VISTASEAL: Package Insert and Label Information (Page 2 of 3)

4 CONTRAINDICATIONS

  • Do not inject directly into the circulatory system. [see Warnings and Precautions (5.1)]
  • Do not use for the treatment of severe or brisk arterial bleeding. In these situations, blood flow will wash away VISTASEAL and prevent hemostasis.
  • Do not use VISTASEAL in patients known to have anaphylactic or severe systemic hypersensitivity reactions to the administration of human blood products. [see Warnings and Precautions (5.2)]
  • Do not use VISTASEAL for spraying unless the minimum recommended distance from the applicator tip to the bleeding site can be achieved. [see Dosage and Administration (2.3)]

5 WARNINGS AND PRECAUTIONS

5.1 Thrombosis

Life-threatening thromboembolic complications may occur if VISTASEAL is administered intravascularly.

5.2 Hypersensitivity

Allergic-type hypersensitivity reactions are possible. Signs of hypersensitivity reactions include hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If these symptoms occur, discontinue the administration of VISTASEAL immediately. Treat the reaction accordingly.

5.3 Transmissible Infectious Agents

Because VISTASEAL is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and theoretically, the Creutzfeldt-Jakob (CJD) agent. This also applies to unknown or emerging viruses and other pathogens. All suspected infections related to this product should be reported by the physician or other healthcare provider to Grifols Therapeutics LLC at 1-800-520-2807. The physician should discuss the risks and benefits of the use of VISTASEAL with the patient. [see Patient Counseling Information (17)]

6 ADVERSE REACTIONS

The most common adverse reactions (reported in > 1% of clinical trial subjects) were nausea and procedural pain.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Three clinical trials were conducted using the same general design, with each being randomized and active controlled. The types of surgeries included in each trial were different. Across all trials, 26% were vascular surgeries, 37% were parenchymous tissue surgeries, and 37% were soft tissue surgeries. The clinical trials were conducted with Fibrin Sealant (Human) using Fibrijet® drip or spray applicators.

Fibrin Sealant (Human) was used to treat vascular bleeding during vascular surgery, or parenchymal bleeding during hepatic surgery, or soft tissue bleeding during retroperitoneal or pelvic surgery, abdominoplasties, or mastopexies, across all clinical trials, involving 500 trial subjects treated with Fibrin Sealant (Human), and 377 control subjects. The number of trial subjects treated with for each type of surgery was 168 for vascular surgery, 163 for parenchymal surgery, and 169 for soft tissue surgery.

The Fibrin Sealant (Human) treatment group had a mean age of 57 years (standard deviation: 15.6 years; range: 0.3 to 86 years). The median age was 60 years. There were 11 subjects younger than 18 years old. There were 51% male subjects. 87% of the subjects exposed to Fibrin Sealant (Human) were White.

The mean volume of Fibrin Sealant (Human) used per subject and target bleeding site was 7 mL (standard deviation 3.5) and ranged from 0.3 to 18 mL. The median volume was 6 mL. Exposure to Fibrin Sealant (Human) consisted of a single intraoperative administration.

The clinical safety database included all subjects who received any amount of Fibrin Sealant (Human) in all clinical studies, with no exclusions.

In the Fibrin Sealant (Human) treatment group, 13% of trial subjects experienced one or more adverse reactions, and 8% of control subjects experienced one or more adverse reactions.

The adverse reactions shown in Tables 3-6 were evaluated as having a possible causal relationship to treatment with Fibrin Sealant (Human) and occurred in >1% of subjects.

Table 3. Adverse Reactions Occurring in >1% of Subjects in Vascular, Parenchyma, and Soft Tissue Surgery
Preferred Term N = 500 n (%)
Nausea 6 (1)
Procedural pain 10 (2)
Table 4. Adverse Reactions Occurring in >1% of Subjects in Vascular Surgery
Preferred Term N = 168 n (%)
Nausea 2 (1)
Pyrexia (fever) 2 (1)
Procedural pain 4 (2)
Vascular graft complication 2 (1)
Parvovirus B19 test positive 2 (1)
Urinary retention (Unable to empty the bladder completely) 2 (1)
Table 5. Adverse Reactions Occurring in >1% of Subjects in Parenchyma Surgery
Preferred Term N = 163 n (%)
Postprocedural bile leak 2 (1)
Procedural pain 2 (1)
Pulmonary embolism (Blood clot in the lungs) 2 (1)
Deep vein thrombosis (Blood clot that forms in a vein deep) 2 (1)
Table 6. Adverse Reactions Occurring in >1% of Subjects in Soft Tissue Surgery
Preferred Term N = 169 n (%)
Anemia (Low red blood cells) 2 (1)
Leukocytosis (Increased white blood cells) 2 (1)
Ileus (Decreased or absent movement of the stomach or intestine) 2 (1)
Nausea 4 (2)
Procedural pain 4 (2)
Alanine aminotransferase increased 2 (1)
Aspartate aminotransferase increased 2 (1)
Hypocalcaemia (Low serum calcium) 2 (1)
Hypokalaemia (Low serum potassium) 2 (1)
Hyponatraemia (Low serum sodium) 2 (1)
Prothrombin time prolonged (Increased bleeding time) 2 (1)
Headache 2 (1)
Insomnia 2 (1)
Pruritus (Itching) 4 (2)
Hypertension 2 (1)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
There are no available data with VISTASEAL use in pregnant women. Animal reproduction studies have not been performed with VISTASEAL. It is unknown whether VISTASEAL can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation

Risk Summary
There is no information regarding the presence of VISTASEAL in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VISTASEAL and any potential adverse effects on the breastfed infant from VISTASEAL or from the underlying maternal condition.

8.4 Pediatric Use

A total of 11 out of 500 subjects administered Fibrin Sealant (Human) in the clinical trials were pediatric subjects. Of these 11 subjects, 5 were infants aged less than 2 years, 5 were children between the ages of 2 and 11 years, and 1 was an adolescent aged between 12 and 16 years. Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical trials included 172 subjects aged 65 years or older treated with Fibrin Sealant (Human). No differences in safety or effectiveness were observed between these subjects and younger subjects.

11 DESCRIPTION

VISTASEAL is a two-component fibrin sealant consisting of human fibrinogen (component 1) and human thrombin with calcium chloride (component 2) sterile solutions filled in syringes which are assembled in a syringe holder.

VISTASEAL is supplied as frozen solutions. After thawing, the human fibrinogen and human thrombin solutions are clear or slightly opalescent and colorless or pale yellow. VISTASEAL does not contain any preservatives.

Fibrinogen

Component 1 is a sterile solution, pH 6.5 – 8.0, which contains concentrated human fibrinogen and excipients. Fibrinogen is a protein from human blood that forms a clot when combined with thrombin. The composition of the human fibrinogen solution is as follows:
Active ingredient: human fibrinogen (80 mg/mL)
Other ingredients: sodium citrate, sodium chloride, arginine, L-isoleucine, L-glutamic acid monosodium and water for injection.

Thrombin

Component 2 is a sterile solution, pH 6.0 – 8.0, which contains purified human thrombin and excipients. Thrombin is a specific protease that activates clotting of the final combined product and converts fibrinogen to fibrin. The composition of the human thrombin solution is as follows:
Active ingredient: human thrombin (500 IU/mL)
Other ingredients: calcium chloride, human albumin, sodium chloride, glycine and water for injection.

The starting material for the production of both fibrinogen and thrombin components of VISTASEAL is pooled human Source Plasma obtained from FDA-licensed plasma collection centers in the United States. Cohn’s plasma fractionation method is used to obtain Fraction I, which is the starting material for the production of fibrinogen, and the prothrombin complex isolated from supernatant of Fraction I, which is the starting material for the production of thrombin. The purification process of fibrinogen includes solvent/detergent treatment, three glycine precipitation steps, and double nanofiltration using 35-nm and 20-nm filters. The purification process of thrombin includes solvent/detergent treatment, ion exchange chromatography, and double nanofiltration through 15-nm filters. After nanofiltration, the fibrinogen and thrombin solutions are formulated, sterile filtered, aseptically filled in syringes, packaged, sterilized, and frozen.

Viral safety Individual plasma donations used in the manufacture of VISTASEAL are collected in FDA-licensed plasma donation centers in the U.S. and are tested for viral markers in compliance with the U.S. regulatory requirements. In addition, mini-pools of plasma units are tested as an in-process control for hepatitis A virus (HAV) and parvovirus B19 (B19V) using validated nucleic acid testing (NAT) methods. All the tests must be non-reactive (negative) except for B19V, for which the limit in plasma manufacturing pools does not exceed a titer of 104 IU/mL. The manufacturing plasma pool is also tested with NAT for HBV, HCV, and HIV, and all the tests must be non‑reactive (negative).

The manufacturing processes for fibrinogen and thrombin include processing steps which are designed to reduce the risk of viral transmission. Both components have two discrete steps with viral clearance capacity, namely solvent/detergent treatment (with 1.0% (v/v) Tween 80/0.30% (v/v) tri-n-butyl phosphate (TNBP) for 6.0 – 6.5 hours at 27.0 ± 1.5 ºC for fibrinogen or 25 ± 1 ºC for thrombin), validated to inactivate enveloped viruses, and a nanofiltration step validated to remove non-enveloped and enveloped viruses (35-nm and 20-nm filters for fibrinogen and two 15-nm filters for thrombin). Additionally, the glycine precipitation steps contribute to the overall safety of the product in the purification process of human fibrinogen. The Fraction I precipitation and ion-exchange chromatography steps contribute to the overall safety of the product in the purification process of human thrombin.

The viral clearance capacity of these virus inactivation/removal procedures has been validated in small-scale in vitro studies using relevant and model viruses with a range of physico-chemical characteristics. The results of viral clearance validation studies are summarized in Tables 7 and 8:

Table 7. Global Virus Reduction Factors (Log10 ) for Human Fibrinogen
Manufacturing step Virus reduction factor (log10 )*
Enveloped viruses Non-enveloped viruses
HIV-1 PRV WNV BVDV HAV PPV
S/D treatment ≥ 5.33 ≥ 6.80 ≥ 5.20 ≥ 5.60 n.a. n.a.
Glycine precipitations n.d. n.d. n.d. n.d. 5.21 2.09
Nanofiltration 35 nm and 20 nm ≥ 5.57 ≥ 6.09 ≥ 4.51 ≥ 4.53 5.22 4.37
Global virus reduction factor (log10 ) ≥ 10.90 ≥ 12.89 ≥ 9.71 ≥ 10.13 10.43 6.46
Table 8. Global Virus Reduction Factors (Log10 ) for Human Thrombin
*: Reduction factor below 1 log10 is not considered in calculating the global virus reduction; n.d.: Not done; n.a.: Not applicable; BVDV: bovine viral diarrhea virus, model for HCV; WNV: West Nile virus; PRV: pseudorabies virus, model for large enveloped DNA viruses; PPV: porcine parvovirus, model for B19V
Manufacturing step Virus reduction factor (log10 )*
Enveloped viruses Non-enveloped viruses
HIV-1 PRV WNV BVDV HAV PPV
Fraction I precipitation < 1.0 2.13 2.78 1.34 1.18 < 1.0
S/D treatment ≥ 5.52 ≥ 5.85 ≥ 5.94 ≥ 5.09 n.a. n.a.
SP-Sepharose XL chromatography n.d. n.d. n.d. n.d. 4.61 3.97
Double nanofiltration 15 nm ≥ 4.03 ≥ 5.95 ≥ 5.42 ≥ 4.93 6.56 6.14
Global virus reduction factor (log10 ) ≥ 9.55 ≥ 13.93 ≥ 14.14 ≥ 11.36 12.35 10.11

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