ChondroCelect

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 

 

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1. NAME OF THE MEDICINAL PRODUCT 
 
ChondroCelect 10,000 cells/microlitre implantation suspension 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
2.1 General description 
 
Characterised viable autologous cartilage cells expanded ex vivo expressing specific marker proteins. 
 
2.2 Qualitative and quantitative composition 
 
Each vial of product contains 4 million autologous human cartilage cells in 0.4 ml cell suspension, 
corresponding to a concentration of 10,000 cells/microlitre. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Implantation suspension 
Before re-suspension the cells are settled to the bottom of the container forming an off-white layer and 
the excipient is a clear colourless liquid. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Repair of single symptomatic cartilage defects of the femoral condyle of the knee (International 
Cartilage Repair Society [ICRS] grade III or IV) in adults. Concomitant asymptomatic cartilage 
lesions (ICRS grade I or II) might be present. Demonstration of efficacy is based on a randomised 
controlled trial evaluating the efficacy of Chondrocelect in patients with lesions between 1-5cm². 
 
4.2 Posology and method of administration 
 
ChondroCelect must be administered by an appropriately qualified surgeon and is restricted to hospital 
use only. ChondroCelect is solely intended for autologous use and should be administered in 
conjunction with debridement (preparation of the defect bed), a physical seal of the lesion (placement 
of a biological membrane, preferentially a collagen membrane) and rehabilitation. 
 
Posology 
The amount of cells to be administered is dependent on the size (surface in cm²) of the cartilage defect. 
Each product contains an individual treatment dose with sufficient number of cells to treat the pre-
defined lesion size, as measured at biopsy procurement. The recommended dose of ChondroCelect is 
0.8 to 1 million cells/cm², corresponding with 80 to 100 microlitre of product/cm² of defect. 
 
Elderly population 
The use of ChondroCelect has not been studied in this age group. 
 
Paediatric population 
The safety and efficacy in children and adolescents (aged less than 18) have not been established.  
ChondroCelect is therefore not recommended for use in children and adolescents below 18 years.  
 
 
 

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Method of administration 
For implantation. 
 
ChondroCelect is intended solely for use in autologous cartilage repair and is administered to patients 
in an Autologous Chondrocyte Implantation procedure (ACI).  
 
Implantation of ChondroCelect is to be performed during arthrotomy under sterile conditions and 
requires both preparation of the defect bed and a seal (biological membrane) to secure the implant. 
Complete joint haemostasis must be achieved prior to membrane fixation and cell implantation. 
During the ACI procedure it is important to ensure that a good, direct contact of the implanted cells 
with the defect bed is obtained as such contact is of paramount importance for optimal tissue 
regeneration. In clinical studies with ChondroCelect a periosteal flap was used as a biological 
membrane. Scientific publications have shown that commercially available collagen membranes can 
be used as an alternative to the periost in ACI procedures. However, ChondroCelect has not been 
evaluated in combination with collagen membranes in clinical studies, although a commercially 
available collagen membrane has been used in patients treated with ChondroCelect under 
compassionate use. The safety data obtained in these patients do not indicate a particular safety 
concern, and confirm a lower incidence of hypertrophy as suggested by scientific literature on the use 
of collagen membranes versus periost. 
 
A technical variant of the ACI procedure is the cell seeding method, whereby the cells are seeded onto 
a collagen membrane prior to implantation. In this technique, a good fixation using stitches on the 
edges of the collagen membrane is required, in order to assure a direct contact of the implanted cells 
with the defect bed. Using fibrin glue only, instead of stitches, to secure the implant is not 
recommended. 
 
The implantation should be followed by an appropriate rehabilitation schedule for approximately one 
year, as recommended by the physician (see section 4.4). 
 
Full technical details on the procedures associated with this implantation technique are provided in the 
ChondroCelect user manual. 
For information on preparation and handling of ChondroCelect, please refer to section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to any of the excipients listed in section 6.1, or to bovine serum. 
ChondroCelect must not be used in case of advanced osteoarthritis of the knee. 
Patients with femoral epiphyseal growth plate that is not fully closed 
 
4.4 Special warnings and precautions for use 
 
General 
ChondroCelect is an autologous product and should under no circumstances be administered to other 
patients. 
Patients with acute or recent history of bone or joint infections should be temporary deferred until 
documented recovery. 
 
Precautions for use 
Concomitant knee problems like early osteoarthritis, osteochondritis dissecans (OCD), instability of 
the knee, cartilage lesions at other locations than the femoral condyle, lesions of knee ligaments or of 
the meniscus, varus or valgus malalignment (abnormal weight distribution in the knee), and 
inflammatory joint disease are potential complicating factors. In the pivotal study of ChondroCelect, 
patients with these comorbidities of the knee were excluded from treatment. Where possible, 
concomitant knee problems should be corrected prior to or at the latest at the time of ChondroCelect 
implantation.  
In the pivotal study there was no influence of Body Mass Index (BMI) on outcome but bibliographic 
data shows that a BMI over 30 may adversely affect the success of the procedure. 

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Rehabilitation 
Upon implantation, the patient should follow an appropriate rehabilitation schedule and physical 
activity should be resumed as recommended by the physician. Depending on the location, the size of 
the lesion and the patient’s profile, appropriate rehabilitation instructions have been developed. Too 
early and vigorous activity may compromise the grafting and the durability of clinical benefit from 
ChondroCelect. Therefore the treated knee should be protected according to the recommendations as 
outlined in the appropriate rehabilitation schedule, to avoid early damage which might lead to graft 
failure. 
Details and information on the appropriate rehabilitation schedule is provided in the ChondroCelect 
user manual. 
 
Cases in which ChondroCelect cannot be supplied 
In some cases it can be possible that the source chondrocytes of the patient are not expandable or that 
the release criteria are not met, due to poor biopsy quality, patient characteristics, or manufacturing 
failure. Therefore it can occur that ChondroCelect cannot be delivered. The surgeon will be informed 
as early in the process as possible, and should hence select an alternative treatment for the patient 
concerned. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Fibrin glues are routinely used in ACI procedures to seal the outside margins and to improve the 
water-tightness of the compartment of the biological membrane used to cover the defect. The use of 
fibrin glue inside the cartilage defect bed is not recommended as this may result in a significantly 
poorer outcome (see section 5.3). 
Fibrin sealant products differ significantly in their quantitative and qualitative composition. In vitro 
interaction studies were performed with a commercially available fibrin glue containing aprotinin (a 
fibrinolysis inhibitor of bovine origin). These studies have demonstrated that this type of fibrin sealant 
can be safely used with ChondroCelect. No interaction studies with any other type of fibrin glues were 
performed. However, the concomitant use of another type of fibrin glue with a synthetic fibrinolysis 
inhibitor (tranexamic acid) in the pivotal clinical trial did not reveal any safety signal. 
 
Pain relief medicinal products should be used according to the recommendations of the responsible 
surgeon. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
Limited clinical data on exposed pregnancies are available. Conventional reproductive and 
developmental toxicity studies are not considered relevant, given the nature and the intended clinical 
use of the autologous cell therapy product. As ChondroCelect is used to repair a cartilage defect of the 
knee and is implanted with the ACI procedure using open-knee surgery, it is not recommended during 
pregnancy.  
 
Breast-feeding  
 
There are no data on the use of ChondroCelect during breast-feeding. Given the local nature of 
ChondroCelect adverse reactions on the nursing infant are not anticipated. A decision should be made 
whether to discontinue breast-feeding taking into account the potential benefits of the treatment for the 
woman and the potential risk to the infant.  
 
Fertility  
 
There are no data on possible effects of ChondroCelect treatment on fertility.  
 

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4.7 Effects on ability to drive and use machines 
 
Due to the surgical nature of the underlying procedure, implantation with ChondroCelect has a major 
influence on the ability to drive and use machines. During the rehabilitation period that follows 
treatment with ChondroCelect, patients should refer to their treating physician and follow their advice 
strictly. 
Driving cars and using machines may be limited during the rehabilitation period. 
 
4.8 Undesirable effects 
 
Summary of the safety profile  
 
In a randomized, controlled study in the target population, 51 patients were treated with 
ChondroCelect. In these patients, a periosteal flap was used to secure the implant. 
Adverse reactions occurred in 78.4% of the patients over a 36-months postoperative follow-up period..  
 
Related to ChondroCelect: 

• arthralgia  
• cartilage hypertrophy  
• joint crepitation  
• joint effusion 
• treatment failure 
• delamination 

 
The adverse reactions listed are those that occurred most frequently, with treatment failure and 
delamination being the most serious. 
 
Related to surgical intervention of the knee 

• (postoperative) joint swelling 
• arthralgia 
• pyrexia 
• arthrofibrosis 
• decreased range of motion of the knee  

 
Most of the reported adverse reactions were expected as related to the open-knee surgical procedure.. 
These were generally mild and disappeared in the weeks following surgery. 
 
Tabulated list of adverse reactions   
 
They are  listed by System Organ Class and frequency. Frequencies are defined according to the 
following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to 
< 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, 
adverse reactions are presented in order of decreasing seriousness. 
 
System organ class Very common 

≥1/10 

Common 

≥1/100 to <1/10 

Uncommon 

≥1/1,000 to <1/100 
Vascular disorders  Deep vein thrombosis, 

Haematoma, 
Superficial phlebitis 

Fat embolism, 
Thrombophlebitis 

Respiratory, thoracic 
and mediastinal 
disorders 

 Apnoea Lung embolism 

General disorders and 
administration site 
conditions 

 Ineffective therapeutic 
product, 
Gait disturbance, 

Atrophy, 
Discomfort, 
Granulomatous lesion 

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System organ class Very common 

≥1/10 

Common 

≥1/100 to <1/10 

Uncommon 

≥1/1,000 to <1/100 
Impaired healing, 
Implant site 
hypersensitivity, 
Peripheral edema, 
Pyrexia 

Injury, poisoning and 
procedural 
complications 

 Graft complication, 
Graft delamination, 
Cartilage injury, 
Injury, 
Joint injury, 
Procedural site reaction 

 

Musculoskeletal and 
connective tissue 
disorders 

Arthralgia, 
Cartilage hypertrophy, 
Joint crepitation, 
Joint swelling 

Arthrofibrosis, 
Joint range of motion 
decreased, 
Joint effusion, 
Joint lock, 
Arthritis, 
Arthropathy, 
Bone cyst, 
Bone swelling, 
Bursitis, 
Chondropathy, 
Exostosis, 
Haemarthrosis, 
Joint instability, 
Joint stiffness, 
Loose body in joint, 
Mobility decreased, 
Muscle atrophy, 
Osteoarthritis, 
Synovial cyst, 
Synovitis, 
Tendon disorder, 
Tendonitis 

Chondromalacia, 
Gonarthrosis 

Nervous system 
disorders 

 Autonomic neuropathy, 
Complex regional pain 
syndrome, 
Pain in extremity, 
Peripheral neuropathy, 
Syncope, 
Trendelenburg’s 
symptom 

Hyperesthesia, 
Migraine, 
Photophobia, 
Transient ischaemic 
attack 

Investigations  Arthroscopy  
Skin and 
subcutaneous tissue 
disorders 

 Wound infection, 
Erysipelas, 
Erythema, 
Hypertrophic scar, 
Postoperative wound 
complication, 
Pruritus, 
Scar pain, 
Wound dehiscence, 
Wound secretion 

Itching scar 
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System organ class Very common 

≥1/10 

Common 

≥1/100 to <1/10 

Uncommon 

≥1/1,000 to <1/100 
Psychiatric disorders   Anxiety 
Gastrointestinal 
disorders 

 Nausea  

 
Description of selected adverse reactions 
 
Arthrofibrosis 
In the compassionate use patients, a higher incidence of arthrofibrosis and decreased joint range of 
motion was observed in a subgroup of patients with a patellar lesion (8.2% and 13.1% respectively) 
compared to non-patellar lesions (0.6% and 2.6% respectively). 
 
Cartilage hypertrophy 
In the majority of the 370 patients included in the Compassionate Use Program, a collagen membrane 
instead of a periosteal flap was used to seal the defect. According to current literature the incidence of 
cartilage hypertrophy can be reduced by using a collagen membrane to cover the lesion site instead of 
using a periosteal flap (Gooding et al., 2006; Niemeyer et al., 2008). When a collagen membrane was 
used to seal the lesion site after application of ChondroCelect, the incidence of cartilage hypertrophy 
was reported to be 1.8% compared to 25% in the randomized, controlled trial alone.  
 
Synovitis and subchondral bone injuries have been reported in animal models and are possible risks 
with the use of ChondroCelect. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation 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 via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
No case of overdose has been reported. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other drugs for disorders of the musculo-skeletal system,  
ATC code: M09AX02 
 
Conventional pharmacodynamic studies for ChondroCelect have not been performed. 
 
Clinical efficacy 
The efficacy of ChondroCelect was studied in a phase III, multicenter, randomized, controlled trial 
(TIG/ACT/01/2000) and the first two years of its 4-year extension phase (TIG/ACT/01/2000EXT). 
ChondroCelect was compared to the procedure of microfracture in the repair of symptomatic single 
cartilage lesions of the femoral condyles of the knee. 51 patients were treated with ChondroCelect, 61 
patients were treated with microfracture. Patients aged between 18 and 50 years, who had a single 
symptomatic cartilage lesion between 1 and 5 cm2 of the femoral condyles met the inclusion criteria. 
Patients could be treatment-naïve or might have undergone previous arthroscopic or other surgical 
repair procedure(s). Patients with patellofemoral cartilage lesion, OCD, depth of lesion >0.5 cm, prior 
meniscal transplant, prior mosaicplasty and prior microfracture within the last 12 month were 

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excluded. Patients had to agree to actively participate in a strict rehabilitation protocol and follow-up 
program.  

The median time since onset of knee injury was slightly longer in the ChondroCelect group than in the 
microfracture group (2.0 years versus 1.6 years). More patients in the ChondroCelect treatment group, 
compared to patients in the microfracture group, had undergone previous knee surgery (88% versus 
77%). In the ChondroCelect group 77% of patients had a medial and 23% a lateral condyle defect. 

Histological examination of the repair biopsy at 12 months showed superior structural repair in the 
ChondroCelect arm compared to the microfracture arm. There was continuous improvement up to 36 
months in the clinical outcome measure KOOS (the Knee Injury and Osteoarthritis Outcome Score) in 
both treatment arms. The estimated benefit was larger in the ChondroCelect group but the results did 
not reach statistical significance. At this time point 41 patients were evaluated in the ChondroCelect 
arm and 49 were evaluated in the microfracture arm. Patients with less than 3 years since onset of 
symptoms (n=27 in the ChondroCelect arm and n=32 in the microfracture arm) benefited most from 
ChondroCelect. For the group with a longer time since onset of symptoms there were no apparent 
differences between the 2 groups. Re-intervention on the treated lesion for graft delamination or 
periost loosening occurred in 2 of 51 patients within 36 months after ChondroCelect implantation, 
compared to 7 of 61 patients treated with microfracture having generally insufficient or inadequate 
cartilage repair. 

After the 5 year follow-up period, 37 patients were evaluated in the ChondroCelect arm and 40 in the 
microfracture arm. Overall, the clinically relevant benefit of ChondroCelect implantation observed 
over baseline after 36 months was maintained up to 60 months after treatment. No statistically 
significant difference could be observed in clinical benefit between ChondroCelect and microfracture 
at that point in time. In the subgroup of patients with recent symptom onset (< 3 years) the clinical 
benefit of ChondroCelect over microfracture was significantly larger, confirming the results at 36 
months after treatment. In patients with a longer time since onset of symptoms, both treatments 
performed equally. Seven patients treated with ChondroCelect needed re-intervention, compared to 10 
patients in the microfracture group. Treatment failure in the ChondroCelect group was generally 
related to delamination of the graft.  

Patients with lesions larger than 5 cm² have been treated under compassionate use only. The safety 
data obtained in these patients do not indicate a particular safety concern. Further clinical data in 
patients with larger lesions are foreseen to be collected in the future. 

Sixteen patients below 18 years have been treated with ChondroCelect under compassionate use. No 
specific safety signal was detected in these patients. If, based on the benefit/risk assessment of the 
responsible surgeon treatment of patients below 18 years is considered, special attention should be 
given to ensure that the growth plate is completely closed. 
 
5.2 Pharmacokinetic properties 
 
The product is implanted locally. 
The nature and intended clinical use of ChondroCelect are such that conventional studies on 
pharmacokinetics, absorption, distribution, metabolism and elimination are not applicable.  
 
5.3 Preclinical safety data 
 
Non-clinical data based on implantation of expanded cartilage cells in goats and mice did not reveal 
special hazard for humans. 
In studies in goats, mild signs of synovitis were observed in the majority of the animals, including 
controls at 10 weeks post surgery. Inflammation resolved with time and parameters returned to 
baseline levels with only some very mild and local signs of synovitis remaining in a few animals. 

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Although it is thought that these reactions are mostly surgery-related, a potential influence of the 
expanded chondrocytes cannot be completely excluded. 
In a study in sheep, the majority of animals showed penetration of the transplanted cells in 
subchondral bone; in two of these cases complete penetration of underlying bone marrow was 
observed. This finding might be related to the inability to perform a progressive loading under non-
weight bearing conditions post-surgery in these models and therefore cannot be fully extrapolated as 
such to the human situation. 
A technical variant of the ACI procedure is the cell seeding method, whereby the cells are seeded onto 
a collagen membrane prior to implantation. From a pre-clinical study in the orthotopic goat model it 
appeared that this technique provided comparable results as the Brittberg technique, on condition that 
a good fixation is established using stitches on the edges of the collagen membrane. Using fibrin glue 
in the defect bed instead of stitches to secure the implant resulted in an overall poor outcome, 
suggesting the need for a direct contact of the implanted cells with the defect bed 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Dulbecco’s Modified Eagles Medium (DMEM) (containing amino acids, vitamins, salts and 
carbohydrates). 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 
 
6.3 Shelf life 
 
48 hours. 
 
6.4 Special precautions for storage 
 
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 irradiate. 
 
6.5 Nature and contents of container and special equipment for use, administration or 

implantation 
 
ChondroCelect is supplied as one individual treatment dose (falcon tube) contained in 1 to 3 Type I 
glass vials of 1 ml. Each vial contains 0.4 ml of autologous human cartilage cells suspension and is 
closed with a chlorobutyl stopper and aluminium seal. 
The vials are placed in a sterile falcon tube with a plastic screw top. 
The falcon tube is placed in a plastic screw top container together with surgery materials (one sterile 
syringe of 1 ml, one 18G intravenous catheter and two pieces of Vicryl 6.0) and a temperature 
monitor. 
 
6.6 Special precautions for disposal and other handling 
 
ChondroCelect is intended solely for autologous use. Prior to implantation match the patient name to 
the patient/donor identification on the shipment documentation and product vial. 
 
Before administration, ChondroCelect should be resuspended by gently tapping the vial to bring the 
cells back into suspension. 

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ChondroCelect should not be sterilised. If the ChondroCelect vial is damaged or its sterility has been 
compromised, the product must not be used and must be shipped back to TiGenix. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
TiGenix N.V.  
Romeinse straat 12/2 
3001 LEUVEN 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/563/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 5 October 2009 
Date of latest renewal: 22 August 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu 

  

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11 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

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

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
 

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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. 
 

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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 follow-
up 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  

 
Not applicable. 
 
  

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14 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

 
  

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15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 
 
  

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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. 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 4 million autologous human cartilage cells in 0.4 ml, corresponding to a 
concentration of 10,000 cells/microlitre. 
 
 
 
3. LIST OF EXCIPIENTS 
 
Dulbecco’s Modified Eagles Medium (DMEM). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Implantation suspension. 
1 falcon tube with 1, 2 or 3 vials (x 0.4 ml) 
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. 

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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 
info@tigenix.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

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18 

 MINIMUM PARTICULARS TO APPEAR ON SMALL INTERMEDIATE PACKAGING 
UNITS 
 
Falcon tube 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ChondroCelect 10,000 cells/microlitre implantation suspension. 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP {DD month YYYY} at {hours} CET 
 
 
4. BATCH NUMBER, DONATION AND PRODUCT CODES 
 
Lot {lot number} 
Pt N° {patient number} 
Pt  initials {patient  initials} 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1, 2 or 3 vials x 0.4 ml 
 
 
6. OTHER 
 
For autologous use only.  

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19 

 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Vial 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ChondroCelect 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP {DD month YYYY} at {hours} CET 
 
 
4. BATCH NUMBER, DONATION AND PRODUCT CODES 
 
Lot {lot number} 
Pt N° {patient number} 
Pt  initials {patient  initials} 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.4 ml 
 
 
6. OTHER 
 
For autologous use only. 
  

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20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
  

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21 

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. This 

includes any possible side effects not listed in this leaflet. See section 4. 
 
 
What is in this leaflet 
 
1. What ChondroCelect is and what it is used for 
2. What you need to know before you use ChondroCelect 
3. How to use ChondroCelect 
4. Possible side effects 
5. How to store ChondroCelect 
6. Contents of the pack and other information 
 
 
1. 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. 
 

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22 

- 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 

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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). 

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24 

 
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 
info@tigenix.com  
 
Manufacturer: 
PharmaCell Cell Manufacturing Facility B.V., Urmonderbaan 20B, 6167 RD Geleen, Netherlands 
 
The leaflet was approved in  
 

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25 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu  

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26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Annex IV 
 

Grounds for one additional renewal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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27 

 
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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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET