Heparin Sodium

Heparin Sodium Injection is indicated for:

• Prophylaxis and treatment of venous thrombosis and pulmonary embolism
• Prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for other reasons, are at risk of developing thromboembolic disease
• Atrial fibrillation with embolization
• Treatment of acute and chronic consumptive coagulopathies (disseminated intravascular coagulation)
• Prevention of clotting in arterial and cardiac surgery
• Prophylaxis and treatment of peripheral arterial embolism
• Anticoagulant use in blood transfusions, extracorporeal circulation, and dialysis procedures

Recommended Adult Dosages:

• Therapeutic Anticoagulant Effect with Full-Dose Heparin Sodium Injection^† (
  2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin

  The dosing recommendations in Table 1are based on clinical experience. Although dosages must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines:

  Table 1: Recommended Adult Full-Dose Heparin Regimens for Therapeutic Anticoagulant Effect

  METHOD OF ADMINISTRATION	FREQUENCY	RECOMMENDED DOSE [based on 150 lb (68 kg) patient]
  Deep Subcutaneous (Intrafat) Injection	Initial dose	5,000 units by intravenous injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously
  A different site should be used for each injection to prevent the development of massive hematoma	Every 8 hours or	8,000 to 10,000 units of a concentrated solution
  	Every 12 hours	15,000 to 20,000 units of a concentrated solution
  Intermittent Intravenous Injection	Initial dose	10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP
  	Every 4 to 6 hours	5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP
  Intravenous Infusion	Initial dose	5,000 units by intravenous injection
  	Continuous	20,000 to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion
  )

Heparin Sodium Injection, USP is available as:

• Heparin Sodium Injection: 1,000 USP units per mL
  preserved with benzyl alcohol
  clear solution in 1 mL vial and 10 mL and 30 mL multiple-dose vials
• Heparin Sodium Injection: 5,000 USP units per mL
  preserved with benzyl alcohol
  clear solution in 1 mL vial and 10 mL multiple-dose vials
• Heparin Sodium Injection: 10,000 USP units per mL
  preserved with benzyl alcohol
  clear solution in 1 mL vial and 4 mL multiple-dose vials

• Pregnancy: Preservative-free formulation recommended. Limited human data in pregnant women. (
  8.1 Pregnancy

  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 45,000 units/ day

  [see Data]

  . Consider the benefits and risks of heparin sodium for the mother and possible risks to the fetus when prescribing heparin sodium to a pregnant woman.

  If available, preservative-free heparin sodium 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 Warnings and Precautions ].

  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 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 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.
  )
• Lactation: Advise females not to breastfeed. (
  8.2 Lactation

  Risk Summary

  If available, preservative-free heparin sodium 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 nursing infant. There is no information regarding the presence of heparin sodium 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 and any potential adverse effects on the breastfed infant from heparin sodium or from the underlying maternal condition

  [see Use in Specific Populations ]

  .
  )
• Pediatric Use: Use preservative-free formulation in neonates and infants. (
  8.4 Pediatric Use

  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 ]

  .

  Carefully examine all heparin sodium 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 vials have been confused with “catheter lock flush” vials

  [see Warnings and Precautions ]

  .

  Benzyl Alcohol Toxicity

  Use preservative-free heparin sodium 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.
  )
• Geriatric Use: A higher incidence of bleeding reported in patients, particularly women, over 60 years of age. (
  8.5 Geriatric Use

  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

  [see Warnings and Precautions ]

  . Patients over 60 years of age may require lower doses of heparin.

  Lower doses of heparin may be indicated in these patients

  [see Clinical Pharmacology ]

  .
  )

• Fatal Medication Errors: Confirm choice of correct strength prior to administration (
  5.1 Fatal Medication Errors

  Do not use heparin sodium as a “catheter lock flush” product. Heparin sodium is supplied in vials containing various strengths of heparin, including vials that contain a highly concentrated solution of 10,000 units in 1 mL. Fatal hemorrhages have occurred in pediatric patients due to medication errors in which 1 mL heparin sodium vials were confused with 1 mL “catheter lock flush” vials. Carefully examine all heparin sodium vials to confirm the correct vial choice prior to administration of the drug.
  )
• Hemorrhage: Fatal cases have occurred. Use caution in conditions with increased risk of hemorrhage (
  5.2 Hemorrhage

  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

  [see Adverse Reactions ]

  . A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age

  [see Clinical Pharmacology ]

  . An unexplained fall in hematocrit, fall in blood pressure or any other unexplained symptom should lead to serious consideration of a hemorrhagic event.

  Use heparin sodium with caution in disease states in which there is increased risk of hemorrhage, including:

  • Cardiovascular - Subacute bacterial endocarditis, severe hypertension.
  • Surgical - During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord, or eye.
  • Hematologic - Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras.
  • 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).
  • Gastrointestinal - Ulcerative lesions and continuous tube drainage of the stomach or small intestine.
  • Other - Menstruation, liver disease with impaired hemostasis.
  )
• HIT and HITTS: Monitor for signs and symptoms and discontinue if indicative of HIT and HITTS (
  5.3 Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis

  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/mm³or 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.
  )
• Benzyl Alcohol Toxicity: Do not use this product in neonates and infants. (
  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 multiple-dose vials. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations.

  When prescribing heparin sodium multiple-dose vials in infants consider the combined daily metabolic load of benzyl alcohol from all sources including heparin sodium 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

  [see Use in Specific Populations ]

  .
  )
• Monitoring: Blood coagulation tests guide therapy for full-dose heparin.
• Monitor platelet count and hematocrit in all patients receiving heparin (
  5.5 Thrombocytopenia

  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. Obtain platelet counts before and periodically during heparin therapy. Monitor thrombocytopenia of any degree closely. If the count falls below 100,000/mm³or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant

  [see Warnings and Precautions ].
  ,
  5.6 Coagulation Testing and Monitoring

  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 ]

  . Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration

  [see Dosage and Administration ]

  .
  )