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

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of TachoSil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been reported in postmarketing experience with TachoSil:

General disorders and administration site conditions: adhesions, drug ineffective, inflammation, granuloma, catheter-related complication, multi-organ failure

Injury, poisoning and procedural complications: foreign body trauma, post-procedural pulmonary embolism

Vascular disorders: thrombosis

Infections and infestations: hepatitis C

Respiratory, thoracic and mediastinal disorders: respiratory distress, laryngeal edema, hemothorax

Blood and lymphatic system disorders: splenic hemorrhage, eosinophilia

Renal and urinary disorders: renal artery thrombosis, renal failure

Endocrine disorders: parathyroid disorder

Eye disorders: mydriasis

Nervous system disorders: nerve compression

Gastrointestinal disorders: intestinal obstruction (in abdominal surgeries), ileus (in abdominal surgeries)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

A review of available data suggests that major birth defects occur in 2-4% of the U.S. general population and that miscarriage occurs in 15-20% of clinically recognized pregnancies, regardless of drug exposure. Animal reproduction studies have not been conducted with TachoSil. There are no adequate and well-controlled studies in pregnant women. It is also not known whether TachoSil can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. TachoSil should be administered to pregnant women only if clearly needed.

8.2 Lactation

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 TachoSil is administered to nursing mothers.

8.4 Pediatric Use

The use of TachoSil has been studied in patients aged one month to 16 years; use in children under the age of one month may be unsafe or ineffective due to small size and limited ability to apply the patch as recommended. Use of TachoSil in the one month to 16 years age group is supported by evidence from adequate and well-controlled studies of TachoSil in adults with additional data from two clinical trials, which included 36 pediatric patients at the age of 16 years or younger. The data supports the use of TachoSil for hemostasis in pediatric patients undergoing cardiovascular and hepatic surgery [see Clinical Studies (14.3)].

8.5 Geriatric Use

Clinical trials to date included 326 patients older than 65 years of age receiving TachoSil. No overall differences in safety or effectiveness were observed between the elderly and younger patients, however, greater susceptibility of some older patients to adverse reactions cannot be ruled out.

11 DESCRIPTION

TachoSil Fibrin Sealant Patch is a sterile, bioabsorbable combination product comprised of two active substances (human plasma-derived fibrinogen and human plasma-derived thrombin) coated onto a collagen sponge of equine origin. The collagen sponge serves as a flexible and mechanically stable carrier for the active substances to facilitate application of the human fibrinogen and thrombin to the wound surface. The active side of the patch is yellow in color due to the presence of a colorant riboflavin (E101); and the non-active side is off-white in color. Each square inch of the patch contains approximately 35.5 mg of human fibrinogen and 12.9 units of human thrombin. Other inactive ingredients include equine collagen, human albumin, sodium chloride, sodium citrate, and L‑arginine hydrochloride.

TachoSil is sterilized by gamma irradiation after completion of inner and outer packaging, resulting in a sterile product in a sterile inner package.

Viral Clearance

The active biological substances of TachoSil (human fibrinogen and human thrombin) are manufactured from pooled human plasma collected in facilities in the United States. Human plasma is tested by a Nucleic Acid Test (NAT) for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus-1 (HIV-1). NAT testing for hepatitis A virus (HAV) and parvovirus B19 is also performed. Human plasma is also tested for the presence of hepatitis B surface antigen (HBsAg), and antibodies to hepatitis C virus (anti-HCV) and human immunodeficiency viruses types 1 and 2 (anti-HIV 1/2).

The manufacturing procedure for each TachoSil component and final product include processing steps designed to reduce the risk of viral transmission. In particular, the virus clearance steps in the manufacture of human fibrinogen and thrombin include pasteurization, precipitation and adsorption. The virus clearance step in the manufacture of the collagen sponge is the pH treatment.

The virus clearance capacity of these procedures in the manufacture of fibrinogen, thrombin and collagen sponge has been validated using viruses with a wide range of physicochemical characteristics. These in vitro validation studies were conducted using samples from manufacturing intermediates spiked with virus suspensions of known titers followed by further processing under conditions equivalent to those in the respective manufacturing steps. The cumulative virus reduction factors (expressed as log10 ) are shown in Table 5 for each virus tested.

*
HIV: Human Immunodeficiency Virus,
HSV: Herpes Simplex Virus
BVDV: Bovine Viral Diarrhea Virus
§
PRV: Pseudorabies Virus
CPV: Canine parvovirus
#
HAV: Hepatitis A Virus
Þ
WNV: West Nile Virus, only single manufacturing step validated
ß
PI-3: Parainfluenza Virus type 3
à
PPV: Porcine Parvovirus
è
Reo 3: ReoVirus type 3

Table 5. Cumulative Virus Reduction Factors for the Components of TachoSil

Cumulative Reduction Factors for Virus Removal/Inactivation of Human Thrombin
Virus Reduction Factors [log10 ]
Manufacturing step Enveloped Viruses Non-enveloped Viruses
HIV * HSV BVDV PRV § CPV HAV #
Pasteurization, precipitation and adsorption steps ≥15.0 ≥20.4 ≥13.2 16.3 5.4 8.4

Cumulative Reduction Factors for Virus Removal/Inactivation of Human Fibrinogen

Virus Reduction Factors [log10 ]

Manufacturing step Enveloped Viruses Non-enveloped Viruses
HIV * PRV § BVDV WNV Þ CPV HAV #
Pasteurization, precipitation and lyophilization steps ≥9.6 8.8 ≥11.2 ≥8.3 4.9 8.6
Reduction Factors for Virus Removal/Inactivation of the Collagen Sponge (equine)
Virus Reduction Factors [log10 ]
Manufacturing step Enveloped Viruses Non-enveloped Viruses
PRV § PI-3ß PPV à Reo3è
pH treatment ≥5.7 ≥5.9

A validation study was also conducted to evaluate the capacity for gamma irradiation to inactivate and/or remove viruses in the final TachoSil product. The virus reduction factors (expressed as log10 ) are shown in Table 6 for each virus tested.

*
PRV: Pseudorabies Virus
PI-3: Parainfluenza Virus type 3
PPV: Porcine Parvovirus
§
Reo 3: ReoVirus type 3
Table 6. Virus Reduction Factors for TachoSil Final Sterilization by Gamma Irradiation
Reduction Factor of Gamma Irradiation (Final Sterilization of TachoSil)
Virus Reduction Factors [log10 ]
Enveloped Viruses Non-enveloped Viruses
Manufacturing step PRV * PI-3 PPV Reo3§
Gamma Irradiation ≥4.7 ≥4.0 3.0 ≥6.2

All infections considered by a physician possibly to have been transmitted by this product should be reported to Baxter [see Warnings and Precautions (5.7)].

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of TachoSil is based on the interaction between the active biological substances (human fibrinogen and human thrombin) and the physiology of the fibrin clot formation (Fig. 3A). Upon contact with a bleeding wound surface, the active substances coated onto the equine collagen patch become dissolved and partly diffuse into the wound surface. The subsequent fibrinogen-thrombin reaction initiates the last step in the cascade of biochemical reactions-conversion of fibrinogen into fibrin monomers that further polymerize to form the fibrin clot.

Hemostasis is achieved when the formed fibrin clot adheres the collagen patch to the wound surface, thus providing a physical barrier to bleeding (Fig 3B). TachoSil exhibits flexibility to accommodate for the physiological movements of tissues and organs and can withstand pressures up to 61.4 hPa (46.1 mmHg).

Figure 3: Scanning Electron Microscopy Photos of TachoSil

FigureFigure

A. The side view of the TachoSil patch shows the coating of the human plasma components anchored to the indentations of the collagen carrier.

B. The deposition of a fibrin clot formed from fibrinogen and thrombin of the coating results in hemostasis and conglutination of the TachoSil patch to the wound surface.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of TachoSil or studies to determine the genotoxicity or the effect of TachoSil on fertility have not been performed. An assessment of the carcinogenic potential of TachoSil was completed to demonstrate minimal carcinogenic risk from product use.

13.2 Animal Toxicology and/or Pharmacology

In a study conducted in swine, TachoSil was applied to liver wounds and showed progressive degradation. However, remnants of the TachoSil patch may remain present for more than 12 months. Histologic examination at 26 and 52 weeks revealed that granulation tissue encapsulates TachoSil remnants and forms a firm capsule around them. Remnants were found in all treated animals after 26 weeks (12/12) and in most animals (6/8) after 52 weeks. No other local reactivity or toxicities were noted.

14 CLINICAL STUDIES

14.1 Cardiovascular

An open-label, multi-center, randomized, parallel-group study comparing TachoSil with comparator (hemostatic fleece without additional active coagulation stimulating compounds) treatment was conducted to evaluate TachoSil for control of bleeding in 119 patients undergoing cardiovascular surgery requiring cardiopulmonary bypass procedure. Of the 119 subjects, 88 (74%) were male and 31 (26%) female. Mean (range) age was 67 (23 to 86) years; subjects older than 65 years constituted 58% of the male and 74% of the female population. All subjects were White/Caucasian.

In the Intent-to-Treat (ITT) population, 59 patients were randomized to treatment with TachoSil and 60 patients were randomized to treatment with the comparator. A larger proportion of patients in the TachoSil treatment group (44/59; 75%) than in the comparator treatment group (20/60; 33%) achieved hemostasis within three minutes, which was a statistically significant difference (p<0.0001).

Fifty-six out of 59 (95%) patients in the TachoSil treatment group achieved hemostasis at six minutes compared to 43 out of 60 (72%) in the comparator treatment group, which also was statistically significant (p=0.0006) (see Table 7).

*
Normal approximation to the binominal distribution is used to construct the asymptotic confidence intervals
Cochran-Mantel-Haenszel test controlling for center
Hemostatic fleece material without additional active coagulation stimulating compounds

Table 7. Efficacy Results in Cardiovascular Surgery, by Treatment, Intent-to-Treat Population

Treatment

Total numberof patients whoachieved hemostasis

Percentage ofpatients whoachieved hemostasis

95% CI forproportion *

p-value

Hemostasis at 3 min

TachoSil (n=59)

44

75%

[0.635; 0.857]

<0.0001

Comparator (n=60)

20

33%

[0.214; 0.453]

Hemostasis at 6 min

TachoSil (n=59)

56

95%

[0.893;1.000]

0.0006

Comparator (n=60)

43

72%

[0.603; 0.831]

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