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BUMINATE 25%, Abumin (Human), USP, 25% Soution

DESCRIPTION

BUMINATE 25%, in 20, 50 and 100 mL glass bottles is a sterile, nonpyrogenic preparation o albuminin a single dosage orm or intravenous administration. Each 100 mL contains 25 g o albumin andwas prepared rom human venous plasma using the Cohn cold ethanol ractionation process. Sourcematerial or ractionation may be obtained rom another U.S. licensed manuacturer. It has beenadjusted to physiological pH with sodium bicarbonate and/or sodium hydroxide and stabilized withN-acetyltryptophan (0.02 M) and sodium caprylate (0.02 M). The sodium content is 145 15 mEq/L.This solution contains no preservative and none o the coagulation actors ound in resh whole bloodor plasma. BUMINATE 25% is a transparent or slightly opalescent solution which may have agreenish tint or may vary rom a pale straw to an amber color.

The likelihood o the presence o viable hepatitis viruses has been minimized by testing the plasmaat three stages or the presence o hepatitis viruses, by ractionation steps with demonstrated virusremoval capacity and by heating the product or 10 hours at 60C. This procedure has been shownto be an eective method o inactivating hepatitis virus in albumin solutions even when thosesolutions were prepared rom plasma known to be inective.1-3

ClINICAl PHARMACOlOgy

Albumin is responsible or 70-80% o the colloid osmotic pressure o normal plasma, thus making ituseul in regulating the volume o circulating blood.4-6 Albumin is also a transport protein and bindsnaturally occurring, therapeutic and toxic materials in the circulation.5,6

BUMINATE 25% is osmotically equivalent to approximately ve times its volume o human plasma.When injected intravenously, 25% albumin will draw about 3.5 times its volume o additional fuidinto the circulation within 15 minutes, except when the patient is markedly dehydrated. This extrafuid reduces hemoconcentration and blood viscosity. The degree and duration o volume expansiondepends upon the initial blood volume. With patients treated or diminished blood volume, the eecto inused albumin may persist or many hours; however, in patients with normal volume, theduration will be shorter.7-9

Total body albumin is estimated to be 350 g or a 70 kg man and is distributed throughout theextracellular compartments; more than 60% is located in the extravascular fuid compartment. Thehal-lie o albumin is 15 to 20 days with a turnover o 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 approximately2.5 g/dL. This concentration provides a plasma oncotic pressure value o 20 mm Hg.4

BUMINATE 25% is manuactured rom human plasma by the modied Cohn-Oncley cold ethanolractionation process, which includes a series o cold-ethanol precipitation, centriugation and/orltration steps ollowed by pasteurization o the nal product at 60 0.5C or 1011 hours. Thisprocess accomplishes both purication o albumin and the reduction o viruses.

In vitrostudies demonstrate that the manuacturing process or BUMINATE 25% provides or signicantviral reduction. These viral reduction studies, summarized in Table 1, demonstrate viral clearance duringthe manuacturing process or BUMINATE 25% using human immunodeciency virus, type 1 (HIV-1)both as a target virus and as model virus or HIV-2 and other lipid-enveloped RNA viruses; bovine viraldiarrhea virus (BVDV), a model or lipid-enveloped RNA viruses, such as hepatitis C virus (HCV); WestNile Virus (WNV), a target virus and model or other similar lipid-enveloped RNA viruses; pseudorabiesvirus (PRV), a model or other lipid-enveloped DNA viruses such as hepatitis B virus (HBV); mice minutevirus (MMV), models or non-enveloped DNA viruses such as human parvovirus B19 10; hepatitis A virus(HAV), a target virus and a model or other non-enveloped RNA viruses.

These studies indicate that specic steps in the manuacture o BUMINATE 25% are capable oeliminating/inactivating a wide range o relevant and model viruses. Since the mechanism o virus

elimination/inactivation by ractionation and by heating is dierent, the overall manuacturingprocess o BUMINATE 25% is robust in reducing viral load.

TABlE 1

Summar o Vira Reduction Factor or Each Virus and Processin Step

Process Step

Vira Reduction Factor (o10

)

lipid Enveoped Non-lipid Enveoped

HIV-1Flaviviridae

PRV HAVParvoviridae

MMVBVDV WNV

Processing o Fraction I+II+III/II+III supernatant

to Fraction IV4Cuno 70C ltrate*

> 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 Cumuative Reduction Factor, o10

> 12.7 > 11.3 > 5.7 > 12.9 > 7.7 4.6

n.d. = not determined

* Other Albumin ractionation process steps (processing o cryo-poor plasma to Fractionation I+II+III/II+III supernatant and processing oFraction V suspension to Cuno 90LP ltrate) showed signicant virus reduction capacity in in-vitroviral clearance studies. These processsteps also contribute to the overall viral clearance robustness o the manuacturing process. However, since the mechanism o virusremoval is similar to that o this particular process step, the viral inactivation data rom other steps were not used in the calculation o theMean Cumulative Reduction Factor.

** Recent scientic data suggests that the actual human parvovirus B19 (B19V), is ar more eectively inactivated by pasteurization thanindicated by model virus data. 10

INDICATIONS AND USAgE

1. Hpovoemia

Hypovolemia is a possible indication or use o BUMINATE 25%. Its eectiveness in reversinghypovolemia depends largely upon its ability to draw interstitial fuid into the circulation. It is mosteective with patients who are well hydrated. When the hypovolemia is long standing andhypoalbuminemia exists accompanied by adequate hydration or edema, 25% albumin is preerableto 5% protein solutions.4,6 However, in the absence o adequate or excessive hydration, 5% proteinsolutions should be used or 25% albumin should be diluted with crystalloid solutions.

Although crystalloid solutions and colloid-containing plasma substitutes can be used inemergency treatment o shock, Albumin (Human) has a prolonged intravascular hal-lie.11

When blood volume decit is the result o hemorrhage, compatible red blood cells or whole bloodshould be administered as quickly as possible.

2. Hpoabuminemia

A. General

Hypoalbuminemia is another possible indication or use o BUMINATE 25%. Hypoalbuminemiacan result rom one or more o the ollowing:5

(1) Inadequate production (malnutrition, burns, major injury, inections, etc.)

(2) Excessive catabolism (burns, major injury, pancreatitis, etc.)

(3) Loss rom the body (hemorrhage, excessive renal excretion, burn exudates, etc.)

(4) Redistribution within the body (major surgery, various infammatory conditions, etc.)

When albumin decit is the result o excessive protein loss, the eect o administration oalbumin will be temporary unless the underlying disorder is reversed. In most cases,increased nutritional replacement o amino acids and/or protein with concurrent treatment othe underlying disorder will restore normal plasma albumin levels more eectively thanalbumin solutions. Occasionally hypoalbuminemia accompanying severe injuries, inections opancreatitis cannot be quickly reversed and nutritional supplements may ail to restore serumalbumin levels. In these cases, BUMINATE 25% might be a useul therapeutic adjunct.

B. Burns

An optimum regimen or the use o albumin, electrolytes and fuid in the early treatment o burnhas not been established, however, in conjunction with appropriate crystalloid therapy,BUMINATE 25% may be indicated or treatment o oncotic decits ater the initial 24-hour periodollowing extensive burns and to replace the protein loss which accompanies any severe burn. 4,

C. Adult Respiratory Distress Syndrome (ARDS)

A characteristic o ARDS is a hypoproteinemic state, which may be causally related to theinterstitial pulmonary edema. Although uncertainty exists concerning the precise indication oalbumin inusion in these patients, i there is a pulmonary overload accompanied byhypoalbuminemia, 25% albumin solution may have a therapeutic eect when used with a diuretic.

D. Nephrosis

BUMINATE 25% may be a useul aid in treating edema in patients with severe nephrosis whoare receiving steroids and/or diuretics.

3. Cardiopumonar Bpass Surer

BUMINATE 25% has been recommended prior to or during cardiopulmonary bypass surgery,although no clear data exist indicating its advantage over crystalloid solutions.4,6,12

4. Hemotic Disease o the Newborn (HDN)BUMINATE 25% may be administered in an attempt to bind and detoxiy unconjugated bilirubin ininants with severe HDN.

There is no valid reason for use of albumin as an intravenous nutrient.

CONTRAINDICATIONS

A history o allergic reactions to albumin and any o the excipients is a specic contraindication tothe use o this product.

BUMINATE 25% is also contraindicated in severely anemic patients and in patients with cardiac ailure.

BUMINATE 25% must not be diluted with Sterile Water or Injection as this may cause hemolysis inrecipients. There exists a risk o potentially atal hemolysis and acute renal ailure rom the use oSterile Water or Injection as a diluent or Albumin (Human). Acceptable diluents include 0.9%Sodium Chloride or 5% Dextrose in Water.

BUMINATE 25% must not be administered to patients with chronic renal insuciencies due to thepotential or accumulations o aluminum. Accumulations o aluminum in patients with chronic renalinsuciencies have led to toxic maniestations such as hypercalcemia, vitamin D-reractoryosteodystrophy, anemia, and severe progressive encephalopathy.13-15, 19

WARNINgSBUMINATE 25% is made rom human pasma. Products made rom human pasma macontain inectious aents, such as viruses, that can cause disease. This aso appies tounknown or emerin viruses and pathoens.

The risk that such products wi transmit an inectious aent has been reduced b screeninpasma donors or prior exposure to certain viruses, b testin or the presence o certaincurrent virus inections, and b inactivatin and/or removin certain viruses (SeeDescription). The measures taken are considered eective or enveoped viruses such as HIV,HBV, and HCV, and or the non-enveoped viruses HAV and Parvovirus B19. Despite thesemeasures, such products can sti potentia transmit disease. Based on eective donorscreenin and product manuacturin processes, abumin carries an extreme remote riskor transmission o vira diseases. A theoretica risk or transmission o Creutzedt-Jakobdisease (CJD) aso is considered extreme remote. No cases o transmission o vira diseasesor CJD have ever been identifed or abumin. All inections thouht b a phsician possibto have been transmitted b this product, shoud be reported b the phsician, or otherheathcare provider to Baxter Heathcare Corporation at 1-800-423-2862. The phsicianshoud discuss the risks and benefts o this product with the patient.

Suspicion o allergic or anaphylactic type reactions requires immediate discontinuation o theinjection. In case o shock, standard medical treatment or shock should be implemented.

PRECAUTIONS

Certain components used in the packaging o this product contain natural rubber latex.

Hemodnamics

Do not administer BUMINATE 25% without very close monitoring o hemodynamics; look orevidence o cardiac or respiratory ailure, renal ailure, or increasing intra-cranial pressure.

Hpervoemia/Hemodiution

BUMINATE 25% should be used with caution in conditions where hypervolemia and itsconsequences or hemodilution could represent a special risk or the patient. Examples may includebut are not limited to: decompensated cardiac insuciency, hypertension, esophageal varices,pulmonary edema, hemorrhagic diathesis, severe anemia, renal and post-renal ailure.

BUMINATE 25% must be administered intravenously. The rate o administration should be adjustedaccording to the solution concentration and the patients hemodynamic measurements and shouldnot exceed 1mL/min to patients with normal blood volume. More rapid administration might causecirculatory overload and pulmonary edema.16 At the rst clinical signs o cardiovascular overload(headache, dyspnea, jugular vein congestion), or increasedblood pressure, raised central venous pressure andpulmonary edema, the inusion is to be stopped immediately.

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Bood Pressure

A rise in blood pressure ater 25% albumin inusion necessitates careul observation o the injured orpost-operative patient in order to detect and treat severed blood vessels that may not have bled at alower blood pressure.

PrenancCateor C, and lactation

There are no adequate data rom the use o BUMINATE 25% in pregnant or lactating women.

Animal reproduction studies have not been conducted with BUMINATE 25%. It is not known whetherBUMINATE 25% can cause etal harm when administered to a pregnant woman or can aectreproductive capacity. Physicians should careully consider the potential risks and benets or eachspecic patient beore prescribing BUMINATE 25%. BUMINATE 25% should be given to a pregnantwoman only i clearly needed.

Pediatric Use

The saety o albumin solutions has been demonstrated in children provided the dose is appropriateor body weight. However, the saety o BUMINATE 25% has not been evaluated in pediatric patients.

lare Voumes

I comparatively large volumes are to be replaced, controls o coagulation and hematocrit arenecessary. Care must be taken to ensure adequate substitution o other blood constituents(coagulation actors, electrolytes, platelets, and erythrocytes). Appropriate hemodynamic monitoringshould be undertaken.

Eectrote Status

When BUMINATE 25% is given, the electrolyte status o the patient should be monitored andappropriate steps taken to restore or maintain the electrolyte balance.

DRUg INTERACTIONS

No interaction studies have been perormed with BUMINATE 25%.

ADVERSE REACTIONS

Adverse Reactions rom Cinica Trias

There are no data available on adverse reactions rom clinical trials conducted with BUMINATE 25%.

Post-Marketin Adverse Reactions

The ollowing adverse reactions have been reported in the post-marketing experience. These reactionsare listed by MedDRA System Organ Class (SOC), then by Preerred Term in order o severity.

IMMUNE SYSTEM DISORDERS: Anaphylactic shock, Anaphylactic reactions, Hypersensitivity/Allergic reactions

NERVOUS SYSTEM DISORDERS: Headache

CARDIAC DISORDERS: Tachycardia

VASCULAR DISORDERS: Hypotension, Flushing

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS: Dyspnea

GASTROINTESTINAL DISORDERS: Vomiting, Nausea, Dysguesia

SKIN AND SUBCUTANEOUS TISSUE DISORDERS: Urticaria, Rash, Pruritis

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Pyrexia, Chills

Overdose

Hypervolemia may occur i the dosage and rate o inusion are too high. (See Precautions:Hypervolemia/Hemodilution)

DOSAgE AND ADMINISTRATION

BUMINATE 25% must be administered intravenously. Do not use i turbid. Do not beinadministration more than 4 hours ater the container has been entered. Discard unused portion.

BUMINATE 25% solutions must not be diluted with Sterile Water or Injection as this may causehemolysis in recipients (see CONTRAINDICATIONS).

Albumin solutions should not be mixed with other medicinal products including blood and bloodcomponents, but can be used concomitantly with other parenterals such as whole blood, plasma,saline, glucose or sodium lactate when deemed medically necessary. The addition o our volumes onormal saline or 5% glucose to 1 volume o BUMINATE 25% gives a solution, which is approximatelyisotonic and isosmotic with citrated plasma.

Albumin solutions should not be mixed with protein hydrolysates or solutions containing alcoholsince these combinations may cause the proteins to precipitate.

Do not add supplementary medication.

Hypervolemia may occur i the dosage and rate o inusion are not adjusted, giving consideration tothe solution concentration and the patients clinical status. Hemodynamic parameters should bemonitored in patients receiving BUMINATE 25% and should be used to check or the risk ohypervolemia and cardiovascular overload. (See PRECAUTIONS: Hypervolemia/Hemodilution).

It is strongly recommended that every time that BUMINATE 25% is administered to a patient, thename and batch number o the product be recorded in order to maintain a link between the patient

and the batch o the product.

Recommended Dosaes

1. Hypovolemic Shock

The dosage o BUMINATE 25% must be individualized. As a guideline, the initial treatment shouldbe in the range o 100 to 200 mL or adults and 2.5 to 5 mL per kilogram body weight orchildren. This may be repeated ater 15 to 30 minutes, i the response is not adequate. Forpatients with signicant plasma volume decits, albumin replacement is best administered in theorm o 5% Albumin (Human).

Upon administration o additional albumin or i hemorrhage has occurred, hemodilutionand a relative anemia will ollow. This condition should be controlled by the supplementaladministration o compatible red blood cells or compatible whole blood.

2. Burns

The optimal therapeutic regimen or administration o crystalloid and colloid solutions aterextensive burns has not been established. When BUMINATE 25% is administered ater the rst 24hours ollowing burns, the dose should be determined according to the patients condition andresponse to treatment.

3. Hypoalbuminemia

Hypoalbuminemia is usually accompanied by a hidden extravascular albumin deciency o equalmagnitude. This total body albumin decit must be considered when determining the amount oalbumin necessary to reverse the hypoalbuminemia. When using patients serum albumin concentrationto estimate the decit, the body albumin compartment should be calculated to be 80 to 100 mL per kgo body weight.5,6Daily dose should not exceed 2 g o albumin per kilogram o body weight.

4. Hemolytic Disease of the Newborn

BUMINATE 25% may be administered prior to or during exchange transusion in a dose o 1 g pekilogram body weight.17

Preparation or Administration

Do not use unless solution is clear o particulate matter and seal is intact. BUMINATE 25% is atransparent or slightly opalescent solution, which may have a greenish tint or may vary rom a palestraw to an amber color. Parenteral drug products should be inspected visually or particulate matter

and discoloration prior to administration, whenever solution and container permit.1. Remove cap rom bottle to expose center portion o rubber stopper.

2. Clean stopper with germicidal solution.

Administration

Follow directions or use printed on the administration set container. Make certain that theadministration set contains an adequate lter (15-micron or smaller).

HOW SUPPlIED

BUMINATE 25% is supplied in 20 mL (NDC 0944-0490-01), 50 mL (NDC 0944-0490-02) and 100 m(NDC 0944-0490-03) bottles.

STORAgE

Store BUMINATE 25% at room temperature, not to exceed 30C (86F). Avoid reezing to preventdamage to the bottle.

Stability testing or BUMINATE 25% showed that aluminum concentration increased over time reachinglevels that could exceed 1000 ppb over the shel lie o the product. (See CONTRAINDICATIONS). 18, 19

REFERENCES

1. Cai K, Gierman T,et al:Ensuring the Biologic Saety o Plasma-Derived Therapeutic Proteins.Department o Preclinical Research and Pathogen Saety, Bayer HealthCare LLC, North Carolina,USA. Biodrus19(2): 79-96 2005.

2. Gerety RJ, Aronson DL: Plasma derivatives and viral hepatitis.Transusion 22:347-351, 1982.

3. Burnou T, Padilla A, Current strategies to prevent transmission o prions by human plasmaderivatives. Transusion Cinique et Biooique 13:320-328, 2006.

4. Tullis JL: Albumin, 1. Background and use, and 2. Guidelines or clinical use. JAMA 237:355-360460-463, 1977.

5. Peters T Jr: Serum albumin, in The Pasma Proteins, 2nd ed, Vo 1. Putnam FW (ed). New York,Academic Press, 1975, pp 133-181.

6. Finlayson JS: Albumin products. Semin Thromb Hemostas. 6:85-120, 1980.

7. Haynes G, Navickis R, Wilkes M, Albumin administration what is the evidence o clinicalbenet? Asystematic review o randomized controlled trials. European Journa oAnesthesioo 20:771-793 2003.

8. Mendez, C, McClain C, Marsano L et al, Albumin Therapy in Clinical Practice. Nutrition in CinicaPractice 20 No. 3:314-320, June 2005.

9. Quinlan G, Martin G, Evans T, Albumin: Biochemical Properties and Therapeutic Potential.

HEMATOlOgy Vol 14, No. 6 1211-1219 2005.10. J. Blmel et al., Inactivation o Parvovirus B19 During Pasteurization o Human Serum Albumin.

Transusion 42:1011-1018, 2002.

11. Shoemaker WC, Schluchter M, Hopkins JA, et al:Comparison o the relative eectiveness ocolloids and crystalloids in emergency resuscitation. Am J Sur 142:73-83, 1981.

12. Lowenstein E, Hallowell P, Bland JHL: Use o colloid and crystalloid solutions in open heartsurgery: Physiological basis and clinical results in, Proceedins o the Workshop on Abumin.Sgouris JT, Rene A (eds). DHEW Publication No. (NIH) 76-925, Washington, DC, US GovernmentPrinting Oce, 1976, pp 195-210.

13. Milliner DS, Shenaberger JH, Shuman P, et al:Inadvertent aluminum administration duringplasma exchange due to aluminum contamination o albumin-replacement solutions. N En JMed 312:165-7,1985

14. Ott SM, Maloney NA, Klein GL, et al:Aluminum is associated with low bone ormation in patientsreceiving chronic parenteral nutrition. Ann Intern Med 98:910-4,1983

15. Wills MR, Savory J: Aluminum poisoning: dialysis encephalopathy, osteomalacia, and anaemia.lancet 2:29-34,1983

16. Grocott, Michael P.W., Mythen, Michael G., and Gan, Tong J. Perioperative Fluid Management andClinical Outcomes in Adults. Anesth Ana. 2005;100:1100.

17. Tsao YC, Yu VYH: Albumin in management o neonatal hyperbilirubinaemia. Arch Dis Chidhood47:250-256, 1972.

18. Data on le; Baxter Healthcare Corporation.

19. Data on le; Baxter Healthcare Corporation.

Baxter Heathcare CorporationWestlake Village, CA 91362 USAU.S. License No. 140

Printed in the USA

To enroll in the condential industry-wide Patient Notication System,call 1-888-UPDATE U (1-888-873-2838).

Baxter and Buminate are trademarks o Baxter International Inc.

Revised September 2009