Artiss Frozen

Presentations and Pack Sizes

ARTISS Kit (Freeze-Dried) is supplied as 2 mL, 4 mL and 10 mL (total volume) pack sizes with and without the DUPLOJECT Preparation and Application System.

ARTISS Pre-filled Syringe (Frozen) is supplied as 2 mL, 4 mL and 10 mL (total volume) pack sizes with the DUO Set.

Package Contents

ARTISS Kit (Freeze-Dried)

1. Sealer Protein Concentrate (Human), Vapor Heated, Solvent/Detergent Treated, Freeze-Dried, Sterile
2. Fibrinolysis Inhibitor Solution (Synthetic), Sterile
3. Thrombin (Human), Vapor Heated, Solvent/Detergent Treated, Freeze-Dried, Sterile
4. Calcium Chloride Solution, Sterile
5. DUPLOJECT Preparation and Application System (if indicated on the carton)

ARTISS Pre-filled Syringe (Frozen)

1. (1) Sealer Protein Solution, Vapor Heated, Solvent/Detergent Treated, Sterile
2. (2) Thrombin Solution, Vapor Heated, Solvent/Detergent Treated, Sterile
3. Sterile accessory devices (DUO Set: 1 plunger, 2 joining pieces and 4 application cannulas) are included with each pre-filled syringe

The reconstituted solution or pre-filled syringe contains:

Sealer Protein Solution

Thrombin Solution

Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with ARTISS. It is also not known whether ARTISS can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Some viruses, such as parvovirus B19, are particularly difficult to remove or inactivate at this time. Parvovirus B19 most seriously affects pregnant women (fetal infection). ARTISS should be given to a pregnant woman only if deemed medically necessary.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ARTISS is administered to a lactating woman.

Pediatric Use

Thirty six pediatric subjects aged 1-16 years old were included in the prospective, randomized, controlled, evaluator-blinded, multicenter burn clinical study. There was no exclusion criterion for age. Overall, the efficacy of ARTISS was demonstrated in subjects less than or equal to 18 years old (Nineteen (13.8%) subjects were less than or equal to 6 years old, 21 (15.2%) subjects were 7 to 18 years old, and 98 (71.0%) were greater than 18 years old) [ITT] (see CLINICAL STUDIES (14)).

Geriatric Use

Clinical studies of ARTISS did not include any subjects aged 65 and over.

Mechanism of Action

Upon mixing Sealer Protein (Human) and Thrombin (Human), soluble fibrinogen is transformed into fibrin that adheres to the wound surface and to the skin graft to be affixed. Due to the low thrombin concentration, polymerization of ARTISS will take approximately 60 seconds.

Pharmacodynamics

Thrombin is a highly specific protease that transforms the fibrinogen contained in Sealer Protein (Human) into fibrin (see Pharmacokinetics (12.3)). Fibrinolysis Inhibitor, Aprotinin (Synthetic), is a polyvalent protease inhibitor that prevents premature degradation of fibrin. Free Aprotinin and its metabolites have a half-life of 30 to 60 minutes and are eliminated by the kidney. Preclinical studies with different fibrin sealant preparations simulating the fibrinolytic activity generated by extracorporeal circulation in patients during cardiovascular surgery have shown that incorporation of aprotinin in the product formulation increases resistance of the fibrin sealant clot to degradation in a fibrinolytic environment.

Pharmacokinetics

Pharmacokinetic studies were not conducted. Because ARTISS is applied only topically, systemic exposure or distribution to other organs or tissues is not expected.

Other Clinical Pharmacology Information

Viral Clearance

The manufacturing procedure for ARTISS includes processing steps designed to further reduce the risk of viral transmission. In particular, vapor heating and solvent/detergent treatment processes are included in the manufacturing of Sealer Protein Concentrate and Thrombin. Validation studies were conducted using samples drawn from manufacturing intermediates for each of the two human plasma derived components. These samples were spiked with stock virus suspensions of known titers followed by further processing under conditions equivalent to those in the respective manufacturing steps. The stock virus suspensions represent HIV, HBV, HCV, HAV and Human Parvovirus B19.

The virus reduction factors (expressed as log10) of independent manufacturing steps are shown in Table 3 for each of the viruses tested:

In addition, Human Parvovirus B19 was used to investigate the upstream Thrombin precursor mass capture step, the Sealer Protein early manufacturing steps and the Thrombin and Sealer Protein vapor heating steps. Using quantitative PCR assays, the estimated log reduction factors obtained were 1.7 and 3.4 for the Thrombin precursor mass capture step and Sealer Protein early manufacturing steps and >4 / 1.0 for the Thrombin / Sealer Protein vapor heating steps, respectively.

ARTISS was investigated for adherence of split thickness sheet skin grafts in burn patients in a prospective, randomized, controlled, evaluator- blinded, multicenter clinical study. In each of the 138 patients, two comparable test sites were identified after burn wound excision. Skin grafts were adhered at one test site using ARTISS, and at the other test site using staples (control). The study product was applied once to the wound bed of the allocated test site during skin grafting surgery.

Of the 138 treated subjects, 94 (68.1%) were male and 44 (31.9%) were female. The mean ± SD age was 30.8 ± 17.6 years; 19 (13.8%) subjects were less than or equal to 6 years old, 21 (15.2%) subjects were 7 to 18 years old, and 98 (71.0%) were greater than 18 years old. The mean ± SD estimated total body surface area (TBSA) for all burn wounds was 13.6 ± 9.2%. The mean ± SD estimated TBSA requiring skin grafting was 8.0 ± 6.9%. The mean ± SD estimated TBSA for ARTISS test sites was 1.7 ± 0.8% and for the stapled test sites was 1.7 ± 0.7%. Burn wound thickness was classified as full thickness in 106 (76.8%) of the 138 treated subjects, and partial thickness in 32 (23.2%) subjects. The mean ± SD volume applied was 2.7 ± 1.9 mL (range: 0.2 to 12.0 mL). The mean ± SD surface area treated was 166.4 ± 95.0 cm2 (range: 26.1 to 602. cm2). The mean ± SD calculated dosing volume was 1.8 ± 1.1 mL/100 cm2 (range: 0.2 to 6.0 mL/100 cm2).

The safety population contained all 138 treated subjects; however, 11 subjects did not have an available primary endpoint assessment, leaving a modified intent-to-treat (ITT) set of 127 patients. Complete wound closure by Day 28 was achieved in 43.3% of the ARTISS test sites and 37.0% of the stapled test sites in the 127 ITT patients. Rate of wound closure decreased with increasing age. Wound closure at Day 28 was complete for 72.2% of the 1-6 years old group (N=18) and 31.6% of the 7-18 years old group (N=19) [ITT]. The lower limit of the 97.5% confidence interval of the difference between ARTISS and staples was –0.029. A similar result was obtained in the per protocol (PP) population: complete wound closure by Day 28 was achieved in 45.3% of the ARTISS test sites and 39.6% of the stapled test sites in the 106 PP patients. The lower limit of the 97.5% confidence interval of the difference between ARTISS and staples was –0.041. Therefore, ARTISS was found to be non-inferior to staples in the ITT and PP populations at the 97.5% one-sided level for complete wound closure by Day 28 because the lower limit of the confidence interval of the difference between ARTISS and staples success rates was greater than the predefined limit of –0.1.