SPHEROX 10-70 SFEROIZI/CM2 implant suspension medication leaflet

Spherox 10-70 spheroids/cm2 implantation suspension

2.1 General description

Spheroids of human autologous matrix-associated chondrocytes for implantation suspended in isotonicsodium 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 defectsize (10-70 spheroids/cm2) to be treated.

For the full list of excipients, see section 6.1.

Implantation suspension.

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

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 defectsizes up to 10 cm2 in adults and adolescents with closed epiphyseal growth plate in the affected joint.

Spherox is intended for autologous use only. It must be administered by a specialised orthopedicsurgeon and in a medical facility.

Posology10-70 spheroids are applied per square centimetre defect.

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

The safety and efficacy of Spherox in children and adolescents with still open epiphyseal growth platein the affected joint have not been established. No data are available.

For intraarticular use.

Spherox is administered to patients by intraarticular implantation.

The treatment with Spherox is a two-step procedure.

In a first step, a biopsy must be performed during a surgical procedure (preferably an arthroscopy ormini-arthrotomy). During arthroscopy or arthrotomy the defect and defect size of the cartilage shouldbe determined as accurately as possible. After biopsy, the cartilage cells will be cultured at themanufacturing site until they will form spheroids that constitute Spherox. The process takes about 6 to8 weeks.

In a second step, the implantation must be performed during a surgical procedure (preferably anarthroscopy or mini-arthrotomy). A debridement of the defect area is required. The subchondral plateshould not be damaged. The spheroids are provided in a pre-filled syringe or an applicator (stemlength 150 mm (co.fix 150)). Spheroids should be applied evenly on the defect ground and, ifnecessary, 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 closedwithout any additional cover of the treated area (e.g. periosteal flap; matrix), or any fixation ofspheroids by using fibrin glue. The treatment of defect sizes up to 10 cm2 is eligible for single as wellas adjacent defects (combined area).

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

* 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.

The traceability requirements of cell-based advanced therapy medicinal products must apply. Toensure traceability the name of the product, the batch number and the name of the treated patientshould be kept for a period of 30 years after expiry date of the product.

Autologous use

Spherox is intended solely for autologous medicinal use and should under no circumstances be givento any other patient than the donor. Spherox must not be administered if the information on theproduct labels and shipping documents do not match the patient’s identity. The order number (lotnumber) on the primary package should also be checked prior to administration.

Spherox must not be applied if the primary or secondary packaging is damaged and therefore unsterile.

The application of Spherox in patients with cartilage defects outside the knee joint is notrecommended. The safety and efficacy of Spherox in patients with cartilage defects outside thefemoral condyle and the patella of the knee have not been established. No data are available.

Precautions for use

Treatment of 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 inflammatorydiseases.

Concomitant joint problems such as early osteoarthritis, subchondral bone defects, instability of thejoint, lesions of ligaments or of the meniscus, abnormal weight distribution in the joint, varus orvalgus malalignment, patellar malalignment or instability, and metabolic, inflammatory,immunological or neoplastic diseases of the affected joint are potential complicating factors. Untreatedbone oedema corresponding with the cartilage defect to be treated may adversely affect the success ofthe procedure. If possible, concomitant joint problems should be corrected prior to or at the latest atthe time of Spherox implantation.

For a decision on treatment of facing defects (“kissing lesions” larger than ICRS grade II) the degreeof 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 poorsurgical haemorrhage control. The haemostatic functions of the patient should be screened prior tosurgery. 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 activityshould be resumed as recommended by the physician. Too early and vigorous activity maycompromise the grafting and the durability of clinical benefit from Spherox.

Compliance with an adequate rehabilitation programme after implantation (especially for patients withmental disorders or addiction) is required.

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 toinsufficient biopsy quality, the medicinal product cannot be delivered. The physician will be informedimmediately.

No interaction studies have been performed.

Locally applied antibiotics or disinfectants may have potential toxicity on articular cartilage and it isnot 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 withcorticosteroids.

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

As Spherox is used to repair cartilage defects of the joint and is therefore implanted during a surgicalprocedure, it is not recommended for use in pregnant women.

As Spherox is used to repair cartilage defects of the joint and is therefore implanted during a surgicalprocedure, it is not recommended for use in breast-feeding women.

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

The surgical procedure (i.e. the biopsy or implantation of Spherox) will have a major influence on theability to drive and use machines. During the rehabilitation period, the ability to drive and usemachines may also be restricted due to reduced mobility. Therefore, patients should consult theirtreating physician and strictly follow their advice.

Information on adverse reactions from clinical trials and a non-interventional study in adolescents aswell as from post-marketing experience are available. During treatment with Spherox surgery-related(implantation) or Spherox-related adverse reactions may occur.

The adverse reactions related to Spherox are displayed by system organ class and frequency in Table 1below: 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 theavailable data). Within each frequency grouping, undesirable effects are presented in order ofdecreasing 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 Common Bone marrow oedemaconnective tissue disorders Joint effusion

Arthralgia

Joint swelling

Uncommon Chondromalacia

Joint noise

Joint lock

Synovial cyst

Chondropathy

Synovitis

Loose body in the joint

System Organ Class (SOC) Frequency Adverse Reaction

Rare Osteochondrosis

Osteophyte formation

Arthritis infective

Not known Arthrofibrosis

General disorders and Common Painadministration siteconditions Uncommon Gait disturbance

Injury, poisoning and Uncommon Hypertrophyprocedural complications Graft loss

Rare Graft delamination

Implant site infection

Infrapatellar fat padinflammation

Graft delamination

Graft delamination describes the partial or complete detachment of the formed tissue from thesubchondral bone and the surrounding cartilage. A complete graft delamination is a seriouscomplication which can be accompanied by pain. Risk factors are, in particular, non-treatment ofconcomitant diseases, such as joint instability or lack of compliance with 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 theclinical 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)

* SOC Musculoskeletal and 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 bodyin 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-relatedcomplication (rare), wound dehiscence (rare)

The recorded product- and surgery-related adverse reactions were in most cases not serious.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In cases where the recommended dose was significantly exceeded (up to 170 spheroids/cm² in aninvestigator-initiated trial with a follow-up period of 12 months), no negative effects were observed.

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

M09AX02

Autologous chondrocyte implantation (ACI) is based on the extraction of the patient’s ownchondrocytes isolated from healthy cartilage, their culture in vitro and their subsequent implantationinto the cartilage defect. Spherox is cultured and implanted as three-dimensional spheroids.

Since 2004, Spherox has been available on a named patient basis for the treatment of cartilage defectsclassified 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 IIclinical trial including 75 patients with focal cartilage defects (ICRS grade III or IV) in the knee with adefect size of 4-10 cm2. Twenty-five patients were treated with 10-30 spheroids/cm² defect, 25 with40-70 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 amean body mass index (BMI) of 25.2. In all three dose groups a significant improvement (α < 0.05) ofthe KOOS (Knee Injury and Osteoarthritis Outcome Score) after 12, 24, 36, 48 and 60 monthscompared to before treatment could be observed. For ‘all dose groups’ the mean overall KOOSincreased in the first year after treatment from 57.0 ± 15.2 to 73.4 ± 17.3 on a scale from 0 (worst) to100 (best) and continued to increase slightly, reaching 74.6 ± 17.6 after 18 months, 73.8 ± 18.4 aftertwo years, 77.0 ± 17.8 after three years, 77.1 ± 18.6 after four years and 76.9 ± 19.3 at final follow-upafter 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; subjectiveevaluation of the knee) and the Lysholm score showed after 12, 24, 36, 48 and 60 months also asignificant 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 animprovement within the first 60 months from 59.8 at Visit 2 (3 months after treatment) up to75.0 points in the group of patients treated with 3-7 spheroids/cm² defect, from 64.5 at Visit 2 up to76.4 points in the dose group of 10-30 spheroids/cm² defect, and from 64.7 at Visit 2 up to 73.6 pointsin 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 cm2) at the femoral condyle of the knee joint with Spherox and microfracturetreatment over a period of 5 years. Pivotal efficacy data were based on an interim analysis at 12months after treatment. Additional statistical assessments were performed 24, 36, 48 and 60 monthsafter treatment.

The treatment groups were balanced with respect to size, demography and disease background. Theanalysis population comprised 102 patients (41 women, 61 men) aged 37 years on average (range from18 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, 22 and 10 patients respectively). Noneof the patients had received prior treatment with microfracture for their lesion less than one yearbefore screening.

The assessment of the ‘overall KOOS’ for the ITT population showed that both treatments yielded astatistically significant improvement relative to baseline (day before arthroscopy). For the patientstreated with Spherox the mean overall KOOS (scale of 0-100 ± SD) increased from 56.6 ± 15.4 atbaseline to 81.5 ± 17.3 at 24 months after treatment. For patients treated by microfracture the meanoverall KOOS increased from 51.7 ± 16.5 to 72.6 ± 19.5 after 24 months (p < 0.0001 for bothtreatment groups). With regard to the between-group analysis, the treatment with Spherox passed thetest of non-inferiority compared with microfracture (Δ of 6.1 with lower bound of CI equal to -0.4 atthe 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 significantlybetween 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 withnumerically slightly better results in the Spherox group but with no statistical significance.

Spherox has been analysed in a non-interventional, open-label, multicentre surveillance study in 60adolescent patients with closed epiphysial growth plates, aged 15 to < 18 years with focal cartilagedefects (ICRS grade 3 or 4) in the knee with a defect size of 0.75 - 12.00 cm2. The mean patient agewas 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 asdocumented by the physician was 48.4 (19.5) months. The mean (SD) overall KOOS score in thepaediatric population at follow-up was 75.5 (18.2). MRI results according to the MOCART scoringsystem (0 = worst result; 100 = best result) at follow-up was mean (SD) 74.9 (18.5) and ranged from aminimum of 30 to a maximum of 100.

Due to the nature and intended clinical use of Spherox, conventional studies on pharmacokinetics,absorption, distribution, metabolism, and elimination are not applicable.

Ex vivo produced spheroids were implanted in mice (subcutaneous implantation of cartilage explantswith human spheroids) or in minipigs (autologous spheroids implanted in cartilage defects). No signsof inflammation, synovitis, infections, rejection, hypertrophy or immune toxicity, tumourigenicity orbiodistribution were observed.

A GLP-compliant examination of biodistribution and tumourigenicity in NSG mice showed no signsof biodistribution and/or migration from implanted human spheroids. No suspicion of potentialtumourigenesis or increased prevalence of tumours due to the implanted spheroids was observed. In asheep 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.

Sodium chloride

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

72 hours

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.

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 additionallysurrounded by an extra pouch. A tube may contain a maximum of two co.fix 150. The catheter of theapplicator is made of thermoplastic polyurethane, the sealing plug on one side of acrylonitrilebutadiene styrene and a silicone stopper on the other side. The applicator is delivered with anapplication 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 steriletube with a screw-type cap and additionally surrounded by an extra pouch. All parts of the pre-filledsyringe are made of polypropylene, the sealing ring of isoprene. Silicone oil serves as lubricant. Thepre-filled syringe is delivered with an application device (indwelling cannula or filter stem).

The number of primary packaging units delivered depends on the type of the primary packaging unitand 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 isotonicsodium chloride solution.

One pre-filled syringe has a maximum capacity of 100 spheroids in a volume of up to 1000 microlitreisotonic sodium chloride solution.

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

Remaining spheroids must not be stored for later application.

Unused medicinal product and all material that has been in contact with Spherox (solid and liquidwaste) should be handled and disposed of as potentially infectious waste in accordance with localguidelines on handling of human-derived material.

CO.DON GmbH

Deutscher Platz 5d04103 Leipzig

Germany

EU/1/17/1181/001

EU/1/17/1181/002

Date of first authorisation: 10th July 2017

Date of latest renewal: 29th April 2022

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

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