Spherox

1 

 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 

 

 

 

 

 

 

 

  



2 

This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Spherox 10-70 spheroids/cm2 implantation suspension 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

2.1 General description 

 

Spheroids of human autologous matrix-associated chondrocytes for implantation suspended in isotonic 

sodium chloride solution. 

 

2.2 Qualitative and quantitative composition 

 

Spheroids are spherical aggregates of ex vivo expanded human autologous chondrocytes and self-

synthesized extracellular matrix. 

 

Each pre-filled syringe or applicator contains a specific number of spheroids according to the defect 

size (10-70 spheroids/cm2) to be treated. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Implantation suspension. 

 

White to yellowish spheroids of matrix-associated autologous chondrocytes in a clear, colourless 

solution. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Repair of symptomatic articular cartilage defects of the femoral condyle and the patella of the knee 

(International Cartilage Regeneration & Joint Preservation Society [ICRS] grade III or IV) with defect 

sizes up to 10 cm2 in adults.  

 

4.2 Posology and method of administration 

 

Spherox is intended for autologous use only. It must be administered by a specialised orthopedic 

surgeon and in a medical facility. 

 

Posology 

 

10-70 spheroids are applied per square centimetre defect. 

 

Paediatric population 

The safety and efficacy of Spherox in children aged 15 to 18 years have not been established.  

 



3 

The safety and efficacy of Spherox in children aged less than 15 years have not been established. No 

data are available. 

 

Elderly 

The safety and efficacy of Spherox in patients aged over 50 years have not been established. No data 

are available.  

 

Method of administration 

 

For intraarticular use. 

  

Spherox is administered to patients by intraarticular implantation. 

 

The implantation must be performed during a surgical procedure (preferably an arthroscopy or mini-

arthrotomy). A debridement of the defect area is required. The subchondral plate should not be 

damaged. The spheroids are provided in a pre-filled syringe or an applicator (stem length 150 mm 

(co.fix 150)). Spheroids should be applied evenly on the defect ground and, if necessary, spread over 

the whole defect area by means of surgical instruments. The spheroids self-adhere within 20 minutes 

onto the defect ground. Afterwards, the surgical wound can be closed without any additional cover of 

the treated area (e.g. periosteal flap; matrix), or any fixation of spheroids by using fibrin glue. The 

treatment of defect sizes up to 10 cm2 is eligible for single as well as adjacent defects (combined area). 

 

Patients treated with Spherox have to undergo a specific rehabilitation program (see section 4.4). The 

program may take up to one year depending on the recommendation of the physician. 

 

For information on preparation and handling of Spherox, please refer to section 6.6. 

 

4.3 Contraindications 

 

• Patients with not fully closed epiphyseal growth plate in the affected joint. 

• Primary (generalised) osteoarthritis. 

• Advanced osteoarthritis of the affected joint (exceeding grade II according to Kellgren and 
Lawrence). 

• Infection with the hepatitits B virus (HBV), hepatitis C virus (HCV) or HIV I/II. 
 

4.4 Special warnings and precautions for use 

 

General 

 

Spherox is an autologous medicinal product and must not be given to any other patient than the donor. 

 

Prior to use, it must be verified if patient name matches the information of the patient/donor provided 

on the shipping documents and the product label. Also it needs to be checked if the correct order 

number (lot number) is on the primary package. 

If the primary or secondary packaging is damaged and therefore unsterile, Spherox must not be 

applied. 

 

The application of Spherox in patients with cartilage defects outside the knee joint is not 

recommended. The safety and efficacy of Spherox in patients with cartilage defects outside the 

femoral condyle and the patella of the knee have not been established. No data are available.  

 

Precautions for use 

 

Patients with local inflammations or acute as well as recent bone or joint infections should be 

temporarily deferred until the recovery from the infection is documented. 

 



4 

In the pivotal studies of Spherox, patients were excluded if they had signs of chronic inflammatory 

diseases. 

 

Concomitant joint problems like early osteoarthritis, subchondral bone defects, instability of the joint, 

lesions of ligaments or of the meniscus, abnormal weight distribution in the joint, varus or valgus 

malalignment, patellar malalignment or instability, and metabolic, inflammatory, immunological or 

neoplastic diseases of the affected joint are potential complicating factors. Untreated bone oedema 

corresponding with the cartilage defect to be treated may adversely affect the success of the procedure. 

If possible, concomitant joint problems should be corrected prior to or at the latest at the time of 

Spherox implantation. 

 

For decision on treatment of facing defects (“kissing lesions” larger than ICRS grade II) the degree of 

overlap and location of the defects in the joint have to be taken into consideration. 

 

Post-operative haemarthrosis occurs mainly in patients with a predisposition to haemorrhage or poor 

surgical haemorrhage control. The patient’s haemostatic functions should be screened prior to surgery. 

Thromboprophylaxis should be administered according to local guidelines. 

 

Application of Spherox in obese patients is not recommended. 

 

Rehabilitation 

 

After implantation, the patient should follow an appropriate rehabilitation schedule. Physical activity 

should be resumed as recommended by the physician. Too early and vigorous activity may 

compromise the grafting and the durability of clinical benefit from Spherox. 

 

Compliance with an adequate rehabilitation programme after implantation (especially for patients with 

mental disorders or addiction) should be warranted. 

 

Cases in which Spherox cannot be supplied 

 

If the manufacturing of spheroids has failed or if the release criteria are not fulfilled, e.g. due to 

insufficient biopsy quality, the medicinal product cannot be delivered. The physician will be informed 

immediately. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

No interaction studies have been performed. 

Locally applied antibiotics or disinfectants may have potential toxicity on articular cartilage and it is 

not recommended that Spherox comes into direct contact with those substances. 

In the pivotal studies of Spherox, patients were excluded if they were under medical treatment with 

corticosteroids. 

 

4.6 Fertility, pregnancy and lactation 

 

Pregnancy and breast-feeding 

 

No clinical data on exposed pregnancies are available for autologous chondrocytes or spheroids from 

autologous chondrocytes. 

As Spherox is used to repair cartilage defects of the joint and is therefore implanted during a surgical 

procedure, it is not recommended for use in pregnant or breast-feeding women. 

 

Fertility 

 

There are no data on possible effects of Spherox treatment on fertility. 

 



5 

4.7 Effects on ability to drive and use machines 

 

The surgical procedure will have a major influence on the ability to drive and use machines. Also, 

during the rehabilitation period, the ability to drive and use machines may be restricted due to reduced 

mobility. Therefore, patients should consult their treating physician and follow his/her advice strictly. 

 

4.8 Undesirable effects  

 

Summary of safety profile 

 

Information on adverse reactions in 127 patients from pivotal clinical trials are available. During 

treatment with Spherox surgery-related (implantation) or Spherox-related adverse reactions may 

occur. 

 

Tabulated list of adverse reactions 

 

The adverse reactions related to Spherox are displayed by system organ class and frequency in Table 1 

below: 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); and not known (cannot be estimated from the 

available data). Within each frequency grouping, undesirable effects are presented in order of 

decreasing seriousness. 

 

Table 1: Undesirable Effects related to Spherox 

System Organ Class (SOC) Frequency Adverse Reaction 

Immune system disorders Uncommon Hypersensitivity 

Musculoskeletal and 

connective tissue disorders 

Very common Joint effusion, 

Arthralgia,  

Joint swelling 

Common Bone marrow oedema, 

Joint noise, 

Joint lock, 

Synovial cyst 

Uncommon Chondromalacia, 

Osteochondrosis, 

Osteonecrosis, 

Extraskeletal ossification 

General disorders and 

administration site 

conditions 

Common Pain, 

Gait disturbance 

Injury, poisoning and 

procedural complications 

Uncommon Hypertrophy, 

Graft delamination 

 

Description of selected adverse reactions 

 

Graft delamination 

Graft delamination describes the partial or complete detachment of the formed tissue from the 

subchondral bone and the surrounding cartilage. A complete graft delamination is a serious 

complication which can be accompanied by pain. Risk factors are in particular non-treatment of 

concomitant diseases, such as joint instability or to renege on the rehabilitation protocol. 

 

Hypertrophy of the transplant 

A symptomatic hypertrophy of the transplant may occur during treatment with Spherox resulting in 

pain. 

 

Adverse reactions related to the surgical procedure: 

 



6 

The following adverse reactions considered surgery-related have been reported during the course of the 

clinical trials and/or from spontaneous sources: 

• SOC Vascular disorders: lymphoedema (common), thrombophlebitis (common), deep vein 
thrombosis (uncommon), haematoma (uncommon) 

• SOC Skin and subcutaneous tissue disorders: scar pain (common) 

• SOC Musculoskeletal and connective tissue disorders: joint effusion (very common), arthralgia 
(very common), joint swelling (very common), tendonitis (common), muscular weakness 

(common), patellofemoral pain syndrome (common), osteonecrosis (uncommon) 

• SOC General disorders and administration site conditions: pain (common), gait disturbance 
(common), discomfort (uncommon) 

• SOC Injury, poisoning and procedural complications: ligament sprain (common), suture-related 
complication (uncommon), wound dehiscence (uncommon)  

 

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 

 

In cases where the recommended dose was significantly exceeded (up to 170 spheroids/cm² in an 

investigator-initiated trial with a follow-up period of 12 months), no negative effects were observed. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1  Pharmacodynamic properties 

 

Pharmacotherapeutic group: Other drugs for disorders of the musculo-skeletal system, ATC code: 

M09AX02  

 

Mechanism of action 

 

Autologous chondrocyte implantation (ACI) is based on the extraction of the patient’s own 

chondrocytes isolated from healthy cartilage, their culture in vitro and their subsequent implantation 

into the cartilage defect. Spherox is cultured and implanted as three-dimensional spheroids.  

 

Clinical efficacy 

 

Since 2004, Spherox has been available on a named patient basis for the treatment of cartilage defects 

classified as Outerbridge grade 3 or 4 or ICRS grade III or IV (Outerbridge 1961, ICRS Cartilage 

Injury Evaluation Package 2000). Mainly, patients were treated with cartilage defects in knee. 

 

Spherox has been analysed in a prospective, randomized, uncontrolled open-label, multicentre Phase II 

clinical trial including 75 patients with focal cartilage defects (ICRS grade III or IV) in the knee with a 

defect size of 4-10 cm2. Twenty-five patients were treated with 10-30 spheroids/cm² defect, 25 with 

40-70 spheroids/cm² defect and 25 with 3-7 spheroids/cm² defect. The intention-to-treat (ITT) 

population consisted of 73 patients. The mean patient age was 34 years (range 19 to 48 years) with a 

mean body mass index (BMI) of 25.2. In all three dose groups a significant improvement (α < 0.05) of 

the KOOS (Knee Injury and Osteoarthritis Outcome Score) after 12, 24, 36, 48 and 60 months 

compared to before treatment could be observed. For ‘all dose groups’ the mean overall KOOS 

increased in the first year after treatment from 57.0 ± 15.2 to 73.4 ± 17.3 on a scale from 0 (worst) to 

100 (best) and continued to increase slightly, reaching 74.6 ± 17.6 after 18 months, 73.8 ± 18.4 after 

two years, 77.0 ± 17.8 after three years, 77.1 ± 18.6 after four years and 76.9 ± 19.3 at final follow-up 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


7 

after five years. Changes within each dose group were of similar magnitude, and the three between-

group (pairwise) analyses did not reveal any statistically significant differences between the groups.  

Further patient scores, e.g. the International Knee Documentation Committee (IKDC; subjective 

evaluation of the knee) and the Lysholm score showed after 12, 24, 36, 48 and 60 months also a 

significant improvement in comparison to the value before treatment.  

Magnetic resonance imaging (MRI) results according to the Magnetic Resonance Observation of 

Cartilage Repair Tissue (MOCART) scoring system (0 = worst result; 100 = best result) showed an 

improvement within the first 60 months from 59.8 at Visit 2 (3 months after treatment) up to 

75.0 points in the group of patients treated with 3-7 spheroids/cm² defect, from 64.5 at Visit 2 up to 

76.4 points in the dose group of 10-30 spheroids/cm² defect, and from 64.7 at Visit 2 up to 73.6 points 

in the dose group of 40-70 spheroids/cm² defect. 

 

Furthermore, a multicentre, prospective, randomised, controlled Phase III clinical trial is ongoing. The 

objective of the study is to compare the efficacy and safety of the treatment of cartilage defects (1 to 

less than 4 cm2) at the femoral condyle of the knee joint with Spherox and microfracture treatment 

over a period of 5 years. Pivotal efficacy data were based on an interim analysis at 12 months after 

treatment. Additional statistical assessments were performed 24 and 36 months after treatment.  

 

The treatment groups were balanced with respect to size, demography and disease background. The 

analysis population comprised 102 patients (41 women, 61 men) aged 37 years on average (range from 

18 to 49 years) with a mean body mass index (BMI) of 25.8. Defect sizes ranged from 0.5 to 4 cm2. 

ICRS grades were mostly IV A, followed by IIIB and IIIA (56, 23 and 10 patients respectively). None 

of the patients had received prior treatment with microfracture for their lesion less than one year 

before screening.  

The assessment of the ‘overall KOOS’ for the ITT population showed that both treatments yielded a 

statistically significant improvement relative to baseline (day before arthroscopy). For the patients 

treated with Spherox the mean overall KOOS (scale of 0-100 ± SD) increased from 56.6 ± 15.4 at 

baseline to 78.7 ± 18.6 at the follow-up visit 12 months after treatment, improved up to the 24 months 

visit to 81.5 ± 17.3, reached 83.2 ± 14.9 at the 36 months visit and 84.4 ± 15.8 at the 48 months visit. 

For patients treated by microfracture the mean overall KOOS increased from 51.7 ± 16.5 to 

68.1 ± 18.6 after 12 months, 72.6 ± 19.5 after 24 months, 76.3 ± 17.1 after 36 months and 76.5 ± 18.2 

after 48 months (p < 0.0001 in all cases for both treatment groups). With regard to the between-group 

analysis, the treatment with Spherox passed the test of non-inferiority compared with microfracture (Δ 

of 5.7 with lower bound of CI equal to –1.0 at the 12 months assessment, Δ of 6.1 with lower bound of 

CI equal to –0.4 at the 24 months assessment, Δ of 4.5 with lower bound of CI equal to -1.3 at the 36 

months assessment, and Δ of 5.5 with lower bound of CI equal to -0.7 at the 48 months assessment). 

The total MOCART scores 3, 12, 18, 24, 36 and 48 months after treatment did not differ substantially 

between the two treatment groups. 

IKDC subscores as well as results from the IKDC Current Health Assessment Form and the modified 

Lysholm score also revealed overall improvements from baseline in both treatment groups with 

numerically slightly better results in the Spherox group but with no statistical significance. 

 

Further follow-up assessments of up to 5 years will be performed to generate long-term efficacy data 

on the treatment with Spherox. 

 

5.2 Pharmacokinetic properties 

 

Due to the nature and intended clinical use of Spherox, conventional studies on pharmacokinetics, 

absorption, distribution, metabolism, and elimination are not applicable. 

 



8 

5.3 Preclinical safety data 

 

Ex vivo produced spheroids were implanted in mice (subcutaneous implantation of cartilage explants 

with human spheroids) or in minipigs (autologous spheroids implanted in cartilage defects). No signs 

of inflammation, synovitis, infections, rejection, hypertrophy or immune toxicity, tumourigenicity or 

biodistribution were observed.  

A GLP-compliant examination of biodistribution and tumourigenicity in NSG mice showed no signs 

of biodistribution and/or migration from implanted human spheroids. No suspicion of potential 

tumourigenesis or increased prevalence of tumours due to the implanted spheroids was observed. In a 

sheep study, also no biodistribution was observed after injection of spheroids into the knee joint. 

This suggests that there are no risks for the use of spheroids in humans. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Sodium chloride 

 

6.2 Incompatibilities 

 

In absence of compatibility studies, this medicinal product should not be mixed with other medicinal 

products.  

 

6.3 Shelf life 

 

72 hours  

 

6.4 Special precautions for storage 

 

Store at temperatures between 1 °C and 10 °C. 

Do not freeze. 

Do not irradiate. 

Do not open the outer packaging before use to prevent microbial contamination. 

 

6.5 Nature and contents of container and special equipment for use, administration or 

implantation 

 

The spheroids are provided in an applicator or a pre-filled syringe as primary packaging unit. 

 

The applicator (stem length 150 mm (co.fix 150)) is packed in a sterile tube and additionally 

surrounded by an extra bag. A tube may contain a maximum of two co.fix 150. The catheter of the 

applicator is made of thermoplastic polyurethane, the sealing plug on one side of acrylonitrile 

butadiene styrene and a silicone stopper on the other side. The applicator is delivered with an 

application device (sterile injection syringe).  

 

The pre-filled syringe consists of a luer lock, a sealing ring and a cover cap. It is packed in a sterile 

tube with a screw-type cap and additionally surrounded by an extra bag. All parts of the pre-filled 

syringe are made of polypropylene, the sealing ring of isoprene. Silicone oil serves as lubricant. The 

pre-filled syringe is delivered with an application device (indwelling cannula or filter stem).  

 

Pack sizes 

 

The number of primary packaging units delivered depends on the type of the primary packaging unit 

and the number of spheroids necessary for the specific defect size (10-70 spheroids/cm²).  

 



9 

One applicator has a maximum capacity of 60 spheroids in a volume of up to 200 microlitre isotonic 

sodium chloride solution. 

One pre-filled syringe has a maximum capacity of 100 spheroids in a volume of up to 1000 microlitre 

isotonic sodium chloride solution. 

 

6.6 Special precautions for disposal and other handling 

 

If the primary or secondary packaging is damaged and therefore unsterile, Spherox should not be 

applied.  

 

Remaining spheroids must not be stored for later application.  

Any unused product or waste material should be disposed in accordance with local requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

CO.DON AG  

Warthestraße 21 

14513 Teltow 

Germany 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/17/1181/001 

EU/1/17/1181/002 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 10th July 2017 

 

 

10. DATE OF REVISION OF THE TEXT 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu. 

  

http://www.ema.europa.eu/


10 

 

 

 

 

 

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 

 

 



11 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer of the biological active substance 

 

CO.DON AG 

Warthestr. 21 

14513 Teltow 

GERMANY 

 

Name and address of the manufacturer responsible for batch release 

 

CO.DON AG 

Warthestr. 21 

14513 Teltow 

GERMANY 

 

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). 

 

C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

• Periodic safety update reports (PSURs) 
 

The requirements for submission of PSURs for this medicinal product are set out in the list of Union 

reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 

subsequent updates published on the European medicines web-portal. 

The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 

months following authorisation. 

 

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 required pharmacovigilance activities and interventions detailed in the 

agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 

updates of the RMP. 

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 or 

as the result of an important (pharmacovigilance or risk minimisation) milestone being 

reached. 

 

• Additional risk minimisation measures  
 

Prior to launch and use of Spherox in each Member State, the Marketing Authorisation Holder (MAH) 

must agree about the content and format of the training programme and the controlled distribution 

programme, including communication media, distribution modalities and any other aspects of the 



12 

programme, with the National Competent Authority.  

The educational programme is aimed at providing training to surgeons and other healthcare 

professionals (HCPs) on proper procurement, storage and handling of tissue and blood samples and 

application of Spherox.  

The MAH shall ensure that in each Member State where Spherox is marketed, all surgeons and other 

healthcare professionals who are expected to use Spherox have access to the educational materials 

including: 

• The Summary of Product Characteristics (SmPC) for Spherox 

• Training material for surgeons and other healthcare professionals  

• Prescriber checklist 

 

• The training material for surgeons and other healthcare professionals (HCPs) shall 

contain the following key elements:  

o Information on Spherox, including the approved indication according to the SmPC 

o Detailed description of the biopsy procedure and blood collection, including the need to 

test for hepatitis B, hepatitis C, HIV and syphilis 

o Detailed description of application of Spherox  

o Patient’s preparation for the procedure and subsequent monitoring, including 

recommendations on a rehabilitation programme post biopsy and implantation 

o Instructions on how to handle adverse events or reactions that might occur during/after 

biopsy and/or implantation 

o The need to officially confirm that the training has been conducted prior to the (first) 

biopsy procedure.  

o The importance to complete the prescriber checklist 

 

• The Prescriber checklist shall contain the following key elements: 

o Corroboration that the patient receiving the medicinal product is the right patient receiving 

the right medicinal product in the approved indication according to the SmPC 

o Instructions on patient’s eligibility including the need for screening and testing for 

hepatitis C, hepatitis B, HIV and syphilis 

o Confirmation of the appropriate side of the implantation 

o A specific reference to the fact that the patient has been informed and understands the 

benefits and risks of the medicinal product and the associated procedures 

o Instructions on how to handle adverse events or reactions that might occur during/after 

biopsy and/or implantation 

 

The MAH shall ensure that in each Member State where Spherox is marketed, a system aimed to 

control access to the product beyond the level of control ensured by routine risk minimisation 

measures. The following requirements need to be fulfilled before the product is prescribed and 

dispensed:  



13 

• Specific testing of the patient to ensure compliance with strictly defined clinical criteria 

• The patient should document the receipt and understanding of the information on the product  

• The product will only be available to surgeons qualified and specialised surgeon trained in the 

ACI procedure of Spherox and is therefore restricted to appropriately specialised healthcare 

facilities 

• Measures to ensure the traceability of the product and guarantee the identification of the 

patient and the product at each step.  

 

• Obligation to conduct post-authorisation measures  
 

The MAH shall complete, within the stated timeframe, the below measures: 

 

Description Due date 

Post-authorisation efficacy study (PAES): 60-month 

follow-up data for study cod 16 HS 13. 

 

In order to evaluate the long-term efficacy and safety of 

Spherox vs. microfracture in patients with cartilage 

defects of the knee with a defect size between 1 and < 4 

cm2, the MAH should conduct and submit the results of 

the ongoing prospective, randomised, open label, 

multicentre study.  

 

Interim reports: 

 

To be submitted annually  

 

Final study report: 

 

01-Mar-2021 

 

  



14 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



15 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

  



16 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

Pouch 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Spherox 10-70 spheroids/cm2 implantation suspension 

spheroids of human autologous matrix-associated chondrocytes 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

This medicine contains a specific number of spheroids of human autologous matrix-associated 

chondrocytes according to the defect size (10-70 spheroids/cm2). 

 

 

3. LIST OF EXCIPIENTS 

 

Excipient: sodium chloride. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Implantation suspension. 

In case of application system co.fix 150 mm as primary packaging unit:  

{1 or 2} application system{s} co.fix 150 mm containing {Number of Spheroids} spheroids in a 

sterile tube  

 

In case of syringe as primary packaging unit:  

1 syringe containing {Number of Spheroids} spheroids in a sterile tube 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For intraarticular use. 

 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

For autologous use only. 

 

 



17 

8. EXPIRY DATE 

 

EXP {DD month YYYY} at {hours} CET 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store between 1 °C and 10 °C, do not freeze, do not irradiate, do not open the outer packaging before 

use to prevent microbial contamination. 

 

 

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 

 

CO.DON AG, Warthestraße 21, 14513 Teltow, Germany 

Tel: +49 (0)3328 43 46 0, Fax: +49 (0)3328 43 46 43, Email: info@codon.de 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

In case of application system co.fix 150 mm as primary packaging unit:  

EU/1/17/1181/001 

 

In case of syringe as primary packaging unit:  

EU/1/17/1181/002 

 

 

13. BATCH NUMBER, DONATION AND PRODUCT CODES 

 

Pt Name, Pt ID: {Patient Name}, {Patient ID} 

Lot {Batch Number} 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including Braille accepted. 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

Not applicable.  

 



18 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

Not applicable. 

 

  



19 

PARTICULARS TO APPEAR ON THE SECONDARY PACKAGING 

 

Tube 

 

Application system co.fix 150 mm 

or 

Syringe 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Spherox 10–70 spheroids/cm2 implantation suspension 

 

 

2. METHOD OF ADMINISTRATION 

 

For intraarticular use 

 

 

3. EXPIRY DATE 

 

EXP {DD month YYYY} at {hours} CET 

 

 

4. BATCH NUMBER, DONATION AND PRODUCT CODES 

 

{Patient ID (including the Batch Number)} 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

In case of application system co.fix 150 mm as primary packaging unit:  

{1 or 2} application system{s} co.fix 150 mm in a sterile tube 

 

In case of syringe as primary packaging unit:  

1 syringe in a sterile tube 

 

 

6. OTHER 

 

For autologous use only. 

 

 

  



20 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGINGUNITS 

 

Application system co.fix 150 mm 

or 

Syringe 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Application system co.fix 150 mm: 

Spherox 10–70 spheroids/cm2 implantation suspension 

 

Syringe: 

Spherox 10–70 spheroids/cm2 implantation suspension 

 

 

2. METHOD OF ADMINISTRATION 

 

For intraarticular use 

 

 

3. EXPIRY DATE 

 

Application system co.fix 150 mm: 

EXP {DD month YYYY} at {hours} CET 

 

Syringe: 

EXP {DD month YYYY} at {hours} CET 

 

 

4. BATCH NUMBER, DONATION AND PRODUCT CODES 

 

{Batch Number} 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

{Number of spheroids} sph 

 

 

6. OTHER 

 

For autologous use only. 

 

  



21 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



22 

Package leaflet: Information for the patient 

 

Spherox 10-70 spheroids/cm2 implantation suspension 

spheroids of human autologous matrix-associated chondrocytes 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects. 

 

Read all of this leaflet carefully before you are given with 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. 

• If you get any side effects, talk to your doctor or physical therapist. This includes any possible 
side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 

 

1. What Spherox is and what it is used for  

2. What you need to know before you are given Spherox  

3. How to use Spherox  

4. Possible side effects  

5. How to store Spherox 

6. Contents of the pack and other information 

 

 

1. What Spherox is and what it is used for 

 

Spherox consists of so-called spheroids. A spheroid looks like a tiny pearl made of cartilage cells and 

cartilage material derived from your own body. Cartilage tissue is present in every joint as a hard 

smooth layer on the surface of bone ends. It protects the bones and allows our joints to work smoothly. 

To make the spheroids, a small cartilage sample is taken from part of one of your joints during a minor 

operation, and then grown in the laboratory to make the medicine. By surgery the spheroids are 

implanted to the defected cartilage area and stick to the defect site. They are then expected to repair 

the defect with healthy and functional cartilage over time. 

 

Spherox is used to repair cartilage defects of knee in adults. These defects can be caused by acute 

injury, such as a fall. They can also be caused by repetitive injury, such as long-term incorrect weight 

bearing on the joint. Spherox is used to treat defects up to 10 cm² in size.  

 

 

2. What you need to know before you are given Spherox  

 

Do not use Spherox if  

 

• the bones in the joint have not finished growing 

• you have advanced joint and bone inflammation with degeneration in the affected joint 
(osteoarthritis) 

• you are infected with HIV (the virus that causes AIDS), hepatitits B virus or with hepatitis C 
virus 

 

Warnings and precautions  

 

Talk to your doctor before you are given Spherox, if you have any other joint problems or excess 

weight, as this may reduce the success of the procedure. 

 



23 

Spherox should preferably be implanted into an otherwise healthy joint. Other joint problems should 

be corrected before or at the time of Spherox implantation.  

 

Rehabilitation program  

 

Follow the rehabilitation program, strictly, after implantation. Only resume physical activity when 

instructed by your doctor. Resuming vigorous activity too soon may reduce the benefit and durability 

of Spherox. 

 

Other cases in which Spherox cannot be supplied 

 

Even if the cartilage sample has already been taken, it may happen that you cannot be treated with 

Spherox. This can occur because the sample taken is not of sufficient quality to manufacture the 

product. Your doctor might have to select an alternative treatment for you. 

 

Children and adolescents 

 

Spherox is not recommended in children or adolescents below 18 years. 

 

Other medicines and Spherox 

 

Tell your doctor if you are using, have recently used or might use any other medicines. 

 

Pregnancy and breast-feeding  

 

Spherox is not recommended for pregnant or breast-feeding women, as it is applied during surgery. If 

you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 

your doctor for advice before using this medicine. 

 

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. Strictly follow the advice of 

your doctor or physical therapist. 

 

 

3. How to use Spherox 

 

Spherox can only be implanted by a specialist doctor in a medical facility and must only be used in the 

patient for whom it has been prepared. 

 

The treatment of adults with Spherox is a two-step procedure: 

 

Visit 1: 

Evaluation of the cartilage defect, sample and blood taking 

 

On the first visit, the doctor will evaluate your cartilage defect during an exploratory operation. This is 

usually done as keyhole surgery through very small incisions (cuts), using a special instrument to look 

inside the knee (arthroscopy). 

If Spherox is appropriate for you, the doctor takes a small cartilage sample from your joint. Your 

cartilage cells are extracted from this sample in a laboratory and are then grown to make the spheroids 

that constitute Spherox. The process takes about 6 to 8 weeks. 

 



24 

Visit 2: 

Spherox implantation 

 

Spherox is implanted into the cartilage defect in the joint during the next operation. This may also be 

carried out by keyhole surgery.  

 

Rehabilitation 

 

In order to allow your joint to recover well, you will have to follow an individual rehabilitation 

program. This may take up to one year. Your doctor or physical therapist will advise you. 

 

Very important: Carefully comply with the recommendations of your doctor and physical therapist. 

The risk of treatment failure may increase if you do not follow your rehabilitation schedule. 

Be very careful when bending and putting weight on your treated joint. During the rehabilitation 

period, the amount of weight you can put on the joint will increase gradually. How quickly this occurs 

depends for example on your body weight and the size of the cartilage defect. Depending on the 

treated joint, you may have to wear a brace. 

 

Ask your doctor or physical therapist if you have any further questions about treatment with Spherox. 

 

 

4. Possible side effects 

 

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

effects appearing after the implantation of Spherox are mostly related to the surgery. In general, these 

side effects are quite mild and disappear during the weeks following surgery. 

 

If you get any of the following serious side effects, you should immediately contact a doctor: 

 

• hypersensitivity (allergy) (symptoms: e.g. skin reactions, low blood pressure, constriction of 
airways, swollen tongue or throat, weak and rapid pulse, sickness, vomiting, diarrhoea, 

dizziness, fainting, fever) 

• blood clot in a deep vein (symptoms: e.g. swelling, pain, increased warmth in the affected area) 
 

Other side effects  

 

Side effects can occur with the following frequencies: 

Very common: may affect more than 1 in 10 people 

• accumulation of fluid in the joint 

• pain in the joint  

• swelling in the joint 
 

Common: may affect up to 1 in 10 people 

• cracking sounds in the joint 

• ligament disorder 

• pain 

• tendon inflammation 

• muscle weakness 

• joint lock 

• impairment of walking 

• pain of the front knee or kneecap 

• tissue lump that may occur in the joint 

• swelling due to obstructed flow of tissue fluid via the lymph vessels 

• scar tissue pain 

• accumulation of excess fluid in the bone marrow 



25 

• inflammation of veins combined with the formation of a blood clot located near the surface of 
the skin (symptoms: e.g. redness and/or warmth of the skin along the vein, tenderness, pain) 

 

Uncommon: may affect up to 1 in 100 people 

• increase in size of the cartilage cells, softening of cartilage, disorder of bone formation, death of 
bone tissue, bone formation outside the skeleton. You may in that case notice symptoms, for 

example swelling or pain of the tissues around the joint. 

• uneasiness 

• wound-related complication 

• reopening of a closed wound 

• partial or complete detachment of the tissue beneath the bone and surrounding cartilage 

• internal bleedings 
 

Reporting side effects 

 

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 Spherox 

 

Do not use this medicine after the expiry date which is stated on the label after EXP. 

Store and transport refrigerated (1 °C to 10 °C). 

Do not freeze. Do not irradiate. 

Do not open the outer packaging before use to prevent microbial contamination. 

 

 

6. Contents of the pack and other information 

 

What Spherox contains  

 

• The active substance of Spherox are spheroids that consist of cartilage cells and cartilage 
material derived from your own body. 

Spherox contains 10-70 spheroids per cm² of the cartilage defect. 

• The other ingredient is sodium chloride used as transport solution. 
 

What Spherox looks like and contents of the package 

 

Implantation suspension. 

 

Spherox contains so-called spheroids that consist of living cartilage cells with a non-cellular portion 

for the repair of cartilage defects. The spheroids look like small white to yellowish pearls. They are 

transported in a clear colourless solution. Spherox is delivered to the doctor in a container ready for 

application. The container may be a syringe or a special application system called co.fix that is a 

catheter with a stem length of 150 mm. 

The applicator co.fix 150 is packed in a sterile tube and additionally surrounded by an extra bag. 

The pre-filled syringe is packed in a sterile tube and additionally surrounded by an extra bag. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


26 

Marketing Authorisation Holder and Manufacturer 

 

CO.DON AG 

Warthestraße 21 

14513 Teltow, Germany 

Tel.: +49 3328 43460 

Fax: +49 3328 434643 

E-mail: info@codon.de 

 

This leaflet was last revised in  

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu.  

 

mailto:info@codon.de

	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