Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 22 May 2017

Indication(s)

1. INDICATIONS AND USAGE Carticel® is indicated for the repair of symptomatic cartilage defects of the femoral condyle (medial, lateral or trochlea), caused by acute or repetitive trauma, in patients who have had an inadequate response to a prior arthroscopic or other surgical repair procedure (e.g., debridement, microfracture, drilling/abrasion arthroplasty, or osteochondral allograft/autograft). Carticel should be used only in conjunction with debridement, placement of a periosteal flap and rehabilitation. The independent contributions of the autologous cultured chondrocytes and other components of the therapy to outcome are unknown. Carticel is not indicated for the treatment of cartilage damage associated with generalized osteoarthritis. Carticel is not recommended for patients with total meniscectomy unless surgically reconstructed prior to or concurrent with Carticel implantation. Carticel is an autologous cellular product indicated for the repair of symptomatic cartilage defects of the femoral condyle (medial, lateral or trochlea), caused by acute or repetitive trauma, in patients who have had an inadequate response to a prior arthroscopic or other surgical repair procedure (e.g., debridement, microfracture, drilling/abrasion arthroplasty, or osteochondral allograft/autograft). (1) Carticel should be used only in conjunction with debridement, placement of a periosteal flap and rehabilitation. (1) Carticel is not indicated for: treatment of cartilage damage associated with generalized osteoarthritis. (1) patients with total meniscectomy unless surgically reconstructed prior to or concurrent with Carticel implantation. (1)

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Advisory information

contraindications
4. CONTRAINDICATIONS Carticel should not be used in patients with a known history of hypersensitivity to gentamicin, other aminoglycosides or materials of bovine origin. Gentamicin is added to both the cartilage biopsy transport media and in the culture media used during the processing of Carticel. Residual quantities of gentamicin up to 5 µg/mL are present in the Carticel product. Fetal bovine serum is a component in the culture medium used to propagate the autologous chondrocytes. Trace quantities of bovine-derived proteins may be present in the Carticel product. Do not use in patients with a known history of hypersensitivity to gentamicin, other aminoglycosides or materials of bovine origin. (4)
Adverse reactions
6. ADVERSE REACTIONS Information on the safety of implanted autologous chondrocytes is derived from the Study of the Treatment of Articular Repair (STAR) [see Clinical Studies (14) ], the Cartilage Repair Registry, the Swedish Series, and post-marketing adverse event reporting. The most common serious adverse events (> 5% of patients) derived from the STAR study include arthrofibrosis/joint adhesion, graft overgrowth, chondromalacia or chondrosis, cartilage injury, graft complication, meniscal lesion and graft delamination. Only serious adverse events were collected in this study. The most common serious adverse events (> 5% of patients), derived from the STAR study include arthrofibrosis/joint adhesions, graft overgrowth, chondromalacia or chondrosis, cartilage injury, graft complication, meniscal lesion and graft delamination. (6.2) To report SUSPECTED ADVERSE REACTIONS, contact Vericel at 1-800-453-6948 or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience The adverse reaction rates as well as the rate and type of subsequent surgical procedures from Carticel® studies of different designs cannot be directly compared amongst each other. Adverse reaction data from these studies do, however, provide a basis for identifying adverse reactions that may be related to product use and for estimating their frequency. Study of the Treatment of Articular Repair (STAR) In the STAR study [see Study of the Treatment of Articular Repair (STAR) (14.2.2) ], patients who had experienced an inadequate response to a prior cartilage repair procedure underwent Carticel implantation to the index lesion. A total of 154 patients were implanted with Carticel; 28 patients discontinued the study early. The numbers of patients completing the 24 and 48 month follow-up visits are 136 and 115, respectively. Mean patient age was 35 years at consent. The majority of patients were Caucasian (135; 88%) and male (106; 69%). Seventy-six (76) (49% of 154) patients underwent 113 subsequent surgical procedures (SSPs) on the treated knee, irrespective of relationship to Carticel, during the 4 year follow-up. Of the 76 patients, 52 patients had 1 SSP, 15 patients had 2 SSPs, and 9 patients had 3 or more SSPs. Sixty-one (61) (80%) of the 76 patients who had an SSP underwent a procedure within the first 24 months after implantation. The majority of patients, 83% (63 of the 76), underwent an arthroscopy or manipulation under anesthesia only. Table 1 shows the interventions during SSPs in > 2% of patients. Table 1: Interventions during Subsequent Surgical Procedures, Regardless of Relationship, in > 2% of Patients Intervention % of 154 Patients Debridement of Cartilage LesionIncludes debridement of index lesion and other defects 31% (47/154) Lysis of Adhesions 14% (21/154) Synovectomy / Synovial Plica Excision 12% (19/154) Other DebridementIncludes debridement of other joint structures in addition to cartilage (e.g., patellar fat pad) 10% (16/154) Chondroplasty 6% (10/154) Meniscectomy 6% (10/154) Loose Body Removal 5% (7/154) Microfracture – Index Lesion 5% (7/154) Scar Tissue Removal 5% (7/154) Release of Patellar Retinaculum 4% (6/154) Hardware Removal 4% (6/154) Microfracture – New Lesion 4% (6/154) Osteotomy 3% (5/154) Lysis of adhesions was the most frequent surgical intervention performed in the first 6 months. After 6 months, cartilage debridement was the most frequently performed intervention. In the STAR study, 61% (46/76) of patients who required an SSP after Carticel did not meet failure criteria by either modified Cincinnati score or surgical criteria (e.g., graft delamination or surgical procedure violating the subchondral bone). The most clinically significant interventions or findings involving the Carticel graft or periosteal patch are as follows: 3 Carticel grafts were completely removed and 1 was partially removed due to delamination. Partial delamination or fraying of the graft or periosteal patch was reported in 10 additional patients. Four (4) of these patients underwent reattachment/repair of the periosteal patch. Finally, a partially intact graft was found in 1 patient who was re-implanted. Detailed lists of interventions and findings that may have been associated with the graft or periosteal patch are presented in Tables 1 and 2, respectively. Table 2 shows the serious adverse events (SAEs) that occurred in ≥ 5% of patients, regardless of relationship to study treatment. Table 2: Most Frequent Serious Adverse Events (in ≥ 5% of Patients), Regardless of Relationship, in the STAR Study Serious Adverse Events % of 154 Patients Arthrofibrosis/Joint Adhesions 16% (25/154) Graft Overgrowth 15% (23/154) Chondromalacia or Chondrosis 12% (18/154) Cartilage InjuryEncompasses cartilage injuries throughout the joint e.g., onset of new defects and tibial plateau fibrillation 11% (17/154) Graft ComplicationIncludes periosteal patch complications, graft fraying or fibrillation 10% (15/154) Meniscal Lesion 8% (12/154) Graft Delamination 6% (9/154) Osteoarthritis 5% (7/154) Registry Based Study (RBS) Data from a cohort of 97 Carticel® treated patients, who were retrospectively evaluated in the Registry Based Study [see Registry-Based Study (RBS) (14.2.1) ], showed that 39% (38/97) of patients had a SSP within 3 years of which 63% (24/38) were assessed as related to Carticel. Shaving or trimming (debridement) of overgrown tissue (hypertrophic) commonly relieved patients' symptoms. In the RBS, 67% (16/24) of patients who required arthroscopy after Carticel had a good clinical benefit in terms of improved function and relief of symptoms. Table 3 shows the findings at surgery for the 38 patients who underwent a surgical procedure after Carticel. Table 3: Most Frequent Findings (in ≥ 5% of Patients) at Subsequent Surgical Procedures in the Registry Based Study Symptoms or Surgical Findings (MedDRA preferred term) % of 97 Patients Graft Overgrowth 10% (10/97) Partial Graft Delamination 8% (8/97) Chondromalacia 8% (8/97) Arthrofibrosis/Joint Adhesions 8% (8/97) Arthralgia 7% (7/97) Synovitis 6% (6/97) Meniscal Lesion 5% (5/97) Loose Body 5% (5/97) Swedish Series Of 153 patients treated with autologous cultured chondrocyte implantation in the Swedish Series [see Clinical Studies (14) ], 22% (34/153) of patients experienced the adverse reactions presented in Table 4 below. Table 4: Initial ACI Experience Swedish Series Serious Adverse Reactions (Occurring at a frequency of 1% or more) Serious Adverse Reactions % of 153 Patients Tissue Hypertrophy See below Intra-articular Adhesions 8% Superficial Wound Infection 3% Hypertrophic Synovitis 3% Post-operative Hematoma 2% Adhesions of the Bursa Suprapatellaris 2% Hypertrophic Synovium 1% About 1% of patients developed severe adhesions resulting in "frozen knee" and requiring lysis. Adverse reactions noted at a level of less than 1% included keloid-like scar, pannus formation, significant swelling of the joint, pain with post-operative fever, and hematoma following arthroscopy. In this series, arthroscopy was scheduled to be undertaken at 18 months of follow-up, regardless of patient symptoms. Of the patients who had arthroscopy, 43% (37/86) had hypertrophic tissue. Forty of the 85 patients had femoral condyle defects. Of these, 25% (10/40) of patients had some hypertrophic tissue noted at follow-up arthroscopy. Some patients had clinical symptoms that included painful crepitations or catching, and these symptoms generally resolved after arthroscopic resection of the hypertrophic tissue. Ten percent (10%) of patients with hypertrophy required additional treatment after hypertrophic tissue recurred following initial resection. Not all patients with tissue hypertrophy noted at arthroscopy were symptomatic. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Carticel®. Most of these reactions are reported voluntarily, and it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Furthermore, the reported frequency of spontaneous reports underestimates the true frequency of adverse reactions. As of July 31, 2006, approximately 12,500 patients have been implanted with Carticel and 559 patients have reported serious adverse reactions after treatment. The most frequently identified operative findings in these patients, in descending order of frequency, were graft overgrowth, graft delamination (partial or complete), arthrofibrosis, joint adhesions, meniscus lesion or tear, graft complications, chondromalacia, loose body in knee joint, and joint malalignment.

Usage information

Dosing and administration
2. DOSAGE AND ADMINISTRATION For Autologous Implantation Only For Autologous Implantation Only Carticel should be administered only by physicians who have completed Vericel's Surgeon Training Program. (2.3) Implantation of the Carticel product is performed during arthrotomy and requires both preparation of the defect bed and a periosteal flap to secure the implant. See the Carticel Surgical Manual, Vericel document #65021 for instructions on the performance of these procedures. (2.3) 2.1 Dosage Patients in the Swedish series [see Clinical Studies (14) ] received a wide range of cell doses per cm2 of defect. Available data on 70 of 78 patients with femoral condyle defects showed a median dose of 1.6 million cells/cm2 of defect. The middle 80% of these patients received from 0.64 million to 3.3 million cells/cm2. Each Carticel finished product vial contains approximately 12 million cells. Vericel provides a single vial for each defect measuring ≤ 7 cm2. Two vials of Carticel are provided for defects 7 to 14 cm2, and three vials are provided for defects > 14 cm2. This is based on Vericel's greater than 10 years of experience with Carticel. 2.2 Handling Precautions and Preparation 2.2.1 Handling Precautions The Carticel product is intended solely for autologous use. Prior to Carticel implantation, match the patient name and ID number on the certificate of analysis to the patient's chart and the patient ID on the shipping box, transport cylinder and vial. Health care providers should employ universal precautions in handling the biopsy samples and the Carticel product [see Risk of Transmissible Infectious Diseases (5.2) ]. Refer to the Indications and Usage (1) and Warnings and Precautions (5) Sections for additional considerations regarding the use of Carticel. 2.2.2 Preparation NOTE: The exterior of the Carticel vial containing the cultured cells is NOT sterile. Follow strict sterile technique protocols. When treating a defect that requires multiple vials of cells, resuspend, aspirate and inject one vial at a time. Remove red plastic lid from vial. Wipe the vial surface and lid with alcohol. Inspect vial contents for particulates, discoloration or turbidity. The cellular product appears as a yellowish clump in the bottom of the vial. Do not administer if contents appear turbid prior to cell suspension. While holding vial in a vertical position, insert the needle of the intraspinal catheter into the vial. The needle must be positioned just above the fluid level. Slowly remove the inner needle from the catheter, leaving flexible tip behind. Attach a tuberculin syringe to catheter. Lower the catheter tip into the media and position just above the cell pellet. Aspirate all the medium from the vial leaving only the cell pellet behind. Slowly expel medium back into the vial. This action will break the cell pellet and resuspend the cells in the medium. Lower the catheter tip to the base of the vial and aspirate all contents into syringe, leaving the vial empty. Slowly inject the contents into the vial again. This will assure complete suspension of the cells. Repeat these steps as needed to ensure all cells are resuspended. Cell resuspension is complete when cell particles are no longer apparent, and the medium is a consistent, "cloudy" mixture. Aspirate all contents of vial into syringe. Always hold syringe vertical to keep an air pocket at the proximal end of syringe. 2.3 Administration Implantation of the Carticel product should be restricted to physicians who have completed Vericel's Surgeon Training Program. Implantation of the Carticel® product is performed during arthrotomy and requires both preparation of the defect bed and a periosteal flap to secure the implant. Complete hemostasis must be achieved prior to periosteal fixation and cell implantation. See the Carticel Surgical Manual, Vericel document #65021 for instructions on the performance of these procedures. 2.3.1 Implantation Insert the catheter tip through the superior opening of the periosteal chamber at the site of the defect. Advance catheter to most inferior aspect of the defect. Slowly inject a cell dose while moving the catheter tip from side to side and withdrawing the catheter proximally. This will ensure an even distribution of the cells throughout the defect. Complete the implantation by closing the superior opening of the periosteum as instructed. See Carticel Surgical Manual, Vericel document #65021.
Use in special populations
8. USE IN SPECIFIC POPULATIONS Use in children or patients over age 65 has not been assessed. (8) 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of Carticel did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

More information

Category Value
Authorisation number BLA103661
Agency product number D5P3K3V822
Orphan designation No
Product NDC 69866-1025
Date Last Revised 06-02-2017
Type HUMAN PRESCRIPTION DRUG
Storage and handling 16.1 How Supplied The Carticel product, NDC 69866-1025-1, consists of viable, autologous cells packaged and labeled for implantation within specified time limits. Each vial contains approximately 12 million autologous cells for a single implantation procedure. The shipping vials containing chondrocytes are accompanied by a technical data sheet with detailed specifications for the processed cells. The vial(s) of cells is placed within secondary packaging capable of maintaining the appropriate storage temperature and cell viability for up to 72 hours.
Marketing authorisation holder Vericel Corporation