Approved Drug Label (PDF)
4
Contraindications
(Additions and/or revisions are underlined)
The use of
Heparin Sodium Injection is contraindicated in patients with the following conditions:
- History of heparin-induced thrombocytopenia and heparin-induced
thrombocytopenia and thrombosis
- Known hypersensitivity to heparin or pork products (e.g.,
anaphylactoid reactions)
5
Warnings and Precautions
5.2 Hemorrhage
(Additions and/or revisions are underlined)
Avoid using
heparin in the presence of major bleeding, except when the benefits of heparin
therapy outweigh the potential risks.
…Fatal
hemorrhages have occurred. Adrenal hemorrhage (with resultant acute adrenal
insufficiency), ovarian hemorrhage, and retroperitoneal hemorrhage have
occurred during anticoagulant therapy with heparin…
Use heparin
sodium with caution in disease states in which there is increased risk of
hemorrhage, including:
- Patients with hereditary antithrombin III deficiency receiving
concurrent antithrombin III therapy
- The anticoagulant effect of heparin is enhanced by concurrent
treatment with antithrombin III (human) in patients with hereditary
antithrombin III deficiency. To reduce the risk of bleeding, reduce the heparin
dose during concomitant treatment with antithrombin III (human).
5.3 Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis
(Additions and/or revisions are underlined)
Heparin-induced
thrombocytopenia (HIT) is a
serious antibody-mediated reaction. HIT occurs in patients treated
with heparin and is due to the development of antibodies to a platelet Factor
4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous
and arterial thromboses, a condition referred to as heparin-induced
thrombocytopenia with thrombosis (HITT). Thrombotic events may also be
the initial presentation for HITT. These serious thromboembolic events
include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis,
limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal
arterial thrombosis, skin necrosis, gangrene of the extremities that may lead
to amputation, and possibly death. If the platelet count falls below
100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate
for HIT and HITT, and, if necessary, administer an alternative
anticoagulant.
HIT or HITT can occur up to several weeks after the
discontinuation of heparin therapy. Patients presenting with thrombocytopenia
or thrombosis after discontinuation of heparin sodium should be evaluated for
HIT or HITT.
5.4 Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative
(Revised subheading; Additions and/or revisions are
underlined)
Serious and
fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with
benzyl alcohol-preserved drugs, including Heparin Sodium Injection
multiple-dose vials. The “gasping
syndrome” is characterized by central nervous system depression, metabolic
acidosis, and gasping respirations.
When prescribing
Heparin Sodium Injection multiple-dose vials in infants consider the combined daily metabolic load
of benzyl alcohol from all sources including Heparin Sodium Injection
multiple-dose vials (contains 10.42 mg of benzyl alcohol per mL) and other
drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at
which toxicity may occur is not known.
5.5 Thrombocytopenia
(Additions and/or revisions are underlined)
Thrombocytopenia in
patients receiving heparin has been reported at frequencies up to 30%. It
can occur 2 to 20 days (average 5 to 9) following the onset of heparin therapy…
If the count falls below 100,000/mm3 or if recurrent thrombosis develops,
promptly discontinue heparin, evaluate for HIT and HITT, and, if
necessary, administer an alternative anticoagulant.
5.6 Coagulation Testing and Monitoring
(Revised subheading; Additions and/or revisions are
underlined)
When using a
full dose heparin regimen, adjust the heparin dose based on frequent blood
coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage
occurs, discontinue heparin promptly. Periodic platelet counts and
hematocrits are recommended during the entire course of heparin therapy,
regardless of the route of administration.
5.7 Heparin Resistance
(Additions and/or revisions are underlined)
Resistance to
heparin is frequently encountered in fever, thrombosis, thrombophlebitis,
infections with thrombosing tendencies, myocardial infarction, cancer, in
postsurgical patients, and patients with antithrombin III deficiency. Close monitoring of coagulation tests is
recommended in these cases. Adjustment of heparin doses based on anti-Factor Xa
levels may be warranted.
5.8 Hypersensitivity
(Additions and/or revisions are underlined)
Patients with
documented hypersensitivity to heparin should be given the drug only in clearly
life- threatening situations.
Because Heparin
Sodium Injection is derived from animal tissue, it should be used with caution
in patients with a history of allergy.
6
Adverse Reactions
(Additions and/or revisions are underlined)
The following
clinically significant adverse reactions are described elsewhere in the
labeling:
- Hemorrhage
- Heparin-Induced Thrombocytopenia and Heparin-Induced
Thrombocytopenia and Thrombosis
- Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol
Preservative
- Thrombocytopenia
- Heparin Resistance
- Hypersensitivity
6.1 Postmarketing Experience
(Additions and/or revisions are underlined)
The following
adverse reactions have been identified during post approval use of Heparin
Sodium Injection. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure.
- Hemorrhage is the chief complication that may result from heparin
therapy. Gastrointestinal or urinary tract bleeding during
anticoagulant therapy may indicate the presence of an underlying occult
lesion. Bleeding can occur at
any site but certain specific hemorrhagic complications may be difficult
to detect:
- Adrenal hemorrhage, with resultant acute adrenal insufficiency,
has occurred with heparin therapy, including fatal cases.
- Histamine-like reactions – Such reactions have been observed at
the site of injections. Necrosis of the skin has been reported at the site
of subcutaneous injection of heparin, occasionally requiring skin grafting
7
Drug Interactions
7.2 Platelet Inhibitors
(Additions and/or revisions are underlined)
Drugs such as NSAIDS
(including salicylic acid, ibuprofen, indomethacin, and celecoxib),
dextran, phenylbutazone, thienopyridines, dipyridamole,
hydroxychloroquine, glycoprotein IIb/IIIa antagonists (including abciximab,
eptifibatide, and tirofiban), and others that interfere with platelet-aggregation
reactions (the main hemostatic defense of heparinized patients) may induce
bleeding and should be used with caution in patients receiving heparin sodium. To
reduce the risk of bleeding, a reduction in the dose of antiplatelet agent or
heparin is recommended.
7.3 Other Interactions
(Additions and/or
revisions are underlined)
Digitalis, tetracyclines, nicotine or antihistamines may partially
counteract the anticoagulant action of heparin sodium. Intravenous
nitroglycerin administered to heparinized patients may result in a decrease of
the partial thromboplastin time with subsequent rebound effect upon
discontinuation of nitroglycerin. Careful monitoring of partial thromboplastin
time and adjustment of heparin dosage are recommended during coadministration
of heparin and intravenous nitroglycerin.
Antithrombin III
(human) – The anticoagulant effect of heparin is enhanced by concurrent
treatment with antithrombin III (human) in patients with hereditary
antithrombin III deficiency. To reduce the risk of bleeding, a reduced dosage
of heparin is recommended during treatment with antithrombin III (human).
8
Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Risk Summary
There are no
available data on Heparin Sodium Injection use in pregnant women to inform a
drug- associated risk of major birth defects and miscarriage. In published reports, heparin exposure during
pregnancy did not show evidence of an increased risk of adverse maternal or
fetal outcomes in humans. No teratogenicity, but early embryo-fetal death
was observed in animal reproduction studies with administration of heparin
sodium to pregnant rats and rabbits during organogenesis at doses approximately
10 times the maximum recommended human dose (MRHD) of 45,000 units/ day.
Consider the benefits and risks of Heparin Sodium Injection for the mother and
possible risks to the fetus when prescribing Heparin Sodium Injection to a
pregnant woman.
…
The background
risk of major birth defects and miscarriage for the indicated population is
unknown. In the U.S. general population, the estimated background risk of major
birth defects and miscarriage in clinically recognized pregnancies is 2-4% and
15-20%, respectively.
Data
Human Data
The maternal and
fetal outcomes associated with uses of heparin via various dosing methods and
administration routes during pregnancy have been investigated in numerous
studies. These studies generally reported normal deliveries with no maternal or
fetal bleeding and no other complications.
Animal Data
In a published
study conducted in rats and rabbits, …
8.2 Lactation
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Risk Summary
… There is no
information regarding the presence of Heparin Sodium Injection in human milk,
the effects on the breastfed infant, or the effects on milk production … The
developmental and health benefits of breastfeeding should be considered along
with the mother's clinical need for Heparin Sodium Injection and any potential
adverse effects on the breastfed infant from Heparin Sodium Injection or from
the underlying maternal condition.
8.4 Pediatric Use
(Additions and/or
revisions are underlined)
Benzyl Alcohol
Toxicity
Serious adverse
reactions including fatal reactions and the “gasping syndrome” occurred
in premature neonates and infants in the neonatal intensive care unit
who received drugs containing benzyl alcohol as a preservative. In these
cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of
benzyl alcohol and its metabolites in the blood and urine (blood levels of
benzyl alcohol were 0.61 to 1.378
mmol/L). Additional adverse reactions included
gradual neurological deterioration, seizures, intracranial hemorrhage,
hematologic abnormalities, skin breakdown, hepatic and renal failure,
hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth
weight infants may be more likely to develop these reactions because they
may be less able to metabolize benzyl alcohol.
8.5 Geriatric Use
(Additions and/or revisions are underlined)
There are
limited adequate and well-controlled studies in patients 65 years and older,
however, a higher incidence
of bleeding has been reported in patients, particularly women, over 60 years of
age…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Newly added subsection)
Hemorrhage
Inform patients
that it may take them longer than usual to stop bleeding, that they may bruise
and/or bleed more easily when they are treated with heparin, and that they
should report any unusual bleeding or bruising to their physician. Hemorrhage
can occur at virtually any site in patients receiving heparin. Fatal
hemorrhages have occurred.
Prior to Surgery
Advise patients to
inform physicians and dentists that they are receiving heparin before any
surgery is scheduled.
Heparin-Induced
Thrombocytopenia
Inform patients of
the risk of heparin-induced thrombocytopenia (HIT). HIT may progress to the
development of venous and arterial thromboses, a condition known as
heparin-induced thrombocytopenia and thrombosis (HITT). HIT and HITT can occur
up to several weeks after the discontinuation of heparin therapy.
Hypersensitivity
Inform patients
that generalized hypersensitivity reactions have been reported. Necrosis of the
skin has been reported at the site of subcutaneous injection of heparin.
Other Medications
Because of the risk
of hemorrhage, advise patients to inform their physicians and dentists of all
medications they are taking, including non-prescription medications, and before
starting any new medication.
Other
(Physician Labeling Rule (PLR) Conversion; please refer to label)
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