s2123 9010q02 Z.S.F ,,,DNDBD Dbebd D D Rjw.a.a.s4455.... Ee e Ebebsbeb 00nlkkkkk Awwr FBCBCBXBX Ilo - Tips - Albumin-Human-25-Solution-Usp
s2123 9010q02 Z.S.F ,,,DNDBD Dbebd D D Rjw.a.a.s4455.... Ee e Ebebsbeb 00nlkkkkk Awwr FBCBCBXBX Ilo - Tips - Albumin-Human-25-Solution-Usp
s2123 9010q02 Z.S.F ,,,DNDBD Dbebd D D Rjw.a.a.s4455.... Ee e Ebebsbeb 00nlkkkkk Awwr FBCBCBXBX Ilo - Tips - Albumin-Human-25-Solution-Usp
Manufacturer’s Standard
Page 1 of 19
Table of Contents
Page 2 of 19
ALBUMIN (HUMAN) 25% SOLUTION, USP
DESCRIPTION
ALBUMIN (HUMAN) 25% SOLUTION, USP (Albumin [Human] 25%, USP) is a 25% sterile
solution of albumin in an aqueous diluent. The preparation is stabilized with 0.02 M sodium
caprylate and 0.02 M acetyltryptophan and buffered with sodium carbonate. The approximate
sodium content of the product is 145 mEq/L. It contains no preservative. ALBUMIN (HUMAN)
25% SOLUTION, USP must be administered intravenously.
ALBUMIN (HUMAN) 25% SOLUTION, USP is made from pooled human venous plasma
using the Cohn cold ethanol fractionation process. It is prepared in accordance with the
applicable requirements established by the U.S. Food and Drug Administration. Plasma used in
the manufacture of the product has been collected in Canada from volunteer donors.
The oncotic and colloid properties of ALBUMIN (HUMAN) 25% SOLUTION, USP are used to
restore and maintain circulating blood volume, when needed, and when the use of a colloid is
appropriate. The choice of ALBUMIN (HUMAN) 25% SOLUTION, USP over artificial colloid
or crystalloid solutions will depend on the clinical situation of the individual patient, according
to current therapeutic guidelines and recommendations.
Page 3 of 19
crystalloids must be given (2) or alternatively, ALBUMIN (HUMAN) 25% SOLUTION, USP
should be used. The patient's hemodynamic response should be monitored and the usual
precautions against circulatory overload observed. The total dose should not exceed the level of
albumin found in the normal individual, i.e., about 2 g per kg body weight in the absence of
active bleeding. Although Albumin (Human) 5% is to be preferred for the usual volume deficits,
ALBUMIN (HUMAN) 25% SOLUTION, USP with appropriate crystalloids may offer
therapeutic advantages in oncotic deficits or in long-standing shock where treatment has been
delayed (3,4).
Removal of ascitic fluid from a patient with cirrhosis may cause changes in cardiovascular
function and even result in hypovolemic shock. In such circumstances, the use of an albumin
infusion may be required to support the blood volume (3,4).
Burn Therapy
An optimal therapeutic regimen with respect to the administration of colloids, crystalloids, and
water following extensive burns has not been established. During the first 24 hours after
sustaining thermal injury, large volumes of crystalloids are infused to restore the depleted
extracellular fluid volume. Beyond 24 hours ALBUMIN (HUMAN) 25% SOLUTION, USP can
be used to maintain plasma colloid osmotic pressure.
Cardiopulmonary Bypass
With the relatively small priming volume required with modern pumps, preoperative dilution of
the blood using albumin and crystalloid has been shown to be safe and well-tolerated. Although
the limit to which the hematocrit and plasma protein concentration can be safely lowered has not
been defined, it is common practice to adjust the albumin and crystalloid pump prime to achieve
a hematocrit of 20% and a plasma albumin concentration of 2.5 g per 100 mL in the patient
(3,4,6).
Page 4 of 19
Acute Liver Failure
In the uncommon situation of rapid loss of liver function with or without coma, administration of
albumin may serve the double purpose of supporting the colloid osmotic pressure of the plasma
as well as binding excess plasma bilirubin (3,4).
Erythrocyte Resuspension
Albumin may be required to avoid excessive hypoproteinemia, during certain types of exchange
transfusion, or with the use of very large volumes of previously frozen or washed red cells.
About 25 g of albumin per liter of erythrocytes is commonly used, although the requirements in
preexistent hypoproteinemia or hepatic impairment can be greater. ALBUMIN (HUMAN) 25%
SOLUTION, USP is added to the isotonic suspension of washed red cells immediately prior to
transfusion (3,4).
Acute Nephrosis
Certain patients may not respond to cyclophosphamide or steroid therapy. The steroids may even
aggravate the underlying edema. In this situation a loop diuretic and 100 mL ALBUMIN
(HUMAN) 25% SOLUTION, USP repeated daily for 7 to 10 days may be helpful in controlling
the edema and the patient may then respond to steroid treatment (3,4).
Renal Dialysis
Although not part of the regular regimen of renal dialysis, ALBUMIN (HUMAN) 25%
SOLUTION, USP may be of value in the treatment of shock or hypotension in these patients.
The usual volume administered is about 100 mL, taking particular care to avoid fluid overload as
these patients are often fluid overloaded and cannot tolerate substantial volumes of salt solution.
Page 5 of 19
cirrhosis, malabsorption, protein losing enteropathies, pancreatic insufficiency, and
undernutrition, the infusion of albumin as a source of protein nutrition is not justified (3,4).
CONTRAINDICATIONS
ALBUMIN (HUMAN) 25% SOLUTION, USP should not be given to patients who are
hypersensitive to albumin or to any ingredient in the formulation or component of the
container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND
PACKAGING section.
ALBUMIN (HUMAN) 25% SOLUTION, USP should not be given to patients at special
risk of developing circulatory overload (i.e., those with a history of congestive cardiac
failure, renal insufficiency or stabilized chronic anemia).
General
ALBUMIN (HUMAN) 25% SOLUTION, USP 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.
Despite these measures, such products can still potentially transmit disease. There is also
the possibility that unknown infectious agents may be present in such products. Individuals
who receive infusions of blood or plasma products may develop signs and/or symptoms of
some viral infections, particularly hepatitis C. 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 Grifols Canada Ltd. [1-866-482-5226].
Albumin is a derivative of human blood. Based on effective donor screening and product
manufacturing processes, it carries an extremely remote risk for transmission of viral
diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD), including
variant Creutzfeldt-Jakob disease (vCJD), also is considered extremely remote. No cases of
transmission of viral diseases or CJD, including vCJD, have ever been identified for
albumin (9,10,14).
The physician should discuss the risks and benefits of this product with the patient, before
prescribing or administering to the patient.
ALBUMIN (HUMAN) 25% SOLUTION, USP must not be diluted with sterile water for
injection as this may cause hemolysis and acute renal failure in recipients (see DOSAGE AND
ADMINISTRATION).
Blood coagulation parameters, the hematocrit and serum electrolytes should be monitored when
a large volume of ALBUMIN (HUMAN) 25% SOLUTION, USP solution is administered.
Page 6 of 19
Patients should always be monitored carefully in order to guard against the possibility of
circulatory overload. ALBUMIN (HUMAN) 25% SOLUTION, USP is hyperoncotic, therefore,
in the presence of dehydration, albumin must be given with or followed by addition of fluids (2).
ALBUMIN (HUMAN) 25% SOLUTION, USP is not tested for aluminum content and may
contain more than 200 µg/L of aluminum. It should, therefore, not be used to treat infants or
patients on hemodialysis.
The rapid rise in blood pressure which may follow the administration of a colloid with positive
oncotic activity necessitates careful observation to detect and treat severed blood vessels which
may not have bled at the lower blood pressure.
Special Populations
Pediatrics
The use of ALBUMIN (HUMAN) 25% SOLUTION, USP in children has not been associated
with any special or specific hazard, if the dose is appropriate for the child’s body weight.
However, its use should be carefully evaluated for risk and benefit in pediatric treatment and
ALBUMIN (HUMAN) 25% SOLUTION, USP should not be used in neonates and infants (see
WARNINGS AND PRECAUTIONS: General).
ADVERSE REACTIONS
Page 7 of 19
The Cochrane Injuries Group published a meta-analysis (July 1998) in which an increase in
mortality was reported in albumin–treated patients compared to patients who had received
crystalloids or no treatment. However, the analysis was criticized by many authors, due to
substantial methodological concerns (15-20).
In 2001, Wilkes et. al. published a revised meta-analysis, which showed no evidence of excess
albumin-associated mortality, but suggested that albumin might actually reduce mortality (16).
The Saline versus Albumin Fluid Evaluation (SAFE) Study (20) reported in the New England
Journal of Medicine in May 2004, involving nearly 7,000 critically ill patients, addressed one of
the most fundamental and contentious issues in critical care: the value of colloids as opposed to
crystalloids in the resuscitation of seriously ill patients. Based on these results, the
administration of albumin appears to be safe for up to 28 days in a heterogeneous population of
critically ill patients, and may be beneficial in patients with severe sepsis. A greater number of
patients with trauma involving brain injury died among those randomly assigned to albumin as
opposed to saline (59 of 241 in the albumin group compared to 38 of 251 in the saline group with
a relative risk of 1.62 and p = 0.009). However, the overall number of these patients was
relatively small. The study had insufficient power to detect differences in mortality among the
predefined subgroups and the authors warn that the observed difference should be interpreted
with caution.
A second review by the Albumin Reviewers of the Cochrane Collaboration, published in October
2004 (19), included the results of the SAFE study and concluded that “there is no evidence that
albumin reduces mortality when compared with cheaper alternatives, such as saline”, for patients
with hypovolemia or in critically ill patients with burns and hypoalbuminemia.
DRUG INTERACTIONS
Drug-Drug Interactions
ALBUMIN (HUMAN) 25% SOLUTION, USP is compatible with the standard isotonic
carbohydrate and electrolyte solutions intended for intravenous use. It should not be mixed with
protein hydrolysates, amino acid solutions or solutions containing alcohol. It should also not be
mixed with whole blood, packed red cells, and other medicinal products. Specialized references
(e.g. Trissel's Handbook of Injectable Drugs) should be consulted for specific compatibility
information.
Page 8 of 19
Hypovolemic Shock
For treatment of hypovolemic shock, the volume administered and the speed of infusion should
be adapted to the response of the individual patient.
Burn Therapy
After a burn injury (usually beyond 24 hours) there is a close correlation between the amount of
albumin infused and the resultant increase in plasma colloid osmotic pressure. The aim should be
to maintain the plasma albumin concentration in the region of 2.5 g ± 0.5 g per 100 mL with a
plasma oncotic pressure of 20 mmHg (equivalent to a total plasma protein concentration of 5.2 g
per 100 mL) (3,4). This is best achieved by the intravenous administration of Albumin (Human)
25%, USP. The duration of therapy is decided by the loss of protein from the burned areas and in
the urine. In addition, oral or parenteral feeding with amino acids should be initiated, as the long-
term administration of albumin should not be considered as a source of nutrition.
Cardiopulmonary Bypass
See INDICATIONS AND CLINICAL USE: Cardiopulmonary Bypass.
Page 9 of 19
Erythrocyte Resuspension
See INDICATIONS AND CLINICAL USE: Erythrocyte Resuspension.
Acute Nephrosis
See INDICATIONS AND CLINICAL USE: Acute Nephrosis.
Renal Dialysis
See INDICATIONS AND CLINICAL USE: Renal Dialysis.
Administration
ALBUMIN (HUMAN) 25% SOLUTION, USP should always be administered by intravenous
infusion. If sodium restriction is required, ALBUMIN (HUMAN) 25% SOLUTION, USP may
be administered either undiluted or diluted in a sodium-free carbohydrate solution such as 5%
dextrose in water. ALBUMIN (HUMAN) 25% SOLUTION, USP must not be diluted with
sterile water for injection to avoid hemolysis and acute renal failure in recipients (see DRUG
INTERACTIONS).
Remove seal to expose stopper. Always swab stopper top immediately with a suitable antiseptic
prior to entering vial.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit.
Dispensing pins or 16 gauge needles should only be used with 20 mL vial sizes and larger.
Needles or dispensing pins should only be inserted within the stopper area delineated by the
raised ring. The stopper should be penetrated perpendicular to the plane of the stopper within the
ring.
Solutions which have been frozen should not be used. Do not use if turbid. Do not begin
administration more than 4 hours after the container has been entered. Partially used vials must
be discarded. Vials which are cracked or which have been previously entered or damaged should
not be used, as this may have allowed the entry of microorganisms. ALBUMIN (HUMAN) 25%
SOLUTION, USP contains no preservative.
Page 10 of 19
OVERDOSAGE
To date, there have been no reported cases of overdose for ALBUMIN (HUMAN) 25%
SOLUTION, USP. No data are available in regard to overdosage in humans; however, because
ALBUMIN (HUMAN) 25% SOLUTION, USP is hyperoncotic, patients should be monitored
against the possibility of circulatory overload. If overdose occurs, provide standard supportive
treatment as necessary.
Hypervolemia may occur if the dosage and rate of infusion are too high. If hypervolemia is
suspected, the infusion should be stopped immediately and the patient’s hemodynamic
parameters should be carefully monitored.
Mechanism of Action
Each 50 mL vial of ALBUMIN (HUMAN) 25% SOLUTION, USP supplies the oncotic (colloid
osmotic) equivalent of approximately 250 mL citrated plasma: 100 mL supplies the oncotic
equivalent of approximately 500 mL citrated plasma.
Albumin is a transport protein that binds to many substances, including drugs and bilirubin.
Infused albumin may reduce the level of free bilirubin in the blood (7).
This could also be of importance in acute liver failure where albumin might serve the dual role of
supporting plasma oncotic pressure, as well as binding excessive plasma bilirubin (3,4).
Store at room temperature not exceeding 30°C (86°F). Do not freeze. Do not use after expiration
date.
The product should be used within 4 hours after the container has been entered.
Page 11 of 19
DOSAGE FORMS, COMPOSITION AND PACKAGING
ALBUMIN (HUMAN) 25% SOLUTION, USP is available in 50 mL, and 100 mL rubber-
stoppered vials. Each vial contains albumin in the amounts listed in Table 2.
Table 2 – Available ALBUMIN (HUMAN) 25% SOLUTION, USP -25 Vial Sizes
Size Grams Albumin
50 mL 12.5
100 mL 25.0
Page 12 of 19
PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION
Drug Substance
Product Characteristics
ALBUMIN (HUMAN) 25% SOLUTION, USP is a 25% sterile solution of albumin in an
aqueous diluent. ALBUMIN (HUMAN) 25% SOLUTION, USP has a pH of 6.4 to 7.4 and a
molecular weight of 66,563 Da. The preparation is stabilized with 0.02 M sodium caprylate and
0.02 M acetyltryptophan and buffered with sodium carbonate. The approximate sodium content
of the product is 145 mEq/L. It contains no preservative. ALBUMIN (HUMAN) 25%
SOLUTION, USP must be administered intravenously.
Viral Inactivation
In addition to the process relevant virus removal/inactivation steps, each vial of ALBUMIN
(HUMAN) 25% SOLUTION, USP is heat treated at 60°C for 10 hours to reduce the possibility
of transmission of some viruses, including HIV and the hepatitis viruses.
CLINICAL TRIALS
The clinical effectiveness of Albumin (Human), in the mentioned indications, has been
determined through many years of clinical use and is described in a number of published studies
and clinical practice guidelines.
DETAILED PHARMACOLOGY
Albumin regulates the volume of blood and accounts for 80% of the colloid osmotic pressure of
plasma (25-33 mmHg) (21). ALBUMIN (HUMAN) 25% SOLUTION, USP supplies the oncotic
equivalent of approximately 5 times the volume of citrated plasma. ALBUMIN (HUMAN) 25%
SOLUTION, USP is hyperoncotic and on intravenous infusion will expand the plasma volume
by three to four times the volume actually administered by withdrawing fluid from interstitial
spaces. In addition to restoring and maintaining blood volume through its stabilizing effect on
the physical environment of blood, albumin also provides benefits as a transport vehicle for
Page 13 of 19
metabolites, as a role player in lipid metabolism, and as a protective agent, binding to toxic
waste. Some of the endogenous substances that bind to albumin and are subsequently transported
include long chain fatty acids (crucial for lipid metabolism), steroid hormones (bind with low
affinity to albumin allowing rapid delivery and release to tissues), peptide hormones, bilirubin
(an exogenous toxin delivered to the liver for biliary excretion; also acts as an anti-oxidant when
bound to albumin), tryptophan, vitamin D3, folate, copper, zinc, calcium, magnesium, and
chloride (21). For many hormones and vitamins, albumin does not serve as the main transport
mechanism but functions as their reservoir, continuously replenishing the more specific transport
proteins (21).
The half-life of albumin reported from multiple radiolabeled studies ranges between 14.8 days
(using albumin prepared by cold-alcohol Cohn techniques [the method used in the manufacture
of ALBUMIN (HUMAN) 25% SOLUTION, USP)] to 19.5 days (albumin prepared using gentle
fractionation conditions). The degradation of albumin, occurring promptly after removal of
albumin from circulation, is first-order with the amount of albumin degraded daily seemingly a
function of total body albumin concentration (21). The large organs, the muscle and skin,
account for most of the degradation of albumin with the kidney, spleen, and lower intestine being
minor contributors as well (21). The end product of albumin degradation is free amino acids that
remain available in the body for new protein formation.
Page 14 of 19
REFERENCES
1. Heyl JT, Gibson JG, 2nd, Janeway CA. Studies on the plasma proteins. V. The effect of
concentrated solutions of human and bovine serum albumin on blood volume after acute
blood loss in man. J Clin Invest 1943;22(6):763-73.
2. Janeway CA, Gibson ST, Woodruff LM, Heyl JT, Bailey OT, Newhouser LR. Chemical,
clinical, and immunological studies on the products of human plasma fractionation. VII.
Concentrated human serum albumin. J Clin Invest 1944;23(4):465-90.
5. Skillman JJ, Tanenbaum BJ. Unrecognized losses of albumin, plasma, and red cells
during abdominal vascular operations. Curr Top Surg Res 1970;2:523-33.
6. Zubiate P, Kay JH, Mendez AM, Krohn BG, Hochman R, Dunne EF. Coronary artery
surgery. A new technique with use of little blood, if any. J Thorac Cardiovasc Surg
1974;68(2):263-7.
8. Clowes GH, Jr., Vucinic M, Weidner MG. Circulatory and metabolic alterations
associated with survival or death in peritonitis: clinical analysis of 25 cases. Ann Surg
1966;163(6):866-85.
9. Lee DC, Stenland CJ, Hartwell RC, Ford EK, Cai K, Miller JL, et al. Monitoring plasma
processing steps with a sensitive Western blot assay for the detection of the prion protein.
J Virol Methods 2000;84(1):77-89.
10. Lee DC, Stenland CJ, Miller JL, Cai K, Ford EK, Gilligan KJ, et al. A direct relationship
between the partitioning of the pathogenic prion protein and transmissible spongiform
encephalopathy infectivity during the purification of plasma proteins. Transfusion
2001;41(4):449-55.
11. Heyl JT, Janeway CA. The use of human albumin in military medicine. I. The theoretical
and experimental basis for its use. US Navy Med Bull 1942;40:785-91.
12. Janeway CA, Berenberg W, Hutchins G. Indications and uses of blood, blood derivatives
and blood substitutes. Med Clin North Am 1945;29:1069-94.
Page 15 of 19
13. Woodruff LM, Gibson ST. The clinical evaluation of human albumin. US Navy Med Bull
1942;40:791-6.
14. Stenland CJ, Lee DC, Brown P, Petteway SR, Jr., Rubenstein R. Partitioning of human
and sheep forms of the pathogenic prion protein during the purification of therapeutic
proteins from human plasma. Transfusion 2002;42(11):1497-500.
16. Wilkes MM, Navickis RJ. Patient survival after human albumin administration. A meta-
analysis of randomized, controlled trials. Ann Intern Med 2001;135(3):149-64.
19. Alderson P, Bunn F, Lefebvre C, Li WP, Li L, Roberts I, et al. Human albumin solution
for resuscitation and volume expansion in critically ill patients. Cochrane Database Syst
Rev 2004(4):CD001208.
21. All About Albumin: Biochemistry, Genetics, and Medical Applications. Theodore Peters,
Jr. San Diego, CA: Academic Press, 1996, pp. 76-132, 234-243, 245-250.
Page 16 of 19
IMPORTANT: PLEASE READ
Albumin is a protein manufactured by the liver. It is most What dosage forms it comes in:
abundant in human plasma. Normally it constitutes about 55% ALBUMIN (HUMAN) 25% SOLUTION, USP comes in 50
of all plasma proteins. Albumin has multiple functions, mL and 100 mL vials (with rubber stoppers).
including transport of many small molecules in the blood, such
as bilirubin, calcium, and magnesium. Albumin also binds to
toxins and heavy metals, thereby preventing damage they might WARNINGS AND PRECAUTIONS
otherwise cause to your body. One of albumin's major roles is
in the maintenance of "osmotic or oncotic pressure" that causes ALBUMIN (HUMAN) 25% SOLUTION, USP like other
fluid to remain within the blood stream instead of leaking out products made from human plasma, part of our blood, may
into the tissues. contain viruses or other agents that can cause infection and
Possible causes of a decrease in the level of albumin in the illness. However, the processes used to make ALBUMIN
blood include liver or kidney disease or increased loss of (HUMAN) 25% SOLUTION, USP are specifically designed
albumin from circulation (e.g., due to shock). A diseased liver with the ability to reduce these agents if they are present. You
produces less albumin. In kidney disease, albumin can escape should discuss the risks and benefits of this product with your
into the urine in large amounts. Severe malnutrition or a very healthcare provider.
low protein diet can also reduce the albumin level. BEFORE you use ALBUMIN (HUMAN) 25% SOLUTION,
If the concentration of albumin gets very low, fluid moves from USP talk to your doctor or pharmacist if:
the blood vessels into the tissues, resulting in swelling in the you are pregnant or breastfeeding
ankles (edema). This fluid can also accumulate in the abdomen you have had an allergic reaction to immune globulin or
(ascites) and in the lungs (pulmonary edema). any of the other ingredients in the medicine
you have had a history of congestive heart failure, renal
What it does:
insufficiency, or stabilized chronic anemia
ALBUMIN (HUMAN) 25% SOLUTION, USP given by
intravenous administration can help restore the fluid balance
and help improve the problems that led to the low albumin
level.
When it should not be used:
You should not use ALBUMIN (HUMAN) 25% SOLUTION,
USP if you are allergic to albumin or to any ingredient in the
formulation or component of the container.
Page 17 of 19
IMPORTANT: PLEASE READ
Usual dose To monitor drug safety, Health Canada through the Canada
Vigilance Program collects information on serious and
Your doctor will determine the amount of ALBUMIN
unexpected side effects of drugs. If you suspect you have had
(HUMAN) 25% SOLUTION, USP that is right for you and
a serious or unexpected reaction to this drug you may notify
when your treatments should be given. A doctor, nurse or other
Canada Vigilance:
caregiver trained to give injections will give you your
treatment.
By toll-free
Overdose 866-234-2345
telephone:
If you or your healthcare professional suspects that you have
received an overdose of ALBUMIN (HUMAN) 25% By toll-free fax: 866-678-6789
SOLUTION, USP, additional supportive treatment may be
required. Online: www.healthcanada.gc.ca/medeffect
Page 18 of 19
IMPORTANT: PLEASE READ
Page 19 of 19