ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1
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 selfsynthesized
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 Repair 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 an appropriately qualified
physician 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.
2
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 miniarthrotomy).
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), 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 viruses.
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.
3
In the pivotal studies of Spherox, patients were excluded if they had signs of chronic inflammatory
diseases.
Concomitant joint problems like early osteoarthritis, subchondral cartilage defects, instability of the
joint, lesions of ligaments or of the meniscus, abnormal weight distribution in the joint, varus or
valgus malalignment, patellar malalignment, 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.
4
5
4.7 Effects on ability to drive and use machines
Due to the surgical nature of the underlying procedure, implantation of Spherox has a major influence
on the ability to drive and use machines. During the rehabilitation period, this ability can 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
During treatment with Spherox adverse reactions associated with the surgical procedure (implantation)
or associated with Spherox may occur.
Adverse reactions associated with Spherox
x Graft delamination
x Hypertrophy
Adverse reactions associated with joint surgery
x Joint effusion
x Arthralgia
Tabulated list of adverse reactions
Information on adverse reactions in 177 patients from pivotal clinical trials are available.
Furthermore, adverse reactions obtained from queries of the treating surgeons as well as from
spontaneous reports were considered.
The adverse reactions are displayed by system organ class and frequency in Table 1 below: very
cRPPRQ FRPPRQ 1/100 to < XQFRPPRQ 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
System Organ Class Frequency Adverse Reaction
Immune system disorders Common Hypersensitivity
Cardiac disorders Uncommon Tachycardia
Vascular disorders Uncommon Haematoma,
Thrombophlebitis superficial,
Deep vein thrombosis,
Lymphoedema
Musculoskeletal and
connective tissue disorders
Very common Joint effusion,
Arthralgia,
Joint swelling
Common Muscular weakness,
Joint lock,
Joint crepitation,
Chondropathy,
Tendonitis
Uncommon Hypertrophy,
Chondromalacia,
Synovial cyst
General disorders and
administration site conditions
Common Gait disturbance,
Pain
Uncommon Discomfort
Injuries, poisoning and Common Meniscus injury,
6
System Organ Class Frequency Adverse Reaction
procedural complications Ligament sprain
Uncommon Suture-related complication,
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 subchondral bone oedema.
Hypertrophy of the transplant
A symptomatic hypertrophy of the transplant may occur during treatment with Spherox resulting in
pain.
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 removal 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 study 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 and25 with 3-7 spheroids/cm² defect. The mean patient age was 34 years
(range 19 to 48 years) with a mean body mass index (BMI) of 25.2. In all 3 dose groups a significant
LPSURYHPHQW Į < 0.05) of the KOOS (Knee Injury and Osteoarthritis Outcome Score) after 12, 24 and
36 months compared to before treatment could be observed. For ‘all dose groups’ the mean overall
KOOS rose in the first year after treatment from 57.0 to 73.4 on a scale from 0 (worst) to 100 (best)
7
and continued to rise slightly, reaching 74.6 after 18 months, 73.8 after two years and 77.0 after three
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 and 36 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 36 months from 59.8 at Visit 2 (3 months after treatment) up to
72.4 points in the group of patients treated with 3-7 spheroids/cm² defect, from 64.5 at Visit 2 up to
79.6 points in the dose group of 10-30 spheroids/cm² defect, and from 64.7 at Visit 2 up to 72.1 points
in the dose group of 40-70 spheroids/cm² defect.
Currently, a multicentre, prospective, randomised, controlled clinical Phase III study 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. The final statistical assessment will be 24 months after treatment. The current
interim analysis 12 months after treatment reveals data as follows:
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.
As part of the interim analysis, the assessment of the ‘overall KOOS’ for the intention-to-treat (ITT)
population showed that both treatments yielded a statistically significant improvement relative to
baseline. For the patients treated with Spherox the mean overall KOOS (scale of 0-100) increased
from 56.6 ± 15.4 at baseline to 78.7 ± 18.6 at the follow-up visit 12 months after treatment. For
patients treated by microfracture the mean overall KOOS increased from 51.7 ± 16.5 to 68.1 ± 18.6
(p < 0.0001 in both cases). With regard to the between-group analysis, the treatment with Spherox
passed the test of non-inferiority compared with microfracture ǻRI 5.7 with lower bound of CI equal
to –1.0). MOCART scores of 67 and 62 for the Spherox and microfracture groups at follow-up visit 3
months after treatment, improved to 81 and 77 at 12 months after treatment (0 = worst result;
100 = best result).
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.
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.
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).
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.
8
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:
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.
9
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
10
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
The requirements for submission of periodic safety update reports 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 shall submit the first periodic safety update report 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 agreeed 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 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
11
programme, including communication media, distribution modalities and any other aspects of the
programme, with the National Competent Authority.
The main objectives of the educational programme are to provide training to surgeons and other health
professionals on proper procurement, storage, handling and administration of Spherox.
The MAH shall ensure that in each Member State where Spherox is marketed, all surgeons and other
health professionals who are expected to prescribe and administer the product have access to the
educational materials including:
• The Summary of Product Characteristics
• Training materials for surgeons and training materials for other health professionals
• Prescriber checklist
• Forms for documentation
• The training material for surgeons and surgical staff shall contain the following key
elements:
o Information on Spherox, including the indication currently approved and legal basis
o Detailed description of the biopsy harvest procedure and the administration procedure,
the implantation by knee-joint arthrotomy and the follow-up protocol
o Preparation of the patient for the procedure and subsequent monitoring
o The need to officially confirm that training has been conducted prior to the biopsy.
o The importance to complete the checklist
o Recommendations on rehabilitation post biopsy and post transplantation
• The training material for other health professionals shall contain the following key
elements:
o Information on Spherox, including the indication currently approved and legal basis
o The need to screen donors for hepatitis B, hepatitis C, HIV and syphilis
o Detailed description of the handling of the biopsy harvest and of the product, elements
on the preparation for the implantation, the schedule for the patient follow-up and
recommended physiotherapy.
o The need to officially confirm that training has been conducted prior to the biopsy.
• The Prescriber checklist shall contain the following key messages:
o Corroboration that the patient receiving the product is the right patient receiving the
appropriate product
o Confirmation of the appropriate side of the implantation
o A reference to the fact that the patient has been informed and understands the benefits
and risks of the product and the associated procedures
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:
12
• Specific testing and examination 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 certified to prescribe and administer Spherox
• Measures to ensure the traceability of the product and guarantee the identification of: patient
data; diagnosis leading to the treatment; information on biopsy including date of the operation,
adverse events reported during the procedure and quality of the biopsy; information on the
implant, including all in-process controls and final product controls.
• 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
To conduct a prospective process validation study post
marketing using batches manufactured with a wellcontrolled
process and to collect quality data from a
sufficient number of batches to demonstrate
consistency, quality and genetic stability of the cells in
the finished product. On the basis of the process
validation study, in process controls should be reviewed
and the acceptance criteria tightened accordingly for the
manufacturing process for P0 culture time, total ML
culture time, spheroid culture time and amount of
synovial impurities.
April 2019
To re-validate the potency assay post marketing and to
monitor its correlation with the efficacy outcome.
March 2018
13
ANNEX III
LABELLING AND PACKAGE LEAFLET
14
A. LABELLING
15
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.
16
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: [email protected]
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.
17
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA
Not applicable.
18
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.
19
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.
20
B. PACKAGE LEAFLET
21
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.
22
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 and full-grown adolescents 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.
23
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
• muscle weakness
• joint lock
• cracking sounds in the joint
• regression of cartilage
• tendon inflammation
• impairment of walking
• meniscus injury
• ligament disorder
• pain
24
Uncommon: may affect up to 1 in 100 people
• increase in size of the cartilage cells
• softening of cartilage
• tissue lump that may occur in the joint
• uneasiness
• wound-related complication
• partial or complete detachment of the tissue beneath the bone and surrounding cartilage
• internal bleedings
• 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)
• swelling due to obstructed flow of tissue fluid via the lymph vessels
• increased heartbeat
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. This is a
catheter with a stem length of 150 mm. The container used varies, depending on the doctor’s
preference.
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.
25
Marketing Authorisation Holder and Manufacturer
CO.DON AG
Warthestraße 21
14513 Teltow, Germany
Tel.: +49 3328 43460
Fax: +49 3328 434643
E-mail: [email protected]
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.
26
