Consumer medicine information

Kadcyla

Trastuzumab emtansine

BRAND INFORMATION

Brand name

Kadcyla

Active ingredient

Trastuzumab emtansine

Schedule

SUMMARY CMI

Kadcyla^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using Kadcyla?

Kadcyla contains the active ingredient trastuzumab emtansine (rch). Kadcyla is used to treat early HER2-positive breast cancer following surgery and advanced or metastatic HER2-positive breast cancer, i.e. the cancer has spread to areas near the breast or to other parts of your body. For more information, see Section 1. Why am I using Kadcyla? in the full CMI.

2. What should I know before I use Kadcyla?

Do not use if you have ever had an allergic reaction to trastuzumab emtansine or any of the ingredients listed at the end of the CMI.
Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use Kadcyla? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Kadcyla and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How is Kadcyla given?

Kadcyla is given by a slow drip into a vein (intravenous (IV) infusion) by a doctor or nurse once every three weeks. The first infusion will be over 90 minutes. If the first infusion is well tolerated, your drip time may be shortened to 30 minutes. More instructions can be found in Section 4. How is Kadcyla given? in the full CMI.

5. What should I know while using Kadcyla?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are receiving Kadcyla. Be sure to keep all of your appointments with your doctor so that your progress can be checked.
Things you should not do	Do not stop using this medicine without speaking to your doctor first. Do not take any other medicines, whether they require a prescription or not, without first telling your doctor or consulting with a pharmacist.
Driving or using machines	Be careful before you drive or use any machines or tools until you know how Kadcyla affects you.

For more information, see Section 5. What should I know while using Kadcyla? in the full CMI.

6. Are there any side effects?

There are a number of side effects associated with Kadcyla. It is important to be aware of them so that you can identify any symptoms if they occur (see the full CMI for more details). Tell your doctor or nurse immediately or go to the nearest hospital Emergency Department if you experience signs or symptoms of a serious allergic reaction such as fever or chills, swelling of the face, lips, tongue, throat or other parts of the body, dizziness or fainting, trouble breathing or wheezing, coughing, rash, itching or hives on the skin.

Some other serious side effects of Kadcyla include burning sensation or tenderness at the site of injection, nausea, vomiting, diarrhoea, pain or discomfort, fatigue, bleeding or bruising, dark urine or yellowing of your skin and eyes.

Tell your doctor or nurse immediately or go to the Emergency Department if you experience any of these side effects. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

WARNING: Do not substitute Kadcyla for or with trastuzumab.

In order to prevent medication errors, check the vial labels to ensure the medicine being prepared and administered is Kadcyla (trastuzumab emtansine) and not trastuzumab.

FULL CMI

Kadcyla^®

Active ingredient(s): trastuzumab emtansine

Consumer Medicine Information (CMI)

This leaflet provides important information about using Kadcyla. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Kadcyla.

Where to find information in this leaflet:

1. Why am I using Kadcyla?
2. What should I know before I use Kadcyla?
3. What if I am taking other medicines?
4. How do I use Kadcyla?
5. What should I know while using Kadcyla?
6. Are there any side effects?
7. Product details

1. Why am I using Kadcyla?

Kadcyla contains the active ingredient trastuzumab emtansine. Kadcyla belongs to a group of medicines known as anti-neoplastic (or anti-cancer) agents.

Kadcyla is made up of two substances:

trastuzumab - a monoclonal antibody which recognises and attaches to a protein called human epidermal growth factor receptor 2 (HER2). HER2 is found in large amounts on the surface of some cancer cells. Monoclonal antibodies are proteins made in a laboratory. These proteins are designed to recognise and bind to other unique proteins in the body.
emtansine - an anti-cancer substance.

Kadcyla is designed to target and deliver the anti-cancer emtansine directly inside HER2-positive cancer cells to stop the growth and spread of the cancer cells.

Kadcyla is used to treat the following stages of HER2-positive breast cancer:

early breast cancer following surgery.
advanced or metastatic breast cancer, i.e the cancer has spread to areas near the breast or to other parts of your body.

It is only used in patients whose tumour has tested positive to HER2. You may have previously received HER2 targeted therapies.

2. What should I know before I use Kadcyla?

Warnings

Do not use Kadcyla if:

you are allergic to trastuzumab emtansine, or any of the ingredients listed at the end of this leaflet.

Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

you have had a serious infusion-related reaction to trastuzumab
you have a history of heart problems.

Your doctor will monitor your heart function closely before and during your treatment with Kadcyla.

you have any breathing or lung problems
you have liver problems
you have bleeding problems
you are receiving anti-coagulant treatment (blood thinning medications) e.g. warfarin, heparin or low molecular weight heparin

Kadcyla can lower the number of platelets in your blood. Platelets help your blood to clot so you might get unexpected bleeding (such as nose bleeds, bleeding from gums).

Your doctor or nurse will monitor your platelet levels during your treatment with Kadcyla.

take any medicines for any other condition
you are allergic to any other medicines or any other substances such as foods, preservatives or dyes

Allergic and/or anaphylactic reactions can occur with Kadcyla treatment (known as infusion related reactions). Your doctor or nurse will check for side effects during your infusion. See Section 6. Are there any side effects? for symptoms to look out for.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Do not use Kadcyla if you are pregnant. Kadcyla may be harmful to your unborn baby.

Your doctor will advise you about using effective contraception to avoid you or your partner becoming pregnant while you are being treated with Kadcyla and for at least 7 months after stopping treatment. It is not known if Kadcyla affects the ability of a woman to become pregnant. Discuss any future child bearing plans with your doctor before starting Kadcyla.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not known if Kadcyla passes into breast milk. It is recommended that you discontinue breast-feeding while you are being treated with Kadcyla and not start breast-feeding until 7 months after completing Kadcyla treatment.

If you have not told your doctor about any of the above, tell them before you are given Kadcyla

Use in children

The safety and effectiveness of Kadcyla in children under 18 years of age have not been established.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Kadcyla and affect how it works.

Oral antifungal medications, e.g. ketoconazole, itraconazole, voriconazole
Some antibiotics used to treat bacterial infections, e.g. clarithromycin
Some medicines used to treat hepatitis
Medicines used to treat depression

Your doctor and pharmacist have more information on medicines to be careful with or avoid while receiving Kadcyla.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Kadcyla.

4. How is Kadcyla given?

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

Kadcyla is prepared by a healthcare professional and will be given in a hospital or clinic by a doctor or nurse.

Kadcyla is given by a slow drip into a vein (intravenous (IV) infusion) once every three weeks.

The first infusion will be given over 90 minutes. If the first infusion is well tolerated, your drip time may be shortened to 30 minutes.

You doctor will decide how long you should receive Kadcyla. This will depend on how you respond to treatment and the state of your disease.

If you miss a dose of Kadcyla

As Kadcyla is given under the supervision of your doctor, you are unlikely to miss a dose. However, if you forget or miss your appointment to receive Kadcyla, make another appointment as soon as possible. Do not wait for your next planned appointment. Your doctor will decide when your next dose of Kadcyla will be.

If you are given too much Kadcyla (overdose)

As Kadcyla is given under the supervision of your doctor it is unlikely that you will be given too much. However, if you experience any side effects after being given Kadcyla, tell your doctor or nurse immediately.

5. What should I know while using Kadcyla?

Things you should do

Tell all doctors, dentists and pharmacists who are treating you that you are receiving Kadcyla.

Tell your doctor if you intend to start a family while receiving Kadcyla.

Tell your doctor if you feel that Kadcyla is not helping your condition.

Be sure to keep all of your appointments with your doctor so that your progress can be checked.

Your doctor will perform regular tests to monitor for;

Liver problems
Heart problems
Bleeding problems
Lung problems

Call your doctor straight away if you:

become pregnant

Remind any doctor, dentist, pharmacist or nurse you visit that you are using Kadcyla.

Things you should not do

Do not stop your Kadcyla treatment without talking to your doctor first.

Do not take any other medicines, whether they require a prescription or not, without first telling your doctor or consulting with a pharmacist.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Kadcyla affects you.

It is not known whether Kadcyla may affect your ability to drive or operate machinery. If you experience infusion-related reactions, such as flushing, shivering episodes, fever, trouble breathing, low blood pressure or a rapid heartbeat, do not drive and use machines until symptoms abate.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

Kadcyla will be stored in the pharmacy or on the hospital ward in a refrigerator at a temperature between 2°C and 8°C. Kadcyla solution should not be frozen.

6. Are there any side effects?

Tell your doctor as soon as possible if you do not feel well while you are receiving Kadcyla.

Kadcyla may have some unwanted side effects in some people.

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may be more serious and need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Serious side effects

Serious side effects

What to do

During an infusion:

swelling of your face, lips, tongue or throat with difficulty breathing
swelling of other parts of your body such as your hands or feet
shortness of breath, wheezing or trouble breathing
abnormal or irregular heartbeat
rash, itching or hives on the skin
flushing (warm, red) skin
pain or swelling at site of injection
burning sensation or tenderness at site of injection
feeling sick (nausea) or vomiting, diarrhoea
pain or discomfort (including stomach pain, back pain, chest or neck pain)
fever or chills
headache
fatigue or tiredness
cough

Tell your doctor or nurse immediately if you notice any of the following while receiving an infusion (particularly during the first infusion).

These may be serious side effects. You may require urgent medical attention.

After an infusion:

any of the side effects listed above;
swelling of ankles or legs
weight gain of more than 2 kilograms in 24 hours
dizziness or fainting
increased cough
shortness of breath, especially when lying down, being woken from your sleep or when exercising
chest pain, especially if it worsens with breathing
abdominal pain
increased pain, discoloration, blistering and sloughing of your skin
jaundice (your skin and whites of your eyes look yellow)
dark urine
rash, itching or hives on the skin
loss of appetite

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Less serious side effects

Less serious side effects

What to do

After an infusion:

getting tired more easily after light physical activity, such as walking
insomnia (difficulty sleeping)
weakness, soreness in muscles and/or joints
numbness or weakness of arms and legs
bleeding or bruising more easily than normal
nose bleeds
bleeding from gums
feeling dizzy, tired, looking pale
flu and/or cold like symptoms, frequent infections such as fever, severe chills, sore throat or mouth ulcers
dry mouth
taste disturbance or loss of taste
constipation
vomiting
indigestion
diarrhoea
eye problems such as producing more tears, swollen runny eyes or conjunctivitis (discharge with itching of the eyes and crusty eyelids)

Speak to your doctor or nurse as soon as possible if you notice any of these.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

This is not a complete list of all possible side effects. Your doctor or pharmacist has a more complete list. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Ask your doctor, nurse or pharmacist if you don't understand anything in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Kadcyla contains

Active ingredient

(main ingredient)

Each vial of Kadcyla contains 100 mg or 160 mg of the active ingredient, trastuzumab emtansine.

The trastuzumab protein is made using Chinese hamster ovary cells.

Other ingredients

(inactive ingredients)

Succinic acid

Sodium hydroxide

Sucrose

Polysorbate 20

Do not take this medicine if you are allergic to any of these ingredients.

What Kadcyla looks like

Kadcyla is a white to off-white powder which is dissolved in sterile water before use.

After dissolving, the Kadcyla solution should appear as a clear colourless to pale brown solution.

Kadcyla is supplied as a single use vial and is available in two strengths, 100 mg and 160 mg.

100 mg: AUST R 201621

160 mg: AUST R 201622

Who distributes Kadcyla

Roche Products Pty Limited
ABN 70 000 132 865
Level 8, 30-34 Hickson Road
Sydney NSW 2000
AUSTRALIA

Medical enquiries: 1800 233 950

This leaflet was prepared in April 2022.

Published by MIMS September 2022

BRAND INFORMATION

Brand name

Kadcyla

Active ingredient

Trastuzumab emtansine

Schedule

1 Name of Medicine

Trastuzumab emtansine.

2 Qualitative and Quantitative Composition

Kadcyla is available as a single-use vial containing 100 mg or 160 mg of trastuzumab emtansine.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for concentrate for solution for infusion.
White to off white lyophilised powder.

4 Clinical Particulars

4.1 Therapeutic Indications

Early breast cancer.

Kadcyla, as a single agent, is indicated for the adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.

Metastatic breast cancer.

Kadcyla, as a single agent, is indicated for the treatment of patients with HER2-positive metastatic (Stage IV) breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for metastatic disease; or developed disease recurrence during or within six months of completing adjuvant therapy.

4.2 Dose and Method of Administration

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.
Kadcyla therapy should only be administered under the supervision of a healthcare professional experienced in the treatment of cancer patients.
In order to prevent medication errors it is important to check the vial labels to ensure the medicine being prepared and administered is Kadcyla (trastuzumab emtansine) and not trastuzumab.
In order to improve traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly recorded in the patient medical record.

Dosage.

The recommended dose of Kadcyla is 3.6 mg/kg, administered as an intravenous (IV) infusion every 3 weeks (21-day cycle).

Duration of treatment.

Patients with early breast cancer should receive treatment for a total of 14 cycles unless there is disease recurrence or unmanageable toxicity.
Patients with metastatic breast cancer should receive treatment until disease progression or unmanageable toxicity.

Missed dose.

If a planned dose of Kadcyla 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.

Method of administration.

For instructions on reconstitution and dilution of the product before administration, see Section 6.6 Special Precautions for Disposal.
Kadcyla must be reconstituted and diluted by a healthcare professional and administrated as an IV infusion. Do not administer as an IV push or bolus.
Once the infusion solution is prepared, it should be administered immediately.
If 0.45% sodium chloride is used, the infusion can be administered without a 0.22 micron in-line polyethersulfone (PES) filter. If 0.9% sodium chloride is used, a 0.22 micron in-line PES filter is required for administration of the infusion.
If the infusion solution is not used immediately, the infusion solution can be stored for up to 24 hours at 2°C - 8°C (see Section 6.4 Special Precautions for Storage).
Administer the initial dose as a 90 minute IV 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 Kadcyla administration (see Section 4.4 Special Warnings and Precautions for Use, Extravasation).
If prior infusions were well tolerated, subsequent doses of Kadcyla may be administered as a 30 minute infusion and patients should be observed during the infusions and for at least 30 minutes after the infusion. The infusion rate of Kadcyla should be slowed or interrupted if the patient develops infusion-related symptoms (see Section 4.4 Special Warnings and Precautions for Use, Infusion-related reactions, Hypersensitivity reactions). Discontinue Kadcyla for life threatening infusion reactions.

Dosage adjustment.

Management of symptomatic adverse events may require temporary interruption, dose reduction, or treatment discontinuation of Kadcyla as per guidelines provided in Tables 1-3.
Kadcyla dose should not be re-escalated after a dose reduction is made.

Special populations.

Elderly.

There are insufficient data to establish the safety and efficacy of Kadcyla in patients 75 years of age or older. No dose adjustment of Kadcyla is required in patients aged ≥ 65 years (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Renal impairment.

No adjustment to the starting dose of Kadcyla is needed in patients with mild or moderate renal impairment (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations). The potential need for dose adjustment in patients with severe renal impairment cannot be determined due to insufficient data.

Hepatic impairment.

No adjustment to the starting dose is required for patients with mild or moderate hepatic impairment (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations). Kadcyla has not been 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 Section 4.4 Special Warnings and Precautions for Use, Hepatotoxicity).

Paediatric population.

The safety and efficacy of Kadcyla in children below 18 years of age have not been established.

4.3 Contraindications

Kadcyla is contraindicated in patients with a known hypersensitivity to Kadcyla or any of its excipients (see Section 4.4 Special Warnings and Precautions for Use, Infusion-related reactions, Hypersensitivity reactions).

4.4 Special Warnings and Precautions for Use

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 Section 4.8 Adverse Effects (Undesirable Effects)). Signs and symptoms include dyspnoea, 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 Section 4.2 Dose and Method of Administration).
Patients with dyspnoea at rest due to complications of advanced malignancy, comorbidities, and receiving concurrent pulmonary radiation therapy may be at increased risk of pulmonary events.

Hepatotoxicity.

Serious hepatotoxicity has been reported, including liver failure and death, in patients treated with Kadcyla. Hepatotoxicity has been observed predominantly in the form of asymptomatic increases in the concentrations of serum transaminases (grade 1-4 transaminitis) in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). 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.
Monitor serum transaminases and bilirubin prior to initiation of Kadcyla treatment and prior to each Kadcyla dose. Reduce the dose or discontinue Kadcyla as appropriate in cases of increased serum transaminases and/or total bilirubin (see Section 4.2 Dose and Method of Administration, Dosage adjustment). Kadcyla has not been studied in patients with serum transaminases > 2.5 x ULN (upper limit of normal) or total bilirubin > 1.5 x ULN prior to initiation of treatment, except in a dedicated pharmacology study of the use of Kadcyla in hepatic impairment (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations). Two out of ten patients with mild hepatic impairment withdrew from the study due to increased levels of bilirubin, and one patient with moderate hepatic impairment developed fatal hepatic encephalopathy, considered to be at least partly related to trastuzumab emtansine. Permanently discontinue Kadcyla treatment in patients with serum transaminases > 3 x ULN and concomitant total bilirubin > 2 x ULN.
Cases of 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 noncirrhotic 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.

Kadcyla may lead to reductions in left ventricular ejection fraction (LVEF). LVEF < 40% has been observed in patients treated with Kadcyla. Symptomatic congestive heart failure (CHF) is a potential risk. In the phase III study TDM4370g/ BO21977 (EMILIA), 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 Section 4.8 Adverse Effects (Undesirable Effects)).
Assess LVEF (echocardiogram or multigated acquisition (MUGA) scanning) prior to initiation and at regular intervals (e.g. every three months) during treatment with Kadcyla to ensure LVEF is within the institution's normal limits.
Events of LVEF drop of > 10% from baseline and/or CHF were observed in approximately 22% of patients with MBC in an observational study (BO39807) with baseline LVEF of 40-49% in a real world setting. Most of these patients had other cardiovascular risk factors. The decision to administer Kadcyla in patients with MBC with low LVEF must be made only after careful benefit risk assessment and cardiac function should be closely monitored in these patients.
Specific guidelines regarding dose modifications and discontinuation are provided (see Section 4.2 Dose and Method of Administration, Dosage adjustment).

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, dyspnoea, hypotension, wheezing, bronchospasm, and tachycardia, have been reported in clinical trials of Kadcyla. In general, these symptoms were not severe (see Section 4.8 Adverse Effects (Undesirable Effects)). 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 Section 4.2 Dose and Method of Administration, Dosage adjustment).

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.

Haemorrhage.

Cases of haemorrhagic events, including central nervous system, respiratory, and gastrointestinal haemorrhage, have been reported with Kadcyla treatment. Some of these bleeding events resulted in fatal outcomes. In some of the observed cases the patients had thrombocytopenia, or were also receiving anti-coagulation therapy or antiplatelet therapy; 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.
In the phase III study TDM4370g/BO21977 (EMILIA) in patients with metastatic breast cancer, the overall frequency of thrombocytopenia was 31.2% in the Kadcyla treated group and 3.3% in the lapatinib plus capecitabine treated group (see Section 4.8 Adverse Effects (Undesirable Effects)). 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.
Thrombocytopenia was reported in 28.5% of early breast cancer patients treated with Kadcyla in study BO27938 (KATHERINE). Independent of race, the incidence of grade 3 or 4 events (< 50,000/mm³) was 5.7% in the Kadcyla-treated group. The overall frequency of thrombocytopenia in Asian patients in the Kadcyla-treated group in study BO27938 (KATHERINE) was 50.0% and that of grade 3 or 4 thrombocytopenia was 18.8%.
Patients with thrombocytopenia (< 100,000/mm³) and patients on anticoagulant treatment should be monitored closely while on Kadcyla treatment. It is recommended that platelet counts are monitored prior to each Kadcyla dose. Rare cases of severe and prolonged thrombocytopenia (≥ grade 3 thrombocytopenia lasting for more than 90 days) have been reported with Kadcyla. In most of these cases, patients received concomitant recombinant human thrombopoietin (rhTPO). 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 Section 4.2 Dose and Method of Administration, Dosage adjustment.

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.
In the phase III study TDM4370g/BO21977 (EMILIA) in patients with metastatic breast cancer, the overall incidence of peripheral neuropathy was 23.3% and 3.1% for grade ≥ 3.
In patients with early breast cancer in study BO27938 (KATHERINE), the overall incidence was 32.3% and 1.6% for grade ≥ 3. Onset of the grade 3 event of peripheral neuropathy ranged between Study day 2 and day 229, with a median of 60 days. In 50% of patients who experienced grade 3 peripheral neuropathy, these events had resolved at the time of the primary IDFS analysis, while events were resolving in 25% of the patients.

Extravasation.

In Kadcyla clinical studies, reactions secondary to extravasation have been observed. These reactions were usually mild and comprised of erythema, tenderness, skin irritation, pain, or swelling at the infusion site. These reactions have been observed more frequently within 24 hours of infusion. In the post marketing setting, very rare cases of epidermal injury or necrosis following extravasation have been observed within days to a few weeks after infusion (see Section 4.8 Adverse Effects (Undesirable effects)). Specific treatment for Kadcyla extravasation is unknown at this time. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration. If extravasation occurs the infusion should be terminated immediately and the patient should be examined regularly as necrosis may occur within days to weeks after infusion.

Use in hepatic impairment.

Please see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations.

Use in renal impairment.

No formal studies of Kadcyla in patients with renal impairment have been conducted (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations).

Use in the elderly.

There are insufficient data to establish the safety and efficacy of Kadcyla in patients 75 years of age or older (see Section 5.1 Pharmacodynamic Properties, Clinical trials, TDM4370g/BO21977 (EMILIA)). Based on a population pharmacokinetic analysis, age does not affect the pharmacokinetics of Kadcyla.

Paediatric use.

The safety and efficacy of Kadcyla in children below 18 years of age have not been established.

Effects on laboratory tests.

Please see Section 4.4 Special Warnings and Precautions for Use, Hepatotoxicity, Thrombocytopenia.

4.5 Interactions with Other Medicines and Other Forms of 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, the cytotoxic 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. Plasma DM1 concentrations may be affected by CYP3A4/5 inhibitors or inducers. Thus, patients who are receiving strong CYP3A4/5 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin) concomitantly with trastuzumab emtansine should be closely monitored for adverse reactions.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of trastuzumab emtansine on human fertility are unknown. No dedicated fertility studies have been conducted with trastuzumab emtansine. However, based on results from rat toxicity studies, adverse effects on fertility may occur.
Single dose toxicity studies of trastuzumab emtansine in rats demonstrated adverse effects on reproductive organs. Male rats exhibited degeneration of seminiferous tubules in the testes and luminal debris in the epididymides at 60 mg/kg (approximately 9 times the anticipated clinical trastuzumab emtansine exposure, based on AUC). At the same dose in female rats, haemorrhage and necrosis of the corpus luteum in the ovaries and mammary gland degeneration and necrosis was observed. Mammary gland degeneration and necrosis was also observed in males at doses from 20 mg/kg (3-fold the anticipated clinical trastuzumab emtansine exposure, based on AUC).
(Category D)
Trastuzumab emtansine can result in embryofoetal death or birth defects when administered to a pregnant woman. There are no clinical studies of trastuzumab emtansine in pregnant women. No reproductive and developmental toxicology studies have been conducted with trastuzumab emtansine. Trastuzumab, a component of trastuzumab emtansine, can cause foetal harm or death when administered to pregnant women. In the postmarketing setting, cases of oligohydramnios, some associated with fatal pulmonary hypoplasia, have been reported in pregnant women receiving trastuzumab. DM1, the cytotoxic component of trastuzumab emtansine, is a microtubule inhibitory drug derived from maytansine. Based on animal studies of maytansine, DM1, is expected to be teratogenic and potentially embryotoxic.
Administration of trastuzumab emtansine to pregnant women is not recommended. Women of child bearing potential and female partners of male patients of child bearing potential should be advised to use effective contraception during treatment with trastuzumab emtansine and for at least 7 months following the last dose of trastuzumab emtansine. Women who become pregnant must contact their doctor and should be advised of the possibility of harm to the foetus. If a pregnant woman is treated with trastuzumab emtansine, close monitoring by a multidisciplinary team is recommended.
It is not known whether trastuzumab emtansine is excreted in human breast milk.
However, trastuzumab was shown to be readily transferred through the placenta (foetal amniotic fluid and sera samples around 20-30% of maternal plasma concentrations), with a small amount (2% of maternal plasma concentrations) excreted in the milk of monkeys after IV doses of 25 mg/kg for 4 consecutive days from gestation day 120 followed by twice weekly until postpartum day 28.
Since many drugs are excreted in human breast milk, and because of the potential for serious adverse reactions in nursing infants from trastuzumab emtansine, women should discontinue nursing prior to initiating treatment with trastuzumab emtansine. Women may begin nursing 7 months following the last dose of Kadcyla.

4.7 Effects on Ability to Drive and Use Machines

On the basis of reported adverse reactions, 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 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.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

Early breast cancer. The safety of Kadcyla has been evaluated in 740 patients with early breast cancer in Study BO27938 KATHERINE. Adverse drug reactions from KATHERINE (see Table 4) are listed by MedDRA system organ class. The corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000).

Laboratory abnormalities.

Table 5 displays laboratory abnormalities observed in patients treated with Kadcyla in clinical trial BO27938 (KATHERINE).

Metastatic breast cancer. The safety of Kadcyla has been evaluated in more than 1,871 patients. Adverse drug reactions from clinical trials (see Table 6) are listed by MedDRA system organ class. The corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000).

Laboratory abnormalities.

Table 7 displays laboratory abnormalities observed in patients treated with Kadcyla in study TDM4370/ BO21977 (EMILIA).

Immunogenicity.

As with all therapeutic proteins, there is the potential for an immune response to Kadcyla. A total of 1243 patients from seven clinical studies were tested at multiple time points for anti-drug antibody (ADA) responses to Kadcyla. Following Kadcyla dosing, 5.1% (63/1243) of patients tested positive for anti-Kadcyla antibodies at one or more postdose time points. In the phase I and phase II studies, 6.4% (24/376) of patients tested positive for anti-Kadcyla antibodies.
In the EMILIA study (TDM4370g/BO21977), 5.2% (24/466) of patients tested positive for anti-Kadcyla antibodies, of which 13 were also positive for neutralising antibodies. In the KATHERINE (BO27938) study, 3.7% (15/401) of patients tested positive for anti-Kadcyla antibodies, of which 5 of were also positive for neutralising antibodies. Due to the low incidence of ADA, conclusions cannot be made on the impact of anti-Kadcyla antibodies on the pharmacokinetics, safety, and efficacy of Kadcyla.
Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, drug interference, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to Kadcyla with the incidence of antibodies to other products may be misleading.

Post market setting.

In the post marketing setting, very rare cases of epidermal injury or necrosis following extravasation have been observed within days to a few weeks after infusion (see Section 4.4 Special Warnings and Precautions for Use).

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

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 treatment, 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.
Treatment of overdose should consist of general supportive measures.
For information on the management of overdose, contact the Poison Information Centre (in Australia call 13 11 26; in New Zealand call 0800 764 766).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antineoplastic agent, other antineoplastic agents, monoclonal antibodies, ATC code: L01XC14.

Mechanism of action.

Trastuzumab emtansine is a HER2 targeted antibody drug conjugate, containing the humanised anti-HER2 IgG1 antibody trastuzumab, covalently linked to the small molecule cytotoxin, DM1. Upon binding to HER2, trastuzumab emtansine undergoes receptor mediated internalisation and subsequent lysosomal degradation, resulting in release of DM1 containing cytotoxic catabolites.
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 HER2 receptor signalling and mediates antibody dependent cell mediated cytotoxicity (ADCC) in human breast cancer cells that overexpress HER2.
DM1, the cytotoxic 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.

Clinical trials.

Early breast cancer.

BO27938 (KATHERINE).

KATHERINE was a randomised, multicentre, open-label trial of 1486 patients with HER2-positive, early breast cancer with residual invasive tumour in the breast and/or axillary lymph nodes following taxane and trastuzumab-based therapy as part of a neoadjuvant regimen before trial enrolment. Patients received radiotherapy and/or hormonal therapy concurrent with study treatment as per local guidelines. Breast tumour samples were required to determine HER2 positive status defined as 3+ IHC or ISH amplification ratio ≥ 2.0 using a Pathway HER2 (4B5) IHC assay and INFORM Dual ISH DNA Probe Cocktail (both Ventana) at a central laboratory. Patients were randomised (1:1) to receive trastuzumab or Kadcyla. Randomisation was stratified by clinical stage at presentation, hormone receptor status, preoperative HER2-directed therapy (trastuzumab, trastuzumab plus additional HER2-directed agent[s]), and pathological nodal status evaluated after preoperative therapy.
Kadcyla was given intravenously at 3.6 mg/kg on day 1 of a 21-day cycle. Trastuzumab was given intravenously at 6 mg/kg on day 1 of a 21-day cycle. Patients were treated with Kadcyla or trastuzumab for a total of 14 cycles unless there was recurrence of disease, withdrawal of consent, or unacceptable toxicity, whichever occurred first. At the time of the primary analysis, median treatment duration was 10 months (range: 1-12) for Kadcyla, and median treatment duration 10 months (range: 1-13) for trastuzumab. Patients who discontinued Kadcyla could complete the duration of their intended study treatment up to 14 cycles of HER2-directed therapy with trastuzumab, if appropriate, based on toxicity considerations and investigator discretion.
The primary efficacy endpoint of the study was invasive disease free survival (IDFS). IDFS was defined as the time from the date of randomization to first occurrence of ipsilateral invasive breast tumour recurrence, ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause. Additional endpoints included IDFS including second primary non-breast cancer, disease free survival (DFS), overall survival (OS), and distant recurrence-free interval (DRFI).
Patient demographics and baseline tumour characteristics were balanced between treatment arms. The median age was approximately 49 years (range 23-80 years), 72.8% were White, 8.7% were Asian and 2.7% were Black or African American. All but 5 patients were women. 22.5 percent of patients were enrolled in North America, 54.2% in Europe and 23.3% throughout the rest of the world. Tumour prognostic characteristics including hormone receptor status (positive: 72.3%, negative: 27.7%), clinical stage at presentation (inoperable: 25.3%, operable: 74.8%) and pathological nodal status after preoperative therapy (node positive: 46.4%, node negative not evaluated: 53.6%) were similar in the study arms.
The majority of the patients (76.9%) had received an anthracycline-containing neoadjuvant chemotherapy regimen. 19.5% of patients received another HER2-targeted agent in addition to trastuzumab as a component of neoadjuvant therapy. Pertuzumab was the second therapy in 93.8% of patients who received a second neoadjuvant HER2-directed agent.
A clinically meaningful and statistically significant improvement in IDFS was observed in patients who received Kadcyla compared with trastuzumab (HR = 0.50, 95% CI [0.39, 0.64], p < 0.0001), corresponding to a 50% reduction in risk of an IDFS event. Estimates of 3 years IDFS rates were 88.3% vs. 77.0% in Kadcyla vs. trastuzumab arms, respectively. See Table 8 and Figure 1.

In KATHERINE, consistent treatment benefit of Kadcyla for IDFS was seen in all the pre-specified subgroups evaluated, supporting the robustness of the overall result.
Metastatic breast cancer.

TDM4370g/BO21977 (EMILIA).

EMILIA is a phase III, randomised, multicentre, international, open label clinical trial conducted in patients with HER2 positive unresectable, locally advanced breast cancer (LABC) or metastatic breast cancer 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 enrolment, breast tumour samples were centrally confirmed to be HER2 positive, 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 Caucasian (72%), and 57% had oestrogen receptor and/or progesterone receptor positive disease. The study compared the safety and efficacy of Kadcyla with that of lapatinib + capecitabine. A total of 991 patients were randomised with Kadcyla or lapatinib + capecitabine as follows:
Kadcyla 3.6 mg/kg IV over 30-90 minutes on day 1 of a 21 day cycle; or
lapatinib 1250 mg/day orally once per day of a 21 day cycle + capecitabine 1000 mg/m² orally twice daily on days 1-14 of a 21 day cycle.
The coprimary efficacy endpoints of the study were progression free survival (PFS) as assessed by an independent review committee (IRC), overall survival (OS) and landmark (1 year and 2 year) survival rates.
Time to symptom progression, as defined by a 5 point decrease in score derived from the trial 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 9.

A treatment benefit was seen in the subgroup of patients who did not receive any prior systemic anticancer therapy in the metastatic setting (n = 118); hazard ratio 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.
Of 495 patients who received Kadcyla in EMILIA, 65 patients (13%) were ≥ 65 years of age and 11 patients (2%) were ≥ 75 years of age. A trend for treatment benefit with Kadcyla compared to the control arm in terms of PFS for the subgroup of patients who were 65 to 74 years old was observed (total n = 113; HR = 0.88, 95% CI: 0.53, 1.45). For patients ≥ 75 years of age, based on IRC assessments, the hazard ratios for PFS and OS were 3.51 (95% CI: 1.22, 10.13) and 3.45 (95% CI: 0.94, 12.65), respectively. The subgroup of patients 75 years or above did not demonstrate a benefit for PFS or OS, but was too small (n = 25) to draw any definitive conclusions. See Figures 2 and 3.

TDM4450g/BO21976.

TDM4450g was a randomised, multicentre, open label phase II study to evaluate the effects of Kadcyla versus trastuzumab plus docetaxel in patients with HER2 positive metastatic breast cancer 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 + docetaxel 75-100 mg/m² IV every 3 weeks (n = 70).
The primary endpoint was PFS assessed by the investigator. The median PFS was 9.2 months in the trastuzumab + docetaxel arm and 14.2 months in the Kadcyla arm (HR: 0.59; p = 0.035), with a median follow-up of approximately 14 months in both arms. The ORR was 58.0% with trastuzumab + 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; HR: 0.58; p = 0.022).

TDM4374g.

TDM4374g was a phase II single arm, open label study to evaluate the effects of Kadcyla in patients with HER2 positive incurable, locally advanced, or metastatic breast cancer. 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 anticancer 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 IV 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 Independent Review Committee was not reached (95% CI: 4.6 months to not estimable).

5.2 Pharmacokinetic Properties

The population pharmacokinetic analysis of trastuzumab emtansine suggested no difference in Kadcyla exposure based on disease status (adjuvant vs. metastatic setting).

Absorption.

Kadcyla is administered as an intravenous (IV) infusion. There have been no studies performed with other routes of administration.

Distribution.

Kadcyla when administered IV 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 the randomised pivotal trials, EMILIA and KATHERINE, who received 3.6 mg/kg of Kadcyla IV every 3 weeks, had a mean maximum serum concentration (Cmax) of trastuzumab emtansine in cycle 1 of 83.4 (± 16.5) microgram/mL and 72.6 (± 24.3) microgram/mL, respectively. Based on population pharmacokinetic analysis, following IV administration of Kadcyla, the central volume of distribution of trastuzumab emtansine was 3.13 L and approximated that of plasma volume.
In in vitro studies, DM1 was 93% bound to human plasma proteins and was shown to be a substrate of P-glycoprotein (P-gp).

Metabolism.

Kadcyla is expected to undergo 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 the randomised trials EMILIA and KATHERINE, mean maximum DM1 levels in cycle 1 following Kadcyla administration were consistently low and averaged 4.61 (± 1.61) nanogram/mL and 4.71 (± 2.25) nanogram/mL, respectively.
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.

Excretion.

Based on population pharmacokinetic analysis, following IV administration of Kadcyla, the clearance of trastuzumab emtansine was 0.68 L/day and the elimination half-life (t_1/2) was approximately 4 days. No accumulation of trastuzumab emtansine was observed after repeated dosing of Kadcyla IV infusions every 3 weeks.
Based on population pharmacokinetic analysis (n = 671), body weight, albumin, sum of longest diameter of target lesions by Response Evaluation Criteria in Solid Tumours (RECIST), HER2 shed 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 rats, trastuzumab emtansine catabolites, including DM1, Lys-MCC-DM1, and MCC-DM1 were shown to be mainly excreted in the bile with minimal elimination in urine.

Pharmacokinetics in special populations.

The population pharmacokinetic analysis of trastuzumab emtansine showed that race did not appear to influence the pharmacokinetics of Kadcyla. Pharmacokinetics of Kadcyla in Asian patients (n = 73) were similar to non-Asian patients (n = 598). Because most of the patients in Kadcyla clinical studies were females, effect of gender on the pharmacokinetics of Kadcyla was not formally evaluated.