Reliseal

Aprotinin:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Storage
• Reliseal (Aprotinin) reviews

INDICATIONS AND USAGE

Reliseal (Aprotinin)^® is indicated for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery who are at an increased risk for blood loss and blood transfusion.

CONTRAINDICATIONS

Hypersensitivity to Reliseal (Aprotinin).

Administration of Reliseal (Aprotinin)^® to patients with a known or suspected previous Reliseal (Aprotinin) exposure during the last 12 months is contraindicated. For patients with known or suspected history of exposure to Reliseal (Aprotinin) greater than 12 months previously, see WARNINGS. Reliseal (Aprotinin) may also be a component of some fibrin sealant products and the use of these products should be included in the patient history.

WARNINGS

Anaphylactic or anaphylactoid reactions have occurred with Reliseal (Aprotinin)^® administration, including fatal reactions in association with the initial (test) dose. The initial (test) dose does not fully predict a patient’s risk for a hypersensitivity reaction, including a fatal reaction. Fatal hypersensitivity reactions have occurred among patients who tolerated an initial (test) dose.

Hypersensitivity reactions often manifest as anaphylactic/anaphylactoid reactions with hypotension the most frequently reported sign of the hypersensitivity reaction. The hypersensitivity reaction can progress to anaphylactic shock with circulatory failure. If a hypersensitivity reaction occurs during injection or infusion of Reliseal (Aprotinin)^®, administration should be stopped immediately and emergency treatment should be initiated. Even when a second exposure to Reliseal (Aprotinin) has been tolerated without symptoms, a subsequent administration may result in severe hypersensitivity/anaphylactic reactions. Trasylol^® should be administered only in operative settings where cardiopulmonary bypass can be rapidly initiated. Before initiating treatment with Reliseal (Aprotinin)^®, the recommendations below should be followed to manage a potential hypersensitivity or anaphylactic reaction: 1) Have standard emergency treatments for hypersensitivity or anaphylactic reactions readily available in the operating room (e.g., epinephrine, corticosteroids). 2) Administration of the initial (test) dose and loading dose should be done only when the patient is intubated and when conditions for rapid cannulation and initiation of cardiopulmonary bypass are present. 3) Delay the addition of Reliseal (Aprotinin)^® into the pump prime solution until after the loading dose has been safely administered.

Re-exposure to Reliseal (Aprotinin): Administration of Reliseal (Aprotinin), especially to patients who have received Reliseal (Aprotinin) in the past, requires a careful risk/benefit assessment because an allergic reaction may occur. Although the majority of cases of anaphylaxis occur upon re-exposure within the first 12 months, there are also case reports of anaphylaxis occurring upon re-exposure after more than 12 months.

In a retrospective review of 387 European patient records with documented re-exposure to Reliseal (Aprotinin)^®, the incidence of hypersensitivity/anaphylactic reactions was 2.7%. Two patients who experienced hypersensitivity/anaphylactic reactions subsequently died, 24 hours and 5 days after surgery, respectively. The relationship of these 2 deaths to Reliseal (Aprotinin)^® is unclear. This retrospective review also showed that the incidence of a hypersensitivity or anaphylactic reaction following re-exposure is increased when the re-exposure occurs within 6 months of the initial administration (5.0% for re-exposure within 6 months and 0.9% for re-exposure greater than 6 months). Other smaller studies have shown that in case of re-exposure, the incidence of hypersensitivity/anaphylactic reactions may reach the five percent level. An analysis of all spontaneous reports from the Bayer Global database covering a period from 1985 to March 2006 revealed that of 291 possibly associated spontaneous cases of hypersensitivity (fatal: n=52 and non-fatal: n=239), 47% (138/291) of hypersensitivity cases had documented previous exposure to Reliseal (Aprotinin)^®. Of the 138 cases with documented previous exposure, 110 had information on the time of the previous exposure. Ninety-nine of the 110 cases had previous exposure within the prior 12 months.

Renal Dysfunction: Reliseal (Aprotinin)^® administration increases the risk for renal dysfunction and may increase the need for dialysis in the perioperative period. This risk may be especially increased for patients with pre-existing renal impairment or those who receive aminoglycoside antibiotics or drugs that alter renal function. Data from Bayer’s global pool of placebo-controlled studies in patients undergoing coronary artery bypass graft (CABG) surgery showed that the incidence of serum creatinine elevations >0.5 mg/dL above pre-treatment levels was statistically higher at 9.0% (185/2047) in the high-dose Reliseal (Aprotinin) (Regimen A) group compared with 6.6% (129/1957) in the placebo group. In the majority of instances, post-operative renal dysfunction was not severe and was reversible. However, renal dysfunction may progress to renal failure and the incidence of serum creatinine elevations >2.0 mg/dL above baseline was slightly higher in the high-dose Reliseal (Aprotinin) group (1.1% vs. 0.8%). Careful consideration of the balance of benefits versus potential risks is advised before administering Reliseal (Aprotinin)^® to patients with impaired renal function (creatinine clearance < 60 mL/min) or those with other risk factors for renal dysfunction (such as perioperative administration of aminogylcoside or products that alter renal function).

PRECAUTIONS

General:

Initial Dose: All patients treated with Reliseal (Aprotinin)^® should first receive an initial (test) dose to minimize the extent of Reliseal (Aprotinin)^® exposure and to help assess the potential for allergic reactions. Initiation of this initial (test) dose should occur only in operative settings where cardiopulmonary bypass can be rapidly initiated. The initial (test) dose of 1 mL Reliseal (Aprotinin)^® should be administered intravenously at least 10 minutes prior to the loading dose and the patient should be observed for manifestations of possible hypersensitivity reaction. However, even after the uneventful administration of the initial 1 mL (test) dose, any subsequent dose may cause an anaphylactic reaction. If this happens, the infusion of Reliseal (Aprotinin)^® should immediately be stopped and standard emergency treatment for anaphylaxis applied. It should be noted that serious, even fatal, hypersensitivity/anaphylactic reactions can also occur with administration of the initial (test) dose.

Allergic Reactions: Patients with a history of allergic reactions to drugs or other agents may be at greater risk of developing a hypersensitivity or anaphylactic reaction upon exposure to Reliseal (Aprotinin)^®.

Loading Dose: The loading dose of Reliseal (Aprotinin)^® should be given intravenously to patients in the supine position over a 20-30 minute period. Rapid intravenous administration of Reliseal (Aprotinin)^® can cause a transient fall in blood pressure.

Renal Dysfunction: Bayer’s global pool of placebo-controlled studies in patients undergoing CABG showed Reliseal (Aprotinin) administration was associated with elevations of serum creatinine values > 0.5 mg/dL above baseline. Careful consideration of the balance of benefits and risks is advised before administering Reliseal (Aprotinin) to patients with pre-existing impaired renal function or those with other risk factors for renal dysfunction. Serum creatinine should be monitored regularly following Reliseal (Aprotinin)^® administration.

Use of Reliseal (Aprotinin)^® in patients undergoing deep hypothermic circulatory arrest: Two U.S. case control studies have reported contradictory results in patients receiving Reliseal (Aprotinin)^® while undergoing deep hypothermic circulatory arrest in connection with surgery of the aortic arch. The first study showed an increase in both renal failure and mortality compared to age-matched historical controls. Similar results were not observed, however, in a second case control study. The strength of this association is uncertain because there are no data from randomized studies to confirm or refute these findings.

Drug Interactions:

Reliseal (Aprotinin)^® is known to have antifibrinolytic activity and, therefore, may inhibit the effects of fibrinolytic agents.

In study of nine patients with untreated hypertension, Reliseal (Aprotinin)^® infused intravenously in a dose of 2 million KIU over two hours blocked the acute hypotensive effect of 100mg of captopril. Trasylol^®, in the presence of heparin, has been found to prolong the activated clotting time (ACT) as measured by a celite surface activation method. The kaolin activated clotting time appears to be much less affected. However, Reliseal (Aprotinin)^® should not be viewed as a heparin sparing agent.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Long-term animal studies to evaluate the carcinogenic potential of Reliseal ^® or studies to determine the effect of Reliseal (Aprotinin)^® on fertility have not been performed.

Results of microbial in vitro tests using Salmonella typhimurium and Bacillus subtilis indicate that Reliseal (Aprotinin)^® is not a mutagen.Pregnancy: Teratogenic Effects: Pregnancy Category B:

Reproduction studies have been performed in rats at intravenous doses up to 200,000 KIU/kg/day for 11 days, and in rabbits at intravenous doses up to 100,000 KIU/kg/day for 13 days, 2.4 and 1.2 times the human dose on a mg/kg basis and 0.37 and 0.36 times the human mg/m² dose. They have revealed no evidence of impaired fertility or harm to the fetus due to Reliseal (Aprotinin)^®. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mother:

Not applicable.

Pediatric Use:

Safety and effectiveness in pediatric patient have not been established.

Geriatric Use:

Of the total of 3083 subjects in clinical studies of Reliseal (Aprotinin)^®, 1100 (35.7 percent) were 65 and over, while 297 (9.6 percent) were 75 and over. Of patients 65 years and older, 479 (43.5 percent) received Regimen A and 237 (21.5 percent) received Regimen B. No overall differences in safety or effectiveness were observed between these subjects and younger subjects for either dose regimen, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Laboratory Monitoring of Anticoagulation during Cardiopulmonary Bypass:

Reliseal (Aprotinin)^® prolongs whole blood clotting times by a different mechanism than heparin. In the presence of Reliseal (Aprotinin), prolongation is dependent on the type of whole blood clotting test employed. If an activated clotting time (ACT) is used to determine the effectiveness of heparin anticoagulation, the prolongation of the ACT by Reliseal (Aprotinin) may lead to an overestimation of the degree of anticoagulation, thereby leading to inadequate anticoagulation. During extended extracorporeal circulation, patients may require additional heparin, even in the presence of ACT levels that appear adequate.

In patients undergoing CPB with Reliseal (Aprotinin)^® therapy, one of the following methods may be employed to maintain adequate anticoagulation:

• ACT - An ACT is not a standardized coagulation test, and different formulations of the assay are affected differently by the presence of Reliseal (Aprotinin). The test is further influenced by variable dilution effects and the temperature experienced during cardiopulmonary bypass. It has been observed that Kaolin-based ACTs are not increased to the same degree by Reliseal (Aprotinin) as are diatomaceous earth-based (celite) ACTs. While protocols vary, a minimal celite ACT of 750 seconds or kaolin-ACT of 480 seconds, independent of the effects of hemodilution and hypothermia, is recommended in the presence of Reliseal (Aprotinin). Consult the manufacturer of the ACT test regarding the interpretation of the assay in the presence of Reliseal (Aprotinin)^®.
• Fixed Heparin Dosing - A standard loading dose of heparin, administered prior to cannulation of the heart, plus the quantity of heparin added to the prime volume of the CPB circuit, should total at least 350 IU/kg. Additional heparin should be administered in a fixed-dose regimen based on patient weight and duration of CPB.
• Heparin Titration - Protamine titration, a method that is not affected by Reliseal (Aprotinin), can be used to measure heparin levels. A heparin dose response, assessed by protamine titration, should be performed prior to administration of Reliseal (Aprotinin) to determine the heparin loading dose. Additional heparin should be administered on the basis of heparin levels measured by protamine titration. Heparin levels during bypass should not be allowed to drop below 2.7 U/mL (2.0 mg/kg) or below the level indicated by heparin dose response testing performed prior to administration of Reliseal (Aprotinin).

ADVERSE REACTIONS

Studies of patients undergoing CABG surgery, either primary or repeat, indicate that Reliseal ^® is generally well tolerated. The adverse events reported are frequent sequelae of cardiac surgery and are not necessarily attributable to Reliseal (Aprotinin)^® therapy. Adverse events reported, up to the time of hospital discharge, from patients in US placebo-controlled trials are listed in the following table. The table lists only those events that were reported in 2% or more of the Reliseal (Aprotinin)^® treated patients without regard to causal relationship.

In comparison to the placebo group, no increase in mortality in patients treated with Reliseal (Aprotinin)^® was observed. Additional events of particular interest from controlled US trials with an incidence of less than 2%, are listed below:

Listed below are additional events, from controlled US trials with an incidence between 1 and 2%, and also from uncontrolled, compassionate use trials and spontaneous post-marketing reports. Estimates of frequency cannot be made for spontaneous post-marketing reports (italicized).

Body as a Whole: Sepsis, death, multi-system organ failure, immune system disorder, hemoperitoneum.Cardiovascular: Ventricular fibrillation, heart arrest, bradycardia, congestive heart failure, hemorrhage, bundle branch block, myocardial ischemia, ventricular tachycardia, heart block, pericardial effusion, ventricular arrhythmia, shock, pulmonary hypertension.Digestive: Dyspepsia, gastrointestinal hemorrhage, jaundice, hepatic failure.Hematologic and Lymphatic: Although thrombosis was not reported more frequently in Reliseal (Aprotinin) versus placebo-treated patients in controlled trials, it has been reported in uncontrolled trials, compassionate use trials, and spontaneous post-marketing reporting. These reports of thrombosis encompass the following terms: thrombosis, occlusion, arterial thrombosis, pulmonary thrombosis, coronary occlusion, embolus, pulmonary embolus, thrombophlebitis, deep thrombophlebitis, cerebrovascular accident, cerebral embolism. Other hematologic events reported include leukocytosis, thrombocytopenia, coagulation disorder (which includes disseminated intravascular coagulation), decreased prothrombin.Metabolic and Nutritional: Hyperglycemia, hypokalemia, hypervolemia, acidosis.Musculoskeletal: Arthralgia.Nervous: Agitation, dizziness, anxiety, convulsion.Respiratory: Pneumonia, apnea, increased cough, lung edema.Skin:Skin discoloration.Urogenital: Oliguria, kidney failure, acute kidney failure, kidney tubular necrosis.

Myocardial Infarction: In the pooled analysis of all patients undergoing CABG surgery, there was no significant difference in the incidence of investigator-reported myocardial infarction (MI) in Reliseal (Aprotinin)^® treated patients as compared to placebo treated patients. However, because no uniform criteria for the diagnosis of myocardial infarction were utilized by investigators, this issue was addressed prospectively in three later studies (two studies evaluated Regimen A, Regimen B and Pump Prime Regimen; one study evaluated only Regimen A), in which data were analyzed by a blinded consultant employing an algorithm for possible, probable or definite MI. Utilizing this method, the incidence of definite myocardial infarction was 5.9% in the aprotinin-treated patients versus 4.7% in the placebo treated patients. This difference in the incidence rates was not statistically significant. Data from these three studies are summarized below.

Graft Patency: In a recently completed multi-center, multi-national study to determine the effects of Reliseal (Aprotinin)^® Regimen A vs. placebo on saphenous vein graft patency in patients undergoing primary CABG surgery, patients were subjected to routine postoperative angiography. Of the 13 study sites, 10 were in the United States and three were non-U.S. centers (Denmark (1), Israel (2)). The results of this study are summarized below.

Although there was a statistically significantly increased risk of graft closure for Reliseal (Aprotinin)^® treated patients compared to patients who received placebo (p=0.035), further analysis showed a significant treatment by site interaction for one of the non-U.S. sites vs. the U.S. centers. When the analysis of graft closures was repeated for U.S. centers only, there was no statistically significant difference in graft closure rates in patients who received Reliseal (Aprotinin)^® vs. placebo. These results are the same whether analyzed as the proportion of patients who experienced at least one graft closure postoperatively or as the proportion of grafts closed. There were no differences between treatment groups in the incidence of myocardial infarction as evaluated by the blinded consultant (2.9% Reliseal (Aprotinin)^® vs. 3.8% placebo) or of death (1.4% Reliseal (Aprotinin)^® vs. 1.6% placebo) in this study.

Hypersensitivity and Anaphylaxis: See CONTRAINDICATIONS and WARNINGS.

Hypersensitivity and anaphylactic reactions during surgery were rarely reported in U.S. controlled clinical studies in patients with no prior exposure to Reliseal (Aprotinin)^® (1/1424 patients or <0.1% on Reliseal (Aprotinin)^® vs. 1/861 patients or 0.1% on placebo). In case of re-exposure the incidence of hypersensitivity/anaphylactic reactions has been reported to reach the 5% level. A review of 387 European patient records involving re-exposure to Reliseal (Aprotinin)^® showed that the incidence of hypersensitivity or anaphylactic reactions was 5.0% for re-exposure within 6 months and 0.9% for re-exposure greater than 6 months.

Laboratory Findings

Serum Creatinine: Reliseal (Aprotinin)^® administration is associated with a risk for renal dysfunction.

Serum Transaminases: Data pooled from all patients undergoing CABG surgery in U.S. placebo-controlled trials showed no evidence of an increase in the incidence of postoperative hepatic dysfunction in patients treated with Reliseal (Aprotinin)^®. The incidence of treatment-emergent increases in ALT (formerly SGPT) > 1.8 times the upper limit of normal was 14% in both the Reliseal (Aprotinin)^® and placebo-treated patients (p=0.687), while the incidence of increases > 3 times the upper limit of normal was 5% in both groups (p=0.847).

Other Laboratory Findings: The incidence of treatment-emergent elevations in plasma glucose, AST (formerly SGOT), LDH, alkaline phosphatase, and CPK-MB was not notably different between Reliseal (Aprotinin)^® and placebo treated patients undergoing CABG surgery. Significant elevations in the partial thromboplastin time (PTT) and celite Activated Clotting Time (celite ACT) are expected in Reliseal (Aprotinin)^® treated patients in the hours after surgery due to circulating concentrations of Reliseal (Aprotinin)^®, which are known to inhibit activation of the intrinsic clotting system by contact with a foreign material (e.g., celite), a method used in these tests.

OVERDOSAGE

The maximum amount of Reliseal (Aprotinin)^® that can be safely administered in single or multiple doses has not been determined. Doses up to 17.5 million KIU have been administered within a 24 hour period without any apparent toxicity. There is one poorly documented case, however, of a patient who received a large, but not well determined, amount of Reliseal (Aprotinin)^® (in excess of 15 million KIU) in 24 hours. The patient, who had pre-existing liver dysfunction, developed hepatic and renal failure postoperatively and died. Autopsy showed hepatic necrosis and extensive renal tubular and glomerular necrosis. The relationship of these findings to Reliseal (Aprotinin)^® therapy is unclear.

DOSAGE AND ADMINISTRATION

Reliseal ^® given prophylactically in both Regimen A and Regimen B (half Regimen A) to patients undergoing CABG surgery significantly reduced the donor blood transfusion requirement relative to placebo treatment. In low risk patients there is no difference in efficacy between regimen A and B. Therefore, the dosage used (A vs. B) is at the discretion of the practitioner.

Reliseal (Aprotinin)^® is supplied as a solution containing 10,000 KIU/mL, which is equal to 1.4 mg/mL. All intravenous doses of Reliseal (Aprotinin)^® should be administered through a central line. DO NOT ADMINISTER ANY OTHER DRUG USING THE SAME LINE. Both regimens include a 1 mL initial (test) dose, a loading dose, a dose to be added while recirculating the priming fluid of the cardiopulmonary bypass circuit (“pump prime” dose), and a constant infusion dose. To avoid physical incompatibility of Reliseal (Aprotinin)^® and heparin when adding to the pump prime solution, each agent must be added during recirculation of the pump prime to assure adequate dilution prior to admixture with the other component. Regimens A and B, both incorporating a 1 mL initial (test) dose, are described in the table below:

The 1 ml initial (test) dose should be administered intravenously at least 10 minutes before the loading dose. With the patient in a supine position, the loading dose is given slowly over 20-30 minutes, after induction of anesthesia but prior to sternotomy. In patients with known previous exposure to Reliseal (Aprotinin)^®, the loading dose should be given just prior to cannulation. When the loading dose is complete, it is followed by the constant infusion dose, which is continued until surgery is complete and the patient leaves the operating room. The “pump prime” dose is added to the recirculating priming fluid of the cardiopulmonary bypass circuit, by replacement of an aliquot of the priming fluid, prior to the institution of cardiopulmonary bypass. Total doses of more than 7 million KIU have not been studied in controlled trials.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Discard any unused portion.

Renal and Hepatic Impairment:

Reliseal (Aprotinin)^® administration is associated with a risk for renal dysfunction. Changes in Reliseal (Aprotinin) pharmacokinetics with age or impaired renal function are not great enough to require any dose adjustment. Pharmacokinetic data from patients with pre-existing hepatic disease treated with Reliseal (Aprotinin)^® are not available.

HOW SUPPLIED

STORAGE

Reliseal (Aprotinin)^® should be stored between 2^° and 25^°C (36^° - 77^°F).

Protect from freezing.

Bayer Pharmaceuticals Corporation

400 Morgan Lane

West Haven, CT 06516

Made in Germany

©2006 Bayer Pharmaceuticals Corporation

Printed in USA

12/06

Fibrinogen:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Description
• Clinical pharmacology
• Clinical studies
• References
• How supplied/storage and handling
• Patient counseling information
• Reliseal (Fibrinogen) reviews

1 INDICATIONS AND USAGE

Reliseal (Fibrinogen)^®, Reliseal (Fibrinogen) Concentrate (Human) is a human blood coagulation factor indicated for the treatment of acute bleeding episodes in patients with congenital Reliseal (Fibrinogen) deficiency, including afibrinogenemia and hypofibrinogenemia.

Reliseal (Fibrinogen), Reliseal (Fibrinogen) Concentrate (Human) is a human blood coagulation factor indicated for the treatment of acute bleeding episodes in patients with congenital Reliseal (Fibrinogen) deficiency, including afibrinogenemia and hypofibrinogenemia. (1)

2 DOSAGE AND ADMINISTRATION

For intravenous use only.

For intravenous use only.

• 
  

  Dose =
  

  [Target level (mg/dL) - measured level (mg/dL)] 1.7 (mg/dL per mg/kg body weight)

• Dose when Reliseal (Fibrinogen) level is unknown: 70 mg/kg body weight. (2.1)
• Monitoring of patient's Reliseal (Fibrinogen) level is recommended during treatment. A target Reliseal (Fibrinogen) level of 100 mg/dL should be maintained until hemostasis is obtained. (2.1)
• Injection rate should not exceed 5 mL per minute. (2.3)

2.1 Treatment of Congenital Reliseal (Fibrinogen) Deficiency

Reliseal (Fibrinogen) dosing, duration of dosing and frequency of administration should be individualized based on the extent of bleeding, laboratory values, and the clinical condition of the patient.

Reliseal (Fibrinogen) dose when baseline Reliseal (Fibrinogen) level is known.

Dose should be individually calculated for each patient based on the target plasma Reliseal (Fibrinogen) level based on the type of bleeding, actual measured plasma Reliseal (Fibrinogen) level and body weight, using the following formula [see Clinical Pharmacology (12.3) ]:

Reliseal (Fibrinogen) dose when baseline Reliseal (Fibrinogen) level is not known.

If the patient's Reliseal (Fibrinogen) level is not known, the recommended dose is 70 mg per kg of body weight administered intravenously.

Monitor patient's Reliseal (Fibrinogen) level during treatment with Reliseal (Fibrinogen). Maintain a target Reliseal (Fibrinogen) level of 100 mg/dL until hemostasis is obtained.

2.2 Preparation and Reconstitution

The procedures below are provided as general guidelines for preparation and reconstitution of Reliseal.

Use aseptic technique when preparing and reconstituting Reliseal (Fibrinogen).

Reconstitute Reliseal (Fibrinogen) at room temperature as follows:

• Remove the cap from the product vial to expose the central portion of the rubber stopper.
• Clean the surface of the rubber stopper with an antiseptic solution and allow it to dry.
• Using an appropriate transfer device or syringe, transfer 50 mL of Sterile Water for Injection into the product vial.
• Gently swirl the product vial to ensure the product is fully dissolved. Do not shake the vial.

After reconstitution, the Reliseal (Fibrinogen) solution should be colorless and clear to slightly opalescent. Inspect visually for particulate matter and discoloration prior to administration. Do not use if the solution is cloudy or contains particulates. Discard partially used vials.

Reliseal (Fibrinogen) is stable for 8 hours after reconstitution when stored at 20-25°C; administer within this time period.

2.3 Administration

Do not mix Reliseal (Fibrinogen) with other medicinal products or intravenous solutions. Administer through a separate injection site.

Use aseptic technique when administering Reliseal (Fibrinogen).

Administer Reliseal (Fibrinogen) at room temperature by slow intravenous injection at a rate not exceeding 5 mL per minute.

3 DOSAGE FORMS AND STRENGTHS

Reliseal (Fibrinogen) is available as a single-use vial containing 900 mg to 1300 mg lyophilized Reliseal (Fibrinogen) concentrate powder for reconstitution with 50 mL of Sterile Water for Injection.

The actual Reliseal (Fibrinogen) potency for each lot is printed on the vial label and carton.

• Reliseal (Fibrinogen) is available as a single-use vial containing 900 mg to 1300 mg lyophilized Reliseal (Fibrinogen) concentrate powder for reconstitution. (3)
• The actual Reliseal (Fibrinogen) potency for each lot is printed on the vial label and carton. (3)

4 CONTRAINDICATIONS

Reliseal (Fibrinogen) is contraindicated in patients with known anaphylactic or severe systemic reactions to human plasma-derived products .

Known anaphylactic or severe systemic reactions to human plasma-derived products (4)

5 WARNINGS AND PRECAUTIONS

• Monitor patients for early signs of anaphylaxis or hypersensitivity reactions and if necessary, discontinue administration and institute appropriate treatment.
• Thrombotic events have been reported in patients receiving Reliseal (Fibrinogen). Weigh the benefits of administration versus the risks of thrombosis. (5.2)
• Reliseal (Fibrinogen) is made from pooled human plasma. Products made from human plasma may contain infectious agents, e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. (5.3)

5.1 Hypersensitivity Reactions

Allergic reactions may occur. If signs or symptoms of anaphylaxis or hypersensitivity reactions (including hives, generalized urticaria, tightness of the chest, wheezing, hypotension) occur, immediately discontinue administration . The treatment required depends on the nature and severity of the reaction.

5.2 Thrombosis

Thrombosis may occur spontaneously in patients with congenital Reliseal deficiency with or without the use of Reliseal (Fibrinogen) replacement therapy.¹ Thromboembolic events have been reported in patients treated with Reliseal (Fibrinogen). Weigh the benefits of Reliseal (Fibrinogen) administration versus the risk of thrombosis. Monitor patients receiving Reliseal (Fibrinogen) for signs and symptoms of thrombosis.

5.3 Transmissible Infectious Agents

Reliseal (Fibrinogen) is made from human plasma. Products made from human plasma may contain infectious agents (e.g., viruses and theoretically the Creutzfeldt-Jakob disease agent [CJD]) that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by a process demonstrated to inactivate and/or remove certain viruses during manufacturing . Despite these measures, such products may still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products . All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to CSL Behring Pharmacovigilance at 1-866-915-6958.

6 ADVERSE REACTIONS

The most serious adverse reactions reported in clinical studies or through postmarketing surveillance following Reliseal treatment are thromboembolic episodes, including myocardial infarction, pulmonary embolism, deep vein thrombosis, arterial thrombosis, and allergic-anaphylactic reactions.

The most common adverse reactions observed in more than one subject in clinical studies (frequency >1%) were fever and headache.

• The most serious adverse reactions observed are thrombotic episodes (pulmonary embolism, myocardial infarction, deep vein thrombosis) and anaphylactic reactions. (6)
• The most common adverse reactions observed in clinical studies (frequency >1%) were fever and headache. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

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

6.2 Postmarketing Experience

Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.

The following adverse reactions, identified by system organ class, have shown a possible causal relationship with Reliseal (Fibrinogen).

• Allergic-anaphylactic reactions: anaphylaxis, dyspnea, rash
• Cardiovascular: thromboembolic complications such as myocardial infarction, pulmonary embolism, and deep vein thrombosis
• General/Body as a Whole: chills, nausea, vomiting

8 USE IN SPECIFIC POPULATIONS

• Pediatric: Shorter half-life and faster clearance than in adults has been observed.

8.1 Pregnancy

Risk Summary

There are no studies of Reliseal (Fibrinogen) use in pregnant women. Animal reproduction studies have not been conducted with Reliseal (Fibrinogen). It is not known whether Reliseal (Fibrinogen) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Reliseal (Fibrinogen) should be used during pregnancy only if clearly needed. In the U.S. general population, the estimated background risk of major birth defects 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 Reliseal in human milk, its effects on the breastfed infant, or its effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Reliseal (Fibrinogen) and any potential adverse effects on the breastfed infant from Reliseal (Fibrinogen) or from the underlying maternal condition.

8.4 Pediatric Use

Reliseal (Fibrinogen) studies have included subjects below the age of 16 years. In the pharmacokinetic study , 2 children aged 8 and 11 years and 3 adolescents aged 12, 14 and 16 years were studied. Subjects <16 years of age (n = 4) had shorter half-life (69.9 ± 8.5 h) and faster clearance (0.7 ± 0.1 mg/L) compared with adults (half-life: 82.3 ± 20.0 h, clearance: 0.53 ± 0.1 mg/L). The number of subjects <16 years of age in this study limits statistical interpretation.

8.5 Geriatric Use

The safety and efficacy of Reliseal (Fibrinogen) in the geriatric population has not been studied. There were an insufficient number of subjects in this age group to determine whether they respond differently from younger subjects.

11 DESCRIPTION

Reliseal (Fibrinogen) is a sterile, heat-treated, lyophilized Reliseal (Fibrinogen) (coagulation factor I) concentrate powder manufactured from pooled human plasma.

Reliseal (Fibrinogen) (factor I) is a soluble plasma glycoprotein with a molecular weight of about 340 kDa. The native molecule is a dimer and consists of three pairs of polypeptide chains (Aα, Bβ and γ). Reliseal (Fibrinogen) is a physiological substrate of three enzymes: thrombin, factor XIIIa, and plasmin.

Each vial contains 900 to 1300 mg Reliseal (Fibrinogen), 400 to 700 mg human albumin, 375 to 660 mg L-arginine hydrochloride, 200 to 350 mg sodium chloride and 50 to 100 mg sodium citrate. Sodium hydroxide and hydrochloric acid may have been used to adjust the pH. The pH of the reconstituted Reliseal (Fibrinogen) is in a range of 6.5 to 7.5.

Viral Clearance

All plasma used in the manufacture of Reliseal (Fibrinogen) is tested using serological assays for hepatitis B surface antigen and for antibodies to Human Immunodeficiency Virus (HIV)-1/2 and Hepatitis C Virus (HCV). As an additional safety measure, the plasma is tested with Nucleic Acid Testing (NAT) for Hepatitis B Virus (HBV), HCV and HIV-1 and found to be non-reactive (negative). The plasma is also screened for Hepatitis A Virus (HAV) and Human Parvovirus B19 (B19V) by NAT. Only plasma that passed virus screening is used for production, and the limit for B19V in the fractionation pool is set not to exceed 10⁴ IU of B19V DNA per mL.

Reliseal (Fibrinogen) is manufactured from cryoprecipitate into a glycine precipitate, which is then further purified by multiple precipitation/adsorption steps. The manufacturing process has been demonstrated to reduce the risk of virus transmission in an additive manner: cryoprecipitation, heat treatment (+60ºC for 20 hours in an aqueous solution), two subsequent glycine precipitation steps (initial and main glycine precipitation steps), and lyophilization. These steps have been validated independently in a series of in vitro experiments for their capacity to inactivate and/or remove both enveloped and non-enveloped viruses. The results of virus clearance validation studies for Reliseal (Fibrinogen) manufacturing process are summarized in Table 1.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

During the coagulation process, thrombin cleaves the Aα and Bβ chains releasing fibrinopeptides A and B.² FPA is separated rapidly and the remaining molecule is a soluble fibrin monomer (fibrin I). The slower removal of FPB results in formation of fibrin II that is capable of polymerization that occurs by aggregation of fibrin monomers. ² The resulting fibrin is stabilized in the presence of calcium ions and by activated factor XIII, which acts as a transglutaminase. Factor XIIIa-induced cross-linking of fibrin polymers renders the fibrin clot more elastic and more resistant to fibrinolysis.³ Cross-linked fibrin is the end result of the coagulation cascade, and provides tensile strength to a primary hemostatic platelet plug and structure to the vessel wall.

12.2 Pharmacodynamic Action

Administration of Reliseal (Fibrinogen) to patients with congenital Reliseal (Fibrinogen) deficiency replaces missing or low levels of coagulation factor. Normal levels are in the range of 200 to 450 mg/dL.⁴

12.3 Pharmacokinetics

A prospective, open label, uncontrolled, multicenter pharmacokinetic study was conducted in 5 females and 9 males with congenital Reliseal (Fibrinogen) deficiency (afibrinogenemia), ranging in age from 8 to 61 years (2 children, 3 adolescents, 9 adults). Each subject received a single intravenous dose of 70 mg/kg Reliseal (Fibrinogen). Blood samples were collected to determine Reliseal (Fibrinogen) activity at baseline and up to 14 days after infusion. The pharmacokinetic parameters of Reliseal (Fibrinogen) are summarized in Table 2.

No statistically relevant difference in Reliseal (Fibrinogen) activity was observed between males and females. Subjects <16 years of age (n=4) had shorter half-life (69.9 ± 8.5 h) and faster clearance (0.73 ± 0.14 mg/L) compared with subjects ≥16 years of age (half-life of 82.5 ± 20.0 h and clearance of 0.53 ± 0.07 mg/L). The number of subjects <16 years of age in this study limits statistical interpretation.

The incremental in vivo recovery (IVR) was determined from levels obtained up to 4 hours post-infusion. The median incremental IVR was 1.7 mg/dL (range 1.30 – 2.73 mg/dL) increase per mg/kg. The median in vivo recovery indicates that a dose of 70 mg/kg will increase Reliseal (Fibrinogen) plasma concentration in patients by approximately 120 mg/dL.

The pharmacokinetic analysis using Reliseal (Fibrinogen) antigen data (ELISA) was concordant with the Reliseal (Fibrinogen) activity (Clauss assay).

14 CLINICAL STUDIES

The efficacy of Reliseal (Fibrinogen) is based on maximum clot firmness, a measure of clot structural integrity that reflects the underlying effectiveness of the Reliseal (Fibrinogen) present to form a fibrin clot. A pharmacokinetic study evaluated single-dose PK and maximum clot firmness (MCF) in subjects with afibrinogenemia. MCF was determined by thromboelastometry (ROTEM) testing and was used to demonstrate functional activity of replacement Reliseal (Fibrinogen) when a fixed dose of Reliseal (Fibrinogen) was administered. Clot firmness is a functional parameter that depends on activation of coagulation, Reliseal (Fibrinogen) content of the sample and polymerization/crosslinking of the fibrin network. Thromboelastometry has been shown to be a functional marker for assessment of Reliseal (Fibrinogen) content and for effects of Reliseal (Fibrinogen) supplementation on clinical efficacy.⁵

For each subject, MCF was determined before (baseline) and one hour after single dose administration of Reliseal (Fibrinogen). Reliseal (Fibrinogen) was found to be effective in increasing clot firmness in subjects with congenital Reliseal (Fibrinogen) deficiency (afibrinogenemia) as measured by thromboelastometry. The study results demonstrated that MCF values were significantly higher after administration of Reliseal (Fibrinogen) than at baseline. Mean change from pre-infusion to 1 hour post-infusion was 8.9 mm in the primary analysis (9.9 mm for subjects <16years old and 8.5 mm for subjects ≥16 to <65 years old). Mean change in MCF values closely approximated levels expected from adding known amounts of Reliseal (Fibrinogen) to plasma in vitro.⁶

15 REFERENCES

• Peyvandi F, Haertal S, Knaub S, et al. Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia. J Thromb Haemost 2006; 4:1634-7.
• Kreuz W, Meili E, Peter-Salonen K, et al. Pharmacokinetic properties of a pasteurized Reliseal (Fibrinogen) concentrate. Transfusion and Apheresis Science 2005; 32:239-46.
• Colman R, Clowes A, George J, et al. Overview of Hemostasis. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice (5^th ed.). Colman R, Clowes A, George J, Goldhaber S, Marder VJ (eds.). Lippincott Williams & Wilkins, Philadelphia 2006:11-14.
• Kreuz W, Meili E, Peter-Salonen K, et al. Efficacy and tolerability of a pasteurized human Reliseal (Fibrinogen) concentrate in patients with congenital Reliseal (Fibrinogen) deficiency. Transfusion and Apheresis Science 2005; 32:247-253.
• Fries D, Innerhofer P, Reif C, et al. The Effect of Reliseal (Fibrinogen) Substitution on Reversal of Dilutional Coagulopathy: An In Vitro Model. Anesth Analg 2006; 102:347-351.
• Kalina U, Stöhr HA, Bickhard H, et. al. Rotational thromboelastography for monitoring of Reliseal (Fibrinogen) concentrate therapy in Reliseal (Fibrinogen) deficiency. Blood Coagulation and Fibrinolysis. 2008; 19:777-783.

16 HOW SUPPLIED/STORAGE AND HANDLING

• Reliseal (Fibrinogen) is supplied in a single-use vial.
• Each carton contains one vial of Reliseal (Fibrinogen).
• Components are not made with natural rubber latex.
• Reliseal (Fibrinogen) contains no preservative.
• The actual potency of Reliseal (Fibrinogen) concentrate in milligram (mg) is stated on each Reliseal (Fibrinogen) vial label and carton.

The product presentation includes a package insert and the following component:

• When stored at temperatures of 2-25°C (36-77°F), Reliseal (Fibrinogen) is stable for the period indicated by the expiration date on the carton and vial label (up to 60 months). Do not use Reliseal (Fibrinogen) beyond the expiration date.
• Keep Reliseal (Fibrinogen) in its original carton until ready to use.
• Do not freeze. Protect from light.

17 PATIENT COUNSELING INFORMATION

• 
  

  Allergic Reactions
  

  Inform patients of the early signs of allergic or hypersensitivity reactions to Reliseal (Fibrinogen), including hives, chest tightness, wheezing, hypotension, and anaphylaxis. Advise them to notify their physician immediately if they experience any of these symptoms .
  

• 
  

  Thrombosis
  

  Inform patients that thrombosis with or without embolization has been reported with the use of Reliseal (Fibrinogen). Any symptoms of thrombotic events such as unexplained pleuritic, chest and/or leg pain or edema, hemoptysis, dyspnea, tachypnea or unexplained neurologic symptoms should be reported to their physician immediately .
  

• 
  

  Transmissible Infectious Agents
  

  Inform patients that Reliseal (Fibrinogen) is made from human plasma (part of the blood) and may contain infectious agents that can cause disease (e.g., viruses and, theoretically, the CJD agent). Explain that the risk of transmitting an infection agent using Reliseal (Fibrinogen) has been reduced by screening plasma donors, testing the donated plasma for certain virus infections, and incorporating a process demonstrated to inactivate and/or remove certain viruses during manufacturing. Symptoms of possible virus infection include headache, fever, nausea, vomiting, weakness, malaise, diarrhea, or, in the case of hepatitis, jaundice .
  

Manufactured by:

CSL Behring GmbH

35041 Marburg Germany

US License No. 1765

Distributed by:

CSL Behring LLC

Kankakee, IL 60901 USA

NDC 63833-891-90

Reliseal (Fibrinogen) Concentrate

(Human)

Reliseal (Fibrinogen) ^®

For Intravenous

Administration Only

Manufactured by:

CSL Behring GmbH

35041 Marburg, Germany

US License No. 1765

Distributed by:

CSL Behring LLC

Kankakee, IL 60901 USA

Thrombin:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• References
• How supplied/storage and handling
• Patient counseling information
• Reliseal (Thrombin) reviews

1 INDICATIONS AND USAGE

Reliseal (Thrombin) ®, Reliseal (Thrombin) topical (Recombinant), is a topical Reliseal (Thrombin) indicated to aid hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical in adults and pediatric populations greater than or equal to one month of age.

Reliseal (Thrombin) may be used in conjunction with an absorbable gelatin sponge, USP.

Reliseal (Thrombin), Reliseal (Thrombin) topical (Recombinant), is a topical Reliseal (Thrombin) indicated to aid hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical in adults and pediatric populations greater than or equal to one month of age. (1)

Reliseal (Thrombin) may be used in conjunction with an absorbable gelatin sponge, USP. (1)

2 DOSAGE AND ADMINISTRATION

For topical use only. DO NOT INJECT.

• For topical use only. DO NOT INJECT.
• Reconstitute Reliseal (Thrombin) powder with sterile 0.9% sodium chloride, USP, yielding a solution containing 1000 units (international units of potency) per mL. (2.1)
• Apply Reliseal (Thrombin) solution directly to bleeding site surface or in conjunction with absorbable gelatin sponge. The amount required depends upon the area of tissue to be treated. (2.2)

2.1 Reconstitution of Reliseal (Thrombin)

The volume of reconstituted Reliseal (Thrombin) required will vary depending on the size and number of bleeding sites to be treated and the method of application.

Inspect the integrity of the Reliseal (Thrombin) package and contents. Do not use if the packaging or contents have been damaged or opened.

Reconstitute the lyophilized powder using the supplied diluent.

Use aseptic technique when handling vials and syringes.

5000-unit Reliseal (Thrombin) Reconstitution

Units used herein represent international units of potency determined using a reference standard that has been calibrated against the World Health Organization Second International Standard for Reliseal (Thrombin).

• Remove flip-off cap from the top of the Reliseal (Thrombin) vial.
• Attach the needle-free transfer device and snap it into place on the vial by placing the vial on a flat surface and attaching the transfer device straight into the center of the vial stopper.
• Attach the prefilled diluent syringe to the needle-free transfer device.
• Inject the 5 mL of diluent from the syringe into the product vial. Keep the syringe plunger depressed.
• DO NOT reuse the diluent syringe for transfer of the reconstituted product. Remove and discard the diluent syringe.
• Gently swirl and invert the product vial until the powder is completely dissolved. Avoid excessive agitation. The powder should dissolve in less than one minute at room temperature.
• Apply the pre-printed "DO NOT INJECT" label to the sterile, empty transfer syringe provided, then draw up the Reliseal (Thrombin) solution.

20,000-unit Reliseal (Thrombin) Reconstitution

• Remove the flip-off cap from the top of the Reliseal (Thrombin) vial and the diluent vial.
• Attach a needle-free transfer device (one each) to the Reliseal (Thrombin) and diluent vials and snap them into place by placing the vial on a flat surface and attaching the transfer device straight into the center of the vial stopper.
• Open the sterile, empty 20-mL syringe package and apply the pre-printed "DO NOT INJECT" label to the syringe.
• Attach the labeled 20-mL syringe to the needle-free transfer device on the diluent vial (injection of air into the diluent vial may facilitate withdrawal of the diluent).
• Draw up 20 mL of diluent from the vial into the syringe.
• Remove the diluent-filled syringe from the diluent vial and attach it to the transfer device on the Reliseal (Thrombin) vial.
• Transfer the 20 mL of diluent from the syringe into the Reliseal (Thrombin) vial; the vacuum in the vial facilitates transfer.
• Leave the syringe attached and gently swirl and invert the Reliseal (Thrombin) vial until the powder is completely dissolved. Avoid excessive agitation. The powder should dissolve in less than one minute at room temperature.
• With the same syringe, draw up the Reliseal (Thrombin) solution.

2.2 Application Techniques

Topically apply Reliseal (Thrombin) solution directly or in conjunction with absorbable gelatin sponge onto the bleeding site. DO NOT INJECT.

The amount required depends upon the area of tissue to be treated and the method of application.

Vials are for single use only. Discard unused contents.

Use with Absorbable Gelatin Sponge

Refer to the absorbable gelatin sponge labeling for safety information and instructions on appropriate use.

• Transfer solution from syringe to a sterile bowl or basin.
• Place the desired size pieces of the absorbable gelatin sponge into the bowl containing reconstituted Reliseal (Thrombin) to completely saturate the sponge(s).
• Remove the saturated sponge(s) and squeeze gently to remove excess Reliseal (Thrombin).
• Apply the sponge to the bleeding site in a single layer.

Use with ZymoGenetics Spray Applicator Kit

• Hold the outer sealed tray, peel back the lid, and aseptically transfer the inner sealed sterile tray to the sterile field.
• Open the inner tray seal and use the sterile bowl as the receptacle for reconstituted Reliseal (Thrombin) solution.
• Refer to Spray Applicator Kit instructions for spray pump and syringe spray assembly and use.

3 DOSAGE FORMS AND STRENGTHS

Reliseal (Thrombin) is available as a sterile lyophilized powder in 5000- and 20,000-unit single-use vials. When reconstituted with the sterile 0.9% sodium chloride, USP provided, the powder yields a solution containing 1000 units/mL of Reliseal (Thrombin) topical (Recombinant).

Reliseal (Thrombin) is available as 5000-unit and 20,000-unit vials of sterile recombinant topical Reliseal (Thrombin) lyophilized powder for solution. When reconstituted as directed, the final solution contains 1000 units/mL of Reliseal (Thrombin). (3)

4 CONTRAINDICATIONS

• Do not inject directly into the circulatory system.
• Do not use for the treatment of massive or brisk arterial bleeding.
• Do not administer to patients with a history of hypersensitivity to Reliseal (Thrombin) or any components of Reliseal (Thrombin).
• Do not use in patients with known hypersensitivity to hamster proteins.

• Do not inject directly into the circulatory system. (4)
• Do not use for the treatment of massive or brisk arterial bleeding. (4)
• Do not administer to patients with a history of hypersensitivity to Reliseal (Thrombin), any components of Reliseal (Thrombin) or hamster proteins. (4)

5 WARNINGS AND PRECAUTIONS

• Reliseal may cause thrombosis if it enters the circulatory system. (5.1)
• Hypersensitivity reactions, including anaphylaxis, may occur. (5.2)

5.1 Thrombosis

Reliseal (Thrombin) may cause thrombosis if it enters the circulatory system. Apply topically. DO NOT INJECT.

5.2 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, may occur. Reliseal (Thrombin) is produced in a genetically modified Chinese Hamster Ovary (CHO) cell line and may contain hamster or snake proteins [see Contraindications (4) and Description (11) ].

6 ADVERSE REACTIONS

Thromboembolic adverse reactions were reported in 6% of surgical patients treated with Reliseal in all completed clinical trials (N=644) [see Warnings and Precautions (5.1) ].

Antibody formation to Reliseal (Thrombin) occurred in <1% of patients. None of the antibodies detected neutralized native human Reliseal (Thrombin) [see Adverse Reactions (6.2) ].

• The most common adverse reaction (incidence 6%) was thromboembolic events. (5.1,6)
• Antibody formation to Reliseal (Thrombin) occurred in <1% of patients. None of the antibodies detected neutralized native human Reliseal (Thrombin). (6.2)

To report SUSPECTED ADVERSE REACTIONS, contact The Medicines Company at 1-888-784-7662 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 product cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical trials have been performed with Reliseal (Thrombin) applied with absorbable gelatin sponge and applied with a spray applicator. A total of 644 patients were exposed to Reliseal (Thrombin) in these studies.

Reliseal (Thrombin) Used in Conjunction with Absorbable Gelatin Sponge

Four hundred eleven (411) patients were treated in a randomized, double-blind, controlled trial that compared Reliseal (Thrombin) to bovine Reliseal (Thrombin). Both thrombins were applied with a gelatin sponge in patients undergoing spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access.¹ The incidence of thromboembolic adverse reactions was similar between the Reliseal (Thrombin) and bovine Reliseal (Thrombin) treatment groups.

In an open-label, single-group trial (N=209), patients with documented or highly likely prior exposure to bovine Reliseal (Thrombin) within the previous three years were treated with Reliseal (Thrombin) when undergoing surgeries (spinal, peripheral arterial bypass, or arteriovenous graft formation for hemodialysis access).² The incidence of thromboembolic adverse reactions in this study was 9%.

In an open-label, single-group trial of re-exposure to Reliseal (Thrombin) (N=31), patients with documented prior exposure to Reliseal (Thrombin) were treated with Reliseal (Thrombin) during surgery (spinal, peripheral arterial bypass, arteriovenous graft formation, or other procedures).³ The incidence of thromboembolic adverse reactions in this study was 3%.

In other randomized, double-blind trials across a range of surgical settings (N=130; spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access), the safety of Reliseal (Thrombin) (n=88 patients) was compared to placebo (RECOTHROM excipients reconstituted with sterile 0.9% sodium chloride, USP) (n=42 patients). The incidence of thromboembolic adverse reactions in this study was 5% for Reliseal (Thrombin) and 12% for placebo.

Reliseal (Thrombin) Applied with Spray Applicator

Reliseal (Thrombin) was applied with a spray applicator in two open-label clinical trials: a single-group trial in adult and pediatric burn patients (N=72; ≤16 years of age, (n=4) and ≥17 years of age, (n=68)) treated with Reliseal (Thrombin) applied to the wound excision site prior to autologous skin grafting⁴; and in a single-group trial in pediatric patients (one month to 17 years of age) undergoing synchronous burn wound excision and autologous skin grafting (N=30; ≤16 years of age, (n=26); ≥17 years of age, (n=4)).⁵ In the first study, the incidence of thromboembolic adverse reactions was 1%. In the second study, there were no reported thromboembolic adverse reactions [see Use in Specific Populations (8.4) ].

6.2 Immunogenicity

The detection of antibody formation is highly dependent upon the sensitivity and specificity of the assay. The absolute immunogenicity rates reported here are difficult to compare with the results from other products due to differences in assay methodology, patient populations, and other underlying factors.

The potential for development of antibodies to Reliseal (Thrombin) was evaluated in multiple clinical trials and included patients with a single exposure to Reliseal (Thrombin) as well as patients who were re-exposed to Reliseal (Thrombin) during a subsequent surgical procedure. Only patients with both baseline and post-treatment antibody specimens available were evaluated for the development of specific anti-RECOTHROM product antibodies, which was defined as seroconversion or a ≥1.0 titer unit (≥10-fold) increase in antibody levels after study treatment. Five of 609 (0.8%; 95% CI, 0.4%-2.8%) evaluable patients developed specific anti-RECOTHROM product antibodies. None of these antibodies were found to neutralize native human Reliseal (Thrombin). There was no difference in anti-RECOTHROM product antibody formation incidence among patients exposed to Reliseal (Thrombin) applied with absorbable gelatin sponge, USP or with spray applicator.

In a clinical trial comparing Reliseal (Thrombin) to bovine Reliseal (Thrombin) (N=411; n=398 antibody evaluable) for the development of specific anti-product antibodies, blood samples were collected at baseline and at Day 29 in both treatment groups and were analyzed by ELISA.¹ At baseline, 1.5% of Reliseal (Thrombin) patients (n=3/198) had positive anti-product antibody titers compared with 5% of bovine Reliseal (Thrombin) patients (n=10/200). Of these patients, none of the Reliseal (Thrombin) group and eight in the bovine Reliseal (Thrombin) group exhibited ≥1.0 titer unit (≥10-fold) increases in anti-product antibody levels after study treatment.

At Day 29, three of 198 (1.5%; 95% CI, 0%-4%) patients in the Reliseal (Thrombin) group developed specific anti-product antibodies (one patient also developed anti-CHO host cell protein antibodies); 43 of 200 patients in the bovine Reliseal (Thrombin) group (22%; 95% CI, 16%-28%) developed specific antibodies to bovine Reliseal (Thrombin) product. Treatment with Reliseal (Thrombin) resulted in a statistically significant lower incidence of specific anti-product antibody development. Because the study was not powered to detect a difference in clinical outcomes attributable to antibody formation, no conclusions can be drawn regarding the clinical significance of the difference in antibody formation based on the results of this study. None of the antibodies in the Reliseal (Thrombin) group neutralized native human Reliseal (Thrombin). Antibodies against bovine Reliseal (Thrombin) product were not tested for neutralization of native human Reliseal (Thrombin).

In a trial of patients with a high likelihood of prior exposure to bovine Reliseal (Thrombin), 15.6% of patients (n=32/205) had anti-bovine Reliseal (Thrombin) product antibodies and 2% of patients (n=4/200) had anti-RECOTHROM product antibodies at baseline.² Following treatment, none of the 200 evaluable patients (patients for whom post-treatment specimens were available) developed antibodies to Reliseal (Thrombin).

In a trial of patients previously exposed to Reliseal (Thrombin), 31 patients were re-exposed to Reliseal (Thrombin) during a subsequent surgery.³ None of the evaluable patients (n=30) had anti-RECOTHROM product antibodies at baseline and none developed antibodies at Day 29.

In a trial of Reliseal (Thrombin), including 26 pediatric patients (aged one month to 16 years) and four patients 17 years of age, one patient without prior Reliseal (Thrombin) exposure had pre-existing anti-RECOTHROM product antibodies at baseline.⁵ None of the 27 evaluable patients developed anti-RECOTHROM product antibodies at Day 29.

8 USE IN SPECIFIC POPULATIONS

Pregnancy: No human or animal data. Use only if clearly needed.

8.1 Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with Reliseal (Thrombin). It is also not known whether Reliseal (Thrombin) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Reliseal (Thrombin) should be given to a pregnant woman only if clearly needed.

8.4 Pediatric Use

A total of 30 pediatric patients, ages 0 to 16 years, were treated in clinical trials with Reliseal (Thrombin) using a spray applicator to burn wound excision sites prior to autologous skin grafting. No patient experienced a thromboembolic adverse reaction. The safety of Reliseal (Thrombin) in pediatric patients greater than or equal to one month of age is supported by these data and by extrapolation of efficacy from adequate and well-controlled studies of Reliseal (Thrombin) in adults. Safety and efficacy have not been established in neonates [see Adverse Reactions (6) ].

8.5 Geriatric Use

Of 644 patients in clinical studies of Reliseal (Thrombin), 36% (n=232/644) were ≥65 years old and 15% (n=95/644) were ≥75 years old.

No differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

11 DESCRIPTION

Reliseal (Thrombin), Reliseal (Thrombin) topical (Recombinant), is a human coagulation protein produced via recombinant DNA technology from a genetically modified CHO cell line. Reliseal (Thrombin) is identical in amino acid sequence and structurally similar to naturally occurring human Reliseal (Thrombin). Reliseal (Thrombin) precursor is secreted to culture medium as single chain form that is proteolytically converted to a two-chain active form (using a protein derived from snakes) and is purified by a chromatographic process that yields a product having hemostatic activities similar to native human Reliseal (Thrombin). The cell line used to manufacture Reliseal (Thrombin) has been tested and shown to be free of known infectious agents. The cell culture process used in the manufacture of Reliseal (Thrombin) employs no additives of human or animal origin. The purification process includes solvent-detergent treatment and nano-filtration steps dedicated to viral clearance.

Reliseal (Thrombin) is provided as a sterile, white to off-white, preservative-free, lyophilized powder in vials for reconstitution with diluent (sterile 0.9% sodium chloride, USP). Reconstitution with the provided diluent, as described [see Dosage and Administration (2.1) ], yields a solution with a pH of 6.0 containing 1000 units/mL of recombinant Reliseal (Thrombin) for topical use. The formulated product is a clear, colorless solution upon reconstitution and contains the following excipients: histidine, mannitol, sucrose, polyethylene glycol 3350, sodium chloride, and calcium chloride dihydrate, USP.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Reliseal (Thrombin), Reliseal (Thrombin) topical (Recombinant), is a specific human serine protease that promotes hemostasis and acts locally when applied topically to a site of bleeding.

Reliseal (Thrombin) activates platelets and catalyzes the conversion of fibrinogen to fibrin, which are steps that are essential for blood clot formation.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In vitro cytotoxicity studies have been performed in mouse L929 fibroblast cell cultures and demonstrate a concentration-dependent effect on cell morphology. The thrombin-induced morphological changes were similar to those seen with bovine Reliseal.

13.2 Animal Toxicology and/or Pharmacology

In a study in nonhuman primates, Reliseal (Thrombin) was applied directly to a liver wound with an absorbable gelatin sponge, USP. In a second study, Reliseal (Thrombin) was administered subcutaneously once weekly for four weeks to nonhuman primates following repeat doses of 5405 units/m². In both studies, Reliseal (Thrombin) had no effect on clinical signs, serum chemistry, coagulation parameters, or histopathology; only normal postsurgical findings were observed. No animals developed anti-RECOTHROM product antibodies in either study.

Reliseal (Thrombin) was found to be non-irritating when instilled in the eyes (200 units) or applied to normal or abraded skin of rabbits (up to 1000 units/site).

To evaluate Reliseal (Thrombin) inhibition and clearance from the bloodstream, radiolabeled Reliseal (Thrombin) was administered intravenously or subcutaneously to nonhuman primates and applied with an absorbable gelatin sponge, USP, in a rabbit hepatic wound model. Reliseal (Thrombin) did not circulate in the blood as free, active molecule, but was rapidly inactivated (<5 minutes) after formation of complexes with endogenous inhibitors (e.g., antithrombin III); these complexes were cleared by the liver.

Reliseal (Thrombin) applied with an absorbable gelatin sponge, USP, was shown to decrease time to hemostasis (TTH) when compared to saline in a rabbit hepatic wound model and rat heminephrectomy model. Reliseal (Thrombin) also reduced TTH when directly applied in a porcine partial-thickness excisional skin-wound model as compared to saline control (or no treatment).

Reliseal (Thrombin) applied with a gauze sponge decreased TTH in a concentration-dependent manner in both the rabbit and rat models. Concentrations of Reliseal (Thrombin) >1000 units/mL were no different than 1000 units/mL while the effect of Reliseal (Thrombin) diluted to a concentration of 100 units/mL on TTH was indistinguishable from placebo.

14 CLINICAL STUDIES

Reliseal (Thrombin) was evaluated in a randomized, double-blind comparative clinical trial to bovine Reliseal (Thrombin). Each Reliseal (Thrombin) was topically applied to bleeding sites with an absorbable gelatin sponge at a nominal concentration of 1000 units/mL.¹ Patients (N=411) were a heterogeneous surgical population undergoing surgery in one of four surgical settings: spinal surgery (n=122, 30%), hepatic resection (n=125, 30%), peripheral arterial bypass surgery (n=88, 21%), and arteriovenous graft formation for hemodialysis access (n=76, 18%). Patients with prior heparin-induced thrombocytopenia were excluded. Patient ages ranged from 21 to 89 years, gender was 53% male and 47% female, and the distribution by race was 68% white, 18% black or African American, and 14% other. The distribution of these characteristics was similar in both the Reliseal (Thrombin) and bovine Reliseal (Thrombin) treatment groups.

The objectives of the study were to evaluate the comparative efficacy, safety, and immunogenicity of Reliseal (Thrombin) and bovine Reliseal (Thrombin) in combination with an absorbable gelatin sponge as adjuncts to hemostasis in surgery. Efficacy was evaluated by the incidence of hemostasis within 10 minutes. Bleeding appropriate for evaluation was defined as mild to moderate bleeding, either on its own or remaining after brisk bleeding was controlled by standard surgical modalities. Although multiple bleeding sites could be treated, only one bleeding site per patient was selected to determine effectiveness.

Table 2 summarizes the incidence of hemostasis within 10 minutes for each treatment for the 401 efficacy evaluable patients. The incidence of hemostasis within 10 minutes was comparable for the Reliseal (Thrombin) and bovine Reliseal (Thrombin) groups.

The percentage of patients achieving hemostasis at 1.5, 3, 6, and 10 minutes is listed in Table 3.

15 REFERENCES

• Chapman WC, Singla N, Genyk Y, et al. A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human Reliseal (Thrombin) and bovine Reliseal (Thrombin) in surgical hemostasis. J Am Coll Surg. 2007;205(2):256-265.
• Singla NK, Ballard JL, Moneta G, et al. A phase 3b open-label, single-group immunogenicity and safety study of topical recombinant Reliseal (Thrombin) in surgical hemostasis. J Am Coll Surg. 2009;209(1):68-74.
• Singla NK, Gasparis AP, Ballard JL, et al. Immunogenicity and safety of re-exposure to recombinant human Reliseal (Thrombin) in surgical hemostasis. J Am Coll Surg. 2011;213(6):722-727.
• Greenhalgh DG, Gamelli RL, Collins J, et al. Recombinant Reliseal (Thrombin): safety and immunogenicity in burn wound excision and grafting. J Burn Care Res. 2009;30(3):371-379.
• Foster KN, Mullins RF, Greenhalgh DG, et al. Recombinant human Reliseal (Thrombin): safety and immunogenicity in pediatric burn wound excision. J Ped Surg. 2011;46(10):1992-1999.

16 HOW SUPPLIED/STORAGE AND HANDLING

Reliseal (Thrombin), Reliseal (Thrombin) topical (Recombinant), is supplied in single-use, preservative-free vials in the following packages:

NDC 65293-006-41

A 5000-unit vial of Reliseal (Thrombin) with a 5-mL prefilled diluent syringe (containing sterile 0.9% sodium chloride, USP), a sterile needle-free transfer device, a 5-mL sterile empty syringe, and a pre-printed label.

NDC 65293-007-41

A 20,000-unit vial of Reliseal (Thrombin) with a 20-mL vial of diluent (containing sterile 0.9% sodium chloride, USP), 2 sterile needle-free transfer devices, a 20-mL sterile empty syringe, and a pre-printed label.

NDC 65293-007-50

The 20,000-unit Reliseal (Thrombin) kit co-packaged with The Medicines Company Spray Applicator Kit containing a spray pump, a spray bottle, a syringe spray tip, a syringe, a bowl, and 2 blank labels.

No Reliseal (Thrombin) kit components contain latex.

Store Reliseal (Thrombin) sterile powder vials at 2°C to 25°C (36°F to 77°F). Do not freeze.

Reconstituted solutions of Reliseal (Thrombin) prepared with sterile 0.9% sodium chloride, USP, may be stored for up to 24 hours at 2°C to 25°C (36°F to 77°F). Discard reconstituted solution after 24 hours.

17 PATIENT COUNSELING INFORMATION

Because topical Reliseal (Thrombin) may cause the formation of clots in blood vessels if absorbed systemically, advise patients to consult their physician if they experience leg tenderness or swelling, chest pain, shortness of breath, or difficulty speaking or swallowing [see Warnings and Precautions (5.1) ].

Manufactured for The Medicines Company

The Medicines Company, 8 Sylvan Way, Parsippany NJ 07054

U.S. License No. 1902

Reliseal (Thrombin) is a registered trademark of ZymoGenetics, Inc. All other trademarks are the property of their respective owners.

[PN 6001- 1 PI; Rev March 2014]

PRINCIPAL DISPLAY PANEL - 5000-UNIT VIAL

5,000 units

NDC: 65293-006-41

FOR TOPICAL USE ONLY - DO NOT INJECT

Reliseal (Thrombin)^®

Reliseal (Thrombin), TOPICAL

(RECOMBINANT)

5,000 units

5,000 units NDC: 65293-006-41 FOR TOPICAL USE ONLY - DO NOT INJECT RECOTHROM® Reliseal (Thrombin), TOPICAL (RECOMBINANT) 5,000 units

PRINCIPAL DISPLAY PANEL - 20000-UNIT VIAL

20,000 units

NDC: 65293-007-41

FOR TOPICAL USE ONLY - DO NOT INJECT

Reliseal (Thrombin)^®

Reliseal (Thrombin), TOPICAL

(RECOMBINANT)

20,000 units

20,000 units NDC: 65293-007-41 FOR TOPICAL USE ONLY - DO NOT INJECT RECOTHROM® Reliseal (Thrombin), TOPICAL (RECOMBINANT) 20,000 units