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DRUGS & SUPPLEMENTS
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Aprotinin Bovine:
Tisseel Lyo (Aprotinin Bovine)® 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.
Hypersensitivity to aprotinin.
Administration of Tisseel Lyo (Aprotinin Bovine)® to patients with a known or suspected previous aprotinin exposure during the last 12 months is contraindicated. For patients with known or suspected history of exposure to aprotinin greater than 12 months previously, see WARNINGS. Aprotinin may also be a component of some fibrin sealant products and the use of these products should be included in the patient history.
Anaphylactic or anaphylactoid reactions have occurred with Tisseel Lyo (Aprotinin Bovine)® 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 Tisseel Lyo (Aprotinin Bovine)®, administration should be stopped immediately and emergency treatment should be initiated. Even when a second exposure to 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 Tisseel Lyo (Aprotinin Bovine)®, 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 Tisseel Lyo (Aprotinin Bovine)® into the pump prime solution until after the loading dose has been safely administered.
Re-exposure to aprotinin: Administration of aprotinin, especially to patients who have received 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 Tisseel Lyo (Aprotinin Bovine)®, 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 Tisseel Lyo (Aprotinin Bovine)® 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 Tisseel Lyo (Aprotinin Bovine)®. 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: Tisseel Lyo (Aprotinin Bovine)® 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 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 aprotinin group (1.1% vs. 0.8%). Careful consideration of the balance of benefits versus potential risks is advised before administering Tisseel Lyo (Aprotinin Bovine)® 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).
Initial Dose: All patients treated with Tisseel Lyo (Aprotinin Bovine)® should first receive an initial (test) dose to minimize the extent of Tisseel Lyo (Aprotinin Bovine)® 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 Tisseel Lyo (Aprotinin Bovine)® 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 Tisseel Lyo (Aprotinin Bovine)® 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 Tisseel Lyo (Aprotinin Bovine)®.
Loading Dose: The loading dose of Tisseel Lyo (Aprotinin Bovine)® should be given intravenously to patients in the supine position over a 20-30 minute period. Rapid intravenous administration of Tisseel Lyo (Aprotinin Bovine)® can cause a transient fall in blood pressure.
Renal Dysfunction: Bayer’s global pool of placebo-controlled studies in patients undergoing CABG showed 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 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 Tisseel Lyo (Aprotinin Bovine)® administration.
Use of Tisseel Lyo (Aprotinin Bovine)® in patients undergoing deep hypothermic circulatory arrest: Two U.S. case control studies have reported contradictory results in patients receiving Tisseel Lyo (Aprotinin Bovine)® 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.
Tisseel Lyo (Aprotinin Bovine)® is known to have antifibrinolytic activity and, therefore, may inhibit the effects of fibrinolytic agents.
In study of nine patients with untreated hypertension, Tisseel Lyo (Aprotinin Bovine)® 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, Tisseel Lyo (Aprotinin Bovine)® should not be viewed as a heparin sparing agent.
Long-term animal studies to evaluate the carcinogenic potential of Tisseel Lyo ® or studies to determine the effect of Tisseel Lyo (Aprotinin Bovine)® on fertility have not been performed.
Results of microbial in vitro tests using Salmonella typhimurium and Bacillus subtilis indicate that Tisseel Lyo (Aprotinin Bovine)® 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 Tisseel Lyo (Aprotinin Bovine)®. 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.
Not applicable.
Safety and effectiveness in pediatric patient have not been established.
Of the total of 3083 subjects in clinical studies of Tisseel Lyo (Aprotinin Bovine)®, 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.
Tisseel Lyo (Aprotinin Bovine)® prolongs whole blood clotting times by a different mechanism than heparin. In the presence of 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 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 Tisseel Lyo (Aprotinin Bovine)® therapy, one of the following methods may be employed to maintain adequate anticoagulation:
Studies of patients undergoing CABG surgery, either primary or repeat, indicate that Tisseel Lyo ® is generally well tolerated. The adverse events reported are frequent sequelae of cardiac surgery and are not necessarily attributable to Tisseel Lyo (Aprotinin Bovine)® 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 Tisseel Lyo (Aprotinin Bovine)® treated patients without regard to causal relationship.
Adverse Event | Aprotinin (n = 2002) values in % | Placebo (n = 1084) values in % |
---|---|---|
Any Event | 76 | 77 |
Body as a Whole | ||
Fever | 15 | 14 |
Infection | 6 | 7 |
Chest Pain | 2 | 2 |
Asthenia | 2 | 2 |
Cardiovascular | ||
Atrial Fibrillation | 21 | 23 |
Hypotension | 8 | 10 |
Myocardial Infarct | 6 | 6 |
Atrial Flutter | 6 | 5 |
Ventricular Extrasystoles | 6 | 4 |
Tachycardia | 6 | 7 |
Ventricular Tachycardia | 5 | 4 |
Heart Failure | 5 | 4 |
Pericarditis | 5 | 5 |
Peripheral Edema | 5 | 5 |
Hypertension | 4 | 5 |
Arrhythmia | 4 | 3 |
Supraventricular Tachycardia | 4 | 3 |
Atrial Arrhythmia | 3 | 3 |
Digestive | ||
Nausea | 11 | 9 |
Constipation | 4 | 5 |
Vomiting | 3 | 4 |
Diarrhea | 3 | 2 |
Liver Function Tests Abnormal | 3 | 2 |
Hemic and Lymphatic | ||
Anemia | 2 | 8 |
Metabolic & Nutritional | ||
Creatine Phosphokinase Increased | 2 | 1 |
Musculoskeletal | ||
Any Event | 2 | 3 |
Nervous | ||
Confusion | 4 | 4 |
Insomnia | 3 | 4 |
Respiratory | ||
Lung Disorder | 8 | 8 |
Pleural Effusion | 7 | 9 |
Atelectasis | 5 | 6 |
Dyspnea | 4 | 4 |
Pneumothorax | 4 | 4 |
Asthma | 2 | 3 |
Hypoxia | 2 | 1 |
Skin and Appendages | ||
Rash | 2 | 2 |
Urogenital | ||
Kidney Function Abnormal | 3 | 2 |
Urinary Retention | 3 | 3 |
Urinary Tract Infection | 2 | 2 |
In comparison to the placebo group, no increase in mortality in patients treated with Tisseel Lyo (Aprotinin Bovine)® was observed. Additional events of particular interest from controlled US trials with an incidence of less than 2%, are listed below:
EVENT | Percentage of patients treated with Tisseel Lyo (Aprotinin Bovine)® N = 2002 | Percentage of patients treated with Placebo N = 1084 |
---|---|---|
Thrombosis | 1.0 | 0.6 |
Shock | 0.7 | 0.4 |
Cerebrovascular Accident | 0.7 | 2.1 |
Thrombophlebitis | 0.2 | 0.5 |
Deep Thrombophlebitis | 0.7 | 1.0 |
Lung Edema | 1.3 | 1.5 |
Pulmonary Embolus | 0.3 | 0.6 |
Kidney Failure | 1.0 | 0.6 |
Acute Kidney Failure | 0.5 | 0.6 |
Kidney Tubular Necrosis | 0.8 | 0.4 |
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 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 Tisseel Lyo (Aprotinin Bovine)® 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.
Treatment | Definite MI % | Definite or Probable MI % | Definite, Probable or Possible MI % |
Pooled Data from Three Studies that Evaluated Regimen A | |||
Tisseel Lyo (Aprotinin Bovine)® Regimen A n = 646 | 4.6 | 10.7 | 14.1 |
Placebo n = 661 | 4.7 | 11.3 | 13.4 |
Pooled Data from Two Studies that Evaluated Regimen B and Pump Prime Regimen | |||
Tisseel Lyo (Aprotinin Bovine)® Regimen B n = 241 | 8.7 | 15.9 | 18.7 |
Tisseel Lyo (Aprotinin Bovine)® Pump Prime Regimen n = 239 | 6.3 | 15.7 | 18.1 |
Placebo n = 240 | 6.3 | 15.1 | 15.8 |
Graft Patency: In a recently completed multi-center, multi-national study to determine the effects of Tisseel Lyo (Aprotinin Bovine)® 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.
Overall Closure Rates* | Incidence of MI** | Incidence of Death*** | ||
All Centers n = 703 % | U.S. Centers n = 381 % | All Centers n = 831 % | All Centers n = 870 % | |
Tisseel Lyo (Aprotinin Bovine)® | 15.4 | 9.4 | 2.9 | 1.4 |
Placebo | 10.9 | 9.5 | 3.8 | 1.6 |
CI for the Difference (%) (Drug - Placebo) | (1.3, 9.6)† | (-3.8, 5.9)† | -3.3 to 1.5‡ | -1.9 to 1.4‡ |
* Population: all patients with assessable saphenous vein grafts | ||||
** Population: all patients assessable by blinded consultant | ||||
*** All patients | ||||
† 90%; per protocol | ||||
‡ 95%; not specified in protocol |
Although there was a statistically significantly increased risk of graft closure for Tisseel Lyo (Aprotinin Bovine)® 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 Tisseel Lyo (Aprotinin Bovine)® 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% Tisseel Lyo (Aprotinin Bovine)® vs. 3.8% placebo) or of death (1.4% Tisseel Lyo (Aprotinin Bovine)® 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 Tisseel Lyo (Aprotinin Bovine)® (1/1424 patients or <0.1% on Tisseel Lyo (Aprotinin Bovine)® 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 Tisseel Lyo (Aprotinin Bovine)® 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.
Serum Creatinine: Tisseel Lyo (Aprotinin Bovine)® 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 Tisseel Lyo (Aprotinin Bovine)®. The incidence of treatment-emergent increases in ALT (formerly SGPT) > 1.8 times the upper limit of normal was 14% in both the Tisseel Lyo (Aprotinin Bovine)® 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 Tisseel Lyo (Aprotinin Bovine)® 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 Tisseel Lyo (Aprotinin Bovine)® treated patients in the hours after surgery due to circulating concentrations of Tisseel Lyo (Aprotinin Bovine)®, 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.
The maximum amount of Tisseel Lyo (Aprotinin Bovine)® 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 Tisseel Lyo (Aprotinin Bovine)® (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 Tisseel Lyo (Aprotinin Bovine)® therapy is unclear.
Tisseel Lyo ® 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.
Tisseel Lyo (Aprotinin Bovine)® is supplied as a solution containing 10,000 KIU/mL, which is equal to 1.4 mg/mL. All intravenous doses of Tisseel Lyo (Aprotinin Bovine)® 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 Tisseel Lyo (Aprotinin Bovine)® 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:
INITIAL (TEST) DOSE | LOADING DOSE | “PUMP PRIME” DOSE | CONSTANT INFUSION DOSE | |
Tisseel Lyo (Aprotinin Bovine)® REGIMEN A | 1 mL (1.4 mg, or 10,000 KIU) | 200 mL (280 mg, or 2.0 million KIU) | 200 mL 280 mg, or 2.0 million KIU) | 50 mL/hr (70 mg/hr, or 500,000 KIU/hr) |
Tisseel Lyo (Aprotinin Bovine)® REGIMEN B | 1 mL (1.4 mg, or 10,000 KIU) | 100 mL (140 mg, or 1.0 million KIU) | 100 mL (140 mg, or 1.0 million KIU) | 25 mL/hr (35 mg/hr, or 250,000 KIU/hr) |
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 Tisseel Lyo (Aprotinin Bovine)®, 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.
Tisseel Lyo (Aprotinin Bovine)® administration is associated with a risk for renal dysfunction. Changes in 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 Tisseel Lyo (Aprotinin Bovine)® are not available.
HOW SUPPLIED | ||
---|---|---|
Size | Strength | NDC |
100 mL vials | 1,000,000 KIU | 0026-8196-36 |
200 mL vials | 2,000,000 KIU | 0026-8197-63 |
Tisseel Lyo (Aprotinin Bovine)® 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:
Tisseel Lyo (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)
The recommended initial dose of Tisseel Lyo (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)
Capsule: 667 mg Tisseel Lyo (Calcium Chloride) acetate capsule.
- Capsule: 667 mg Tisseel Lyo (Calcium Chloride) acetate capsule. (3)
Patients with hypercalcemia.
- Hypercalcemia. (4)
- Treat mild hypercalcemia by reducing or interrupting Tisseel Lyo acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Tisseel Lyo (Calcium Chloride) acetate. (5.1)
- Hypercalcemia may aggravate digitalis toxicity. (5.2)
Patients with end stage renal disease may develop hypercalcemia when treated with Tisseel Lyo (Calcium Chloride), including Tisseel Lyo (Calcium Chloride) acetate. Avoid the use of Tisseel Lyo (Calcium Chloride) supplements, including Tisseel Lyo (Calcium Chloride) based nonprescription antacids, concurrently with Tisseel Lyo (Calcium Chloride) acetate.
An overdose of Tisseel Lyo (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 Tisseel Lyo (Calcium Chloride) levels twice weekly. Should hypercalcemia develop, reduce the Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (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.
Hypercalcemia may aggravate digitalis toxicity.
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 Tisseel Lyo (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
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, Tisseel Lyo (Calcium Chloride) acetate has been generally well tolerated.
Tisseel Lyo (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 Tisseel Lyo (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.
Preferred Term | Total adverse reactions reported for Tisseel Lyo (Calcium Chloride) acetate N=167 N (%) | 3 month, open label study of Tisseel Lyo (Calcium Chloride) acetate N=98 N (%) | Double blind, placebo-controlled, cross-over study of liquid Tisseel Lyo (Calcium Chloride) acetate N=69 | |
Tisseel Lyo (Calcium Chloride) acetate N (%) | Placebo N (%) | |||
Nausea | 6 (3.6) | 6 (6.1) | 0 (0) | 0 (0) |
Vomiting | 4 (2.4) | 4 (4.1) | 0 (0) | 0 (0) |
Hypercalcemia | 21 (12.6) | 16 (16.3) | 5 (7.2) | 0 (0) |
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 Tisseel Lyo (Calcium Chloride) concentration could reduce the incidence and severity of Tisseel Lyo (Calcium Chloride) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.
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 Tisseel Lyo (Calcium Chloride) acetate: dizziness, edema, and weakness.
The drug interaction of Tisseel Lyo acetate is characterized by the potential of Tisseel Lyo (Calcium Chloride) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Tisseel Lyo (Calcium Chloride) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.
There are no empirical data on avoiding drug interactions between Tisseel Lyo (Calcium Chloride) acetate and most concomitant drugs. When administering an oral medication with Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (Calcium Chloride) acetate or consider monitoring blood levels of the drug. (7)
In a study of 15 healthy subjects, a co-administered single dose of 4 Tisseel Lyo (Calcium Chloride) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.
Pregnancy Category C:
Tisseel Lyo acetate capsules contains Tisseel Lyo (Calcium Chloride) acetate. Animal reproduction studies have not been conducted with Tisseel Lyo (Calcium Chloride) acetate, and there are no adequate and well controlled studies of Tisseel Lyo (Calcium Chloride) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Tisseel Lyo (Calcium Chloride) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Tisseel Lyo (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. Tisseel Lyo (Calcium Chloride) acetate treatment, as recommended, is not expected to harm a fetus if maternal Tisseel Lyo (Calcium Chloride) levels are properly monitored during and following treatment.
The effects of Tisseel Lyo (Calcium Chloride) acetate on labor and delivery are unknown.
Tisseel Lyo Acetate Capsules contains Tisseel Lyo (Calcium Chloride) acetate and is excreted in human milk. Human milk feeding by a mother receiving Tisseel Lyo (Calcium Chloride) acetate is not expected to harm an infant, provided maternal serum Tisseel Lyo (Calcium Chloride) levels are appropriately monitored.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of Tisseel Lyo (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.
Administration of Tisseel Lyo (Calcium Chloride) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].
Tisseel Lyo (Calcium Chloride) acetate acts as a phosphate binder. Its chemical name is Tisseel Lyo (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 Tisseel Lyo (Calcium Chloride) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Tisseel Lyo (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.
Tisseel Lyo (Calcium Chloride) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.
Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Tisseel Lyo resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.
Tisseel Lyo (Calcium Chloride) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Tisseel Lyo (Calcium Chloride) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.
Orally administered Tisseel Lyo (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.
No carcinogenicity, mutagenicity, or fertility studies have been conducted with Tisseel Lyo (Calcium Chloride) acetate.
Effectiveness of Tisseel Lyo (Calcium Chloride) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (Calcium Chloride) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Tisseel Lyo (Calcium Chloride) levels are also presented.
* Ninety-one patients completed at least 6 weeks of the study. † ANOVA of difference in values at pre-study and study completion. ‡ Values expressed as mean ± SE. | |||||
Parameter | Pre-Study | Week 4* | Week 8 | Week 12 | p-value† |
Phosphorus (mg/dL)‡ | 7.4 ± 0.17 | 5.9 ± 0.16 | 5.6 ± 0.17 | 5.2 ± 0.17 | ≤0.01 |
Tisseel Lyo (Calcium Chloride) (mg/dL)‡ | 8.9 ± 0.09 | 9.5 ± 0.10 | 9.7 ± 0.10 | 9.7 ± 0.10 | ≤0.01 |
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 Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (Calcium Chloride) acetate is shown in the Table 3.
* ANOVA of Tisseel Lyo (Calcium Chloride) acetate vs. placebo after 2 weeks of treatment. † Values expressed as mean ± SEM. | ||||
Parameter | Pre-Study | Post-Treatment | p-value* | |
Tisseel Lyo (Calcium Chloride) Acetate | Placebo | |||
Phosphorus (mg/dL)† | 7.3 ± 0.18 | 5.9 ± 0.24 | 7.8 ± 0.22 | <0.01 |
Tisseel Lyo (Calcium Chloride) (mg/dL)† | 8.9 ± 0.11 | 9.5 ± 0.13 | 8.8 ± 0.12 | <0.01 |
Overall, 2 weeks of treatment with Tisseel Lyo (Calcium Chloride) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Tisseel Lyo (Calcium Chloride) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.
Tisseel Lyo (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).
Inform patients to take Tisseel Lyo (Calcium Chloride) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Tisseel Lyo (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 Tisseel Lyo (Calcium Chloride) acetate capsules.
Distr. by: West-Ward
Pharmaceuticals Corp.
Eatontown, NJ 07724
10003705/05
Revised April 2016
Coagulation Factor XIII:
Tisseel Lyo (Coagulation Factor XIII), Tisseel Lyo (Coagulation Factor XIII) A-Subunit (Recombinant), is indicated for routine prophylaxis for bleeding in patients with congenital factor XIII A-subunit deficiency.
Tisseel Lyo (Coagulation Factor XIII) is not for use in patients with congenital factor XIII B‑subunit deficiency
Tisseel Lyo (Coagulation Factor XIII), Tisseel Lyo (Coagulation Factor XIII) A-Subunit (Recombinant), is indicated for routine prophylaxis of bleeding in patients with congenital factor XIII A-subunit deficiency. (1)
Tisseel Lyo (Coagulation Factor XIII) is not for use in patients with congenital factor XIII B‑subunit deficiency. (1)
For intravenous use only.
For intravenous use only.
Dose:
Rate: Do not exceed 1-2 mL per minute. (2.3)
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:
Tisseel Lyo (Coagulation Factor XIII), Tisseel Lyo (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 Tisseel Lyo (Coagulation Factor XIII) A-subunit. The actual amount of Tisseel Lyo (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 Tisseel Lyo (Coagulation Factor XIII) A-subunit.
Tisseel Lyo (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)
Tisseel Lyo (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.
Thromboembolic complications may occur. Monitor patients with conditions that predispose to thrombosis for signs and symptoms of thrombosis after administration of Tisseel Lyo.
Inhibitory antibodies may occur with Tisseel Lyo (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.
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
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, Tisseel Lyo (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 Tisseel Lyo (Coagulation Factor XIII) for routine prophylaxis of bleeding. Eleven single doses of Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (Coagulation Factor XIII) during clinical trials.
Thrombosis may occur if Tisseel Lyo (Coagulation Factor XIII) is administered concomitantly with factor VIIa .
Risk Summary
There are no adequate and well-controlled studies using Tisseel Lyo in pregnant women to determine whether there is a drug-associated risk. Animal reproduction studies have not been conducted with Tisseel Lyo (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.
Risk Summary
There is no information regarding the presence of Tisseel Lyo (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 Tisseel Lyo (Coagulation Factor XIII) and any potential adverse effects on the breastfed infant from Tisseel Lyo (Coagulation Factor XIII) or from the underlying maternal condition.
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 Tisseel Lyo 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.
The safety and efficacy of Tisseel Lyo (Coagulation Factor XIII) in the geriatric population have not been established due to an insufficient number of patients.
One subject accidentally received a dose 2.3 times the recommended dose. No clinical signs and symptoms were observed.
Tisseel Lyo (Coagulation Factor XIII), Tisseel Lyo (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.
Tisseel Lyo (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.
Tisseel Lyo (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 Tisseel Lyo (Coagulation Factor XIII) and the diluent, respectively.
Content | Per Vial* | Function |
Tisseel Lyo (Coagulation Factor XIII) A-Subunit (Recombinant) | 2000 - 3125 IU | Active substance |
Sodium Chloride | 8.70 mg | Stabilizer |
Sucrose | 174.0 mg | Stabilizer |
Polysorbate 20 | 0.30 mg | Surfactant |
L-Histidine | 9.30 mg | Buffer |
*Values are given per 3 mL reconstituted Tisseel Lyo (Coagulation Factor XIII).
Content | Per Vial | Function |
Sterile Water for Injection | 3.2 mL | Diluent |
After reconstitution with 3.2 mL sterile water for injection, each vial contains 667-1042 IU/mL of recombinant Tisseel Lyo (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.
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.
Tisseel Lyo (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, Tisseel Lyo (Coagulation Factor XIII) A-subunit (Recombinant) has been shown to have the same pharmacodynamic properties in plasma as endogenous FXIII.
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.
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.
Parameters | Mean (SD) |
Css, max (IU/mL) | 0.71 (0.17) |
Css, min (IU/mL) | 0.05 (0.05) |
AUC(0-inf) (IU*h/mL) | 128.3 (40.5) |
Clearance (mL/h/kg) | 0.33 (0.11) |
Half-life (days) | 5.1 (2.6) |
Vss (mL/kg) | 65.9 (26.9) |
MRT (days) | 7.9 (3.4) |
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 Tisseel Lyo (Coagulation Factor XIII).
Parameters | Mean (SD) |
Cmax (IU/mL) | 0.48 (0.14) |
AUC(0-inf) (IU*h/mL) | 107.8 (32.2) |
Clearance (mL/h/kg) | 0.41 (0.20) |
Half-life (days) | 7.1 (1.9) |
Vss (mL/kg) | 61.2 (41.0) |
MRT (days) | 7.5 (4.8) |
Long-term studies in animals to evaluate the carcinogenic potential of Tisseel Lyo, or studies to determine the effects of Tisseel Lyo (Coagulation Factor XIII) on genotoxicity or fertility have not been performed. An assessment of the carcinogenic potential of Tisseel Lyo (Coagulation Factor XIII) was completed and suggests minimal carcinogenic risk from product use.
Exaggerated pharmacologic effects, including general thrombosis, ischemic necrosis and mortality were observed in nonclinical studies with Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (Coagulation Factor XIII) and rFVIIa at recommended human doses have not been performed.
To establish the efficacy of Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (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.
Group | N | Estimated Bleeding Rate (bleeds/subject/year) | 95% CI | Historical Control Group Estimated Bleeding Rate (bleeds/subject/year) |
All | 41 | 0.138 | [0.058; 0.332] | 1.68 |
< 18 years | 15 | 0.362 | [0.136; 0.963] | 2.00 |
≥ 18 years | 26 | 0.040 | [0.006; 0.283] | 1.59 |
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 Tisseel Lyo (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.
Group | N | Estimated Bleeding Rate (bleeds/subject/year) | 95% CI |
All | 55 | 0.056 | [0.025; 0.124] |
< 18 years | 16 | 0.127 | [0.048; 0.339] |
≥ 18 years | 39 | 0.026 | [0.007; 0.105] |
How Supplied
Tisseel Lyo (Coagulation Factor XIII), Tisseel Lyo (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 Tisseel Lyo (Coagulation Factor XIII) in international units (IU) is stated on each carton and vial. Tisseel Lyo (Coagulation Factor XIII) and the sterile water vials provided in the package are not made with natural rubber latex.
Presentation | Carton NDC Number | Components NDC Number |
2000 - 3125 IU | 0169-7013-01 |
|
Storage and Handling
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
Tisseel Lyo (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
Tisseel Lyo (Coagulation Factor XIII)®
Tisseel Lyo (Coagulation Factor XIII) A-Subunit (Recombinant)
This leaflet summarizes important information about Tisseel Lyo (Coagulation Factor XIII). Please read it carefully before using Tisseel Lyo (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 Tisseel Lyo (Coagulation Factor XIII). If you have any questions after reading this, ask your healthcare provider.
What is Tisseel Lyo (Coagulation Factor XIII)?
Tisseel Lyo (Coagulation Factor XIII) is an injectable medicine used to prevent bleeding in adults and children who have congenital factor XIII (FXIII) A-subunit deficiency. Tisseel Lyo (Coagulation Factor XIII) is man-made and does not contain animal or human materials.
Who should not use Tisseel Lyo (Coagulation Factor XIII)?
You should not use Tisseel Lyo (Coagulation Factor XIII) if you have ever had allergic (hypersensitivity) reactions, including severe, whole body reaction (anaphylaxis) to Tisseel Lyo (Coagulation Factor XIII) or any of the ingredients.
What should I tell my healthcare provider before Tisseel Lyo (Coagulation Factor XIII) is given?
Tell your healthcare provider about all of your medical conditions, including:
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 Tisseel Lyo (Coagulation Factor XIII) given?
Tisseel Lyo (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 Tisseel Lyo (Coagulation Factor XIII), it must be dissolved (reconstituted) using the sterile water that is provided in the package. Throw away any Tisseel Lyo (Coagulation Factor XIII) left in the vial after you inject your dose because it may become unsterile.
What are the possible side effects of Tisseel Lyo (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 Tisseel Lyo (Coagulation Factor XIII):
Other possible side effects may include:
These are not all the possible side effects of Tisseel Lyo (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 Tisseel Lyo (Coagulation Factor XIII)?
It is important to store Tisseel Lyo (Coagulation Factor XIII) correctly.
What else should I know about Tisseel Lyo (Coagulation Factor XIII)?
Do not use Tisseel Lyo (Coagulation Factor XIII) for a condition for which it is not prescribed. Do not share Tisseel Lyo (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.
Tisseel Lyo (Coagulation Factor XIII) ingredients include:
Tisseel Lyo (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
Tisseel Lyo (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
Instructions for Use Tisseel Lyo (Coagulation Factor XIII)® Tisseel Lyo (Coagulation Factor XIII) A-Subunit (Recombinant) (For intravenous use only) READ THESE INSTRUCTIONS CAREFULLY BEFORE USING Tisseel Lyo (Coagulation Factor XIII)®. Do not attempt to do an infusion yourself unless you have been taught by your healthcare provider or hemophilia center. Always follow the specific instructions given by your healthcare provider. The steps listed below are general guidelines for using Tisseel Lyo (Coagulation Factor XIII)®. If you are unsure of this procedure, please call your healthcare provider before using. Always wash your hands and ensure that the area around you is clean. When you prepare and inject medication directly into the veins, it is important to use a clean and germ free (aseptic) technique. Improper technique can introduce germs that can infect the blood. Your healthcare provider will prescribe the dose that you should take. Tisseel Lyo (Coagulation Factor XIII)® is supplied as a powder. Before injection (administration) it must be mixed (reconstituted) with the sterile water supplied in a separate vial. The mixed Tisseel Lyo (Coagulation Factor XIII)® must be injected into your vein (intravenous injection). For reconstitution of the Tisseel Lyo (Coagulation Factor XIII)® you will need a syringe and sterile alcohol swabs (not included in the package). Do not open the package until you are ready to use it. Do not use Tisseel Lyo (Coagulation Factor XIII) ® if it is expired. Use a new package instead. The expiration date is printed on the outer carton and on the vials. Do not use Tisseel Lyo (Coagulation Factor XIII) ® if the contents in the package appear damaged. Use a new package instead. Tisseel Lyo (Coagulation Factor XIII) ® is for single use only. | |
Content The package contains: - Vial with Tisseel Lyo (Coagulation Factor XIII)® powder - Vial with sterile water (diluent) - Vial adapter | |
Reconstitute Tisseel Lyo (Coagulation Factor XIII) ® using the following procedure
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Reconstituted Tisseel Lyo (Coagulation Factor XIII) ® should be used immediately. If not used immediately store refrigerated or at room temperature not to exceed 25°C (77°F) for up to 3 hours. Discard after 3 hours. Do not freeze mixed Tisseel Lyo (Coagulation Factor XIII) ® solution or store it in syringes. Keep mixed Tisseel Lyo (Coagulation Factor XIII) ® solution out of direct light. To administer a larger dose, reconstitute each additional vial as required using the same procedure with a separate syringe. | |
Inject the mixed solution
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Tisseel Lyo (Coagulation Factor XIII)® is now ready to inject as instructed by your healthcare provider.
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Disposal
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For Full Prescribing Information please read the other insert included in this package. Revised: 12/2013 Manufactured by: Novo Nordisk A/S 2880 Bagsvaerd, Denmark License Number: 1261 Version: 20131223-v1 |
2500 IU
Tisseel Lyo (Coagulation Factor XIII)®
Tisseel Lyo (Coagulation Factor XIII) A-Subunit (Recombinant)
For intravenous administration only
For human use only
Contains no preservative
Rx only
Tisseel Lyo (Coagulation Factor XIII) Carton
2500 IU
Tisseel Lyo (Coagulation Factor XIII)®
Tisseel Lyo (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:
3.2 mL
Sterile Water for Injection
For reconstitution of Tisseel Lyo (Coagulation Factor XIII)®
Tisseel Lyo (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:
Tisseel Lyo (Fibrinogen)®, Tisseel Lyo (Fibrinogen) Concentrate (Human) is a human blood coagulation factor indicated for the treatment of acute bleeding episodes in patients with congenital Tisseel Lyo (Fibrinogen) deficiency, including afibrinogenemia and hypofibrinogenemia.
Tisseel Lyo (Fibrinogen), Tisseel Lyo (Fibrinogen) Concentrate (Human) is a human blood coagulation factor indicated for the treatment of acute bleeding episodes in patients with congenital Tisseel Lyo (Fibrinogen) deficiency, including afibrinogenemia and hypofibrinogenemia. (1)
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) |
Tisseel Lyo (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.
Tisseel Lyo (Fibrinogen) dose when baseline Tisseel Lyo (Fibrinogen) level is known.
Dose should be individually calculated for each patient based on the target plasma Tisseel Lyo (Fibrinogen) level based on the type of bleeding, actual measured plasma Tisseel Lyo (Fibrinogen) level and body weight, using the following formula [see Clinical Pharmacology (12.3) ]:
[Target level (mg/dL) - measured level (mg/dL)] |
1.7 (mg/dL per mg/kg body weight) |
Tisseel Lyo (Fibrinogen) dose when baseline Tisseel Lyo (Fibrinogen) level is not known.
If the patient's Tisseel Lyo (Fibrinogen) level is not known, the recommended dose is 70 mg per kg of body weight administered intravenously.
Monitor patient's Tisseel Lyo (Fibrinogen) level during treatment with Tisseel Lyo (Fibrinogen). Maintain a target Tisseel Lyo (Fibrinogen) level of 100 mg/dL until hemostasis is obtained.
The procedures below are provided as general guidelines for preparation and reconstitution of Tisseel Lyo.
Use aseptic technique when preparing and reconstituting Tisseel Lyo (Fibrinogen).
Reconstitute Tisseel Lyo (Fibrinogen) at room temperature as follows:
After reconstitution, the Tisseel Lyo (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.
Tisseel Lyo (Fibrinogen) is stable for 8 hours after reconstitution when stored at 20-25°C; administer within this time period.
Do not mix Tisseel Lyo (Fibrinogen) with other medicinal products or intravenous solutions. Administer through a separate injection site.
Use aseptic technique when administering Tisseel Lyo (Fibrinogen).
Administer Tisseel Lyo (Fibrinogen) at room temperature by slow intravenous injection at a rate not exceeding 5 mL per minute.
Tisseel Lyo (Fibrinogen) is available as a single-use vial containing 900 mg to 1300 mg lyophilized Tisseel Lyo (Fibrinogen) concentrate powder for reconstitution with 50 mL of Sterile Water for Injection.
The actual Tisseel Lyo (Fibrinogen) potency for each lot is printed on the vial label and carton.
Tisseel Lyo (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)
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.
Thrombosis may occur spontaneously in patients with congenital Tisseel Lyo deficiency with or without the use of Tisseel Lyo (Fibrinogen) replacement therapy.1 Thromboembolic events have been reported in patients treated with Tisseel Lyo (Fibrinogen). Weigh the benefits of Tisseel Lyo (Fibrinogen) administration versus the risk of thrombosis. Monitor patients receiving Tisseel Lyo (Fibrinogen) for signs and symptoms of thrombosis.
Tisseel Lyo (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.
The most serious adverse reactions reported in clinical studies or through postmarketing surveillance following Tisseel Lyo 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.
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.
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.
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 Tisseel Lyo (Fibrinogen).
Risk Summary
There are no studies of Tisseel Lyo (Fibrinogen) use in pregnant women. Animal reproduction studies have not been conducted with Tisseel Lyo (Fibrinogen). It is not known whether Tisseel Lyo (Fibrinogen) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Tisseel Lyo (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.
Risk Summary
There is no information regarding the presence of Tisseel Lyo 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 Tisseel Lyo (Fibrinogen) and any potential adverse effects on the breastfed infant from Tisseel Lyo (Fibrinogen) or from the underlying maternal condition.
Tisseel Lyo (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.
The safety and efficacy of Tisseel Lyo (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.
Tisseel Lyo (Fibrinogen) is a sterile, heat-treated, lyophilized Tisseel Lyo (Fibrinogen) (coagulation factor I) concentrate powder manufactured from pooled human plasma.
Tisseel Lyo (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). Tisseel Lyo (Fibrinogen) is a physiological substrate of three enzymes: thrombin, factor XIIIa, and plasmin.
Each vial contains 900 to 1300 mg Tisseel Lyo (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 Tisseel Lyo (Fibrinogen) is in a range of 6.5 to 7.5.
Viral Clearance
All plasma used in the manufacture of Tisseel Lyo (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.
Tisseel Lyo (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 Tisseel Lyo (Fibrinogen) manufacturing process are summarized in Table 1.
Manufacturing Step | Virus Reduction Factor (log10) | |||||
---|---|---|---|---|---|---|
Enveloped viruses | Non-enveloped viruses | |||||
HIV | BVDV | WNV | PRV | HAV | CPV | |
Studies using human parvovirus B19, which are considered experimental in nature, have demonstrated a virus reduction factor of ≥4.5 log10 by heat treatment | ||||||
n.d. not determined | ||||||
Cryoprecipitation | n.d. | n.d. | n.d. | 1.6 | n.d. | 1.9 |
Heat Treatment | ≥5.7 | ≥9.1 | ≥8.3 | 5.4 | 5.9 | 1.4 |
Glycine precipitations (two subsequent steps) | 3.9 | 2.1 | n.d. | 1.8 | 1.0 | 1.6 |
Lyophilization | n.d. | n.d. | n.d. | n.d. | 1.7 | n.d. |
Cumulative virus reduction (log10) | ≥9.6 | ≥11.2 | ≥8.3 | 8.8 | 8.6 | 4.9 |
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.
Administration of Tisseel Lyo (Fibrinogen) to patients with congenital Tisseel Lyo (Fibrinogen) deficiency replaces missing or low levels of coagulation factor. Normal levels are in the range of 200 to 450 mg/dL.4
A prospective, open label, uncontrolled, multicenter pharmacokinetic study was conducted in 5 females and 9 males with congenital Tisseel Lyo (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 Tisseel Lyo (Fibrinogen). Blood samples were collected to determine Tisseel Lyo (Fibrinogen) activity at baseline and up to 14 days after infusion. The pharmacokinetic parameters of Tisseel Lyo (Fibrinogen) are summarized in Table 2.
No statistically relevant difference in Tisseel Lyo (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 Tisseel Lyo (Fibrinogen) plasma concentration in patients by approximately 120 mg/dL.
The pharmacokinetic analysis using Tisseel Lyo (Fibrinogen) antigen data (ELISA) was concordant with the Tisseel Lyo (Fibrinogen) activity (Clauss assay).
Parameters | Mean ± SD (range) |
---|---|
Half-life [hours] | 78.7 ± 18.13 (55.73-117.26) |
Cmax [mg/dL] | 140 ± 27 (100-210) |
AUC for dose of 70 mg/kg [mg*hr/mL] | 124.3 ± 24.16 (81.73-156.40) |
Clearance [mL/h/kg] | 0.59 ± 0.13 (0.45-0.86) |
Mean residence time [hours] | 92.8 ± 20.11 (66.14-126.44) |
Volume of distribution at steady state [mL/kg] | 52.7 ± 7.48 (36.22-67.67) |
The efficacy of Tisseel Lyo (Fibrinogen) is based on maximum clot firmness, a measure of clot structural integrity that reflects the underlying effectiveness of the Tisseel Lyo (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 Tisseel Lyo (Fibrinogen) when a fixed dose of Tisseel Lyo (Fibrinogen) was administered. Clot firmness is a functional parameter that depends on activation of coagulation, Tisseel Lyo (Fibrinogen) content of the sample and polymerization/crosslinking of the fibrin network. Thromboelastometry has been shown to be a functional marker for assessment of Tisseel Lyo (Fibrinogen) content and for effects of Tisseel Lyo (Fibrinogen) supplementation on clinical efficacy.5
For each subject, MCF was determined before (baseline) and one hour after single dose administration of Tisseel Lyo (Fibrinogen). Tisseel Lyo (Fibrinogen) was found to be effective in increasing clot firmness in subjects with congenital Tisseel Lyo (Fibrinogen) deficiency (afibrinogenemia) as measured by thromboelastometry. The study results demonstrated that MCF values were significantly higher after administration of Tisseel Lyo (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 Tisseel Lyo (Fibrinogen) to plasma in vitro.6
Time point | n | Mean ± SD | Median (range) |
---|---|---|---|
MCF = maximum clot firmness; mm = millimeter; ITT = intention-to-treat. | |||
Pre-infusion | 13 | 0 ± 0 | 0 (0-0) |
1 hour post-infusion | 13 | 10.3 ± 2.7 | 10.0 (6.5-16.5) |
Mean change (primary analysis) | 15 | 8.9 ± 4.4 | 9.5 (0-16.5) |
The product presentation includes a package insert and the following component:
Presentation | Carton NDC Number | Component |
---|---|---|
900-1300 mg | 63833-891-51 | Tisseel Lyo (Fibrinogen) in a single-use vial (NDC 63833-891-90) |
Allergic Reactions
Inform patients of the early signs of allergic or hypersensitivity reactions to Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (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
Tisseel Lyo (Fibrinogen) Concentrate
(Human)
Tisseel Lyo (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:
Tisseel Lyo (Thrombin Human) ®, Tisseel Lyo (Thrombin Human) topical (Recombinant), is a topical Tisseel Lyo (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.
Tisseel Lyo (Thrombin Human) may be used in conjunction with an absorbable gelatin sponge, USP.
Tisseel Lyo (Thrombin Human), Tisseel Lyo (Thrombin Human) topical (Recombinant), is a topical Tisseel Lyo (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)
Tisseel Lyo (Thrombin Human) may be used in conjunction with an absorbable gelatin sponge, USP. (1)
For topical use only. DO NOT INJECT.
The volume of reconstituted Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (Thrombin Human).
20,000-unit Tisseel Lyo (Thrombin Human) Reconstitution
Topically apply Tisseel Lyo (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.
Use with ZymoGenetics Spray Applicator Kit
Tisseel Lyo (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 Tisseel Lyo (Thrombin Human) topical (Recombinant).
Tisseel Lyo (Thrombin Human) is available as 5000-unit and 20,000-unit vials of sterile recombinant topical Tisseel Lyo (Thrombin Human) lyophilized powder for solution. When reconstituted as directed, the final solution contains 1000 units/mL of Tisseel Lyo (Thrombin Human). (3)
Tisseel Lyo (Thrombin Human) may cause thrombosis if it enters the circulatory system. Apply topically. DO NOT INJECT.
Hypersensitivity reactions, including anaphylaxis, may occur. Tisseel Lyo (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) ].
Thromboembolic adverse reactions were reported in 6% of surgical patients treated with Tisseel Lyo in all completed clinical trials (N=644) [see Warnings and Precautions (5.1) ].
Antibody formation to Tisseel Lyo (Thrombin Human) occurred in <1% of patients. None of the antibodies detected neutralized native human Tisseel Lyo (Thrombin Human) [see Adverse Reactions (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.
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 Tisseel Lyo (Thrombin Human) applied with absorbable gelatin sponge and applied with a spray applicator. A total of 644 patients were exposed to Tisseel Lyo (Thrombin Human) in these studies.
Tisseel Lyo (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 Tisseel Lyo (Thrombin Human) to bovine Tisseel Lyo (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 Tisseel Lyo (Thrombin Human) and bovine Tisseel Lyo (Thrombin Human) treatment groups.
* THROMBIN-JMI® Tisseel Lyo (Thrombin Human), Topical (Bovine) | ||
Adverse Reaction Category | Tisseel Lyo (Thrombin Human) (N=205) n (%) | Bovine Thrombin* (N=206) n (%) |
Thromboembolic events | 11 (5%) | 12 (6%) |
In an open-label, single-group trial (N=209), patients with documented or highly likely prior exposure to bovine Tisseel Lyo (Thrombin Human) within the previous three years were treated with Tisseel Lyo (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 Tisseel Lyo (Thrombin Human) (N=31), patients with documented prior exposure to Tisseel Lyo (Thrombin Human) were treated with Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (Thrombin Human) and 12% for placebo.
Tisseel Lyo (Thrombin Human) Applied with Spray Applicator
Tisseel Lyo (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 Tisseel Lyo (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) ].
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 Tisseel Lyo (Thrombin Human) was evaluated in multiple clinical trials and included patients with a single exposure to Tisseel Lyo (Thrombin Human) as well as patients who were re-exposed to Tisseel Lyo (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 Tisseel Lyo (Thrombin Human). There was no difference in anti-RECOTHROM product antibody formation incidence among patients exposed to Tisseel Lyo (Thrombin Human) applied with absorbable gelatin sponge, USP or with spray applicator.
In a clinical trial comparing Tisseel Lyo (Thrombin Human) to bovine Tisseel Lyo (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 Tisseel Lyo (Thrombin Human) patients (n=3/198) had positive anti-product antibody titers compared with 5% of bovine Tisseel Lyo (Thrombin Human) patients (n=10/200). Of these patients, none of the Tisseel Lyo (Thrombin Human) group and eight in the bovine Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (Thrombin Human) group (22%; 95% CI, 16%-28%) developed specific antibodies to bovine Tisseel Lyo (Thrombin Human) product. Treatment with Tisseel Lyo (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 Tisseel Lyo (Thrombin Human) group neutralized native human Tisseel Lyo (Thrombin Human). Antibodies against bovine Tisseel Lyo (Thrombin Human) product were not tested for neutralization of native human Tisseel Lyo (Thrombin Human).
In a trial of patients with a high likelihood of prior exposure to bovine Tisseel Lyo (Thrombin Human), 15.6% of patients (n=32/205) had anti-bovine Tisseel Lyo (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 Tisseel Lyo (Thrombin Human).
In a trial of patients previously exposed to Tisseel Lyo (Thrombin Human), 31 patients were re-exposed to Tisseel Lyo (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 Tisseel Lyo (Thrombin Human), including 26 pediatric patients (aged one month to 16 years) and four patients 17 years of age, one patient without prior Tisseel Lyo (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.
Pregnancy: No human or animal data. Use only if clearly needed.
Pregnancy Category C
Animal reproduction studies have not been conducted with Tisseel Lyo (Thrombin Human). It is also not known whether Tisseel Lyo (Thrombin Human) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Tisseel Lyo (Thrombin Human) should be given to a pregnant woman only if clearly needed.
A total of 30 pediatric patients, ages 0 to 16 years, were treated in clinical trials with Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (Thrombin Human) in adults. Safety and efficacy have not been established in neonates [see Adverse Reactions (6) ].
Of 644 patients in clinical studies of Tisseel Lyo (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.
Tisseel Lyo (Thrombin Human), Tisseel Lyo (Thrombin Human) topical (Recombinant), is a human coagulation protein produced via recombinant DNA technology from a genetically modified CHO cell line. Tisseel Lyo (Thrombin Human) is identical in amino acid sequence and structurally similar to naturally occurring human Tisseel Lyo (Thrombin Human). Tisseel Lyo (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 Tisseel Lyo (Thrombin Human). The cell line used to manufacture Tisseel Lyo (Thrombin Human) has been tested and shown to be free of known infectious agents. The cell culture process used in the manufacture of Tisseel Lyo (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.
Tisseel Lyo (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 Tisseel Lyo (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.
Tisseel Lyo (Thrombin Human), Tisseel Lyo (Thrombin Human) topical (Recombinant), is a specific human serine protease that promotes hemostasis and acts locally when applied topically to a site of bleeding.
Tisseel Lyo (Thrombin Human) activates platelets and catalyzes the conversion of fibrinogen to fibrin, which are steps that are essential for blood clot formation.
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 Tisseel Lyo.
In a study in nonhuman primates, Tisseel Lyo (Thrombin Human) was applied directly to a liver wound with an absorbable gelatin sponge, USP. In a second study, Tisseel Lyo (Thrombin Human) was administered subcutaneously once weekly for four weeks to nonhuman primates following repeat doses of 5405 units/m2. In both studies, Tisseel Lyo (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.
Tisseel Lyo (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 Tisseel Lyo (Thrombin Human) inhibition and clearance from the bloodstream, radiolabeled Tisseel Lyo (Thrombin Human) was administered intravenously or subcutaneously to nonhuman primates and applied with an absorbable gelatin sponge, USP, in a rabbit hepatic wound model. Tisseel Lyo (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.
Tisseel Lyo (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. Tisseel Lyo (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).
Tisseel Lyo (Thrombin Human) applied with a gauze sponge decreased TTH in a concentration-dependent manner in both the rabbit and rat models. Concentrations of Tisseel Lyo (Thrombin Human) >1000 units/mL were no different than 1000 units/mL while the effect of Tisseel Lyo (Thrombin Human) diluted to a concentration of 100 units/mL on TTH was indistinguishable from placebo.
Tisseel Lyo (Thrombin Human) was evaluated in a randomized, double-blind comparative clinical trial to bovine Tisseel Lyo (Thrombin Human). Each Tisseel Lyo (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 Tisseel Lyo (Thrombin Human) and bovine Tisseel Lyo (Thrombin Human) treatment groups.
The objectives of the study were to evaluate the comparative efficacy, safety, and immunogenicity of Tisseel Lyo (Thrombin Human) and bovine Tisseel Lyo (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 Tisseel Lyo (Thrombin Human) and bovine Tisseel Lyo (Thrombin Human) groups.
* Evaluation of hemostasis at ≤10 minutes for patients treated at 1 of 4 primary TTH bleeding site types: epidural venous plexus, hepatic resection site, peripheral arterial bypass proximal anastomosis, and arteriovenous graft arterial anastomosis. † THROMBIN-JMI® Tisseel Lyo (Thrombin Human), Topical (Bovine) | ||
Tisseel Lyo (Thrombin Human) (N=198) (%) | Bovine Thrombin* (N=203) (%) | |
Overall | 95% | 95% |
Spinal surgery | 98% | 98% |
Hepatic resection | 98% | 97% |
Peripheral arterial bypass | 85% | 86% |
Arteriovenous graft formation | 97% | 97% |
The percentage of patients achieving hemostasis at 1.5, 3, 6, and 10 minutes is listed in Table 3.
* THROMBIN-JMI® Tisseel Lyo (Thrombin Human), Topical (Bovine) | ||
Time (Minutes) | Tisseel Lyo (Thrombin Human) (N=198) (%) | Bovine Thrombin* (N=203) (%) |
1.5 | 48% | 46% |
3 | 81% | 72% |
6 | 92% | 88% |
10 | 95% | 95% |
Tisseel Lyo (Thrombin Human), Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (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 Tisseel Lyo (Thrombin Human) kit components contain latex.
Store Tisseel Lyo (Thrombin Human) sterile powder vials at 2°C to 25°C (36°F to 77°F). Do not freeze.
Reconstituted solutions of Tisseel Lyo (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.
Because topical Tisseel Lyo (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
Tisseel Lyo (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
Tisseel Lyo (Thrombin Human)®
Tisseel Lyo (Thrombin Human), TOPICAL
(RECOMBINANT)
5,000 units
5,000 units NDC: 65293-006-41 FOR TOPICAL USE ONLY - DO NOT INJECT RECOTHROM® Tisseel Lyo (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
Tisseel Lyo (Thrombin Human)®
Tisseel Lyo (Thrombin Human), TOPICAL
(RECOMBINANT)
20,000 units
20,000 units NDC: 65293-007-41 FOR TOPICAL USE ONLY - DO NOT INJECT RECOTHROM® Tisseel Lyo (Thrombin Human), TOPICAL (RECOMBINANT) 20,000 units
Depending on the reaction of the Tisseel Lyo after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Tisseel Lyo not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.
Is Tisseel Lyo addictive or habit forming?Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
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The information was verified by Dr. Rachana Salvi, MD Pharmacology