HEPARIN SODIUM injection
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Patient Information ⮝

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[see Warnings and Precautions (5.2)].

Prior to Surgery

Advise patients to inform physicians and dentists that they are receiving heparin before any surgery is scheduled[see Warnings and Precautions (5.2)].

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[see Warnings and Precautions (5.3)].

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[see Warnings and Precautions (5.8), Adverse Reactions (6.1)].

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[see Drug Interactions (7.1)].

Revised: January 2019

Distributed by

Sandoz Inc., Princeton, NJ 08540

Manufactured For: ⮝

Mylan Institutional LLC

Rockford, IL 61103 U.S.A.

Manufactured By: ⮝

Mylan Laboratories Limited

Bangalore, India

SEPTEMBER 2019

1. Heparin Sodium Injection, Usp
2. 3 Dosage Forms And Strengths
3. 4 Contraindications
4. 6 Adverse Reactions
5. 7 Drug Interactions
6. 8 Use In Specific Populations
7. 10 Overdosage
8. 11 Description
9. 12 Clinical Pharmacology
10. 13 Nonclinical Toxicology
11. 16 How Supplied/storage And Handling
12. Package/label Display Panel
13. Highlights Of Prescribing Information
14. Indications And Usage
15. Dosage And Administration
16. Dosage Forms And Strengths
17. Contraindications
18. Warnings And Precautions
19. Adverse Reactions
20. Drug Interactions
21. Use In Specific Populations
22. 1 Indications And Usage
23. 2 Dosage And Administration
24. 3 Dosage Forms And Strengths
25. 4 Contraindications
26. 5 Warnings And Precautions
27. 6 Adverse Reactions
28. 7 Drug Interactions
29. 8 Use In Specific Populations
30. 10 Overdosage
31. 11 Description
32. 12 Clinical Pharmacology
33. 13 Nonclinical Toxicology
34. 16 How Supplied/storage And Handling
35. Package/label Principal Display Panel
36. Description
37. Clinical Pharmacology
38. Warnings
39. Precautions
40. Overdosage
41. How Supplied
42. References
43. Directions For Useheparin Sodium Injection, Usp
44. Principal Display Panel
45. Heparin Sodium Injection, Usp
46. Description
47. Clinical Pharmacology
48. Indications And Usage
49. Contraindications
50. Warnings
51. Precautions
52. Adverse Reactions
53. Overdosage
54. Dosage And Administration
55. How Supplied
56. References
57. Storage Conditions
58. Principal Display Panel Heparin Sodium Injection, Usp 2000 Usp Units Vial Label
59. Principal Display Panel Heparin Sodium Injection, Usp 2000 Usp Units Carton
60. Recent Major Changes
61. Principal Display Panel - 10,000 Usp Units/10 Ml Multidose Vial Label
62. Principal Display Panel - 10,000 Usp Units/10 Ml Multidose Vial Carton
63. Principal Display Panel - 50,000 Usp Units/10 Ml Multidose Vial Label
64. Principal Display Panel - 50,000 Usp Units/10 Ml Multidose Vial Carton
65. Principal Display Panel - 1 Ml Multidose Vial Label
66. Principal Display Panel - 1 Ml Multidose Vial Carton
67. Principal Display Panel - 2 Ml Single Dose Vial Label
68. Principal Display Panel - 2 Ml Single Dose Vial Carton
69. Principal Display Panel - 30 Ml Multidose Vial Label
70. Principal Display Panel - 30 Ml Vial Carton
71. 1 Indications & Usage
72. 2 Dosage & Administration
73. 3 Dosage Forms & Strengths
74. Package Label.principal Display Panel
75. 1 Indications And Usage
76. 2 Dosage And Administration
77. 5 Warnings And Precautions
78. 7 Drug Interactions
79. Package/label Principal Display Panel
80. 10,000 Usp Units Per 10 Ml Carton
81. 5,000 Usp Units Per Ml Carton
82. 10,000 Usp Units Per Ml Carton

Heparin Sodium Injection, Usp  ⮝

Derived from Porcine Intestinal Mucosa
Available as: Preservative-free or Contains Benzyl Alcohol

SAGENT
Rx only

3 Dosage Forms And Strengths ⮝

Heparin Sodium Injection, USP is available as:

Injection: 1,000 USP units/mL preserved with benzyl alcohol clear solution in 1 mL single-dose and 30 mL multiple-dose vials

Injection: 5,000 USP units/mL preserved with benzyl alcohol clear solution in 1 mL single-dose and 10 mL multiple-dose vials

Injection: 10,000 USP units/mL preserved with benzyl alcohol clear solution in 1 mL single-dose vials

4 Contraindications ⮝

The use of heparin sodium is contraindicated in patients with the following conditions:

History of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis [see Warnings and Precautions (5.3)]
Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse Reactions (6.1)]
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 Warnings and Precautions (5.4)], except when this is due to disseminated intravascular coagulation

6 Adverse Reactions ⮝

The following clinically significant adverse reactions are described elsewhere in the labeling:

Hemorrhage [see Warnings and Precautions (5.2)]
Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis [see Warnings and Precautions (5.3)]
Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative [see Warnings and Precautions (5.4)]
Thrombocytopenia [see Warnings and Precautions (5.5)]
Heparin Resistance [see Warnings and Precautions (5.7)]
Hypersensitivity [see Warnings and Precautions (5.8)]

6.1 Postmarketing Experience

The following adverse reactions have been identified during post approval use of heparin sodium. 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 [see Drug
Interactions (7.4)].
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.

7 Drug Interactions ⮝

Oral Anticoagulants
Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn, if a valid prothrombin time is to be obtained.

Platelet Inhibitors
Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine 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.

Other Interactions
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.

7.1 Oral Anticoagulants

Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn, if a valid prothrombin time is to be obtained.

7.2 Platelet Inhibitors

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

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

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 (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 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.

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 (8.4)].

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 (2.4)].

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 (5.1)].

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.

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 (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)].

10 Overdosage ⮝

Bleeding is the chief sign of heparin overdosage.

Neutralization of Heparin Effect

When clinical circumstances (bleeding) require reversal of the heparin effect, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium. No more than 50 mg should be administered, very slowly, in any 10-minute period. Each mg of protamine sulfate neutralizes approximately 100 USP heparin units. The amount of protamine required decreases over time as heparin is metabolized. Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about 1/2 hour after intravenous injection.

Because fatal reactions often resembling anaphylaxis have been reported with protamine, it should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available.

For additional information consult the labeling of Protamine Sulfate Injection.

11 Description ⮝

Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans, having anticoagulant properties. Although others may be present, the main sugars occurring in heparin are: (1) -L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino- -D-glucose 6-sulfate, (3) -D-glucuronic acid, (4) 2-acetamido-2-deoxy- -D-glucose and (5) -L-iduronic acid. These sugars are present in decreasing amounts, usually in the order (2)> (1)> (4)> (3)> (5), and are joined by glycosidic linkages, forming polymers of varying sizes. Heparin is strongly acidic because of its content of covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acidic protons of the sulfate units are partially replaced by sodium ions.
Structural formula of Heparin Sodium (representative sub-units):

Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity. It is to be administered by intravenous or deep subcutaneous route. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram.

Heparin Sodium Injection, USP is available in the following concentration per mL:

Heparin Sodium Sodium Chloride Benzyl Alcohol

5000 USP units 7 mg 0.01 mL

pH 5.0-7.5; sodium hydroxide and/or hydrochloric acid added, if needed, for pH adjustment.

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

Heparin interacts with the naturally occurring plasma protein, Antithrombin III, to induce a conformational change, which markedly enhances the serine protease activity of Antithrombin III, thereby inhibiting the activated coagulation factors involved in the clotting sequence, particularly Xa and IIa. Small amounts of heparin inhibit Factor Xa, and larger amounts inhibit thrombin (Factor IIa). Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.

12.2 Pharmacodynamics

Various times (activated clotting time, activated partial thromboplastin time, prothrombin time, whole blood clotting time) are prolonged by full therapeutic doses of heparin; in most cases, they are not measurably affected by low doses of heparin. The bleeding time is usually unaffected by heparin.

12.3 Pharmacokinetics

Absorption

Heparin is not absorbed through the gastrointestinal tract and therefore administered via parenteral route. Peak plasma concentration and the onset of action are achieved immediately after intravenous administration.

Distribution

Heparin is highly bound to antithrombin, fibrinogens, globulins, serum proteases and lipoproteins. The volume of distribution is 0.07 L/kg.

Elimination

Metabolism

Heparin does not undergo enzymatic degradation.

Excretion

Heparin is mainly cleared from the circulation by liver and reticuloendothelial cells mediated uptake into extravascular space. Heparin undergoes biphasic clearance, a) rapid saturable clearance (zero order process due to binding to proteins, endothelial cells and macrophage) and b) slower first order elimination. The plasma half-life is dose-dependent and it ranges from 0.5 to 2 h.

Specific Populations

Geriatric patients

Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years of age [see Use in Specific Populations (8.5)].

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate carcinogenic potential of heparin. Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment of fertility.

16 How Supplied/storage And Handling ⮝

Heparin Sodium Injection, USP preserved with benzyl alcohol is available as follows:

NDC	Concentration/mL	Vial Fill Volume	Vial Type	Package Factor
68083-136-25	5,000 USP units per mL	1 mL	1 mL Vial	25 vials per carton

Sterile, Nonpyrogenic.
The container closure is not made with natural rubber latex.

Storage Conditions
Store at 20 to 25 C (68 to 77 F). [See USP Controlled Room Temperature.]

Package/label Display Panel  ⮝

Heparin Sodium Injection, USP

5,000 USP units/mL

5 x 1 mL Vials

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:55154-5130(NDC:0641-0400) Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 5000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) 7 mg in 1 mL BENZYL ALCOHOL (UNII: LKG8494WBH) 0.01 mL in 1 mL

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:55154-5130-5 5 in 1 BAG 03/22/1972 1 1 mL in 1 VIAL; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA017037 03/22/1972

Labeler - Cardinal Health (603638201)

Revised: 6/2019 Document Id: 62cfd1bb-894f-4429-b362-1e40981dccc6 34391-3 Set id: 62cfd1bb-894f-4429-b362-1e40981dccc6 Version: 1 Effective Time: 20190604 Cardinal Health

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use HEPARIN SODIUM INJECTION safely and effectively. See full prescribing information for HEPARIN SODIUM INJECTION.
HEPARIN SODIUM injection, for intravenous or subcutaneous use
Initial U.S. Approval: 1939

Indications And Usage ⮝

Heparin Sodium Injection is an anticoagulant indicated for (1)

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

Use as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures

Dosage And Administration ⮝

Recommended Adult Dosages:

Therapeutic Anticoagulant Effect with Full-Dose Heparin (2.3)

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 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 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.

Dosage Forms And Strengths ⮝

Injection: Preserved with Benzyl Alcohol, single-dose vials (3)	Injection: Preserved with Benzyl Alcohol, multi-dose vials (3)
1,000 USP units/mL Vial: (3) 1,000 USP units per mL	1,000 USP units/mL Vial: (3) 10,000 USP units per 10 mL 30,000 USP units per 30 mL
5,000 USP units/mL Vial: (3) 5,000 USP units per mL	5,000 USP units/mL Vial: (3) 50,000 USP units per 10 mL
10,000 USP units/mL Vial: (3) 10,000 USP units per mL	10,000 USP units/mL Vial: (3) 40,000 USP units per 4 mL

Contraindications ⮝

Severe thrombocytopenia (4)

When suitable blood coagulation tests, e.g., the whole blood clotting time, partial thromboplastin time, etc., cannot be performed at appropriate intervals (4)

An uncontrolled active bleeding state, except when this is due to disseminated intravascular coagulation (4)

Warnings And Precautions ⮝

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

Hemorrhage: Fatal cases have occurred. Use caution in conditions with increased risk of hemorrhage (5.2)

HIT and HITTS: Monitor for signs and symptoms and discontinue if indicative of HIT and HITTS (5.3)

Benzyl Alcohol Toxicity: Do not use this product in neonates and infants. (5.4)

Monitoring: Blood coagulation tests guide therapy for full-dose heparin.

Monitor platelet count and hematocrit in all patients receiving heparin (5.5, 5.6)

Adverse Reactions ⮝

Most common adverse reactions are hemorrhage, thrombocytopenia, HIT and HITTS, injection site irritation, general hypersensitivity reactions, and elevations of aminotransferase levels. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions ⮝

Drugs that interfere with platelet aggregation: May induce bleeding (7.2)

Use In Specific Populations ⮝

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

Lactation: Advise females not to breastfeed. (8.2)

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

Geriatric Use: A higher incidence of bleeding reported in patients, particularly women, over 60 years of age. (8.5)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 9/2019

1 Indications And Usage ⮝

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.

2 Dosage And Administration ⮝

2.1 Preparation for Administration

Confirm the choice of the correct heparin sodium injection vial to ensure that the 1 mL vial is not confused with a catheter lock flush vial or other 1 mL vial of incorrect strength [see Warnings and Precautions (5.1)].Confirm the selection of the correct formulation and strength prior to administration of the drug.

To lessen this risk, the 1 mL vial includes a red cautionary label that extends above the main label. Read the cautionary statement and confirm that you have selected the correct medication and strength. Then locate the Tear Here point on the label, and remove this red cautionary label prior to removing the flip-off cap.

When heparin is added to an infusion solution for continuous intravenous administration, invert the container repeatedly to ensure adequate mixing and prevent pooling of the heparin in the solution.

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains a precipitate.

Administer heparin sodium injection by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. Do not administer heparin sodium injection by intramuscular injection because of the risk of hematoma at the injection site [see Adverse Reactions (6)].

2.2 Laboratory Monitoring for Efficacy and Safety

Adjust the dosage of heparin sodium injection according to the patient s coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. When initiating treatment with heparin sodium injection by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection.

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

2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin

The 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) 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 Every 12 hours	8,000 to 10,000 units of a concentrated solution 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 1000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion

2.4 Pediatric Use

Do not use this product in neonates and infants. Use preservative-free heparin sodium injection in neonates and infants [see Warnings and Precautions (5.4)].

There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients:

Initial Dose	75 to 100 units/kg (IV bolus over 10 minutes) Infants: 25 to 30 units/kg/hour; Infants < 2 months have the highest requirements (average 28 units/kg/hour)
Maintenance Dose	Children > 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage
Monitoring	Adjust heparin to maintain APTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70

2.5 Cardiovascular Surgery

Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes.

2.6 Low-Dose Prophylaxis of Postoperative Thromboembolism

The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25 to 26-gauge) needle to minimize tissue trauma.

2.7 Blood Transfusion

Add 450 to 600 USP units of heparin sodium per 100 mL of whole blood to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 to 8 mL are added per 100 mL of whole blood.

2.8 Converting to Warfarin

To ensure continuous anticoagulation when converting from heparin sodium injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions (7.1)].

2.9 Converting to Oral Anticoagulants other than Warfarin

For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered.

2.10 Extracorporeal Dialysis

Follow equipment manufacturers operating directions carefully. A dose of 25 to 30 units/kg followed by an infusion rate of 1,500 to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers recommendations are not available.

3 Dosage Forms And Strengths  ⮝

Heparin Sodium Injection, USP is available as:

Injection: 1,000 USP units per mL preserved with benzyl alcohol clear solution in 1 mL single-dose, 10 mL and 30 mL multi-dose vials

Injection: 5,000 USP units per mL preserved with benzyl alcohol clear solution in 1 mL single-dose and 10 mL multi-dose vials

Injection: 10,000 USP units per mL preserved with benzyl alcohol clear solution in 1 mL single-dose and 4 mL multi-dose vials

4 Contraindications  ⮝

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 Warnings and Precautions (5.3)];

Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse Reactions (6.1)]

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 Warnings and Precautions (5.4)], except when this is due to disseminated intravascular coagulation.

5 Warnings And Precautions ⮝

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.

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 (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.

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/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

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 [see Use in Specific Populations (8.4)].

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/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions (5.3)].

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 (10)]. Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration [see Dosage and Administration (2.2)].

5.7 Heparin Resistance

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

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  ⮝

The following clinically significant adverse reactions are described elsewhere in the labeling:

Hemorrhage [see Warnings and Precautions (5.2)]

Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis [see Warnings and Precautions (5.3)]

Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative [see Warnings and Precautions (5.4)]

Thrombocytopenia [see Warnings and Precautions (5.5)]

Heparin Resistance [see Warnings and Precautions (5.7)]

Hypersensitivity [see Warnings and Precautions (5.8)]

6.1 Postmarketing Experience

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 [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 [see Drug Interactions (7)].

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.

7 Drug Interactions ⮝

7.1 Oral Anticoagulants

Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn, if a valid prothrombin time is to be obtained.

7.2 Platelet Inhibitors

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

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

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 [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 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.

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 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)].

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 (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.

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 (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)].

10 Overdosage  ⮝

Bleeding is the chief sign of heparin overdosage.

Neutralization of Heparin Effect

When clinical circumstances (bleeding) require reversal of the heparin effect, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium. No more than 50 mg should be administered, very slowly, in any 10-minute period. Each mg of protamine sulfate neutralizes approximately 100 USP heparin units. The amount of protamine required decreases over time as heparin is metabolized. Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about 1/2 hour after intravenous injection.

Because fatal reactions often resembling anaphylaxis have been reported with protamine, it should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available.

For additional information consult the labeling of protamine sulfate injection.

11 Description  ⮝

Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans, possessing anticoagulant properties. It is composed of polymers of alternating derivations of -D-glucosamido (N-sulfated O-sulfated O-sulfated or N-acetylated) and O-sulfated uronic acid ( -L-iduronic acid or -D-glucoronic acid).

Structure of heparin sodium, USP (representative subunits):

Heparin Sodium Injection, USP is a sterile solution of heparin sodium, USP derived from porcine intestinal mucosa, standardized for anticoagulant activity. It is to be administered by intravenous or deep subcutaneous routes. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram.

Heparin Sodium Injection, USP preserved with benzyl alcohol is available in the following concentrations/mL:

Heparin Sodium	Sodium Chloride	Benzyl Alcohol
1,000 USP units	8.6 mg	10.4 mg
5,000 USP units	7 mg	10.4 mg
10,000 USP units	5 mg	10.4 mg

pH 5.0 to 7.5; sodium hydroxide and/or hydrochloric acid added, if needed, for pH adjustment.

12 Clinical Pharmacology  ⮝

12.1 Mechanism of Action

Heparin interacts with the naturally occurring plasma protein, Antithrombin III, to induce a conformational change, which markedly enhances the serine protease activity of Antithrombin III, thereby inhibiting the activated coagulation factors involved in the clotting sequence, particularly Xa and IIa. Small amounts of heparin inhibit Factor Xa, and larger amounts inhibit thrombin (Factor IIa). Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.

12.2 Pharmacodynamics

Various times (activated clotting time, activated partial thromboplastin time, prothrombin time, whole blood clotting time) are prolonged by full therapeutic doses of heparin; in most cases, they are not measurably affected by low doses of heparin. The bleeding time is usually unaffected by heparin.

12.3 Pharmacokinetics

Absorption

Heparin is not absorbed through the gastrointestinal tract and therefore administered via parenteral route. Peak plasma concentration and the onset of action are achieved immediately after intravenous administration.

Distribution

Heparin is highly bound to antithrombin, fibrinogens, globulins, serum proteases and lipoproteins. The volume of distribution is 0.07 L/kg.

Elimination

Metabolism

Heparin does not undergo enzymatic degradation.

Excretion

Heparin is mainly cleared from the circulation by liver and reticuloendothelial cells mediated uptake into extravascular space. Heparin undergoes biphasic clearance, a) rapid saturable clearance (zero order process due to binding to proteins, endothelial cells and macrophage) and b) slower first order elimination. The plasma half-life is dose-dependent and it ranges from 0.5 to 2 h.

Specific Populations

Geriatric patients

Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years of age [see Use in Specific Populations (8.5)].

13 Nonclinical Toxicology  ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate carcinogenic potential of heparin. Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment of fertility.

16 How Supplied/storage And Handling  ⮝

Heparin Sodium Injection, USP preserved with benzyl alcohol is available in the following strengths and in single-dose vials as a package of 25 s carton:

DESCRIPTION	NDC
1,000 USP units per mL (1 mL-fill)
1 vial: 1,000 USP units per mL, single-dose*	67457-372-12
25 vials: 1,000 USP units per mL, single-dose*	67457-372-99
5,000 USP units per mL (1 mL-fill)
1 vial: 5,000 USP units per mL, single-dose*	67457-374-12
25 vials: 5,000 USP units per mL, single-dose*	67457-374-99
10,000 USP units per mL (1 mL-fill)
1 vial: 10,000 USP units per mL, single-dose*	67457-602-02
25 vials: 10,000 USP units per mL, single-dose*	67457-602-99

*Discard unused portion

Heparin Sodium Injection, USP preserved with benzyl alcohol is available in the following strengths and in multiple-dose vials as a package of 25 s carton:

DESCRIPTION	NDC
1,000 USP units per mL (10 mL-fill)
1 vial: 10,000 USP units per 10 mL, multi-dose	67457-385-10
25 vials: 10,000 USP units per 10 mL, multi-dose	67457-385-99
1,000 USP units per mL (30 mL-fill)
1 vial: 30,000 USP units per 30 mL, multi-dose	67457-384-31
25 vials: 30,000 USP units per 30 mL, multi-dose	67457-384-99
5,000 USP units per mL (10 mL-fill)
1 vial: 50,000 USP units per 10 mL, multi-dose	67457-383-10
25 vials: 50,000 USP units per 10 mL, multi-dose	67457-383-99
10,000 USP units per mL (4 mL-fill)
1 vial: 40,000 USP units per 4 mL, multi-dose	67457-603-05
25 vials: 40,000 USP units per 4 mL, multi-dose	67457-603-99

Store at 20 to 25 C (68 to 77 F). [See USP Controlled Room Temperature.]

Package/label Principal Display Panel ⮝

NDC 67457-603-99

HEPARIN Sodium Injection, USP

40,000 USP units per 4 mL (10,000 USP units per mL)

Rx only

For Intravenous or Subcutaneous Use

NOT for LOCK FLUSH

Mylan

(Derived from Porcine Intestinal Mucosa)

25 x 4 mL Multi-Dose Vials

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67457-372 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 1000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) 8.6 mg in 1 mL BENZYL ALCOHOL (UNII: LKG8494WBH) 10.4 mg in 1 mL SODIUM HYDROXIDE (UNII: 55X04QC32I) HYDROCHLORIC ACID (UNII: QTT17582CB) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:67457-372-99 25 in 1 CARTON 05/25/2018 1 NDC:67457-372-12 1 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA203851 05/25/2018

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67457-374 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 5000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) 7 mg in 1 mL BENZYL ALCOHOL (UNII: LKG8494WBH) 10.4 mg in 1 mL SODIUM HYDROXIDE (UNII: 55X04QC32I) HYDROCHLORIC ACID (UNII: QTT17582CB) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:67457-374-99 25 in 1 CARTON 03/16/2018 1 NDC:67457-374-12 1 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA203851 03/16/2018

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67457-602 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 10000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) 5 mg in 1 mL BENZYL ALCOHOL (UNII: LKG8494WBH) 10.4 mg in 1 mL SODIUM HYDROXIDE (UNII: 55X04QC32I) HYDROCHLORIC ACID (UNII: QTT17582CB) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:67457-602-99 25 in 1 CARTON 05/25/2018 1 NDC:67457-602-02 1 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA203851 05/25/2018

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67457-385 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 1000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) 8.6 mg in 1 mL BENZYL ALCOHOL (UNII: LKG8494WBH) 10.4 mg in 1 mL SODIUM HYDROXIDE (UNII: 55X04QC32I) HYDROCHLORIC ACID (UNII: QTT17582CB) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:67457-385-99 25 in 1 CARTON 03/16/2018 1 NDC:67457-385-10 10 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA203851 03/16/2018

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67457-384 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 1000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) 8.6 mg in 1 mL BENZYL ALCOHOL (UNII: LKG8494WBH) 10.4 mg in 1 mL SODIUM HYDROXIDE (UNII: 55X04QC32I) HYDROCHLORIC ACID (UNII: QTT17582CB) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:67457-384-99 25 in 1 CARTON 03/16/2018 1 NDC:67457-384-31 30 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA203851 03/16/2018

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67457-383 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 5000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) 7 mg in 1 mL BENZYL ALCOHOL (UNII: LKG8494WBH) 10.4 mg in 1 mL SODIUM HYDROXIDE (UNII: 55X04QC32I) HYDROCHLORIC ACID (UNII: QTT17582CB) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:67457-383-99 25 in 1 CARTON 06/14/2018 1 NDC:67457-383-10 10 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA203851 06/14/2018

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67457-603 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 10000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) 5 mg in 1 mL BENZYL ALCOHOL (UNII: LKG8494WBH) 10.4 mg in 1 mL SODIUM HYDROXIDE (UNII: 55X04QC32I) HYDROCHLORIC ACID (UNII: QTT17582CB) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:67457-603-99 25 in 1 CARTON 06/14/2018 1 NDC:67457-603-05 4 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA203851 06/14/2018

Labeler - Mylan Institutional LLC (790384502)

Revised: 9/2019 Document Id: 0a3bd3ef-b106-43a5-9ff6-8a1aa531b0b3 34391-3 Set id: 88114716-5759-4bc9-8a85-d28da12962cc Version: 6 Effective Time: 20190911 Mylan Institutional LLC

Description ⮝

Heparin is a heterogenous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans, having anticoagulant properties. Although others may be present, the main sugars occurring in heparin are: (1) -L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino- -D-glucose 6- sulfate, (3) -D-glucuronic acid, (4) 2-acetamido-2-deoxy- -D-glucose, and (5) -L-iduronic acid. These sugars are present in decreasing amounts, usually in the order (2)> (1)> (4)> (3)> (5), and are joined by glycosidic linkages, forming polymers of varying sizes. Heparin is strongly acidic because of its content of covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acidic protons of the sulfate units are partially replaced by sodium ions.

Structural formula of Heparin Sodium (representative subunits):

Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for use as an anticoagulant. It is to be administered by intravenous or deep subcutaneous routes. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram.

Each mL contains 10,000 USP units heparin sodium, in water for injection, and hydrochloric acid or sodium hydroxide for pH adjustment. The pH range is 5.0 to 7.5.

Clinical Pharmacology ⮝

Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo. Heparin acts at multiple sites in the normal coagulation system. Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor.

Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full therapeutic doses of heparin; in most cases, it is not measurably affected by low doses of heparin.
Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years of age.

Peak plasma levels of heparin are achieved 2 to 4 hours following subcutaneous administration, although there are considerable individual variations. Loglinear plots of heparin plasma concentrations with time, for a wide range of dose levels, are linear, which suggests the absence of zero order processes. Liver and reticulo-endothelial system are the sites of biotransformation. The biphasic elimination curve, a rapidly declining alpha phase (t 1/2 = 10 min.), and after the age of 40 a slower beta phase, indicates uptake in organs. The absence of a relationship between anticoagulant half-life and concentration half-life may reflect factors such as protein binding of heparin.

Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.

Warnings ⮝

Heparin is not intended for intramuscular use.

Fatal Medication Errors

Do not use Heparin Sodium Injection as a catheter lock flush product. Heparin Sodium Injection is supplied in sterile syringes that contain a highly concentrated solution of 5,000 units in 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 vials and cartridges to confirm the correct product choice prior to administration of the drug.

Hypersensitivity

Patients with documented hypersensitivity to heparin should be given the drug only in clearly life- threatening situations (See ADVERSE REACTIONS, Hypersensitivity).

Hemorrhage

Hemorrhage can occur at virtually any site in patients receiving heparin. An unexplained fall in hematocrit, fall in blood pressure or any other unexplained symptom should lead to serious consideration of a hemorrhagic event.

Heparin sodium should be used with extreme caution in disease states in which there is increased danger of hemorrhage. Some of the conditions in which increased danger of hemorrhage exists are:

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.

Gastrointestinal Ulcerative lesions and continuous tube drainage of the stomach or small intestine.

Other Menstruation, liver disease with impaired hemostasis.

Coagulation Testing

When heparin sodium is administered in therapeutic amounts, its dosage should be regulated by frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, heparin sodium should be promptly discontinued (see OVERDOSAGE).

Thrombocytopenia

Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence up to 30%. Platelet counts should be obtained at baseline and periodically during heparin administration. Mild thrombocytopenia (count greater than 100,000/mm3) may remain stable or reverse even if heparin is continued. However, thrombocytopenia of any degree should be monitored closely. If the count falls below 100,000/mm3 or if recurrent thrombosis develops (see Heparin-induced Thrombocytopenia (HIT) With or Without Thrombosis)), the heparin product should be discontinued and, if necessary, an alternative anticoagulant administered.

Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis)

HIT is a serious immune-mediated reaction resulting from irreversible aggregation of platelets. HIT may progress to the development of venous and arterial thromboses, a condition referred to as HIT with thrombosis. Thrombotic events may also be the initial presentation for HIT. 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 fatal outcomes.

Once HIT (with or without thrombosis) is diagnosed or strongly suspected, all heparin sodium sources (including heparin flushes) should be discontinued and an alternative anticoagulant used. Future use of heparin sodium, especially within 3 to 6 months following the diagnosis of HIT (with or without thrombosis), and while patients test positive for HIT antibodies, should be avoided.

Immune-mediated HIT is diagnosed based on clinical findings supplemented by laboratory tests confirming the presence of antibodies to heparin sodium, or platelet activation induced by heparin sodium. A drop in platelet count greater than 50% from baseline is considered indicative of HIT. Platelet counts begin to fall 5 to 10 days after exposure to heparin sodium in heparin sodium-na ve individuals, and reach a threshold by days 7 to 14. In contrast, rapid onset HIT can occur very quickly (within 24 hours following heparin sodium initiation), especially in patients with a recent exposure to heparin sodium (i.e. previous 3 months). Thrombosis development shortly after documenting thrombocytopenia is a characteristic finding in almost half of all patients with HIT.

Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, the heparin product should be promptly discontinued and alternative anticoagulants considered if patients require continued anticoagulation.

Delayed Onset of HIT (With or Without Thrombosis)

Heparin-induced Thrombocytopenia (with or without thrombosis) 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 (with or without thrombosis).

Use in Neonates

Carefully examine all Heparin Sodium Injection vials and syringes 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, Fatal Medication Errors.)

Precautions ⮝

General

Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) and Delayed Onset of HIT (With or Without Thrombosis)
See WARNINGS.

Heparin Resistance

Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients.

Increased Risk to Older Patients, Especially Women

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

Laboratory Tests

Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration (see DOSAGE AND ADMINISTRATION).

Drug Interactions

Oral Anticoagulants
Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn, if a valid prothrombin time is to be obtained.

Platelet Inhibitors
Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine 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.

Other Interactions
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.

Drug/Laboratory Test Interactions

Hyperaminotransferasemia
Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease and pulmonary emboli, increases that might be caused by drugs (like heparin) should be interpreted with caution.

Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been performed to evaluate carcinogenic potential of heparin. Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment of fertility.

Pregnancy

There are no adequate and well-controlled studies on heparin use in pregnant women. In published reports, heparin exposure during pregnancy did not show evidence of an increased risk of adverse maternal or fetal outcomes in humans. Heparin sodium does not cross the placenta based on human and animal studies. Administration of heparin to pregnant animals at doses higher than the maximum human daily dose based on body weight resulted in increased resorptions. Use heparin sodium during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 PRECAUTIONS, Pediatric Use).

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.

Nursing Mothers

If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during lactation. 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. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. Exercise caution when administering Heparin Sodium Injection, USP to a nursing mother (see PRECAUTIONS, Pediatric Use).

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, Pediatric Use).

Carefully examine all Heparin Sodium Injection syringes 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, USP vials have been confused with catheter lock flush vials (see WARNINGS, Fatal Medication Errors).

Geriatric Use

A higher incidence of bleeding has been reported in patients over 60 years of age, especially women (see PRECAUTIONS, General). Clinical studies indicate that lower doses of heparin may be indicated in these patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Overdosage ⮝

Symptoms

Bleeding is the chief sign of heparin overdosage. Nosebleeds, blood in urine or tarry stools may be noted as the first sign of bleeding. Easy bruising or petechial formations may precede frank bleeding.

Treatment Neutralization of heparin effect

When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium. No more than 50 mg should be administered, very slowly, in any 10-minute period. Each mg of protamine sulfate neutralizes approximately 100 USP heparin units. The amount of protamine required decreases over time as heparin is metabolized. Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about 1/2 hour after intravenous injection.
Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions often resembling anaphylaxis have been reported, the drug should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available.

For additional information consult the labeling of Protamine Sulfate Injection, USP products.

How Supplied ⮝

(derived from porcine intestinal mucosa)

Heparin Sodium Injection, USP, is available in Prefilled Syringe Needle Units. Each prefilled syringe contains the following concentration of heparin sodium:
5,000 USP Units per 0.5 mL (10, 000 USP Units per mL)
NDC 0264-5705-10 REF PFS5705 (27 gauge x inch needle), in packages of 10 prefilled syringes.

Store at 20 -25 C (68 -77 F) [See USP Controlled Room Temperature].
Do not freeze.
Do not use if solution is discolored or contains precipitate.

References ⮝

1. Tahata T, Shigehito M, Kusuhara K, Ueda Y, et al. Delayed-Onset of Heparin Induced Thrombocytopenia A Case Report J Jpn Assn Torca Surg. 1992;40(3):110-111.
2. Warkentin T, Kelton J. Delayed-Onset Heparin-Induced Thrombocytopenia and Thrombosis. Annals of Internal Medicine. 2001;135:502-506.
3. Rice L, Attisha W, Drexler A, Francis J. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of Internal Medicine, 2002;136:210-215.
4. Dieck, J., C. Rizo-Patron, et al. (1990). A New Manifestation and Treatment Alternative for Heparin-Induced Thrombosis. Chest. 1990; 98:1524-26.
5. Smythe M, Stephens J, Mattson. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of Emergency Medicine, 2005;45(4):417-419.
6. Divgi A. (Reprint), Thumma S., Hari P., Friedman K., Delayed Onset Heparin-Induced Thrombocytopenia (HIT) Presenting After Undocumented Drug Exposure as Post-Angiography Pulmonary Embolism. Blood. 2003;102(11):127b.

Directions For Useheparin Sodium Injection, Usp  ⮝

Read this Directions for Use before you inject Heparin Sodium Injection and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment.

Important information:

• Do not inject yourself or someone else until you have been shown how to inject Heparin Sodium Injection using the prefilled syringe.
• Your healthcare provider or nurse will show you how to inject Heparin Sodium Injection properly using the prefilled syringe with needle shield; and how to cover the needle after injection. The needle shield will help prevent needle stick injuries to anyone who handles the prefilled syringe.
• Keep the Heparin Sodium Injection prefilled syringe in the blister packaging until you are ready to use it.
• Heparin Sodium Injection prefilled syringes are for single, one-time use only. Do not re-use a Heparin Sodium Injection prefilled syringe.
• The prefilled syringe may have air bubbles. To avoid loss of medicine when using the prefilled syringe, do not push out (expel) any air bubbles from the prefilled syringe before giving the injection.

Heparin Sodium Injection prefilled syringe parts:

Directions for Subcutaneous Injection of Heparin Sodium Injection

Step 1: Gather supplies needed for your injection Included in the Heparin Sodium Injection box: A Heparin Sodium Injection prefilled syringe. Make sure you have the right medicine at the right dose. Not included in the box: 1 alcohol wipe sharps disposal container 1 piece of gauze 1 adhesive bandage (optional)
Step 2: Wash your hands well with soap and water Dry your hands.
Step 3: Remove the prefilled syringe from the blister packaging Do not remove by pulling on the plunger as this may damage the syringe. Place the syringe on a flat surface.
Step 4: Choose and clean your injection site. Sit or lie down in a comfortable position. Choose an injection site on your stomach area (abdomen) to give your injection. Choose a different injection site each time you give yourself an injection, alternating between the left and right side of your stomach area. Clean the injection site with the alcohol wipe. Let it dry before injecting.
Step 5: Prepare the prefilled syringe. Pick up the prefilled syringe. Bend the needle shield towards the body of the prefilled syringe by approximately a 90-degree angle. Hold the body of the prefilled syringe firmly in one hand. Remove the protective needle cap by pulling it straight off the syringe. Throw away the needle cap in the sharps disposal container. Do not touch the needle or let it come in contact with any surface before you give your injection.
Step 6: Give your injection. Gently pinch the skin that has been cleaned to make a fold. Hold the fold between the thumb and the forefinger of one hand. Using the other hand, hold the prefilled syringe firmly and insert the full length of the needle at a 90-degree angle into the skin fold. The skin fold should be held during the entire injection. Inject all the medicine in the prefilled syringe by pressing down on the plunger as far as it will go. Inject the product slowly. When all the medicine has been injected, remove the needle from the skin fold. Press the injection site with a piece of gauze for a few seconds. To minimize bruising, do not rub the injection site after you have given your injection. There may be a small amount of blood at the injection site. You may cover the injection site with a small adhesive bandage if needed
Step 7: Secure needle in needle shield. Do not try to secure the needle in the needle shield with your fingers. Secure the needle in the groove of the safety shield by pressing it against a stable surface.
Step 8: Dispose of used Heparin Sodium Injection prefilled syringes. Put the used prefilled syringe in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the prefilled syringe in the household trash. If you do not have a FDA- cleared sharps disposal container, you may use a household container that is: Made of heavy-duty plastic. Can be closed with a tight-fitting, puncture- resistant lid, without sharps being able to come out. Upright and stable during use. Leak-resistant, and Properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow you community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state you live in, go to the FDA s website at: http://www.fda.gov/safesharpsdisposal. Do not reuse the prefilled syringe. Do not throw away (dispose of) your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Important: Always keep the sharps disposal container out of the reach of children.

How should I store Heparin Sodium Injection prefilled syringes?

• Store at 68 F to 77 F (20 C to 25 C).
• Do not freeze

Keep Heparin Sodium Injection prefilled syringes and all medicines out of the reach of children.

Intravenous Injection of Heparin Sodium Technique
For intravenous injection, the multiple-dose vial should be used. Heparin Sodium Injection USP should be administered through an intravenous line. Heparin Sodium Injection USP should not be mixed or co-administered with other medications. To avoid the possible mixture of Heparin Sodium Injection USP with other drugs, the intravenous access chosen should be flushed with a sufficient amount of saline or dextrose solution prior to and following the intravenous bolus administration of Heparin Sodium Injection USP to clear the port of drug.

Heparin Sodium Injection USP may be safely administered with normal saline solution (0.9%). (See DOSAGE AND ADMINISTRATION).

This Directions for Use has been approved by the U.S. Food and Drug Administration.

To report SUSPECTED ADVERSE REACTIONS, contact B. Braun Medical Inc. at 1-800-854-6851 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Not made with natural rubber latex. Rx Only

Manufactured by:
Sterinova Inc.
St. Hyacinthe, QC, Canada J2S 0J9

Distributed by:
B. Braun Medical Inc.
Bethlehem, PA 18018-3524 USA
1-800-227-2862

Prepared in Canada. API from Spain.

LD-589-1

Issued: July/2018

Principal Display Panel ⮝

Blister Label

Pack Label

Syringe Label

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0264-5705 Route of Administration SUBCUTANEOUS, INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 5000 [USP'U] in 0.5 mL

Inactive Ingredients Ingredient Name Strength WATER (UNII: 059QF0KO0R) HYDROCHLORIC ACID (UNII: QTT17582CB) SODIUM HYDROXIDE (UNII: 55X04QC32I)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0264-5705-10 10 in 1 CARTON 04/08/2019 1 NDC:0264-5705-05 1 in 1 BLISTER PACK 1 0.5 mL in 1 SYRINGE; Type 2: Prefilled Drug Delivery Device/System (syringe, patch, etc.)

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA208827 04/08/2019

Labeler - B. Braun Medical Inc. (002397347)

Revised: 9/2019 Document Id: 319993d3-19d0-418f-b48c-6de7c266bfca 34391-3 Set id: 83c0c7c4-96ff-4e2d-85be-628bfd5ed771 Version: 3 Effective Time: 20190906 B. Braun Medical Inc.

Heparin Sodium Injection, Usp  ⮝

Derived from Porcine Intestinal Mucosa
Available as: Preservative-free or Contains Benzyl Alcohol

SAGENT
Rx only

Description  ⮝

Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans, having anticoagulant properties. Although others may be present, the main sugars occurring in heparin are: (1) -L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino- -D-glucose 6-sulfate, (3) -D-glucuronic acid, (4) 2-acetamido-2-deoxy- -D-glucose and (5) -L-iduronic acid. These sugars are present in decreasing amounts, usually in the order (2)> (1)> (4)> (3)> (5), and are joined by glycosidic linkages, forming polymers of varying sizes. Heparin is strongly acidic because of its content of covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acidic protons of the sulfate units are partially replaced by sodium ions.

Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from porcine intestinal mucosa, standardized for anticoagulant activity, in water for injection. It is to be administered by intravenous or deep subcutaneous route. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram.

Structure of Heparin Sodium (representative subunits):

Heparin Sodium Injection, USP (porcine), preservative-free, is available as follows:

Each mL of the 1,000 units per mL preparation contains: 1,000 USP Heparin units (porcine); 9 mg sodium chloride; Water for Injection q.s. Made isotonic with sodium chloride. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0-7.5).

Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol, is available as follows:

Each mL of the 20,000 units per mL preparation contains: 20,000 USP Heparin units (porcine); 0.01 mL benzyl alcohol (as a preservative); Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0-7.5).

Clinical Pharmacology  ⮝

Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo. Heparin acts at multiple sites in the normal coagulation system. Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor.

Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full therapeutic doses of heparin; in most cases, it is not measurably affected by low doses of heparin.

Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years of age.

Peak plasma levels of heparin are achieved two to four hours following subcutaneous administration, although there are considerable individual variations. Loglinear plots of heparin plasma concentrations with time, for a wide range of dose levels, are linear, which suggests the absence of zero order processes. Liver and the reticuloendothelial system are the sites of biotransformation. The biphasic elimination curve, a rapidly declining alpha phase (t =10 minutes) and after the age of 40 a slower beta phase, indicates uptake in organs. The absence of a relationship between anticoagulant half-life and concentration half-life may reflect factors such as protein binding of heparin.

Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.

Indications And Usage  ⮝

Heparin Sodium Injection is indicated for:

Anticoagulant therapy in prophylaxis and treatment of venous thrombosis and its extension;

Low-dose regimen for 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 (see DOSAGE AND ADMINISTRATION);

Prophylaxis and treatment of pulmonary embolism;

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.

Heparin may also be employed as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures.

Contraindications  ⮝

Heparin sodium should NOT be used in patients with the following conditions:

Severe thrombocytopenia;

When 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 uncontrollable active bleeding state (see WARNINGS), except when this is due to disseminated intravascular coagulation.

Warnings  ⮝

Heparin is not intended for intramuscular use.

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.

Benzyl Alcohol Toxicity

Use preservative-free Heparin Sodium Injection in neonates and infants. The preservative benzyl alcohol has been associated with serious adverse events and death in pediatric patients. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants may be more likely to develop toxicity (see PRECAUTIONS, Pediatric Use).

Hypersensitivity

Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations (see ADVERSE REACTIONS, Hypersensitivity).

Hemorrhage

Hemorrhage can occur at virtually any site in patients receiving heparin. An unexplained fall in hematocrit, fall in blood pressure or any other unexplained symptom should lead to serious consideration of a hemorrhagic event.

Heparin sodium should be used with extreme caution in disease states in which there is increased danger of hemorrhage. Some of the conditions in which increased danger of hemorrhage exists are:

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.

Gastrointestinal - Ulcerative lesions and continuous tube drainage of the stomach or small intestine.

Other - Menstruation, liver disease with impaired hemostasis.

Coagulation Testing

When heparin sodium is administered in therapeutic amounts, its dosage should be regulated by frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, heparin sodium should be promptly discontinued (see OVERDOSAGE).

Thrombocytopenia

Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of up to 30%. Platelet counts should be obtained at baseline and periodically during heparin administration. Mild thrombocytopenia (count greater than 100,000/mm3) may remain stable or reverse even if heparin is continued. However, thrombocytopenia of any degree should be monitored closely. If the count falls below 100,000/mm3 or if recurrent thrombosis develops (see Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis), the heparin product should be discontinued, and, if necessary, an alternative anticoagulant administered.

Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT)

Heparin-induced Thrombocytopenia (HIT) is a serious antibody-mediated reaction resulting from irreversible aggregation of platelets. HIT may progress to the development of venous and arterial thromboses, a condition referred to as Heparin-induced Thrombocytopenia and 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. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, the heparin product should be promptly discontinued and alternative anticoagulants considered, if patients require continued anticoagulation.

Delayed Onset of HIT and HITT

Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and Thrombosis can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT and HITT.

Precautions  ⮝

General

Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT)

See WARNINGS.

Heparin Resistance - Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients.

Increased Risk to Older Patients, Especially Women - A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age.

Laboratory Tests

Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration (see DOSAGE AND ADMINISTRATION).

Drug Interactions

Oral Anticoagulants - Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least five hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn, if a valid prothrombin time is to be obtained.

Platelet Inhibitors - Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine 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.

Other Interactions - 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.

Drug/Laboratory Tests Interactions

Hyperaminotransferasemia - Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin. Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease and pulmonary emboli, increases that might be caused by drugs (like heparin) should be interpreted with caution.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate carcinogenic potential of heparin. Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment of fertility.

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies on heparin use in pregnant women. In published reports, heparin exposure during pregnancy did not show evidence of an increased risk of adverse maternal or fetal outcomes in humans. Heparin sodium does not cross the placenta, based on human and animal studies. Administration of heparin to pregnant animals at doses higher than the maximum human daily dose based on body weight resulted in increased resorptions. Use heparin sodium during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 PRECAUTIONS, Pediatric Use).

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.

Nursing Mothers

If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during lactation. 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. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. Exercise caution when administering Heparin Sodium Injection to a nursing mother (see PRECAUTIONS, Pediatric Use).

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, Pediatric Use).

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, Fatal Medication Errors).

Benzyl Alcohol Toxicity

Use preservative-free Heparin Sodium Injection in neonates and infants. The preservative benzyl alcohol has been associated with serious adverse events and death in pediatric patients. The "gasping syndrome" (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.

Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the "gasping syndrome", the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

Geriatric Use

A higher incidence of bleeding has been reported in patients over 60 years of age, especially women (see PRECAUTIONS, General). Clinical studies indicate that lower doses of heparin may be indicated in these patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Adverse Reactions  ⮝

Hemorrhage

Hemorrhage is the chief complication that may result from heparin therapy (see WARNINGS). An overly prolonged clotting time or minor bleeding during therapy can usually be controlled by withdrawing the drug (see OVERDOSAGE). It should be appreciated that 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:

1. Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred during anticoagulant therapy. Therefore, such treatment should be discontinued in patients who develop signs and symptoms of acute adrenal hemorrhage and insufficiency. Initiation of corrective therapy should not depend on laboratory confirmation of the diagnosis, since any delay in an acute situation may result in the patient's death.
2. Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term anticoagulant therapy. This complication, if unrecognized, may be fatal.
3. Retroperitoneal hemorrhage.

Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) and Delayed Onset of HIT and HITT

See WARNINGS.

Local Irritation

Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous (intrafat) injection of heparin sodium. These complications are much more common after intramuscular use, and such use is not recommended.

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 more rarely. Itching and burning, especially on the plantar side of the feet, may occur (see WARNINGS and PRECAUTIONS).

Certain episodes of painful, ischemic and cyanosed limbs have in the past been attributed to allergic vasospastic reactions. Whether these are in fact identical to the thrombocytopenia-associated complications, remains to be determined.

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.

Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy subjects) who have received heparin.

Overdosage  ⮝

Symptoms

Bleeding is the chief sign of heparin overdosage. Nosebleeds, blood in urine or tarry stools may be noted as the first sign of bleeding. Easy bruising or petechial formations may precede frank bleeding.

Treatment

Neutralization of Heparin Effect - When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium. No more than 50 mg should be administered, very slowly, in any 10 minute period. Each mg of protamine sulfate neutralizes approximately 100 USP heparin units. The amount of protamine required decreases over time as heparin is metabolized. Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about hour after intravenous injection.

Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions often resembling anaphylaxis have been reported, the drug should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available.

For additional information consult the labeling of Protamine Sulfate Injection, USP products.

Dosage And Administration  ⮝

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Confirm the choice of the correct Heparin Sodium Injection vial prior to administration of the drug to a patient (see WARNINGS, Fatal Medication Errors). The 1 mL vial must not be confused with a catheter lock flush vial or other 1 mL vial of inappropriate strength. Confirm that you have selected the correct medication and strength prior to administration of the drug.

When heparin is added to an infusion solution for continuous intravenous administration, the container should be inverted at least six times to ensure adequate mixing and prevent pooling of the heparin in the solution.

Heparin sodium is not effective by oral administration and should be given by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. The intramuscular route of administration should be avoided because of the frequent occurrence of hematoma at the injection site.

The dosage of heparin sodium should be adjusted according to the patient's coagulation test results. When heparin is given by continuous intravenous infusion, the coagulation time should be determined approximately every four hours in the early stages of treatment. When the drug is administered intermittently by intravenous injection, coagulation tests should be performed before each injection during the early stages of treatment and at appropriate intervals thereafter. Dosage is considered adequate when the activated partial thromboplastin time (APTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn four to six hours after the injection.

Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration.

Converting to Oral Anticoagulant

When an oral anticoagulant of the coumarin or similar type is to be begun in patients already receiving heparin sodium, baseline and subsequent tests of prothrombin activity must be determined at a time when heparin activity is too low to affect the prothrombin time. This is about five hours after the last IV bolus and 24 hours after the last subcutaneous dose. If continuous IV heparin infusion is used, prothrombin time can usually be measured at any time.

In converting from heparin to an oral anticoagulant, the dose of the oral anticoagulant should be the usual initial amount and thereafter prothrombin time should be determined at the usual intervals. To ensure continuous anticoagulation, it is advisable to continue full heparin therapy for several days after the prothrombin time has reached the therapeutic range. Heparin therapy may then be discontinued without tapering.

Therapeutic Anticoagulant Effect with Full-Dose Heparin

Although dosage must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines:

METHOD OF ADMINISTRATION	FREQUENCY	RECOMMENDED DOSE [based on 150 lb (68 kg) patient]
Deep Subcutaneous (Intrafat) Injection	Initial Dose	5,000 units by IV 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 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 IV injection 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

Pediatric Use

Use preservative-free Heparin Sodium Injection in neonates and infants (see WARNINGS, Benzyl Alcohol Toxicity and PRECAUTIONS, Pediatric Use).

There are no adequate and well-controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients:

Initial Dose	75 to 100 units/kg (IV bolus over 10 minutes)
Maintenance Dose	Infants: 25 to 30 units/kg/hour; Infants < 2 months have the highest requirements (average 28 units/kg/hour)
	Children > 1 year of age: 18 to 20 units/kg/hour; Older children may require less heparin, similar to weight-adjusted adult dosage
Monitoring	Adjust heparin to maintain aPTT of 60 to 85 seconds, assuming this reflects an anti Factor Xa level of 0.35 to 0.70.

Geriatric Use

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

Surgery of the Heart and Blood Vessels

Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units of heparin sodium per kilogram of body weight is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes.

Low-Dose Prophylaxis of Postoperative Thromboembolism

A number of well-controlled clinical trials have demonstrated that low-dose heparin prophylaxis, given just prior to and after surgery, will reduce the incidence of postoperative deep vein thrombosis in the legs (as measured by the I-125 fibrinogen technique and venography) and of clinical pulmonary embolism. The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for seven days or until the patient is fully ambulatory, whichever is longer. The heparin is given by deep subcutaneous injection in the arm or abdomen with a fine needle (25 to 26 gauge) to minimize tissue trauma. A concentrated solution of heparin sodium is recommended. Such prophylaxis should be reserved for patients over the age of 40 who are undergoing major surgery. Patients with bleeding disorders and those having neurosurgery, spinal anesthesia, eye surgery or potentially sanguineous operations should be excluded, as well as patients receiving oral anticoagulants or platelet-active drugs (see WARNINGS). The value of such prophylaxis in hip surgery has not been established. The possibility of increased bleeding during surgery or postoperatively should be borne in mind. If such bleeding occurs, discontinuance of heparin and neutralization with protamine sulfate are advisable. If clinical evidence of thromboembolism develops despite low-dose prophylaxis, full therapeutic doses of anticoagulants should be given unless contraindicated. All patients should be screened prior to heparinization to rule out bleeding disorders, and monitoring should be performed with appropriate coagulation tests just prior to surgery. Coagulation test values should be normal or only slightly elevated. There is usually no need for daily monitoring of the effect of low-dose heparin in patients with normal coagulation parameters.

Extracorporeal Dialysis

Follow equipment manufacturers' operating directions carefully.

Blood Transfusion

Addition of 400 to 600 USP units per 100 mL of whole blood is usually employed to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units/1,000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 to 8 mL are added per 100 mL of whole blood.

Laboratory Samples

Addition of 70 to 150 units of heparin sodium per 10 to 20 mL sample of whole blood is usually employed to prevent coagulation of the sample. Leukocyte counts should be performed on heparinized blood within two hours after addition of the heparin. Heparinized blood should not be used for isoagglutinin, complement, or erythrocyte fragility tests or platelet counts.

How Supplied  ⮝

Heparin Sodium Injection, USP (porcine), preservative-free, is available as follows:

NDC	Strength (Concentration)	Vial Fill Volume	Vial Type	Package Factor
25021-401-02	2,000 USP units per 2 mL (1,000 USP units per mL)	2 mL	Single-Dose Vial	25 vials per carton

Use only if solution is clear and seal intact. Do not use if solution is discolored or contains a precipitate. Discard unused portion.

Sterile, Nonpyrogenic, Preservative-free.
The container closure is not made with natural rubber latex.

Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol, is available as follows:

NDC	Strength (Concentration)	Vial Fill Volume	Vial Type	Package Factor
25021-404-01	20,000 USP units per mL	1 mL	Multi-Dose Vial	25 vials per carton

Use only if solution is clear and seal intact. Do not use if solution is discolored or contains a precipitate.

Sterile, Nonpyrogenic.
The container closure is not made with natural rubber latex.

Storage Conditions

Store at 20 to 25 C (68 to 77 F). [See USP Controlled Room Temperature.]

To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals, Inc. at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

References  ⮝

1. Tahata T, Shigehito M, Kusuhara K, Ueda Y, et al. Delayed-Onset of Heparin Induced Thrombocytopenia A Case Report J Jpn Assn Torca Surg. 1992;40(3):110-111.
2. Warkentin T, Kelton J. Delayed-Onset Heparin-Induced Thrombocytopenia and Thrombosis. Annals of Internal Medicine. 2001;135:502-506.
3. Rice L, Attisha W, Drexler A, Francis J. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of Internal Medicine. 2002;136:210-215.
4. Dieck J., C. Rizo-Patron, et al. (1990). A New Manifestation and Treatment Alternative for Heparin-Induced Thrombosis. Chest 98(1524-26).
5. Smythe M, Stephens J, Mattson. Delayed-Onset Heparin Induced Thrombocytopenia. Annals of Emergency Medicine, 2005;45(4):417-419.
6. Divgi A. (Reprint), Thumma S., Hari P., Friedman K., Delayed Onset Heparin-Induced Thrombocytopenia (HIT) Presenting After Undocumented Drug Exposure as Post-Angiography Pulmonary Embolism. Blood. 2003;102(11):127b.

SAGENT

Mfd. for SAGENT Pharmaceuticals
Schaumburg, IL 60195 (USA)
Made in India
2013 Sagent Pharmaceuticals, Inc.

Revised: February 2013

PACKAGE LABEL PRINCIPAL DISPLAY PANEL Vial Label

NOT FOR LOCK FLUSH

NDC 25021-404-01 Rx only

HEPARIN Sodium Injection, USP

20,000 USP units per mL

1 mL Multi-Dose Vial

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:25021-404 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength heparin sodium (UNII: ZZ45AB24CA) (heparin - UNII:T2410KM04A) heparin 20000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength benzyl alcohol (UNII: LKG8494WBH) 0.01 mL in 1 mL hydrochloric acid (UNII: QTT17582CB) sodium hydroxide (UNII: 55X04QC32I) water (UNII: 059QF0KO0R) nitrogen (UNII: N762921K75)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:25021-404-01 25 in 1 CARTON 07/06/2010 1 1 mL in 1 VIAL; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA090809 07/06/2010

Labeler - Sagent Pharmaceuticals (796852890)

Revised: 10/2019 Document Id: 7ea23c8a-6c58-4223-9517-0df08f3f5ae5 34391-3 Set id: feec2820-502f-4a97-84c9-f173729c51d3 Version: 16 Effective Time: 20191016 Sagent Pharmaceuticals

Storage Conditions  ⮝

Store at 20 to 25 C (68 to 77 F); excursions permitted between 15 and 30 C (59 and 86 F). [See USP Controlled Room Temperature.]

Discard unused portion.

Principal Display Panel Heparin Sodium Injection, Usp 2000 Usp Units Vial Label  ⮝

NDC 71288-400-02

Rx Only

Heparin Sodium Injection, USP

2,000 USP units per 2 mL

(1,000 USP units per mL)

NOT for Lock Flush

Preservative-Free

For Intravenous or Subcutaneous Use

Principal Display Panel Heparin Sodium Injection, Usp 2000 Usp Units Carton  ⮝

NDC 71288-400-03

25 x 2 mL Single-Dose Vials

Discard unused portion

Rx Only

Heparin Sodium Injection, USP

2,000 USP units per 2 mL

(1,000 USP units per mL)

NOT for Lock Flush

Preservative-Free

For Intravenous or Subcutaneous Use

From Porcine Intestinal Mucosa

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:71288-400 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength heparin sodium (UNII: ZZ45AB24CA) (heparin - UNII:T2410KM04A) heparin 1000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength sodium chloride (UNII: 451W47IQ8X) hydrochloric acid (UNII: QTT17582CB) sodium hydroxide (UNII: 55X04QC32I) water (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:71288-400-03 25 in 1 CARTON 06/15/2019 1 NDC:71288-400-02 2 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA211005 06/15/2019

Labeler - Meitheal Pharmaceuticals Inc. (080548348)

Revised: 3/2019 Document Id: d5d27be8-1287-43dd-a0d2-212d5182d673 34391-3 Set id: 83a59e7d-63e9-4eb8-87f0-52039d6893a5 Version: 2 Effective Time: 20190306 Meitheal Pharmaceuticals Inc.

Recent Major Changes ⮝

Contraindications (4)	9/2019
Warnings and Precautions (5)	9/2019

Principal Display Panel - 10,000 Usp Units/10 Ml Multidose Vial Label ⮝

NDC 0069-0058-02

Multidose Vial

Heparin
Sodium Injection, USP

10,000 USP units /
10 mL
(1,000 USP units/mL)

Warning: Contains
Benzyl Alcohol

Rx only

Principal Display Panel - 10,000 Usp Units/10 Ml Multidose Vial Carton ⮝

NDC 0069-0058-01
Contains 25 of NDC 0069-0058-02
Rx only

Twenty-five 10 mL Multidose Vials

Heparin
Sodium Injection, USP

10,000 USP units/10 mL
(1,000 USP units per mL)

Derived from porcine intestinal tissue

For subcutaneous or intravenous use

Warning: Contains Benzyl Alcohol

NOT for Lock Flush

Pfizer Injectables

Principal Display Panel - 50,000 Usp Units/10 Ml Multidose Vial Label ⮝

NDC 0069-0059-02

Multidose Vial

Heparin
Sodium Injection, USP

50,000 USP units /
10 mL
(1,000 USP units/mL)

Warning: Contains
Benzyl Alcohol

Rx only

Principal Display Panel - 50,000 Usp Units/10 Ml Multidose Vial Carton ⮝

NDC 0069-0059-01
Contains 25 of NDC 0069-0059-02
Rx only

Twenty-five 10 mL Multidose Vials

Heparin
Sodium Injection, USP

50,000 USP units/10 mL
(5,000 USP units per mL)

Derived from porcine intestinal tissue

For subcutaneous or intravenous use

Warning: Contains Benzyl Alcohol

NOT for Lock Flush

Pfizer Injectables

Principal Display Panel - 1 Ml Multidose Vial Label ⮝

NDC 0069-0062-02

Multidose Vial

Heparin
Sodium Injection, USP

10,000 USP units / mL

Warning: Contains
Benzyl Alcohol

Rx only

Principal Display Panel - 1 Ml Multidose Vial Carton ⮝

NDC 0069-0062-01
Contains 25 of
NDC 0069-0062-02
Rx only

Twenty-five 1 mL Multidose Vials

Heparin
Sodium Injection, USP

10,000 USP units /mL

Derived from porcine intestinal tissue

For subcutaneous or intravenous use

Warning: Contains Benzyl Alcohol

Pfizer Injectables

NOT for Lock Flush

Principal Display Panel - 2 Ml Single Dose Vial Label ⮝

NDC 0069-0043-02

Single Dose Vial

Heparin
Sodium Injection, USP

2,000 USP units / 2 mL
(1,000 USP units/mL)

Preservative-Free
Rx only

Principal Display Panel - 2 Ml Single Dose Vial Carton ⮝

NDC 0069-0043-01
Contains 25 of
NDC 0069-0043-02
Rx only

Twenty-five 2 mL Single Dose Vials

Heparin
Sodium Injection, USP

2,000 USP units /2 mL
(1,000 USP units per mL)

Derived from porcine intestinal tissue

For subcutaneous or intravenous use

Pfizer Injectables

Preservative-Free

NOT for Lock Flush

Principal Display Panel - 30 Ml Multidose Vial Label ⮝

NDC 0069-0137-01

HEPARIN
Sodium Injection, USP

30,000 USP units/30 mL
(1,000 USP units/mL)

Warning: Contains Benzyl Alcohol

Multidose Vial

NOT for Lock Flush

Principal Display Panel - 30 Ml Vial Carton ⮝

Ten 30 mL Multidose Vials

NDC 0069-0137-03
Contains 10 of
NDC 0069-0137-01

HEPARIN
Sodium Injection, USP

30,000 USP units/30 mL
(1,000 USP units per mL)

Derived from porcine intestinal tissue

For subcutaneous or intravenous use

Pfizer Injectables

Warning: Contains Benzyl Alcohol

NOT for Lock Flush

Rx only

Multidose Vials

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0069-0058 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 1000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) 9 mg in 1 mL BENZYL ALCOHOL (UNII: LKG8494WBH) 9.45 mg in 1 mL HYDROCHLORIC ACID (UNII: QTT17582CB) SODIUM HYDROXIDE (UNII: 55X04QC32I) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0069-0058-02 10 mL in 1 VIAL; Type 0: Not a Combination Product 07/21/2011 2 NDC:0069-0058-01 25 in 1 CONTAINER 07/21/2011 2 NDC:0069-0058-02 10 mL in 1 VIAL; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA201370 07/21/2011

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0069-0059 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 5000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) 9 mg in 1 mL BENZYL ALCOHOL (UNII: LKG8494WBH) 9.45 mg in 1 mL HYDROCHLORIC ACID (UNII: QTT17582CB) SODIUM HYDROXIDE (UNII: 55X04QC32I) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0069-0059-02 10 mL in 1 VIAL; Type 0: Not a Combination Product 07/21/2011 2 NDC:0069-0059-01 25 in 1 CONTAINER 07/21/2011 2 NDC:0069-0059-02 10 mL in 1 VIAL; Type 0: Not a Combination Product 3 NDC:0069-0059-04 1 mL in 1 VIAL; Type 0: Not a Combination Product 07/21/2011 4 NDC:0069-0059-03 25 in 1 CONTAINER 07/21/2011 4 NDC:0069-0059-04 1 mL in 1 VIAL; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA201370 07/21/2011

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0069-0062 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 10000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) 9 mg in 1 mL BENZYL ALCOHOL (UNII: LKG8494WBH) 9.45 mg in 1 mL HYDROCHLORIC ACID (UNII: QTT17582CB) SODIUM HYDROXIDE (UNII: 55X04QC32I) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0069-0062-02 1 mL in 1 VIAL; Type 0: Not a Combination Product 07/21/2011 2 NDC:0069-0062-01 25 in 1 CONTAINER 07/21/2011 2 NDC:0069-0062-02 1 mL in 1 VIAL; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA201370 07/21/2011

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0069-0043 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 1000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) 9 mg in 1 mL WATER (UNII: 059QF0KO0R) HYDROCHLORIC ACID (UNII: QTT17582CB) SODIUM HYDROXIDE (UNII: 55X04QC32I)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0069-0043-02 2 mL in 1 VIAL; Type 0: Not a Combination Product 07/21/2011 2 NDC:0069-0043-01 25 in 1 CONTAINER 07/21/2011 2 NDC:0069-0043-02 2 mL in 1 VIAL; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA201370 07/21/2011

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0069-0137 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 1000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) BENZYL ALCOHOL (UNII: LKG8494WBH) HYDROCHLORIC ACID (UNII: QTT17582CB) SODIUM HYDROXIDE (UNII: 55X04QC32I) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0069-0137-01 30 mL in 1 VIAL; Type 0: Not a Combination Product 03/11/2013 2 NDC:0069-0137-03 10 in 1 CARTON 03/11/2013 2 NDC:0069-0137-01 30 mL in 1 VIAL; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA201370 03/11/2013

Labeler - Pfizer Laboratories Div Pfizer Inc (134489525)

Establishment
Name	Address	ID/FEI	Business Operations
Pharmacia and Upjohn Company LLC		618054084	API MANUFACTURE(0069-0043, 0069-0058, 0069-0059, 0069-0062, 0069-0137) , MANUFACTURE(0069-0043, 0069-0058, 0069-0059, 0069-0062, 0069-0137)

Establishment
Name	Address	ID/FEI	Business Operations
Pharmacia Hepar LLC		030945307	API MANUFACTURE(0069-0043, 0069-0058, 0069-0059, 0069-0062, 0069-0137)

Revised: 9/2019 Document Id: 292f342a-63c9-415c-a211-7a902ed4826c 34391-3 Set id: 56dc3074-f1c5-45a3-b923-f1d14858e06d Version: 22 Effective Time: 20190926 Pfizer Laboratories Div Pfizer Inc

1 Indications & Usage ⮝

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

2 Dosage & Administration ⮝

2.1 Preparation for Administration

Confirm the choice of the correct heparin sodium injection vial to ensure that the 1 mL vial is not confused with a catheter lock flush vial or other 1 mL vial of incorrect strength [see Warnings and Precautions (5.1)]. Confirm the selection of the correct formulation and strength prior to administration of the drug.

When heparin is added to an infusion solution for continuous intravenous administration, invert the container repeatedly to ensure adequate mixing and prevent pooling of the heparin in the solution.

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and the seal is intact. Do not use if solution is discolored or contains a precipitate.

Administer heparin sodium injection by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. Do not administer heparin sodium injection by intramuscular injection because of the risk of hematoma at the injection site [see Adverse Reactions (6)].

2.2 Laboratory Monitoring for Efficacy and Safety

Adjust the dosage of heparin sodium injection according to the patient s coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. When initiating treatment with heparin sodium injection by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection.

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

2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin

The 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) 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 Every 12 hours	8,000 to 10,000 units of a concentrated solution 15,000 to 20,000 units of a concentrated solution
Intermittent 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 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion

2.4 Pediatric Use

Do not use this product in neonates and infants. Use preservative-free heparin sodium injection in neonates and infants [see Warnings and Precautions (5.4)].

There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. In general, the following dosage schedule may be used as a guideline in pediatric patients:

Initial Dose 75 to 100 units/kg (IV bolus over 10 minutes)
Infants: 25 to 30 units/kg/hour;
Infants < 2 months have the highest requirements (average 28 units/kg/hour)

Maintenance Dose Children > 1 year of age: 18 to 20 units/kg/hour;
Older children may require less heparin, similar to weight-adjusted adult dosage

Monitoring Adjust heparin to maintain APTT of 60 to 85 seconds, assuming this reflects an anti-Factor Xa level of 0.35 to 0.70

2.5 Cardiovascular Surgery

Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes.

2.6 Low-Dose Prophylaxis of Postoperative Thromboembolism

The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25 to 26-gauge) needle to minimize tissue trauma.

2.7 Blood Transfusion

Add 450 to 600 USP units of heparin sodium per 100 mL of whole blood to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1,000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 to 8 mL are added per 100 mL of whole blood.

2.8 Converting to Oral Anticoagulants other than Warfarin

To ensure continuous anticoagulation when converting from heparin sodium injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions (7.1)].

2.9 Extracorporeal Dialysis

For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered.

2.10 Laboratory Samples

Follow equipment manufacturers operating directions carefully. A dose of 25 to 30 units/kg followed by an infusion rate of 1,500 to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers recommendations are not available.

3 Dosage Forms & Strengths ⮝

Heparin Sodium Injection, USP is available as 5,000 USP units per mL preserved with benzyl alcohol clear solution in 1 mL single-dose vials.

Package Label.principal Display Panel ⮝

Vial Label
Heparin Sodium Injection, USP
5000 USP units per mL
NDC 68083-136-01

Carton Label
Heparin Sodium Injection, USP
5000 USP units per mL
NDC 68083-136-25

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68083-136 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 5000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) 7 mg in 1 mL BENZYL ALCOHOL (UNII: LKG8494WBH) 0.01 mL in 1 mL

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68083-136-25 25 in 1 CARTON 03/09/2017 1 NDC:68083-136-01 1 mL in 1 VIAL; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA205323 03/09/2017

Labeler - Gland Pharma Limited (918601238)

Establishment
Name	Address	ID/FEI	Business Operations
Gland Pharma Limited		918601238	ANALYSIS(68083-136) , MANUFACTURE(68083-136)

Revised: 11/2017 Document Id: 403bc1b5-f5b6-4c7f-8cf8-360289755ca9 34391-3 Set id: 301b19bc-21c2-4a35-9d29-569b08d855c4 Version: 6 Effective Time: 20171106 Gland Pharma Limited

1 Indications And Usage  ⮝

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

2 Dosage And Administration  ⮝

2.1 Preparation for Administration

Confirm the selection of the correct formulation and strength prior to administration of the drug.

Confirm the choice of the correct heparin sodium injection vial prior to administration of the drug to a patient [see Warnings and Precaution (5.1)]. The 1 mL vial must not be confused with a catheter lock flush vial or other 1 mL vial of inappropriate strength. Confirm that you have selected the correct medication and strength prior to administration of the drug.

When heparin is added to an infusion solution for continuous intravenous administration, the container should be inverted at least six times to ensure adequate mixing and prevent pooling of the heparin in the solution.

Heparin sodium is not effective by oral administration and should be given by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection. The intramuscular route of administration should be avoided because of the frequent occurrence of hematoma at the injection site.

Converting to Oral Anticoagulant

When an oral anticoagulant of the coumarin or similar type is to be begun in patients already receiving heparin sodium, baseline and subsequent tests of prothrombin activity must be determined at a time when heparin activity is too low to affect the prothrombin time. This is about five hours after the last IV bolus and 24 hours after the last subcutaneous dose. If continuous IV heparin infusion is used, prothrombin time can usually be measured at any time.

In converting from heparin to an oral anticoagulant, the dose of the oral anticoagulant should be the usual initial amount and thereafter prothrombin time should be determined at the usual intervals. To ensure continuous anticoagulation, it is advisable to continue full heparin therapy for several days after the prothrombin time has reached the therapeutic range. Heparin therapy may then be discontinued without tapering.

Low-Dose Prophylaxis of Postoperative Thromboembolism

A number of well-controlled clinical trials have demonstrated that low-dose heparin prophylaxis, given just prior to and after surgery, will reduce the incidence of postoperative deep vein thrombosis in the legs (as measured by the I-125 fibrinogen technique and venography) and of clinical pulmonary embolism. The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for seven days or until the patient is fully ambulatory, whichever is longer. The heparin is given by deep subcutaneous injection in the arm or abdomen with a fine needle (25 to 26 gauge) to minimize tissue trauma. A concentrated solution of heparin sodium is recommended. Such prophylaxis should be reserved for patients over the age of 40 who are undergoing major surgery. Patients with bleeding disorders and those having neurosurgery, spinal anesthesia, eye surgery or potentially sanguineous operations should be excluded, as well as patients receiving oral anticoagulants or plateletactive drugs (see WARNINGS). The value of such prophylaxis in hip surgery has not been established. The possibility of increased bleeding during surgery or postoperatively should be borne in mind. If such bleeding occurs, discontinuance of heparin and neutralization with protamine sulfate are advisable. If clinical evidence of thromboembolism develops despite low-dose prophylaxis, full therapeutic doses of anticoagulants should be given unless contraindicated. All patients should be screened prior to heparinization to rule out bleeding disorders, and monitoring should be performed with appropriate coagulation tests just prior to surgery. Coagulation test values should be normal or only slightly elevated. There is usually no need for daily monitoring of the effect of low-dose heparin in patients with normal coagulation parameters.

Extracorporeal Dialysis

Follow equipment manufacturers operating directions carefully.

Blood Transfusion

Addition of 400 to 600 USP units per 100 mL of whole blood is usually employed to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units/1,000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 to 8 mL are added per 100 mL of whole blood.

Laboratory Samples

Addition of 70 to 150 units of heparin sodium per 10 to 20 mL sample of whole blood is usually employed to prevent coagulation of the sample. Leukocyte counts should be performed on heparinized blood within two hours after addition of the heparin. Heparinized blood should not be used for isoagglutinin, complement, or erythrocyte fragility tests or platelet counts.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2.2 Laboratory Monitoring for Efficacy and Safety

Adjust the dosage of heparin sodium injection according to the patient s coagulation test results. Dosage is considered adequate when the activated partial thromboplastin time (aPTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value. When initiating treatment with heparin sodium injection by continuous intravenous infusion, determine the coagulation status (aPTT, INR, platelet count) at baseline and continue to follow aPTT approximately every 4 hours and then at appropriate intervals thereafter. When the drug is administered intermittently by intravenous injection, perform coagulation tests before each injection during the initiation of treatment and at appropriate intervals thereafter. After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn 4 to 6 hours after the injection.

Periodically monitor platelet counts and hematocrits during the entire course of heparin therapy, regardless of the route of administration.

2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin

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

2.4 Cardiovascular Surgery

Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes.

2.5 Low-Dose Prophylaxis of Postoperative Thromboembolism

The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for 7 days or until the patient is fully ambulatory, whichever is longer. Administer the heparin by deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer, arm, or thigh) injection with a fine (25 to 26-gauge) needle to minimize tissue trauma.

2.6 Blood Transfusion

Add 450 USP units to 600 USP units of heparin sodium per 100 mL of whole blood to prevent coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units per 1,000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 mL to 8 mL are added per 100 mL of whole blood.

2.7 Converting to Warfarin

To ensure continuous anticoagulation when converting from Heparin Sodium Injection to warfarin, continue full heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range. Heparin therapy may then be discontinued without tapering [see Drug Interactions (7.1)].

2.8 Converting to Oral Anticoagulants other than Warfarin

For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose of heparin was to have been administered.

2.9 Extracorporeal Dialysis

Follow equipment manufacturers operating directions carefully. A dose of 25 units/kg to 30 units/kg followed by an infusion rate of 1,500 units/hour to 2,000 units/hour is suggested based on pharmacodynamic data if specific manufacturers recommendations are not available.

5 Warnings And Precautions  ⮝

5.1 Fatal Medication Errors

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.

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 (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.

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/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.

5.5 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/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions (5.3)].

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 (10)]. Periodic platelet counts and hematocrits are recommended during the entire course of heparin therapy, regardless of the route of administration [see Dosage and Administration (2.2)].

5.7 Heparin Resistance

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

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.

7 Drug Interactions  ⮝

7.1 Oral Anticoagulants

Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least five hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn, if a valid prothrombin time is to be obtained.

7.2 Platelet Inhibitors

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

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).

Package/label Principal Display Panel  ⮝

NDC 0781-3332-25

Heparin Sodium Injection, USP

50,000 USP Units/10 mL

(5,000 USP Units/mL)

(Derived from Porcine Intestinal Mucosa)

For IV or SC Use

Sterile, Nonpyrogenic

Rx only

Warning: Contains Benzyl Alcohol

NOT for Lock Flush

25 x 10 mL Multiple Dose Vials

SANDOZ

10,000 Usp Units Per 10 Ml Carton ⮝

NDC 0781-3331-25

Heparin Sodium Injection, USP

10,000 USP Units/10 mL

(1,000 USP Units/mL)

(Derived from Porcine Intestinal Mucosa)

For IV or SC Use

Sterile, Nonpyrogenic

Rx only

NOT for Lock Flush

25 x 10 mL Multiple Dose Vials

SANDOZ

5,000 Usp Units Per Ml Carton ⮝

NDC 0781-3327-96

Heparin Sodium Injection, USP

5,000 USP Units/mL

(Derived from Porcine Intestinal Mucosa)

For IV or SC Use

Sterile, Nonpyrogenic

Rx only

NOT for Lock Flush

25 x 1 mL Multiple Dose Vials

SANDOZ

10,000 Usp Units Per Ml Carton ⮝

NDC 0781-3333-96

Heparin Sodium Injection, USP

10,000 USP Units/mL

(Derived from Porcine Intestinal Mucosa)

For IV or SC Use

Sterile, Nonpyrogenic

Rx only

NOT for Lock Flush

25 x 1 mL Multiple Dose Vials

SANDOZ

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0781-3332 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 5000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength BENZYL ALCOHOL (UNII: LKG8494WBH) 15 mg in 1 mL HYDROCHLORIC ACID (UNII: QTT17582CB) SODIUM CHLORIDE (UNII: 451W47IQ8X) 6 mg in 1 mL SODIUM HYDROXIDE (UNII: 55X04QC32I) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0781-3332-25 25 in 1 TRAY 06/08/2011 06/08/2011 1 NDC:0781-3332-70 10 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA091659 06/08/2011 06/08/2011

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0781-3331 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 1000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength METHYLPARABEN (UNII: A2I8C7HI9T) 1.5 mg in 1 mL PROPYLPARABEN (UNII: Z8IX2SC1OH) 0.15 mg in 1 mL HYDROCHLORIC ACID (UNII: QTT17582CB) SODIUM CHLORIDE (UNII: 451W47IQ8X) 9 mg in 1 mL SODIUM HYDROXIDE (UNII: 55X04QC32I) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0781-3331-96 25 in 1 TRAY 06/08/2011 06/08/2011 1 NDC:0781-3331-71 1 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product 2 NDC:0781-3331-25 25 in 1 TRAY 06/08/2011 06/08/2011 2 NDC:0781-3331-70 10 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product 3 NDC:0781-3331-35 25 in 1 TRAY 06/08/2011 06/08/2011 3 NDC:0781-3331-90 30 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA091682 06/08/2011 06/08/2011

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0781-3327 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 5000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength METHYLPARABEN (UNII: A2I8C7HI9T) 1.5 mg in 1 mL PROPYLPARABEN (UNII: Z8IX2SC1OH) 0.15 mg in 1 mL HYDROCHLORIC ACID (UNII: QTT17582CB) SODIUM CHLORIDE (UNII: 451W47IQ8X) 5 mg in 1 mL SODIUM HYDROXIDE (UNII: 55X04QC32I) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0781-3327-95 10 in 1 TRAY 12/08/2016 04/30/2020 1 NDC:0781-3327-71 1 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product 2 NDC:0781-3327-96 25 in 1 TRAY 06/08/2011 06/08/2011 2 NDC:0781-3327-71 1 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA091682 06/08/2011 04/30/2020

HEPARIN SODIUM heparin sodium injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0781-3333 Route of Administration INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HEPARIN SODIUM (UNII: ZZ45AB24CA) (HEPARIN - UNII:T2410KM04A) HEPARIN 10000 [USP'U] in 1 mL

Inactive Ingredients Ingredient Name Strength METHYLPARABEN (UNII: A2I8C7HI9T) 1.5 mg in 1 mL PROPYLPARABEN (UNII: Z8IX2SC1OH) 0.15 mg in 1 mL HYDROCHLORIC ACID (UNII: QTT17582CB) SODIUM HYDROXIDE (UNII: 55X04QC32I) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0781-3333-96 25 in 1 TRAY 06/08/2011 06/08/2011 1 NDC:0781-3333-71 1 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA201002 06/08/2011 06/08/2011

Labeler - Sandoz Inc (110342024)

Revised: 1/2019 Document Id: acd26ba3-bd84-48db-9824-07984dfb11df 34391-3 Set id: 6bfbbf70-320b-4f30-a80b-cbe3ca936dfd Version: 13 Effective Time: 20190111 Sandoz Inc