1.1 Sensory Nerve Discontinuity (≤25 mm)

AVANCE is indicated for the treatment of adult and pediatric patients aged one month and older with sensory nerve discontinuity ≤25 mm.

1.2 Sensory Nerve Discontinuity (>25 mm)

AVANCE is indicated for the treatment of adult and pediatric patients aged one month and older with peripheral sensory nerve discontinuity >25 mm.

This indication is approved under accelerated approval based on improvement in static two-point discrimination (s2PD) at 12 months in sensory nerve gaps ≤ 25 mm, which provided empirical evidence to reasonably predict clinical benefit given similarities in pathophysiology and anticipated therapeutic effects. [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory clinical trials.

1.3 Mixed and Motor Nerve Discontinuity

AVANCE is indicated for the treatment of adult and pediatric patients aged one month and older with mixed and motor nerve discontinuity.

This indication is approved under accelerated approval based on improvement in s2PD at 12 months in sensory nerve gaps, which provided empirical evidence to reasonably predict clinical benefit given similarities in pathophysiology and anticipated therapeutic effects. [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial.

2.1 Recommended Dose

AVANCE is intended for surgical implantation.

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The recommended number of AVANCE required is based on the nerve deficits identified for repair.

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AVANCE may be trimmed to accommodate the size of the deficits. Each AVANCE is intended for implantation in a single patient only.

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AVANCE is available in 16 size combinations of different lengths and diameters to fit the size and diameter of the nerve(s) to be treated. Healthcare professionals should carefully assess the length and diameter of the nerve deficit(s) to be treated to determine the most suitable quantity and sizes of AVANCE required for treatment. [see Dosage and Administration (2.3)]. 

Refer to Table 1 for the available sizes of AVANCE:

2.2 Preparation

Receipt and Storage of AVANCE:

AVANCE is shipped on dry ice in validated insulated shipping containers. AVANCE must remain frozen at ≤-40°C (≤-40°F) and be kept frozen until use. For a complete description of the AVANCE packaging configuration and storage conditions, [see How Supplied/Storage and Handling (16)].

AVANCE is to be prepared in an appropriate surgical environment.

Supplies:

The following supplies are not included but are needed for preparation:

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Room temperature sterile normal saline or sterile Lactated Ringer’s solution (LRS).

Preparation Instructions:

Following standard surgical site preparation for exposure, mobilization, and trimming of the peripheral nerve to be treated, determine the size and/or number of AVANCE that need to be thawed. [see Dosage and Administration (2.3)].

The following instructions are for preparing one AVANCE. Two team members (one sterile field team member and one team member outside the sterile field) are required.

If two or more AVANCE are required, prepare them individually. AVANCE thawing should take approximately 6 minutes.

1.

The team member outside the sterile field removes the desired AVANCE from the freezer and transports it to the operating room.

2.

The team member outside the sterile field removes the zip top bag and opens and removes the carton.

3.

The team member outside the sterile field peels open the seal of the outer foil-poly pouch and aseptically presents the inner Tyvek®-poly pouch to the sterile field team member for placement in the sterile field. The sterile field team member aseptically removes the inner Tyvek-poly pouch presented by the team member outside the sterile field from the inside of the outer foil-poly pouch and places it in the sterile field.

4.

In the sterile field, the sterile field team member peels open the inner Tyvek-poly pouch and removes the clamshell tray.

5.

The sterile field team member opens the clamshell tray and fills the pre-molded thawing reservoir with room temperature sterile normal saline or sterile LRS (Figure 1). Do not heat AVANCE or add heated saline or LRS to the graft.

Figure 1: Thawing AVANCE with sterile saline or LRS.

Figure 1: Thawing AVANCE with sterile saline or LRS.

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Do not implant a partially or fully frozen product. Allow AVANCE to thaw completely before use, which will take approximately 6 minutes. AVANCE must be thawed until it reaches room temperature without heating. Once thawed, AVANCE must be either implanted or discarded within 12 hours.

2.3 Administration

AVANCE is implanted in appropriate sterile conditions by a trained licensed physician. Follow the steps below for surgical implantation of AVANCE:

1.

Prior to implanting AVANCE, it is important to trim back the nerve to be repaired until healthy nerve tissue is reached. Healthy nerve tissue can be identified by pouching fascicles and punctate bleeding.

2.

After trimming, if applicable, place the extremity in extension and measure the deficit as well as the diameter of the nerve to be repaired.

3.

Select an AVANCE of an appropriate length that ensures there will be no tension on the graft when implanted and of a diameter that most closely approximates the nerve to be repaired. AVANCE may be trimmed to accommodate the size of the deficits.

4.

When handling AVANCE, only hold it by the outermost epineurium and avoid crimping or crushing the graft.

5.

Coaptation can be achieved by multiple methods. Surgical methods should be tailored to the type of injury and goals of reconstruction, as well as body region, nerve type, and size of discontinuity. One method is to use appropriately sized non-absorbable sutures such as 8-‑0 or 9-0, which should be placed only through the epineurium of the nerve. Either end of AVANCE can be coapted to the proximal nerve to be repaired.

6.

To bridge the defect, secure the sutures, ensuring that they are not overtightened. The nerve being repaired and AVANCE should be lightly touching, but they should not overlap.

5.1 Procedural Complications

Procedural complications have occurred with the AVANCE implantation procedure and have included pain, hyperesthesia, infection, implant site swelling, adhesions, hypertrophic scar formation, impaired motor or sensory function, bleeding, and neuroma formation [see Adverse Reactions (6)]. Additional procedural complications may include risk of bleeding and complications related to anesthesia. Monitor patients for procedural complications with AVANCE implantation and manage accordingly.

5.2 Transmission of Infectious Diseases

Transmission of infectious diseases or agents may occur with AVANCE administration, as it is manufactured using tissues from human cadaveric donors. Donors are screened and tested for Human Immune-deficiency Virus 1 (HIV-1); Human Immune-deficiency Virus 2 (HIV-2); Hepatitis B Virus (HBV); Hepatitis C Virus (HCV); and Syphilis (Treponema pallidum). Additional testing for Human T-cell Leukemia-lymphoma Virus 1 (HTLV-1) and Human T-cell Leukemia-lymphoma Virus 2 (HTLV-2) may be performed as required by local regulatory authorities in US states. Only screening was performed for Creutzfeldt-Jakob disease (CJD). These measures do not eliminate the risk of transmitting these or other infectious diseases or agents.

All infections thought to be transmitted by AVANCE should be reported to Axogen Corporation at 1‑888-296-4361.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice.

The safety database described in this section reflects exposure to AVANCE in the RECON Study. A total of 112 patients received AVANCE and 108 patients received NeuraGen® (bovine nerve cuff) and were followed for a duration of 12 months. [see Clinical Studies (14)].

A serious adverse reaction occurred in 1 patient, which was wound dehiscence.

Table 2 lists the most common adverse reactions that occurred in ≥ 2% of patients in the RECON Study.

Other clinically significant adverse reactions that occurred in <2% of patients in AVANCE group include: implant site swelling (n=2), paraesthesia (n=2), hypertrophic scar (n=2), pyogenic granuloma (n=2), grade 3 neuroma (n=1), wound dehiscence (n=1), tendon adhesion (n=1), implant site nodule (n=1), osteomyelitis (n=1), and dermal cyst (n=1).

6.2 Postmarketing Experience

Adverse Reactions from Observational Studies

The safety of AVANCE was evaluated in an ongoing, multicenter, observational registry study in patients undergoing nerve repair. The registry assessed repairs using the Medical Research Council Classification (MRCC) across nerve types (sensory, motor, and mixed), gap lengths (5–210 mm), and body regions (upper extremity, head and neck, torso including breast, and lower extremity).

Adverse reactions reported in the study include neuroma, seromas, implant site infection, tissue necrosis, nerve regeneration failure, hyperesthesia, hypoesthesia, AVANCE implantation error, and hematoma.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of AVANCE have been established in pediatric patients aged one month and older. The use of AVANCE in pediatric patients for the treatment of nerve discontinuity was supported by extrapolation of adult data from the RECON Study. [see Clinical Studies (14)].

8.5 Geriatric Use

There were 8 patients (4%) who were 65 years of age and older in the RECON Study. Clinical studies of AVANCE did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger subjects.

12.1 Mechanism of Action

AVANCE is an acellular nerve scaffold intended to restore nerve function in the distal tissue.

AVANCE provides structural and biochemical cues for axonal regeneration. The structural cue is provided by the intact endoneurial tubes. The biochemical cue is provided by the basement membrane proteins of the endoneurial tubes. The basement membrane of the endoneurial tubes includes many proteins, such as collagen, laminin, fibronectin, and proteoglycans. The laminin lining the endoneurial tubes of AVANCE has been shown in in vitro assays and animal studies to be bioactive by supporting Schwann cell migration, axon growth cone interactions, and neurite extension. Without the specific bioactive laminin composition, the neuroregenerative capacity is hindered. However, the exact mechanism of action is unknown.

12.2 Pharmacodynamics

The pharmacodynamic effects of AVANCE are not known.

12.3 Pharmacokinetics

The pharmacokinetic effects of AVANCE are not known.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Conventional carcinogenicity and reproductive and developmental toxicity studies have not been conducted. Results from an in vitro bacterial reverse mutation assay demonstrated that AVANCE extracts are non-mutagenic.

16.1 How Supplied

AVANCE is shipped on dry ice and supplied frozen, as a single, intact graft of varying color from white, off-white, pink, pale pink, and yellow to pale yellow. Do not use if broken or otherwise compromised.

AVANCE is sterile packaged. The immediate container closure system consists of a clamshell (thermoformed tray) within two pouches, a sealed Tyvek-poly pouch within a foil-poly pouch. The foil-poly pouch is the sterile barrier for AVANCE. The immediate container closure system is packaged in a commercial carton, which is sealed with a Carton Seal Tape and placed in a zip top bag for freezer storage protection, see Figure 2.

Figure 2: AVANCE Packaging.

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AVANCE is available in the following lengths and diameters (Table 4):

16.2 Storage and Handling

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Ensure the shipping container was received by the date indicated on the shipping container label and that sufficient dry ice is present within the shipping container. The amount of dry ice present within the shipping container can be assessed by the overall shipping container weight. The overall shipping container weight should be at least 12.0 lbs. for the 48-hour shipping container, 15.0 lbs. for the 72-hour shipping container, and 21.0 lbs. for the 120-hour shipping container.

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Store AVANCE at ≤-40°C (≤-40°F) and keep frozen until use.

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Do not use AVANCE if any component of the immediate container closure system or commercial carton has been compromised.

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Thaw AVANCE to room temperature without heating using room temperature sterile normal saline or Lactated Ringer’s Solution (LRS). Do not implant a partially or fully frozen product. Once thawed, it should not be placed back into the freezer. Thawed AVANCE must be implanted or discarded within 12 hours.

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Do not use if the lot number on the outer foil-poly pouch does not match the lot number on the outer carton.

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Any expired or thawed AVANCE that is not used in a surgical procedure should be destroyed in accordance with local, state, and federal or country regulations for disposal of human tissue.

Contact Axogen Customer Care at 888-296-4361 for any issues with the condition of the packaging or graft, or for further instructions.