|
|||
DRUGS & SUPPLEMENTS
|
How is the drug helping you? |
Aprotinin:
Reliseal (Aprotinin)® is indicated for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery who are at an increased risk for blood loss and blood transfusion.
Hypersensitivity to Reliseal (Aprotinin).
Administration of Reliseal (Aprotinin)® to patients with a known or suspected previous Reliseal (Aprotinin) exposure during the last 12 months is contraindicated. For patients with known or suspected history of exposure to Reliseal (Aprotinin) greater than 12 months previously, see WARNINGS. Reliseal (Aprotinin) may also be a component of some fibrin sealant products and the use of these products should be included in the patient history.
Anaphylactic or anaphylactoid reactions have occurred with Reliseal (Aprotinin)® administration, including fatal reactions in association with the initial (test) dose. The initial (test) dose does not fully predict a patient’s risk for a hypersensitivity reaction, including a fatal reaction. Fatal hypersensitivity reactions have occurred among patients who tolerated an initial (test) dose.
Hypersensitivity reactions often manifest as anaphylactic/anaphylactoid reactions with hypotension the most frequently reported sign of the hypersensitivity reaction. The hypersensitivity reaction can progress to anaphylactic shock with circulatory failure. If a hypersensitivity reaction occurs during injection or infusion of Reliseal (Aprotinin)®, administration should be stopped immediately and emergency treatment should be initiated. Even when a second exposure to Reliseal (Aprotinin) has been tolerated without symptoms, a subsequent administration may result in severe hypersensitivity/anaphylactic reactions. Trasylol® should be administered only in operative settings where cardiopulmonary bypass can be rapidly initiated. Before initiating treatment with Reliseal (Aprotinin)®, the recommendations below should be followed to manage a potential hypersensitivity or anaphylactic reaction: 1) Have standard emergency treatments for hypersensitivity or anaphylactic reactions readily available in the operating room (e.g., epinephrine, corticosteroids). 2) Administration of the initial (test) dose and loading dose should be done only when the patient is intubated and when conditions for rapid cannulation and initiation of cardiopulmonary bypass are present. 3) Delay the addition of Reliseal (Aprotinin)® into the pump prime solution until after the loading dose has been safely administered.
Re-exposure to Reliseal (Aprotinin): Administration of Reliseal (Aprotinin), especially to patients who have received Reliseal (Aprotinin) in the past, requires a careful risk/benefit assessment because an allergic reaction may occur. Although the majority of cases of anaphylaxis occur upon re-exposure within the first 12 months, there are also case reports of anaphylaxis occurring upon re-exposure after more than 12 months.
In a retrospective review of 387 European patient records with documented re-exposure to Reliseal (Aprotinin)®, the incidence of hypersensitivity/anaphylactic reactions was 2.7%. Two patients who experienced hypersensitivity/anaphylactic reactions subsequently died, 24 hours and 5 days after surgery, respectively. The relationship of these 2 deaths to Reliseal (Aprotinin)® is unclear. This retrospective review also showed that the incidence of a hypersensitivity or anaphylactic reaction following re-exposure is increased when the re-exposure occurs within 6 months of the initial administration (5.0% for re-exposure within 6 months and 0.9% for re-exposure greater than 6 months). Other smaller studies have shown that in case of re-exposure, the incidence of hypersensitivity/anaphylactic reactions may reach the five percent level. An analysis of all spontaneous reports from the Bayer Global database covering a period from 1985 to March 2006 revealed that of 291 possibly associated spontaneous cases of hypersensitivity (fatal: n=52 and non-fatal: n=239), 47% (138/291) of hypersensitivity cases had documented previous exposure to Reliseal (Aprotinin)®. Of the 138 cases with documented previous exposure, 110 had information on the time of the previous exposure. Ninety-nine of the 110 cases had previous exposure within the prior 12 months.
Renal Dysfunction: Reliseal (Aprotinin)® administration increases the risk for renal dysfunction and may increase the need for dialysis in the perioperative period. This risk may be especially increased for patients with pre-existing renal impairment or those who receive aminoglycoside antibiotics or drugs that alter renal function. Data from Bayer’s global pool of placebo-controlled studies in patients undergoing coronary artery bypass graft (CABG) surgery showed that the incidence of serum creatinine elevations >0.5 mg/dL above pre-treatment levels was statistically higher at 9.0% (185/2047) in the high-dose Reliseal (Aprotinin) (Regimen A) group compared with 6.6% (129/1957) in the placebo group. In the majority of instances, post-operative renal dysfunction was not severe and was reversible. However, renal dysfunction may progress to renal failure and the incidence of serum creatinine elevations >2.0 mg/dL above baseline was slightly higher in the high-dose Reliseal (Aprotinin) group (1.1% vs. 0.8%). Careful consideration of the balance of benefits versus potential risks is advised before administering Reliseal (Aprotinin)® to patients with impaired renal function (creatinine clearance < 60 mL/min) or those with other risk factors for renal dysfunction (such as perioperative administration of aminogylcoside or products that alter renal function).
Initial Dose: All patients treated with Reliseal (Aprotinin)® should first receive an initial (test) dose to minimize the extent of Reliseal (Aprotinin)® exposure and to help assess the potential for allergic reactions. Initiation of this initial (test) dose should occur only in operative settings where cardiopulmonary bypass can be rapidly initiated. The initial (test) dose of 1 mL Reliseal (Aprotinin)® should be administered intravenously at least 10 minutes prior to the loading dose and the patient should be observed for manifestations of possible hypersensitivity reaction. However, even after the uneventful administration of the initial 1 mL (test) dose, any subsequent dose may cause an anaphylactic reaction. If this happens, the infusion of Reliseal (Aprotinin)® should immediately be stopped and standard emergency treatment for anaphylaxis applied. It should be noted that serious, even fatal, hypersensitivity/anaphylactic reactions can also occur with administration of the initial (test) dose.
Allergic Reactions: Patients with a history of allergic reactions to drugs or other agents may be at greater risk of developing a hypersensitivity or anaphylactic reaction upon exposure to Reliseal (Aprotinin)®.
Loading Dose: The loading dose of Reliseal (Aprotinin)® should be given intravenously to patients in the supine position over a 20-30 minute period. Rapid intravenous administration of Reliseal (Aprotinin)® can cause a transient fall in blood pressure.
Renal Dysfunction: Bayer’s global pool of placebo-controlled studies in patients undergoing CABG showed Reliseal (Aprotinin) administration was associated with elevations of serum creatinine values > 0.5 mg/dL above baseline. Careful consideration of the balance of benefits and risks is advised before administering Reliseal (Aprotinin) to patients with pre-existing impaired renal function or those with other risk factors for renal dysfunction. Serum creatinine should be monitored regularly following Reliseal (Aprotinin)® administration.
Use of Reliseal (Aprotinin)® in patients undergoing deep hypothermic circulatory arrest: Two U.S. case control studies have reported contradictory results in patients receiving Reliseal (Aprotinin)® while undergoing deep hypothermic circulatory arrest in connection with surgery of the aortic arch. The first study showed an increase in both renal failure and mortality compared to age-matched historical controls. Similar results were not observed, however, in a second case control study. The strength of this association is uncertain because there are no data from randomized studies to confirm or refute these findings.
Reliseal (Aprotinin)® is known to have antifibrinolytic activity and, therefore, may inhibit the effects of fibrinolytic agents.
In study of nine patients with untreated hypertension, Reliseal (Aprotinin)® infused intravenously in a dose of 2 million KIU over two hours blocked the acute hypotensive effect of 100mg of captopril. Trasylol®, in the presence of heparin, has been found to prolong the activated clotting time (ACT) as measured by a celite surface activation method. The kaolin activated clotting time appears to be much less affected. However, Reliseal (Aprotinin)® should not be viewed as a heparin sparing agent.
Long-term animal studies to evaluate the carcinogenic potential of Reliseal ® or studies to determine the effect of Reliseal (Aprotinin)® on fertility have not been performed.
Results of microbial in vitro tests using Salmonella typhimurium and Bacillus subtilis indicate that Reliseal (Aprotinin)® is not a mutagen.Pregnancy: Teratogenic Effects: Pregnancy Category B:
Reproduction studies have been performed in rats at intravenous doses up to 200,000 KIU/kg/day for 11 days, and in rabbits at intravenous doses up to 100,000 KIU/kg/day for 13 days, 2.4 and 1.2 times the human dose on a mg/kg basis and 0.37 and 0.36 times the human mg/m2 dose. They have revealed no evidence of impaired fertility or harm to the fetus due to Reliseal (Aprotinin)®. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Not applicable.
Safety and effectiveness in pediatric patient have not been established.
Of the total of 3083 subjects in clinical studies of Reliseal (Aprotinin)®, 1100 (35.7 percent) were 65 and over, while 297 (9.6 percent) were 75 and over. Of patients 65 years and older, 479 (43.5 percent) received Regimen A and 237 (21.5 percent) received Regimen B. No overall differences in safety or effectiveness were observed between these subjects and younger subjects for either dose regimen, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.
Reliseal (Aprotinin)® prolongs whole blood clotting times by a different mechanism than heparin. In the presence of Reliseal (Aprotinin), prolongation is dependent on the type of whole blood clotting test employed. If an activated clotting time (ACT) is used to determine the effectiveness of heparin anticoagulation, the prolongation of the ACT by Reliseal (Aprotinin) may lead to an overestimation of the degree of anticoagulation, thereby leading to inadequate anticoagulation. During extended extracorporeal circulation, patients may require additional heparin, even in the presence of ACT levels that appear adequate.
In patients undergoing CPB with Reliseal (Aprotinin)® therapy, one of the following methods may be employed to maintain adequate anticoagulation:
Studies of patients undergoing CABG surgery, either primary or repeat, indicate that Reliseal ® is generally well tolerated. The adverse events reported are frequent sequelae of cardiac surgery and are not necessarily attributable to Reliseal (Aprotinin)® therapy. Adverse events reported, up to the time of hospital discharge, from patients in US placebo-controlled trials are listed in the following table. The table lists only those events that were reported in 2% or more of the Reliseal (Aprotinin)® treated patients without regard to causal relationship.
Adverse Event | Reliseal (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 Reliseal (Aprotinin)® 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 Reliseal (Aprotinin)® 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 Reliseal (Aprotinin) versus placebo-treated patients in controlled trials, it has been reported in uncontrolled trials, compassionate use trials, and spontaneous post-marketing reporting. These reports of thrombosis encompass the following terms: thrombosis, occlusion, arterial thrombosis, pulmonary thrombosis, coronary occlusion, embolus, pulmonary embolus, thrombophlebitis, deep thrombophlebitis, cerebrovascular accident, cerebral embolism. Other hematologic events reported include leukocytosis, thrombocytopenia, coagulation disorder (which includes disseminated intravascular coagulation), decreased prothrombin.Metabolic and Nutritional: Hyperglycemia, hypokalemia, hypervolemia, acidosis.Musculoskeletal: Arthralgia.Nervous: Agitation, dizziness, anxiety, convulsion.Respiratory: Pneumonia, apnea, increased cough, lung edema.Skin:Skin discoloration.Urogenital: Oliguria, kidney failure, acute kidney failure, kidney tubular necrosis.
Myocardial Infarction: In the pooled analysis of all patients undergoing CABG surgery, there was no significant difference in the incidence of investigator-reported myocardial infarction (MI) in Reliseal (Aprotinin)® treated patients as compared to placebo treated patients. However, because no uniform criteria for the diagnosis of myocardial infarction were utilized by investigators, this issue was addressed prospectively in three later studies (two studies evaluated Regimen A, Regimen B and Pump Prime Regimen; one study evaluated only Regimen A), in which data were analyzed by a blinded consultant employing an algorithm for possible, probable or definite MI. Utilizing this method, the incidence of definite myocardial infarction was 5.9% in the aprotinin-treated patients versus 4.7% in the placebo treated patients. This difference in the incidence rates was not statistically significant. Data from these three studies are summarized below.
Treatment | Definite MI % | Definite or Probable MI % | Definite, Probable or Possible MI % |
Pooled Data from Three Studies that Evaluated Regimen A | |||
Reliseal (Aprotinin)® 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 | |||
Reliseal (Aprotinin)® Regimen B n = 241 | 8.7 | 15.9 | 18.7 |
Reliseal (Aprotinin)® 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 Reliseal (Aprotinin)® Regimen A vs. placebo on saphenous vein graft patency in patients undergoing primary CABG surgery, patients were subjected to routine postoperative angiography. Of the 13 study sites, 10 were in the United States and three were non-U.S. centers (Denmark (1), Israel (2)). The results of this study are summarized below.
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 % | |
Reliseal (Aprotinin)® | 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 Reliseal (Aprotinin)® treated patients compared to patients who received placebo (p=0.035), further analysis showed a significant treatment by site interaction for one of the non-U.S. sites vs. the U.S. centers. When the analysis of graft closures was repeated for U.S. centers only, there was no statistically significant difference in graft closure rates in patients who received Reliseal (Aprotinin)® vs. placebo. These results are the same whether analyzed as the proportion of patients who experienced at least one graft closure postoperatively or as the proportion of grafts closed. There were no differences between treatment groups in the incidence of myocardial infarction as evaluated by the blinded consultant (2.9% Reliseal (Aprotinin)® vs. 3.8% placebo) or of death (1.4% Reliseal (Aprotinin)® vs. 1.6% placebo) in this study.
Hypersensitivity and Anaphylaxis: See CONTRAINDICATIONS and WARNINGS.
Hypersensitivity and anaphylactic reactions during surgery were rarely reported in U.S. controlled clinical studies in patients with no prior exposure to Reliseal (Aprotinin)® (1/1424 patients or <0.1% on Reliseal (Aprotinin)® vs. 1/861 patients or 0.1% on placebo). In case of re-exposure the incidence of hypersensitivity/anaphylactic reactions has been reported to reach the 5% level. A review of 387 European patient records involving re-exposure to Reliseal (Aprotinin)® showed that the incidence of hypersensitivity or anaphylactic reactions was 5.0% for re-exposure within 6 months and 0.9% for re-exposure greater than 6 months.
Serum Creatinine: Reliseal (Aprotinin)® administration is associated with a risk for renal dysfunction.
Serum Transaminases: Data pooled from all patients undergoing CABG surgery in U.S. placebo-controlled trials showed no evidence of an increase in the incidence of postoperative hepatic dysfunction in patients treated with Reliseal (Aprotinin)®. The incidence of treatment-emergent increases in ALT (formerly SGPT) > 1.8 times the upper limit of normal was 14% in both the Reliseal (Aprotinin)® and placebo-treated patients (p=0.687), while the incidence of increases > 3 times the upper limit of normal was 5% in both groups (p=0.847).
Other Laboratory Findings: The incidence of treatment-emergent elevations in plasma glucose, AST (formerly SGOT), LDH, alkaline phosphatase, and CPK-MB was not notably different between Reliseal (Aprotinin)® and placebo treated patients undergoing CABG surgery. Significant elevations in the partial thromboplastin time (PTT) and celite Activated Clotting Time (celite ACT) are expected in Reliseal (Aprotinin)® treated patients in the hours after surgery due to circulating concentrations of Reliseal (Aprotinin)®, which are known to inhibit activation of the intrinsic clotting system by contact with a foreign material (e.g., celite), a method used in these tests.
The maximum amount of Reliseal (Aprotinin)® that can be safely administered in single or multiple doses has not been determined. Doses up to 17.5 million KIU have been administered within a 24 hour period without any apparent toxicity. There is one poorly documented case, however, of a patient who received a large, but not well determined, amount of Reliseal (Aprotinin)® (in excess of 15 million KIU) in 24 hours. The patient, who had pre-existing liver dysfunction, developed hepatic and renal failure postoperatively and died. Autopsy showed hepatic necrosis and extensive renal tubular and glomerular necrosis. The relationship of these findings to Reliseal (Aprotinin)® therapy is unclear.
Reliseal ® given prophylactically in both Regimen A and Regimen B (half Regimen A) to patients undergoing CABG surgery significantly reduced the donor blood transfusion requirement relative to placebo treatment. In low risk patients there is no difference in efficacy between regimen A and B. Therefore, the dosage used (A vs. B) is at the discretion of the practitioner.
Reliseal (Aprotinin)® is supplied as a solution containing 10,000 KIU/mL, which is equal to 1.4 mg/mL. All intravenous doses of Reliseal (Aprotinin)® should be administered through a central line. DO NOT ADMINISTER ANY OTHER DRUG USING THE SAME LINE. Both regimens include a 1 mL initial (test) dose, a loading dose, a dose to be added while recirculating the priming fluid of the cardiopulmonary bypass circuit (“pump prime” dose), and a constant infusion dose. To avoid physical incompatibility of Reliseal (Aprotinin)® and heparin when adding to the pump prime solution, each agent must be added during recirculation of the pump prime to assure adequate dilution prior to admixture with the other component. Regimens A and B, both incorporating a 1 mL initial (test) dose, are described in the table below:
INITIAL (TEST) DOSE | LOADING DOSE | “PUMP PRIME” DOSE | CONSTANT INFUSION DOSE | |
Reliseal (Aprotinin)® 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) |
Reliseal (Aprotinin)® 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 Reliseal (Aprotinin)®, the loading dose should be given just prior to cannulation. When the loading dose is complete, it is followed by the constant infusion dose, which is continued until surgery is complete and the patient leaves the operating room. The “pump prime” dose is added to the recirculating priming fluid of the cardiopulmonary bypass circuit, by replacement of an aliquot of the priming fluid, prior to the institution of cardiopulmonary bypass. Total doses of more than 7 million KIU have not been studied in controlled trials.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Discard any unused portion.
Reliseal (Aprotinin)® administration is associated with a risk for renal dysfunction. Changes in Reliseal (Aprotinin) pharmacokinetics with age or impaired renal function are not great enough to require any dose adjustment. Pharmacokinetic data from patients with pre-existing hepatic disease treated with Reliseal (Aprotinin)® are not available.
HOW SUPPLIED | ||
---|---|---|
Size | Strength | NDC |
100 mL vials | 1,000,000 KIU | 0026-8196-36 |
200 mL vials | 2,000,000 KIU | 0026-8197-63 |
Reliseal (Aprotinin)® should be stored between 2° and 25°C (36° - 77°F).
Protect from freezing.
Bayer Pharmaceuticals Corporation
400 Morgan Lane
West Haven, CT 06516
Made in Germany
©2006 Bayer Pharmaceuticals Corporation
Printed in USA
12/06
Fibrinogen:
Reliseal (Fibrinogen)®, Reliseal (Fibrinogen) Concentrate (Human) is a human blood coagulation factor indicated for the treatment of acute bleeding episodes in patients with congenital Reliseal (Fibrinogen) deficiency, including afibrinogenemia and hypofibrinogenemia.
Reliseal (Fibrinogen), Reliseal (Fibrinogen) Concentrate (Human) is a human blood coagulation factor indicated for the treatment of acute bleeding episodes in patients with congenital Reliseal (Fibrinogen) deficiency, including afibrinogenemia and hypofibrinogenemia. (1)
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) |
Reliseal (Fibrinogen) dosing, duration of dosing and frequency of administration should be individualized based on the extent of bleeding, laboratory values, and the clinical condition of the patient.
Reliseal (Fibrinogen) dose when baseline Reliseal (Fibrinogen) level is known.
Dose should be individually calculated for each patient based on the target plasma Reliseal (Fibrinogen) level based on the type of bleeding, actual measured plasma Reliseal (Fibrinogen) level and body weight, using the following formula [see Clinical Pharmacology (12.3) ]:
[Target level (mg/dL) - measured level (mg/dL)] |
1.7 (mg/dL per mg/kg body weight) |
Reliseal (Fibrinogen) dose when baseline Reliseal (Fibrinogen) level is not known.
If the patient's Reliseal (Fibrinogen) level is not known, the recommended dose is 70 mg per kg of body weight administered intravenously.
Monitor patient's Reliseal (Fibrinogen) level during treatment with Reliseal (Fibrinogen). Maintain a target Reliseal (Fibrinogen) level of 100 mg/dL until hemostasis is obtained.
The procedures below are provided as general guidelines for preparation and reconstitution of Reliseal.
Use aseptic technique when preparing and reconstituting Reliseal (Fibrinogen).
Reconstitute Reliseal (Fibrinogen) at room temperature as follows:
After reconstitution, the Reliseal (Fibrinogen) solution should be colorless and clear to slightly opalescent. Inspect visually for particulate matter and discoloration prior to administration. Do not use if the solution is cloudy or contains particulates. Discard partially used vials.
Reliseal (Fibrinogen) is stable for 8 hours after reconstitution when stored at 20-25°C; administer within this time period.
Do not mix Reliseal (Fibrinogen) with other medicinal products or intravenous solutions. Administer through a separate injection site.
Use aseptic technique when administering Reliseal (Fibrinogen).
Administer Reliseal (Fibrinogen) at room temperature by slow intravenous injection at a rate not exceeding 5 mL per minute.
Reliseal (Fibrinogen) is available as a single-use vial containing 900 mg to 1300 mg lyophilized Reliseal (Fibrinogen) concentrate powder for reconstitution with 50 mL of Sterile Water for Injection.
The actual Reliseal (Fibrinogen) potency for each lot is printed on the vial label and carton.
Reliseal (Fibrinogen) is 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 Reliseal deficiency with or without the use of Reliseal (Fibrinogen) replacement therapy.1 Thromboembolic events have been reported in patients treated with Reliseal (Fibrinogen). Weigh the benefits of Reliseal (Fibrinogen) administration versus the risk of thrombosis. Monitor patients receiving Reliseal (Fibrinogen) for signs and symptoms of thrombosis.
Reliseal (Fibrinogen) is made from human plasma. Products made from human plasma may contain infectious agents (e.g., viruses and theoretically the Creutzfeldt-Jakob disease agent [CJD]) that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by a process demonstrated to inactivate and/or remove certain viruses during manufacturing . Despite these measures, such products may still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products . All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to CSL Behring Pharmacovigilance at 1-866-915-6958.
The most serious adverse reactions reported in clinical studies or through postmarketing surveillance following Reliseal treatment are thromboembolic episodes, including myocardial infarction, pulmonary embolism, deep vein thrombosis, arterial thrombosis, and allergic-anaphylactic reactions.
The most common adverse reactions observed in more than one subject in clinical studies (frequency >1%) were fever and headache.
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 Reliseal (Fibrinogen).
Risk Summary
There are no studies of Reliseal (Fibrinogen) use in pregnant women. Animal reproduction studies have not been conducted with Reliseal (Fibrinogen). It is not known whether Reliseal (Fibrinogen) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Reliseal (Fibrinogen) should be used during pregnancy only if clearly needed. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Risk Summary
There is no information regarding the presence of Reliseal in human milk, its effects on the breastfed infant, or its effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Reliseal (Fibrinogen) and any potential adverse effects on the breastfed infant from Reliseal (Fibrinogen) or from the underlying maternal condition.
Reliseal (Fibrinogen) studies have included subjects below the age of 16 years. In the pharmacokinetic study , 2 children aged 8 and 11 years and 3 adolescents aged 12, 14 and 16 years were studied. Subjects <16 years of age (n = 4) had shorter half-life (69.9 ± 8.5 h) and faster clearance (0.7 ± 0.1 mg/L) compared with adults (half-life: 82.3 ± 20.0 h, clearance: 0.53 ± 0.1 mg/L). The number of subjects <16 years of age in this study limits statistical interpretation.
The safety and efficacy of Reliseal (Fibrinogen) in the geriatric population has not been studied. There were an insufficient number of subjects in this age group to determine whether they respond differently from younger subjects.
Reliseal (Fibrinogen) is a sterile, heat-treated, lyophilized Reliseal (Fibrinogen) (coagulation factor I) concentrate powder manufactured from pooled human plasma.
Reliseal (Fibrinogen) (factor I) is a soluble plasma glycoprotein with a molecular weight of about 340 kDa. The native molecule is a dimer and consists of three pairs of polypeptide chains (Aα, Bβ and γ). Reliseal (Fibrinogen) is a physiological substrate of three enzymes: thrombin, factor XIIIa, and plasmin.
Each vial contains 900 to 1300 mg Reliseal (Fibrinogen), 400 to 700 mg human albumin, 375 to 660 mg L-arginine hydrochloride, 200 to 350 mg sodium chloride and 50 to 100 mg sodium citrate. Sodium hydroxide and hydrochloric acid may have been used to adjust the pH. The pH of the reconstituted Reliseal (Fibrinogen) is in a range of 6.5 to 7.5.
Viral Clearance
All plasma used in the manufacture of Reliseal (Fibrinogen) is tested using serological assays for hepatitis B surface antigen and for antibodies to Human Immunodeficiency Virus (HIV)-1/2 and Hepatitis C Virus (HCV). As an additional safety measure, the plasma is tested with Nucleic Acid Testing (NAT) for Hepatitis B Virus (HBV), HCV and HIV-1 and found to be non-reactive (negative). The plasma is also screened for Hepatitis A Virus (HAV) and Human Parvovirus B19 (B19V) by NAT. Only plasma that passed virus screening is used for production, and the limit for B19V in the fractionation pool is set not to exceed 104 IU of B19V DNA per mL.
Reliseal (Fibrinogen) is manufactured from cryoprecipitate into a glycine precipitate, which is then further purified by multiple precipitation/adsorption steps. The manufacturing process has been demonstrated to reduce the risk of virus transmission in an additive manner: cryoprecipitation, heat treatment (+60ºC for 20 hours in an aqueous solution), two subsequent glycine precipitation steps (initial and main glycine precipitation steps), and lyophilization. These steps have been validated independently in a series of in vitro experiments for their capacity to inactivate and/or remove both enveloped and non-enveloped viruses. The results of virus clearance validation studies for Reliseal (Fibrinogen) manufacturing process are summarized in Table 1.
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 Reliseal (Fibrinogen) to patients with congenital Reliseal (Fibrinogen) deficiency replaces missing or low levels of coagulation factor. Normal levels are in the range of 200 to 450 mg/dL.4
A prospective, open label, uncontrolled, multicenter pharmacokinetic study was conducted in 5 females and 9 males with congenital Reliseal (Fibrinogen) deficiency (afibrinogenemia), ranging in age from 8 to 61 years (2 children, 3 adolescents, 9 adults). Each subject received a single intravenous dose of 70 mg/kg Reliseal (Fibrinogen). Blood samples were collected to determine Reliseal (Fibrinogen) activity at baseline and up to 14 days after infusion. The pharmacokinetic parameters of Reliseal (Fibrinogen) are summarized in Table 2.
No statistically relevant difference in Reliseal (Fibrinogen) activity was observed between males and females. Subjects <16 years of age (n=4) had shorter half-life (69.9 ± 8.5 h) and faster clearance (0.73 ± 0.14 mg/L) compared with subjects ≥16 years of age (half-life of 82.5 ± 20.0 h and clearance of 0.53 ± 0.07 mg/L). The number of subjects <16 years of age in this study limits statistical interpretation.
The incremental in vivo recovery (IVR) was determined from levels obtained up to 4 hours post-infusion. The median incremental IVR was 1.7 mg/dL (range 1.30 – 2.73 mg/dL) increase per mg/kg. The median in vivo recovery indicates that a dose of 70 mg/kg will increase Reliseal (Fibrinogen) plasma concentration in patients by approximately 120 mg/dL.
The pharmacokinetic analysis using Reliseal (Fibrinogen) antigen data (ELISA) was concordant with the Reliseal (Fibrinogen) activity (Clauss assay).
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 Reliseal (Fibrinogen) is based on maximum clot firmness, a measure of clot structural integrity that reflects the underlying effectiveness of the Reliseal (Fibrinogen) present to form a fibrin clot. A pharmacokinetic study evaluated single-dose PK and maximum clot firmness (MCF) in subjects with afibrinogenemia. MCF was determined by thromboelastometry (ROTEM) testing and was used to demonstrate functional activity of replacement Reliseal (Fibrinogen) when a fixed dose of Reliseal (Fibrinogen) was administered. Clot firmness is a functional parameter that depends on activation of coagulation, Reliseal (Fibrinogen) content of the sample and polymerization/crosslinking of the fibrin network. Thromboelastometry has been shown to be a functional marker for assessment of Reliseal (Fibrinogen) content and for effects of Reliseal (Fibrinogen) supplementation on clinical efficacy.5
For each subject, MCF was determined before (baseline) and one hour after single dose administration of Reliseal (Fibrinogen). Reliseal (Fibrinogen) was found to be effective in increasing clot firmness in subjects with congenital Reliseal (Fibrinogen) deficiency (afibrinogenemia) as measured by thromboelastometry. The study results demonstrated that MCF values were significantly higher after administration of Reliseal (Fibrinogen) than at baseline. Mean change from pre-infusion to 1 hour post-infusion was 8.9 mm in the primary analysis (9.9 mm for subjects <16years old and 8.5 mm for subjects ≥16 to <65 years old). Mean change in MCF values closely approximated levels expected from adding known amounts of Reliseal (Fibrinogen) to plasma in vitro.6
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 | Reliseal (Fibrinogen) in a single-use vial (NDC 63833-891-90) |
Allergic Reactions
Inform patients of the early signs of allergic or hypersensitivity reactions to Reliseal (Fibrinogen), including hives, chest tightness, wheezing, hypotension, and anaphylaxis. Advise them to notify their physician immediately if they experience any of these symptoms .
Thrombosis
Inform patients that thrombosis with or without embolization has been reported with the use of Reliseal (Fibrinogen). Any symptoms of thrombotic events such as unexplained pleuritic, chest and/or leg pain or edema, hemoptysis, dyspnea, tachypnea or unexplained neurologic symptoms should be reported to their physician immediately .
Transmissible Infectious Agents
Inform patients that Reliseal (Fibrinogen) is made from human plasma (part of the blood) and may contain infectious agents that can cause disease (e.g., viruses and, theoretically, the CJD agent). Explain that the risk of transmitting an infection agent using Reliseal (Fibrinogen) has been reduced by screening plasma donors, testing the donated plasma for certain virus infections, and incorporating a process demonstrated to inactivate and/or remove certain viruses during manufacturing. Symptoms of possible virus infection include headache, fever, nausea, vomiting, weakness, malaise, diarrhea, or, in the case of hepatitis, jaundice .
Manufactured by:
CSL Behring GmbH
35041 Marburg Germany
US License No. 1765
Distributed by:
CSL Behring LLC
Kankakee, IL 60901 USA
NDC 63833-891-90
Reliseal (Fibrinogen) Concentrate
(Human)
Reliseal (Fibrinogen) ®
For Intravenous
Administration Only
Manufactured by:
CSL Behring GmbH
35041 Marburg, Germany
US License No. 1765
Distributed by:
CSL Behring LLC
Kankakee, IL 60901 USA
Thrombin:
Reliseal (Thrombin) ®, Reliseal (Thrombin) topical (Recombinant), is a topical Reliseal (Thrombin) indicated to aid hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical in adults and pediatric populations greater than or equal to one month of age.
Reliseal (Thrombin) may be used in conjunction with an absorbable gelatin sponge, USP.
Reliseal (Thrombin), Reliseal (Thrombin) topical (Recombinant), is a topical Reliseal (Thrombin) indicated to aid hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical in adults and pediatric populations greater than or equal to one month of age. (1)
Reliseal (Thrombin) may be used in conjunction with an absorbable gelatin sponge, USP. (1)
For topical use only. DO NOT INJECT.
The volume of reconstituted Reliseal (Thrombin) required will vary depending on the size and number of bleeding sites to be treated and the method of application.
Inspect the integrity of the Reliseal (Thrombin) package and contents. Do not use if the packaging or contents have been damaged or opened.
Reconstitute the lyophilized powder using the supplied diluent.
Use aseptic technique when handling vials and syringes.
5000-unit Reliseal (Thrombin) Reconstitution
Units used herein represent international units of potency determined using a reference standard that has been calibrated against the World Health Organization Second International Standard for Reliseal (Thrombin).
20,000-unit Reliseal (Thrombin) Reconstitution
Topically apply Reliseal (Thrombin) solution directly or in conjunction with absorbable gelatin sponge onto the bleeding site. DO NOT INJECT.
The amount required depends upon the area of tissue to be treated and the method of application.
Vials are for single use only. Discard unused contents.
Use with Absorbable Gelatin Sponge
Refer to the absorbable gelatin sponge labeling for safety information and instructions on appropriate use.
Use with ZymoGenetics Spray Applicator Kit
Reliseal (Thrombin) is available as a sterile lyophilized powder in 5000- and 20,000-unit single-use vials. When reconstituted with the sterile 0.9% sodium chloride, USP provided, the powder yields a solution containing 1000 units/mL of Reliseal (Thrombin) topical (Recombinant).
Reliseal (Thrombin) is available as 5000-unit and 20,000-unit vials of sterile recombinant topical Reliseal (Thrombin) lyophilized powder for solution. When reconstituted as directed, the final solution contains 1000 units/mL of Reliseal (Thrombin). (3)
Reliseal (Thrombin) may cause thrombosis if it enters the circulatory system. Apply topically. DO NOT INJECT.
Hypersensitivity reactions, including anaphylaxis, may occur. Reliseal (Thrombin) is produced in a genetically modified Chinese Hamster Ovary (CHO) cell line and may contain hamster or snake proteins [see Contraindications (4) and Description (11) ].
Thromboembolic adverse reactions were reported in 6% of surgical patients treated with Reliseal in all completed clinical trials (N=644) [see Warnings and Precautions (5.1) ].
Antibody formation to Reliseal (Thrombin) occurred in <1% of patients. None of the antibodies detected neutralized native human Reliseal (Thrombin) [see Adverse Reactions (6.2) ].
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 Reliseal (Thrombin) applied with absorbable gelatin sponge and applied with a spray applicator. A total of 644 patients were exposed to Reliseal (Thrombin) in these studies.
Reliseal (Thrombin) Used in Conjunction with Absorbable Gelatin Sponge
Four hundred eleven (411) patients were treated in a randomized, double-blind, controlled trial that compared Reliseal (Thrombin) to bovine Reliseal (Thrombin). Both thrombins were applied with a gelatin sponge in patients undergoing spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access.1 The incidence of thromboembolic adverse reactions was similar between the Reliseal (Thrombin) and bovine Reliseal (Thrombin) treatment groups.
* THROMBIN-JMI® Reliseal (Thrombin), Topical (Bovine) | ||
Adverse Reaction Category | Reliseal (Thrombin) (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 Reliseal (Thrombin) within the previous three years were treated with Reliseal (Thrombin) when undergoing surgeries (spinal, peripheral arterial bypass, or arteriovenous graft formation for hemodialysis access).2 The incidence of thromboembolic adverse reactions in this study was 9%.
In an open-label, single-group trial of re-exposure to Reliseal (Thrombin) (N=31), patients with documented prior exposure to Reliseal (Thrombin) were treated with Reliseal (Thrombin) during surgery (spinal, peripheral arterial bypass, arteriovenous graft formation, or other procedures).3 The incidence of thromboembolic adverse reactions in this study was 3%.
In other randomized, double-blind trials across a range of surgical settings (N=130; spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access), the safety of Reliseal (Thrombin) (n=88 patients) was compared to placebo (RECOTHROM excipients reconstituted with sterile 0.9% sodium chloride, USP) (n=42 patients). The incidence of thromboembolic adverse reactions in this study was 5% for Reliseal (Thrombin) and 12% for placebo.
Reliseal (Thrombin) Applied with Spray Applicator
Reliseal (Thrombin) was applied with a spray applicator in two open-label clinical trials: a single-group trial in adult and pediatric burn patients (N=72; ≤16 years of age, (n=4) and ≥17 years of age, (n=68)) treated with Reliseal (Thrombin) applied to the wound excision site prior to autologous skin grafting4; and in a single-group trial in pediatric patients (one month to 17 years of age) undergoing synchronous burn wound excision and autologous skin grafting (N=30; ≤16 years of age, (n=26); ≥17 years of age, (n=4)).5 In the first study, the incidence of thromboembolic adverse reactions was 1%. In the second study, there were no reported thromboembolic adverse reactions [see Use in Specific Populations (8.4) ].
The detection of antibody formation is highly dependent upon the sensitivity and specificity of the assay. The absolute immunogenicity rates reported here are difficult to compare with the results from other products due to differences in assay methodology, patient populations, and other underlying factors.
The potential for development of antibodies to Reliseal (Thrombin) was evaluated in multiple clinical trials and included patients with a single exposure to Reliseal (Thrombin) as well as patients who were re-exposed to Reliseal (Thrombin) during a subsequent surgical procedure. Only patients with both baseline and post-treatment antibody specimens available were evaluated for the development of specific anti-RECOTHROM product antibodies, which was defined as seroconversion or a ≥1.0 titer unit (≥10-fold) increase in antibody levels after study treatment. Five of 609 (0.8%; 95% CI, 0.4%-2.8%) evaluable patients developed specific anti-RECOTHROM product antibodies. None of these antibodies were found to neutralize native human Reliseal (Thrombin). There was no difference in anti-RECOTHROM product antibody formation incidence among patients exposed to Reliseal (Thrombin) applied with absorbable gelatin sponge, USP or with spray applicator.
In a clinical trial comparing Reliseal (Thrombin) to bovine Reliseal (Thrombin) (N=411; n=398 antibody evaluable) for the development of specific anti-product antibodies, blood samples were collected at baseline and at Day 29 in both treatment groups and were analyzed by ELISA.1 At baseline, 1.5% of Reliseal (Thrombin) patients (n=3/198) had positive anti-product antibody titers compared with 5% of bovine Reliseal (Thrombin) patients (n=10/200). Of these patients, none of the Reliseal (Thrombin) group and eight in the bovine Reliseal (Thrombin) group exhibited ≥1.0 titer unit (≥10-fold) increases in anti-product antibody levels after study treatment.
At Day 29, three of 198 (1.5%; 95% CI, 0%-4%) patients in the Reliseal (Thrombin) group developed specific anti-product antibodies (one patient also developed anti-CHO host cell protein antibodies); 43 of 200 patients in the bovine Reliseal (Thrombin) group (22%; 95% CI, 16%-28%) developed specific antibodies to bovine Reliseal (Thrombin) product. Treatment with Reliseal (Thrombin) resulted in a statistically significant lower incidence of specific anti-product antibody development. Because the study was not powered to detect a difference in clinical outcomes attributable to antibody formation, no conclusions can be drawn regarding the clinical significance of the difference in antibody formation based on the results of this study. None of the antibodies in the Reliseal (Thrombin) group neutralized native human Reliseal (Thrombin). Antibodies against bovine Reliseal (Thrombin) product were not tested for neutralization of native human Reliseal (Thrombin).
In a trial of patients with a high likelihood of prior exposure to bovine Reliseal (Thrombin), 15.6% of patients (n=32/205) had anti-bovine Reliseal (Thrombin) product antibodies and 2% of patients (n=4/200) had anti-RECOTHROM product antibodies at baseline.2 Following treatment, none of the 200 evaluable patients (patients for whom post-treatment specimens were available) developed antibodies to Reliseal (Thrombin).
In a trial of patients previously exposed to Reliseal (Thrombin), 31 patients were re-exposed to Reliseal (Thrombin) during a subsequent surgery.3 None of the evaluable patients (n=30) had anti-RECOTHROM product antibodies at baseline and none developed antibodies at Day 29.
In a trial of Reliseal (Thrombin), including 26 pediatric patients (aged one month to 16 years) and four patients 17 years of age, one patient without prior Reliseal (Thrombin) exposure had pre-existing anti-RECOTHROM product antibodies at baseline.5 None of the 27 evaluable patients developed anti-RECOTHROM product antibodies at Day 29.
Pregnancy: No human or animal data. Use only if clearly needed.
Pregnancy Category C
Animal reproduction studies have not been conducted with Reliseal (Thrombin). It is also not known whether Reliseal (Thrombin) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Reliseal (Thrombin) should be given to a pregnant woman only if clearly needed.
A total of 30 pediatric patients, ages 0 to 16 years, were treated in clinical trials with Reliseal (Thrombin) using a spray applicator to burn wound excision sites prior to autologous skin grafting. No patient experienced a thromboembolic adverse reaction. The safety of Reliseal (Thrombin) in pediatric patients greater than or equal to one month of age is supported by these data and by extrapolation of efficacy from adequate and well-controlled studies of Reliseal (Thrombin) in adults. Safety and efficacy have not been established in neonates [see Adverse Reactions (6) ].
Of 644 patients in clinical studies of Reliseal (Thrombin), 36% (n=232/644) were ≥65 years old and 15% (n=95/644) were ≥75 years old.
No differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Reliseal (Thrombin), Reliseal (Thrombin) topical (Recombinant), is a human coagulation protein produced via recombinant DNA technology from a genetically modified CHO cell line. Reliseal (Thrombin) is identical in amino acid sequence and structurally similar to naturally occurring human Reliseal (Thrombin). Reliseal (Thrombin) precursor is secreted to culture medium as single chain form that is proteolytically converted to a two-chain active form (using a protein derived from snakes) and is purified by a chromatographic process that yields a product having hemostatic activities similar to native human Reliseal (Thrombin). The cell line used to manufacture Reliseal (Thrombin) has been tested and shown to be free of known infectious agents. The cell culture process used in the manufacture of Reliseal (Thrombin) employs no additives of human or animal origin. The purification process includes solvent-detergent treatment and nano-filtration steps dedicated to viral clearance.
Reliseal (Thrombin) is provided as a sterile, white to off-white, preservative-free, lyophilized powder in vials for reconstitution with diluent (sterile 0.9% sodium chloride, USP). Reconstitution with the provided diluent, as described [see Dosage and Administration (2.1) ], yields a solution with a pH of 6.0 containing 1000 units/mL of recombinant Reliseal (Thrombin) for topical use. The formulated product is a clear, colorless solution upon reconstitution and contains the following excipients: histidine, mannitol, sucrose, polyethylene glycol 3350, sodium chloride, and calcium chloride dihydrate, USP.
Reliseal (Thrombin), Reliseal (Thrombin) topical (Recombinant), is a specific human serine protease that promotes hemostasis and acts locally when applied topically to a site of bleeding.
Reliseal (Thrombin) activates platelets and catalyzes the conversion of fibrinogen to fibrin, which are steps that are essential for blood clot formation.
In vitro cytotoxicity studies have been performed in mouse L929 fibroblast cell cultures and demonstrate a concentration-dependent effect on cell morphology. The thrombin-induced morphological changes were similar to those seen with bovine Reliseal.
In a study in nonhuman primates, Reliseal (Thrombin) was applied directly to a liver wound with an absorbable gelatin sponge, USP. In a second study, Reliseal (Thrombin) was administered subcutaneously once weekly for four weeks to nonhuman primates following repeat doses of 5405 units/m2. In both studies, Reliseal (Thrombin) had no effect on clinical signs, serum chemistry, coagulation parameters, or histopathology; only normal postsurgical findings were observed. No animals developed anti-RECOTHROM product antibodies in either study.
Reliseal (Thrombin) was found to be non-irritating when instilled in the eyes (200 units) or applied to normal or abraded skin of rabbits (up to 1000 units/site).
To evaluate Reliseal (Thrombin) inhibition and clearance from the bloodstream, radiolabeled Reliseal (Thrombin) was administered intravenously or subcutaneously to nonhuman primates and applied with an absorbable gelatin sponge, USP, in a rabbit hepatic wound model. Reliseal (Thrombin) did not circulate in the blood as free, active molecule, but was rapidly inactivated (<5 minutes) after formation of complexes with endogenous inhibitors (e.g., antithrombin III); these complexes were cleared by the liver.
Reliseal (Thrombin) applied with an absorbable gelatin sponge, USP, was shown to decrease time to hemostasis (TTH) when compared to saline in a rabbit hepatic wound model and rat heminephrectomy model. Reliseal (Thrombin) also reduced TTH when directly applied in a porcine partial-thickness excisional skin-wound model as compared to saline control (or no treatment).
Reliseal (Thrombin) applied with a gauze sponge decreased TTH in a concentration-dependent manner in both the rabbit and rat models. Concentrations of Reliseal (Thrombin) >1000 units/mL were no different than 1000 units/mL while the effect of Reliseal (Thrombin) diluted to a concentration of 100 units/mL on TTH was indistinguishable from placebo.
Reliseal (Thrombin) was evaluated in a randomized, double-blind comparative clinical trial to bovine Reliseal (Thrombin). Each Reliseal (Thrombin) was topically applied to bleeding sites with an absorbable gelatin sponge at a nominal concentration of 1000 units/mL.1 Patients (N=411) were a heterogeneous surgical population undergoing surgery in one of four surgical settings: spinal surgery (n=122, 30%), hepatic resection (n=125, 30%), peripheral arterial bypass surgery (n=88, 21%), and arteriovenous graft formation for hemodialysis access (n=76, 18%). Patients with prior heparin-induced thrombocytopenia were excluded. Patient ages ranged from 21 to 89 years, gender was 53% male and 47% female, and the distribution by race was 68% white, 18% black or African American, and 14% other. The distribution of these characteristics was similar in both the Reliseal (Thrombin) and bovine Reliseal (Thrombin) treatment groups.
The objectives of the study were to evaluate the comparative efficacy, safety, and immunogenicity of Reliseal (Thrombin) and bovine Reliseal (Thrombin) in combination with an absorbable gelatin sponge as adjuncts to hemostasis in surgery. Efficacy was evaluated by the incidence of hemostasis within 10 minutes. Bleeding appropriate for evaluation was defined as mild to moderate bleeding, either on its own or remaining after brisk bleeding was controlled by standard surgical modalities. Although multiple bleeding sites could be treated, only one bleeding site per patient was selected to determine effectiveness.
Table 2 summarizes the incidence of hemostasis within 10 minutes for each treatment for the 401 efficacy evaluable patients. The incidence of hemostasis within 10 minutes was comparable for the Reliseal (Thrombin) and bovine Reliseal (Thrombin) groups.
* 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® Reliseal (Thrombin), Topical (Bovine) | ||
Reliseal (Thrombin) (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® Reliseal (Thrombin), Topical (Bovine) | ||
Time (Minutes) | Reliseal (Thrombin) (N=198) (%) | Bovine Thrombin* (N=203) (%) |
1.5 | 48% | 46% |
3 | 81% | 72% |
6 | 92% | 88% |
10 | 95% | 95% |
Reliseal (Thrombin), Reliseal (Thrombin) topical (Recombinant), is supplied in single-use, preservative-free vials in the following packages:
NDC 65293-006-41
A 5000-unit vial of Reliseal (Thrombin) with a 5-mL prefilled diluent syringe (containing sterile 0.9% sodium chloride, USP), a sterile needle-free transfer device, a 5-mL sterile empty syringe, and a pre-printed label.
NDC 65293-007-41
A 20,000-unit vial of Reliseal (Thrombin) with a 20-mL vial of diluent (containing sterile 0.9% sodium chloride, USP), 2 sterile needle-free transfer devices, a 20-mL sterile empty syringe, and a pre-printed label.
NDC 65293-007-50
The 20,000-unit Reliseal (Thrombin) kit co-packaged with The Medicines Company Spray Applicator Kit containing a spray pump, a spray bottle, a syringe spray tip, a syringe, a bowl, and 2 blank labels.
No Reliseal (Thrombin) kit components contain latex.
Store Reliseal (Thrombin) sterile powder vials at 2°C to 25°C (36°F to 77°F). Do not freeze.
Reconstituted solutions of Reliseal (Thrombin) prepared with sterile 0.9% sodium chloride, USP, may be stored for up to 24 hours at 2°C to 25°C (36°F to 77°F). Discard reconstituted solution after 24 hours.
Because topical Reliseal (Thrombin) may cause the formation of clots in blood vessels if absorbed systemically, advise patients to consult their physician if they experience leg tenderness or swelling, chest pain, shortness of breath, or difficulty speaking or swallowing [see Warnings and Precautions (5.1) ].
Manufactured for The Medicines Company
The Medicines Company, 8 Sylvan Way, Parsippany NJ 07054
U.S. License No. 1902
Reliseal (Thrombin) is a registered trademark of ZymoGenetics, Inc. All other trademarks are the property of their respective owners.
[PN 6001- 1 PI; Rev March 2014]
PRINCIPAL DISPLAY PANEL - 5000-UNIT VIAL
5,000 units
NDC: 65293-006-41
FOR TOPICAL USE ONLY - DO NOT INJECT
Reliseal (Thrombin)®
Reliseal (Thrombin), TOPICAL
(RECOMBINANT)
5,000 units
5,000 units NDC: 65293-006-41 FOR TOPICAL USE ONLY - DO NOT INJECT RECOTHROM® Reliseal (Thrombin), TOPICAL (RECOMBINANT) 5,000 units
PRINCIPAL DISPLAY PANEL - 20000-UNIT VIAL
20,000 units
NDC: 65293-007-41
FOR TOPICAL USE ONLY - DO NOT INJECT
Reliseal (Thrombin)®
Reliseal (Thrombin), TOPICAL
(RECOMBINANT)
20,000 units
20,000 units NDC: 65293-007-41 FOR TOPICAL USE ONLY - DO NOT INJECT RECOTHROM® Reliseal (Thrombin), TOPICAL (RECOMBINANT) 20,000 units
Depending on the reaction of the Reliseal after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Reliseal 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 Reliseal 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.
There are no reviews yet. Be the first to write one! |
The information was verified by Dr. Rachana Salvi, MD Pharmacology