Maci - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

MACI 500,000 to 1,000,000 cells/cm2 implantation matrix

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each implant contains matrix applied characterised autologous cultured chondrocytes.

• 2.1 General description

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

Implantation matrix.

The implant is an opaque, off-white membrane, seeded with chondrocytes, supplied in 18 ml of colourless solution in a dish.

4. CLINICAL PARTICULARS4.1 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) 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.

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.

The implantation should be followed by an appropriate rehabilitation schedule (see section 4.4).

For 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.

4.4 Special warnings and precautions for use

General

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.

Precautions for use

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

In the pivotal study of MACI, patients were excluded if they had a history of osteoarthr (Kellgren-Lawrence Grade 3 or 4) in the target knee, or concomitant inflammatory dise

Meniscal pathology: unstable or torn meniscus requires r

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.

4.5 Interaction with other medicinal products and other forms of interaction

Fibrin sealants containing formaldehyde must not be used with MACI, si the chondrocytes.

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

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.

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 breastfeeding taking into account the benefits of treatment for the woman and the risk to the infant.

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

4.7 Effects on ability to drive and use machines

4.8 Undesirable effects

System organ class	Uncommon	Rare
Infections and infestations		Infective arthritis Wound infection Localised infection
Musculoskeletal and connective tissue disorders		Arthrofibrosis Synovitis Tendonitis Haemarthrosis Arthralgia Joint effusion Joint swelling Joint stiffness Bone oedema Joint range-of-motion decreased
General disorders and administration site conditions		Inflammation Hyperthermia Pyrexia Implant site oedema
Investigations		C-reactive protein increased
Injury, poisoning and procedural complications	Graft delamination Graft complication Graft hypertrophy	Graft loss Cartilage injury

Description of selected adverse reactions

Graft delamination:

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

ymptomatic graft hypertrophy is acomplication that may occur with MACI.

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

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

Not applicable.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

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

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

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 assessment histology scores of biopsies, and MRI defect fill scores.

Table 1: KOOS Response Rate*: Full Analysis Set

n (%)	MACI N=72	Microfracture N=72	p-value
Visit 10 (Week 104) Stratified by centre Responded Not Responded Missing	63 (87.50) 9 (12.50) 0	49 (68.06) 20 (27.78) 3 (4.17)	0.016 o
Visit 10 (Week 104) Unstratified Responded Not Responded Missing	62 (86.11) 7 (9.72) 3 (4.17)	48 (66.67) 18 (25.00) 6 (8.33)	0.011 _

* 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.

Paediatric population

The European Medicines Agency has 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. See section 4.2 for information on paediatric use.

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.

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Non-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 PARTICULARS6.1 List of excipients

Dulbecco’s Modified Eagles Medium (DMEM; Calcium Chloride anhydrous, Ferric 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.

6.2 Incompatibilities

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 no 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 green polycarbonate cover for shipment.

Each 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.

closed 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 y 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.

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 o 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 Marketin 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 with local requirements.

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

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 27 June 2013