HISTOACRYL AND HISTOACRYL BLUE TOPICAL SKIN ADHESIVE

P050013 · Tissue Seal, LLC · MPN · Feb 16, 2007 · General, Plastic Surgery

Device Facts

• Record ID: P050013
• Device Name: HISTOACRYL AND HISTOACRYL BLUE TOPICAL SKIN ADHESIVE
• Applicant: Tissue Seal, LLC
• Product Code: MPN · General, Plastic Surgery
• Decision Date: Feb 16, 2007
• Decision: APRL
• Regulation: 21 CFR 878.4010
• Device Class: Class 2
• Attributes: Therapeutic, Pediatric

Intended Use

Histoacryl and Histoacryl Blue topical skin adhesives are intended for topical application to hold closed easily approximated skin edges of minimum-tension wounds from clean surgical incisions and simple, thoroughly cleansed, trauma-induced lacerations. Histoacryl and Histoacryl Blue may be used in conjunction with, but not in place of, dermal sutures.

Device Story

Histoacryl/Histoacryl Blue are sterile, liquid n-butyl-2-cyanoacrylate monomer topical skin adhesives. Supplied in single-use plastic ampoules; Histoacryl Blue contains D&C Violet #2 for visualization. Applied topically by clinicians to approximate skin edges of low-tension wounds; polymerizes upon contact with water/tissue to form a bonding film. Used in clinical/emergency settings; often used alongside dermal sutures for deeper wounds. Provides non-invasive closure; reduces need for suture removal; benefits include ease of application and patient comfort. Output is a physical adhesive bond; healthcare providers monitor wound healing post-application.

Clinical Evidence

Evidence includes 11 publications and 4 primary prospective/randomized controlled trials (Amiel et al., Barnett et al., Quinn et al., Bruns et al.) involving 1,183 patients. Studies compared Histoacryl to sutures for pediatric lacerations/incisions. Primary endpoints included wound dehiscence and infection rates. Dehiscence rates ranged from 0-8.1%; infection rates 0-3.0%. Results demonstrated safety and effectiveness comparable to sutures for indicated wound types.

Technological Characteristics

Composition: n-butyl-2-cyanoacrylate monomer. Histoacryl Blue includes D&C Violet #2. Form factor: 0.5 ml single-use plastic ampoule. Polymerization: exothermic reaction triggered by water/tissue. Standards: ASTM F 2458 (wound closure strength), ASTM C633-01 (adhesion strength), ASTM D882-02 (tensile properties), ASTM D 3330 (peel adhesion). Biocompatibility: ISO 10993-1 compliant.

Indications for Use

Indicated for topical closure of clean surgical incisions and simple, thoroughly cleansed, trauma-induced lacerations with minimum skin tension. Contraindicated for internal organs, blood vessels, nerves, mucosal surfaces, mucocutaneous junctions, dense hair, eyes, high-tension areas (joints), infected/gangrenous wounds, decubitus ulcers, or patients with systemic infections, uncontrolled diabetes, or hypersensitivity to cyanoacrylate, formaldehyde, or D&C Violet #2.

Regulatory Classification

Identification

A tissue adhesive for the topical approximation of skin is a device intended for topical closure of surgical incisions, including laparoscopic incisions, and simple traumatic lacerations that have easily approximated skin edges. Tissue adhesives for the topical approximation of skin may be used in conjunction with, but not in place of, deep dermal stitches.

Special Controls

*Classification.* Class II (special controls). The special control for this device is FDA's “Class II Special Controls Guidance Document: “Tissue Adhesive for the Topical Approximation of Skin.” See § 878.1(e) of this chapter for the availability of this guidance document.(b) *Tissue adhesive for non-topical use* —(1)*Identification.* A tissue adhesive for non-topical use, including adhesives intended for use in the embolization of brain arteriovenous malformation or for use in ophthalmic surgery, is a device used for adhesion of internal tissues and vessels.(2) *Classification.* Class III (premarket approval). As of May 28, 1976, an approval under section 515 of the act is required before this device may be commercially distributed. See § 878.3 of this chapter.

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA

I. GENERAL INFORMATION

Device Generic Name: Tissue Adhesive

Device Trade Name: Histoacryl and Histoacryl Blue

Applicant: Tissue Seal LLC
5643 Plymouth Rd.
Ann Arbor MI. 48105

Premarket Approval (PMA) Application Number: P050013

Date of Panel Recommendation: None

Date of Notice of Approval to the Applicant: February 16, 2007

II. INDICATIONS FOR USE

Histoacryl and Histoacryl Blue topical skin adhesives are intended for topical application to hold closed easily approximated skin edges of minimum-tension wounds from clean surgical incisions and simple, thoroughly cleansed, trauma-induced lacerations. Histoacryl and Histoacryl Blue may be used in conjunction with, but not in place of, dermal sutures.

III. CONTRAINDICATIONS

- Histoacryl topical skin adhesive is not to be applied to below the surface of the skin, epidermis. The liquid adhesive will react exothermically with tissue; the polymerized adhesive is not absorbed by any tissues and may elicit a foreign body reaction.

- The topical skin adhesive is not to be applied to any internal organs, blood vessels, nerve tissue, mucosal surfaces or mucocutaneous junctions, areas with dense natural hair, or within the conjunctival sac of the eye.

- The topical skin adhesive is not to be applied to the surface of the eye. If the eyelids are accidentally bonded closed, release eyelashes with warm water by covering with a wet pad. The adhesive will bond to eye protein and will cause periods of weeping which will help to debond the adhesive. Keep the eye covered until debonding is complete – usually within 1 to 3 days. Do not force the eye open.

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- The topical skin adhesive is not to be applied to wounds subject to high skin tension, or on areas of increased skin tension such as the elbows, knees, or knuckles. The topical skin adhesive is not to be used in areas of skin excision.
- The topical skin adhesive is not to be applied to wounds that show evidence of infection, gangrene or wounds of decubitus etiology.
- The topical skin adhesive is not to be used on patients with known preoperative systemic infections, uncontrolled diabetes, or diseases or conditions that are known to interfere with the wound healing process.
- The topical skin adhesive is not to be used on patients with a known hypersensitivity to cyanoacrylate, formaldehyde, or the dye D&C Violet #2.

## IV. WARNINGS AND PRECAUTIONS

Warnings and precautions can be found in the Histoacryl physician’s labeling.

## V. DEVICE DESCRIPTION

Histoacryl and Histoacryl Blue are sterile liquid topical skin adhesives composed of n-butyl-2-cyanoacrylate monomer. The two products are different in only one respect: Histoacryl is provided as a colorless liquid, and Histoacryl Blue is colored with the dye D&C Violet #2 with intent to ease visualization of the device during application. Histoacryl and Histoacryl Blue topical skin adhesives are supplied in 0.5 ml single patient use plastic ampoules. Each ampoule is sealed within a plastic vial so the exterior of the ampoule can remain sterile. Both tissue adhesives remain liquid until exposed to water or water-containing substances/tissue, after which it cures (polymerizes) and forms a film that bonds to the underlying surface. All references to Histoacryl below refer to both Histoacryl (without dye) and Histoacryl Blue (with dye) unless stated otherwise.

## VI. ALTERNATE PRACTICES AND PROCEDURES

Topical skin closure can be achieved with various medical devices. Some commonly used topical skin closure devices approximate only the epidermis, for example adhesive strips and liquid adhesives; such devices typically shed from the skin in 7 to 10 days. Other commonly used topical skin closure devices approximate the epidermis and include, for example non-absorbable monofilament suture and metallic skin staples. Non-absorbable sutures and staples often are in place for approximately 7-10 days, at which time the patient returns to have the sutures removed.

## VII. MARKETING HISTORY

Histoacryl has been marketed by B. Braun outside the U.S. since 1979.

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# VIII. POTENTIAL ADVERSE EFFECTS ON HEALTH

In studies¹⁻⁴ with 1338 patients and 1492 wounds, the following adverse reactions were reported:

Table 1: Adverse Reactions¹⁻⁴

| Adverse Reactions | Amiel et al¹ | Barnett et al² | | Quinn et al³ | | Bruns et al⁴ | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | Histoacryl | Histoacryl | Sutures | Histoacryl | Sutures | Histoacryl | Sutures |
| N, patients treated | 1033 | 83 | 80 | 41 | 40 | 30 | 31 |
| N, wounds treated | 1150 | 100 | 100 | 41 | 40 | 30 | 31 |
| Dehiscence** | | | | | | | |
| Dehiscence-at Any Time | 11 (1.1%) | 0/62 | 0/40 | 3(8.1%) | 2 (5.3%) | 1 (3.0%) | 1 (3.0%) |
| Wound Edge Separation Requiring Re-Treatment | 1 | 0 | 0 | 2 | 1 | 0 | 0 |
| Infection*** | | | | | | | |
| Suspected Infection | ND | 0/62 | 2/49 (4.1%) | 1/37 (2.7%) | 1/38 (2.6%) | 1/30 (3.0%) | ND |
| Acute Inflammation | | | | | | | |
| Erythema | 57 (5.5%) | ND | ND | 1 (2.7%) | 4 (11.5%) | ND | ND |
| Edema | 5 (0.5%) | ND | ND | ND | ND | ND | ND |
| Drainage | 20 (1.9%) | ND | ND | ND | ND | ND | ND |

ND - No data reported
** Dehiscence was defined as: 1) separation of the incision that required medical attention and that almost exclusively was closed by secondary intention (i.e., Amiel et al¹) or 2) a wound coming apart by the 7 days follow up visit (i.e., Barnett et al²) or a wound requiring delayed primary closure (Quinn et al³). A prospective definition for dehiscence was not provided in Bruns et al⁴.
*** Infection was defined as: 1) a wound requiring antibiotic treatment (i.e., Amiel et al¹ and Bruns et al⁴) or 2) an area of redness around the wound with or without discharge (i.e., Barnett et al²). A prospective definition for wound infection was not provided in Quinn et al³.

- Potential Adverse Effects

Clinical experience with Histoacryl used outside the United States suggests that the following adverse events, (not reported in the above cited studies) may occur: bonding to unintended tissues, thermal discomfort during polymerization, allergic reaction, foreign body reaction, tattooing, and chronic non-healing of a wound.

# IX. NONCLINICAL STUDIES

Preclinical testing for Histoacryl examined whether it was biocompatible (Table 2), possessed adequate performance characteristics and was sufficiently stable to claim a 2 year expiration date (Tables 3 and 4).

## Biocompatibility studies

Histoacryl was tested in accordance with International Organization for Standardization (ISO) 10993-1, Biological Evaluation of Medical Devices—Part 1: Evaluation and Testing, for a surface-contacting device with a prolonged contact duration of between 24 hours and 30 days. The results of the Histoacryl biocompatibility testing are presented in Table 2.

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Table 2: Summary of Biocompatibility Tests

| Test | Results / Conclusions |
| --- | --- |
| Cytotoxicity | Serum-free media extracts of Histoacryl did not cause cell lysis or toxicity |
| Mouse Lymphoma Forward Mutation Assay | Neither polymerized Histoacryl nor serum-free media extracts of the device were mutagenic in the presence or absence of metabolic activation |
| Systemic Toxicity | Saline, alcohol, polyethylene glycol (PEG), and sesame oil extracts of Histoacryl did not cause systemic toxicity |
| ISO Maximization Sensitization | Saline extracts of Histoacryl did not cause sensitization in guinea pigs |
| Hemolysis | Saline extracts of Histoacryl did not cause hemolysis of human erythrocytes |
| Intramuscular Implantation | Implantation of polymerized Histoacryl did not cause tissue reactions or toxic effects in rabbits followed for 3 days |
| Intracutaneous Irritation | Saline, alcohol, PEG, and sesame oil extracts of Histoacryl did not cause a skin reaction or adverse effects in rabbits |

Table 3: Summary of Performance Tests

| Test | Results / Conclusions |
| --- | --- |
| Setting Time | Polymerization times of 1, 3-10 and 5-30 seconds were observed when drops of Histoacryl were placed in aqueous solutions of 1%, 0.1% and 0.01% g/l histidine, respectively. |
| Hydrolytic Degradation | A 15 day incubation of samples from two lots of polymerized Histoacryl in a 50°C saline solution resulted in 1-butanol concentrations of 232 µg and 89 µg per gram of Histoacryl. The amount of formaldehyde (another decomposition product) was below the limit of detection (i.e., 5 ppm) for both lots |
| Bond Strength | The bond strength of Histoacryl tested in accordance with American Society for Testing and Materials ASTM F 2458 Standard Test Method for Wound Closure Strength of Tissue Adhesives and Sealants (with freshly harvested porcine skin) was 21.73 Newtons (after cure times of 30 and 60 seconds) compared to 11.47 Newtons for another legally marketed tissue adhesive device. Histoacryl bond strengths of 8.24 and 9.32 Newtons were observed when shorter cure times (i.e., 35-45 and 60-67 seconds, respectively) were used |

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Table 3: Summary of Performance Tests

| Test | Results / Conclusions |
| --- | --- |
| Bond Strength Testing of Aged Material | The average bond strengths of Histoacryl samples tested in accordance with ASTM F 2458-0 and stored for 6, 12, and 24 months were 19.9, 15.5 and 14.6 Newtons, respectively |
| Dye extraction | The amount of D&C Violet #2 dye extracted from polymerized Histoacryl Blue was below the level of detection (i.e., less than 5.6 μg of dye / gram of adhesive) |
| Tensile strength | As per the ASTM C633-01 (Standard Test Method for Adhesion or Cohesion Strength of Thermal Spray Coatings) forces of 655 ± 78 lbs (Histoacryl) and 551 ± 93 lbs (another legally marketed tissue adhesive) were required to separate two ½” diameter steel rods after a 2 hour cure time |
| Adhesive Force Test | The force required to separate two pieces of lyophilized bovine pericardium glued together with Histoacryl (and cured for 75 minutes) was 105.70 ± 24.38 N |
| Overlap shear strength | The lap shear strength of Histoacryl (i.e., 34.6 lbs) tested in accordance with ASTM D882-02 (Standard Test Method for Tensile Properties of Thin Plastic Sheeting) was similar to that observed with another legally marketed tissue adhesive device (i.e., 36.91 lbs) |
| Peel adhesion strength | The peel strength of Histoacryl cured for 2 hours and tested in accordance with ASTM D 3330 (Standard Test Method for Peel Adhesion of Pressure-Sensitive Tape) was 3.5 lbs |
| Ease of Expression | A force of 1 pound was required to express Histoacryl from its packaging |
| Differential Scanning Calorimetry (DSC) | DSC analyses of Histoacryl from two lots displayed normalized cure peaks of approximately 260 J/g and 310 J/g |
| Heat of Polymerization | 33 – 76° C (57°C mean) increases in temperature were observed when 20 μl of a 0.1 g/l histidine solution was added to 50 μl of NBCA in the presence of a thermocouple |
| Antibacterial Activity | Carriers coated with polymerized Histoacryl were inoculated with approximately 10⁹ cfu/ml suspensions of P. aeruginosa, E. coli, S. aureus, M. ferrae, B. atrophaeus, C. albicans and A. niger. Test organisms were not detected on carriers after incubating for 30 seconds, 10 minutes and 1 hour |
| Shelf-life | The 24 month stability of 3 lots of Histoacryl was assessed for liquid appearance, chemical composition, adhesive strength, absence of packaging leaks and sterility |

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Table 4: Animal Studies

| Test | Results / Conclusions |
| --- | --- |
| Wound Healing in Guinea Pigs | The tensile strength associated with Histoacryl closure alone (188 ± 101 g) was significantly lower than percutaneous suture closure alone (420 ± 253 g) in a model where incisions to deep fascia were made on the backside of albino guinea pigs |
| Wound Healing in Guinea Pigs- 2 | The breaking strength of a wound closed by sutures was greater than by Histoacryl-closure on the day of treatment (day 0). After healing for 7 days the breaking strength for suture and Histoacryl-closed wounds were not significantly different |

X. CLINICAL STUDIES

While the original PMA submission included eleven publications on the clinical applications of Histoacryl, the sponsor and FDA agreed that the results from four major studies were the best reflection of product performance. The issues critical in selecting these publications included, (when possible), 1) prospectively-designed and controlled studies, 2) adverse event data collected by active monitoring of patient outcomes rather than voluntary reporting, and 3) a description of baseline demographics (e.g., age, race, wound-type), so that patients at a greater risk for the incidence, type or severity of any adverse event beyond that reported for the overall patient population could be identified. The four clinical studies best meeting these criteria are described below:

1. Amiel et al¹

A. Study Design

The study was an open-label retrospective trial designed to evaluate the safety and effectiveness of Histoacryl Blue in approximating surgical incisions at three Israeli centers.

The study population included pediatric patients undergoing elective surgical incisions (i.e., orchipexy, inguinal hernia, umbilical hernia or hydrocele repair). All incisions were 2 and 5 cm in length, closure was achieved with standard surgical techniques by attending physicians, and final cutaneous closure was performed with Histoacryl.

Patients were discharged after 4-6 hours of observation. Follow-up visits were 7 days and 4 to 8 weeks (if needed) after surgery. A 12-item questionnaire was completed during a telephone interview with a family member within 6 months after treatment.

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# B. Study Results

## Patient Accounting and Demographics

A summary of patient accounting and demographics as well as wound characteristics is presented in Table 5.

Table 5: Patient Accounting, Demographics, Wound Characteristics
Summary reported by Amiel et. al¹

| Patient Accounting | No. of pts (%) |
| --- | --- |
| Patient records reviewed | 1098 |
| Patients treated with Histoacryl | 1033 (100%) |
| Wounds treated with Histoacryl | 1150 |
| Patients completing 7 day follow-up | 905 (87.6%) |
| Patients attending 4 week follow-up | 401 (38.8%) |
| Surgical Procedure | N (%) |
| Right inguinal hernia repair | 407 (37%) |
| Left inguinal hernia repair | 199 (18%) |
| Bilateral inguinal hernia repair | 119 (11%) |
| Umbilical hernia repair | 43 (4%) |
| Hydrocele repair | 167 (15%) |
| Orchipexy | 163 (15%) |
| Patient Age | 1 mo – 16 yrs |
| Wound Characteristics | |
| Length (cm) (range) | 2 – 5 |
| Depth | ND |
| Width | ND |
| Class | ND |
| Incisions | 1150 |
| Lacerations | 0 |
| Local Anesthetic use | |
| Patients using local anesthetic | 1033 (100%) |

ND - No data reported

## Study Outcomes

The adverse reactions observed in patients are described in Table 1. 1022/1033 (98.9%) of the patients treated with Histoacryl achieved wound closure without dehiscence (i.e., separation of the incision that required medical attention).

## 2. Barnett et al.²

### A. Study Design

The study was a prospective, randomized trial designed to compare the safety and effectiveness of Histoacryl Blue and sutures in closing simple pediatric lacerations in an emergency room setting at three facilities in Australia and New Zealand.

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Patients between the ages of 4 -12 years were enrolled if they had a clean laceration on any part of the body that was less than 5 cm in length. Patients were excluded if the wound occurred on the eyelid, mucous membrane or a joint margins (i.e. under any added tension) or if the wound required debridement or plastic surgery.

Patients were assessed after wound closure and at 1 week, 3 and 12 months after treatment.

## B. Study Results

### Patient Accounting and Demographics

A summary of patient accounting and demographics as well as wound characteristics is presented in Table 6.

Table 6: Patient Accounting, Baseline Demographics and Wound Characteristics Reported in Barnett et al²

| | Histoacryl Blue | Control Sutures |
| --- | --- | --- |
| Patient Accounting | | |
| N, patients enrolled | 83 | 80 |
| N, patients treated | 83 | 80 |
| Patients completed: 1 week | 62 (74.6%) | 49 (61.2%) |
| 90 days | 46 (55.0%) | 44 (55.0%) |
| 12 months | 36 (43.0%) | 34 (43.0%) |
| Patient Demographics | | |
| Mean Age in months (standard deviation) | 69.5 (29) | 68.4 (30) |
| Males | 48 (57.8%) | 68 (85%) |
| Wound Characteristics | | |
| Length in cm (mean) | 1.54 | 1.68 |
| Depth in cm (mean) | ND | ND |
| Width in cm (mean) | 0.34 | 0.28 |
| Wound Class: Clean | 83 (100%) | 80 (100%) |
| Incisions | 0 | 0 |
| Lacerations | 83 (100%) | 80 (100%) |
| Face | 49 | 64 |
| Scalp | 39 | 29 |
| Other | 16 | 7 |
| Use of Anesthesia | | |
| General | 0 | 0 |
| Local only | 0 | 80 (100%) |
| None | 83 (100%) | 0 |

ND – No data reported

### Study Outcomes

The adverse reactions observed in patients are described in Table 1. Closure of all wounds was achieved in both treatment groups without dehiscence (i.e., a wound that came apart by the 7 day follow up visit).

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# 3. Quinn et al³

## A. Study Design

This study was a prospective, randomized controlled trial comparing closure of pediatric facial lacerations with Histoacryl Blue and sutures in a single Canadian Emergency room facility.

Patients, under the age of 18, with clean facial lacerations less than 4 cm in length and 0.5 cm in width were eligible for enrollment. Patients with wounds requiring deep layer closure, caused by animal bites, lacerations on hair-bearing surface, crossing mucocutaneous junctions or heavily soiled and requiring debridement were excluded from enrollment.

Patients were evaluated immediately after treatment as well as 5 days and 3 months after wound approximation.

## B. Study Results

### Patient Accounting and Demographics

A summary of patient accounting and demographics as well as wound characteristics are presented in Table 7.

Table 7: Summary of Patient Accounting, Baseline Demographics and Wound Characteristics Reported by Quinn³ et al.

| | Histoacryl Blue | Control Sutures |
| --- | --- | --- |
| Patient Accounting | | |
| N, patients enrolled | 41 | 40 |
| N, patients treated | 37 | 38 |
| Patients completed: 90 days | 33 (89.1%) | 36 (94.7%) |
| Patient Demographics | | |
| Age (years) | 0.7-16 | 0.5-15 |
| Mean (years) | 4.7 | 4.5 |
| Sex (Male) | 58% | 42% |
| Wound Characteristics | | |
| Length in cm (mean) | 1.53 | 1.52 |
| Depth | ND | ND |
| Width | ND | ND |
| Wound Class: | ND | ND |
| Incisions | 0 | 0 |
| Lacerations (Facial) | 37 (100%) | 38 (100%) |
| Use of Anaesthesia | | |
| General | 0 | 0 |
| Local only | 0 | 38 (100%) |
| None | 37(100%) | 0 |

ND – No data reported

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# Study Outcomes

The adverse reactions observed in patients are described in Table 1. Wound closure without dehiscence (i.e., wounds requiring delayed primary closure) was achieved in 34/37 (91.9%) of the Histoacryl and 36/38 (94.7%) of the suture-treated patients.

## 4. Bruns et al⁴

### A. Study Design

This study was a prospective, randomized trial comparing closure of pediatric lacerations with Histoacryl Blue and sutures at three emergency rooms within the U.S. All lacerations received routine wound management and lacerations greater than 5 mm in depth were initially repaired with subcutaneous sutures. Patients were then randomized to final cutaneous closure by either Histoacryl or suture.

Patients between the ages of 1 – 18 years old with lacerations less than 5 cm were enrolled. Wounds requiring the use of subcutaneous sutures were enrolled in this study. Patients with lacerations in areas of high skin mobility or tension (e.g., joints, hands, feet, eyelids, ears, nose, mouth or perineum) were excluded from the study as were lacerations caused by dog bites or extending to the muscle or bone.

Patients were evaluated after wound closure and at 1 week and 2 months after treatment.

### B. Study Results

#### Patient Accounting and Demographics

A summary of patient accounting and demographics as well as wound characteristics is presented in Table 8.

Table 8: Summary of Patient Accounting, Baseline Demographics and Wound Characteristics Reported by Bruns et al⁴

| | Histoacryl | Sutures |
| --- | --- | --- |
| Patient Accounting | | |
| N, patients treated | 30 | 31 |
| N, wounds treated | 30 | 31 |
| Attending 2 month visit | 30 | 25 |
| Baseline Demographics | | |
| Median Age | 4 years | 3 years |
| Gender (Male) | 24 (80) | 25 (80) |
| Race | | |
| White | 14 (47) | 19 (61) |
| Black | 16 (53) | 12 (39) |
| Wound Characteristics | | |
| Length in cm (median) | 1.5 | 1.5 |
| Depth < 5 mm | 22 (73%) | 22 (71%) |
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| | Histoacryl | Sutures |
| --- | --- | --- |
| > 5 mm | 8 (27%) | 9 (29%) |
| Width | ND | ND |
| Wound Class: | ND | ND |
| Incisions | 0 | 0 |
| Lacerations (Facial) | 37 (100%) | 38 (100%) |
| Local Anesthetic used | | |
| Patients treated with anesthetic | 13/30 (43%) | 31/31 (100%) |

ND – No data reported

## Study Outcomes

The adverse reactions observed in patients after surgery are described in Table 1. Wound closure without dehiscence (i.e., no prospective definition was provided) was achieved in 29/30 (96.7%) of the Histoacryl and 30/31 (96.8%) of the suture-treated patients.

## XI. CONCLUSIONS DRAWN FROM THE STUDIES

The chemical structures and anticipated clinical performance of Histoacryl and Histoacryl Blue are sufficiently similar, so that the preclinical and clinical data collected with Histoacryl Blue may be used in support of approval of Histoacryl without D&amp;C Violet Dye #2.

Preclinical testing of Histoacryl demonstrated that the device is biocompatible, displays adequate performance characteristics, and was sufficiently stable to claim a 2 year expiration date.

The 11 publications submitted in this PMA document the safe and effective use of Histoacryl in approximating the skin edges associated with minimum-tension wounds from clean surgical incisions and simple, thoroughly cleansed, trauma-induced lacerations in 6452 patients.

Based upon the criteria of: 1) prospectively-designed and controlled studies (when possible), 2) adverse event data collected by active monitoring of patient outcomes rather than voluntary reporting, and 3) a description of baseline demographics (e.g., age, race, wound-type), FDA and the sponsor selected four publications that describe the treatment of 1183 patients over a 5 year period, for preparing the product label. In these studies skin edge approximation was achieved in almost every simple, thoroughly cleansed, minimum-tension surgical incision and lacerations wound, (as long as Histoacryl was used in conjunction with, but not in place of, dermal sutures). Similarly, the incidence of wound dehiscence (i.e., a range of 0-8.1%), infection (i.e., a range 0-3.0%), redness/tenderness, (i.e., range 0-5.5%), swelling (0-0.5%) and fever (0-0.1%) were consistently low in each study and similar in incidence to wounds closed with sutures.

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While the publications submitted in this PMA described the impact of Histoacryl use on scar appearance, time to wound closure, and level of pain associated with wound closure, FDA does not believe that these data meet the definition of valid scientific evidence presented in 21 CFR 860.7. This determination was based on the subjective nature of each claim and the inability of FDA to review individual patient outcomes. Because wound healing is a complex process, several different issues can alter the final outcome (e.g., underlying disease, wound bed preparation methods and patient compliance with post-treatment care), evaluating individual patient conditions is important when attempting to correlate wound outcome with Histoacryl use.

## XII. PANEL RECOMMENDATION

In accordance with the provisions of section 515c(2) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the General and Plastic Surgery Devices Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel.

## XIII. FDA DECISION

FDA issued an approval order on February 16, 2007

The applicant’s manufacturing facility was inspected and was found to be in compliance with the Quality System Regulation (21 CFR 820).

## XIV. APPROVAL SPECIFICATIONS

Directions for Use: See product labeling.

Hazard to Health from Use of the Device: See Indications, Contraindications, Warnings, Precautions, and Adverse Reactions in the labeling.

Postapproval Requirement and Restrictions: See the approval order.

## XV. REFERENCES

1. G.E. Amiel, I. Sukhotnik, B. Kawar, and L. Siplovich, "Use of N-butyl-2-cyanoacrylate in elective surgical incisions—long-term outcomes," J. Am. Coll. Surg. Jul;189(1): 21-5 (1999)

2. P. Barnett, F.C. Jarman, J. Goodge, G. Silk, and R. Aickin. "Randomized trial of Histoacryl blue tissue adhesive glue versus suturing in the repair of pediatric lacerations," J. Paediatr. Child Health 34, 548-550 (1998)

3. J.V. Quinn, A. Drzewiecki, M.M. Li, I.G. Stiell, T. Sutcliffe, T.J. Elmslie, and W.E. Wood, "A randomized, controlled trial comparing a tissue adhesive with suturing in the repair of pediatric facial lacerations," Ann. Emerg. Med. Jul;22(7):1130-5 (1993)

4. T.B. Bruns, H.K. Simon, D.J. McLario, K.M. Sullivan, R.J. Wood, and K.J.S. Anand, "Laceration Repair Using a Tissue Adhesive in a Children’s Emergency Department," Pediatrics, 98: 673-675 (1996)

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