"Section Title","Title","Description","Appl No","Appl Type","Drug Name","Active Ingredient","Sub No","Sub Type","URL","URL Text"
"Contraindications","n/a","
(addition underlined)
…
- An uncontrolled active bleeding state ","017029","NDA","HEPARIN SODIUM IN PLASTIC CONTAINER","HEPARIN SODIUM","141","SUPPL ","http://www.accessdata.fda.gov/drugsatfda_docs/label/2018/017029s141lbl.pdf","Approved Drug Label"
"Warnings and Precautions","5.1 Fatal Medication Errors","
(additions underlined)
Do
not use Heparin Sodium Injection as a “catheter lock flush” product. Heparin
Sodium Injection is supplied in syringes containing a highly concentrated
solution of 10,000 units in 1 mL (5,000 units per 0.5 mL). Fatal
hemorrhages have occurred in pediatric patients due to medication errors
in which 1 mL Heparin Sodium Injection vials were confused with 1 mL
“catheter lock flush” vials. Carefully examine all Heparin Sodium Injection
syringes to confirm the correct syringe choice prior to administration
of the drug. ","017029","NDA","HEPARIN SODIUM IN PLASTIC CONTAINER","HEPARIN SODIUM","141","SUPPL ","http://www.accessdata.fda.gov/drugsatfda_docs/label/2018/017029s141lbl.pdf","Approved Drug Label"
"Warnings and Precautions","5.2 Hemorrhage","
(additions
underlined)
Avoid using heparin in the presence of major bleeding,
except when the benefits of heparin therapy outweigh the potential risks.
Hemorrhage can occur at virtually any site in patients
receiving heparin. Fatal hemorrhages have occurred. Adrenal hemorrhage (with
resultant acute adrenal insufficiency), ovarian hemorrhage, and retroperitoneal
hemorrhage have occurred during anticoagulant therapy with heparin. A higher incidence of bleeding has been reported in patients,
particularly women, over 60 years of age.
An unexplained fall in hematocrit, fall in blood pressure or any other
unexplained symptom should lead to serious consideration of a hemorrhagic
event.
… ","017029","NDA","HEPARIN SODIUM IN PLASTIC CONTAINER","HEPARIN SODIUM","141","SUPPL ","http://www.accessdata.fda.gov/drugsatfda_docs/label/2018/017029s141lbl.pdf","Approved Drug Label"
"Warnings and Precautions","5.5 Coagulation Testing and Monitoring","
(additions
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. ","017029","NDA","HEPARIN SODIUM IN PLASTIC CONTAINER","HEPARIN SODIUM","141","SUPPL ","http://www.accessdata.fda.gov/drugsatfda_docs/label/2018/017029s141lbl.pdf","Approved Drug Label"
"Adverse Reactions","6.1 Postmarketing Experience","
(additions
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.
...
- Local Irritation – Local
irritation, erythema, mild pain, hematoma or ulceration may follow deep
subcutaneous (intrafat) injection of heparin sodium. Because these
complications are much more common after intramuscular use, the intramuscular
route is not recommended. - 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.
… ","017029","NDA","HEPARIN SODIUM IN PLASTIC CONTAINER","HEPARIN SODIUM","141","SUPPL ","http://www.accessdata.fda.gov/drugsatfda_docs/label/2018/017029s141lbl.pdf","Approved Drug Label"
"Use in Specific Populations","8.1 Pregnancy","
(additions
underlined)
…
If available, preservative-free Heparin
Sodium Injection is recommended when heparin therapy is needed during
pregnancy.
… ","017029","NDA","HEPARIN SODIUM IN PLASTIC CONTAINER","HEPARIN SODIUM","141","SUPPL ","http://www.accessdata.fda.gov/drugsatfda_docs/label/2018/017029s141lbl.pdf","Approved Drug Label"
"Use in Specific Populations","8.4 Pediatric Use","
(subsection
revised, additions underlined)
Pediatric dosing is not achievable with the
prefilled syringe presentation. Use another heparin product
presentation when dosing pediatric patients. ","017029","NDA","HEPARIN SODIUM IN PLASTIC CONTAINER","HEPARIN SODIUM","141","SUPPL ","http://www.accessdata.fda.gov/drugsatfda_docs/label/2018/017029s141lbl.pdf","Approved Drug Label"
"Use in Specific Populations","8.5 Geriatric Use","
(additions
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.Patients over
60 years of age may require lower doses of heparin. Lower doses of heparin
may be indicated in these patients. ","017029","NDA","HEPARIN SODIUM IN PLASTIC CONTAINER","HEPARIN SODIUM","141","SUPPL ","http://www.accessdata.fda.gov/drugsatfda_docs/label/2018/017029s141lbl.pdf","Approved Drug Label"
"MG/PCI/PI (Medication Guide/Patient Counseling Information/Package Insert)","PATIENT COUNSELING INFORMATION","
(additions underlined)
…
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.
… ","017029","NDA","HEPARIN SODIUM IN PLASTIC CONTAINER","HEPARIN SODIUM","141","SUPPL ","http://www.accessdata.fda.gov/drugsatfda_docs/label/2018/017029s141lbl.pdf","Approved Drug Label"
"Use in Specific Populations","8.1 Pregnancy","
(PLLR conversion)
Risk Summary
There are no available data on heparin sodium 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 40,000 units/24 hours infusion (see Data).
Consider the benefits and risks of Heparin Sodium in 0.45% Sodium Chloride
Injection or Heparin Sodium in 5% Dextrose Injection to a pregnant woman and
possible risks to the fetus when prescribing Heparin Sodium in 0.45% Sodium
Chloride Injection or Heparin Sodium in 5% Dextrose Injection to a pregnant
woman.
The estimated background risk of major birth defects
and miscarriage for the indicated population is unknown. All pregnancies have a
background risk of birth defect, loss, or other adverse outcomes. In the U.S.
general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 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,
pregnant animals received heparin intravenously during organogenesis at a dose
of 10,000 USP units/kg/day, approximately 10 times the maximum human daily dose
based on body weight. The number of early resorptions increased in both
species. There was no evidence of teratogenic effects. ","017029","NDA","HEPARIN SODIUM IN PLASTIC CONTAINER","HEPARIN SODIUM","140","SUPPL ","http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017029s140lbl.pdf","Approved Drug Label"
"Use in Specific Populations","8.2 Lactation","
(PLLR conversion)
Risk Summary
There is no information regarding the presence of
Heparin Sodium in 0.45% Sodium Chloride Injection or Heparin Sodium in 5%
Dextrose Injection in human milk, the effects on the breastfed infant, or the
effects on milk production. Due to its large molecular weight, heparin is
not likely to be excreted in human
milk, and any heparin in milk would not be orally absorbed by a nursing infant. The developmental and
health benefits of breastfeeding should be considered along with the mother’s
clinical need for Heparin Sodium in 0.45% Sodium Chloride Injection or Heparin
Sodium in 5% Dextrose Injection and any potential adverse effects on the
breastfed infant from Heparin Sodium in 0.45% Sodium Chloride Injection or
Heparin Sodium in 5% Dextrose Injection or from the underlying maternal
condition. ","017029","NDA","HEPARIN SODIUM IN PLASTIC CONTAINER","HEPARIN SODIUM","140","SUPPL ","http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017029s140lbl.pdf","Approved Drug Label"
"Other","n/a","
PLR conversion, please refer to label ","017029","NDA","HEPARIN SODIUM IN PLASTIC CONTAINER","HEPARIN SODIUM","140","SUPPL ","http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017029s140lbl.pdf","Approved Drug Label"
"Warnings and Precautions","n/a","
5.1
Fatal Medication Errors
Additions and/or revisions underlined:
Do not use Heparin Sodium Injection as a
“catheter lock flush” product. Heparin Sodium Injection is supplied in vials
containing various strengths of heparin, including vials that contain a
highly concentrated solution of 10,000 units in 1 mL …
Newly added subsection:
5.4
Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative
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 and other drugs containing benzyl alcohol. The minimum
amount of benzyl alcohol at which toxicity may occur is not known [see Use in Specific Populations (8.4)].
5.6
Coagulation Testing and Monitoring
Additions and/or revisions 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 [see Overdosage (10)]. Periodically monitor platelet counts,
hematocrit, and occult blood in stool during the entire course of
heparin therapy, regardless of the route of administration [see Dosage and Administration (2.2)]. ","017029","NDA","HEPARIN SODIUM IN PLASTIC CONTAINER","HEPARIN SODIUM","156","SUPPL ","http://www.accessdata.fda.gov/drugsatfda_docs/label/2020/017029s156,017651s066lbl.pdf","Approved Drug Label"
"Adverse Reactions","n/a","
Newly
added to bulleted line listing:
- Risk
of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative [see Warnings and Precautions (5.4)] ","017029","NDA","HEPARIN SODIUM IN PLASTIC CONTAINER","HEPARIN SODIUM","156","SUPPL ","http://www.accessdata.fda.gov/drugsatfda_docs/label/2020/017029s156,017651s066lbl.pdf","Approved Drug Label"
"Use in Specific Populations","n/a","
8.1
Pregnancy
Revised to adhere to PLLR; additions and/or
revisions underlined:
… If
available, preservative-free Heparin Sodium Injection is recommended when
heparin therapy is needed during pregnancy. There are no known adverse
outcomes associated with fetal exposure to the preservative benzyl alcohol
through maternal drug administration; however, the preservative benzyl alcohol
can cause serious adverse events and death when administered intravenously to
neonates and infants [see Use in Specific
Populations (8.4)].
The
estimated background risk of major birth defects and miscarriage for the
indicated population is unknown …
8.2
Lactation
Revised to adhere to PLLR; additions and/or
revisions underlined:
Risk Summary
If available, preservative-free Heparin
Sodium Injection is recommended when heparin therapy is needed during
lactation. Benzyl alcohol present in maternal serum is likely to cross into
human milk and may be orally absorbed by a breastfed infant. 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.
Due to its large molecular weight, heparin is not likely to be excreted in
human milk, and any heparin in milk would not be orally absorbed by a breastfed
infant …
8.4
Pediatric Use
Additions and/or revisions underlined:
There are no adequate and well controlled
studies on
heparin use in pediatric patients. Pediatric dosing recommendations
are based on clinical experience [see
Dosage and Administration (2.4)].
Carefully examine all Heparin Sodium
Injection vials to confirm choice of the correct strength prior to
administration of the drug. Pediatric patients, including neonates, have died
as a result of medication errors in which Heparin Sodium Injection vials have
been confused with “catheter lock flush” vials [see Warnings and Precautions (5.1)].
Benzyl Alcohol Toxicity
Use preservative-free Heparin Sodium
Injection in neonates and infants.
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. ","017029","NDA","HEPARIN SODIUM IN PLASTIC CONTAINER","HEPARIN SODIUM","156","SUPPL ","http://www.accessdata.fda.gov/drugsatfda_docs/label/2020/017029s156,017651s066lbl.pdf","Approved Drug Label"