Flexbumin（软袋装人血白蛋白）获美国FDA批准 2014年8月5日，Flexbumin（软袋人血白蛋白，USP，5%溶液）获FDA批准，该药的适应症包括：常见原因导致的血容量不足（hypovolemia）、低白蛋白血症（ hypoalbuminemia ）、烧伤、心肺旁路手术患者。 此次批准，扩大了Flexbumin的产品组合，规格包括：5%溶液（250ml），25%溶液（50ml），25%溶液（100ml）。 Flexbumin是全球首个及唯一一个软袋白蛋白，同时也是全球首个、迄今唯一获低碳认证的医疗产品。 百特计划在今年晚些时候在美国推出Flexbumin（5%溶液）新品 与传统瓶装白蛋白相比，Flexbumin软袋白蛋白带来了更多的应用利益，包括： （1）升级为闭合输注系统，降低中心静脉导管相关输液感染风险； （2）缩短输液准备时间达40%，减少操作失误； （3）抗摔抗压，可以避免高值药品的损耗； （4）质量轻40%，体积小60%，可以降低运输和仓储成本； （5）医用废物处置成本比瓶装白蛋白减少88.2%。 闭合式输液系统极大地提高了静脉输液的安全性，是目前临床输液的发展方向。Flexbumin采用了百特专有的Galaxy柔性容器，该容器采用了Galaxy专利膜，由4层特殊结构层组成，实现了白蛋白溶液从瓶装升级为软袋装的历史性突破。 FLEXBUMIN (albumin human) solution DESCRIPTION FLEXBUMIN 25%, Albumin (Human), 25% Solution is a sterile, nonpyrogenic preparation of albumin in a single dosage form for intravenous administration. Each 100 ml contains 25 g of albumin and was prepared from human venous plasma using the Cohn cold ethanol fractionation process. Source material for fractionation may be obtained from another U.S. licensed manufacturer. It has been adjusted to physiological pH with sodium bicarbonate and/or sodium hydroxide and stabilized with N-acetyltryptophan and sodium caprylate. The sodium content is 145 ± 15 mEq/L. This solution contains no preservative and none of the coagulation factors found in fresh whole blood or plasma. FLEXBUMIN 25%, Albumin (Human), 25% Solution is a transparent or slightly opalescent solution which may have a greenish tint or may vary from a pale straw to an amber color. The likelihood of the presence of viable hepatitis viruses has been minimized by heating the product for 10 hours at 60°C. This procedure has been shown to be an effective method of inactivating hepatitis virus in albumin solutions even when those solutions were prepared from plasma known to be infective.1-3 The GALAXY plastic container is fabricated from a specially designed multilayered plastic (PL 2501). Solutions are in contact with the polyethylene layer of the container and can leach out certain chemical components of the plastic in very small amounts within the expiration period. The suitability and safety of the plastic have been confirmed in tests in animals according to the USP biological tests for plastic containers, as well as by tissue culture toxicity studies. CLINICAL PHARMACOLOGY Albumin is responsible for 70-80% of the colloid osmotic pressure of normal plasma, thus making it useful in regulating the volume of circulating blood.4-6 Albumin is also a transport protein and binds naturally occurring, therapeutic and toxic materials in the circulation.5,6 FLEXBUMIN 25%, Albumin (Human), 25% Solution is osmotically equivalent to approximately five times its volume of human plasma. When injected intravenously, 25% albumin will draw about 3.5 times its volume of additional fluid into the circulation within 15 minutes, except when the patient is markedly dehydrated. This extra fluid reduces hemoconcentration and blood viscosity. The degree and duration of volume expansion depends upon the initial blood volume. With patients treated for diminished blood volume, the effect of infused albumin may persist for many hours; however, in patients with normal volume, the duration will be shorter.7,8 Total body albumin is estimated to be 350 g for a 70 kg man and is distributed throughout the extracellular compartments; more than 60% is located in the extravascular fluid compartment. The half-life of albumin is 15 to 20 days with a turnover of approximately 15 g per day.5 The minimum plasma albumin level necessary to prevent or reverse peripheral edema is unknown. Some investigators recommend that plasma albumin levels be maintained at approximately 2.5 g/dL. This concentration provides a plasma oncotic value of 20 mm Hg.4 FLEXBUMIN 25%, Albumin (Human) 25% Solution is manufactured from human plasma by the modified Cohn-Oncley cold ethanol fractionation process, which includes a series of cold-ethanol precipitation, centrifugation and/or filtration steps followed by pasteurization of the final product at 60 ± 0.5°C for 10 - 11 hours. This process accomplishes both purification of albumin and reduction of viruses. In vitro studies, demonstrate that the manufacturing process for FLEXBUMIN 25%, Albumin (Human), 25% Solution provides for significant viral reduction. These viral reduction studies, summarized in Table 1, demonstrate viral clearance during the manufacturing process for FLEXBUMIN 25%, Albumin (Human), 25% Solution using human immunodeficiency virus, type 1 (HIV-1) both as a target virus and as model virus for HIV-2 and other enveloped RNA viruses; bovine viral diarrheal virus (BVDV), a model for lipid enveloped RNA viruses, such as hepatitis C virus (HCV); West Nile Virus (WNV), a target virus and model for other similar enveloped RNA viruses; pseudorabies virus (PRV), a model for other enveloped DNA viruses such as hepatitis B virus (HBV); mice minute virus (MMV), models for non-lipid enveloped DNA viruses such as human parvovirus B 1912; and hepatitis A virus (HAV), a target virus and a model for other non-lipid enveloped RNA viruses. These studies indicate that specific steps in the manufacture of FLEXBUMIN 25%, Albumin (Human), 25% Solution are capable of eliminating/inactivating a wide range of relevant and model viruses. Since the mechanism of virus elimination/inactivation at specific process steps is different, the overall manufacturing process of FLEXBUMIN 25%, Albumin (Human), 25% Solution is robust in reducing viral load. TABLE 1 Summary of Viral Reduction Factor for Each Virus and Processing Step * Other Abumin fractionation process steps (processing of cryo-poor plasma to Fraction I+II+III/II+III supernatant and processing of Fraction V suspension to Cuno 90LP filtrate) showed significant virus reduction capacity in in vitro viral clearance studies. These process steps also contribute to the overall viral clearance robustness of the manufacturing process. However, since the mechanism of virus removal is similar to that of this particular process step, the viral inactivation data from other steps were not used in the calculation of the Mean Cumulative Reduction Factor. † n.d. = not determined ‡ Recent scientific data suggest that the actual human parvovirus B19 (B19V), is far more effectively inactivated by pasteurization than indicated by model virus data12. Process Step Viral Reduction Factor (log10) Lipid Enveloped Non-Lipid Enveloped HIV-1 Flaviviridae PRV HAV Parvoviridae BVDV WNV MMV Processing of Fraction I+II+III/II + III supernatant to Fraction IV4 Cuno 70C filtrate* > 4.9 > 4.8 > 5.7 >5.5 >4.5 3.0 Pasteurization > 7.8 > 6.5 n.d.† > 7.4 3.2 1.6‡ Mean Cumulative Reduction Factor > 12.7 > 11.3 > 5.7 > 12.9 > 7.7 4.6 INDICATIONS AND USAGE 1. Hypovolemia Hypovolemia is a possible indication for FLEXBUMIN 25%, Albumin (Human), 25% Solution. Its effectiveness in reversing hypovolemia depends largely upon its ability to draw interstitial fluid into the circulation. It is most effective with patients who are well hydrated. When hypovolemia is long standing and hypoalbuminemia exists accompanied by adequate hydration or edema, 25% albumin is preferable to 5% protein solutions.4,6 However, in the absence of adequate or excessive hydration, 5% protein solutions should be used or 25% albumin should be diluted with crystalloid. Although crystalloid solutions and colloid-containing plasma substitutes can be used in emergency treatment of shock, Albumin (Human) has a prolonged intravascular half-life.9 When blood volume deficit is the result of hemorrhage, compatible red blood cells or whole blood should be administered as quickly as possible. 2. Hypoalbuminemia A. General Hypoalbuminemia is another possible indication for use of FLEXBUMIN 25%, Albumin (Human), 25% Solution. Hypoalbuminemia can result from one or more of the following:5 (1) Inadequate production (malnutrition, burns, major injury, infections, etc.) (2) Excessive catabolism (burns, major injury, pancreatitis, etc.) (3) Loss from the body (hemorrhage, excessive renal excretion, burn exudates, etc.) (4) Redistribution within the body (major surgery, various inflammatory conditions, etc.) When albumin deficit is the result of excessive protein loss, the effect of administration of albumin will be temporary unless the underlying disorder is reversed. In most cases, increased nutritional replacement of amino acids and/or protein with concurrent treatment of the underlying disorder will restore normal plasma albumin levels more effectively than albumin solutions. Occasionally hypoalbuminemia accompanying severe injuries, infections or pancreatitis cannot be quickly reversed and nutritional supplements may fail to restore serum albumin levels. In these cases, FLEXBUMIN 25%, Albumin (Human), 25% Solution might be a useful therapeutic adjunct. B. Burns An optimum regimen for the use of albumin, electrolytes and fluid in the early treatment of burns has not been established, however, in conjunction with appropriate crystalloid therapy, FLEXBUMIN 25%, Albumin (Human), 25% Solution may be indicated for treatment of oncotic deficits after the initial 24 hour period following extensive burns and to replace the protein loss which accompanies any severe burn.4,6 C. Adult Respiratory Distress Syndrome (ARDS) A characteristic of ARDS is a hypoproteinemic state, which may be causally related to the interstitial pulmonary edema. Although uncertainty exists concerning the precise indication of albumin infusion in these patients, if there is a pulmonary overload accompanied by hypoalbuminemia, 25% albumin solution may have a therapeutic effect when used with a diuretic.4 D. Nephrosis FLEXBUMIN 25%, Albumin (Human), 25% Solution may be a useful aid in treating edema in patients with severe nephrosis who are receiving steroids and/or diuretics. 3. Cardiopulmonary Bypass Surgery FLEXBUMIN 25%, Albumin (Human), 25% Solution has been recommended prior to or during cardiopulmonary bypass surgery, although no clear data exist indicating its advantage over crystalloid solutions. 4,6,10 4. Hemolytic Disease of the Newborn (HDN) FLEXBUMIN 25%, Albumin (Human), 25% Solution may be administered in an attempt to bind and detoxify unconjugated bilirubin in infants with severe HDN. There is no valid reason for use of albumin as an intravenous nutrient. CONTRAINDICATONS A history of allergic reactions to albumin is a specific contraindication to the use of this product. FLEXBUMIN 25%, Albumin (Human), 25% Solution is also contraindicated in severely anemic patients and in patients with cardiac failure. WARNINGS Do not use if turbid. Do not begin administration more than 4 hours after the container has been entered. Discard unused portion. There exists a risk of potentially fatal hemolysis and acute renal failure from the inappropriate use of Sterile Water for Injection as a diluent for FLEXBUMIN 25%, Albumin (Human), 25% Solution. Acceptable diluents include 0.9% Sodium Chloride or 5% Dextrose in Water. FLEXBUMIN 25%, Albumin (Human), 25% Solution is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, 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 inactivating and/or removing certain viruses (See Description). Despite these measures, such products can still potentially transmit disease. Based on effective donor screening and product manufacturing processes, albumin carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. 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 Baxter Healthcare Corporation at 1-800-423-2862. The physician should discuss the risks and benefits of this product with the patient. PRECAUTIONS FLEXBUMIN 25%, Albumin (Human), 25% Solution must be administered intravenously at a rate not to exceed 1ml/min to patients with normal blood volume. More rapid administration might cause circulatory overload and pulmonary edema. A rise in blood pressure after 25% albumin infusion necessitates careful observation of the injured or post-operative patient in order to detect and treat severed blood vessels that may not have bled at a lower blood pressure. Pregnancy-Category C Animal reproduction studies have not been conducted with FLEXBUMIN 25%, Albumin (Human), 25% Solution. It is not known whether FLEXBUMIN 25%, Albumin (Human), 25% Solution can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. FLEXBUMIN 25%, Albumin (Human), 25% Solution should be given to a pregnant woman only if clearly needed. Pediatric Use The safety of albumin solutions has been demonstrated in children provided the dose is appropriate for body weight, however, the safety of FLEXBUMIN 25%, Albumin (Human), 25% Solution has not been eva luated in pediatric patients. ADVERSE REACTIONS Untoward reactions to FLEXBUMIN 25%, Albumin (Human), 25% Solution are extremely rare, although nausea, fever, chills or urticaria may occasionally occur. Such symptoms usually disappear when the infusion is slowed or stopped for a short period of time. DOSAGE AND ADMINISTRATION FLEXBUMIN 25%, Albumin (Human), 25% Solution must be administered intravenously. This solution may be administered in conjunction with or combined with other parenterals such as whole blood, plasma, saline, glucose or sodium lactate. The addition of four volumes of normal saline or 5% glucose to 1 volume of FLEXBUMIN 25%, Albumin (Human), 25% Solution gives a solution, which is approximately isotonic and isosmotic with citrated plasma. Albumin solutions should not be mixed with protein hydrolysates or solutions containing alcohol. Recommended Dosages 1. Hypovolemic Shock The dosage of FLEXBUMIN 25%, Albumin (Human), 25% Solution must be individualized. As a guideline, the initial treatment should be in the range of 100 to 200 ml for adults and 2.5 to 5 ml per kilogram body weight for children. This may be repeated after 15 to 30 minutes, if the response is not adequate. For patients with significant plasma volume deficits, albumin replacement is best administered in the form of 5% Albumin (Human). Upon administration of additional albumin or if hemorrhage has occurred, hemodilution and a relative anemia will follow. This condition should be controlled by the supplemental administration of compatible red blood cells or compatible whole blood. 2. Burns The optimal therapeutic regimen for administration of crystalloid and colloid solutions after extensive burns has not been established. When FLEXBUMIN 25%, Albumin (Human), 25% Solution is administered after the first 24 hours following burns, the dose should be determined according to the patient’s condition and response to treatment. 3. Hypoalbuminemia Hypoalbuminemia is usually accompanied by a hidden extravascular albumin deficiency of equal magnitude. This total body albumin deficit must be considered when determining the amount of albumin necessary to reverse the hypoalbuminemia. When using patient’s serum albumin concentration to estimate the deficit, the body albumin compartment should be calculated to be 80 to100 ml per kg of body weight.5,6 Daily dose should not exceed 2 g of albumin per kilogram of body weight. 4. Hemolytic Disease of the Newborn FLEXBUMIN 25%, Albumin (Human), 25% Solution may be administered prior to or during exchange transfusion in a dose of 1 g per kilogram body weight.11 Preparation of Administration Check the GALAXY container for minute leaks prior to use by squeezing the bag firmly. If leaks are found, discard solution as sterility may be impaired. Do not add supplementary medication. Do not use unless solution is clear and seal is intact. CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before the administration of the fluid from the secondary container is complete. Preparation for administration: 1. Suspend container from eyelet support. 2. Remove plastic protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. Make certain that the administration set contains an adequate filter. HOW SUPPLIED FLEXBUMIN 25%, Albumin (Human), 25% Solution is supplied in 50 ml (NDC 0944-0493-01) and 100 ml (NDC 0944-0493-02) in single dose GALAXY plastic container (PL 2501). STORAGE Store FLEXBUMIN 25%, Albumin (Human), 25% Solution at room temperature, not to exceed 30°C (86°F). Protect from freezing.