Heparin Sodium Injection
Name: Heparin Sodium Injection
Heparin is a heterogenous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans, possessing anticoagulant properties. It is composed of polymers of alternating derivations of α-D-glucosamido (N-sulfated O-sulfated or N-acetylated) and O-sulfated uronic acid (α-L-iduronic acid or β-D-glucuronic acid).
Structure of heparin sodium (representative subunits):
HEPARIN SODIUM INJECTION is a sterile preparation of heparin sodium derived from porcine intestinal tissue, standardized for anticoagulant activity, in water for injection. It is intended for intravenous or deep subcutaneous administration. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram.
For formulations preserved with benzyl alcohol, each mL of the 1,000 and 5,000 USP units per mL preparations contains: heparin sodium 1,000 or 5,000 USP units; 9 mg sodium chloride; 9.45 mg benzyl alcohol added as preservative. Each mL of the 10,000 USP units per mL preparations contains: heparin sodium 10,000 USP units; 9.45 mg benzyl alcohol added as preservative.
The preservative-free product contains (per mL): 1,000 USP units of heparin sodium and 9 mg sodium chloride.
When necessary, the pH of HEPARIN SODIUM INJECTION is adjusted with hydrochloric acid and/or sodium hydroxide. The pH range is 5.0 to 7.5.
Included as part of the PRECAUTIONS section.
Mechanism Of Action
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 Factor XIII, the fibrin stabilizing factor. Heparin does not have fibrinolytic activity.
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.
Peak plasma levels of heparin are achieved 2–4 hours following subcutaneous administration, although there are considerable individual variations. Log-linear 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 reticulo-endothelial system are the sites of biotransformation. The biphasic elimination curve, a rapidly declining alpha phase (t½ = 10 minutes) and, after the age of 40 a slower beta phase, indicate uptake in organs. The absence of a relationship between anticoagulant half-life and concentration halflife may reflect factors such as protein binding 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 [see Use in Specific Populations].
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.
- Hemorrhage - Hemorrhage is the chief complication that may result from heparin therapy [see WARNINGS AND PRECAUTIONS]. 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 including:
- 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].
- Local irritation - Local irritation, erythema, mild pain, hematoma, or ulceration have occurred following deep subcutaneous (intrafat) injection of heparin sodium. Because such reactions occur more frequently after intramuscular administration, the IM route is not recommended.
- Histamine-like reactions - Such reactions have been observed at the site of injection. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin, occasionally requiring skin grafting [see WARNINGS AND PRECAUTIONS].
- Hypersensitivity - Generalized hypersensitivity reactions have been reported with chills, fever, and urticaria as the most usual manifestations; asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occur less frequently. Itching and burning, especially on the plantar site of the feet, may occur.
- Elevations of serum aminotransferases - Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin.
- Others - 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 been reported.
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