MACI Implantation matrix Ref.[50008] Active ingredients: Autologous chondrocytes

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 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 concurrent with implantation of MACI. These include:

• 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 surgical haemorrhage control. The patient’s haemostatic functions should be screened prior to surgery. 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 weightbearing 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

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.

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

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.

Breast-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 breastfeeding 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.

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.

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:

• 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 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).

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

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.

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.

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