ChondroCelect - patient leaflet, side effects, dosage

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) of the biological active substance(s)

PharmaCell Cell Manufacturing Facility B.V.

Urmonderbaan 20B

6167 RD Geleen

Netherlands

Name and address of the manufacturer(s) responsible for batch release

TiGenix N.V.

Romeinse straat 12/2

B-3001 LEUVEN

Belgium

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, section 4.2).

The Marketing Authorisation Holder (MAH) shall ensure that the medicinal product will be distributed only to Healthcare Establishments that meet criteria described in the Risk Management Plan.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

• Pharmacovigilance system

The MAH must ensure that the system of pharmacovigilance presented in Module 1.8.1. of the Marketing Authorisation, is in place and functioning before and whilst the product is on the market.

The marketing authorisation holder shall submit the periodic safety update reports for this product in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

• Risk Management Plan (RMP)

The MAH shall perform the pharmacovigilance activities as agreed in the RMP presented in Module 1.8.2. of the Marketing Authorisation and any subsequent updates.

An updated RMP should be submitted:

• At the request of the European Medicines Agency;
• Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time.

• Additional risk minimisation measures

The Marketing Authorisation Holder (MAH) shall ensure, prior to the distribution of the product to a particular healthcare establishment, that all surgeons and other healthcare professionals involved in the handling and administration of ChondroCelect or its components, as well as those involved in followup of patients treated with ChondroCelect in the healthcare establishment, receive training as per the educational programme described in the risk management plan.

The educational programme for healthcare professionals contains the following components:

• Training material for surgeons
• Training material for other healthcare professionals
• Informed consent for the patients to be signed prior to the treatment with ChondroCelect

The training materials for surgeons shall include the following key messages and components:

• Summary of Product Characteristics
• The biopsy harvest procedure
• The surgical checklist to be completed at the operating theatre immediately prior to the first incision confirming the right patient, the right product, the right side of the implantation, and the type of biological membrane and fibrin sealant to be used in the procedure.
• The implantation procedure by knee-joint arthrotomy
• The follow-up protocol

The training material for other healthcare professionals shall include the following key messages and components:

• Summary of Product Characteristics
• The need for screening of donors using patient questionnaire and laboratory tests for hepatitis C, hepatitis B, HIV, and syphilis
• The handling of the biopsy harvest
• The handling of ChondroCelect and its preparation for the implantation
• The schedule of follow-up of patients
• The recommended physiotherapy
• Obligation to conduct post-authorisation measures

LABELLING AND PACKAGE LEAFLET

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

White screw top container

1. NAME OF THE MEDICINAL PRODUCT

ChondroCelect 10,000 cells/mi­crolitre implantation suspension.

Characterised viable autologous cartilage cells expanded ex vivo expressing specific marker proteins.

Vials are supplied with surgery materials (one sterile syringe of 1 ml, one 18G IV catheter and two pieces of Vicryl 6.0 sutures)

• 5. METHOD AND ROUTE(S) OF ADMINISTRATION

For implantation.

Read the package leaflet before use.

• 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACHOF CHILDREN

Keep out of the sight and reach of children.

• 7. OTHER SPECIAL WARNING(S), IF NECESSARY

For autologous use only.

• 8. EXPIRY DATE

EXP {DD month YYYY} at {hours} CET

• 9. SPECIAL STORAGE CONDITIONS

Store between 15°C – 25 °C. Do not refrigerate or freeze. Keep the product vial(s) within the falcon tube in the outer plastic screw top container in order to protect from light and bacterial/fungal contamination.

Do not expose to radioactive irradiation (X-rays).

• 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

Dispose of in accordance with local requirements.

• 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

TiGenix N.V., Romeinse straat 12/2, 3001 Leuven, Belgium

Tel: +32-(0)16 39 60 60

Fax: +32-(0)16 39 60 70

mfo@>tigemx. com

• 12. MARKETING AUTHORISATION NUMBER(S)

EU/1/09/563/001

• 13. BATCH NUMBER, DONATION AND PRODUCT CODES

Lot {lot number}

Patient number (Pt N°) {patient number}

Patient initials (Pt initials) {patient initials

• 14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

• 15. INSTRUCTIONS ON USE

[16 INFORMATION IN BRAILLE

Justification for not including Braille accepted

MINIMUM PARTICULARS TO APPEAR ON SMALL INTERMEDIATE PACKAGING UNITS

Falcon tube

1. NAME OF THE MEDICINAL PRODUCT

ChondroCelect 10,000 cells/mi­crolitre implantation suspension.

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

Vial

1. NAME OF THE MEDICINAL PRODUCT

ChondroCelect

Package leaflet: information for the user

ChondroCelect 10,000 cells/mi­crolitre implantation suspension

Characterised viable autologous cartilage cells expanded ex vivo expressing specific marker proteins

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• – Keep this leaflet. You may need to read it again.

• – If you have any further questions, ask your doctor, surgeon or physical therapist.

  
  

• – If you get any of the side effects, talk to your doctor, surgeon or physical therapist.

includes any possible side effects not listed in this leaflet. See section 4.

What ChondroCelect is and what it is used for

ChondroCelect consists of autologous cultured cartilage cells. The product is made from a small sample of cartilage cells (a biopsy) taken from your knee.

• Autologous means that your own cells are used to make ChondroCelect.
• Cartilage is a tissue that is present in every joint. It protects the ends of our bones and allows our joints to function smoothly.

ChondroCelect is used to repair single symptomatic cartilage defects in the femoral condyle of the knee in adults. A defect can be caused by acute trauma, such as a fall. It can also be caused by repetitive trauma, as a result of overweight or due to incorrect weight-bearing on the knee as a result of a knee deformity.

• The femoral condyle is the end of the thigh bone, which forms part of your knee.

2. What you need to know before you use ChondroCelect

Do not use ChondroCelect if you:

• – are allergic to any of the ingredients of ChondroCelect (listed in section 6) or to bovine serum

• – suffer from advanced osteoarthritis (degenerative joint disease) in your knee.

• – have a growth plate of the knee that is not fully closed

Warnings and precautions

Talk to your doctor, surgeon or physiotherapist before using ChondroCelect.

• – If you have an acute or recent history of bone or joint infections, you should be temporary deferred until documented recovery.

• – The use of ChondroCelect is generally not recommended when you are overweight (i.e. a Body Mass Index over 30) because it could compromise the result of the treatment. Your surgeon will give you more information.

• – ChondroCelect is not recommended for the repair of cartilage defects in other locations than the femoral condyle.

• – ChondroCelect should be implanted in an otherwise healthy knee. This means that other knee problems such as lesions of the knee ligament or of the meniscus should be corrected before or during ChondroCelect implantation.

• – You should resume physical activity according to the rehabilitation plan recommended by the physical therapist. Too early and vigorous activity may compromise the implant and the durability of clinical benefit from ChondroCelect.

Other cases in which ChondroCelect cannot be supplied

Even if the surgeon has already taken a small sample of cartilage cells (a biopsy) needed to produce the product, it is possible that you will not be eligible for treatment with ChondroCelect. This is the case if the biopsy is of insufficient quality to make ChondroCelect, or in some instances, it may be the cells cannot be grown in the laboratory or that the cells after expansion do not meet all the quality requirements Your surgeon will be informed and might have to select an alternative treatment for you.

Children and adolescents

The use of ChondroCelect is not recommended in children and adolescents below 18 years.

Other medicines and ChondroCelect

Please tell your doctor or physical therapist if you are taking, have recently taken or might take any other medicines.

The safe use of ChondroCelect with other medicines has not been studied.

Ask your doctor for more information as to which pain medication you can safely use.

Pregnancy and breast-feeding

The safe use of ChondroCelect has not been demonstrated during pregnancy or breast-feeding. ChondroCelect is not recommended for pregnant and breast-feeding women.

Please inform your doctor if you are pregnant or think you may be pregnant.

Driving and using machines

The surgical procedure will have a major influence on your ability to drive and use machines. Driving cars and using machines may be limited during the rehabilitation period, and the advice of your doctor, surgeon or physical therapist should be strictly followed during this period.

3. How to use ChondroCelect

ChondroCelect can only be prescribed and implanted by an orthopaedic surgeon in a hospital. Treatment with ChondroCelect: a two-step procedure.

Visit 1: evaluation of the cartilage defect and biopsy

On the first visit, the surgeon will evaluate your cartilage defect during an exploratory operation (arthroscopy). An arthroscopy is performed through very small incisions in the skin, using a narrow telescope (arthroscope) to look at the inside of the knee. If the surgeon decides that treatment with ChondroCelect is appropriate for you, he/she will take a small sample of cartilage cells (a biopsy) from your knee. This cartilage sample will be used to make ChondroCelect.

It will take at least four weeks to select and culture the cells to make ChondroCelect.

Visit 2: ChondroCelect implantation

During open-knee surgery, the cartilage cells are implanted into the cartilage defect. This is called ‘autologous chondrocyte implantation’ (ACI). The purpose is to repair the defect with healthy and functional cartilage over time.

To keep the cartilage cells in place, a biological membrane is sewn over the defect.

Rehabilitation

After surgery, you will have to follow a rehabilitation program for approximately one year, to allow your knee to heal well. Your doctor or physical therapist will give you more details on your rehabilitation.

It is very important to carefully observe the recommendations of your doctor and/or physical therapist. If you do not follow your rehabilitation schedule, the risk of treatment failure may increase.

You should be very cautious when bending and putting weight on your treated knee. During the rehabilitation period, the level of weight-bearing will increase gradually, depending on your weight and the size of the cartilage defect. To protect your knee, you will have to wear a brace.

If you have any further questions on the use of this medicine, ask your doctor or physical therapist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Most side effects of ChondroCelect implantation are side effects related to open-knee surgery. In general, these side effects are quite mild and disappear in the weeks following surgery.

You can recognize most of the joint- related side effects if you have symptoms like pain, snapping, grinding, locking, swelling, bending limitations and stiffness in the knee. Tell your doctor immediately if you notice any of these symptoms.

Very common side effects (affects more than 1 user in 10) include: joint pain (arthralgia), overgrowth of cartilage cells (cartilage hypertrophy), crackling or clicking sensation when articulating the knee (joint crepitation), and joint swelling.

Common side effects ( affects in 1 to 10 users in 100) include: restriction of knee motion (arthrofibrosis, decreased joint range of motion, decreased mobility), excessive amount of joint fluid in the joint (joint effusion), joint lock, joint inflammation (arthritis, bursitis, synovitis), cavity filled with fluid in the knee (bone cyst, synovial cyst), bone swelling, cartilage disorder (chondropathy), benign bony growth (exostosis), blood in a joint (haemarthrosis), joint instability, joint stiffness, loose body in joint, weakening of muscle (muscle atrophy, Trendelenburg’s sig­n), degenerative joint disorder (osteoarthritis), tendon disorder, inflammation of the tendon (tendonitis), impaired healing, treatment failure, gait disturbance, implant site hypersensitivity, peripheral edema, fever (pyrexia), postoperative wound complication (wound site reaction) ,wound infection (including erysipelas), redness, scar overgrowth, itching, scar pain, wound loosening, wound secretion loosening of the graft or membrane (graft complication, graft delamination), injury (cartilage injury, joint injury), blood clot in the deep vein of the leg (deep vein thrombosis), large bruise (haematoma), superficial vein inflammation (phlebitis), nausea, pain or nerve disorder (pain in extremity, peripheral neuropathy, complex regional pain syndrome, autonomic neuropathy), syncope, apnea, arthroscopy.

Uncommon side effects (affects in 1 to 10 users in 1,000 include: anxiety, dermal and visual hypersensitivity ), migraine, mini stroke (transient ischaemic attack), fat entering the circulatory system (fat embolism), vein blockage and inflammation (thrombophlebitis), blockage in a lung artery (lung embolism), itching scar, pain at the front of the knee (chondromalacia), breakdown of knee tissue (gonartrhosis, atrophy), discomfort, chronic inflammation (granulomatous lesion).

Reporting of side effect

If you get any side effects, talk to your doctor or physical therapist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store ChondroCelect

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the container and vial after EXP.

Store between 15°C – 25 °C.

Do not refrigerate or freeze.

Keep the product vial(s) within the falcon tube in the plastic screw top container in order to protect from light and bacterial/fungal contamination.

Do not irradiate.

Since this product will be used during your knee surgery, the hospital staff is responsible for the correct storage of the product both before and during its use, as well as for the correct disposal

6. Contents of the pack and other information

What ChondroCelect contains

• – The active substance of ChondroCelect consists of a treatment dose of viable autologous human cartilage cells in vials containing 4 million cells in 0.4 ml, corresponding to a concentration of 10,000 cells/mi­crolitre.

• – The other ingredient is sterile, buffered Dulbecco’s Modified Eagles Medium (DMEM), a liquid containing amino acids, vitamins, salts and carbohydrates to store the cells in the vial.

What ChondroCelect looks like and contents of the pack

ChondroCelect is a cell suspension (a fluid) for implantation. The cells are kept alive in a small sterile vial. The product is packaged in several layers of packaging material which guarantee sterility and stable temperature conditions for 48 hours if stored at room temperature.

Each pack contains an individual treatment dose consisting of 1 to 3 vials, depending on the number of cells needed to treat the specific lesion size.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

TiGenix N.V.

Romeinse straat 12/2, 3001 LEUVEN

Belgium

+32 16 39 60 60

+32 16 39 60 70

Manufacturer:

PharmaCell Cell Manufacturing Facility B.V., Urmonderbaan 20B, 6167 RD Geleen, Netherlands

The leaflet was approved in

Grounds for one additional renewal

Based upon the data that have become available since the granting of the initial Marketing Authorisation, the CHMP considers that the benefit-risk balance of ChondroCelect remains positive, but considers that its safety profile is to be closely monitored for the following reasons:

Only 907 patients have been exposed up to now, including patients treated with ChondroCelect within the clinical trials conducted to support the MA of ChondroCelect. Post-marketing experience with respect to patient number, i.e. 444 patients and duration of follow-up is still quite limited, and doesn’t warrant granting a renewal with unlimited validity.

The CHMP decided that the MAH should continue to submit 1-yearly PSURs.

Therefore, based upon the safety profile of ChondroCelect, which requires the submission of 1-yearly PSURs, the CHMP concluded that the MAH should submit one additional renewal application in 5 years’ time.

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