Kadcyla: detailed information

Package leaflet: Information for the user

Kadcyla 100 mg powder for concentrate for solution for infusion, 160 mg powder for concentrate for solution for infusion

trastuzumab emtansine
Please read all of this leaflet carefully before you are given this medicine because it
contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor, pharmacist or nurse.
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of this leaflet

What Kadcyla is and what it is used for
What you need to know before you are given Kadcyla
How Kadcyla is given
Possible side effects
How to store Kadcyla
Contents of the pack and other information

1. What Kadcyla is and what it is used for

What Kadcyla is
Kadcyla contains the active substance trastuzumab emtansine, which consists of two parts linked together:

trastuzumab – a monoclonal antibody that selectively binds to an antigen (a target protein) called human epidermal growth factor receptor 2 (HER2). HER2 is present in large amounts on the surface of certain tumor cells, stimulating their growth. When trastuzumab binds to HER2, it blocks the growth of these cells and causes their death.
DM1 – an antitumor agent that becomes active after Kadcyla enters the tumor cell.

What Kadcyla is used for
Kadcyla is used to treat breast cancer in adults when:

high levels of HER2 protein are present on the tumor cells – your doctor will perform a test on tumor cells to confirm this;
you have already been treated with the medicine trastuzumab and a medicine from the taxane family;
the cancer has spread to areas near the breast or to other parts of the body (metastatic);
the cancer has not spread to other parts of the body and treatment will be given after surgery (treatment after surgery is called adjuvant therapy).

2. What you should know before being given Kadcyla

Do not be given Kadcyla

if you are allergic to trastuzumab emtansine or to any of the other ingredients of this medicine (listed in section 6). If this applies to you, Kadcyla must not be given to you. If you have any doubts, consult your doctor or nurse before receiving Kadcyla.

Warnings and precautions
Before you are given Kadcyla, speak to your doctor or nurse if:

you have previously experienced severe infusion-related reactions while receiving trastuzumab, characterized by symptoms such as flushing, chills, fever, shortness of breath, difficulty breathing, rapid heartbeat, or low blood pressure.
you are currently receiving treatment with blood-thinning medicines (e.g. warfarin, heparin).
you have a history of liver problems. Your doctor will perform blood tests to check your liver function before and regularly during treatment.

If any of the above conditions apply to you (or if you have any doubts), consult your doctor or
pharmacist before receiving Kadcyla.
Be aware of side effects
Kadcyla may worsen existing conditions or cause side effects. For more information on side effects to watch for, see section 4.
If you notice any of the following serious side effects while taking Kadcyla, inform your doctor or nurse immediately:

Breathing problems: Kadcyla can cause serious breathing problems, such as shortness of breath (at rest or during any kind of activity) and cough. These may be signs of lung inflammation, which can be severe and even fatal. If you develop a lung disease, your doctor may discontinue treatment with this medicine.
Liver problems: Kadcyla can cause inflammation or damage to liver cells, impairing the normal function of this organ. Inflamed or damaged liver cells may release higher-than-normal levels of certain substances (liver enzymes) into the bloodstream, leading to elevated liver enzymes detected in blood tests. In most cases, you may not experience any symptoms. Some possible symptoms include yellowing of the skin and whites of the eyes (jaundice). Your doctor will perform blood tests to monitor your liver function before treatment and regularly during treatment.
Another rare liver abnormality that may occur is a condition known as nodular regenerative hyperplasia (NRH). This condition causes changes in the liver's structure and may interfere with its normal functioning. Over time, this disease may cause symptoms such as a feeling of abdominal swelling or abdominal distension due to fluid accumulation, or bleeding from abnormal blood vessels in the esophagus or rectum.
Heart problems: Kadcyla can weaken the heart muscle. Weakening of the heart muscle may lead patients to develop symptoms such as shortness of breath at rest or during sleep, chest pain, swelling of the legs or arms, or a sensation of rapid or irregular heartbeat. Your doctor will check your heart function before treatment and regularly during treatment. Inform your doctor immediately if you notice any of the symptoms listed above.
Infusion-related reactions or allergic reactions: Kadcyla may cause flushing, chills, fever, difficulty breathing, low blood pressure, rapid heartbeat, sudden swelling of the face or tongue, or difficulty swallowing during or after the infusion on the first day of treatment. Your doctor or nurse will monitor you to ensure you do not experience any of these side effects. If you have a reaction, your doctor or nurse may slow down or stop the infusion and may give you treatment to manage the side effects. After symptoms improve, the infusion may be resumed.
Bleeding problems: Kadcyla may reduce the number of platelets in your blood. Since platelets help blood to clot, you may experience unexpected bruising or bleeding (e.g. from the nose or gums). Your doctor will perform regular blood tests to check for a possible drop in platelet count. Inform your doctor immediately if you notice unexpected bruising or bleeding.
Nervous system problems: Kadcyla may damage nerves. You may experience tingling, pain, numbness, itching, a sensation of "crawling insects," or pins and needles in your hands and feet. Your doctor will monitor you for signs and symptoms of nervous system problems.
Injection site reaction: if you feel a burning sensation, pain, or tenderness at the infusion site during the infusion, this may indicate that Kadcyla has leaked out of the blood vessel. Inform your doctor or nurse immediately. If Kadcyla leaks out of the blood vessel, increased pain, skin discoloration, blistering, and skin peeling (skin necrosis) may occur in the days or weeks following the infusion.

Inform your doctor or nurse immediately if you notice any of the side effects listed above.
Children and adolescents
Kadcyla is not recommended for individuals under 18 years of age. This is because there is no information available on its effectiveness in this age group.
Other medicines and Kadcyla
Inform your doctor or nurse if you are taking, have recently taken, or might take any other medicines.
In particular, inform your doctor or pharmacist if you are taking:

blood-thinning medicines such as warfarin, or medicines that reduce the blood's ability to form clots, such as aspirin;
antifungal medicines such as ketoconazole, itraconazole, or voriconazole;
antibiotics for infections such as clarithromycin or telithromycin;
medicines for HIV such as atazanavir, indinavir, nelfinavir, ritonavir, or saquinavir;
an antidepressant medicine such as nefazodone. If any of the above conditions apply to you (or if you have any doubts), consult your doctor or pharmacist before receiving Kadcyla.

Pregnancy
Kadcyla is not recommended during pregnancy as it may cause harm to the unborn child.

Inform your doctor before taking Kadcyla if you are pregnant, suspect you may be pregnant, or are planning a pregnancy.
Use an effective method of contraception to prevent pregnancy during treatment with Kadcyla. Ask your doctor for advice on the most suitable contraceptive method for you.
You must continue using contraception for at least 7 months after receiving the last dose of Kadcyla. Inform your doctor before stopping the use of contraception.
Male patients or their partners should also use an effective method of contraception.
If you become pregnant during treatment with Kadcyla, inform your doctor immediately.

Breastfeeding
Do not breastfeed during treatment with Kadcyla or for 7 months after the last infusion of Kadcyla. It is not known whether the components of Kadcyla pass into breast milk. Discuss this with your doctor.
Driving and using machines
Kadcyla is not expected to affect your ability to drive, ride a bicycle, or use tools or machinery. However, if you experience flushing, chills, fever, difficulty breathing, low blood pressure, rapid heartbeat (infusion-related reaction), blurred vision, fatigue, headache, or dizziness, do not drive, ride a bicycle, or use tools or machinery until these reactions have subsided.
Important information on some of the excipients in Kadcyla
This medicine contains less than 1 mmol of sodium (23 mg) per dose, i.e., essentially "sodium-free".
Kadcyla 100 mg powder for concentrate for solution for infusion
This medicine contains 1.1 mg of polysorbate 20 per vial, equivalent to 0.22 mg/mL.
Kadcyla 160 mg powder for concentrate for solution for infusion
This medicine contains 1.7 mg of polysorbate 20 per vial, equivalent to 0.21 mg/mL.
Polysorbates may cause allergic reactions. Inform your doctor if you have known allergies.

3. How Kadcyla is administered

Kadcyla will be administered to you by a doctor or nurse at a hospital or clinic:

The medicine is given as an intravenous infusion (a drip into a vein).
You will receive an infusion every 3 weeks.

How much medicine you will receive

You will receive 3.6 mg of Kadcyla per kilogram of your body weight. Your doctor will calculate the correct dose for you.
The first infusion will be given over 90 minutes. You will be monitored by a doctor or nurse during the infusion and for at least 90 minutes after the first dose to detect any adverse reactions.
If the first infusion is well tolerated, the infusion during your next visit may be given over 30 minutes. You will be monitored by a doctor or nurse during the infusion and for at least 30 minutes after the dose to detect any adverse reactions.
The total number of infusions you will receive depends on how you respond to treatment and the condition being treated.
If you experience side effects, your doctor may decide to continue treatment at a lower dose, delay the next dose, or discontinue treatment.

If you miss a Kadcyla treatment
If you miss or skip an appointment for Kadcyla administration, schedule another appointment as soon as possible. Do not wait until your next scheduled visit.
If you stop Kadcyla treatment
Do not stop treatment with this medicine without first talking to your doctor.
If you have any questions about how to use this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you notice any of the following serious side effects, inform your doctor or nurse immediately.
Very common (may affect more than 1 in 10 people):

Kadcyla may cause inflammation or damage to liver cells, leading to increased liver enzymes in blood test results. However, in most cases, during treatment with Kadcyla, the increase in liver enzyme levels is mild and temporary, causes no symptoms, and does not affect liver function.
Unexpected bruising and bleeding (e.g. from the nose).
Tingling, pain, numbness, itching, chills, or tingling sensations in the hands and feet. These symptoms may indicate nerve damage.

Common (may affect up to 1 in 10 people):

Hot flushes, chills, fever, breathing difficulties, low blood pressure, or rapid heartbeat during or up to 24 hours after infusion – these are known as infusion-related reactions.
Heart problems may occur, most patients will not have symptoms. If symptoms do occur, they may include cough, shortness of breath at rest or when lying flat, chest pain, swelling of the ankles or arms, and a sensation of rapid or irregular heartbeat.

Uncommon (may affect up to 1 in 100 people):

Inflammation of the lungs may cause breathing problems such as shortness of breath (at rest or during activity), cough, or dry coughing fits – these are signs of inflammation of the lung tissue.
Allergic reactions may occur. Most patients will have mild symptoms such as itching or chest tightness. In more severe cases, swelling of the face or tongue, difficulty swallowing or breathing may occur.

Rare (may affect up to 1 in 1,000 people):

Yellowing of the skin and whites of the eyes (jaundice) – these may be signs of severe liver damage.

Frequency not known:

If the Kadcyla infusion solution leaks into the area around the infusion site, you may develop pain, skin color changes, blistering, and skin peeling (skin necrosis) at the infusion site. Contact your doctor or nurse immediately.

Inform your doctor or nurse immediately if you notice any of the serious side effects listed above.
Other side effects include
Very common: may affect more than 1 in 10 people

decrease in red blood cell count (detected in blood tests)
feeling unwell (vomiting)
diarrhoea
dry mouth
urinary tract infection
constipation
stomach ache
cough
shortness of breath
mouth inflammation
difficulty sleeping
muscle or joint pain
fever
headache
feeling tired
weakness

Common: may affect up to 1 in 10 people

chills or flu-like symptoms
low potassium levels (detected in blood tests)
skin rashes
decrease in white blood cell count (detected in blood tests)
dry, watery eyes or blurred vision
redness or infection of the eyes
indigestion
swelling of arms and/or legs
bleeding gums
increased blood pressure
dizziness
taste changes
itching
memory difficulties
hair loss
skin reaction on hands and feet (hand-foot syndrome, also known as palmar-plantar erythrodysesthesia)
nail disorders

Uncommon: may affect up to 1 in 100 people

Another abnormality that may be caused by Kadcyla is a condition known as nodular regenerative hyperplasia of the liver. This condition causes changes in the structure of the liver. Patients develop multiple nodules in the liver which may interfere with its normal function. Over time, this disease may cause symptoms such as a feeling of abdominal fullness or swelling due to fluid accumulation, or bleeding from abnormal blood vessels in the esophagus or rectum.
If the Kadcyla infusion solution leaks into the area around the infusion site, you may develop tenderness, redness, or swelling at the infusion site.

If you experience any side effects after stopping treatment with Kadcyla, talk to your doctor or nurse and inform them that you have been treated with Kadcyla.
Reporting of side effects
If you get any side effects, including those not listed in this leaflet, talk to your doctor or nurse. You can also report side effects directly via the national reporting system listed in Annex V. Reporting side effects can help provide more information on the safety of this medicine.

5. How to store Kadcyla

Kadcyla will be stored by healthcare professionals at the hospital or clinic.

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and vial following Scad./EXP. The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C–8 °C). Do not freeze.
Once prepared, the Kadcyla infusion solution is stable for up to 24 hours at 2 °C–8 °C, after which it must be discarded.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Kadcyla contains

The active substance is trastuzumab emtansine.
Kadcyla 100 mg: one vial of powder for concentrate for solution for infusion contains 100 mg of trastuzumab emtansine. After reconstitution, one vial yields 5 mL of solution at a concentration of 20 mg/mL of trastuzumab emtansine.
Kadcyla 160 mg: one vial of powder for concentrate for solution for infusion contains 160 mg of trastuzumab emtansine. After reconstitution, one vial yields 8 mL of solution at a concentration of 20 mg/mL of trastuzumab emtansine.
The other components are succinic acid, sodium hydroxide (see section 2, “Important information about some of the excipients of Kadcyla”), sucrose and polysorbate 20.

Description of the appearance of Kadcyla and contents of the pack

Kadcyla is a lyophilized powder for concentrate for solution for infusion, white to off-white in colour, supplied in glass vials.
Kadcyla is available in packs containing 1 vial.

Marketing Authorisation Holder
Roche Registration GmbH
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

Manufacturer
Roche Pharma AG
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien, Latvija
Luxembourg/Luxemburg
Roche Latvija SIA
N.V. Roche S.A.
Tel: +371 - 6 7039831
België/Belgique/Belgien
Tél/Tel: +32 (0) 2 525 82 11

България, Lietuva
Рош България ЕООД
UAB “Roche Lietuva”
Тел: +359 2 474 5444
Tel: +370 5 2546799

Česká republika, Magyarország
Roche s. r. o.
Roche (Magyarország) Kft.
Tel: +420 - 2 20382111
Tel: +36 1 279 4500

Danmark, Nederland
Roche Pharmaceuticals A/S
Roche Nederland B.V.
Tlf.: +45 - 36 39 99 99
Tel: +31 (0) 348 438050

Deutschland, Norge
Roche Pharma AG
Roche Norge AS
Tel: +49 (0) 7624 140
Tlf: +47 - 22 78 90 00

Eesti, Österreich
Roche Eesti OÜ
Roche Austria GmbH
Tel: + 372 - 6 177 380
Tel: +43 (0) 1 27739

Ελλάδα, Kύπρος, Polska
Roche (Hellas) A.E.
Roche Polska Sp.z o.o.
Ελλάδα
Τηλ: +30 210 61 66 100
Tel: +48 - 22 345 18 88

España, Portugal
Roche Farma S.A.
Roche Farmacêutica Química, Lda
Tel: +34 - 91 324 81 00
Tel: +351 - 21 425 70 00

France, România
Roche
Roche România S.R.L.
Tél: +33 (0)1 47 61 40 00
Tel: +40 21 206 47 01

Hrvatska, Slovenija
Roche d.o.o
Roche farmacevtska družba d.o.o.
Tel: +385 1 4722 333
Tel: +386 - 1 360 26 00

Ireland, Malta, Slovenská republika
Roche Products (Ireland) Ltd.
Roche Slovensko, s.r.o.
Ireland/L-Irlanda
Tel: +353 (0) 1 469 0700
Tel: +421 - 2 52638201

Ísland, Suomi/Finland
Roche Pharmaceuticals A/S
Roche Oy
c/o Icepharma hf
Sími: +354 540 8000
Puh/Tel: +358 (0) 10 554 500

Italia, Sverige
Roche S.p.A.
Roche AB
Tel: +39 - 039 2471
Tel: +46 (0) 8 726 1200

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu.

The following information is intended exclusively for medical or healthcare professionals:
To avoid medication errors, it is important to check the vial labels to ensure that the medicine being prepared is Kadcyla (trastuzumab emtansine) and not another medicine containing trastuzumab (e.g. trastuzumab or trastuzumab deruxtecan).
Kadcyla must be reconstituted and diluted by a healthcare professional and administered as an intravenous infusion. It must not be administered as an intravenous injection or intravenous bolus.
This medicinal product should always be stored in its original closed packaging in a refrigerator at 2°C–8°C. A vial of Kadcyla reconstituted with water for injections (not supplied) is stable for 24 hours at 2°C–8°C after reconstitution and must not be frozen.
Appropriate aseptic techniques must be used. Follow appropriate procedures for handling cytotoxic medicinal products.
The reconstituted Kadcyla solution must be diluted in infusion bags made of non-latex, non-PVC polyolefin or polyvinyl chloride (PVC).
When the infusion concentrate is diluted with sodium chloride 9 mg/mL (0.9%) infusion solution, an in-line filter made of polyethersulfone (PES) with a pore size of 0.20 or 0.22 microns must be used.

Instructions for reconstitution

Kadcyla 100 mg: using a sterile syringe, slowly inject 5 mL of sterile water for injections into the 100 mg vial of trastuzumab emtansine.
Kadcyla 160 mg: using a sterile syringe, slowly inject 8 mL of sterile water for injections into the 160 mg vial of trastuzumab emtansine.
Gently rotate the vial until complete dissolution. Do not shake.

The reconstituted solution must be visually inspected for particulate matter and discoloration prior to administration. The reconstituted solution must be free of visible particles and may appear from transparent to slightly opalescent. The solution should be colourless to light brown. Do not use if the reconstituted solution is cloudy or has changed colour.
Discard any unused portion. The reconstituted product contains no preservatives and is for single use only.

Instructions for dilution
Determine the volume of reconstituted solution required based on a dose of trastuzumab emtansine of 3.6 mg/kg body weight:

Volume (mL) = Total dose to be administered ( body weight (kg) x dose (mg/kg))
20 (mg/mL, concentration of reconstituted solution)

The correct volume should be withdrawn from the vial and added to an infusion bag containing 250 mL of either sodium chloride 4.5 mg/mL (0.45%) infusion solution or sodium chloride 9 mg/mL (0.9%) infusion solution. Do not use a glucose (5%) solution. The sodium chloride 4.5 mg/mL (0.45%) infusion solution may be used without an in-line polyethersulfone (PES) filter of 0.20 or 0.22 μm. If sodium chloride 9 mg/mL (0.9%) infusion solution is used for the infusion, an in-line polyethersulfone (PES) filter of 0.20 or 0.22 microns must be used. The infusion solution should be administered immediately after preparation. Do not freeze or shake the infusion solution during storage. If prepared under aseptic conditions, the diluted solution may be stored for up to 24 hours at a temperature of 2°C to 8°C.