Heparin Sodium - Heparin Sodium injection
(Heparin Sodium)Heparin Sodium - Heparin Sodium injection Prescribing Information
Warnings and Precautions, Hyperkalemia (
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† ()2.4 Therapeutic Anticoagulant Effect with Full-Dose HeparinThe dosing recommendations in Table 1 are 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)
InjectionA different site should be used for each injection to prevent the development of massive hematoma
Initial dose
Every 8 hours
or
Every 12 hours
5,000 units by intravenous injection, followed by
10,000 to 20,000 units of a concentrated solution,
subcutaneously8,000 to 10,000 units of a concentrated solution
15,000 to 20,000 units of a concentrated solutionIntermittent Intravenous Injection
Initial dose
Every 4 to 6 hours
10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP
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
Continuous
5,000 units by intravenous injection
20,000 to 40,000 units/24 hours in 1000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion
Deep Subcutaneous (Intrafat) Injection Use a different site for each injection | 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 Every 12 hours | 8,000 to 10,000 units of a concentrated solution
15,000 to 20,000 units of a concentrated solution | |
Intermittent | 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 | Initial dose | 5,000 units by intravenous injection |
Continuous | 20,000 to 40,000 units/24 hours in 1000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion | |
†Based on 150 lb (68 kg) patient. Adjust dose based on laboratory monitoring. | ||
Heparin Sodium Injection, USP is available as:
• Injection: 1,000 USP units per mLpreserved with benzyl alcoholclear solution in 1 mL single-dose, 10 mL and 30 mL multiple-dose vials• Injection: 5,000 USP units per mLpreserved with benzyl alcoholclear solution in 1 mL single-dose and 10 mL multiple-dose vials• Injection: 10,000 USP units per mLpreserved with benzyl alcoholclear solution in 1 mL single-dose and 4 mL multiple-dose vials
• Pregnancy: Preservative-free formulation recommended. Limited human data in pregnant women. ()8.1 PregnancyRisk SummaryThere 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 [
see Data]. 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.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 Warnings and Precautions (5.4)]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.
DataHuman DataThe 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 DataIn 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 LactationRisk SummaryIf 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 nursing 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 nursing infant. 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 [
see Use in Specific Populations (8.4)].• Pediatric Use: Use preservative-free formulation in neonates and infants. ()8.4 Pediatric UseThere 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 (2.5)].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 ToxicityUse 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.
• Geriatric Use: A higher incidence of bleeding reported in patients, particularly women, over 60 years of age. ()8.5 Geriatric UseThere 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 (5.2)]. 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 (12.3)].
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[see;]5.3 Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and ThrombosisHeparin-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 vivoplatelet 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.
• Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions)[see];6.1 Postmarketing ExperienceThe 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 [see Warnings and Precautions (5.2)].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.• Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term heparin therapy.• Retroperitoneal hemorrhage
• HIT and HITT, including delayed onset cases [see Warnings and Precautions (5.3)].• 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 [see Warnings and Precautions (5.3)].• Hypersensitivity–Generalized hypersensitivity reactions have been reported, with chills, fever and urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occurring less frequently. Itching and burning, especially on the plantar side of the feet, may occur. [see Warnings and Precautions (5.8)].• Elevations of aminotransferases – Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin.• Miscellaneous-Osteoporosis following long-term administration of high doses of heparin, cutaneous necrosis after systemic administration, suppression of aldosterone synthesis, delayed transient alopecia, priapism, and rebound hyperlipemia on discontinuation of heparin sodium have also been reported.• Metabolism and Nutrition Disorders – Hyperkalemia.
• In whom suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin);• An uncontrolled active bleeding state [see], except when this is due to disseminated intravascular coagulation.5.2 HemorrhageAvoid 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 (6.1)]. A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age[see Clinical Pharmacology (12.3)]. 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.