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Maci (autologous cultured chondrocytes) – Summary of product characteristics - M09AX02

Updated on site: 08-Oct-2017

Medication nameMaci
ATC CodeM09AX02
Substanceautologous cultured chondrocytes
ManufacturerVericel Denmark ApS
Implantation matrix.
MACI 500,000 to 1,000,000 cells/cm2 implantation matrix

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

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each implant contains matrix applied characterised autologous cultured chondrocytes.

2.1

General description

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Characterised viable autologous chondrocytes expanded ex vivo expressing chondrocyte-specific marker

 

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genes, seeded onto a CE marked porcine derived Type I/III collagen membrane.

2.2

Qualitative and quantitative composition

 

Each implantation matrix consists of characterised autologous chondrocytes on a 14.5 cm² Type I/III collagen membrane, at a density of 500,000 to 1,000,000 cells per cm2, to be trimmed by the surgeon to the size and shape of the defect.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

The implant is an opaque, off-white membrane, seeded with chondrocytes, supplied in 18 ml of

colourless solution in a dish.

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4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

MACI is indicated for the repair of symptomatic, full-thickness cartilage defects of the knee (grade III and IV of the Modified Outerbridge Scale) of 3-20 cm2 in skeletally mature adult patients.

4.2 Posology and method of administration

MACI is intended for autologous use only.

MACI must be administered by a surgeon specifically trained and qualified in the use of MACI.

Posology

The amount of MACI administered is dependent upon the size (surface in cm2) of the cartilage defect. The implantation matrix is trimmed by the treating surgeon to the size and shape of the defect, to ensure the damaged area is completely covered, and implanted cell-side down. The administered dose corresponds to 500,000 to 1,000,000 autologous cells/cm2 of implantation matrix.

Special populations

Older people (over 65 years of age)

The use of MACI in this age group has not been studied. The use of MACI in elderly with generalised

degeneration of the cartilage or osteoarthritis is not recommended.

 

Paediatric population

 

The safety and efficacy of MACI in children less than 18 years of age have not been established.

No data are available.

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Method of administration

 

For implantation.

The defect bed should be debrided only down to the subchondral plate and not through it. Bleeding through the subchondral plate should be avoided, but if it occurs, it must be controlled. Epinephrine or fibrin sealant (see section 4.5), applied sparingly directly to bleeding points, is a suitable haemostatic agent.

Implantation of MACI is performed using sterile surgical techniques and requires both the preparation of the defect bed and the application of fibrin sealant to the base and rim of the defect in order to secure the implant. At the surgeon’s discretion, a few interrupted absorbable sutures may also be used to provide extra security.

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The implantation should be followed by an appropriate rehabilitation schedule (see section 4.4). MarketingFor information on preparation and handling of MACI, please refer to section 6.6.

4.3 Contraindications

• Hypersensitivity to any of the excipients listed in section 6.1, or porcine products, or any residual component carried over from manufacture of MACI, including bovine serum, and gentamicin.

• Severe osteoarthritis of the knee.

• Inflammatory arthritis, inflammatory joint disease, or uncorrected congenital blood coagulation disorders.

• Patients with a femoral epiphyseal growth plate that is not fully closed.

Precautions for use

4.4 Special warnings and precautions for use

 

General

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concurrent with implantation of MACI. These include:

MACI is an autologous implant and must only be administered to the patient for whom it was manufactured. Implantation of MACI is to be performed during arthrotomy under sterile conditions. There is limited experience with delivery of MACI to the knee via arthroscopy, however, arthroscopic techniques may be used to apply MACI at the discretion of the treating physician.

Patients with local inflammations or active infections in the bone, joint, and surrounding soft tissue should be temporarily deferred until documented recovery.

In the pivotal study of MACI, patients were excluded if they had a history of osteoarthritis

(Kellgren-Lawrence Grade 3 or 4) in the target knee, or concomitant inflammatory disease.

To create a favourable environment for healing, concomitant pathologies must be addressed prior to or

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

Meniscal pathology: unstable or torn meniscus requires repair, replacement, or partial

 

meniscectomy. MACI is not recommended in patients with a total menisectomy unless the

 

meniscal deficiency can be addressed with a staged or concurrent meniscal graft.

Cruciate ligament instability: the joint should not possess excessive laxity. Both anterior and

 

posterior cruciate ligaments should be stable or undergo reconstruction to reduce shearing forces

 

and rotation stresses across the joint.

Malalignment: the tibio-femoral joint should be properly aligned. Abnormal varus or valgus

 

loading of the tibio-femoral joint may jeopardise the implant and should be addressed with a

 

corrective osteotomy or similar procedure. When treating trochlear and patellar defects,

 

abnormal patellar tracking must be corrected, prior to or concurrent with MACI implantation.

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

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Thromboprophylaxis should be administered according to local guidelines.

Local treatment guidelines regarding the use of antibiotic prophylaxis around orthopaedic surgery should be followed.

Due to limited experience, the use of MACI in joints other than the knee is not recommended.

MACI is shipped following a validated rapid microbial sterility assay to determine absence of microbial growth. Final sterility test results are not available at the time of shipping. If positive sterility results are obtained, the treating physician will be contacted to discuss either cancellation of the implantation or a plan of action based on the patient-specific circumstances and risk assessment.

Rehabilitation

Controlled physiotherapy, including early mobilisation, range-of-motion exercises, and partial weight- bearing is recommended as soon as possible to promote graft maturation and to reduce the risk of postoperative thromboembolic events and joint stiffness. Following implantation, the patient should follow an appropriately controlled, phased rehabilitation programme as recommended by the treating physician based on the MACI Rehabilitation Manual. This should include specified or staged physical activity in order to minimise the likelihood of arthrofibrosis and graduated partial weight-bearing. Return to sporting activity should be personalised in consultation with healthcare professionals.

Cases in which MACI cannot be supplied

While oral use of pain medication is recommended for post-surgical pain relief, intra-articular administration of analgesics is not recommended as studies have shown adverse effects on articular cartilage and chondrocytes with exposure.

4.6 Fertility, pregnancy and lactation

In some cases, it may occur that source chondrocytes of the patient are not expandable or that the release

criteria (see section 6.6) are not met due to poor biopsy quality, patient characteristics, or manufacturing

failure. Therefore, it may occur that MACI cannot be delivered.

4.5 Interaction with other medicinal products and other forms of interaction

Fibrin sealants containing formaldehyde must not be used with MACI, sinceSuspendedformaldehyde is cytotoxic to

the chondrocytes.

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Pregnancy

Limited clinical data on exposed pregnancies are available. Conventional reproductive and developmental toxicity studies are not considered relevant, given the nature and the intended clinical use of the medicinal product. Given the local nature of the medicinal product, adverse reactions of MACI on pregnancy are not anticipated. However as MACI will be implanted using invasive surgical techniques, it

is not recommended during pregnancy. MarketingBreast-feeding

There are no data on the use of MACI during breast-feeding. Given the local nature of the product, adverse reactions of MACI on the nursing infant are not anticipated. However as MACI will be implanted using invasive surgical techniques, a decision must be made whether to discontinue breast- feeding taking into account the benefits of treatment for the woman and the risk to the infant.

Fertility

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

4.7Effects on ability to drive and use machines

Due to the surgical nature of the underlying procedure, implantation with MACI has a major influence on the ability to drive and use machines. During the rehabilitation period that follows MACI treatment patients should refer to their treating physician and follow their advice.

4.8Undesirable effects

Summary of the safety profile

Based on the exposure of more than 6,000 patients to MACI treatment in the knee, complications may be related to the arthrotomy procedure, general complications related to surgical intervention, other knee pathology (such as ligamentous or meniscal pathology), or the biopsy procurement. Complications related to knee surgery in general may also include deep vein thrombosis and pulmonary embolism. Other complications have been identified as causally related to MACI. The following important risks have been identified related to either MACI or peri-operative complications:

Related to MACI:

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Symptomatic graft hypertrophy

 

Graft delamination (complete or partial, possibly leading to loose bodies in the joint or graft

 

failure)

 

Peri-operative complications related to surgical intervention of the knee:

Haemarthrosis

 

Arthrofibrosis

 

Localised surgical site inflammation

 

Localised surgical site infection

 

Thromboembolic events

 

Tabulated list of adverse reactions

Adverse reactions are listed by System Organ Class and frequency. Frequencies are defined according to

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the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

System organ class

Uncommon

Rare

 

 

 

 

 

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Infections and infestations

 

Infective arthritis

 

 

Wound infection

 

 

Localised infection

 

 

 

Musculoskeletal and

 

Arthrofibrosis

connective tissue disorders

 

Synovitis

 

 

Tendonitis

 

 

Haemarthrosis

 

 

Arthralgia

 

 

Joint effusion

 

 

Joint swelling

 

 

Joint stiffness

 

 

Bone oedema

 

 

Joint range-of-motion decreased

 

 

 

General disorders and

 

Inflammation

administration site

 

Hyperthermia

conditions

 

Pyrexia

 

 

Implant site oedema

 

 

 

Investigations

 

C-reactive protein increased

 

 

 

Injury, poisoning and

Graft delamination

Graft loss

procedural complications

Graft complication

Cartilage injury

 

Graft hypertrophy

 

Graft delamination refers toAuthorisationa loosening, either partial or total, of the graft from the subchondral bone and Marketingfrom the surrounding cartilage. A total graft delamination is a serious complication and the patient may

Description of selected adverse reactions

Graft delamination:

experience locking, pain, and swelling after an acute distortion of the knee.

Risk factors for graft delamination can include but are not limited to poor patient selection, poor adherence to recommended surgical technique, failure to address concomitant pathologies, poor compliance with the rehabilitation protocol or post-operative trauma to the knee.

Graft hypertrophy:

Symptomatic graft hypertrophy is acomplication that may occur with MACI.

Symptoms may include catching or pain. There are no known risk groups or specific risk factors for graft hypertrophy in patients treated with MACI. Patients may require debridement of the hypertrophic tissue

via arthroscopy.

Not applicable.

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.

4.9Overdose

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: Other Medicines for Disorders of the MusculoSuspended-Skeletal system, ATC code: M09AX02

proliferation and re-differentiation of seeded cells, and may result in synthesis of hyaline-like cartilage repair tissue.

MACI has been investigated in a parallel, randomised, open-label trial in 144 patients with Outerbridge Grade III or IV focal cartilage defects of the knee of 3-20 cm2 (median 4 cm2). Seventy-two patients received MACI, and 72 were treated with microfracture. The median age of patients was 34 to 35 years (age range: 18 to 54), and the mean body mass index was 26. The majority of patients had undergone at least 1 prior orthopaedic knee surgery. MACI was superior compared to microfracture regarding the improvement of pain and function according to the KOOS scale (Knee Injury and Osteoarthritis Outcome Score). See responder rates in Table 1 below.

Clinical pharmacology studiesAuthorisationhave not been conducted on MACI. Current clinical and nonclinical evidence suggests that delivery of autologous chondrocytes on the collagen membrane promotes

Four patients were treatment failures in the microfracture treatment arm, versus one in the MACI treatment arm. There were no significant differences observed in the structural markers of cartilage repair

between both treatments, as assessed by International Cartilage Repair Society (ICRS) II overall Marketingassessment histology scores of biopsies, and MRI defect fill scores.

Table 1: KOOS Response Rate*: Full Analysis Set

 

MACI

Microfracture

 

 

n (%)

N=72

N=72

p-value

 

Visit 10 (Week 104) Stratified by

 

 

 

 

 

 

centre

 

 

 

 

 

 

Responded

(87.50)

(68.06)

0.016

 

Not Responded

9 (12.50)

(27.78)

 

 

Missing

 

(4.17)

 

 

Visit 10 (Week 104) Unstratified

 

 

 

 

 

 

Responded

(86.11)

(66.67)

0.011

 

Not Responded

(9.72)

(25.00)

 

 

Missing

(4.17)

(8.33)

 

 

* KOOS Response Rate: Responder is defined as an improvement of

the Knee Injury and Osteoarthritis

 

Outcome Score from baseline of minimal 10 points of a scale of 100.

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Paediatric population

 

 

 

 

 

See section 4.2 for information on paediatric use.

The European Medicines AgencyAuthorisationhas deferred the obligation to submit the results of studies with MACI in paediatric patients from the closure of the femoral epiphyseal growth plate to less than 18 years of age.

5.2 Pharmacokinetic properties

Typical clinical pharmacokinetic (ADME) studies have not been performed on MACI. The pharmacokinetic behaviour of MACI is related to the resorption of the collagen membrane, a proteolytic process performed by cells in the vicinity of the defects. The membrane is resorbed over the months following implantation.

5.3 Preclinical safety data

Non-clinical data based on implantation of MACI in rabbits and horses did not reveal any special hazard

for humans.

MarketingNon-clinical in vitro investigations have shown that the collagen membrane is non-cytotoxic, non- mutagenic, non-reactive (short- and long-term implantation), non-sensitising, a negligible irritant, and

non-toxic (acute systemic).

A rabbit study demonstrated that at 3 months post-implantation, minimal numbers of inflammatory cells were present in the vicinity of the defect, with variable chondrogenesis. In a horse study, signs of a minor inflammatory response, characterised by a slight increase in synovial fluid volume and a mild lymphoid accumulation in the synovium, were observed at 3 months. By 6 months, these signals had subsided, resulting in a normal synovial appearance. There were no indications of gross inflammatory reaction.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Dulbecco’s Modified Eagles Medium (DMEM; Calcium Chloride anhydrous,SuspendedFerric Nitrate.9H2O, Potassium Chloride, Magnesium Sulphate anhydrous, Sodium Chloride, Sodium Bicarbonate, Potassium

Phosphate Monobasic.H2O, D-Glucose, L-Arginine.HCl, L-Cystine.2HCl, L-Glutamine, Glycine, L-Histidine.HCl.H2O, L-Isoleucine, L-Leucine, L-Lysine.HCl, L-Methionine, L-Phenylalanine, L-Serine, L-Threonine, L-Tryptophan, L-Tyrosine.2Na.2H2O, L-Valine, D-Calcium Pantothenate, Choline Chloride, Folic Acid, i-Inositol, Niacinamide, Riboflavin, Thiamine.HCl, Pyridoxine.HCl) with 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid sodium (HEPES) adjusted for pH with HCl or NaOH and osmality with NaCl.

6.2Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

6 days.

6.4 Special precautions for storage

Keep MACI in the outer carton until ready to use. Do not refrigerate or freeze. Store shipping box in an area below 37°C.

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

MACI is shipped in custom-designed, sterile, sealed, clear polystyrene dishes.

Each dish contains 1 implantation matrix, held in place by a green polycarbonate x-ring and closed with a

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green polycarbonate cover for shipment. MarketingEach dish is sealed in a gamma-irradiated clear plastic bag.

MACI is supplied in 1 to 2 dishes, which are placed into a 95kPa pouch (outer bag) with absorbent material for transport.

This package is enclosed in an outer carton insulated with ambient gel packs.

6.6 Special precautions for disposal and other handling

During the first procedure, a sample of healthy cartilage tissue (a biopsy) will be taken from the affected joint by an arthrotomy or arthroscopy.

The biopsy will be sent to the cell processing facility. At the cell processing facility, the cartilage cells will be grown aseptically in culture to expand the number of cells and placed onto a sterile CE marked porcine derived type I/III collagen membrane, to make MACI. MACI will be released following

successful results from assays which assess chondrocyte viability, identity, potency, minimum cell number, endotoxin, pre-release sterility, and mycoplasma.

with local requirements.

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MACI will be sent to the treatment facility. At this time, MACI will be implanted into the cartilage defect in the affected joint via a second procedure. The MACI implant will be secured in place using a fibrin sealant.

The timing between the removal of the biopsy and MACI implantation can vary depending on logistical factors in addition to the quality and number of cells obtained from the biopsy. The minimum amount of time is 6 weeks; however, cells can also be cryopreserved and held in storage for up to 24 months until a surgical date is established.

The surgeon will organise the date for MACI implantation in consultation with the Marketing Authorisation Holder (MAH) or its local representative. In rare cases the MAH will not be able to produce a MACI implant from the available cells. If this occurs, the surgeon will advise the patient on the best course of action.

Any unused medicinal product or waste material should be disposed of as surgical waste in accordance Please consult the Surgical Technique Manual for further information.

7.

MARKETING AUTHORISATION HOLDER

Vericel Denmark ApS

 

Amaliegade 10

 

DK-1256 Copenhagen K

 

Denmark

 

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/13/847/001

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9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 27 June 2013

10.

DATE OF REVISION OF THE TEXT

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Detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu.

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