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.

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.

5. WARNINGS AND PRECAUTIONS

5.1 Subsequent Surgical Procedures

Review of the data from the Study of the Treatment of Articular Repair (STAR) and the Registry Based Study (RBS) [see Clinical Trials Experience (6.1)] as well as the Carticel worldwide experience (adverse reactions solicited through the Cartilage Repair Registry (CRR) and spontaneous reports) as of November 21, 1997 showed that the occurrence of a subsequent surgical procedure, primarily arthroscopic, following Carticel implantation is common. In the STAR study, 49% of patients underwent a subsequent surgical procedure, irrespective of relationship to Carticel (6.2). Symptoms leading to arthroscopic intervention included catching, locking, clicking or pain. Patients who develop clinical signs of tissue hypertrophy, including catching or clicking, should be evaluated and arthroscopy may be indicated for treatment or further assessment.

5.2 Risk of Transmissible Infectious Diseases

The Carticel product is intended solely for autologous use. Patients undergoing the surgical procedures associated with Carticel are not routinely tested for transmissible infectious diseases. Therefore, the cartilage biopsy and the Carticel product may carry the risk of transmitting infectious diseases to the health care provider handling these tissues. Accordingly, health care providers should employ universal precautions in handling the biopsy samples and the Carticel product.

5.3 Pre-surgical Assessment of Comorbidities

The following conditions should be assessed and treated prior to or concurrent with implantation with Carticel:

1. Unstable meniscus tears should be repaired or resected.
2. If the patient has had a total meniscectomy, absent meniscus should be reconstructed.
3. Instability of the knee may adversely affect the success of the procedure and should be corrected. The anterior and posterior cruciate ligaments should be free of laxity as well as stable and intact. It is recommended that cruciate deficiencies be corrected.
4. Abnormal weight-distribution within the joint may adversely affect the success of the procedure and should be corrected. The tibial/femoral joint should be properly aligned. When treating trochlear defects, abnormal patellar mechanics should be assessed and corrected.

5.4 Product Safety and Sterility

The safety of the Carticel product is unknown in patients with malignancy in the area of cartilage biopsy or implant. The potential exists for in vitro expansion and subsequent implantation of malignant or dysplastic cells present in biopsy tissue. In addition, implantation of normal autologous chondrocytes could theoretically stimulate growth of malignant cells in the area of the implant, although there have been no reported incidents in humans or animals.

The Carticel product is shipped following a preliminary sterility test with a 48-hour incubation to determine absence of microbial growth. Final (14 day incubation) sterility test results are not available at the time of implantation.

3. DOSAGE FORMS AND STRENGTHS

One vial of Carticel (autologous cultured chondrocytes) contains approximately 12 million cells.

11. DESCRIPTION

Autologous cultured chondrocytes, the Carticel product, are derived from in vitro expansion of chondrocytes harvested from the patient's normal, femoral articular cartilage. Biopsies from a lesser-weight bearing area are the source of chondrocytes, which are isolated, expanded through cell culture, and implanted into articular cartilage defects beneath an autologous periosteal flap. Prior to final packaging, cell viability is assessed to be at least 80%.

Each single use container of autologous cultured chondrocytes has approximately 12 million cells aseptically processed and suspended in 0.4 mL of sterile, buffered Dulbecco's Modified Eagles Medium (DMEM). Both the biopsy transport media and the cell culture media contain gentamicin. Residual quantities of gentamicin up to 5 µg/mL may be present in the Carticel product.

12. CLINICAL PHARMACOLOGY

Hyaline cartilage forms the articular surface of the femoral condyle. Studies have shown that implantation of autologous chondrocytes into the articular defect can result in the development of hyaline-like cartilage [see Clinical Studies (14)].1,2,3,4,5 Normal hyaline cartilage consists of chondrocytes (≤ 5% total volume) and extracellular matrix (≥ 95% total volume). The matrix contains a variety of macromolecules, including type II collagen and proteoglycan. The structure of the matrix allows the hyaline cartilage to absorb shock and withstand shearing and compression forces. Normal hyaline cartilage also has an extremely low coefficient of friction at the articular surface. Damage to articular cartilage from acute or repetitive trauma often results in pain and disability. However, because hyaline cartilage is avascular, spontaneous healing of large defects is not believed to occur in humans.

A variety of surgical procedures have been used in attempts to promote repair of articular cartilage, and a few studies have evaluated the histology resulting from these interventions. Generally, procedures such as marrow stimulation techniques (MST) have been shown to produce fibrocartilage or hybrid mixtures of fibrocartilage and hyaline cartilage. Published data show that autologous chondrocyte implantation (ACI) is more likely than MST to result in hyaline-like cartilage at the repair site. 1,2,4,5 However, because of differences in study design, lesion size and concomitant patient conditions, these data are not sufficient to draw conclusions concerning the long-term correlation of histology and clinical outcomes.

15. REFERENCES

1. Knutsen G, Engebretsen L, Ludvigsen T, et al. Autologous chondrocyte implantation compared with microfracture in the knee. J Bone Joint Surg, 2004; 86A:455-464.
2. Bentley G, Biant LC, Carrington RWJ, et al. A prospective, randomized comparison of autologous chondrocyte implantation versus mosaicplasty for osteochondral defects in the knee. J Bone Joint Surg Br. 2003;85-B:223-230.
3. Brittberg M, Lindahl A, Nilsson A, et al. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med. 1994;331:889-895.
4. Peterson L, Minas T, Brittberg M, et al. Two- to 9-year outcome after autologous chondrocyte transplantation of the knee. Clin Orthop. 2000;1(374):212-234.
5. Peterson L, Brittberg M, Kiviranta I, et al. Autologous chondrocyte transplantation. Biomechanics and long-term durability. Am J Sports Med. 2002;30:2-12.
6. Peterson L, Menche D, Grande D, et al. Chondrocyte transplantation-an experimental model in the rabbit. Transactions from the 30th Annual Orthopedic Research Society, Atlanta, February 7-9, 1984. Palatine, III.:Orthopedic Research Society, 1984:218. Abstract.
7. Grande DA, Pitman MI, Peterson L, et al. The repair of experimentally produced defects in rabbit articular cartilage by autologous chondrocyte transplantation. J Orthop Res. 1989;7(2):208-18.
8. Brittberg M, Nilsson A, Lindahl A, et al. Rabbit articular cartilage defects treated with autologous cultured chondrocytes. Clin Orthop Relat Res. 1996 May;(326):270-83.
9. Breinan H, Minas T, Barone L, et al. Histological evaluation of the course of healing of canine articular cartilage defects treated with cultured autologous chondrocytes. Tiss Engin 1998; 4(1):101-14.
10. Dell'Accio F, Vanlauwe J, Bellemans, et al. Expanded phenotypically stable chondrocytes persist in the repair tissue and contribute to cartilage matrix formation and structural integration in a goat model of autologous chondrocyte implantation. Journal of Orthopaedic Research 21 2003; 21: 123–131.

17. PATIENT COUNSELING INFORMATION

Patients receiving autologous cultured chondrocytes for treatment of an articular cartilage defect should receive the following information and instructions.

• Physical activity should be resumed according to the rehabilitation plan recommended by the physician. Generally, protected weight bearing is recommended for the first 6 to 8 weeks following implantation. The patient should receive specific instructions on crutch use, ambulation and weight bearing advancement on the treated limb.
• If pain starts to develop as the next level of activity is increased, decrease activity to the former level until the pain resolves.
• If exercise causes pain and/or swelling, reduce the amount of physical activity.
• Swelling should be controlled using ice packs.
• Patient adherence to the prescribed rehabilitation program is important and activity at variance from the rehabilitation program may compromise clinical benefit from Carticel.
• At anytime during the rehabilitation process or after, if sharp pain with locking or swelling is experienced, contact the physician for medical advice.

Vericel Corporation
64 Sidney Street
Cambridge, MA 02139-4136 USA
Telephone: 800-453-6948 or 617-588-5566
Fax: 844-333-2847

Carticel® is a Registered Trademark of Vericel Corporation.

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Revision M
11/2015