Prescription Drug Information: TachoSil (Page 2 of 4)

6 ADVERSE REACTIONS

The adverse reactions reported in more than one percent of patients during clinical trials were anemia, nausea and vomiting, fever, abdominal pain, increased white blood cell count, ascites, itching, atrial fibrillation, pleural effusion, gastrointestinal hemorrhage, wound infection, hypophosphatemia, urinary tract infection, and post-procedural bile leakage in hepatic surgery.

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 practice.

Cardiovascular Surgery

In the cardiovascular trial, the most frequently reported adverse reactions were atrial fibrillation and pleural effusion. Seventy-four percent (74%) of patients treated with TachoSil and 75% of comparator treated patients experienced one or more clinically relevant adverse reactions (see Table 2).

*
Comparator: Hemostatic fleece material without additional active coagulation stimulating compounds.
As treated population (safety data set).

Table 2. Most Frequent Adverse Reactions (Cardiovascular Trial)

Adverse Reaction

TachoSil

Comparator *

N = 62n (%)

N = 57n (%)

Atrial fibrillation

18 (29%)

14 (25%)

Pleural effusion

14 (23%)

11 (19%)

Pyrexia

4 (6%)

3 (5%)

Hepatic Surgery

In the hepatic surgery trial, the most frequently reported adverse reactions were nausea and anemia (see Table 3). Ninety-four percent (94%) of patients treated with TachoSil and 94% of comparator treated patients experienced one or more clinically relevant adverse reactions.

*
Comparator: Hemostatic fleece material without additional active coagulation stimulating compounds.
As treated population (safety data set).

Table 3. Most Frequent Adverse Reactions (Hepatic Resection Trial)

Adverse Reaction

TachoSil

Comparator *

N = 114n (%)

N = 109n (%)

Nausea

34 (30%)

29 (27%)

Anemia

26 (23%)

23 (21%)

Post-operative bile leakage was observed in 8 (7%) of patients after treatment with TachoSil and 13 (12%) after treatment with comparator.

Immunogenicity

Antibodies against components of fibrin sealant/hemostatic products may occur.

However in a clinical trial with human fibrinogen/human thrombin sponge (patch) in hepatic surgery, in which patients were investigated for the development of antibodies, 26% of the 96 patients tested and treated with human fibrinogen/human thrombin sponge (patch) developed antibodies to equine collagen. The equine collagen antibodies that developed in some patients after human fibrinogen/human thrombin sponge (patch) use were not reactive with human collagen. One patient developed antibodies to human fibrinogen.

There were no adverse events attributable to the development of human fibrinogen or equine collagen antibodies.

There is very limited clinical data available regarding re-exposure of the human fibrinogen/human thrombin sponge (patch). Two subjects have been re-exposed in a clinical trial and have not reported any immune-mediated adverse events, however, their antibody status to collagen or fibrinogen is unknown.

Pediatric Clinical Trial Experience

In pediatric patients, the most frequently reported adverse reactions were diarrhea, hypertension and increased transaminases (see Table 4). Ninety-four percent (94%) of patients treated with TachoSil and 100% of comparator treated patients experienced one or more clinically relevant adverse reactions.

*
Comparator: Hemostatic fleece material compounds without additional active coagulation stimulating compounds.
As treated population (safety data set).

Table 4. Most Frequent Adverse Reactions in Pediatric Patients (All Trials)

Adverse Reaction

TachoSil

Comparator *

N = 36n (%)

N = 9n (%)

Diarrhea

6 (17%)

0

Hypertension

6 (17%)

1 (11%)

Transaminases Increased

4 (11%)

0

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)].

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