Spherox

European Union - English - EMA (European Medicines Agency)

Active ingredient:
spheroids of human autologous matrix-associated chondrocytes
Available from:
CO.DON AG
ATC code:
M09AX02
INN (International Name):
spheroids of human autologous matrix-associated chondrocytes
Therapeutic group:
Other drugs for disorders of the musculo-skeletal system
Therapeutic area:
Cartilage Diseases
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.
Product summary:
Revision: 5
Authorization status:
Authorised
Authorization number:
EMEA/H/C/002736
Authorization date:
2017-07-10
EMEA code:
EMEA/H/C/002736

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Read the complete document

B. PACKAGE LEAFLET

Package leaflet: Information for the patient

Spherox 10-70 spheroids/cm

2

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

What Spherox is and what it is used for

What you need to know before you are given Spherox

How to use Spherox

Possible side effects

How to store Spherox

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 and in adolescents whose bones in the

joint have finished growing. 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.

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 whose bones in the knee joint have not

finished growing.

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 adolescents (whose bones in the joint have finished growing) 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.

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:

Common

: may affect up to 1 in 10 people

accumulation of fluid in the joint

pain in the joint

swelling in the joint

accumulation of excess fluid in the bone marrow

pain

Uncommon

: may affect up to 1 in 100 people

increase in size of the cartilage cells, softening of cartilage.

You may in that case notice

symptoms, for example swelling or pain of the tissues around the joint.

cracking sounds in the joint

joint lock

impairment of walking

tissue lump that may occur in the joint

loss of the implanted cells

any disease of cartilage

ligament disorder

tendon inflammation

muscle weakness

pain of the front knee or kneecap

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

scar tissue pain

blockage of a blood vessel in the lung

fragment of cartilage or bone that freely floats in the knee joint space

inflammation of the inner layer of the joint capsule

Rare

: may affect up to 1 in 1000 people

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.

infection at the site of implantation

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

inflammation of the joint caused by bacteria

inflammation of the bone marrow caused by bacteria

inflammation of the skin and/or the soft tissue caused by bacteria

pain below the kneecap due to inflammation of the soft tissue

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)

wound-related complication

reopening of a closed wound

internal bleedings

Very rare

: may affect up to 1 in 10.000 people

uneasiness

Not known:

frequency cannot be determined

excessive scar tissue formation within the joint and/or surrounding of soft tissues

inflammation of the lung

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.

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

Manufacturer

CO.DON AG

Deutscher Platz 5d

04103 Leipzig, Germany

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.

Read the complete document

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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/cm

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/cm

) 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 cm

in adults and adolescents with closed epiphyseal growth plate in the affected joint.

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 and adolescents with still open epiphyseal growth plate

in the affected joint 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 cm

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.

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.

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 from clinical trials and a non-interventional study in adolescents as

well as from post-marketing experience are available. During treatment with Spherox surgery-related

(implantation) or Spherox-related adverse reactions may occur.

Paediatric population

In general, the adverse reactions in paediatric patients were similar in frequency and type to those seen

in adult patients.

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

Infections and infestations

Rare

Cellulitis,

Osteomyelitis

Immune system disorders

Rare

Hypersensitivity

Musculoskeletal and

connective tissue disorders

Common

Bone marrow oedema,

Joint effusion,

Arthralgia,

Joint swelling

Uncommon

Chondromalacia,

Joint noise,

Joint lock,

Synovial cyst,

Chondropathy,

Synovitis,

Loose body in the joint

Rare

Osteochondrosis,

Osteonecrosis,

Osteophyte formation,

Arthritis infective

Not known

Arthrofibrosis

General disorders and

administration site

conditions

Common

Pain

Uncommon

Gait disturbance

Injury, poisoning and

procedural complications

Uncommon

Hypertrophy,

Graft loss

Rare

Graft delamination,

Implant site infection,

System Organ Class (SOC)

Frequency

Adverse Reaction

Infrapatellar fat pad

inflammation

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

A symptomatic implant site hypertrophy may occur during treatment with Spherox resulting in pain.

Adverse reactions related to the surgical procedure:

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

clinical trials and/or from spontaneous sources:

SOC Infections and infestations: pneumonia (not known)

SOC Vascular disorders: lymphoedema (uncommon), thrombophlebitis (rare), deep vein thrombosis

(uncommon), haematoma (rare)

SOC Respiratory, thoracic and mediastinal disorders: pulmonary embolism (uncommon)

SOC Skin and subcutaneous tissue disorders: scar pain (uncommon)

Musculoskeletal

connective

tissue

disorders:

joint

effusion

(common),

arthralgia

(common), joint swelling (common), tendonitis (uncommon), muscular weakness (uncommon),

patellofemoral pain syndrome (uncommon), osteonecrosis (rare), synovitis (uncommon), loose body

in the joint (uncommon)

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

(uncommon), discomfort (very rare)

SOC Injury, poisoning and procedural complications: ligament sprain (uncommon), suture-related

complication (rare), wound dehiscence (rare)

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 cm

. 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

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 was conducted.

The objective of the study was to compare the efficacy and safety of the treatment of cartilage defects

(1 to less than 4 cm

) 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, 36, 48 and 60 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 cm

ICRS grades were mostly IV A, followed by IIIB and IIIA (56, 22 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 81.5 ± 17.3 at 24 months after treatment. For patients treated by microfracture the mean

overall KOOS increased from 51.7 ± 16.5 to 72.6 ± 19.5 after 24 months (p < 0.0001 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 6.1 with lower bound of CI equal to –0.4 at

the 24 months assessment).

The results at later time points were consistent with these findings. At 60 months follow-up, overall

KOOS was 84.5 ± 16.1 after treatment with Spherox as compared to 75.4 ± 19.6 after microfracture.

The total MOCART scores 3, 12, 18, 24 until 60 months after treatment did not differ significantly

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.

Paediatric population

Spherox has been analysed in a non-interventional, open-label, multicentre surveillance study in 60

adolescent patients with closed epiphysial growth plates, aged 15 to < 18 years with focal cartilage

defects (ICRS grade 3 or 4) in the knee with a defect size of 0.75 – 12.00 cm

. The mean patient age

was 16.5 years (range 15 to 17 years) with a mean body mass index (BMI) of 23.9. Mean (SD) follow-

up time, defined as the interval between the date of implantation and date of the follow-up visit as

documented by the physician was 48.4 (19.5) months. The mean (SD) overall KOOS score in the

paediatric population at follow-up was 75.5 (18.2). MRI results according to the MOCART scoring

system (0 = worst result; 100 = best result) at follow-up was mean (SD) 74.9 (18.5) and ranged from a

minimum of 30 to a maximum of 100.

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.

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

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.

Read the complete document

Official address

Domenico Scarlattilaan 6

1083 HS Amsterdam

The Netherlands

An agency of the European Union

Address for visits and deliveries

Refer to www.ema.europa.eu/how-to-find-us

Send us a question

Go to www.ema.europa.eu/contact

Telephone

+31 (0)88 781 6000

© European Medicines Agency, 2021. Reproduction is authorised provided the source is acknowledged.

EMA/326451/2021

EMEA/H/C/002736

Spherox (spheroids of human autologous matrix-

associated chondrocytes)

An overview of Spherox and why it is authorised in the EU

What is Spherox and what is it used for?

Spherox is a medicine used to repair defects to the cartilage in the knee in patients who are

experiencing symptoms (such as pain and problems moving the knee). It is used where the affected

area is no larger than 10 cm². Spherox is used in adults and in adolescents whose bones in the joints

have finished growing.

Spherox contains spheroids (spherical aggregates) of chondrocytes, cells found in healthy cartilage,

that have been prepared from the patient’s own tissues.

How is Spherox used?

Spherox is available as a suspension for implantation into the knee joint. The medicine is prepared

specifically for each individual patient and must be given by a qualified doctor in a medical facility.

To prepare the medicine, a small sample is taken by arthroscopy (a type of keyhole surgery) from the

patient’s cartilage in the knee. The cartilage cells are then grown in the laboratory to prepare a

suspension of chondrocyte spheroids. During another arthroscopy, the medicine is placed into the

damaged area of the patient’s cartilage in the knee. The chondrocyte spheroids attach to the cartilage

within 20 minutes. Patients treated with Spherox should follow a specific rehabilitation programme,

including physiotherapy. This allows the chondrocyte spheroids to fill in the cartilage defect.

The medicine can only be obtained with a prescription.

How does Spherox work?

Cartilage in the knee can be damaged because of an accident, such as a fall or a sports injury. Spherox

contains spheroids made from the patient’s own healthy cartilage cells. When the spheroids are

implanted into the patient’s knee cartilage, they attach to the area of the defect and produce new

tissue, thereby repairing the defects in the knee.

Spherox (spheroids of human autologous matrix-associated chondrocytes)

EMA/326337/2017

Page 2/3

What benefits of Spherox have been shown in studies?

Spherox has been shown to improve patients’ symptoms and knee function in two studies in adults

between 18 and 50 years of age. The main measure of effectiveness was the KOOS (knee injury and

osteoarthritis outcome score), which is graded on a scale from 0 to 100 (where 0 means severest

symptoms and 100 means no symptoms). The KOOS was self-measured by patients, who rated the

severity of their symptoms such as pain, impact on daily living, sport and recreational activities, and

quality of life.

In the first study involving 100 adults, Spherox was compared with microfracture (a type of surgery

used to treat defects in cartilage). The knee cartilage defects were between 1 and 4 cm

in size. Data

from this study showed that Spherox improved the outcome score by 22 points to 28 points until 5

years after treatment and was as effective as microfracture.

The second study looked at 73 adults with large cartilage defects of the knee from 4 to 10 cm². All

these patients received treatment with Spherox, as microfracture is not recommended to repair such

large defects. In this study, patients’ outcome scores with Spherox improved by 16 points in the first

year and further improvements were seen up to three years after treatment and remained stable until

five years after treatment.

A third study looked at the treatment effect with Spherox in 105 adolescents aged between 15 and 17

years with cartilage defects of the knee joint. Overall, the results indicated that there was no major

difference in terms of effectiveness between the adolescents included in this study and the young

adults (from 18 to 34 years of age) who participated in the previous two studies.

What are the risks associated with Spherox?

The most common side effects with Spherox (which may affect up to 1 in 10 people) are bone marrow

oedema (accumulation of fluid in the bone marrow), arthralgia (joint pain), joint effusion

(accumulation of fluid in the knee),swelling of the joint and pain. For the full list of side effects of

Spherox, see the package leaflet.

Spherox must not be used in patients with primary generalised osteoarthritis or with advanced

osteoarthritis of the knee (conditions causing swelling and pain in the joints) and in patients whose

bones in the knee joint are still growing. It must also not be used in patients infected with hepatitis B,

C and/or HIV.

Why is Spherox authorised in the EU?

Spherox has been shown to be effective at treating knee cartilage defects between 1 and 10 cm

size. Using chondrocyte spheroids that attach to the knee cartilage allows for less invasive surgery.

The safety profile was considered acceptable; most side effects are expected to be due to the surgery.

The European Medicines Agency therefore decided that Spherox’s benefits are greater than its risks

and it can be authorised for use in the EU.

What measures are being taken to ensure the safe and effective use of

Spherox?

The company that markets Spherox will ensure that all surgeons and other healthcare professionals

handling or using the medicine receive training materials on how to use and store it, and that systems

are in place to ensure that only healthcare professionals trained in using Spherox can use it, and that

patients are tested to ensure they meet strictly defined clinical criteria. The training materials will

Spherox (spheroids of human autologous matrix-associated chondrocytes)

EMA/326337/2017

Page 3/3

include guidance on how to safely collect and handle the cartilage sample from patients, implant

Spherox as well as how to inform and follow up patients.

Recommendations and precautions to be followed by healthcare professionals and patients for the safe

and effective use of Spherox have also been included in the summary of product characteristics and

the package leaflet.

As for all medicines, data on the use of Spherox are continuously monitored. Side effects reported with

Spherox are carefully evaluated and any necessary action taken to protect patients.

Other information about Spherox

Spherox received a marketing authorisation valid throughout the EU on 10 July 2017.

Further information on Spherox can be found on the Agency’s website:

ema.europa.eu/medicines/human/EPAR/spherox

This overview was last updated in 06-2021.

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