GINTUIT - allogeneic cultured keratinocytes and fibroblasts in bovine collagen cellular sheet
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use GINTUIT safely and effectively. See full prescribing information for GINTUIT.
GINTUIT (Allogeneic Cultured Keratinocytes and Fibroblasts in Bovine Collagen)
Cellular Sheet for Topical Oral Application
Initial U.S. Approval: 2012
INDICATIONS AND USAGE
GINTUIT (Allogeneic Cultured Keratinocytes and Fibroblasts in Bovine Collagen) is an allogeneic cellularized scaffold product indicated for topical (non-submerged) application to a surgically created vascular wound bed in the treatment of mucogingival conditions in adults. (1)
GINTUIT is not intended to provide root coverage. (1)
DOSAGE AND ADMINISTRATION
For topical application in the oral cavity only
GINTUIT is used as one application over a surgically created vascular wound bed in the oral cavity. The size of GINTUIT is adjusted for the size of the wound bed. (2.1)
For single patient use only.
DOSAGE FORMS AND STRENGTHS
GINTUIT is available as a ready-to-use circular cellular sheet, 75 millimeter (mm) in diameter and approximately 0.75 mm thick, consisting of human keratinocyte and fibroblast cells, human extracellular matrix proteins, and bovine collagen. Approximately 4 million cells are initially used to manufacture the product. (3)
GINTUIT is contraindicated for use on clinically infected wounds and in patients with known allergies to bovine collagen or hypersensitivity to the components of the gel medium (agarose). (4)
WARNINGS AND PRECAUTIONS
The most common adverse reactions observed in the clinical trials (≥1%) included sinusitis, nasopharyngitis, respiratory tract infection, aphthous stomatitis, and the local effects of oral surgery. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Organogenesis Inc. at 1-888-943-8235 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Topical cytotoxic antiseptics can degrade GINTUIT.
Exposure to topical cytotoxic antibiotics reduces GINTUIT cell viability. (7)
USE IN SPECIFIC POPULATIONS
Pregnancy: No human or animal data are available. Use only if clearly needed. (8)
See 17 for PATIENT COUNSELING INFORMATION.
FULL PRESCRIBING INFORMATION: CONTENTS*
GINTUIT (Allogeneic Cultured Keratinocytes and Fibroblasts in Bovine Collagen) is an allogeneic cellularized scaffold product indicated for topical (non-submerged) application to a surgically created vascular wound bed in the treatment of mucogingival conditions in adults.
GINTUIT is not intended to provide root coverage.
For topical application in the oral cavity only
For single patient use only.
GINTUIT is used as one application over a surgically created vascular wound bed in the oral cavity. The size of GINTUIT is adjusted for the size of the wound bed.
The safety and efficacy of repeat application(s) of GINTUIT have not been established.
Preparation of the Surgical Site
Following local anesthesia, surgically create a vascular wound bed with viable wound edges and establish adequate hemostasis.
Preparation of GINTUIT
GINTUIT is available as a circular cellular sheet, 75 millimeters (mm) in diameter and approximately 0.75 mm thick, consisting of human keratinocyte and fibroblast cells, human extracellular matrix proteins, and bovine collagen. Approximately 4 million cells are initially used to manufacture the product.
GINTUIT is stored on a semi-permeable polycarbonate base within a plastic insert, which separates the product from an agarose gel medium in a sterile transparent shipping tray.
There is a potential for hypersensitivity reactions to occur with GINTUIT.
Monitor for both early and later signs of hypersensitivity reaction following GINTUIT application. Evaluate and treat signs and symptoms of potential allergic reactions according to standard practice. If necessary, remove GINTUIT as part of the treatment for the allergic reaction.
Monitor for signs and symptoms of wound infection. Signs of surgical site infection may include pain, edema, erythema, drainage, odor, warmth, or fever. The diagnosis of wound infection may be complicated by the white or yellow appearance of GINTUIT after it becomes hydrated with wound fluid.
The safety of this product for oral administration has not been evaluated beyond six months. The long-term potential for oral mucosal cancers to arise from, or in response to, this product is unknown.
Transmission of infectious diseases by known or unknown infectious agents may occur with GINTUIT.
GINTUIT contains cells derived from donated human newborn foreskin tissue. The foreskin donor’s mother was tested and found negative for human pathogens, including antibodies to human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2), human T-lymphotropic virus types 1 and 2 (HTLV-1 and HTLV-2), hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), West Nile virus (WNV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and syphilis. GINTUIT cells are tested for human and animal viruses, retroviruses, bacteria, fungi, yeast, and mycoplasma.
Product manufacture also includes reagents derived from animal materials, including bovine pituitary extract (BPE). All animal-derived reagents are tested for viruses, retroviruses, bacteria, fungi, yeast, and mycoplasma before use. Bovine materials are sourced to minimize bovine spongiform encephalopathy (BSE), the cause of a rare fatal condition in humans called variant Creutzfeldt-Jakob disease (vCJD). vCJD has never been attributed to use of any medical product manufactured with BPE, but the theoretical possibility cannot be dismissed.
These measures do not totally eliminate the risk of transmitting these or other transmissible infectious diseases and disease agents. Report the occurrence of a transmitted infection to Organogenesis Inc. at 1-888-943-8235.
GINTUIT is shipped after passing primary test results from in-process microbial tests. A final sterility test is initiated prior to shipping, but the result will not be available for up to 14 days. If microbial contamination is detected after the product has been shipped, Organogenesis will notify health care providers and recommend appropriate actions.
The most common adverse reactions observed in the clinical trials (≥1%) included sinusitis, nasopharyngitis, respiratory tract infections, aphthous stomatitis, and the local effects of oral surgery.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of GINTUIT cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in clinical practice.
GINTUIT has been studied in two randomized, within-subject controlled (i.e., each subject received both GINTUIT and control treatment) clinical studies. The control treatment was a free gingival graft (FGG), using donor graft tissue from the subject’s palate. The duration of the studies was six months following GINTUIT application. Study One was a single-center study (n=25) to evaluate the safety and efficacy of GINTUIT in establishing a zone of attached gingiva. Study Two was a multicenter study (n=96) to evaluate the safety and efficacy of GINTUIT in establishing keratinized tissue (KT) in a similar study population.
Overall, 34% of subjects reported at least one adverse reaction. Table 1 lists all reported adverse reactions that occurred at an incidence of 1% or greater.
|Reported Adverse Reaction (MedDRA Preferred Term)||Subject
|Respiratory Tract Infection||2 (2%)||2|
|Upper Respiratory Tract Infection||2 (2%)||2|
|Aphthous Stomatitis||2 (2%)||2|
|Oral Pain||2 (2%)||2|
|Mouth Injury||2 (2%)||2|
|Hypoaesthesia Facial||2 (2%)||2|
|* Study One (n=25); Study Two (n=96)|
In Studies One and Two, local (occurring at the site of GINTUIT application) adverse reactions included gingival pain, gingival injury (due to inadvertent failure to remove a polycarbonate base from GINTUIT before application), and ulceration.
In another study (n=15), in which the placement of GINTUIT was under a mucosal flap, local (occurring at the site of GINTUIT application) adverse reactions included impaired healing and suture-related complications.
The safety of GINTUIT beyond six months was not evaluated in the clinical trials.
GINTUIT is manufactured using a similar process as Apligraf, an FDA-approved medical device. Localized allergic reaction, skin inflammation and erosion, skin blistering, localized wound infection, and cellulitis have been reported during post-approval use of Apligraf for the treatment of chronic cutaneous wounds. Because these reactions are reported voluntarily by a population of uncertain size, and because there are no controls, it is not possible to determine their frequency in the exposed population or establish a causal relationship to exposure to Apligraf. It is uncertain whether information obtained from the postmarketing safety database from use of Apligraf in chronic cutaneous wounds can be extrapolated to use of GINTUIT in the oral environment.
Exposure to topical antiseptics, such as povidone-iodine solution and chlorhexidine (concentrations greater than 0.12%), has been shown to degrade GINTUIT during in vitro and in vivo histological studies.
Exposure to topical antibiotics such as polymyxin/nystatin also reduces GINTUIT cell viability.
If cytotoxic topical antiseptics or antibiotics, including those listed above, have been used, then irrigate the wound thoroughly with saline and allow a suitable wash-out period to elapse before applying GINTUIT.
Pregnancy Category C. Animal reproduction studies have not been conducted with GINTUIT. It is also unknown whether GINTUIT can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. GINTUIT should be used in a pregnant woman only if clearly needed.
The safety and efficacy of GINTUIT in infants and children have not been established.
GINTUIT, Allogeneic Cultured Keratinocytes and Fibroblasts in Bovine Collagen, is a cellular sheet that contains allogeneic human cells, human extracellular matrix proteins, and bovine collagen for topical application in the oral cavity. GINTUIT appears off-white in color and is comprised of two main layers: an upper cornified layer formed by keratinocytes, and a lower layer constructed of bovine-derived collagen, human extracellular matrix proteins, and dermal fibroblasts. These components interact and produce the final bilayered structure. GINTUIT does not contain Langerhans cells, melanocytes, macrophages, lymphocytes, blood vessels, or hair follicles.
The active ingredients of GINTUIT are the allogeneic keratinocytes, allogeneic dermal fibroblasts, and bovine Type I collagen. In vitro studies have shown that GINTUIT secretes human growth factors and cytokines, and contains extracellular matrix proteins. Growth factors, cytokines, and extracellular matrix proteins are known to be involved in wound repair and regeneration.
The cells are isolated from donated human newborn foreskin tissue and are multiplied into cell banks used in large-scale manufacturing. The donor’s mother is tested and found negative for human pathogens, and the cell banks are extensively tested for microbiological safety [See Warnings and Precautions (5.4)].
Product manufacture also uses reagents derived from animal materials including bovine collagen and bovine pituitary extract (BPE). These reagents are tested for viruses, retroviruses, bacteria, fungi, yeast, and mycoplasma before use.
GINTUIT is shipped in an agarose gel medium to maintain product potency and therefore may contain low amounts of inactive components present from the media. These include agarose Type IV HI EEO, L-glutamine, hydrocortisone, full-chain human recombinant insulin, ethanolamine, O-phosphorylethanolamine, adenine, selenious acid, Dulbecco’s Modified Eagle Medium (DMEM) nutrients, Ham’s F-12 nutrients, sodium bicarbonate, calcium chloride, and water for injection.
A final sterility test is initiated prior to shipping, but the result will not be available for up to 14 days. Passing results from in-process microbial tests are required for release of GINTUIT for shipping.
The efficacy analysis of GINTUIT was based on two six-month, prospective, randomized, within subject controlled (matched for teeth and gingival condition), treatment comparison clinical trials. A total of 107 subjects from the two trials were included in the efficacy analysis. Each subject received GINTUIT and a free gingival graft (FGG) taken from the subject’s palate (control), with placement sites randomized to two non-adjacent teeth on contralateral sides of the jaw. Treatment of the underlying disease was not addressed in the studies. All subjects completed all study visits in both trials. Subjects in Study One (n=22) were predominantly White (86%) and female (68%), with a mean age of 50 years (range, 31-70). Subjects in Study Two (n=85) were predominantly White (91%) and female (54%), with a mean age of 47 years (range, 18-71).
Study One was a non-inferiority study, conducted at a single center (n=25). The three subjects who participated as training subjects were not included in the efficacy analysis (n=22 for efficacy analysis). The study was designed to rule out a greater than 1 mm decrease in the change in attached gingiva for GINTUIT relative to control. In addition, the amount of keratinized tissue (KT) at the application site was measured. For inclusion, subjects had an insufficient zone of attached gingiva (≤ mm) that required soft tissue grafting. At six months, 14/22 (63.6%) GINTUIT sites and 21/22 (95%) control sites showed an increase in attached gingiva. The mean increase in the amount of attached gingiva was 0.85 mm (95% CI 0.48, 1.21) for GINTUIT and 2.43 mm (95% CI 2.06, 2.79) for control. At least 2 mm of KT width was established in 18/22 (81.8 %) of GINTUIT sites and in 22/22 (100%) of control sites. The mean increase in KT width was 1.37 mm (95% CI 0.97, 1.77) at GINTUIT sites and 3.33 mm (95% CI 2.93, 3.74) at control sites.
Study Two was a multi-center study conducted at four sites in the United States (n = 96). Eleven subjects participated as training subjects and were not included in the efficacy analysis (n=85 for efficacy analysis). The study was designed to determine the percentage of sites with ≥2 mm KT at six months. Eighty-one of the 85 subjects (95.3%) demonstrated ≥2 mm KT at the GINTUIT site (See Table 2). All 96 subjects demonstrated ≥2 mm KT at the control site.
|Subjects with KT width ≥2 mm
KT width (mm)
* Comparison to a pre-defined standard of 50% of subjects with KT width ≥2 mm
In Study Two, GINTUIT sites exhibited superiority for color matching and texture matching (p< 0.0001) and subject preference (p<0.0001) when compared to control.
The effectiveness of GINTUIT beyond six months or with repeat administration was not evaluated in the clinical trials.
GINTUIT is supplied ready for use as a cellular sheet approximately 75 mm in diameter and 0.75 mm thick, in a sealed heavy-gauge polyethylene bag (polybag) with a 10% CO2/air atmosphere. GINTUIT is stored on a semi-permeable polycarbonate base within a plastic insert, which separates the product from the agarose gel medium in a sterile transparent shipping tray.
Storage and Handling
Prior to application of GINTUIT, the healthcare provider should
Following application of GINTUIT, provide post-procedure instructions, including the following
allogeneic cultured keratinocytes and fibroblasts in bovine collagen cellular sheet
|Labeler - Organogenesis, Inc (152165817)|
|Registrant - Organogenesis, Inc (152165817)|
|Organogenesis, Inc||152165817||manufacture, analysis, pack, label|