Consumer medicine information

Kymriah

Tisagenlecleucel

BRAND INFORMATION

Brand name

Kymriah

Active ingredient

Tisagenlecleucel

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Kymriah.

SUMMARY CMI

Kymriah*

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 Kymriah?

Kymriah, also known as tisagenlecleucel, is made from some of your own white blood cells called T-cells. A new gene is put into the T-cells so that they can target the cancer cells in your body. Kymriah is used to treat B-cell precursor acute lymphoblastic leukaemia (B-cell ALL) in children and young adults up to 25 years, that is refractory in relapse post-transplant, or in second or later relapse. It is also used to treat relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy.

For more information, see Section 1. Why am I given Kymriah? in the full CMI.

2. What should I know before I use Kymriah?

Do not use if you have ever had an allergic reaction to tisagenlecleucel 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 am given Kymriah? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Kymriah 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 am I given Kymriah?

  • Your doctor will give you Kymriah by infusion which means it will be given as a drip through a tube in your vein. This usually takes less than 1 hour.

More instructions can be found in Section 4. How you will be given Kymriah? in the full CMI.

5. What should I know after receiving Kymriah?

Things you should do
  • Plan to stay within proximity (2 hours travel) from where you were treated for at least 4 weeks after you have been given Kymriah.
  • Remind any doctor, dentist or pharmacist you visit that you have been given Kymriah.
  • If you have surgery, tell the surgeon or anaesthetist that you have received Kymriah.
  • If you are about to have any blood tests, tell your doctor that you have received Kymriah.
Things you should not do
  • Do not donate blood, organs, tissues, sperms, oocytes and other cells.
Driving or using machines
  • Do not drive, use machines or engage in activities that you need to be alert for in the 8 weeks after receiving Kymriah.

For more information, see Section 5. What should I know after I am given Kymriah? in the full CMI.

6. Are there any side effects?

There can be some serious side effects before and after Kymriah treatment.

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: CYTOKINE RELEASE SYNDROME

Cytokine Release Syndrome (CRS), including fatal or life threatening reactions, occurred in patients receiving KYMRIAH. Do not administer KYMRIAH to patients with active infection or inflammatory disorders. Treat severe or life threatening CRS with tocilizumab as per the CRS management algorithm.



FULL CMI

Kymriah*

Active ingredient(s): tisagenlecleucel

Consumer Medicine Information (CMI)

This leaflet provides important information about using Kymriah. 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 Kymriah.

Where to find information in this leaflet:

1. Why am I given Kymriah?
2. What should I know before I am given Kymriah?
3. What if I am taking other medicines?
4. How am I given Kymriah?
5. What should I know after I am given Kymriah?
6. Are there any side effects?
7. Product details

1. Why am I given Kymriah?

Kymriah (also known as tisagenlecleucel) is made from some of your own white blood cells called ‘T-cells’. T-cells are important for your immune system (the body's defences) to work properly.

Kymriah is used to treat:

  • B-cell precursor acute lymphoblastic leukaemia (B-cell ALL) that is refractory, in relapse post-transplant, or in second or later relapse - a form of cancer that affects some types of white blood cells.
  • Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy - a form of cancer that affects some types of white blood cells, mostly in the lymph nodes. Kymriah is not used for patients with primary central nervous system lymphoma.

How Kymriah works:

The T-cells are taken from your blood and a new gene is put into the T-cells so that they can target the cancer cells in your body. When Kymriah is infused into your blood, the modified T-cells find and kill the cancer cells.

2. What should I know before I am given Kymriah?

Warnings

Do not use Kymriah:

  • If you are allergic to tisagenlecleucel, or any of the ingredients listed at the end of this leaflet including dimethyl sulfoxide (DMSO) and dextran 40.

Tell your doctor (or your doctor will check) if you:

  • had a stem cell transplant in the last 4 months. Your doctor will check if you have signs or symptoms of graft versus host disease (GvHD). This happens when transplanted cells attack your body, causing symptoms such as rash, nausea, vomiting, diarrhoea and bloody stools
  • have any lung, heart, blood pressure or kidney problems
  • notice that the symptoms of your lymphoma or leukaemia are getting worse. If you have leukaemia this might include fever, feeling weak, bleeding gums, bruising. If you have lymphoma, this might include unexplained fever, feeling weak, night sweats, sudden weight loss
  • have had hepatitis B (HBV) or hepatitis C (HBC) or human immunodeficiency virus (HIV) infection
  • had a vaccination in the previous 6 weeks or are planning to have one in the next few months
  • have an infection. The infection will be treated before the Kymriah infusion

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

Kymriah is not recommended during pregnancy. Women of child-bearing potential should use effective birth control after being given Kymriah. Your doctor will check if you are pregnant. Discuss pregnancy or fathering a child with your doctor if you are planning to have a baby after receiving Kymriah.

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

The effects of Kymriah in pregnant or breast feeding women are not known, and it may harm your unborn baby or your newborn/infant. If you become pregnant or think you may be pregnant after treatment with Kymriah, talk to your doctor immediately.

Sexually active males receiving Kymriah should use a condom during intercourse.

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 (such as corticosteroids) may interfere with Kymriah and affect how it works.

Do not receive “live” vaccines before, during or after Kymriah treatment. Do not receive “live” vaccines in the 6 weeks before you are given a short course of chemotherapy to prepare your body for Kymriah cells (called “lymphodepleting” chemotherapy).

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

4. How will I receive Kymriah?

How much you will be given

  • Kymriah is made from your own white blood cells
  • Your doctor will collect blood to manufacture Kymriah using a catheter placed in your vein (a procedure called ‘leukapheresis’). This can take 3 to 6 hours and may need to be repeated.
  • Your white blood cells are frozen and sent away to manufacture Kymriah. It takes about 3 to 4 weeks to make Kymriah, but the time may vary. Your dose will consist of 1 or more infusion bags.
  • Kymriah is a treatment manufactured specifically for you. There are situations where Kymriah cannot be successfully manufactured. In some instances, a second manufacturing of Kymriah may be attempted.

When will you be given Kymriah

  • While awaiting Kymriah manufacture, the underlying disease may worsen and progress.
  • While Kymriah is being manufactured, additional therapy (a type of chemotherapy known as 'bridging therapy') may be needed to stabilize your cancer. This may induce side effects which can be severe or life-threatening. The treating physician will inform you about potential side effects of this therapy.
  • Before you are given Kymriah, your doctor may give you a type of treatment called lymphodepleting chemotherapy for a few days to prepare your body.
  • During the 30 to 60 minutes before being given Kymriah you may receive other medicines to help to decrease infusion reactions and/or fever. These may include paracetamol and an antihistamine.

How you are given Kymriah

  • Kymriah will always be given to you by a qualified healthcare professional. Appropriate handling precautions will be taken as Kymriah contains human blood cells. Prior to Kymriah infusion, your doctor will check that your identity matches with the patient details on the Kymriah infusion bag(s). Kymriah is made from your own white blood cells and should only be given to you.
  • Your doctor will give you Kymriah by infusion which means it will be given as a drip through a tube in your vein. This usually takes less than 1 hour.
  • During the infusion your doctor will check if you have difficulty breathing or dizziness (possible symptoms of allergic reactions).
  • Kymriah is given to you only once.

5. What should I know after I am given Kymriah?

Things you should do

Plan to stay within 2 hours distance of where you were given your treatment for at least 4 weeks after you have been given Kymriah. Your doctor will recommend that you return to the hospital 2 to 3 times a week for at least the first week. Your doctor will check to see if your treatment is working and help you with any side effects.

If you miss an appointment, call your doctor or the hospital as soon as possible to reschedule.

Your doctor will regularly monitor your blood counts after you receive Kymriah as you may experience a decrease in the number of blood cells and blood components.

Your doctor will regularly check for signs of cytokine release syndrome (CRS) or neurological problems.

Some types of HIV testing may be affected.

For your entire life, you should be checked in case your lymphoma or leukaemia returns or a new cancer occurs. If a new cancer occurs, your doctor or you should contact Novartis (1 800 671 203).

You should be checked regularly for neurological events (disorders of the nervous system).

You should be checked regularly for signs and symptoms of infection.

You should be checked regularly for signs and symptoms of tumour lysis syndrome (TLS).

Call your doctor straight away if you:

  • Have high fever, dizziness, light-headedness and blue discoloration of lips or limbs which may be symptoms of a serious condition called Cytokine Release Syndrome (CRS). Other symptoms of CRS are changes in heart rate, chills muscle pain, joint pain, nausea, vomiting, diarrhoea, excessive sweating, rash, loss of appetite, fatigue, headache, personality changes, confusion, inability to move part or all of the body, stiff neck, abnormal speech or eye movements, shortness of breath, heavy breathing, rapid breathing. When occurring these signs are almost always noticed within the first 10 days after infusion, but can occur later.
  • If you experience neurological problems like altered or decreased awareness, delirium, anxiety, dizziness, tremor, headache, confusion, agitation, seizures, difficulty speaking and understanding speech and loss of balance. This is usually in the first 8 weeks after the infusion, but it can occur later as well.
  • If you experience feeling warm, fever, chills or shivering. These can be symptoms of an infection.
  • If you develop frequent infections with sore throat or mouth ulcers, these may be symptoms of a low level of white blood cells.
  • Extreme tiredness, weakness and shortness of breath which may be symptoms of a lack of red blood cells.
  • Bleeding or bruising more easily which may be symptoms of low levels of cells in the blood known as platelets.

Remind any doctor, dentist or pharmacist you visit that you were given Kymriah.

If you are going to have surgery, tell the surgeon or anaesthetist that you were given Kymriah.

Things you should not do

Do not donate blood, organs, tissues, sperms, oocytes and other cells.

Driving or using machines

Do not drive, use machines or take part in activities that need you to be alert for. Kymriah can cause problems such as altered or decreased awareness or coordination and fits in the 8 weeks following infusion.

6. Are there any side effects?

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 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.

Less serious side effects

Less serious side effectsWhat to do
Very common (more than 1 in 10 people)
  • Infusion reactions including fever, chills, shivering, nausea, vomiting, tiredness, dizziness, pain where the infusion needle is inserted, blisters, itching, shortness of breath or wheezing
  • Side effects affecting the gut like loss of appetite, belly pain, nausea, vomiting, diarrhoea, constipation, weight loss
  • Side effects linked to your general condition including pain, fever, tiredness or chills
  • Side effects affecting the blood circulation including headache, dizziness (symptoms of high blood pressure)
  • Muscle weakness, muscle spasms, abnormal heart rhythm
  • Swollen ankles
  • Anxiety
  • Sleep disturbances
  • Cramps
  • Pain in the joints
  • Side effects affecting lungs and airways like coughing, rapid breathing, shortness of breath or laboured breathing
  • Rash
  • Personality changes, headaches, confusion, inability to move part or all of the body, stiff neck, abnormal speech and eye movements
  • Severe confusion (delirium)
  • Dizziness, lightheadedness (symptoms of low blood pressure)
  • Blue discolouration of the lips or limbs especially the hands or feet
  • Breathlessness
  • Severely decreased urine output
Common (up to 1 in 10 people)
  • Rash, nausea, vomiting, diarrhoea including bloody stools (possible graft versus host disease)
  • Decreased urination and/or muscle spasms (twitches) (possible symptoms of tumour lysis syndrome)
  • Convulsions, fits (seizures)
  • Severe nerve pain
  • Swelling and buildup of fluid, swelling of limbs, face or general swelling
  • Swelling of the belly
  • Changes or loss of vision
  • Side effects linked to your general condition including sore throat, stuffy nose, joint or muscles aching, headache, dizziness
  • Side effects affecting the gut like bloating,mouth sores, dry mouth
  • Pain in muscles, pain in the bones, pain in the limbs, back pain
  • Side effects affecting the nervous system including involuntary shaking of the body (tremor), tingling or numbness, impaired memory or thinking, numbness or tingling in fingers or toes, uncontrollable movements or actions of the body including tremors, jerks, twitches, spasms, contractions or problem walking, difficulty in speaking or understanding speech
  • Side effects affecting the lungs and airways like difficulty breathing, painful breathing
  • Side effects affecting the skin including hot flushes, night sweats, itching, skin reddening, excessive sweating
  • Side effects affecting your metabolism including symptoms of high blood sugar (thirst, low urine output, dark urine, dry flushed skin, irritability) or possible symptoms of excess circulating blood volume (shortness of breath, labored breathing, breathlessness)
  • Liver and gall bladder side effects such as yellow skin and eyes
  • Temporary enlargement of organs (due to increased pressure in the stomach)
  • High fever, chills, difficulty breathing, yellow skin and eyes, bloody stools, severely decreased urine output (multiple organ dysfunction syndrome resulting from increased pressure thereby reducing blood flow to organs)
  • Tiredness, confusion, muscle twitching, convulsions
  • Extreme inflammation (caused by overactive immune cells
Speak to your doctor if you have any of these less serious side effects and they worry you.

Very common serious side effects

Serious side effectsWhat to do
  • Signs and symptoms of cytokine release syndrome (a condition caused by a large, rapid release of proteins called cytokines into the blood) such as high fever, dizziness, light-headedness, blue discoloration of lips or limbs especially the hands and feet, shortness of breath, heavy breathing, rapid breathing, chills, muscle pain, joint pain, nausea, vomiting, loss of appetite, fatigue, changes in heart rate, headache, personality changes, confusion, inability to move part or all of the body, stiff neck, abnormal speech or eye movements
  • Signs and symptoms of blood disorders such as frequent infections, weakness, fatigue, fever, chills and/or shivering, sore throat, mouth ulcers, rash, swelling, yellow or pale skin, yellow eyes, sudden bleeding or bruising, uncontrolled bleeding, blood in the urine, breathlessness, abnormal body movement, irritability
  • Signs and symptoms of heart failure, worsening of heart failure or cardiac arrest such as fast and/or irregular heartbeat, breathlessness, difficulty breathing when lying down, swelling of the legs or feet, stopped heartbeat
  • Signs and symptoms of infection such as feeling warm, fever, chills or shivering
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.

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

Other side effects not listed here may occur in some people.

Some side effects (for example problems with blood clotting, high levels of uric acid in the blood) can only be found when your doctor does laboratory tests from time to time to check your progress.

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.

7. Product details

Kymriah is only given in a qualified treatment centre.

What Kymriah contains

Active ingredient
(main ingredient)		Tisagenlecleucel
Each infusion bag of Kymriah contains autologous T cells genetically modified to express an anti-CD19 chimeric antigen receptor. 1 or more bags contain a total of 1.2 x 106 to 6.0 x 108 CAR-positive viable T-cells.
Other ingredients
(inactive ingredients)

The cryo-media solution contains:

  • Potassium
  • Magnesium
  • Sodium
  • Aluminium
  • Acetate
  • Chloride
  • Dextran 40
  • Glucose
  • Albumin (HSA)
  • Dimethyl sulfoxide (DMSO)
  • Dimethyl sulfone
  • D-gluconic acid
  • Acetytriptophan
  • Hydroxymethylfurfural
  • Caprylate

Kymriah contains 24.3 to 121.5 mg sodium per dose, equivalent to 1% to 6% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Kymriah contains potassium, less than 1 mmol (39mg) per dose, ie essentially “potassium free”.

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

What Kymriah looks like

Kymriah is supplied as an infusion bag containing a cloudy to clear, colourless to slightly yellow suspension of cells (tisagenlecleucel). Each bag contains 10 mL to 50 mL of the suspension. Kymriah is stored at or below minus 120°C.

The product is thawed at bedside when it is ready to be used.

(Aust R 312685, 312686, 354832 and 354833).

Who distributes Kymriah

Kymriah is supplied in Australia by:

Novartis Pharmaceuticals Australia Pty Limited
(ABN 18 004 244 160)
54 Waterloo Road
Macquarie Park NSW 2113
Telephone 1 800 671 203
Website: www.novartis.com.au

This leaflet was prepared in May 2022.

Internal Document Code: (kym120522c.doc) based on PI (kym120522i.doc)

Published by MIMS July 2022

BRAND INFORMATION

Brand name

Kymriah

Active ingredient

Tisagenlecleucel

Schedule

Unscheduled

 

1 Name of Medicine

T Cells - Tisagenlecleucel, cryopreserved - T - Kymriah.

2 Qualitative and Quantitative Composition

Tisagenlecleucel: Autologous T cells genetically modified ex vivo using a lentiviral vector encoding an anti-CD19 chimeric antigen receptor (CAR).
1 or more infusion bags containing a total of 1.2 x 106 to 6.0 x 108 CAR-positive viable T cells in 10 to 50 mL. The quantitative information regarding total cells in the product is presented in the Certificate of Analysis.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Cell suspension.
Appearance: colourless to slightly yellow suspension of cells.

4 Clinical Particulars

4.1 Therapeutic Indications

Kymriah is a genetically modified autologous immunocellular therapy indicated for:
the treatment of paediatric and young adult patients up to 25 years of age with B-cell precursor acute lymphoblastic leukaemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse;
the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. Kymriah is not indicated for patients with primary central nervous system lymphoma.

4.2 Dose and Method of Administration

Manufacture and release of Kymriah usually takes about 3 to 4 weeks.
Kymriah must be administered in a treatment centre that has been qualified by the sponsor. Therapy should be initiated under the direction of and supervised by a healthcare professional experienced in the treatment of haematological malignancies and trained for Kymriah administration and management of patients treated with Kymriah.
A minimum of two doses of tocilizumab per patient for use in the event of cytokine release syndrome and emergency equipment must be available on site prior to infusion. The treatment centre should have timely access to additional doses of tocilizumab (see Section 4.4 Special Warnings and Precautions for Use, Management of cytokine release syndrome associated with Kymriah).
For autologous use only.

Dosage.

Kymriah is provided as a single, one-time treatment. The amount of tisagenlecleucel provided by the manufacturing facility equates to the dose to be used for each patient, and is within the target dose range indicated below.

Dosage in paediatric and young adult B-cell ALL patients.

For patients 50 kg and below: 0.2 to 5.0 x 106 CAR-positive viable T cells/kg body weight.
For patients above 50 kg: 0.1 to 2.5 x 108 CAR-positive viable T cells (non-weight based).

Dosage in DLBCL patients.

0.6 to 6.0 x 108 CAR-positive viable T cells (non-weight based).

Pre-treatment conditioning (lymphodepleting chemotherapy).

Lymphodepleting chemotherapy is recommended to be administered before Kymriah infusion unless the white blood cell (WBC) count within one week prior to infusion is ≤ 1,000 cells/microliter. Kymriah is recommended to be infused 2 to 14 days after completion of the lymphodepleting chemotherapy. The availability of Kymriah must be confirmed prior to starting the lymphodepleting regimen. If there is a delay of more than 4 weeks between completing lymphodepleting chemotherapy and the Kymriah infusion and the WBC count is > 1,000 cells/microliter, then the patient should be re-treated with lymphodepleting chemotherapy prior to receiving Kymriah.

B-cell ALL.

The recommended lymphodepleting chemotherapy regimen is:
Fludarabine (30 mg/m2 IV daily for 4 days) and cyclophosphamide (500 mg/m2 IV daily for 2 days starting with the first dose of fludarabine).
If the patient experienced a previous Grade 4 haemorrhagic cystitis with cyclophosphamide, or demonstrated a chemorefractory state to a cyclophosphamide-containing regimen administered shortly before lymphodepleting chemotherapy, then the following should be used:
Cytarabine (500 mg/m2 IV daily for 2 days) and etoposide (150 mg/m2 IV daily for 3 days starting with the first dose of cytarabine).

DLBCL.

The recommended lymphodepleting chemotherapy regimen is:
Fludarabine (25 mg/m2 IV daily for 3 days) and cyclophosphamide (250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine).
If the patient experienced a previous Grade 4 haemorrhagic cystitis with cyclophosphamide, or demonstrated a chemorefractory state to a cyclophosphamide-containing regimen administered shortly before lymphodepleting chemotherapy, then the following should be used:
Bendamustine (90 mg/m2 IV daily for 2 days).

Method of administration.

For intravenous use only. Do not use a leukocyte depleting filter.

Premedication.

To minimize potential acute infusion reactions, it is recommended to pre-medicate patients with paracetamol and diphenhydramine or another H1 antihistamine within approximately 30 to 60 minutes prior to Kymriah infusion. The prophylactic use of systemic corticosteroids should be avoided as it may interfere with the activity of Kymriah (see Section 4.4 Special Warnings and Precautions for Use, Cytokine release syndrome).

Clinical assessment prior to infusion.

Kymriah treatment should be delayed in certain patients with safety risk factors as detailed in Section 4.4 Special Warnings and Precautions for Use.

Precautions to be taken before handling or administering Kymriah.

Kymriah contains genetically-modified human blood cells. Local biosafety guidelines applicable for handling and disposal of such products should be followed (see Section 6.6 Special Precautions for Disposal).
Kymriah is prepared from autologous blood of the patient collected by leukapheresis. Patient leukapheresis material and Kymriah may carry a risk of transmitting infectious viruses to healthcare professionals handling the product. Accordingly, healthcare professionals should employ appropriate precautions (wearing gloves and glasses) when handling leukapheresis material or Kymriah to avoid potential transmission of infectious diseases as for any human derived materials.

Preparation for infusion.

Patient identity confirmation: Prior to Kymriah infusion, the patient's identity must be matched with the patient identifiers on the Kymriah infusion bag(s).
Inspection and thawing of the infusion bag(s): The timing of thaw of Kymriah and infusion should be coordinated. The infusion start time should be confirmed in advance, and adjusted for thaw so that Kymriah is available for infusion when the recipient is ready.
The infusion bag should be placed inside a second bag in case of a leak and to protect ports from contamination during the thawing process. The infusion bag(s) should be examined for any breaks or cracks prior to thawing.
Kymriah should be thawed at 37°C using either water bath or dry thaw method until there is no visible ice in the infusion bag. The infusion bag should be removed immediately from the thawing device and should not be stored at 37°C after thawing is completed.
Inspect the contents of the thawed infusion bag for any visible cell clumps. If visible cell clumps remain, gently mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing. Do not infuse Kymriah if clumps are not dispersed.
If the Kymriah bag appears to have been damaged or to be leaking, it should not be infused, and should be disposed of according to local biosafety procedures.
Once Kymriah has been thawed and is at room temperature (20°C to 25°C), it should be infused within 30 minutes to maintain maximum product viability, including any interruption during the infusion.
If more than one infusion bag has been received for the treatment dose, the second bag should not be thawed until after the contents of the first bag have been safely infused.

Administration.

Kymriah should not be manipulated. For example, Kymriah should not be washed (spun down and resuspended in new media) prior to infusion. All contents of the infusion bag(s) should be infused to complete a single dose.
Kymriah should be administered as an IV infusion through latex free tubing without a leukocyte depleting filter, approximately at 10 to 20 mL per minute by gravity flow. Sodium chloride 9 mg/mL (0.9%) solution for injection should be used to prime the tubing prior to infusion as well as to rinse it afterwards. When the full volume of Kymriah has been infused, Kymriah infusion bag should be rinsed with 10 to 30 mL sodium chloride 9 mg/mL (0.9%) solution for injection by back priming to assure as many cells as possible are infused into the patient.
In clinical trials intravenous push was an alternate method for the administration of low volumes of Kymriah.

Monitoring after infusion.

Following infusion with Kymriah patients should be monitored 2-3 times per week for at least the first week for signs and symptoms of potential cytokine release syndrome, neurological events and other toxicities. Physicians should consider hospitalisation at the first signs/symptoms of cytokine release syndrome and/or neurological events.
Instruct patients to remain within proximity (i.e. within 2 hours travel) of the qualified clinical facility for at least 4 weeks following infusion.

Dosage adjustment.

Renal and hepatic impairment.

As a cell based therapy and based on the mechanism of action, renal and hepatic impairment is not expected to impact tisagenlecleucel expansion and cellular kinetics; hence no formal renal and hepatic impairment studies were performed.

Geriatric patients (65 years of age or above).

DLBCL: No dose adjustment is required in patients over 65 years of age (see Section 5.2, Cellular kinetics, Special populations).

Special populations.

Paediatric patients.

B-cell ALL: No formal studies have been performed in paediatric patients below 3 years of age.
DLBCL: No formal studies have been performed in paediatric patients below 18 years of age.

Geriatric patients (65 years of age or above).

B-cell ALL: The safety and efficacy of Kymriah in this population has not been established.
Patients seropositive for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) There is no experience with manufacturing Kymriah for patients with a positive test for HIV or with active HBV or active HCV infection. Leukapheresis material from patients with HIV, active HCV or active HBV will not be accepted for Kymriah manufacturing. Perform screening for HIV, HBV, and HCV in accordance with institutional procedures before collection of cells for manufacturing.

Active central nervous system (CNS) leukaemia or lymphoma.

There is limited experience of use of Kymriah in patients with active CNS leukaemia and active CNS lymphoma. Therefore the risk/benefit of Kymriah has not been established in these populations.

Concomitant diseases.

Patients with active CNS disorder or inadequate renal, hepatic, pulmonary or cardiac function were excluded from the studies. These patients are likely to be more vulnerable to the consequences of the adverse reactions described after Kymriah infusion and require special attention.

4.3 Contraindications

Kymriah is contraindicated in patients with known hypersensitivity to tisagenlecleucel or to any component of the product formulation, (see Section 6.1) including dimethyl sulfoxide (DMSO) or dextran 40 (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Reasons to delay treatment.

Due to the risks associated with Kymriah treatment, infusion should be withheld until resolution of any of the following conditions:
Unresolved serious adverse reactions (especially pulmonary reactions, cardiac reactions or hypotension) from preceding chemotherapies.
Active uncontrolled infection.
Active Graft Versus Host Disease (GVHD).
Significant clinical worsening of leukaemia burden or rapid progression of lymphoma with unstable clinical presentation following lymphodepleting chemotherapy.

Patient information.

Prior to infusion, the patient should read the information from "Patient Education Leaflet". In particular, the patient should be carefully educated to inform their doctor immediately if cytokine release syndrome (CRS), neurological symptoms or other toxicities occur after infusion with Kymriah, and be informed that they should stay within 2 hours distance of where they are given Kymriah treatment for at least 4 weeks. Ensure that patients understand the risk of manufacturing failure. In case of a manufacturing failure, a second manufacturing of Kymriah may be attempted. In addition, while the patient awaits the product, additional chemotherapy (not the lymphodepletion) may be necessary and may increase the risk of adverse events during the pre-infusion period.

Blood, organ, tissue and cell donation.

Patients treated with Kymriah should not donate blood, organs, tissues, sperms, oocytes and other cells.

Active central nervous system (CNS) leukaemia or lymphoma.

There is limited experience of use of Kymriah in patients with active CNS leukaemia and active CNS lymphoma. Therefore the risk/benefit of Kymriah has not been established in these populations.

Cytokine release syndrome.

Cytokine release syndrome (CRS), including fatal or life threatening events, occurred frequently after Kymriah infusion. In all but 4 cases, development of CRS occurred between 1 to 10 days (median onset 3 days) after Kymriah infusion in paediatric and young adult B-cell ALL patients and between 1 and 9 days (median onset 3 days) after Kymriah infusion in adult DLBCL patients. The median time to resolution of CRS was 8 days in B-cell ALL and 7 days in DLBCL patients.
Signs and symptoms of CRS may include high fever, hypotension, hypoxia, dyspnoea, tachypnoea, arrhythmia (including tachycardia), fatigue, headache, rigors, myalgia, arthralgia, nausea, vomiting, diarrhoea, diaphoresis, rash and anorexia. Organ dysfunction, including cardiac insufficiency, renal insufficiency and liver injury with accompanying elevated aspartate aminotransferase (AST), elevated alanine aminotransferase (ALT) or elevated total bilirubin may also be observed. In addition, disseminated intravascular coagulation (DIC), with low fibrinogen levels, capillary leak syndrome (CLS), macrophage activation syndrome (MAS) and haemophagocytic lymphohistiocytosis (HLH) may occur in the setting of CRS. Patients should be closely monitored for signs or symptoms of these events including fever.
Risk factors for severe CRS in paediatric and young adult B-cell ALL patients are high pre-infusion tumour burden, uncontrolled or accelerating tumour burden following lymphodepleting chemotherapy, active infection and early onset of fever or CRS following Kymriah infusion. High tumour burden prior to Kymriah infusion was identified as a risk factor for developing severe CRS in adult DLBCL patients.
Prior to administration of Kymriah in paediatric and young adult B-cell ALL patients, efforts should be made to lower and control the patient's tumour burden.
In all indications, appropriate prophylactic and therapeutic treatment for infections should be provided, and complete resolution of any existing infections should be ensured. Infections may also occur during CRS and may increase the risk of a fatal event.

Management of cytokine release syndrome associated with Kymriah.

To reduce the risk of or manage CRS complications (see above), patients treated with Kymriah may receive anti-interleukin-6 based intervention (e.g. tocilizumab) with or without a corticosteroid based therapy. CRS management strategies may be implemented based on the most recent American Society of Clinical Oncology (ASCO) guideline, and/or appropriate local institutional/academic guidelines.
A minimum of two doses of tocilizumab per patient must be available on site prior to Kymriah infusion. The treatment centre should have timely access to additional doses of tocilizumab. Tisagenlecleucel continues to expand and persist following administration of tocilizumab and corticosteroids. Patients with medically significant cardiac dysfunction should be managed by standards of critical care; measures such as echocardiography should be considered. Tumour Necrosis Factor (TNF) antagonists are not recommended for management of Kymriah associated CRS.

Neurological toxicities.

Neurological toxicities (including immune effector cell-associated neurotoxicity syndrome (ICANS), in particular encephalopathy, confusional state and/or delirium, occur frequently with Kymriah and can be severe or life threatening. Other manifestations include depressed level of consciousness, seizures, aphasia and speech disorder. The majority of neurological events occurred within 8 weeks following Kymriah infusion and were transient. The median time to onset of the first neurological events occurring at any time following Kymriah infusion was 8 days for B-cell ALL (range: 2-489) and the median time to resolution was 7 days. The median time to onset of the first neurological events occurring at any time following Kymriah infusion was 6 days for DLBCL (range: 1-323) and the median time to resolution was 13 days.
Neurological events can be concurrent with CRS, following resolution of CRS or in the absence of CRS.
Patients should be monitored for neurological events. To reduce the risk of neurological toxicities (including ICANS) (see above), patients treated with Kymriah may receive supportive treatment.

Infections and febrile neutropenia.

Patients with active, uncontrolled infection should not start Kymriah treatment until the infection is resolved. Prior to Kymriah infusion, infection prophylaxis should follow standard guidelines based on the degree of preceding immunosuppression.
Serious infections, including life threatening or fatal infections, occurred in patients after Kymriah infusion. Patients should be monitored for signs and symptoms of infection and treated appropriately. As appropriate, prophylactic antibiotics should be administered and surveillance testing should be employed prior to and during treatment with Kymriah. Infections are known to complicate the course and management of concurrent CRS.
Febrile neutropenia was frequently observed in patients after Kymriah infusion and may be concurrent with CRS. In the event of febrile neutropenia, infection should be evaluated and managed appropriately with broad spectrum antibiotics, fluids and other supportive care, as medically indicated.
In patients achieving complete remission following Kymriah, resulting low immunoglobulin levels can increase the risk for infections. In patients with low immunoglobulin levels pre-emptive measures such as immunoglobulin replacement and rapid attention to signs and symptoms of infection should be implemented according to age and standard specific guidelines.

Prolonged cytopenias.

Patients may continue to exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Kymriah and should be managed per standard guidelines. The majority of patients who had cytopenias at day 28 following Kymriah treatment resolved to Grade 2 or below within three months after treatment. Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth factors, particularly granulocyte macrophage-colony stimulating factor (GM-CSF), have the potential to worsen CRS symptoms and are not recommended during the first 3 weeks after Kymriah infusion and until CRS has resolved.

Secondary malignancies.

Patients treated with Kymriah may develop secondary malignancies or recurrence of their cancer. T-cell malignancies have occurred following treatment of haematologic malignancies with BCMA and CD19-directed genetically modified autologous T-cell immunotherapies, including Kymriah. Mature T-cell malignancies, including CAR-positive tumours, may present as soon as weeks following infusion, and may include fatal outcomes.
Patients should be monitored life-long for secondary malignancies, including those of T-cell origin. In the event that a secondary malignancy occurs, the company should be contacted (see Section 8 Sponsor) to obtain instructions on patient samples to collect for testing.

Hypogammaglobulinemia.

Hypogammaglobulinemia and agammaglobulinemia can occur in patients after Kymriah infusion. Immunoglobulin levels should be monitored after treatment with Kymriah. In patients with low immunoglobulin levels pre-emptive measures such as infection precautions, antibiotic prophylaxis and immunoglobulin replacement should be taken according to age and standard guidelines.

Live vaccines.

The safety of immunization with live vaccines during or following Kymriah treatment has not been studied. Vaccination with live vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Kymriah treatment, and until immune recovery following treatment with Kymriah.

Tumour lysis syndrome.

Tumour lysis syndrome (TLS), which may be severe, has been observed. To minimize risk of TLS, patients with elevated uric acid or high tumour burden should receive allopurinol, or an alternative prophylaxis, prior to Kymriah infusion. Signs and symptoms of TLS should be monitored and events managed according to standard guidelines.

Concomitant disease.

Patients with active CNS disorder or inadequate renal, hepatic, pulmonary or cardiac function were excluded from the studies. These patients are likely to be more vulnerable to the consequences of the adverse reactions described after Kymriah infusion (see Section 4.8 Adverse Effects (Undesirable Effects)) and require special attention.

Prior stem cell transplantation.

It is not recommended that patients undergo allogeneic stem cell transplant (SCT) within 4 months prior to Kymriah because of the potential risk of Kymriah worsening graft versus host disease (GVHD). Leukapheresis for Kymriah manufacturing should be performed at least 12 weeks after allogeneic SCT.

HIV, hepatitis B, hepatitis C and viral reactivation.

It is not recommended that patients receive Kymriah if they have viral hepatitis because of the potential risk of viral reactivation. It is not recommended that patients receive Kymriah if they have HIV because of the possible effect on loss of HIV viral suppression and the theoretical risk of recombination events.

Viral reactivation.

Viral reactivation, e.g. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs directed against B cells.

Prior treatment with an anti-CD19 therapy.

There is limited experience with Kymriah in patients exposed to prior CD19-directed therapy. Kymriah is not recommended if the patient has relapsed with CD19-negative leukaemia after prior anti-CD19 therapy.

Use in the elderly.

B-cell ALL: The safety and efficacy of Kymriah in this population has not been established.
DLBCL: The safety and efficacy of Kymriah have been established in geriatric patients (see Section 5.1, Clinical trials). No dose adjustment is required in patients over 65 years of age (see Section 5.2, Cellular kinetics, Special populations).

Paediatric use.

B-cell ALL: No formal studies have been performed in paediatric patients below 3 years of age.
DLBCL.: No formal studies have been performed in paediatric patients below 18 years of age.

Effects on laboratory tests.

Due to limited and short spans of identical genetic information between the lentiviral vector used to create Kymriah and HIV, some commercial HIV nucleic acid tests (NAT) may give a false positive result post-treatment with Kymriah.

Content of dextran 40 and dimethyl sulfoxide (DMSO).

This medicinal product contains 11 mg dextran 40 and 82.5 mg dimethyl sulfoxide (DMSO) per mL. Serious hypersensitivity reactions, including anaphylaxis have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)). Each of these excipients are known to possibly cause anaphylactic reaction following parenteral administration. All patients should be observed closely during the infusion period.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No cellular kinetic or biodynamic drug interaction studies with tisagenlecleucel have been performed.
The co-administration of agents known to inhibit T-cell function has not been formally studied.
The co-administration of agents known to stimulate T-cell function has not been investigated and the effects are unknown.

Live vaccines.

The safety of immunisation with live vaccines during or following Kymriah treatment has not been studied. Vaccination with live vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Kymriah treatment, and until immune recovery following treatment with Kymriah.

Concomitant therapy with tocilizumab and corticosteroids.

Administration of tocilizumab and corticosteroids as per the cytokine release syndrome treatment algorithm does not impact the expansion and persistence of CAR-T cells.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no animal or human data available on the effect of Kymriah on male or female fertility. Effects of Kymriah on male and female fertility have not been evaluated in animal studies.
(Category C)

Risk summary.

There are no available data with Kymriah use in pregnant women. No animal studies have been conducted with Kymriah to assess whether it can cause fetal harm when administered to a pregnant woman. Kymriah has the potential to be transferred to the fetus via the placenta and could cause fetal toxicity, including B-cell lymphocytopenia.
Kymriah is not recommended during pregnancy and in women of child-bearing potential not using contraception.
If a patient intends to become pregnant after receiving Kymriah, the patient should be apprised of the potential risks to the fetus.
Pregnant women who have received Kymriah may have hypogammaglobulinemia. Assessment of immunoglobulin levels is indicated in newborns of mothers treated with Kymriah.
 There are no data regarding the presence of Kymriah in human milk, the effect on the breast-fed child or the effects of Kymriah on milk production. A risk to the newborn/infant cannot be excluded. Women who are breast-feeding should be advised of the potential risk to the breast-fed infant.
Following administration of Kymriah, breast-feeding should be discussed with the treating physician.

Females and males of reproductive potential.

There is a potential for Kymriah to cause fetal toxicity.

Pregnancy testing.

The pregnancy status of females of reproductive potential should be verified prior to starting treatment with Kymriah.

Contraception.

Females of reproductive potential should use highly effective contraception (i.e. methods that result in less than 1% pregnancy rates) after Kymriah administration.
Sexually active males who have received Kymriah should use a condom during intercourse with a female of reproductive potential or a pregnant woman.
Pregnancy or fathering a child after Kymriah, therapy should be discussed with the treating physician.
See the prescribing information for lymphodepleting chemotherapy for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy.
There are insufficient exposure data to provide a recommendation concerning the duration of contraception following treatment with Kymriah.

4.7 Effects on Ability to Drive and Use Machines

Due to the potential for neurological toxicities, patients receiving Kymriah are at risk of altered or decreased consciousness or coordination, and seizures in the 8 weeks following infusion. Patients are advised to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery during this initial period.

4.8 Adverse Effects (Undesirable Effects)

Pediatric and young adult B-cell ALL (13-Apr-2018 data-cut).

The adverse reactions described in this section were characterized in 79 patients infused with Kymriah in the multi-center pivotal clinical study CCTL019B2202 (N=79).
The most common non-haematological adverse reactions (≥ 40%) were cytokine release syndrome (77%), infections (72%), hypogammaglobulinemia (53%) and pyrexia (42%).
The most common haematological laboratory abnormalities were decreased white blood cells (100%), decreased haemoglobin (100%), decreased neutrophils (98%), decreased lymphocytes (98%) and decreased platelets (97%).
Grade 3 and Grade 4 adverse reactions were reported in 89% of patients.
The most common (> 40%) Grade 3 and Grade 4 non-haematological adverse reaction was CRS (48%).
The most common (> 40%) Grade 3 and Grade 4 haematological laboratory abnormalities were white blood cells decreased (97%), neutrophils decreased (95%), lymphocytes decreased (96%), platelets decreased (77%), and haemoglobin decreased (48%).
Grade 3 or 4 adverse events were more often observed within the initial 8 weeks post-infusion (82% of patients) compared to after 8 weeks post-infusion (51% of patients).
Six fatalities not related to disease progression occurred following Kymriah infusion, of which 1 death occurred within 30 days of infusion due to cerebral haemorrhage. Three deaths were due to infections (encephalitis, lower respiratory tract bacterial infection and mycosis), 1 due to hepatobiliary disease, and 1 death was due to unknown reason.

Tabulated summary of adverse drug reactions from B2202.

Adverse drug reactions from B2202 in Table 1 are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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).

Diffuse large B-cell lymphoma (11-Dec-2018 data-cut).

The adverse reactions described in this section were characterised in 115 patients, infused with Kymriah, in one global multi-centre international study, i.e. the ongoing pivotal clinical study CCTL019C2201.
The most common non-haematological adverse reactions were CRS (57%), infections (58%), pyrexia (35%), diarrhoea (31%), nausea (29%), hypotension (25%) and fatigue (27%).
The most common haematological laboratory abnormalities were lymphocytes decreased (100%), haemoglobin decreased (99%), white blood cells decreased (99%), neutrophils decreased (97%), and platelet decreased (95%).
Grade 3 and Grade 4 adverse reactions were reported in 88% of patients. The most common Grade 3 and Grade 4 non-haematological adverse reaction was infections (34%) and CRS (23%).
The most common (> 25%) Grade 3 and Grade 4 haematological laboratory abnormalities were lymphocyte count decreased (95%), neutrophil count decreased (82%), white blood cell count decreased (78%), haemoglobin decreased (59%), and platelet count decreased (56%).
Grade 3 or 4 adverse events were more often observed within the initial 8 weeks post-infusion (82% of patients) compared to after 8 weeks post-infusion (48% of patients).
Twelve fatalities not related to disease progression occurred following Kymriah infusion, all after 30 days from infusion. Of those, there were 2 deaths due to multiple organ dysfunction syndrome, 2 deaths (unspecified) and one death each due to AML, cardiopulmonary failure, cerebral haemorrhage, chronic kidney disease, duodenal ulcer haemorrhage, neuroendocrine carcinoma, pulmonary haemorrhage and sepsis.

Tabulated summary of adverse drug reactions from C2201.

Adverse drug reactions from C2201 in Table 2 are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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).

Adverse drug reactions from spontaneous reports and literature cases (frequency not known).

The following adverse drug reactions have been derived from post-marketing experience with Kymriah via spontaneous case reports, literature cases, expanded access programs, and clinical studies other than the global registration trials. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to tisagenlecleucel exposure.
Frequency not known: anaphylactic reaction/infusion related reaction, neurotoxicity, immune effector cell-associated neurotoxicity syndrome (ICANS), and secondary malignancy of T-cell origin.

Description of selected adverse drug reactions.

Cytokine release syndrome (CRS).

In the ongoing clinical study in paediatric and young adult B-cell ALL (N=79), CRS reactions classified based on the PENN Grading system for CRS (Porter et al 2015) were reported in 77% of patients (48% with Grade 3 or 4) with a median time to onset of 3 days and a median CRS duration of 8 days. Two deaths occurred within 30 days of Kymriah infusion, including one patient, who died from progressive leukaemia in the setting of possible CRS and one patient, who experienced fatal intracranial haemorrhage that developed during the course of resolved CRS, abdominal compartment syndrome, coagulopathy and renal failure.
In the ongoing clinical study in DLBCL (N=115), CRS was reported in 57% of patients, (23% with Grade 3 or 4), with a median time to onset of 3 days and a median duration of 7 days.
Of the 61 patients with r/r ALL who had CRS, 31 (51%) received tocilizumab. Ten (16%) patients received two doses of tocilizumab, 3 (5%) patients received three doses of tocilizumab, and 16 (26%) patients received addition of corticosteroids (e.g. methylprednisolone).
Of the 66 patients with r/r DLBCL who had CRS, 19 (29%) received systemic tocilizumab or corticosteroids. Eight (12%) patients received a single dose of tocilizumab, 10 (15%) patients received two doses of tocilizumab, and 11 (17%) patients received corticosteroids in addition to tocilizumab. One patient with r/r DLBCL received corticosteroids for CRS without concomitant tocilizumab.
Cytokine release syndrome was graded per the Penn criteria in the paediatric and young adult B-cell ALL and DLBCL trials as follows: Grade 1: mild reactions, requiring supportive care; Grade 2: moderate reactions, requiring intravenous therapies; Grade 3: severe reactions, requiring low dose vasopressors or supplemental oxygen; Grade 4: life threatening reactions, requiring high dose vasopressors or intubation; Grade 5: death.
For clinical management of CRS, see Section 4.4 Special Warnings and Precautions for Use.

Infections and febrile neutropenia.

In B-cell ALL patients severe infections (Grade 3 or 4), which can be life-threatening or fatal, occurred in 48% of patients after Kymriah infusion. The overall incidence was 72% (unspecified 57%, bacterial 27%, viral 38% and fungal 15%) (see Section 4.4 Special Warnings and Precautions for Use). Forty three percent of the patients experienced an infection of any type within 8 weeks after Kymriah infusion.
In DLBCL patients severe infections (Grade 3 or 4), which can be life-threatening or fatal, occurred in 34% of patients. The overall incidence (all grades) was 58% (unspecified 48%, bacterial 15%, fungal 11% and viral 11%) (see Section 4.4 Special Warnings and Precautions for Use). Thirty seven percent of the patients experienced an infection of any type within 8 weeks.
Severe febrile neutropenia (Grade 3 or 4) was observed in 34% of paediatric and young adult B-cell ALL patients and 17% of DLBCL patients. See Section 4.4 Special Warnings and Precautions for Use for the management of febrile neutropenia before Kymriah and after Kymriah infusion.

Hematopoietic cytopenias not resolved by day 28.

Cytopenias are very common based on prior chemotherapies and Kymriah therapy.
All paediatric and young B-cell ALL patients, had a Grade 3 or 4 cytopenia at any time post Kymriah infusion. Grade 3 and 4 cytopenias not resolved by day 28 after Kymriah infusion were based on laboratory findings included a decreased count of white blood cells (57%), neutrophils (54%), lymphocytes (44%), thrombocytes (42%) and a decreased haemoglobin (13%).
All adult patients with DLBCL had Grade 3 and 4 cytopenias at any time post Kymriah infusion. Grade 3 and 4 cytopenias not resolved by day 28 after Kymriah infusion based on laboratory findings included a decreased count of thrombocytes (39%), lymphocytes (29%), neutrophils (25%), white blood cells (21%) and decreased haemoglobin (14%).

Neurotoxic events.

The majority of neurotoxic events occurred within 8 weeks following infusion and were transient.
In paediatric and young adult B-cell ALL patients, manifestations of encephalopathy and/or delirium occurred in 39% of patients (13% Grade 3 or 4) within 8 weeks after Kymriah infusion. In DLBCL patients, these occurred in 20% of patients (11% were Grade 3 or 4) within 8 weeks after Kymriah infusion.
The other most common neurological event at any time post Kymriah infusion was headache (35% in paediatric and young adult B-cell ALL patients and 21% in DLBCL patients).
For clinical management of neurological toxicities, see Section 4.4 Special Warnings and Precautions for Use.

Reporting suspected adverse effects.

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

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Biodynamic properties.

ATC code: L01XL04.
Mechanism of action. Tisagenlecleucel is an autologous, immunocellular cancer therapy that involves reprogramming a patient's own T-cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19 expressing cells. CD19 is expressed by malignant and normal B cells. The CAR is comprised of a murine single chain antibody fragment that recognizes CD19 and is fused to intracellular signalling domains from 4-1BB (CD137) and CD3 zeta. The CD3 zeta component is critical for initiating T cell activation and antitumor activity while 4-1BB enhances the expansion and persistence of tisagenlecleucel. Upon binding to CD19 expressing cells, the CAR transmits a signal to promote T cell expansion, activation, target cell elimination and persistence of tisagenlecleucel.
Biodynamic effects.

Cardiac electrophysiology.

Kymriah is a cell product and is not expected to prolong the QT interval; hence no formal QT study was conducted.

Clinical trials.

Acute lymphoblastic leukaemia (ALL). The safety and efficacy of Kymriah treatment in patients with relapsed and refractory (r/r) paediatric and young adults B-cell ALL, were evaluated in one pivotal study (B2202) and two supportive studies (B2205J and B2101J) with a total of 160 patients treated. All patients had leukapheresis products collected and cryopreserved prior to or during study entry.
Pivotal study B2202 used tisagenlecleucel exclusively sourced from the Novartis registered manufacturing facility. A small number of tisagenlecleucel batches (3/29) were manufactured at Novartis for study B2205J and no batches came from Novartis for study B2101J. A formal comparability study of Novartis-made tisagenlecleucel batches and other manufacturing sites has not taken place.

CCTL019B2202 (25-April-2017 data-cut).

The pivotal study (B2202) is a multicenter, single-arm, open label, phase II study in paediatric and young adult patients with r/r B-cell acute lymphoblastic leukaemia. Of 92 patients enrolled, 75 received infusion with Kymriah; for 7 patients (8%) Kymriah could not be manufactured; reasons for discontinuation prior to Kymriah infusion included death (n=7; 8%) or adverse events (n=3; 3%) while awaiting Kymriah manufacturing in the clinical study.
The 75 infused patients included 43 males and 32 females of median age 11 years (range: 3-23 years). Seventy-seven percent of patients were White, 8% were Asian, and 15% were of other races. Six (8%) had primary refractory disease, 40 (53%) had one prior stem cell transplantation, 6 patients (8%) had two stem cell transplantations. Treatment consisted of lymphodepleting chemotherapy (fludarabine 30 mg/m2 daily for 4 days and cyclophosphamide 500 mg/m2 daily for 2 days) followed by a single dose of Kymriah. Among the 75 patients who received Kymriah infusion, a total of 65 and 72 received bridging chemotherapy and lymphodepleting chemotherapy respectively after enrollment and prior to the Kymriah infusion (see Table 3).
Efficacy was established through the primary endpoint of overall remission rate (ORR), within 3 months post infusion, as determined by Independent Review Committee (IRC) assessment. Secondary endpoints included duration of remission (DOR) and the proportion of patients who achieved complete remission (CR) or complete remission with incomplete blood count (Cri) with minimal residual disease (MRD) < 0.01% by flow cytometry (MRD-negative). The ORR at 3 months was 81% (61/75). The median time from Kymriah infusion to the data cut-off date was 13.11 months (range: 2.1 to 23.5). See Table 4 and Figure 1 and Figure 2 for efficacy results from this study. Fifty-seven of 61 responders achieved CR/CRi by the Day 28 assessment. ORR was consistent across all subgroups. Seven patients who received Kymriah infusion went to transplant while in remission. Seventy six percent of patients were hospitalized at the time of infusion and 24% were not hospitalized at the time of Kymriah infusion.
Health related quality of life (HRQoL) were evaluated by PedsQL and EQ-5D questionnaires completed by patients aged 8 and above. Among patients responding, the mean change from baseline in the PedsQL total score was 13.5 at Month 3 and 16.9 at Month 6 and 27.2 at Month 12, and the mean change from baseline in the EQ VAS score was 16.5 at Month 3 and 15.9 at Month 6 and 24.7 at Month 12, indicating overall clinically meaningful improvement in HRQoL following Kymriah infusion.
Diffuse large B-cell lymphoma (DLBCL).

CCTL019C2201 (08-Dec-17 data-cut).

The pivotal study (C2201) is a multicentre, single-arm, open label, phase II study in adult patients with relapsed or refractory DLBCL. Of 165 patients enrolled, 111 patients received infusion with Kymriah (4 infusions were pending at the time of analysis); Twelve out of 165 patients did not receive Kymriah due to manufacturing failure. Other reasons for discontinuation prior to Kymriah infusion included death (n=16), physician decision/primary disease progression (n=16), adverse event (n=3), subject decision (n=3) or adverse events (n=2) while awaiting Kymriah manufacturing in the clinical trial.
Median age of infused patients was 56 years (range 22 to 76 years), 76% of patients had Stage III-IV disease, 51% had received 3 or more prior lines of treatment for DLBCL. Forty-nine percent of patients had received prior stem cell transplant. Fifty-five percent of patients were refractory to last line of treatment. All patients had leukapheresis starting material collected and cryopreserved prior to or during study entry. The majority of patients 102/111 received bridging therapy while waiting for Kymriah and 103/111 received lymphodepleting chemotherapy prior to Kymriah infusion. Kymriah was given as a single dose intravenous infusion.
The efficacy of Kymriah was evaluated through the primary endpoint of best overall response rate (ORR), which includes complete response (CR) and partial response (PR) as determined by IRC assessment based on the Lugano Classification (Cheson et al 2014) as well as secondary endpoints including duration of response (DOR) (Table 5). The primary endpoint was assessed in 93 patients who received Kymriah manufactured at the Novartis U.S. facility and who have been followed for at least 3 months or discontinued earlier after Kymriah administration.
Among the 93 patients (Table 5) included in the primary analysis, the best ORR was 51.6% (48/93) with a 95% confidence interval (CI) of (41.0%, 62.1%). Thirty-seven patients (39.8%) achieved CR and 11 (11.8%) achieved PR. No patient who received Kymriah infusion went to transplant after achieving CR or PR.
Subgroup analyses demonstrated a homogeneous and consistent treatment effect across major demographic and prognostic subgroups regardless of prior lines of therapy (ORR 53.1% and 50.0% in patients with ≤ 2 lines of therapies and > 2 lines of therapies, respectively), prior SCT (ORR of 50.0% and 53.7% in patients without or with previous SCT, respectively), relapsed or refractory disease (ORR 64.4% and 39.6%, respectively) or biological factors such as cell of origin (ORR 52.5% in non-GCB and 48.0% in GCB subtype) and double-hit/triple hit lymphoma with Bcl-2 and c-myc expression (ORR of 50.0% in patients with double-hit/triple hit lymphoma). See Figure 3 and Figure 4.

5.2 Pharmacokinetic Properties

Cellular kinetics.

Following infusion of Kymriah into paediatric and young adult r/r B-cell ALL and r/r DLBCL patients, Kymriah typically exhibited an initial rapid expansion followed by a slower bi-exponential decline.

Cellular kinetics in paediatric B-cell ALL patients.

A summary of cellular kinetic parameters of tisagenlecleucel is provided in Table 6.
The maximal expansion (Cmax) was approximately 2-fold higher in CR/CRi patients (n=79) compared with non-responding (NR) patients (n=10) as measured by qPCR. Transgene persistence has been detected up to 784 days in peripheral blood (B2101J) and up to 617 days in responding patients in the pooled studies B2202 and B2205J. Together these data, signify the potential role of expansion and persistence for eliciting a clinical response.

Cellular kinetics in DLBCL patients.

A summary of cellular kinetic parameters of tisagenlecleucel in DLBCL patients is provided in Table 7.
Tisagenlecleucel undergoes significant in vivo expansion following infusion and demonstrated persistence of the CAR transgene up to 693 days in responding patients (CR/PR) with shorter persistence in non-responding patients up to 374 days.
AUC0-28d and Cmax were similar between responder (CR and PR) and non-responder patients (SD, PD, and patients with unknown response status) based on clinical response at month 3. The geometric mean estimate for expansion (Cmax) in DLBCL patients was observed to be lower than that in paediatric ALL patients (geometric mean Cmax (%CV): 5,530 (303.3) copies/microgram, n=86, Study C2201; 35,800 (157.4) copies/microgram, n=72, Study B2202).
A trend for longer half-life was noted in responding patients compared to non-responding patients geometric mean T1/2: 91.3 days in responders, and 15.4 days in non-responders.

Absorption.

Not applicable. Kymriah is a T-cell immunocellular therapy and is administered via intravenous infusion.

Distribution.

In paediatric and young adult B-cell ALL patients, Kymriah has been shown to be present in the blood as well as bone marrow beyond 2 years. The blood to bone marrow partitioning of Kymriah in bone marrow was 47.2% of that present in blood at Day 28 while at Months 3 and 6 it distributes at 68.3% and 69%, respectively, demonstrating high trafficking to bone marrow (Studies B2202 and B2205J). In addition, Kymriah also traffics and persists in cerebrospinal fluid in paediatric and young adult B-cell ALL patients (Study B2101J) for up to 1 year.
In DLBCL patients (Study C2201), Kymriah has been detected for up to 2 years in peripheral blood and up to Month 9 in bone marrow for complete responder patients. The blood to bone marrow partitioning in bone marrow was nearly 70% of that present in blood at Day 28 and 50% at Month 3 in responder and non-responder patients.

Metabolism.

Not applicable, Kymriah is an immunocellular therapy.

Excretion.

The elimination profile of Kymriah includes a bi-exponential decline in peripheral blood and bone marrow.

Linearity/non-linearity.

Dose and cellular kinetic parameters are independent, thus there is no apparent relationship with AUC0-28d and Cmax with dose.

Special populations.

Geriatric population (65 years of age or above).

The impact of age on cellular kinetics was evaluated across the age range of 22 to 76 years in DLBCL patients (Study C2201). The scatter plots of cellular kinetic parameters versus age revealed no relevant relationship between cellular kinetic parameters (AUC0-28d and Cmax) with age. The AUC0-28d in patients with ≥ 65 years of age was observed to be 49.1% and 64.0% lower than patients ≥ 40 to < 65 years and < 40 years, respectively. However, the data should be interpreted with caution due to the high inter-individual variability associated with the parameter.

Gender.

Gender is not a significant characteristic influencing tisagenlecleucel expansion in B-cell ALL and DLBCL patients.

Race/ethnicity.

The majority of patients treated with Kymriah are Caucasian, therefore, there is limited evidence that race/ethnicity impact the expansion of Kymriah in paediatric and young adult ALL and DLBCL patients. In Studies B2202 and B2205J there were 79.8% of Caucasian, 7.7% of Asian and 12.5% of other ethnicities.
In Study C2201, there were 88% Caucasian, 5% Asian, 4% Black or African American patients and three patients (3%) of unknown race.

Body weight.

In DLBCL patients, across the weight ranges (38.4 to 186.7 kg), the scatter plots of qPCR cellular kinetic parameters versus weight revealed no apparent relationship between cellular kinetic parameters with weight.

Renal impairment.

Kymriah is a cell based product, and based on the mechanism of action renal impairment is not expected to impact tisagenlecleucel expansion and cellular kinetics; hence no formal renal impairment studies were performed.

Prior stem cell transplantation.

Prior stem cell transplantation did not impact the expansion/persistence of tisagenlecleucel in paediatric and young adult B-cell ALL patients or adult DLBCL patients.

Hepatic impairment.

Kymriah is a cell based product, and based on the mechanism of action hepatic impairment is not expected to impact tisagenlecleucel expansion and cellular kinetics; hence no formal hepatic impairment studies were performed.

Immunogenicity.

Cell based therapeutics carry the potential for immunogenicity. Humoral immunogenicity of tisagenlecleucel was measured by determination of anti-murine CAR19 antibodies (anti-mCAR19) in serum pre- and post-administration. In paediatric and young adult ALL, the majority of patients (84.6%) tested positive for pre-dose anti-mCAR19, however, the pre-existing antibodies were not associated with an impact on clinical response nor have an impact on the expansion and persistence of tisagenlecleucel. Additionally treatment induced anti-mCAR19 antibodies were detected in 34.6% of patients in the SCP pool. The treatment induced anti-mCAR19 antibodies did not impact cellular kinetics or clinical response.
In Study C2201, the majority of patients (91.4%) tested positive for pre-infusion humoral immunogenicity by the detection of anti-mCAR19 antibodies and 5% of patients had treatment-induced anti-mCAR19 antibodies detected. Anti-mCAR19 antibodies, both pre-existing and treatment-induced, were not associated with any apparent impact on clinical response nor have an impact on the in vivo initial expansion and persistence (Cmax and AUC0-28d) of tisagenlecleucel.
Cellular immunogenicity assessment was performed in paediatric and young adult ALL patients and r/r DLBCL patients to test for mCAR19 peptide-activated responses by stimulated intracellular interferon-gamma production. The cellular immunogenicity responses did not correlate with in vivo expansion and persistence and Month 3 response, for CD4 and CD8 T cell responses, for patients in both the indications.
As with any immunogenicity assay, the detection of anti-mCAR19 antibodies is highly dependent on assay sensitivity and specificity. Furthermore, the observed pre- and post-dose anti-mCAR19 may be influenced by several factors, including assay specifications, sample handling, timing of sample collection, prior therapy, administration of intravenous immunoglobulin or other concomitant medications as well as underlying disease. In addition, 90% of healthy volunteer samples screened during assay development were positive for anti-mCAR19 antibodies.

5.3 Preclinical Safety Data

Genotoxicity.

Conventional genotoxicity assays have not been performed with tisagenlecleucel, and are not appropriate for cell therapy products. A genomic insertion site analysis of the lentiviral vector was performed on Kymriah products from 14 individual donors (12 patients and 2 healthy volunteers). There was no evidence for preferential integration near genes of concern or preferential outgrowth of cells harbouring integration sites of concern. However, a risk for insertional mutagenesis in mature T cells leading to oncogenic transformation cannot be excluded.

Carcinogenicity.

Standard rodent carcinogenicity studies have not been performed with tisagenlecleucel. In vitro expansion studies with CAR-positive T-cells (Kymriah) from healthy donors and patients (Kymriah) showed no evidence for transformation and/or immortalization of T-cells. In vivo studies in immunocompromised mice did not show signs of abnormal cell growth or signs of clonal cell expansion for up to 7 months after cell injection.

6 Pharmaceutical Particulars

6.1 List of Excipients

The cryo-media solution contains potassium 0.082 g/L, magnesium 0.012 g/L, sodium 2.43 g/L, aluminium 40.0 microgram/L, acetate 0.549 g/L, chloride 2.15 g/L, dextran 40 11.000 g/L, glucose 21.906 g/L, albumin (HSA) 52.400 g/L, dimethyl sulfoxide (DMSO) 82.500 g/L, dimethyl sulfone 0.03 g/L, d-gluconic acid 1.543 g/L, acetytriptophan 1.079 g/L, hydroxymethylfurfural 0.097 mg/L, caprylate 0.630 g/L.
This medicinal product contains 2.43 mg sodium per mL and 24.3 to 121.5 mg sodium per dose, equivalent to 1 to 6% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
This medicinal product contains potassium, less than 1 mmol (39 mg) per dose, i.e. essentially "potassium free."

6.2 Incompatibilities

In the absence of compatibility studies, this product must not be mixed with other medicinal products.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Kymriah must be stored in a temperature monitored system at ≤ -120°C e.g. in the vapour phase liquid nitrogen. Do not thaw the product until it is ready to be used. See Table 8.

6.5 Nature and Contents of Container

Container.

Ethylene vinyl acetate (EVA) infusion bags with polyvinyl chloride (PVC) tubing and a luer spike interconnector closed by a luer-lock cap. Target volume 10 mL to 50 mL.

Pack size.

Single dose unit.

6.6 Special Precautions for Disposal

Any unused product or waste material should be disposed of in accordance with local requirements. Refer to local biosafety guidelines applicable for handling and disposal of products containing genetically-modified cells.
Kymriah products should be transported within the facility in closed, break-proof, leak-proof containers.
Solid and liquid waste: All material having been in contact with Kymriah should be handled and disposed of as potentially infectious waste in accordance with local hospital procedures.

6.7 Physicochemical Properties

Chemical structure.

The CAR-19 protein is comprised of a murine single chain antibody fragment, a CD8 hinge and transmembrane region, a 4-1BB (CD137) and CD3-zeta signalling domain.

CAS number.

Not established.

7 Medicine Schedule (Poisons Standard)

Not determined.

Summary Table of Changes