Trastuzumab Emtansine

Registered South African indications:

• Early Breast Cancer (EBC)
  - Adjuvant treatment of patients with HER2-positive early breast cancer who have residual disease, after pre-operative systemic treatment
• Metastatic Breast Cancer (MBC) 
   - As monotherapy for the treatment of patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who have received prior treatment with trastuzumab and a taxane

Contraindications

• Hypersensitivity to the active ingredient or to any of its excipients
• Pregnancy
• Breastfeeding

Cautions

• Severe renal impairment
• Hepatic impairment
• Breastfeeding up to 7 months after discontinuation of treatment
• Patients ≥75 years
• Thrombocytopenia
• Patients on anticoagulant treatment
• Haemorrhagic risk
• Pulmonary impairment
• Low baseline LVEF values (< 55%)
• Low LVEF levels prior to or following the use of paclitaxel in the adjuvant setting
• Prior or concomitant use of antihypertensive medicinal products, previous therapy with an anthracycline
• High BMI (> 25 kg/m²)
• History of congestive heart failure
• History of serious cardiac arrhythmia requiring treatment
• History of myocardial infarction
• History of unstable angina
• Interstitial lung disease or pneumonitis
• Dyspnoea at rest
• Patients receiving concurrent pulmonary radiation therapy
• Nodular regenerative hyperplasia
• Bleeding risk
• Serum transaminases >3 x ULN and concomitant total bilirubin >2 x ULN
• Left ventricular dysfunction
• History of infusion-related reactions
• Diabetes mellitis
• Fructose intolerance
• Glucose-galactose mal-absorption
• Sucrose-isomaltase insufficiency
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Used in the treatment of

• Early Breast Cancer (EBC)
  - As a single agent for the adjuvant treatment of HER2-positive early breast cancer who have residual invasive disease, in the breast and/or lymph nodes, after neoadjuvant taxane-based and HER2-targeted therapy
• Metastatic Breast Cancer (MBC)
  - As a single agent for the treatment of 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

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Patients treated with trastuzumab emtansine 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) or by fluorescence in situ hybridization (FISH) assessed by a CE-marked In Vitro Diagnostic (IVD) medical device. If a CE-marked IVD is not available, the HER2-status should be assessed by an alternate validated test

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Consult specialist for dosages and regimens 

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South African manufacturer recommendations

Used in the treatment of

• Early Breast Cancer (EBC)
  - Adjuvant treatment of patients with HER2-positive early breast cancer who have residual disease, after pre-operative systemic treatment
• Metastatic Breast Cancer (MBC) 
   - As monotherapy for the treatment of patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who have received prior treatment with trastuzumab and a taxane

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Patients treated with trastuzumab emtansine 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) or by fluorescence in situ hybridization (FISH) assessed by a validated test

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Consult specialist for dosages and regimens

Not established for use in children below 18 years

Pregnancy

• Contraindicated
• There are no data from the use of trastuzumab emtansine in pregnant women
• Trastuzumab, a component of trastuzumab emtansine, can cause foetal 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 component of trastuzumab emtansine, is expected to be teratogenic and potentially embryotoxic
• Administration of trastuzumab emtansine to pregnant women is not recommended and women should be informed of the possibility of harm to the foetus before they become pregnant. Women who become pregnant must immediately contact their doctor. If a pregnant woman is treated with trastuzumab emtansine, close monitoring by a multidisciplinary team is recommended.

Breastfeeding

• Contraindicated
• It is not known whether trastuzumab emtansine is excreted in human milk. Women should discontinue breast-feeding prior to initiating treatment with trastuzumab emtansine. Women may begin breast-feeding 7 months after concluding treatment

Fertility

• No reproductive and developmental toxicology studies have been conducted with trastuzumab emtansine
• Patients should be advised to use effective contraception during treatment  and for at least 7 months after treatment has completed

Renal impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no information available

Hepatic impairment

• Mild to moderate (Child-Pugh class A and B): Caution; no dose adjustment recommended
• Severe (Child-Pugh class C): Caution; no information available

Elderly

• ≥65 years: No dose adjustment recommended
• ≥75 years: Caution; no information available

Porphyria Information

• Not yet classified (NC)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders 

• Insomnia
• Peripheral neuropathy
• Headache
• Dizziness
• Dysgeusia
• Memory impairment
• Fatigue

Cardiovascular Disorders

• Left ventricular dysfunction
• Haemorrhage
• Hypertension

Respiratory Disorders

• Epistaxis
• Cough
• Dyspnoea
• Pneumonitis (ILD)
• Radiation pneumonitis

Gastrointestinal Disorders

• Stomatitis
• Diarrhoea
• Nausea and vomiting
• Constipation
• Dry mouth
• Abdominal pain
• Dyspepsia
• Gingival bleeding

Hepatobiliary Disorders

• Hepatotoxicity
• Hepatic failure
• Nodular regenerative hyperplasia
• Portal hypertension
• Increased blood bilirubin
• Increased blood alkaline phosphatase
• Increased transminases (AST/ALT)

Genitourinary Disorders

• Urinary tract infection

Endocrine and Metabolic Disorders

• Hypokalaemia

Musculoskeletal Disorders

• Musculoskeletal pain
• Arthralgia
• Myalgia

Skin and Subcutaneous Tissue Disorders

• Rash
• Pruritus
• Alopecia
• Nail disorder
• Palmar-plantar erythrodysaesthesia syndrome
• Urticaria

Immune, Blood and Lymphatic System Disorders

• Thrombocytopenia
• Anaemia
• Neutropenia
• Leucopoenia
• Decreased platelets
• Decreased haemoglobin
• Decreased neutrophils
• Hypersensitivity
• Pyrexia
• Chills

Sensory Disorders

• Dry eye
• Conjunctivitis
• Blurred vision
• Increased lacrimation

Others

• Decreased potassium
• Injection site extravasation
• Infusion-related reactions
• Peripheral oedema

• Potent CYP3A4 inhibitors
  - Ketoconazole
  - Itraconazole
  - Clarithromycin
  - Atazanavir
  - Indinavir
  - Nefazodone
  - Nelfinavir
  - Ritonavir
  - Saquinavir
  - Telithromycin
  - Voriconazole
• Anti-coagulant agents
  - Warfarin
  - Heparin
  - Low molecular weight heparins
• Antiplatelet agents

• HER2 expression status
• Hepatic function
• Platelet count
• Left ventricular function

Specific cases may require

• Pregnancy test

• In order to prevent medicinal product errors it is important to check the vial labels to ensure that the medicinal product being prepared and administered is trastuzumab emtansine and not trastuzumab.
• In order to improve traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded (or stated) in the patient file.

Missed doses

• 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

Reconstitution directions

• Using a sterile syringe, slowly inject 5ml of Sterile Water for Injection into the trastuzumab emtansine 100mg vial, or 8ml of Sterile Water for Injection into the trastuzumab emtansine 160mg 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
• Appropriate aseptic technique should be used. Appropriate procedures for the preparation of chemotherapeutic medicines should be used.The reconstituted product contains no preservative and is intended for single use only
• Reconstituted solution should be inspected visually for particulate matter and discoloration 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 3,6mg trastuzumab emtansine/kg body weight

• The appropriate amount of solution should be withdrawn from the vial and added to an infusion bag containing 250ml of 0,45% sodium chloride or 0,9% sodium chloride. Glucose (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 2‑8°C. Do not freeze or shake the infusion during storage

Incompatibilities

• Glucose (5%) solution should not be used since it causes aggregation of the protein
• Trastuzumab emtansine should not be mixed or diluted with other medicines

Trastuzumab emtansine is a HER2-targeted antibody-drug conjugate which contains the humanised anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitor DM1 (a maytansine derivative) via the stable thioether linker MCC (4-[N- maleimidomethyl] cyclohexane- 1-carboxylate). Emtansine refers to the MCC-DM1 complex. 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). Trastuzumab emtansine 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, trastuzumab emtansine, 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 component of trastuzumab emtansine, binds to tubulin. By inhibiting tubulin polymerisation, DM1 causes cells to arrest in the G2/M phase of the cell cycle, ultimately leading to apoptotic cell death

- 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

Infusion 100mg

• Kadcyla 100 (Roche Products)

Infusion 160mg

• Kadcyla 160 (Roche Products)