RxMed: Pharmaceutical Information – HEPARINS

HEPARINS: LOW MOLECULAR WEIGHT

General Monograph,

Dalteparin

Enoxaparin

Nadroparin

Tinzaparin

Anticoagulant

Action And Clinical Pharmacology: Low molecular weight heparins (LMWHs) are fragments of heparin produced by enzymatic or chemical depolymerization. They have an average molecular weight of 4 000 to 5 000 daltons (range 1 000 to 10 000 daltons) which is approximately one-third that of standard heparin.

Most heparin molecules with molecular weights smaller than 5 400 daltons are unable to bind thrombin and antithrombin simultaneously, as can unfractionated heparin. Therefore, LMWHs are less able to accelerate the inactivation of thrombin (factor II) but retain the ability to catalyze the inhibition of factor Xa. The anti-factor Xa to anti-factor IIa ratio of LMWHs ranges from 2:1 to 4:1, compared to 1:1 for unfractionated heparin. These ratios are based on in vitro testing and may not reflect the relative anticoagulant activity in humans (see Table I).

Pharmacokinetics: Unlike heparin, LMWHs do not bind significantly to plasma proteins. This accounts for the different pharmacokinetic properties, dosing regimens and laboratory monitoring requirements of these two classes of heparins. Furthermore, LMWHs do not bind to endothelial cells and macrophages, which is felt, in part, to contribute to their longer plasma half-lives in comparison with unfractionated heparin.

The biological half-life of LMWHs is not dose-dependent and is about 2 to 4 times longer than that of unfractionated heparin at therapeutic doses. In contrast, unfractionated heparin exhibits a dose-dependent biological half-life due to a rapid phase of saturable intracellular elimination followed by nonsaturable renal elimination.

LMWHs are cleared primarily by the renal route. The half-life is extended in patients with renal failure. Consult individual product monographs for recommendations regarding dosage adjustment in renal failure. Table II compares the pharmacokinetics of LMWHs and unfractionated heparin.

Indications And Clinical Uses: Currently, no data are available which directly compare the efficacy of different LMWHs for a given indication using recommended doses; therefore, the available agents cannot be used interchangeably.

Contra-Indications: LMWHs should not be used when the following medical problems exist: uncontrolled active bleeding, severe hypertension (because of increased risk of cerebral hemorrhage), hemorrhagic stroke, allergy or hypersensitivity to heparin, pork products or to the LMWH, or a history of thrombocytopenia with the specific LMWH.

LMWHs should be avoided in patients with a history of heparin-induced thrombocytopenia (HIT). Specialists recommend danaparoid or ancrod as alternatives in these patients.

Manufacturers’ Warnings In Clinical States: LMWHs should not be injected by the i.m. route because of the risk of hematoma.

There have been reports of intraspinal hematoma resulting in long-term or permanent paralysis in patients undergoing spinal or epidural anesthesia while on LMWH therapy. The risk may be higher with repeated or traumatic catheter insertion or with concurrent use of other drugs affecting hemostasis. Caution is advised if concurrent LMWH therapy and spinal or epidural anesthesia is considered.

LMWHs, like other anticoagulants, should be used with extreme caution in any medical procedure or condition in which the risk of bleeding or hemorrhage is present such as: septic endocarditis, major blood clotting disorders, blood dyscrasias, active gastric or duodenal ulceration, injuries to or surgery involving the CNS, eyes or ears, diabetic or hemorrhagic retinopathy, or severe hepatic or renal insufficiency.

Doses of LMWHs recommended for prophylaxis are lower and not appropriate for the treatment of acute thrombosis.

Precautions: Periodic complete blood counts including platelet counts and stool occult blood tests are recommended during the course of treatment. Physical examinations should be performed to monitor for bleeding complications.

With usual dosing, LMWHs do not consistently modify global clotting tests of activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin clotting time (TT); therefore, treatment cannot be monitored with these tests. Anti-factor-Xa activity has been used for assessing the activity of LMWHs. However, it does not correlate directly with therapeutic efficacy. The proposed therapeutic range is 0.5 to 1 IU anti-Xa/mL, between 3 and 4 hours after a s.c. injection.

Drug Interactions: Caution should be exercised when using LMWHs together with oral anticoagulants or platelet inhibitors because of an increased risk of bleeding.

Pregnancy: Large and well-controlled studies in humans have not been done. In animal studies LMWHs were shown not to be teratogenic or embryotoxic. LMWHs do not cross the placental barrier, and individual case reports have described the use of LMWH during pregnancy without maternal or fetal complications. Small studies have suggested that LMWH prophylaxis is safe during pregnancy. However, LMWHs should not be used in pregnancy unless the therapeutic benefits to the patient outweigh the possible risks.

Lactation: It is not known if LMWHs are distributed into breast milk. The manufacturers recommend that patients receiving LMWHs should avoid breast-feeding; however, given that these agents have a high molecular weight when compared with many other classes of drugs, it is highly probable that the extent of excretion into breast milk would be negligible.

Children: Safety and efficacy has not been established.

Adverse Reactions: The incidence of hemorrhagic complications during treatment with LMWHs has been low. The incidence of bleeding may increase with higher doses.

The most commonly reported side effect is hematoma at the injection site. Mild local irritation, pain and erythema following s.c. injection are reported less frequently.

The following side effects have been reported rarely: allergic reactions (e.g., pruritus, rash, fever, injection site reaction, hives), skin necrosis, anaphylactoid reactions and thrombocytopenia. To date, LMWHs have been associated with a lower risk of thrombocytopenia than standard heparin; however, until a greater number of patients have been exposed, the exact incidence cannot be reliably estimated.

A slight to moderate elevation of liver transaminases (AST, ALT) has been reported but has not correlated to any long-term effect on liver function. Transaminase determinations are important in the differential diagnosis of myocardial infarction, liver disease or pulmonary embolism; elevations should be interpreted carefully.

Bleeding complications associated with overdose may include: hematuria, bloody or black tarry stools, bruising, hemoptysis, hematemesis, ecchymosis, hematoma, hypochromic anemia, nosebleed, persistent bleeding or oozing from mucous membranes or surgical wounds, shortness of breath, vomiting of material that resembles coffee grinds.

Osteoporosis has been reported with prolonged use of LMWHs.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Accidental overdosage with LMWHs may lead to severe bleeding. This may be reduced by slow i.v. injection of protamine sulfate. A dose of 1 mg of protamine sulfate is administered for every 100 anti-factor Xa IU of dalteparin or tinzaparin, for each 158 anti-factor Xa IU of nadroparin, or for each 1 mg of enoxaparin. If the APTT measured 2 to 4 hours after the first infusion remains prolonged, a second infusion of 0.5 mg protamine sulfate per 100 anti-factor Xa IU of dalteparin or tinzaparin or per mg of enoxaparin may be administered. Even after an additional dose of protamine, the APTT may remain more prolonged following administration of a LMWH than after standard heparin. Protamine sulfate should completely neutralize the anti-factor IIa effect but not the anti-factor Xa effect which is neutralized to a maximum of only 60 to 75%, depending on the particular LMWH.

Protamine sulfate should be administered cautiously to avoid overdosing. Severe hypotension and anaphylactoid reactions, including death, may occur with protamine sulfate. It should be administered only when treatment of anaphylactic shock and resuscitation techniques are readily available.

Dosage And Administration: In general, LMWHs are administered by deep s.c. injection once or twice daily as recommended by the manufacturer. They should not be injected by the i.m. route (see Warnings). Dalteparin may also be administered by intermittent or continuous i.v. infusion; however, the manufacturer suggests that s.c. administration may be the route of choice because of the long half-life, high bioavailability, low incidence of side effects and ease of administration.

Depending on the product, injection sites include: a U-shaped area around the navel, the upper outer aspect of the thigh, or upper outer quadrangle of the buttock. The site should be varied daily. The patient should be sitting or lying down during injection. If giving the injection around the navel or the thigh, a fold of skin must be lifted up with thumb and forefinger and the entire length of the needle inserted at a 45 to 90 degree angle.

There has been limited clinical experience with the use of LMWHs in the treatment of deep vein thrombosis in very obese patients. Some experts recommend periodic monitoring of anti-Xa levels in such patients.

LMWHs cannot be used interchangeably (unit for unit) with unfractionated heparin or with other LMWHs since they differ in their relative inhibition of factor Xa and factor IIa.

HEPARINS: LOW MOLECULAR WEIGHT General Monograph, DalteparinEnoxaparinNadroparinTinzaparin Anticoagulant