Heparin Sodium - Heparin Sodium injection

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^† (
  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

  *Based on 68 kg patient
  METHOD OF ADMINISTRATION	FREQUENCY	RECOMMENDED DOSE
  Deep Subcutaneous (Intrafat) Injection Use a different site for each injection to prevent the development of hematoma	Initial Dose	5,000 units by intravenous injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously
  	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
  Continuous 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,

• 2,000 USP units per 2 mL, single-dose vial

• Pregnancy: Preservative-free formulation recommended. (
  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 injection to a pregnant woman.

  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 ]

  .

  The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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 2-4% 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, 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: Preservative-free formulation recommended. (
  8.2 Lactation

  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. 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 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 ].

  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.
  )

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

  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. 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 vials to confirm the correct vial choice prior to administration of the drug.
  )
• Hemorrhage: Hemorrhage, including fatal events, has occurred in patients receiving heparin. 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: Use preservative-free formulation in neonates and infants
• Monitoring: Blood coagulation tests guide therapy for full-dose heparin. Periodically monitor platelet count, hematocrit, and occult blood in stool 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 sodium regimen, adjust the heparin sodium dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, discontinue heparin sodium promptly

  [see Overdosage ]

  . 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 ]

  .
  )
• Hyperkalemia: Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients. (
  5.9 Hyperkalemia

  Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia, particularly in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium, or taking potassium sparing drugs. The risk of hyperkalemia appears to increase with duration of therapy but is usually reversible upon discontinuation of heparin.

  Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients treated for more than 5 days or earlier as deemed fit by the clinician.
  )