PRODUCT MONOGRAPH

PENTASPAN*
(10% Pentastarch in 0.9% Sodium Chloride Injection)

Injection

Plasma Volume Expander

Bristol-Myers Squibb Canada

Montreal, Canada
*

TM auth. user
Bristol-Myers Squibb Canada

Date of Preparation:
November 19, 2001
Date of Revision:
August 22, 2013

Control No.: 166295

PRODUCT MONOGRAPH
PENTASPAN
(10% Pentastarch in 0.9% Sodium Chloride Injection)
Injection
THERAPEUTIC CLASSIFICATION
Plasma Volume Expander
ACTION AND CLINICAL PHARMACOLOGY
The colloidal properties of pentastarch render it useful as a plasma volume expander.
Intravenous infusion of PENTASPAN (pentastarch) results in expansion of the plasma volume in
excess of the volume infused. This expansion persists for approximately 18 to 24 hours and is
expected to improve the hemodynamic status for 12 to 18 hours.
Pentastarch molecules below 50,000 molecular weight are rapidly eliminated by renal excretion.
A single dose of approximately 500 mL of PENTASPAN results in elimination in the urine of
approximately 70% of the dose within 24 hours, and approximately 80% of the dose within one
week. The remaining percentage of the administered dose is presumed to be eliminated at a
slower rate. Although this process is variable, it generally results in an intravascular pentastarch
concentration below the level of detection by one week. The hydroxyethyl group is not cleaved,
but remains intact and attached to glucose units when excreted.
INDICATIONS AND CLINICAL USE
PENTASPAN (pentastarch) is indicated when plasma volume expansion is desired as an adjunct
in the management of shock due to hemorrhage, surgery, sepsis, burns or other trauma. It is not a
substitute for red blood cells or coagulation factors in plasma.
CONTRAINDICATIONS
PENTASPAN (pentastarch) is contraindicated in patients with sepsis.
PENTASPAN is contraindicated in patients with severe liver disease.
PENTASPAN is contraindicated in patients with known hypersensitivity to hydroxyethyl starch,
or with bleeding disorders, or with congestive heart failure where volume overload is a potential
problem. PENTASPAN should not be used in renal disease with oliguria or anuria not related to
hypovolemia.

WARNINGS
Serious Warnings and Precautions
In patients with hypovolemia requiring intensive or emergent care, a careful evaluation of the risk
of sustaining renal injury or liver failure should be undertaken before instituting treatment with
PENTASPAN. The use of crystalloid solutions in preference to PENTASPAN should be
considered in patients deemed at risk of these adverse reactions.
General
Administration of large volumes of PENTASPAN (pentastarch) will decrease haemoglobin
concentration and dilute plasma proteins excessively. Administration should be kept below the
recommended ceiling of 2000 mL in 24 hours (see Dosage and Administration).
As with other plasma volume expanders, large volumes of PENTASPAN will alter the
coagulation mechanisms in as much as a prolongation of prothrombin, partial thromboplastin and
clotting times will occur. The physician should also be alert to the possibility of transient
prolongation of bleeding time.
Hypersensitivity has been seen (wheezing, urticaria and hypotension). Anaphylactic/
anaphylactoid reactions have been reported with PENTASPAN; a causal relationship has not
been established. If hypersensitivity effects occur, discontinue the drug and, if necessary,
administer appropriate therapy.
Immume
Anaphylactoid reactions (mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm,
non-cardiac pulmonary edema) have been reported with solutions containing hydroxyethyl starch.
Use in Pregnancy
PENTASPAN has been shown to be embryocidal in New Zealand rabbits and in Swiss mice
when given in doses 5 times the human dose. There are no adequate and well-controlled clinical
studies using pentastarch in pregnant women. PENTASPAN should not be used during
pregnancy unless potential benefits justify the potential risk to the fetus.
Nursing Mothers
It is not known whether pentastarch is excreted in human milk. Because many drugs are excreted
in human milk, caution should be exercised when PENTASPAN is administered to a nursing
woman.
Pediatric Use
The safety and effectiveness of PENTASPAN in children have not been established.

PRECAUTIONS
PENTASPAN (pentastarch), like all plasma volume expanders, is not a substitute for red blood
cells or coagulation factors in plasma.
The possibility of circulatory overload should be kept in mind.
Caution should be used when the risk of pulmonary edema and/or congestive heart failure is
increased. Special care should be exercised in patients who have impaired renal clearance since
this is the principal route by which pentastarch is eliminated.
The serum chemistries of sixteen normal volunteers who were given PENTASPAN in doses of
500 to 2000 mL (2x1000mL infusions on separate days) were essentially unchanged from pre- to
seven days post-infusion, except for dilutional effects. There were no clinically significant
abnormal values except for one creatinine phosphokinase level following an episode of
venospasm. However, indirect bilirubin levels of 8.3 mg/L (normal 0 - 7 mg/L) have been
reported in 2 out of 20 normal subjects who received multiple infusions of a 6% hetastarch
product. Total bilirubin was within normal limits at all times; indirect bilirubin returned to
normal by 96 hours following the final infusion. The significance, if any, of these elevations is
not known; however, caution should be observed before administering PENTASPAN to patients
with a history of liver disease.
Caution should be exercised when administering PENTASPAN to patients allergic to corn
because such patients can also be allergic to PENTASPAN.
Elevated serum amylase levels may be observed temporarily following administration of
PENTASPAN although no association with pancreatitis has been demonstrated. A 6% hetastarch
injection product has not been shown to increase serum lipase. Similar effects may be expected
with PENTASPAN.
ADVERSE REACTIONS
Coagulation disorders or hemorrhage have been reported in association with the use of
PENTASPAN(pentastarch) as a plasma volume expander. Headache, diarrhea, nausea,
weakness, temporary weight gain, insomnia, fatigue, fever, edema, paresthesia, acne, malaise,
shakiness, dizziness, chest pain, chills, nasal congestion, anxiety, and increased heart rate have
also been reported in clinical studies involving PENTASPAN.
It is uncertain whether any of these adverse experiences are attributable to the drug, medical
procedures, concurrent adjunctive medication, or a combination of these factors.
Hypersensitivity has been seen (wheezing, urticaria and hypotension).
Anaphylactic/anaphylactoid reactions have been reported with PENTASPAN (see WARNINGS).
SYMPTOMS AND TREATMENT OF OVERDOSAGE
The treatment of overdosage of PENTASPAN (pentastarch) would be essentially symptomatic

and supportive.
DOSAGE AND ADMINISTRATION
PENTASPAN (pentastarch) is administered by intravenous infusion only. Total dosage and rate
of infusion depend upon the amount of blood or plasma lost. In adults, the amount usually
administered is 500 to 2000 mL. Total dosage does not usually exceed 2000 mL per day or
approximately 28 mL per kg of body weight for the typical 70 kg patient. In acute hemorrhagic
shock, an administration rate approaching 20 mL per kg per hour may be used. Use beyond 72
hours has not been studied.
Parenteral drug products should be inspected for particulate matter and discoloration prior to
administration whenever solution and container permit.
The solution is intended for intravenous administration using sterile equipment. It is
recommended that intravenous administration apparatus be replaced at least once every 24 hours.

PHARMACEUTICAL INFORMATION
Drug Substance
Proper Name:

Pentastarch (USAN)

Chemical Name:

Low molecular weight, low molar substitution hydroxyethyl starch

Structural Formula:
Amylopectin derivative in which R2, R3, and R6 are H or CH2CH2OH, or R6 is a branching point
in the starch polymer connected through a 1-6 linkage to additional -D-glucopyranosyl units.
Average Molecular Weight:

200,000 - 300,000

Pentastarch is an artificial colloid derived from a waxy starch composed almost entirely of
amylopectin. Hydroxyethyl ether groups are introduced into the glucose units of the starch and
the resultant material is hydrolyzed to yield a product with a molecular weight suitable for use as
a plasma volume expander. Pentastarch is characterized by its molar substitution, and also by its
molecular weight.
The degree of substitution is 0.40 - 0.50 which means pentastarch has approximately 45
hydroxyethyl groups for every 100 glucose units. The average molecular weight of pentastarch is
200,000 - 300,000. Hydroxyethyl groups are attached by an ether linkage primarily at C-2 of the
glucose unit and to a lesser extent at C-3 and C-6. The polymer resembles glycogen, and the
polymerized glucose units are joined primarily by 1-4 linkages with occasional 1-6 branching
linkages. The degree of branching is approximately 1:20 which means that there is one 1-6
branch for every 20 glucose polymer units.
Composition
PENTASPAN is supplied sterile and nonpyrogenic in 250 and 500 mL plastic, intravenous
infusion bags. The composition of each 100 mL is as follows:
Pentastarch
10.0 g
Sodium Chloride USP
0.9 g
Water for Injection USP
qs
pH adjusted with Sodium Hydroxide
Approximate Concentration of Electrolytes (mEq/Litre): Sodium 154, Chloride 154
pH: Approx. 5.0
Calculated osmolality: Approx. 326 mOsm/Kg

Stability and Storage

PENTASPAN is supplied sterile and nonpyrogenic in 250 mL and 500 mL plastic, intravenous
infusion bags. Exposure of pharmaceutical products to heat should be minimized. Avoid
excessive heat. Protect from freezing. It is recommended that the product be stored at room
temperature (15-25C).
PENTASPAN is a clear, pale yellow to amber solution. Exposure to prolonged adverse storage
conditions may result in a change to a turbid deep brown or the formation of a crystalline
precipitate. Do not use the solution if these conditions are evident.
Special Instructions
Caution - Before administering to patient, review these directions:
Visual Checking
1.
2.
3.
4.

Do not remove the plastic infusion container from its overwrap until immediately before
use.
While the overwrap is intact, identify the solution (PENTASPAN), lot number and
expiration date.
Check that the solution is clear.
Inspect the intact unit for signs of obvious damage. If present, the unit should not be used.

Removal of Overwrap
A peelable area is located in the lower right hand corner of the unit (the label facing upward and
the port facing downward). Pull apart the two edges. You can also tear at any notch located at
either end of the unit. After removing overwrap, check for minute leaks by squeezing container
firmly. If leaks are found, discard unit as sterility may be impaired.
Preparation for Administration (Use aseptic technique)
1.
2.
3.
4.
5.
6.

Close flow control clamp of administration set.

Twist off plug from port designated "Infusion Set Port".
Insert spike of infusion set into port with a twisting motion until the set is firmly sealed.
Suspend container from hanger.
Follow manufacturer's recommended procedures for the administration set.
Discontinue administration and notify physician immediately if patient exhibits signs of
adverse reactions.
DOSAGE FORMS

Availability
PENTASPAN (pentastarch) is supplied sterile and nonpyrogenic in 250 mL and 500 mL plastic,
intravenous infusion bags.

PHARMACOLOGY
In a clinical study using pentastarch as an erythrocyte sedimenting agent in leukapheresis, a
number of pharmacokinetic parameters were evaluated. In the leukapheresis procedure, 500 mL
of pentastarch (10% in 0.9% NaCl) were added to the input line of the cell separator in a 1:13
ratio with whole blood. The elimination half-life, area under the curve (AUC) and renal
clearance were measured at selected times pre-, during and post-treatment. The results indicated
that elimination of approximately 70% of the dose occurred within 24 hours and approximately
80% within one week. The half-life measured over the seven-day period was 1.9 0.5 days.
This rapid elimination of pentastarch decreases the potential for accumulation after repeated
dosing.
In a second pharmacokinetic study, pentastarch (10% in 0.9% NaCl) was administered as a single
intravenous infusion of 500 mL over 30 minutes. Plasma volume was measured directly by the
125
I human serum albumin technique and indirectly from total protein and albumin levels and
from hematocrit and hemoglobin determinations. Assessments were conducted pre-treatment and
at specified intervals during the 24 hours after infusion of pentastarch. Plasma and urine
specimens were collected prior to treatment and at frequent intervals up to 24 hours after
infusion. Pentastarch was assessed by determining total carbohydrate in plasma and urine.
As measured by 125I albumin there was a statistically significant increase over baseline plasma
volume by one hour post pentastarch infusion which endured for six hours. Measurement by the
protein/albumin method revealed a significant increase over baseline plasma volume immediately
after infusion which continued for the duration of the follow-up period (24 hours). Similar
results were evident when plasma volume was estimated by the hematocrit/hemoglobin method.
Elevation of plasma volume over baseline levels endured for 9 hours post administration.
Following pentastarch administration, an immediate and consistent decline in plasma
concentration was also observed. The cumulative excretion of pentastarch reflects the finding,
such that 24 hours after administration, 72% of the dose was accounted for by urinary
hydroxyethyl starch.
TOXICOLOGY
In addition to the following toxicology studies, pentastarch did not demonstrate mutagenicity in
the Salmonella (Ames) Test or the Mouse Micronucleus Test.

Species

Route

Test Article

No. & Sex

Dose

Dose Duration

Parameters Evaluated

Significant Observations and

Conclusions

ACUTE TOXICITY
Mouse

I.V.

Pentastarch

10F, 10M
10F, 10M
10F, 10M
10F, 10M
10M

14.4 g/kg
17.3 g/kg
20.8 g/kg
25.0 g/kg
12.0 g/kg

Single Dose

Clinical observations and mortality LD50 (female) = 19.8 g/kg

during two weeks following
LD50 (male) = 18.1 g/kg
administration.

SUBACUTE TOXICITY
Rabbit

I.V.

Control saline

5F, 5M
5F, 5M
1F, 1M

15 mL/kg/day
40 mL/kg/day
80 mL/kg/day

Pentastarch 10%

5F, 5M
5F, 5M
1F, 1M

15 mL/kg/day
40 mL/kg/day
80 mL/kg/day

Hetastarch 6%

5F, 5M
5F, 5M
1F, 1M

15 mL/kg/day
40 mL/kg/day
80 mL/kg/day

Dextran 40

5F, 5M
5F, 5M
1F, 1M

15 mL/kg/day
40 mL/kg/day
80 mL/kg/day

Rheomacrodex

5F, 5M
5F, 5M
1F, 1M

15 mL/kg/day
40 mL/kg/day
80 mL/kg/day

5 days/ week for 4 Clinical observation, body weight,

weeks
mortality, hematology serum
biochemistry, urinalysis, function
tests, carbohydrate levels.
Macroscopic and microscopic study
of organs, organ weight.
Determination of total lipids,
phospholipids, triglycerides,
cholesterol and polysaccharides in
the liver.

Pentastarch produced a slight decrease

in plasma fibrinogen and increases in
serum glucose and amylase levels. The
latter changes were related to
metabolism of pentastarch.
Microscopically, the presence of highly
vacuolated macrophages was observed
in several tissues, especially those of the
reticulo-endothelial system. Similar
administration of 80 mL/kg proved
lethal in all rabbits within the first week
of treatment.

Test Article

No. & Sex

Dose

Dose Duration

Parameters Evaluated

Significant Observations and

Conclusions

Species

Route

Dog

I.V.

Control saline
Pentastarch 10%
Rheomacrodex

2F, 2M
2F, 2M
2F, 2M

40 mL/kg/day
40 mL/kg/day
40 mL/kg/day

6 days/ week for 3 Clinical observation, food intake,

weeks
body weight, hematology, serum
biochemistry, urinalysis, function
tests, macroscopic and microscopic
examination of organs.

Pentastarch produced only several

instances of vomiting and diarrhea and
slightly elevated relative kidneys
weight. Microscopically, small islands
of disseminated fatty degeneration in
the liver and discrete vacuolization of
some renal cells were observed in two
females. Additionally, one female
demonstrated signs of fibrohyperplastic
mastopathy.

Dog

I.V.

Saline control
Pentastarch 10%
Dextran 40

3F, 3M
6F, 6M
3F, 3M

45 mL/kg/day
45 mL/kg/day
45 mL/kg/day

5 consecutive days
followed by 2
dose-free days.
Cycle repeated 4
times for a total
duration of 28
days.

Clinical observation, vital signs,

blood biochemistry, serum
amylase, hematology, coagulation,
serum polysaccharide, plasma
albumin, hemoglobin, hematocrit,
oncotic pressure and plasma
volume.
131
I-labelled human serum albumin
was used to determine plasma
volume. Necroscopy.

Uptake and storage by liver of

pentastarch was reversible and no
permanent pathological changes were
caused by pentastarch administration.

Mouse

I.V.

Saline Control
Pentastarch 10%
Dextran 40

5F, 5M
5F, 5M
5F, 5M

50 mL/kg/day
50 mL/kg/day
50 mL/kg/day

14 consecutive
days

Blood analysis; necroscopy.

Uptake and storage of pentastarch by

the liver was reversible.

SUBACUTE TOXICITY (Contd)

Species

Route

Test Article

No. & Sex

Dose

Dose Duration

Parameters Evaluated

Significant Observations and

Conclusions

TERATOLOGY
Rabbit

I.V.

Saline control
Pentastarch 10%
Pentastarch 10%
Pentastarch 10%

12F
12F
12F
12F

40 mL/kg/day
10 mL/kg/day
20 mL/kg/day
40 mL/kg/day

Daily from days 6 Maternal observations: Daily

to 18 of gestation observation for toxic effects and
mortality; body weights taken
periodically through gestation.
Sacrifice of dose on Day 29 of
gestation followed by cesarean
delivery. Postmortem examination:
Weight and examination of uterus;
number of dead and live fetuses;
number of implants; number of
resorption sites. Fetal examination:
viability; number and weight;
visceral, skeletal and organ
examinations.

The intravenous administration of

pentastarch at 10 and 20 mL/kg/day,
during organogenesis, does not result in
teratogenesis or embryotoxicity.
However, at 40 mL/kg/day, pentastarch
seems to increase the number of
resorptions and minor visceral
anomalities.

Mouse

I.V.

Saline control
Pentastarch 10%
Pentastarch 10%
Pentastarch 10%

20F
20F
20F
20F

40 mL/kg/day
10 mL/kg/day
20 mL/kg/day
40 mL/kg/day

Daily from days 6 Maternal observation: Daily

to 15 of gestation observation for toxic effects and
mortality; body weights taken
periodically through gestation.
Sacrifice of dams on Day 20 of
gestation since litters had been
unexpectedly delivered on Day 19.
Postmortem examination: Weight
and examination of uterus; number
of dead and live fetuses; number of
resorption sites.

Pentastarch is not teratogenic or

embryotoxic in doses up to 40
mL/kg/day. At the high dose
pentastarch diminished nidation.

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