ≥ 65 years of age and 11 patients (2%) were ≥ 75 years of age. In patients ≥ 65 years old (n=138 across both treatment arms) the hazard ratios for progression-free survival (PFS) and Overall Survival (OS) were 1.06 (95% CI: 0.68, 1.66) and 1.05 (95% CI: 0.58, 1.91), respectively.

Population pharmacokinetic analysis indicates that age does not have a clinically meaningful effect on the pharmacokinetics of ado-trastuzumab emtansine [see CLINICAL PHARMACOLOGY].

Females Of Reproductive Potential

KADCYLA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving KADCYLA and for 6 months following the last dose of KADCYLA.

If KADCYLA is administered during pregnancy or if the patient becomes pregnant while receiving KADCYLA, immediately report exposure to the Genentech Adverse Event Line at 1888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see PATIENT INFORMATION].

Renal Impairment

No dedicated renal impairment trial for KADCYLA has been conducted. Based on the population pharmacokinetics, as well as analysis of Grade 3 or greater adverse drug reactions and dose modifications, dose adjustments of KADCYLA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 89 mL/min) or moderate (CLcr 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited data available [see CLINICAL PHARMACOLOGY].

Hepatic Impairment

In vitro studies in human liver microsomes indicates that DM1 is metabolized by CYP3A4/5. The influence of hepatic impairment on the pharmacokinetics of ado-trastuzumab emtansine conjugate has not been determined.

Last reviewed on RxList: 7/29/2014
This monograph has been modified to include the generic and brand name in many instances.

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