Beriplast P Combi-Set

Aprotinin:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Storage
• Beriplast P Combi-Set (Aprotinin) reviews

INDICATIONS AND USAGE

Beriplast P Combi-Set (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 Beriplast P Combi-Set (Aprotinin).

Administration of Beriplast P Combi-Set (Aprotinin)^® to patients with a known or suspected previous Beriplast P Combi-Set (Aprotinin) exposure during the last 12 months is contraindicated. For patients with known or suspected history of exposure to Beriplast P Combi-Set (Aprotinin) greater than 12 months previously, see WARNINGS. Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (Aprotinin)^®, administration should be stopped immediately and emergency treatment should be initiated. Even when a second exposure to Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (Aprotinin)^® into the pump prime solution until after the loading dose has been safely administered.

Re-exposure to Beriplast P Combi-Set (Aprotinin): Administration of Beriplast P Combi-Set (Aprotinin), especially to patients who have received Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (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: Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (Aprotinin) group (1.1% vs. 0.8%). Careful consideration of the balance of benefits versus potential risks is advised before administering Beriplast P Combi-Set (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 Beriplast P Combi-Set (Aprotinin)^® should first receive an initial (test) dose to minimize the extent of Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (Aprotinin)^®.

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

Renal Dysfunction: Bayer’s global pool of placebo-controlled studies in patients undergoing CABG showed Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (Aprotinin)^® administration.

Use of Beriplast P Combi-Set (Aprotinin)^® in patients undergoing deep hypothermic circulatory arrest: Two U.S. case control studies have reported contradictory results in patients receiving Beriplast P Combi-Set (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:

Beriplast P Combi-Set (Aprotinin)^® is known to have antifibrinolytic activity and, therefore, may inhibit the effects of fibrinolytic agents.

In study of nine patients with untreated hypertension, Beriplast P Combi-Set (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, Beriplast P Combi-Set (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 Beriplast P Combi-Set ^® or studies to determine the effect of Beriplast P Combi-Set (Aprotinin)^® on fertility have not been performed.

Results of microbial in vitro tests using Salmonella typhimurium and Bacillus subtilis indicate that Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (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:

Beriplast P Combi-Set (Aprotinin)^® prolongs whole blood clotting times by a different mechanism than heparin. In the presence of Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (Aprotinin). Consult the manufacturer of the ACT test regarding the interpretation of the assay in the presence of Beriplast P Combi-Set (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 Beriplast P Combi-Set (Aprotinin), can be used to measure heparin levels. A heparin dose response, assessed by protamine titration, should be performed prior to administration of Beriplast P Combi-Set (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 Beriplast P Combi-Set (Aprotinin).

ADVERSE REACTIONS

Studies of patients undergoing CABG surgery, either primary or repeat, indicate that Beriplast P Combi-Set ^® is generally well tolerated. The adverse events reported are frequent sequelae of cardiac surgery and are not necessarily attributable to Beriplast P Combi-Set (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 Beriplast P Combi-Set (Aprotinin)^® treated patients without regard to causal relationship.

In comparison to the placebo group, no increase in mortality in patients treated with Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (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% Beriplast P Combi-Set (Aprotinin)^® vs. 3.8% placebo) or of death (1.4% Beriplast P Combi-Set (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 Beriplast P Combi-Set (Aprotinin)^® (1/1424 patients or <0.1% on Beriplast P Combi-Set (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 Beriplast P Combi-Set (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: Beriplast P Combi-Set (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 Beriplast P Combi-Set (Aprotinin)^®. The incidence of treatment-emergent increases in ALT (formerly SGPT) > 1.8 times the upper limit of normal was 14% in both the Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (Aprotinin)^® treated patients in the hours after surgery due to circulating concentrations of Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (Aprotinin)^® therapy is unclear.

DOSAGE AND ADMINISTRATION

Beriplast P Combi-Set ^® 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.

Beriplast P Combi-Set (Aprotinin)^® is supplied as a solution containing 10,000 KIU/mL, which is equal to 1.4 mg/mL. All intravenous doses of Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (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:

Beriplast P Combi-Set (Aprotinin)^® administration is associated with a risk for renal dysfunction. Changes in Beriplast P Combi-Set (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 Beriplast P Combi-Set (Aprotinin)^® are not available.

HOW SUPPLIED

STORAGE

Beriplast P Combi-Set (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

Calcium Chloride:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Beriplast P Combi-Set (Calcium Chloride) reviews

1 INDICATIONS AND USAGE

Beriplast P Combi-Set (Calcium Chloride) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Beriplast P Combi-Set (Calcium Chloride) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Beriplast P Combi-Set (Calcium Chloride) acetate capsule.

- Capsule: 667 mg Beriplast P Combi-Set (Calcium Chloride) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Beriplast P Combi-Set acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Beriplast P Combi-Set (Calcium Chloride) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Beriplast P Combi-Set (Calcium Chloride), including Beriplast P Combi-Set (Calcium Chloride) acetate. Avoid the use of Beriplast P Combi-Set (Calcium Chloride) supplements, including Beriplast P Combi-Set (Calcium Chloride) based nonprescription antacids, concurrently with Beriplast P Combi-Set (Calcium Chloride) acetate.

An overdose of Beriplast P Combi-Set (Calcium Chloride) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Beriplast P Combi-Set (Calcium Chloride) levels twice weekly. Should hypercalcemia develop, reduce the Beriplast P Combi-Set (Calcium Chloride) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Beriplast P Combi-Set (Calcium Chloride) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Beriplast P Combi-Set (Calcium Chloride) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Beriplast P Combi-Set (Calcium Chloride) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Beriplast P Combi-Set (Calcium Chloride) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg²/dL².

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Beriplast P Combi-Set (Calcium Chloride) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial 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.

In clinical studies, Beriplast P Combi-Set (Calcium Chloride) acetate has been generally well tolerated.

Beriplast P Combi-Set (Calcium Chloride) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Beriplast P Combi-Set (Calcium Chloride) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.

Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Beriplast P Combi-Set (Calcium Chloride) concentration could reduce the incidence and severity of Beriplast P Combi-Set (Calcium Chloride) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Beriplast P Combi-Set (Calcium Chloride) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Beriplast P Combi-Set acetate is characterized by the potential of Beriplast P Combi-Set (Calcium Chloride) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Beriplast P Combi-Set (Calcium Chloride) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Beriplast P Combi-Set (Calcium Chloride) acetate and most concomitant drugs. When administering an oral medication with Beriplast P Combi-Set (Calcium Chloride) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Beriplast P Combi-Set (Calcium Chloride) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Beriplast P Combi-Set (Calcium Chloride) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Beriplast P Combi-Set (Calcium Chloride) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Beriplast P Combi-Set (Calcium Chloride) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Beriplast P Combi-Set acetate capsules contains Beriplast P Combi-Set (Calcium Chloride) acetate. Animal reproduction studies have not been conducted with Beriplast P Combi-Set (Calcium Chloride) acetate, and there are no adequate and well controlled studies of Beriplast P Combi-Set (Calcium Chloride) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Beriplast P Combi-Set (Calcium Chloride) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Beriplast P Combi-Set (Calcium Chloride) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Beriplast P Combi-Set (Calcium Chloride) acetate treatment, as recommended, is not expected to harm a fetus if maternal Beriplast P Combi-Set (Calcium Chloride) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Beriplast P Combi-Set (Calcium Chloride) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Beriplast P Combi-Set Acetate Capsules contains Beriplast P Combi-Set (Calcium Chloride) acetate and is excreted in human milk. Human milk feeding by a mother receiving Beriplast P Combi-Set (Calcium Chloride) acetate is not expected to harm an infant, provided maternal serum Beriplast P Combi-Set (Calcium Chloride) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Beriplast P Combi-Set (Calcium Chloride) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Administration of Beriplast P Combi-Set (Calcium Chloride) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Beriplast P Combi-Set (Calcium Chloride) acetate acts as a phosphate binder. Its chemical name is Beriplast P Combi-Set (Calcium Chloride) acetate. Its molecular formula is C₄H₆CaO₄, and its molecular weight is 158.17. Its structural formula is:

Each white opaque/blue opaque capsule contains 667 mg of Beriplast P Combi-Set (Calcium Chloride) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Beriplast P Combi-Set (Calcium Chloride), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Beriplast P Combi-Set (Calcium Chloride) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Beriplast P Combi-Set resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Beriplast P Combi-Set (Calcium Chloride) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Beriplast P Combi-Set (Calcium Chloride) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Beriplast P Combi-Set (Calcium Chloride) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Beriplast P Combi-Set (Calcium Chloride) acetate.

14 CLINICAL STUDIES

Effectiveness of Beriplast P Combi-Set (Calcium Chloride) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Beriplast P Combi-Set (Calcium Chloride) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Beriplast P Combi-Set (Calcium Chloride) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Beriplast P Combi-Set (Calcium Chloride) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Beriplast P Combi-Set (Calcium Chloride) levels are also presented.

There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Beriplast P Combi-Set (Calcium Chloride) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Beriplast P Combi-Set (Calcium Chloride) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Beriplast P Combi-Set (Calcium Chloride) acetate is shown in the Table 3.

Overall, 2 weeks of treatment with Beriplast P Combi-Set (Calcium Chloride) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Beriplast P Combi-Set (Calcium Chloride) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Beriplast P Combi-Set (Calcium Chloride) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Beriplast P Combi-Set (Calcium Chloride) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Beriplast P Combi-Set (Calcium Chloride) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Beriplast P Combi-Set (Calcium Chloride) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Coagulation Factor XIII:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• References
• How supplied/storage and handling
• Patient counseling information
• Patient package insert
• Beriplast P Combi-Set (Coagulation Factor XIII) reviews

1 INDICATIONS AND USAGE

Beriplast P Combi-Set (Coagulation Factor XIII), Beriplast P Combi-Set (Coagulation Factor XIII) A-Subunit (Recombinant), is indicated for routine prophylaxis for bleeding in patients with congenital factor XIII A-subunit deficiency.

Beriplast P Combi-Set (Coagulation Factor XIII) is not for use in patients with congenital factor XIII B‑subunit deficiency

Beriplast P Combi-Set (Coagulation Factor XIII), Beriplast P Combi-Set (Coagulation Factor XIII) A-Subunit (Recombinant), is indicated for routine prophylaxis of bleeding in patients with congenital factor XIII A-subunit deficiency. (1)

Beriplast P Combi-Set (Coagulation Factor XIII) is not for use in patients with congenital factor XIII B‑subunit deficiency. (1)

2 DOSAGE AND ADMINISTRATION

For intravenous use only.

For intravenous use only.

Dose:

• 35 international units per kilogram body weight once monthly to achieve a target trough level of FXIII activity at or above 10% using a validated assay.
• Consider dose adjustment if adequate coverage is not achieved with a 35 IU/kg dose. (2.1)
• Once reconstituted, Beriplast P Combi-Set (Coagulation Factor XIII) may be diluted with 0.9% sodium chloride to facilitate measurement of small volumes. (2.2)

Rate: Do not exceed 1-2 mL per minute. (2.3)

2.1 Dose

• Treatment should be initiated under the supervision of a physician experienced in the treatment of rare bleeding disorders.
• The dose for routine prophylaxis for bleeding in patients with congenital factor XIII (FXIII) A-subunit deficiency is 35 international units (IU) per kilogram body weight once monthly to achieve a target trough level of FXIII activity at or above 10% using a validated assay.
• Consider dose adjustment if adequate coverage is not achieved with the recommended 35 IU/kg dose.
• A pharmacokinetic study was conducted in the FXIII congenitally deficient population evaluating five dose cohorts (2, 7, 24, 60 and 89 IU/kg) with blood sampling at 0.5, 1, 4, 8, 24, 48, 72 hours, and 7, 14, and 28 days. Samples were tested for FXIII activity by a chromogenic assay and for FXIII A₂B₂ tetramer levels by an ELISA, as well as for other analytes. It was found that FXIII tetramer levels were proportional to the observed FXIII activity up to the point of replacement of 100% of normal FXIII activity, but there was no increase in FXIII tetramer levels at higher levels of FXIII activity. A dose of 35 IU/kg is sufficient to replace 100% of FXIII activity in this population, and higher doses may not increase the levels of tetrameric Factor XIII.

2.2 Reconstitution

Reconstitute only with sterile water for injection ). The product can be reconstituted using the vial adapter included or a needle.

Reconstitute using the following procedures:

• 1. Use aseptic technique.
• 2. Wash hands before starting.
• 3. Bring Beriplast P Combi-Set (Coagulation Factor XIII) (white lyophilized powder) and sterile water for injection (diluent) to room temperature, but not above 25°C (77°F).
• 4. Remove the plastic caps from the two vials.
• 5. Clean the rubber stoppers on the vials with sterile alcohol swabs and allow them to dry before use.
• 6. Remove the protective paper from the vial adapter, but do not unscrew the protective cap. Attach the vial adapter to the diluent vial, without taking the vial adapter out of the protective cap. Once attached, remove the protective cap from the vial adapter by lightly squeezing the protective cap with your thumb and index finger as shown on the figure below.

• 7. Draw back the plunger of the sterile syringe and admit a volume of 3.2 mL air into the syringe.

• 8. Screw the syringe onto the vial adapter on the diluent vial.

• 9. Inject the air from the syringe into the diluent vial until resistance is felt. Then hold the syringe with the diluent vial upside down and withdraw 3.2 mL water into the syringe.

• 10. Remove the empty diluent vial by tipping the syringe with the attached vial adapter.

• 11. Attach the syringe with the vial adapter to the powder vial. Hold the syringe slightly tilted with vial facing downwards. Push the plunger slowly to inject all water (3.2 mL) into the powder vial. Do not inject the diluent directly on the Beriplast P Combi-Set (Coagulation Factor XIII) powder to avoid foaming.

• 12. Gently swirl the vial until all material is dissolved. Do not shake the vial. The reconstituted Beriplast P Combi-Set (Coagulation Factor XIII) is a clear and colorless solution. Use the reconstituted Beriplast P Combi-Set (Coagulation Factor XIII) immediately. If not, store the solution refrigerated or at room temperature not to exceed 25°C (77°F) for up to three hours. Discard after three hours.

• NOTE:

• For larger dose that requires multiple vials of Beriplast P Combi-Set (Coagulation Factor XIII), reconstitute each additional vial using the same procedure with a separate syringe.
• For smaller dose that requires less than the full volume in the vial, reconstituted Beriplast P Combi-Set (Coagulation Factor XIII) may be diluted with 0.9% sodium chloride to facilitate measurement of small volumes. Discard remaining product.
• For home administration, any such changes should be communicated by the pharmacist or healthcare provider to the patient or family.

2.3 Administration

• Inspect the reconstituted Beriplast P Combi-Set (Coagulation Factor XIII) visually for particulate matter and discoloration prior to administration. Do not use if particulate matter or discoloration is observed.
• Administer at a rate not exceeding 1-2 mL per minute.
• Do not administer with other infusion solutions.
• Do not administer as drip.

3 DOSAGE FORMS AND STRENGTHS

Beriplast P Combi-Set (Coagulation Factor XIII), Beriplast P Combi-Set (Coagulation Factor XIII) A-Subunit (Recombinant), is available as a white lyophilized powder in single-use vial containing nominally 2500 IU per vial (2000 – 3125 IU) of recombinant Beriplast P Combi-Set (Coagulation Factor XIII) A-subunit. The actual amount of Beriplast P Combi-Set (Coagulation Factor XIII) in IU is stated on each carton and vial.

After reconstitution with the provided Sterile Water for Injection, each vial contains 667-1042 IU/mL recombinant Beriplast P Combi-Set (Coagulation Factor XIII) A-subunit.

• Lyophilized powder in single-use vial containing 2000 - 3125 IU of recombinant Beriplast P Combi-Set (Coagulation Factor XIII) A-subunit.
• After reconstitution with 3.2 mL of sterile water for injection, each vial contains 667-1042 IU/mL of recombinant Beriplast P Combi-Set (Coagulation Factor XIII) A-subunit.

4 CONTRAINDICATIONS

Beriplast P Combi-Set (Coagulation Factor XIII) is contraindicated in patients who have known hypersensitivity to the active substance or to any of the excipients .

Hypersensitivity to the active substance or to any of the excipients. (4)

5 WARNINGS AND PRECAUTIONS

• Discontinue if allergic or hypersensitivity reactions occur.
• Monitor patients for thrombosis. (5.2)
• Analyze for neutralizing antibodies if FXIII activity fails to reach expected levels or if reduced therapeutic effect is observed. (5.3)

5.1 Hypersensitivity Reactions

Beriplast P Combi-Set (Coagulation Factor XIII) may cause allergic reactions. If signs or symptoms of anaphylaxis or hypersensitivity reactions (including urticaria, rash, tightness of the chest, wheezing, hypotension) occur, discontinue immediately and institute appropriate treatment.

5.2 Thromboembolic Risk

Thromboembolic complications may occur. Monitor patients with conditions that predispose to thrombosis for signs and symptoms of thrombosis after administration of Beriplast P Combi-Set.

5.3 Inhibitors

Inhibitory antibodies may occur with Beriplast P Combi-Set (Coagulation Factor XIII). Patients with inhibitory antibodies may manifest as an inadequate response to treatment. If expected plasma FXIII activity levels are not attained, or if breakthrough bleeding occurs while receiving prophylaxis, perform an assay that measures FXIII inhibitory antibody concentrations.

6 ADVERSE REACTIONS

The most common adverse reactions reported in clinical trials, were headache, pain in the extremities, injection site pain, and increase in fibrin D dimer levels.

The most common adverse reactions reported in the clinical trials (≥1%) were headache, pain in the extremities, injection site pain, D dimer increase. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-844-873-8836 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 cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

During clinical development, Beriplast P Combi-Set (Coagulation Factor XIII) was administered to 77 subjects with congenital factor XIII A-subunit deficiency (3:2, male: female ratio) for a total of 1990 doses. Fifty subjects (65%) were between the ages of 18 and 77 years (received 1338 doses), 21 subjects (27%) were between the ages of 6 and less than 18 years old (received 560 doses), and 6 subjects (8%) were less than 6 years old (received 92 doses). Subjects were exposed for up to 4.5 years.

Of the 77 subjects, 68 received 1979 monthly doses of 35 IU/kg of Beriplast P Combi-Set (Coagulation Factor XIII) for routine prophylaxis of bleeding. Eleven single doses of Beriplast P Combi-Set (Coagulation Factor XIII) have been administered to nine subjects for pharmacokinetic investigations.

The adverse drug reactions reported included headache, pain in the extremities, pain at the injection site, and increase in fibrin D dimer levels (without evidence of thromboembolic events).

Immunogenicity

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Beriplast P Combi-Set (Coagulation Factor XIII) with the incidence of antibodies to other products may be misleading.

Transient non-neutralizing antibodies were seen in one out of 50 healthy subjects after one dose, four out of 77 trial subjects (age < 18 years) with congenital factor XIII A-subunit deficiency after one or two doses (3 discontinued from the trial), and in one subject (age < 18 years) in a post marketing safety study after 3.5 years of treatment. In two subjects, the non-neutralizing antibodies disappeared after continued treatment with Beriplast P Combi-Set (Coagulation Factor XIII). In all cases, the non-neutralizing antibodies were found to be of no clinical significance. No subjects developed neutralizing antibodies (inhibitors) against Beriplast P Combi-Set (Coagulation Factor XIII) during clinical trials.

7 DRUG INTERACTIONS

Thrombosis may occur if Beriplast P Combi-Set (Coagulation Factor XIII) is administered concomitantly with factor VIIa .

• Do not administer Beriplast P Combi-Set (Coagulation Factor XIII) with recombinant factor VIIa. (7)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies using Beriplast P Combi-Set in pregnant women to determine whether there is a drug-associated risk. Animal reproduction studies have not been conducted with Beriplast P Combi-Set (Coagulation Factor XIII).

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.

Miscarriage is a known complication of congenital FXIII deficiency. Pooling data from 39 publications, the miscarriage rate was 66% in 63 patients with 192 pregnancies (70% in 179 pregnancies in FXIII A-subunit deficiency women). Miscarriage rate was 91% in the 136 pregnancies without routine prophylaxis with FXIII concentrates and 11% in the 45 pregnancies treated with routine FXIII prophylaxis².

8.2 Lactation

Risk Summary

There is no information regarding the presence of Beriplast P Combi-Set (Coagulation Factor XIII) in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Beriplast P Combi-Set (Coagulation Factor XIII) and any potential adverse effects on the breastfed infant from Beriplast P Combi-Set (Coagulation Factor XIII) or from the underlying maternal condition.

8.4 Pediatric Use

Pediatric subjects in the phase 3 study and the extension study included 6 children in the age range 0-5, 12 children in the age range 6-12, and 9 adolescents in the age range 13-17 who were treated with Beriplast P Combi-Set for a total of 652 exposures. Adverse reactions were more frequently reported in subjects aged from 6 to less than 18 years old than in adults; a greater number of possible/probably trial drug related events were reported in the subjects below 18 years of age (6 subjects with 11 events in 27 enrolled subjects) than in those above 18 years (3 subjects with 3 events in 41 enrolled subjects). Three subjects under 18 years experienced non-neutralizing antibodies and were withdrawn from the study. A fourth pediatric subject who had a non-neutralizing antibody remained in the trial. No dose adjustment is required for pediatric age group.

8.5 Geriatric Use

The safety and efficacy of Beriplast P Combi-Set (Coagulation Factor XIII) in the geriatric population have not been established due to an insufficient number of patients.

10 OVERDOSAGE

One subject accidentally received a dose 2.3 times the recommended dose. No clinical signs and symptoms were observed.

11 DESCRIPTION

Beriplast P Combi-Set (Coagulation Factor XIII), Beriplast P Combi-Set (Coagulation Factor XIII) A-Subunit (Recombinant), is a recombinant human factor XIII-A₂ homodimer composed of two factor XIII (FXIII) A-subunits. The FXIII A-subunit is a 731 amino acid chain with an acetylated N-terminal serine. When FXIII is activated by thrombin, a 37 amino acid peptide is cleaved from the N-terminus of the A‑subunit.

Beriplast P Combi-Set (Coagulation Factor XIII) is manufactured as an intracellular, soluble protein in yeast (Saccharomyces cerevisiae) production strain containing the episomal expression vector, pD16. It is subsequently isolated by homogenization of cells and purification by several chromatography steps, including hydrophobic interaction and ion exchange chromatography. No human or animal derived products are used in the manufacturing process.

Beriplast P Combi-Set (Coagulation Factor XIII) is supplied as a sterile, white lyophilized powder in a single use vial. Table 1 and Table 2 list the vial content of reconstituted Beriplast P Combi-Set (Coagulation Factor XIII) and the diluent, respectively.

*Values are given per 3 mL reconstituted Beriplast P Combi-Set (Coagulation Factor XIII).

After reconstitution with 3.2 mL sterile water for injection, each vial contains 667-1042 IU/mL of recombinant Beriplast P Combi-Set (Coagulation Factor XIII) A-subunit. The reconstituted solution has a pH of approximately 8.0. The formulation contains no preservative and must only be administered intravenously.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

FXIII is the terminal enzyme in the blood coagulation cascade. When activated by thrombin at the site of vessel wall injury, FXIII plays an important role in the maintenance of hemostasis through cross-linking of fibrin and other proteins in the fibrin clot.

In plasma, FXIII circulates as a heterotetramer [A₂B₂] composed of two FXIII A-subunits and two FXIII B-subunits held together by strong non-covalent interactions. The FXIII A is the catalytic subunit and FXIII B-subunit acts as carrier molecule for the FXIII A-subunit in circulation, and is present in excess in plasma. When FXIII A-subunit is bound to FXIII B-subunit [A₂B₂] the half-life of the FXIII A-subunit [A₂] is prolonged. FXIII is a pro-enzyme, which is activated by thrombin in the presence of Ca²⁺. The enzymatic activity resides with the FXIII A-subunit. Upon activation, the FXIII A‑subunit dissociates from the FXIII B-subunit and thereby exposes the active site of the FXIII A-subunit. The active transglutaminase cross-links fibrin and other proteins resulting in increased mechanical strength and resistance to fibrinolysis of the fibrin clot and contributes to enhance platelet and clot adhesion to injured tissue.

Beriplast P Combi-Set (Coagulation Factor XIII) A-Subunit (Recombinant) is a protransglutaminase (rFXIII [rA₂] homodimer) and binds to free human FXIII B-subunit resulting in a heterotetramer [rA₂B₂] with a similar half-life to [A₂B₂]. rFXIII has been shown to be activated by thrombin in the presence of Ca²⁺. Activated rFXIII has been shown in dose-dependent manner to increase mechanical strength of fibrin clots, retard fibrinolysis, and rFXIII has been shown to enhance platelet adhesion to the site of injury. After combining with available plasma B-subunits, Beriplast P Combi-Set (Coagulation Factor XIII) A-subunit (Recombinant) has been shown to have the same pharmacodynamic properties in plasma as endogenous FXIII.

12.2 Pharmacodynamics

A qualitative assay of clot solubility is widely used as an indicator of FXIII deficiency; when performed correctly the test is positive only when the FXIII activity in the sample is close to zero. The results of standard coagulation tests are normal as it is the quality of the clot that is affected. In addition, at present there are no markers that can quantitatively assess the in vivo pharmacodynamics of FXIII.

12.3 Pharmacokinetics

Steady State in Subjects with Congenital Factor XIII Deficiency

In 23 subjects with congenital FXIII A-subunit deficiency on prophylaxis, the pharmacokinetics of rFXIII were evaluated over a dosing interval of 28 days during steady state.

The pharmacokinetic parameters based on steady state baseline adjusted FXIII activity (Berichrom assay) values are shown in Table 3.

• Table 3 Pharmacokinetic parameters based on steady state baseline adjusted FXIII activity

At steady state, the pharmacokinetics of rFXIII are comparable with the single dose pharmacokinetics of rFXIII.

Pediatric (Ages 1 to < 6 Years Old)

In a pharmacokinetic trial six children with congenital FXIII A-subunit deficiency on prophylaxis treatment were administered a single intravenous dose of 35 IU/kg. The pharmacokinetic parameters based on baseline adjusted FXIII activity (Berichrom assay) values are shown in Table 4. No dose adjustment is needed for pediatric patients as there is no influence of age on the pharmacokinetics of Beriplast P Combi-Set (Coagulation Factor XIII).

• Table 4 The pharmacokinetic parameters based on baseline adjusted FXIII activity

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate the carcinogenic potential of Beriplast P Combi-Set, or studies to determine the effects of Beriplast P Combi-Set (Coagulation Factor XIII) on genotoxicity or fertility have not been performed. An assessment of the carcinogenic potential of Beriplast P Combi-Set (Coagulation Factor XIII) was completed and suggests minimal carcinogenic risk from product use.

13.2 Animal Toxicology and/or Pharmacology

Exaggerated pharmacologic effects, including general thrombosis, ischemic necrosis and mortality were observed in nonclinical studies with Beriplast P Combi-Set (Coagulation Factor XIII) and non-proteolytically activated recombinant FXIII at a dose of 1670 IU/kg, i.e., 48 times the recommended human dose of 35 IU/kg.

In a monkey cardiovascular safety pharmacology model evaluating the combination of excessive doses of Beriplast P Combi-Set (Coagulation Factor XIII) (585 IU/kg, 17 times the expected human dose) in combination with rFVIIa (1000 mcg/kg, 11 times the expected human dose), one of the twelve monkeys died 4 hours after treatment due to thrombosis. Procoagulant risk factors, including 6 indwelling catheters per monkey and the induction of anesthesia, may have complicated the study results. It is unclear whether the mortality was related to the overdose of one or both products, or a specific interaction between them. Nonclinical and clinical studies with the combination of Beriplast P Combi-Set (Coagulation Factor XIII) and rFVIIa at recommended human doses have not been performed.

14 CLINICAL STUDIES

To establish the efficacy of Beriplast P Combi-Set (Coagulation Factor XIII) for the prevention of bleeding in patients with congenital FXIII A-subunit deficiency, a multi-center, open-label, non-controlled trial was conducted for 52 weeks in forty-one (41) subjects ≥ 6 years. All subjects received monthly doses of Beriplast P Combi-Set (Coagulation Factor XIII) at 35 IU/kg. Bleeding episodes that required treatment with a FXIII-containing product were observed to evaluate the efficacy of monthly replacement therapy with Beriplast P Combi-Set (Coagulation Factor XIII) on prevention of bleeding episodes.

Subjects with congenital FXIII A-subunit deficiency confirmed by genotyping were included. Subjects who before entering the trial had received regular replacement therapy were to have initiated regular replacement therapy at least 6 months prior to screening and were to have a documented history of at least one treatment-requiring bleeding episode before initiation of regular replacement therapy or a documented family history of FXIII congenital deficiency. Subjects who before entering the trial had only received on-demand treatment were to have a documented history of at least two treatment-requiring bleeding episodes within 12 months of the screening visit. Severe bleeders as defined by a documented history of ≥2 treatment requiring bleedings per year during regular FXIII replacement therapy were excluded.

During the prophylaxis treatment period with Beriplast P Combi-Set (Coagulation Factor XIII) (434 subject months), five bleeding episodes treated with FXIII-containing products were observed in four subjects. All five were associated with trauma. When calculated for all 41 subjects, this translated into a mean annual rate of bleeding episodes that required treatment of 0.14 [95% CI:0.058- 0.332] per subject year, which was statistically significantly lower than the historic bleeding rate of 1.68 per subject year for on-demand treatment. The age-adjusted rate of bleeding episodes that required treatment during the Beriplast P Combi-Set (Coagulation Factor XIII) treatment period was 0.05 [95% CI: 0.0094 - 0.2501] per subject year with a model-based estimate corresponding to the mean age of 26.4 years. The mean annual bleeding rate in subjects below 18 years of age was higher compared to that in adults (0.362 versus 0.040 bleeds/subject/year). Table 5 below lists the estimated bleeding rates by age.

• Table 5 Estimated Bleeding Rates by Age

Thirty-four (34) of the 41 subjects and an additional 21 new subjects were enrolled in an ongoing second trial. During a total treatment period of 107.5 subject years (mean of 1.95 years per subject), 5 subjects experienced 6 bleeds that required treatment with a FXIII-containing product. The mean annual rate of bleeding episodes that required treatment was determined to be 0.056 per subject year. The age-adjusted rate of bleeding episodes that required treatment during the Beriplast P Combi-Set (Coagulation Factor XIII) treatment period was 0.022 per subject year [95% CI:0.0045; 0.1023] with a model-based estimate corresponding to a mean age of 29.5 years. The annual mean bleeding rate in subjects below age 18 was higher compared to that in adults (0.127 versus 0.026 bleeds/subject/year) with some overlap of the respective 95% confidence intervals. Table 6 lists the estimated bleeding rates by age.

• Table 6 Estimated Bleeding Rates by Age

15 REFERENCES

• Inbal, A., et.al.:Recombinant factor XIII: a safe and novel treatment for congenital factor XIII deficiency, Blood. 2012;119(22): 5111-5117
• Sharief, LAT., Kadir RA.:Congenital factor XIII deficiency in women: a systemic review of literature, Hemophilia. 2013; 19: e349-e357

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Beriplast P Combi-Set (Coagulation Factor XIII), Beriplast P Combi-Set (Coagulation Factor XIII) A-Subunit (Recombinant), is supplied as a white, lyophilized powder in single-use vial along with the diluent (Sterile Water for Injection) vial.

The actual amount of Beriplast P Combi-Set (Coagulation Factor XIII) in international units (IU) is stated on each carton and vial. Beriplast P Combi-Set (Coagulation Factor XIII) and the sterile water vials provided in the package are not made with natural rubber latex.

Storage and Handling

• Store refrigerated at 2°C – 8°C (36°F – 46°F) prior to reconstitution. Beriplast P Combi-Set (Coagulation Factor XIII) is stable until the expiration date on the carton and vial label. Do not freeze. Store protected from light.
• Use reconstituted Beriplast P Combi-Set (Coagulation Factor XIII) within 3 hours.
• If the reconstituted product is not used immediately, store the solution refrigerated or at room temperature not to exceed 25°C (77°F) for up to 3 hours following reconstitution.

17 PATIENT COUNSELING INFORMATION

• Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
• Discuss the signs and symptoms of allergic hypersensitivity reactions, such as urticaria, rash, tightness of the chest, wheezing, hypotension and/or anaphylaxis experienced during or after injection of Beriplast P Combi-Set (Coagulation Factor XIII) .
• Discuss signs and symptoms of thrombosis, such as limb or abdomen swelling and/or pain, chest pain, shortness of breath, loss of sensation or motor power, altered consciousness, vision, or speech .
• Inform patients that breakthrough bleeding may be the sign and symptom of inhibitor formation .

License Number: 1261

Patent information: http://novonordisk-us.com/patients/products/product-patents.html

Novo Nordisk^® is a registered trademark of Novo Nordisk A/S

Beriplast P Combi-Set (Coagulation Factor XIII)^® is a registered trademark of Novo Nordisk Health Care AG

© 2013-2016 Novo Nordisk

For Information contact:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, NJ 08536

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd, Denmark

Patient Package Insert

Beriplast P Combi-Set (Coagulation Factor XIII)^®

Beriplast P Combi-Set (Coagulation Factor XIII) A-Subunit (Recombinant)

This leaflet summarizes important information about Beriplast P Combi-Set (Coagulation Factor XIII). Please read it carefully before using Beriplast P Combi-Set (Coagulation Factor XIII) and each time you get a refill because there may be new information provided. This information does not take the place of talking with your healthcare provider, and it does not include all of the important information about Beriplast P Combi-Set (Coagulation Factor XIII). If you have any questions after reading this, ask your healthcare provider.

What is Beriplast P Combi-Set (Coagulation Factor XIII)?

Beriplast P Combi-Set (Coagulation Factor XIII) is an injectable medicine used to prevent bleeding in adults and children who have congenital factor XIII (FXIII) A-subunit deficiency. Beriplast P Combi-Set (Coagulation Factor XIII) is man-made and does not contain animal or human materials.

Who should not use Beriplast P Combi-Set (Coagulation Factor XIII)?

You should not use Beriplast P Combi-Set (Coagulation Factor XIII) if you have ever had allergic (hypersensitivity) reactions, including severe, whole body reaction (anaphylaxis) to Beriplast P Combi-Set (Coagulation Factor XIII) or any of the ingredients.

What should I tell my healthcare provider before Beriplast P Combi-Set (Coagulation Factor XIII) is given?

Tell your healthcare provider about all of your medical conditions, including:

• If you are pregnant, think you may be pregnant or planning to become pregnant. It is not known if Beriplast P Combi-Set (Coagulation Factor XIII) can harm you or your unborn baby.
• Labor and Delivery: It is not known if Beriplast P Combi-Set (Coagulation Factor XIII) is safe and effective during labor and delivery.
• Breast feeding: It is not known if Beriplast P Combi-Set (Coagulation Factor XIII) passes into your breast milk.
• If you have a history of blood clots.

Tell your healthcare provider about all of the medicines you take, including all prescription and non-prescription medicines such as over-the-counter medicines, supplements, or herbal remedies.

How is Beriplast P Combi-Set (Coagulation Factor XIII) given?

Beriplast P Combi-Set (Coagulation Factor XIII) is given as an injection into your vein (intravenous injection). These injections are given once a month. Your dose will depend on your body weight. Use the dose that your healthcare provider has prescribed for you based on your weight.

Before injecting Beriplast P Combi-Set (Coagulation Factor XIII), it must be dissolved (reconstituted) using the sterile water that is provided in the package. Throw away any Beriplast P Combi-Set (Coagulation Factor XIII) left in the vial after you inject your dose because it may become unsterile.

What are the possible side effects of Beriplast P Combi-Set (Coagulation Factor XIII)?

Call your healthcare provider or go to the emergency department right away if you have any of the following symptoms after using Beriplast P Combi-Set (Coagulation Factor XIII):

• Signs of allergic reaction including
  • shortness of breath
  • rash
  • itching (pruritus)
  • redness of the skin (erythema)
  • fainting/dizziness
• Signs of a blood clot including pain, swelling, warmth, redness, or a lump in your legs or arms, chest pain, or sudden severe headache and/or loss of consciousness or function
• Unexpected bleeding

Other possible side effects may include:

• pain in your arms or legs
• headache
• pain at the injection site

These are not all the possible side effects of Beriplast P Combi-Set (Coagulation Factor XIII). Tell your healthcare provider about any side effect that bothers you or that does not go away. You can also report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088.

How should I store Beriplast P Combi-Set (Coagulation Factor XIII)?

It is important to store Beriplast P Combi-Set (Coagulation Factor XIII) correctly.

• Before preparing Beriplast P Combi-Set (Coagulation Factor XIII) for injection
• Keep Beriplast P Combi-Set (Coagulation Factor XIII) in a refrigerator at 36°F to 46°F (2°C to 8°C) and in the original package in order to protect it from light. Do not freeze Beriplast P Combi-Set (Coagulation Factor XIII).
• After preparing Beriplast P Combi-Set (Coagulation Factor XIII) for injection (reconstituted)

• Use Beriplast P Combi-Set (Coagulation Factor XIII) immediately after it is dissolved (reconstituted) using the sterile water provided in the package.
• If you cannot inject it immediately, either leave Beriplast P Combi-Set (Coagulation Factor XIII) at room temperature not above 25°C (77°F) or put
• Beriplast P Combi-Set (Coagulation Factor XIII) in the refrigerator at 36°F to 46°F (2°C to 8°C) for no more than 3 hours. After more than 3 hours, DO
• NOT USE IT-THROW IT AWAY.
• Beriplast P Combi-Set (Coagulation Factor XIII) does not contain a preservative. Do not store Beriplast P Combi-Set (Coagulation Factor XIII) in the syringe or placed in the freezer.

What else should I know about Beriplast P Combi-Set (Coagulation Factor XIII)?

Do not use Beriplast P Combi-Set (Coagulation Factor XIII) for a condition for which it is not prescribed. Do not share Beriplast P Combi-Set (Coagulation Factor XIII) with other people, even if they have the same symptoms that you have.

Talk to your healthcare provider if you would like more information.

Beriplast P Combi-Set (Coagulation Factor XIII) ingredients include:

• Beriplast P Combi-Set (Coagulation Factor XIII) A-Subunit (Recombinant)
• Sodium Chloride
• Sucrose
• Polysorbate 20
• L-Histidine

Beriplast P Combi-Set (Coagulation Factor XIII) and the sterile water vials provided in the package are not made with natural rubber latex.

This Patient Package Insert has been approved by the US Food and Drug Administration

Revised: 12/2013

Version: 1

Novo Nordisk^® is a registered trademark of Novo Nordisk A/S

Beriplast P Combi-Set (Coagulation Factor XIII)^® is a registered trademark of Novo Nordisk Health Care AG

© 2013 Novo Nordisk

For Information contact:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, NJ 08536

www.novonordisk-us.com

1-844-TRETTEN

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd, Denmark

• NDC 0169-7013-01 LIST: 701301

2500 IU

Beriplast P Combi-Set (Coagulation Factor XIII)^®

Beriplast P Combi-Set (Coagulation Factor XIII) A-Subunit (Recombinant)

For intravenous administration only

For human use only

Contains no preservative

Rx only

Beriplast P Combi-Set (Coagulation Factor XIII) Carton

• NDC 0169-7113-11 LIST: 711311

2500 IU

Beriplast P Combi-Set (Coagulation Factor XIII)^®

Beriplast P Combi-Set (Coagulation Factor XIII) A-Subunit (Recombinant)

For intravenous administration only

Store refrigerated at 2-8°C (36-46°F)

Reconstitute with 3.2 mL sterile water for injection only

Rx only

Novo Nordisk Inc.

1-844-TRETTEN

Expiry/Lot/rFXIII IU per vial:

• NDC 0169-7000-93 LIST: 700093

3.2 mL

Sterile Water for Injection

For reconstitution of Beriplast P Combi-Set (Coagulation Factor XIII)^®

Beriplast P Combi-Set (Coagulation Factor XIII) A-Subunit (Recombinant)

Store at 2-25°C (36-77°F)

Novo Nordisk Inc.

1-844-TRETTEN

Expiry/Lot/:

Sterile water for injection

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
• Beriplast P Combi-Set (Fibrinogen) reviews

1 INDICATIONS AND USAGE

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

Beriplast P Combi-Set (Fibrinogen), Beriplast P Combi-Set (Fibrinogen) Concentrate (Human) is a human blood coagulation factor indicated for the treatment of acute bleeding episodes in patients with congenital Beriplast P Combi-Set (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 Beriplast P Combi-Set (Fibrinogen) level is unknown: 70 mg/kg body weight. (2.1)
• Monitoring of patient's Beriplast P Combi-Set (Fibrinogen) level is recommended during treatment. A target Beriplast P Combi-Set (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 Beriplast P Combi-Set (Fibrinogen) Deficiency

Beriplast P Combi-Set (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.

Beriplast P Combi-Set (Fibrinogen) dose when baseline Beriplast P Combi-Set (Fibrinogen) level is known.

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

Beriplast P Combi-Set (Fibrinogen) dose when baseline Beriplast P Combi-Set (Fibrinogen) level is not known.

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

Monitor patient's Beriplast P Combi-Set (Fibrinogen) level during treatment with Beriplast P Combi-Set (Fibrinogen). Maintain a target Beriplast P Combi-Set (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 Beriplast P Combi-Set.

Use aseptic technique when preparing and reconstituting Beriplast P Combi-Set (Fibrinogen).

Reconstitute Beriplast P Combi-Set (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 Beriplast P Combi-Set (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.

Beriplast P Combi-Set (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 Beriplast P Combi-Set (Fibrinogen) with other medicinal products or intravenous solutions. Administer through a separate injection site.

Use aseptic technique when administering Beriplast P Combi-Set (Fibrinogen).

Administer Beriplast P Combi-Set (Fibrinogen) at room temperature by slow intravenous injection at a rate not exceeding 5 mL per minute.

3 DOSAGE FORMS AND STRENGTHS

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

The actual Beriplast P Combi-Set (Fibrinogen) potency for each lot is printed on the vial label and carton.

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

4 CONTRAINDICATIONS

Beriplast P Combi-Set (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 Beriplast P Combi-Set (Fibrinogen). Weigh the benefits of administration versus the risks of thrombosis. (5.2)
• Beriplast P Combi-Set (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 Beriplast P Combi-Set deficiency with or without the use of Beriplast P Combi-Set (Fibrinogen) replacement therapy.¹ Thromboembolic events have been reported in patients treated with Beriplast P Combi-Set (Fibrinogen). Weigh the benefits of Beriplast P Combi-Set (Fibrinogen) administration versus the risk of thrombosis. Monitor patients receiving Beriplast P Combi-Set (Fibrinogen) for signs and symptoms of thrombosis.

5.3 Transmissible Infectious Agents

Beriplast P Combi-Set (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 Beriplast P Combi-Set 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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (Fibrinogen) use in pregnant women. Animal reproduction studies have not been conducted with Beriplast P Combi-Set (Fibrinogen). It is not known whether Beriplast P Combi-Set (Fibrinogen) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Beriplast P Combi-Set (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 Beriplast P Combi-Set 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 Beriplast P Combi-Set (Fibrinogen) and any potential adverse effects on the breastfed infant from Beriplast P Combi-Set (Fibrinogen) or from the underlying maternal condition.

8.4 Pediatric Use

Beriplast P Combi-Set (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 Beriplast P Combi-Set (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

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

Beriplast P Combi-Set (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). Beriplast P Combi-Set (Fibrinogen) is a physiological substrate of three enzymes: thrombin, factor XIIIa, and plasmin.

Each vial contains 900 to 1300 mg Beriplast P Combi-Set (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 Beriplast P Combi-Set (Fibrinogen) is in a range of 6.5 to 7.5.

Viral Clearance

All plasma used in the manufacture of Beriplast P Combi-Set (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.

Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (Fibrinogen) to patients with congenital Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (Fibrinogen). Blood samples were collected to determine Beriplast P Combi-Set (Fibrinogen) activity at baseline and up to 14 days after infusion. The pharmacokinetic parameters of Beriplast P Combi-Set (Fibrinogen) are summarized in Table 2.

No statistically relevant difference in Beriplast P Combi-Set (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 Beriplast P Combi-Set (Fibrinogen) plasma concentration in patients by approximately 120 mg/dL.

The pharmacokinetic analysis using Beriplast P Combi-Set (Fibrinogen) antigen data (ELISA) was concordant with the Beriplast P Combi-Set (Fibrinogen) activity (Clauss assay).

14 CLINICAL STUDIES

The efficacy of Beriplast P Combi-Set (Fibrinogen) is based on maximum clot firmness, a measure of clot structural integrity that reflects the underlying effectiveness of the Beriplast P Combi-Set (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 Beriplast P Combi-Set (Fibrinogen) when a fixed dose of Beriplast P Combi-Set (Fibrinogen) was administered. Clot firmness is a functional parameter that depends on activation of coagulation, Beriplast P Combi-Set (Fibrinogen) content of the sample and polymerization/crosslinking of the fibrin network. Thromboelastometry has been shown to be a functional marker for assessment of Beriplast P Combi-Set (Fibrinogen) content and for effects of Beriplast P Combi-Set (Fibrinogen) supplementation on clinical efficacy.⁵

For each subject, MCF was determined before (baseline) and one hour after single dose administration of Beriplast P Combi-Set (Fibrinogen). Beriplast P Combi-Set (Fibrinogen) was found to be effective in increasing clot firmness in subjects with congenital Beriplast P Combi-Set (Fibrinogen) deficiency (afibrinogenemia) as measured by thromboelastometry. The study results demonstrated that MCF values were significantly higher after administration of Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (Fibrinogen) concentrate in patients with congenital Beriplast P Combi-Set (Fibrinogen) deficiency. Transfusion and Apheresis Science 2005; 32:247-253.
• Fries D, Innerhofer P, Reif C, et al. The Effect of Beriplast P Combi-Set (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 Beriplast P Combi-Set (Fibrinogen) concentrate therapy in Beriplast P Combi-Set (Fibrinogen) deficiency. Blood Coagulation and Fibrinolysis. 2008; 19:777-783.

16 HOW SUPPLIED/STORAGE AND HANDLING

• Beriplast P Combi-Set (Fibrinogen) is supplied in a single-use vial.
• Each carton contains one vial of Beriplast P Combi-Set (Fibrinogen).
• Components are not made with natural rubber latex.
• Beriplast P Combi-Set (Fibrinogen) contains no preservative.
• The actual potency of Beriplast P Combi-Set (Fibrinogen) concentrate in milligram (mg) is stated on each Beriplast P Combi-Set (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), Beriplast P Combi-Set (Fibrinogen) is stable for the period indicated by the expiration date on the carton and vial label (up to 60 months). Do not use Beriplast P Combi-Set (Fibrinogen) beyond the expiration date.
• Keep Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (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 Beriplast P Combi-Set (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

Beriplast P Combi-Set (Fibrinogen) Concentrate

(Human)

Beriplast P Combi-Set (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 Human:

• 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
• Beriplast P Combi-Set (Thrombin Human) reviews

1 INDICATIONS AND USAGE

Beriplast P Combi-Set (Thrombin Human) ®, Beriplast P Combi-Set (Thrombin Human) topical (Recombinant), is a topical Beriplast P Combi-Set (Thrombin Human) 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.

Beriplast P Combi-Set (Thrombin Human) may be used in conjunction with an absorbable gelatin sponge, USP.

Beriplast P Combi-Set (Thrombin Human), Beriplast P Combi-Set (Thrombin Human) topical (Recombinant), is a topical Beriplast P Combi-Set (Thrombin Human) 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)

Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) powder with sterile 0.9% sodium chloride, USP, yielding a solution containing 1000 units (international units of potency) per mL. (2.1)
• Apply Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human)

The volume of reconstituted Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human).

• Remove flip-off cap from the top of the Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) solution.

20,000-unit Beriplast P Combi-Set (Thrombin Human) Reconstitution

• Remove the flip-off cap from the top of the Beriplast P Combi-Set (Thrombin Human) vial and the diluent vial.
• Attach a needle-free transfer device (one each) to the Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) vial.
• Transfer the 20 mL of diluent from the syringe into the Beriplast P Combi-Set (Thrombin Human) vial; the vacuum in the vial facilitates transfer.
• Leave the syringe attached and gently swirl and invert the Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) solution.

2.2 Application Techniques

Topically apply Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) to completely saturate the sponge(s).
• Remove the saturated sponge(s) and squeeze gently to remove excess Beriplast P Combi-Set (Thrombin Human).
• 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 Beriplast P Combi-Set (Thrombin Human) solution.
• Refer to Spray Applicator Kit instructions for spray pump and syringe spray assembly and use.

3 DOSAGE FORMS AND STRENGTHS

Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) topical (Recombinant).

Beriplast P Combi-Set (Thrombin Human) is available as 5000-unit and 20,000-unit vials of sterile recombinant topical Beriplast P Combi-Set (Thrombin Human) lyophilized powder for solution. When reconstituted as directed, the final solution contains 1000 units/mL of Beriplast P Combi-Set (Thrombin Human). (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 Beriplast P Combi-Set (Thrombin Human) or any components of Beriplast P Combi-Set (Thrombin Human).
• 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 Beriplast P Combi-Set (Thrombin Human), any components of Beriplast P Combi-Set (Thrombin Human) or hamster proteins. (4)

5 WARNINGS AND PRECAUTIONS

• Beriplast P Combi-Set may cause thrombosis if it enters the circulatory system. (5.1)
• Hypersensitivity reactions, including anaphylaxis, may occur. (5.2)

5.1 Thrombosis

Beriplast P Combi-Set (Thrombin Human) may cause thrombosis if it enters the circulatory system. Apply topically. DO NOT INJECT.

5.2 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, may occur. Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set in all completed clinical trials (N=644) [see Warnings and Precautions (5.1) ].

Antibody formation to Beriplast P Combi-Set (Thrombin Human) occurred in <1% of patients. None of the antibodies detected neutralized native human Beriplast P Combi-Set (Thrombin Human) [see Adverse Reactions (6.2) ].

• The most common adverse reaction (incidence 6%) was thromboembolic events. (5.1,6)
• Antibody formation to Beriplast P Combi-Set (Thrombin Human) occurred in <1% of patients. None of the antibodies detected neutralized native human Beriplast P Combi-Set (Thrombin Human). (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 Beriplast P Combi-Set (Thrombin Human) applied with absorbable gelatin sponge and applied with a spray applicator. A total of 644 patients were exposed to Beriplast P Combi-Set (Thrombin Human) in these studies.

Beriplast P Combi-Set (Thrombin Human) Used in Conjunction with Absorbable Gelatin Sponge

Four hundred eleven (411) patients were treated in a randomized, double-blind, controlled trial that compared Beriplast P Combi-Set (Thrombin Human) to bovine Beriplast P Combi-Set (Thrombin Human). 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 Beriplast P Combi-Set (Thrombin Human) and bovine Beriplast P Combi-Set (Thrombin Human) treatment groups.

In an open-label, single-group trial (N=209), patients with documented or highly likely prior exposure to bovine Beriplast P Combi-Set (Thrombin Human) within the previous three years were treated with Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) (N=31), patients with documented prior exposure to Beriplast P Combi-Set (Thrombin Human) were treated with Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) (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 Beriplast P Combi-Set (Thrombin Human) and 12% for placebo.

Beriplast P Combi-Set (Thrombin Human) Applied with Spray Applicator

Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) was evaluated in multiple clinical trials and included patients with a single exposure to Beriplast P Combi-Set (Thrombin Human) as well as patients who were re-exposed to Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human). There was no difference in anti-RECOTHROM product antibody formation incidence among patients exposed to Beriplast P Combi-Set (Thrombin Human) applied with absorbable gelatin sponge, USP or with spray applicator.

In a clinical trial comparing Beriplast P Combi-Set (Thrombin Human) to bovine Beriplast P Combi-Set (Thrombin Human) (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 Beriplast P Combi-Set (Thrombin Human) patients (n=3/198) had positive anti-product antibody titers compared with 5% of bovine Beriplast P Combi-Set (Thrombin Human) patients (n=10/200). Of these patients, none of the Beriplast P Combi-Set (Thrombin Human) group and eight in the bovine Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) group developed specific anti-product antibodies (one patient also developed anti-CHO host cell protein antibodies); 43 of 200 patients in the bovine Beriplast P Combi-Set (Thrombin Human) group (22%; 95% CI, 16%-28%) developed specific antibodies to bovine Beriplast P Combi-Set (Thrombin Human) product. Treatment with Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) group neutralized native human Beriplast P Combi-Set (Thrombin Human). Antibodies against bovine Beriplast P Combi-Set (Thrombin Human) product were not tested for neutralization of native human Beriplast P Combi-Set (Thrombin Human).

In a trial of patients with a high likelihood of prior exposure to bovine Beriplast P Combi-Set (Thrombin Human), 15.6% of patients (n=32/205) had anti-bovine Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human).

In a trial of patients previously exposed to Beriplast P Combi-Set (Thrombin Human), 31 patients were re-exposed to Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human), including 26 pediatric patients (aged one month to 16 years) and four patients 17 years of age, one patient without prior Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human). It is also not known whether Beriplast P Combi-Set (Thrombin Human) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) using a spray applicator to burn wound excision sites prior to autologous skin grafting. No patient experienced a thromboembolic adverse reaction. The safety of Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human), 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

Beriplast P Combi-Set (Thrombin Human), Beriplast P Combi-Set (Thrombin Human) topical (Recombinant), is a human coagulation protein produced via recombinant DNA technology from a genetically modified CHO cell line. Beriplast P Combi-Set (Thrombin Human) is identical in amino acid sequence and structurally similar to naturally occurring human Beriplast P Combi-Set (Thrombin Human). Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human). The cell line used to manufacture Beriplast P Combi-Set (Thrombin Human) has been tested and shown to be free of known infectious agents. The cell culture process used in the manufacture of Beriplast P Combi-Set (Thrombin Human) employs no additives of human or animal origin. The purification process includes solvent-detergent treatment and nano-filtration steps dedicated to viral clearance.

Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) 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

Beriplast P Combi-Set (Thrombin Human), Beriplast P Combi-Set (Thrombin Human) topical (Recombinant), is a specific human serine protease that promotes hemostasis and acts locally when applied topically to a site of bleeding.

Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set.

13.2 Animal Toxicology and/or Pharmacology

In a study in nonhuman primates, Beriplast P Combi-Set (Thrombin Human) was applied directly to a liver wound with an absorbable gelatin sponge, USP. In a second study, Beriplast P Combi-Set (Thrombin Human) was administered subcutaneously once weekly for four weeks to nonhuman primates following repeat doses of 5405 units/m². In both studies, Beriplast P Combi-Set (Thrombin Human) 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.

Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) inhibition and clearance from the bloodstream, radiolabeled Beriplast P Combi-Set (Thrombin Human) was administered intravenously or subcutaneously to nonhuman primates and applied with an absorbable gelatin sponge, USP, in a rabbit hepatic wound model. Beriplast P Combi-Set (Thrombin Human) 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.

Beriplast P Combi-Set (Thrombin Human) 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. Beriplast P Combi-Set (Thrombin Human) also reduced TTH when directly applied in a porcine partial-thickness excisional skin-wound model as compared to saline control (or no treatment).

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

14 CLINICAL STUDIES

Beriplast P Combi-Set (Thrombin Human) was evaluated in a randomized, double-blind comparative clinical trial to bovine Beriplast P Combi-Set (Thrombin Human). Each Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) and bovine Beriplast P Combi-Set (Thrombin Human) treatment groups.

The objectives of the study were to evaluate the comparative efficacy, safety, and immunogenicity of Beriplast P Combi-Set (Thrombin Human) and bovine Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) and bovine Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) and bovine Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) in surgical hemostasis. J Am Coll Surg. 2011;213(6):722-727.
• Greenhalgh DG, Gamelli RL, Collins J, et al. Recombinant Beriplast P Combi-Set (Thrombin Human): 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 Beriplast P Combi-Set (Thrombin Human): safety and immunogenicity in pediatric burn wound excision. J Ped Surg. 2011;46(10):1992-1999.

16 HOW SUPPLIED/STORAGE AND HANDLING

Beriplast P Combi-Set (Thrombin Human), Beriplast P Combi-Set (Thrombin Human) topical (Recombinant), is supplied in single-use, preservative-free vials in the following packages:

NDC 65293-006-41

A 5000-unit vial of Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) kit components contain latex.

Store Beriplast P Combi-Set (Thrombin Human) sterile powder vials at 2°C to 25°C (36°F to 77°F). Do not freeze.

Reconstituted solutions of Beriplast P Combi-Set (Thrombin Human) 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 Beriplast P Combi-Set (Thrombin Human) 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

Beriplast P Combi-Set (Thrombin Human) 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

Beriplast P Combi-Set (Thrombin Human)^®

Beriplast P Combi-Set (Thrombin Human), TOPICAL

(RECOMBINANT)

5,000 units

5,000 units NDC: 65293-006-41 FOR TOPICAL USE ONLY - DO NOT INJECT RECOTHROM® Beriplast P Combi-Set (Thrombin Human), 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

Beriplast P Combi-Set (Thrombin Human)^®

Beriplast P Combi-Set (Thrombin Human), TOPICAL

(RECOMBINANT)

20,000 units

20,000 units NDC: 65293-007-41 FOR TOPICAL USE ONLY - DO NOT INJECT RECOTHROM® Beriplast P Combi-Set (Thrombin Human), TOPICAL (RECOMBINANT) 20,000 units