Kadcyla

Kadcyla

Manufacturer:

Roche

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Trastuzumab emtansine.
Description
Active ingredient: Trastuzumab emtansine.
100 mg single-use vial containing powder for concentrate for infusion solution designed to deliver 5 ml of 20 mg/ml of trastuzumab emtansine.
160 mg single-use vial containing powder for concentrate for infusion solution designed to deliver 8 ml of 20 mg/ml of trastuzumab emtansine.
Excipients/Inactive Ingredients: Succinic acid, sodium hydroxide, polysorbate 20, sucrose.
Action
Pharmacotherapeutic Group: Antibody drug conjugate antineoplastic agent. ATC Code: Not yet available.
Pharmacology: Pharmacodynamics: Mechanism of Action: Kadcyla, trastuzumab emtansine, is a HER2-targeted antibody-drug conjugate which contains the humanised anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitory drug DM1 (a maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate). Emtansine refers to the MCC-DM1 complex. An average of 3.5 DM1 molecules are conjugated to each molecule of trastuzumab.
Conjugation of DM1 to trastuzumab confers selectivity of the cytotoxic agent for HER2-overexpressing tumour cells, thereby increasing intracellular delivery of DM1 directly to malignant cells. Upon binding to HER2, trastuzumab emtansine undergoes receptor-mediated internalisation and subsequent lysosomal degradation, resulting in release of DM1-containing cytotoxic catabolites (primarily lysine-MCC-DM1). Kadcyla has the mechanisms of action of both trastuzumab and DM1.
Trastuzumab emtansine, like trastuzumab, binds to domain IV of the HER2 extracellular domain (ECD), as well as to Fcγ receptors and complement C1q. In addition, Kadcyla, like trastuzumab, inhibits shedding of the HER2 ECD, inhibits signalling through the phosphatidylinositol 3-kinase (PI3-K) pathway, and mediates antibody-dependent cell-mediated cytotoxicity (ADCC) in human breast cancer cells that overexpress HER2.
DM1, the cytotoxic drug component of Kadcyla, binds to tubulin. By inhibiting tubulin polymerisation, both DM1 and Kadcyla cause cells to arrest in the G2/M phase of the cell cycle, ultimately leading to apoptotic cell death. Results from in vitro cytotoxicity assays show that DM1 is 20-200 times more potent than taxanes and vinca alkaloids.
The MCC linker is designed to limit systemic release and increase targeted delivery of DM1, as demonstrated by detection of very low levels of free DM1 in plasma.
Clinical/Efficacy Studies: Efficacy: Metastatic Breast Cancer: A Phase III, randomised, multicentre, international, open-label clinical trial (TDM4370g/BO21977) was conducted in patients with HER2-positive unresectable locally advanced breast cancer or MBC who had received prior taxane and trastuzumab-based therapy, including patients who received prior therapy with trastuzumab and a taxane in the adjuvant setting and who relapsed within six months of completing adjuvant therapy. Prior to enrollment, breast tumour samples were required to be centrally confirmed for HER2-positive disease defined as a score of 3+ by IHC or gene amplification by ISH. Baseline patient and tumour characteristics were well balanced between treatment groups. For patients randomised to Kadcyla, the median age was 53 years, most patients were female (99.8%), the majority were Caucasian (72%), and 57% had estrogen-receptor and/or progesterone-receptor positive disease. The study compared the safety and efficacy of Kadcyla with that of lapatinib plus capecitabine. A total of 991 patients were randomised with Kadcyla or lapatinib plus capecitabine as follows: Kadcyla Arm: Kadcyla 3.6 mg/kg intravenously (IV) over 30-90 minutes on Day 1 of a 21-day cycle.
Control Arm (lapatinib plus capecitabine): lapatinib 1250 mg/day orally once per day of a 21-day cycle plus capecitabine 1000 mg/m2 orally twice daily on Days 1-14 of a 21-day cycle.
The co-primary efficacy endpoints of the study were progression-free survival (PFS) as assessed by an independent review committee (IRC), and overall survival (OS) and landmark (1-year and 2-year) survival rates.
Time to symptom progression, as defined by a 5-point decrease in the score derived from the trials outcome index-breast (TOI-B) subscale of the Functional Assessment of Cancer Therapy-Breast Quality of Life (FACT-B QoL) questionnaire was also assessed during the clinical trial. A change of 5 points in the TOI-B is considered clinically significant. (See Table 1.)

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A treatment benefit was seen in the subgroup of patients who had not received any prior systemic anti-cancer therapy in the metastatic setting (n=118); hazard ratios for PFS and OS were 0.51 (95% CI: 0.30, 0.85) and 0.61 (95% CI: 0.32, 1.16), respectively. The median PFS and OS for the KADCYLA group were 10.8 months and not reached, respectively, compared with 5.7 months and 27.9 months, respectively, for the lapatinib plus capecitabine group. (See Figure 1 and Figure 2.)

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A randomised, multicentre, open-label Phase II study (TDM4450g/BO21976) evaluated the effects of Kadcyla versus trastuzumab plus docetaxel in patients with HER2-positive MBC who had not received prior chemotherapy for metastatic disease. Patients were randomised to receive Kadcyla 3.6 mg/kg IV every 3 weeks (n=67) or trastuzumab 8 mg/kg IV loading dose followed by 6 mg/kg IV every 3 weeks plus docetaxel 75-100 mg/m2 IV every 3 weeks (n=70).
The primary endpoint was PFS assessed by investigator. The median PFS was 9.2 months in the trastuzumab plus docetaxel arm and 14.2 months in the Kadcyla arm (hazard ratio, 0.59; p = 0.035), with a median follow-up of approximately 14 months in both arms. The ORR was 58.0% with trastuzumab plus docetaxel and 64.2% with Kadcyla. The median duration of response was not reached with Kadcyla vs. median duration 9.5 months in the control arm.
The worsening of the FACT-B TOI scores was delayed in the Kadcyla arm compared with the control arm (median time to symptom progression was 7.5 months in the Kadcyla arm vs. 3.5 months in the control arm; hazard ratio, 0.58; p = 0.022).
A Phase II, single-arm, open-label study (TDM4374g) evaluated the effects of Kadcyla in patients with HER2-positive incurable advance breast cancer, or MBC. All patients were previously treated with HER2-directed therapies (trastuzumab and lapatinib), and chemotherapy (anthracycline, taxane, and capecitabine) in the neoadjuvant, adjuvant, locally advanced, or metastatic setting. The median number of anti-cancer agents that patients received in any setting was 8.5 (range 5-19) and in the metastatic setting was 7.0 (range 3-17), including all agents intended for the treatment of breast cancer.
Patients (n=110) received 3.6 mg/kg of Kadcyla intravenously every 3 weeks until disease progression or unacceptable toxicity.
The key efficacy analyses were ORR based on independent radiologic review and duration of objective response. The ORR was 32.7% (95% CI: 24.1, 42.1), n=36 responders, by both IRC and investigator review. The median duration of response by IRC was not reached (95% CI, 4.6 months to not estimable).
Immunogenicity: As with all therapeutic proteins, there is the potential for an immune response to trastuzumab emtansine. Among 836 patients from six clinical studies tested at multiple time points for anti-therapeutic antibody (ATA) responses to Kadcyla. Forty four patients (5.3%) tested positive for anti-Kadcyla antibodies at one or more postdose time points; 28 of these patients had negative baseline samples. The clinical significance of anti-trastuzumab emtansine antibodies is not yet known.
Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of incidence of antibodies to Kadcyla with the incidence of antibodies to other products may be misleading.
Pharmacokinetics: Absorption: Kadcyla is administered IV. There have been no studies performed with other routes of administration.
Distribution: Kadcyla when administered intravenously every 3 weeks exhibited linear pharmacokinetics across doses ranging from 2.4 to 4.8 mg/kg; patients who received doses less than or equal to 1.2 mg/kg had faster clearance.
Patients in TDM4370g/BO21977 who received 3.6 mg/kg of Kadcyla intravenously every 3 weeks had a mean maximum serum concentration (Cmax) of trastuzumab emtansine of 83.4 (±16.5) μg/ml. Based on population pharmacokinetic analysis, following intravenous administration, the central volume of distribution of trastuzumab emtansine was (3.13 l) and approximated that of plasma volume.
Metabolism: Trastuzumab emtansine is expected to undergo deconjugation and catabolism by means of proteolysis in cellular lysosomes, with no significant involvement of cytochrome P450 isoenzymes. Catabolites including Lys-MCC-DM1, MCC-DM1 and DM1 are detected at low levels in human plasma.
In vitro metabolism studies in human liver microsomes suggest that DM1, a small molecule component of trastuzumab emtansine, is metabolised mainly by CYP3A4 and to a lesser extent by CYP3A.
DM1 did not inhibit major CYP450 enzymes in vitro. In vitro, DM1 was a substrate of P-glycoprotein (P-gp).
Elimination: Based on population pharmacokinetic (PK) analysis, following IV administration of Kadcyla in patients with HER2-positive metastatic breast cancer, the clearance of Kadcyla was 0.68 l/day and the elimination half-life (t1/2) was approximately 4 days. No accumulation of Kadcyla was observed after repeated dosing of IV infusion every 3 weeks.
Based on a population PK analysis (n=671), body weight, albumin, sum of longest diameter of target lesions by RECIST, HER2 ECD, baseline trastuzumab concentrations and AST were identified as statistically significant covariates for trastuzumab emtansine pharmacokinetic parameters. However, the magnitude of effect of these covariates on trastuzumab emtansine exposure suggests that, with the exception of body weight, these covariates are unlikely to have any clinically meaningful effect on KADCYLA exposure. Therefore, the body weight based dose of 3.6 mg/kg every 3 weeks without correction for other covariates is considered appropriate. In nonclinical studies, catabolites of trastuzumab emtansine including DM1, Lys-MCC-DM1, and MCC-DM1 are mainly excreted in the bile with minimal elimination in urine.
Pharmacokinetics in Special Populations: The population pharmacokinetic analysis of Kadcyla showed that race did not appear to influence the pharmacokinetics of Kadcyla. Because most of the patients in Kadcyla clinical studies were females, effect of gender on the pharmacokinetics of Kadcyla was not formally evaluated.
Geriatric use: The population pharmacokinetic analysis of Kadcyla showed that age did not affect the pharmacokinetics of Kadcyla. No significant difference was observed in the pharmacokinetics of Kadcyla among patients <65 years (n=577), patients between 65 and 75 years (n=78) and patients >75 years (n=16).
Renal impairment: The population pharmacokinetic analysis of Kadcyla showed that creatinine clearance does not affect pharmacokinetics of Kadcyla. Pharmacokinetics of Kadcyla in patients with mild (creatinine clearance CLcr 60-89 ml/min, n=254) or moderate (CLcr 30-59 ml/min, n=53) renal impairment were similar to those in patients with normal renal function (CLcr ≥90 ml/min, n=361). Pharmacokinetic data in patients with severe renal impairment (CLcr 15-29 ml/min) is limited (n=1), therefore no dosage recommendations can be made.
Hepatic impairment: The liver is a primary organ for eliminating DM1 and DM1-containing catabolites. The pharmacokinetics of trastuzumab emtansine and DM1-containing catabolites were evaluated after the administration of 3.6 mg/kg of Kadcyla to metastatic HER2- positive breast cancer patients with normal hepatic function (n=10), mild (Child-Pugh A; n=10) and moderate (Child-Pugh B; n=8) hepatic impairment.
Plasma concentrations of DM1 and DM1-containing catabolites (Lys-MCC-DM1 and MCC-DM1) were low and comparable between patients with and without hepatic impairment.
Systemic exposures (AUC) of trastuzumab emtansine at Cycle 1 in patients with mild and moderate hepatic impairment were approximately 38% and 67% lower than that of patients with normal hepatic function, respectively. Trastuzumab emtansine exposure (AUC) at Cycle 3 after repeated dosing in patients with mild or moderate hepatic dysfunction was within the range observed in patients with normal hepatic function.
Kadcyla has not been studied in patients with severe hepatic impairment (Child-Pugh class C).
Toxicology: Preclinical Safety: Administration of trastuzumab emtansine was well tolerated in rats and monkeys at doses up to 20 and 10 mg/kg, respectively, corresponding to 2040 μg DM1/m2 in both species, which is approximately equivalent to the clinical dose of trastuzumab emtansine in patients. In the GLP toxicity studies, with the exception of irreversible peripheral axonal toxicity (observed only in monkeys at ≥ 10 mg/kg) and reproductive organ toxicity (observed only in rats at 60 mg/kg), partially or completely reversible dose dependent toxicities were identified in both animal models. Principal toxicities included liver (liver enzyme elevations) at ≥ 20 mg/kg and ≥ 10 mg/kg, bone marrow (reduced platelet and white blood cell count)/hematologic at ≥ 20 mg/kg and ≥ 10 mg/kg, and lymphoid organs at ≥ 20 mg/kg and ≥ 3 mg/kg, in rat and monkey, respectively.
Carcinogenicity: Trastuzumab emtansine has not been tested for carcinogenicity.
Mutagenicity: No evidence of mutagenic activity was observed in an in vitro bacterial reverse mutation assay of DM1. In an in vivo micronucleus assay of trastuzumab emtansine in cynomolgus monkeys, no evidence of chromosomal damage to bone marrow cells was observed. However, in a rat bone marrow micronucleus assay, DM1 was positive for micronuclei formation after a single low dose in the DM1 concentration range measured in humans given trastuzumab emtansine, confirming that trastuzumab emtansine is an aneugen and/or clastogen.
Impairment of Fertility: Dedicated fertility have not been conducted with trastuzumab emtansine. However, based on results from general animal toxicity studies, adverse effects on fertility can be expected.
Teratogenicity: Dedicated embryo-fetal development studies have not been conducted in animals with trastuzumab emtansine. Development toxicity of trastuzumab has been identified in the clinical setting although it was not predicted in the non-clinical programme. In addition, developmental toxicity of maytansine has been identified in non-clinical studies which suggests that DM1, the microtubule-inhibiting cytotoxic maytansinoid drug component of trastuzumab emtansine, will be similarly teratogenic and potentially embryotoxic.
Indications/Uses
Breast Cancer: Metastatic Breast Cancer (MBC): Kadcyla, as a single agent, is indicated for the treatment of adult patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: Received prior therapy for locally advanced or metastatic disease, or Developed disease recurrence during or within six months of completing adjuvant therapy.
Dosage/Direction for Use
In order to prevent medication errors it is important to check the vial labels to ensure that the drug being prepared and administered is Kadcyla (trastuzumab emtansine) and not trastuzumab.
Kadcyla therapy should only be administered under the supervision of a healthcare professional experienced in the treatment of cancer patients.
Patients treated with Kadcyla should have HER2 positive tumour status, defined as a score of 3+ by immunohistochemistry (IHC) or a ratio of ≥2.0 by in situ hybridization (ISH) assessed by a validated test.
In order to improve traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly recorded (or stated) in the patient file.
Substitution by any other biological medicinal product requires the consent of the prescribing physician.
Kadcyla must be reconstituted and diluted by a healthcare professional and administrated as an intravenous infusion (see Special Instructions for Use, Handling and Disposal under Cautions for Usage). Do not administer as an intravenous push or bolus.
Schedule: The recommended dose of Kadcyla is 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. Administer the initial dose as a 90-minute intravenous infusion. Patients should be observed during the infusion and for at least 90 minutes following the initial dose for fever, chills, or other infusion-related reactions. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration (see General: Extravasation under Precautions).
If prior infusions were well tolerated, subsequent doses of Kadcyla may be administered as 30-minute infusions and patients should be observed during the infusions and for at least 30 minutes after infusion.
The infusion rate of Kadcyla should be slowed or interrupted if the patient develops infusion-related symptoms (see General under Precautions). Discontinue Kadcyla for life-threatening infusion reactions.
Delayed or missed dose: If a planned dose is missed, it should be administered as soon as possible; do not wait until the next planned cycle. The schedule of administration should be adjusted to maintain a 3-week interval between doses. The infusion may be administered at the rate the patient tolerated the most recent infusion.
Dose modifications: Management of symptomatic adverse events may require temporary interruption, dose reduction, or treatment discontinuation of Kadcyla as per guidelines provided in Tables 2-6.
Kadcyla dose should not be re-escalated after a dose reduction is made. (See Table 2, Table 3, Table 4, Table 5 and Table 6.)

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Special Dosage Instructions: Elderly: No dose adjustment of Kadcyla is required in patients aged ≥65 years (see Use in Elderly under Precautions).
Children: The safety and efficacy of Kadcyla in pediatric patients have not been established.
Renal impairment: No adjustment to the starting dose of Kadcyla is needed in patients with mild or moderate renal impairment (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions). The potential need for dose adjustment in patients with severe renal impairment cannot be determined due to insufficient data and therefore patients with severe renal impairment should be monitored carefully).
Method of administration: Trastuzumab emtansine must be reconstituted and diluted by a healthcare professional and administered as an intravenous infusion. It must not be administered as an intravenous push or bolus.
For instructions on reconstitution and dilution of the medicinal product before administration, see Special Instructions for Use, Handling and Disposal under Cautions for Usage.
Hepatic impairment: No adjustment to the starting dose is required for patients with mild or moderate hepatic impairment (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions). Kadcyla was not studied in patients with severe hepatic impairment. Treatment of patients with hepatic impairment should be undertaken with caution due to known hepatotoxicity observed with Kadcyla (see General: Hepatotoxicity under Precautions).
Overdosage
There is no known antidote for trastuzumab emtansine overdose. In case of overdose, the patient should be closely monitored. Cases of overdose have been reported with trastuzumab emtansine, most associated with thrombocytopenia, and there was one death. In the fatal case, the patient incorrectly received trastuzumab emtansine 6 mg/kg and died approximately 3 weeks following the overdose; a cause of death and a causal relationship to Kadcyla were not established.
Contraindications
Kadcyla is contraindicated in patients with a known hypersensitivity to Kadcyla or any of its excipients.
Special Precautions
General: Patients treated with Kadcyla must have confirmed HER2-positive tumour status as assessed by either HER2 protein over-expression or gene amplification.
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.
Patients with dyspnea at rest due to complications of advanced malignancy and co-morbidities 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 >2.5 × ULN or total bilirubin >1.5 × ULN prior to initiation of treatment. Kadcyla treatment in patients with serum transaminases >3 × ULN and concomitant total bilirubin >2 × 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 characterised 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, characterised 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). See Dose modifications under Dosage & Administration.
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.
Ability to Drive and Use Machines: Studies on the effects on the ability to drive and use machines have not been performed.
Renal Impairment: See Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Hepatic Impairment: See Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Use in Children: The safety and efficacy of Kadcyla in children below 18 years of age have not been established.
Use in Elderly: There are insufficient data to established the safety and efficacy of Kadcyla in patients 75 years of age or older.
Use In Pregnancy & Lactation
Pregnancy: There are no clinical studies of Kadcyla in pregnant women. No reproductive and developmental toxicology studies have been conducted with Kadcyla.
Trastuzumab, a component of Kadcyla, can cause fetal harm or death when administered to a pregnant woman. In the post-marketing setting, cases of oligohydramnios, some associated with fatal pulmonary hypoplasia, have been reported in pregnant women receiving trastuzumab. Animal studies of maytansine, a closely related chemical entity of the same maytansinoid class as DM1, suggest that DM1, the microtubule inhibiting cytotoxic drug component of Kadcyla, is expected to be teratogenic and potentially embryotoxic.
Administration of Kadcyla to pregnant women is not recommended. Women who become pregnant must contact their doctor and should be advised of the possibility of harm to the fetus. If a pregnant woman is treated with Kadcyla, close monitoring by a multidisciplinary team is recommended.
Women of childbearing potential: Patients should be advised to use effective contraception during treatment with Kadcyla and for at least 7 months after treatment has concluded.
Nursing Mothers: It is known whether Kadcyla is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Kadcyla, women should discontinue nursing prior to initiating treatment with Kadcyla. Women may begin nursing 7 months after concluding treatment.
Adverse Reactions
Clinical Trials: The safety of Kadcyla has been evaluated in 1871 patients in clinical trials. Table 7 summarises the adverse drug reactions (ADRs) that have been reported in association with the use of Kadcyla in clinical trials.
In this section, the following categories of frequency have been used: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100). (See Table 7.)

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Laboratory Abnormalities: The following table displays laboratory abnormalities observed in patients treated with Kadcyla in clinical trials TDM4370g/BO21977. (See Table 8.)

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Drug Interactions
No formal drug-drug interaction studies with Kadcyla in humans have been conducted. In vitro metabolism studies in human liver microsomes suggest that DM1, a component of trastuzumab emtansine, is metabolised mainly by CYP3A4 and, to a lesser extent, by CYP3A5. DM1 does not induce or inhibit P450-mediated metabolism in vitro. Caution should be taken when Kadcyla is co-administered with potent CYP3A4 inhibitors.
Laboratory Tests: See General: Hepatotoxicity, Thrombocytopenia under Precautions.
Caution For Usage
Special Instructions for Use, Handling and Disposal: Appropriate aseptic technique should be used. Appropriate procedures for the preparation of chemotherapeutic drugs should be used.
The reconstituted product contains no preservative and is intended for single use only.
Discard any unused portion.
Using a sterile syringe, slowly inject 5 ml of Sterile Water for Injection into the 100 mg vial, or 8 ml of Sterile Water for Injection into the 160 mg trastuzumab emtansine vial.
Swirl the vial gently until completely dissolved. DO NOT SHAKE.
Store reconstituted trastuzumab emtansine at 2-8ºC; discard unused trastuzumab emtansine after 24 hours.
Reconstituted solution should be inspected visually for particulate matter and discolouration prior to administration. The reconstituted solution should be free of visible particulates, clear to slightly opalescent. The colour of the reconstituted solution should be colourless to pale brown. Do not use if reconstituted solution contains visible particulates, or is cloudy, or is discoloured.
Instructions for dilution: Determine the volume of the solution required based on a dose of 3.6 mg trastuzumab emtansine per kg body weight (see Table 2 under Dosage & Administration): (See equation.)

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The appropriate amount of solution should be withdrawn from the vial and added to an infusion bag containing 250 ml of 0.45% sodium chloride or 0.9% sodium chloride. Dextrose (5%) solution should not be used. 0.45% sodium chloride may be used without a 0.2 or 0.22 micron in-line polyethersulfone (PES) filter. If 0.9% sodium chloride is used for infusion, a 0.2 or 0.22 micron in-line polyethersulfone (PES) filter is required. Once the infusion is prepared it should be administered immediately. If not used immediately, the infusion can be stored for up to 24 hours in a refrigerator at 2°C - 8°C. Do not freeze or shake the infusion during storage.
Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Use established "collection systems", if available in the location.
Incompatibilities: Dextrose (5%) solution should not be used since it causes aggregation of the protein. Trastuzumab emtansine should not be mixed or diluted with other drugs.
Storage
Store vials at 2-8°C.
Shelf-Life: Shelf-life of the reconstituted solution: Product vials reconstituted with sterile water for injection should be used immediately following reconstitution. If not used immediately, the reconstituted vials can be stored for up to 24 hours at 2-8°C, and must be discarded thereafter.
Do not freeze the reconstituted solution.
Shelf-life of the solution for infusion containing the reconstituted product: The reconstituted trastuzumab emtansine solution diluted in polyvinyl chloride (PVC) or latex-free PVC-free polyolefin bags containing 0.9% Sodium Chloride Injection, or 0.45% Sodium Chloride Injection, may be stored at 2-8°C for up to 24 hours prior to use. Particulates may be observed on storage if diluted in 0.9% Sodium Chloride Injection, therefore, a 0.2 or 0.22 micron in-line polyethersulfone (PES) filter is required for administration (see Special Instructions for Use, Handling and Disposal under Cautions for Usage).
Do not freeze the solution for infusion containing the reconstituted product.
ATC Classification
L01XC14 - trastuzumab emtansine ; Belongs to the class of monoclonal antibodies, other antineoplastic agents. Used in the treatment of cancer.
Presentation/Packing
Powd for infusion (white to off-white lyophilised in a vial) 100 mg x 1's. 160 mg x 1's.
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