PROTAMINE SULPHATE
DESCRIPTION:
Protamines are simple proteins of low molecular weight that are rich in arginine
and strongly basic. They occur in the sperm of salmon and certain other species
of fish.
Protamine sulfate occurs as fine white or off- white amorphous or crystalline
powder. It is sparingly soluble in water. The pH is between 6 and 7. The
cationic hydrogenated protamine at a pH of 6.8 to 7.1 reacts with anionic
heparin at a pH of 5.0 to 7.5 to form an inactive complex.
Protamine Sulfate Injection, USP, is a sterile, isotonic solution of protamine
sulfate. It acts as a heparin antagonist. It is also a weak anticoagulant.
Each 25-mL vial contains protamine sulfate equivalent to 250 mg of activity.
Product also contains 0.9% Sodium Chloride Reagent in Water for Injection, USP.
Sodium phosphate and/or sulfuric acid may have been added during manufacture to
adjust the pH. Contains no preservative.
Protamine sulfate is administered intravenously.
ACTIONS/CLINICAL PHARMACOLOGY:
When administered alone, protamine has an anticoagulant effect. However, when it
is given in the presence of heparin (which is strongly acidic), a stable salt is
formed and the anticoagulant activity of both drugs is lost.
Protamine sulfate has a rapid onset of action. Neutralization of heparin occurs
within 5 minutes after intravenous administration of an appropriate dose of
protamine sulfate. Although the metabolic fate of the heparin-protamine complex
has not been elucidated, it has been postulated that protamine sulfate in the
heparin- protamine complex may be partially metabolized or may be attacked by
fibrinolysin, thus freeing heparin.
INDICATIONS AND USAGE:
Protamine sulfate is indicated in the treatment of heparin overdosage.
CONTRAINDICATIONS:
Protamine sulfate is contraindicated in patients who have shown previous
intolerance to the drug.
WARNINGS:
Hyperheparinemia or bleeding has been reported in experimental animals and in
some patients 30 minutes to 18 hours after cardiac surgery (under
cardiopulmonary bypass) in spite of complete neutralization of heparin by
adequate doses of protamine sulfate at the end of the operation. It is important
to keep the patient under close observation after cardiac surgery. Additional
doses of protamine sulfate should be administered if indicated by coagulation
studies, such as the heparin titration test with protamine and the determination
of plasma thrombin time.
TOO-RAPID ADMINISTRATION OF PROTAMINE SULFATE CAN CAUSE SEVERE HYPOTENSIVE AND
ANAPHYLACTOID REACTIONS (SEE DOSAGE AND ADMINISTRATION). Facilities to treat
shock should be available.
PRECAUTIONS:
GENERAL--BECAUSE OF THE ANTICOAGULANT EFFECT OF PROTAMINE, IT IS UNWISE TO GIVE
MORE THAN 50 MG OVER A SHORT PERIOD UNLESS A LARGER DOSE IS CLEARLY NEEDED.
Patients with a history of allergy to fish may develop hypersensitivity
reactions to protamine, although to date no relationship has been established
between allergic reactions to protamine and fish allergy.
Previous exposure to protamine can induce a humoral immune response and
predispose susceptible individuals to the development of untoward reactions from
the subsequent use of this drug. Patients exposed to protamine through the use
of protamine-containing insulin or during heparin neutralization may experience
life- threatening reactions and fatal anaphylaxis upon receiving large doses of
protamine intravenously. Severe reactions to intravenous protamine can occur in
the absence of local or systemic allergic reactions to subcutaneous injection of
protamine-containing insulin. Reports of the presence of antiprotamine
antibodies in the sera of infertile or vasectomized men suggest that some of
these individuals may react to use of protamine sulfate.
Fatal anaphylaxis has been reported in one patient with no prior history of
allergies.
Drug Interactions--Protamine sulfate has been shown to be incompatible with
certain antibiotics, including several of the cephalosporins and penicillins
(See Dosage and Administration).
Carcinogenesis, Mutagenesis, Impairment Of Fertility--Studies have not been
performed to determine potential for carcinogenicity, mutagenicity, or
impairment of fertility.
Pregnancy--Pregnancy Category C--Animal reproduction studies have not been
conducted with protamine sulfate. It is also not known whether protamine sulfate
can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Protamine sulfate should be given to a pregnant woman
only if clearly needed.
Nursing Mothers--It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when
protamine sulfate is administered to a nursing woman.
Pediatric Use--Safety and effectiveness in pediatric patients have not been
established.
DRUG INTERACTIONS:
Protamine sulfate has been shown to be incompatible with certain antibiotics,
including several of the cephalosporins and penicillins (See Dosage and
Administration).
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
The intravenous administration of protamine sulfate may cause a sudden fall in
blood pressure and bradycardia. Other reactions include transitory flushing and
feeling of warmth, dyspnea, nausea, vomiting, and lassitude. Back pain has been
reported in conscious patients undergoing such procedures as cardiac
catheterization.
Severe adverse reactions have been reported including: (1) Anaphylaxis that
resulted in severe respiratory distress, circulatory collapse, and capillary
leak (See Precautions). Fatal anaphylaxis has been reported in one patient with
no prior history of allergies; (2) Anaphylactoid reactions with circulatory
collapse, capillary leak, and noncardiogenic pulmonary edema; acute pulmonary
hypertension.
Complement activation by the heparin-protamine complexes, release of lysosomal
enzymes from neutrophils, and prostaglandin and thromboxane generation have been
associated with the development of anaphylactoid reactions.
Severe and potentially irreversible circulatory collapse associated with
myocardial failure and reduced cardiac output can also occur. The mechanism(s)
of this reaction and the role played by concurrent factors are unclear.
High-protein, noncardiogenic pulmonary edema associated with the use of
protamine has been reported in patients on cardiopulmonary bypass who are
undergoing cardiovascular surgery. The etiologic role of protamine in the
pathogenesis of this condition is uncertain, and multiple factors have been
present in most cases. The condition has been reported in association with
administration of certain blood products, other drugs, cardiopulmonary bypass
alone, and other etiologic factors. It is difficult to treat, and it can be life
threatening. Because fatal anaphylactic and anaphylactoid reactions have been
reported after the administration of protamine sulfate, the drug should be given
only when resuscitation techniques and treatment of anaphylactic and
anaphylactoid shock are readily available.
OVERDOSAGE:
Signs And Symptoms--Overdose of protamine sulfate may cause bleeding. Protamine
has a weak anticoagulant effect due to an interaction with platelets and with
many proteins including fibrinogen. This effect should be distinguished from the
rebound anticoagulation that may occur 30 minutes to 18 hours following the
reversal of heparin with protamine.
Rapid administration of protamine is more likely to result in bradycardia,
dyspnea, a sensation of warmth, flushing, and severe hypotension. Hypertension
has also occurred.
The median lethal intravenous dose of protamine sulfate is 50 mg/kg in mice.
Serum concentrations of protamine sulfate are not clinically useful. Information
is not available on the amount of drug in a single dose that is associated with
overdosage or is likely to be life threatening.
Treatment--To obtain up-to-date information about the treatment of overdose, a
good resource is your certified Regional Poison Control Center. Telephone
numbers of certified poison control centers are listed in the Physicians' Desk
Reference (PDR). In managing overdosage, consider the possibility of multiple
drug overdoses, interaction among drugs, and unusual drug kinetics in your
patient.
Replace blood loss with blood transfusions or fresh frozen plasma.
If the patient is hypotensive, consider fluids, epinephrine, dobutamine, or
dopamine.
DOSAGE AND ADMINISTRATION:
Each mg of protamine sulfate neutralizes approximately 90 USP units of heparin
activity derived from lung tissue or about 115 USP units of heparin activity
derived from intestinal mucosa.
PROTAMINE SULFATE INJECTION SHOULD BE GIVEN BY VERY SLOW INTRAVENOUS INJECTION
OVER A 10-MINUTE PERIOD IN DOSES NOT TO EXCEED 50 MG (SEE WARNINGS).
Protamine sulfate is intended for injection without further dilution; however,
if further dilution is desired, D5-W or normal saline may be used. Diluted
solutions should not be stored since they contain no preservative.
Protamine sulfate should not be mixed with other drugs without knowledge of
their compatibility, because protamine sulfate has been shown to be incompatible
with certain antibiotics, including several of the cephalosporins and
penicillins.
Because heparin disappears rapidly from the circulation, the dose of protamine
sulfate required also decreases rapidly with the time elapsed following
intravenous injection of heparin. For example, if the protamine sulfate is
administered 30 minutes after the heparin, one half the usual dose may be
sufficient.
The dosage of protamine sulfate should be guided by blood coagulation studies
(See Warnings).
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit.
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