Lovenox (Enoxaparin Sodium)

LOVENOX®

Rhône-Poulenc Rorer

Enoxaparin Sodium

Anticoagulant – Antithrombotic

Action And Clinical Pharmacology: Enoxaparin is a low molecular weight heparin fragment, which is obtained by controlled depolymerization of natural heparin from porcine intestinal mucosa. It possesses antithrombotic action. Enoxaparin is composed of molecules with and without a specially characterized pentasaccharide, the antithrombin binding site, that is essential for high affinity binding to the plasma protein antithrombin (formerly referred to as antithrombin III). With a molecular weight range of 3 500-5 000 Daltons (versus 15 000 Daltons for heparin), the enoxaparin molecule is too small to bind simultaneously to thrombin and antithrombin, the primary anticoagulant factor in blood.

The mechanism of action of enoxaparin is antithrombin-dependent. It acts mainly by accelerating the rate of the neutralization of certain activated coagulation factors by antithrombin, but other mechanisms may also be involved. Enoxaparin potentiates preferentially the inhibition of coagulation factors Xa and IIa and only slightly affects other hemostatic mechanisms such as clotting time. The antithrombotic effect of enoxaparin is well correlated to the inhibition of factor Xa.

The ratio of anti-Xa/anti-IIa activity is greater than 4 with enoxaparin (whereas this ratio is equal to 1 with heparin). This dissociation between anti-Xa and anti-IIa activities has been shown in experimental models with an antithrombotic activity comparable to that of heparin while the bleeding effect is reduced. In man, clinical trials have not shown a causal relationship between the ratio of anti-Xa/anti-IIa activity and clinical/pharmacological effect.

Enoxaparin cannot be measured directly in the blood stream. Rather the effect on clotting mechanisms is measured. Heparin dosage is monitored by both prolongation of APTT, and by anti-Xa activity. For enoxaparin, the APTT may not be significantly prolonged relative to unfractionated heparin at prophylactic doses, and at therapeutic doses APTT prolongation is not used to measure the therapeutic effect of enoxaparin. Enoxaparin potency is described in international anti-Xa units (e.g., 30 mg=3 000 IU).

Pharmacokinetics: The pharmacokinetics of enoxaparin have been studied on the basis of plasma levels of anti-Xa activity.

Following a single s.c. injection, enoxaparin is rapidly and almost completely absorbed, with peak plasma activity appearing after 3 hours. Maximum anti-Xa levels and AUCs are positively correlated to the dose levels; between the doses of 20 and 80 mg s.c.

The t 1/2 of plasma anti-Xa activity is between 4.18 (±2.21) and 3.46 (±0.86) hours and the mean residence time (MRT) of anti-Xa activity is about 6 hours, independent of the dose (between 20 and 80 mg s.c.), although anti-Xa activity can still be measured after 12 hours.

Information from a clinical trial with a very small number of volunteers indicates that enoxaparin, as detected by anti-factor Xa activity, does not appear to cross the placental barrier, at least during the second trimester of pregnancy.

Following repeated s.c. doses of enoxaparin the Tmax for anti-Xa activity remained at 3 hours and there was no evidence of accumulation or alterations in distribution and clearance.

Enoxaparin is weakly metabolized in the liver by desulfation and depolymerization. Small amounts of the drug are eliminated by the kidneys in the intact or slightly degraded form.

In the elderly, peak concentration (Tmax) was delayed by approximately 1 hour and there was some lengthening of both the apparent half-life (t 1/2) and the mean residence time (MRT). There were no significant changes in the pharmacokinetic profiles of enoxaparin in elderly patients or in hemodialyzed patients with renal failure when compared to those of healthy subjects.

The dose and frequency of dosing do not have to be modified in elderly patients or dialyzed patients with renal insufficiency.

In nondialyzed patients with severe renal impairment (mean renal creatinine clearance: 11.4 mL/min), total clearance of enoxaparin was 1.9 times slower and the apparent half-lives of absorption and elimination 1.7 times more prolonged than in healthy subjects. These effects suggest that dose modifications may have to be considered in patients with severe renal impairment who are not hemodialyzed, when repeated high doses are required.

Indications And Clinical Uses: For the prophylaxis of thromboembolic disorders (deep vein thrombosis) in patients undergoing: orthopedic surgery of the hip or knee; high-risk abdominal, gynecological, or urological surgeries; colorectal surgery.

For the treatment of deep vein thrombosis and pulmonary embolism.

For the treatment of unstable angina and non-Q-wave myocardial infarction, concurrently with ASA.

Contra-Indications: Enoxaparin must not be administered by the i.m. route. Allergy to enoxaparin or any of its constituents. Acute or subacute bacterial endocarditis. Major blood clotting disorders. History of thrombocytopenia with enoxaparin or in patients in whom an in vitro platelet-aggregation test in the presence of enoxaparin is positive. Active gastric or duodenal ulcer. Hemorrhagic cerebrovascular accident (except if there are systemic emboli). Severe untreated hypertension. Diabetic or hemorrhagic retinopathy. Other conditions or diseases involving an increased risk of hemorrhage. Injuries to and operations on the brain, spinal cord, eyes and ears. tag_WarningWarnings

Manufacturers’ Warnings In Clinical States: Enoxaparin should be used with care in patients with hepatic insufficiency, renal insufficiency or a history of gastrointestinal ulceration.

Determination of anti-factor Xa levels in plasma is the only method available for monitoring enoxaparin activity. The effect of enoxaparin on global clotting tests such as APTT, PT and TT is dose-dependent. At lower doses, used in prophylaxis, enoxaparin does not prolong these tests. At higher doses, APTT prolongation is observed but treatment cannot be monitored with these tests.

There have been cases of intra-spinal hematomas with the concurrent use of enoxaparin and spinal/epidural anesthesia resulting in long-term or permanent paralysis. The risk of these events may be higher with the use of post-operative indwelling epidural catheters or by the concomitant use of drugs affecting hemostasis: nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other drugs affecting coagulation. The risk also appears to be increased by traumatic or repeated epidural or spinal procedure. Enoxaparin should only be used concurrently with spinal/epidural anaesthesia when the therapeutic benefits to the patients outweigh the possible risks. When used concurrently, no spinal invasion should be performed for at least 12 hours following the last dose of enoxaparin and the next dose should be held until at least 2 hours after the anaesthetic procedure. The same rules apply to the withdrawal or manipulation of the catheter. Careful vigilance for neurological signs is recommended with rapid diagnosis and treatment if signs occur (see also Adverse Effects).

Enoxaparin should be used with caution in the presence of known hypersensitivity to heparin and/or low molecular weight heparins (see Precautions).

Enoxaparin dosage should be carefully monitored in patients with severely impaired renal function. The main route of elimination is via the kidney. The half-life for anti-Xa activity in patients with impaired renal function is much longer than for people with normal renal function (t 1/2=5.12 h in patients with chronic renal failure vs 2.94 h in young healthy volunteers).

Except under special circumstances enoxaparin should not be used when abortion is imminent or threatened. It may be used in such cases only when, in the opinion of the physician, the increased risk of bleeding is outweighed by the risk of thrombosis and thromboembolism.

Pregnancy, Lactation and Children: The safety of enoxaparin in pregnant women and in children has not been established, although it is known that the drug does not appear to cross the placental barrier, at least during the second trimester, and that it exhibited no embryotoxic or teratogenic effects in experimental animals. Enoxaparin should not be used in pregnant women and in children unless the therapeutic benefits to the patients outweigh the possible risks.

There has been no experience with enoxaparin during human lactation. Mothers receiving enoxaparin should avoid breast-feeding.

Use in Unstable Coronary Artery Disease: When thrombolytic treatment is considered appropriate, the concomitant use of an anticoagulant such as enoxaparin is not recommended since there is no data available on this combination therapy.

Precautions: Enoxaparin cannot be used interchangeably (unit for unit) with unfractionated heparin (UFH) or other low molecular weight heparins (LMWHs) as they differ in their manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units and dosages. Special attention and compliance with instructions for use of each specific product is required during any change in treatment.

Biochemical Monitoring: Enoxaparin has only a moderate prolonging effect on clotting time assays such as APTT or thrombin time. For lab monitoring of effect, anti-Xa methods are recommended. Prolongation of APTT during therapy with enoxaparin to the same extent as with unfractionated heparin should only be used as a criteria of overdose. Dose increases aimed at prolonging APTT to the same extent as with unfractionated heparin could cause overdose and bleeding.

Enoxaparin is administered s.c. and, therefore, the individual patient’s antifactor Xa activity level will not remain within the range that would be expected with unfractionated heparin by continuous i.v. infusion throughout the entire dosing interval. The peak plasma antifactor Xa level occurs 3 to 4 hours after s.c. administration. The mean maximum plasma antifactor Xa activity achieved is approximately 1.0 and 1.5 antifactor Xa IU/mL following s.c. administration of 1 mg/kg and 1.5 mg/kg doses in healthy volunteers, respectively. In patients treated with enoxaparin 1.0 mg/kg twice daily for proximal deep vein thrombosis, mean peak plasma anti-Xa levels were 0.91 IU/mL. In patients given enoxaparin 1.0 mg/kg twice daily for acute treatment of unstable angina, peak anti-Xa activity levels were 1.0 -1.1 IU/mL. At steady-state in patients given a 1.5 mg/kg qd regimen for treatment of DVT, mean peak activity was 1.7 IU anti-Xa/mL. The steady-state is practically achieved at the second or the third dose depending on the dosage regimen, once or twice daily, respectively. Enoxaparin should be administered as directed in the Dosage section.

Patient Monitoring: As with all anti-thrombotic agents, there is a risk of systemic bleeding with enoxaparin administration. Consequently, therapy should not be started before primary hemostasis has been established and preferably no sooner than 12 hours after surgery (see Dosage). Care should be taken with enoxaparin use in high dose treatment of newly operated patients.

After treatment is initiated patients should be carefully monitored for bleeding complications. This may be done by regular physical examination of the patients, close observation of the surgical drain and periodic measurements of hemoglobin and anti-factor Xa determinations. Bleeding complications may be considered major if hemoglobin is decreased by 2 g/dL or if a transfusion of 2 or more units has been required. With normal prophylactic doses, enoxaparin does not modify global clotting tests of activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombing clotting time (TT). Therefore, treatment cannot be monitored with these tests.

Enoxaparin is administered s.c. and, therefore, the individual patient’s antifactor Xa activity level will not remain within the range that would be expected with unfractionated heparin by continuous i.v. infusion throughout the entire dosing interval. The peak plasma antifactor Xa level occurs 3 to 4 hours after s.c. administration. The mean maximum plasma antifactor Xa activity achieved is approximately 1.0 and 1.5 antifactor Xa IU/mL following s.c. administration of 1 mg/kg and 1.5 mg/kg doses in healthy volunteers, respectively. In patients treated with enoxaparin 1.0 mg/kg twice daily for proximal deep vein thrombosis, mean peak plasma anti-Xa levels were 0.91 IU/mL. In patients given enoxaparin 1.0 mg/kg twice daily for acute treatment of unstable angina, peak anti-Xa activity levels were 1.0 to 1.1 IU/mL. At steady state in patients given a 1.5 mg/kg qd regimen for treatment of DVT, mean peak activity was 1.7 IU anti-Xa/mL. The steady-state is practically achieved at the second or the third dose depending on the dosage regimen, once or twice daily, respectively. Enoxaparin should be administered as directed in the Dosage section.

Platelets: Platelet counts should be determined prior to the commencement of treatment with enoxaparin and, subsequently, twice weekly for the duration of therapy.

Caution is recommended when administering enoxaparin to patients with congenital or drug-induced thrombocytopenia, or platelet defects.

In patients who have a history of heparin-induced thrombocytopenia (HIT), the risk of this occurrence for the individual patient in response to the low molecular weight heparins cannot be estimated, but would be expected to be increased relative to the general population. The frequency of this potentially life-threatening event that has been observed during clinical development of enoxaparin was observed in patients who had received one course of therapy only. Since the frequency of HIT in patients who had received more than one course of therapy of enoxaparin is not known, the physician should weigh all the therapeutic options before deciding on the antithrombotic therapy in patients with a history of HIT. If enoxaparin is prescribed, an in vitro platelet aggregation test should be performed prior to instituting enoxaparin. A positive result contraindicates enoxaparin. With a negative result, treatment with enoxaparin may be instituted, but patients must be monitored with particular care to include platelet counts at least once daily.

Cardiovascular: See Contraindications and Warnings.

Lipid Metabolism: Enoxaparin increases lipolytic activity, although to a lesser degree than heparin.

Selection of General Surgery Patients: Risk factors associated with postoperative venous thromboembolism following general surgery include history of venous thromboembolism, varicose veins, obesity, heart failure, malignancy, previous long bone fracture of a lower limb, bed rest for more than 5 days prior to surgery, predicted duration of surgery of more than 30 minutes, age 60 years or above.

Geriatrics: Age is highly correlated to risk of thrombosis. No increased bleeding tendency has been observed in the clinical studies with enoxaparin in elderly patients with normal kidney and liver function. No dose reduction should be necessary unless kidney or liver function is impaired.

Drug Interactions: There have been no pharmacologic/toxicologic studies into the possible interaction between enoxaparin and other drugs. Because of the possibility of an interaction with blood clotting mechanisms, caution should be exercised if enoxaparin is combined with any of the following drugs: oral anticoagulants, inhibitors of platelet aggregation, nonsteroidal anti-inflammatory agents, preparations containing ASA or dextran. For information concerning the antidote in cases of excess, see Overdose: Symptoms and Treatment.

Adverse Reactions: Bleeding: As with any antithrombotic treatment, hemorrhagic manifestations can occur. Injection site hematomas are a common side effect with enoxaparin occurring at a frequency of 5% or less with lower (prophylaxis) doses to 10% or more with higher (treatment) doses.

The incidence of major hemorrhagic complications during enoxaparin treatment has been low and generally did not differ from that observed with unfractionated heparin. Patients taking enoxaparin are at risk for major bleeding complications when the plasma anti-factor Xa levels approach 2.0 IU/mL. Other risk factors associated with bleeding on therapy with heparins include a serious concurrent illness, chronic heavy alcohol consumption, use of platelet inhibiting drugs, renal failure, age and possibly, the female gender. Petechiae or easy bruising may precede frank hemorrhage. Bleeding may range from minor local hematoma to major hemorrhage. The early signs of bleeding may include epistaxis, hematuria, or melena. Bleeding may occur at any site and may be difficult to detect; such as retroperitoneal bleeding. Bleeding may also occur from surgical sites.

There have been cases of intra-spinal hematomas with the concurrent use of low molecular weight heparins and spinal/epidural anesthesia resulting in long-term or permanent paralysis (incidence of 1:45 000). See also Warnings.

Liver: Transient, asymptomatic elevations of liver transaminases (AST and ALT) to greater than three times the upper limit of normal has been observed in up to 6% of patients taking enoxaparin. This is a consistent finding with all members of the LMWH class, as well as with unfractionated heparin. The mechanism associated with the increased levels of liver transaminases has not been elucidated. No consistent irreversible liver damage has been observed. Transaminase levels returned to normal within 3 to 7 days after discontinuation of enoxaparin.

Hypersensitivity: Thrombocytopenia, skin rash, and allergic reactions are rare, but occur with all low molecular weight heparins. Enoxaparin should be discontinued in patients showing local or systemic allergic responses. Anaphylactoid reactions to unfractionated heparin and the low molecular weight heparins have been observed rarely.

Skeletal: Osteopenic effects of enoxaparin have not been reported, possibly because enoxaparin has not been given to many patients for the long-term. Since this symptom has been reported as an adverse effect after long-term treatment with unfractionated heparin at high doses, the risk of osteoporosis cannot be ruled out.

Lipid Metabolism: Enoxaparin increases lipolytic activity, although to a lesser degree than heparin.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Hemorrhage is the major clinical sign of overdosage. In case of accidental overdosage, the platelet count and other coagulation parameters should be measured. Minor bleeding rarely requires specific therapy and reducing or delaying subsequent doses of enoxaparin is usually sufficient. Enoxaparin should be discontinued in cases of major bleeding. Protamine (either the sulphate or hydrochloride salt) should be administered in more serious cases.

The anticoagulant effect of the drug is inhibited by protamine. A slow i.v. injection of protamine will almost completely neutralize the anticoagulant activity of enoxaparin (i.e., the anti-IIa activity); however, the anti-Xa activity is only partially neutralized (maximum about 60%). The dose of protamine should be identical to the dose of enoxaparin injected, that is, 1 mg or 100 units of protamine to neutralize the anti-IIa activity generated by 1 mg enoxaparin. Particular care should be taken to avoid overdosage with protamine. The half-life of enoxaparin should be taken into account when calculating the neutralizing dose of protamine to avoid overdosage. The rate of administration of protamine should not exceed 50 mg in any 10-minute period since administration that is too rapid can cause severe hypotensive and anaphylactoid-like reactions.

Dosage And Administration: Enoxaparin is administered by s.c. injection only and is not to be injected by any other route or added to i.v. solutions. The s.c. injection of enoxaparin should be carried out with the patient in the decubitus position. Inject in the s.c. cellular tissue of the anterolateral and posterolateral abdominal girdle, alternatively on the left and right sides. With the thickness of skin held between the operator’s thumb and finger, introduce the entire length of the needle vertically into the skin.

Prophylaxis in Conjunction with Orthopedic Surgery: Enoxaparin should be administered between 12 and 24 hours after orthopedic surgery, after primary hemostasis has been established. When using enoxaparin supplied in prefilled syringes of 0.3 mL, administer 30 mg (3 000 IU) enoxaparin, the contents of 1 syringe, every 12 hours, by the s.c. route in the abdomen. When using the multiple-dose vial, which also contains 10 mg/0.1 mL enoxaparin sterile solution, a tuberculin syringe or the equivalent is recommended to assure accurate withdrawal of the appropriate volume of drug. The usual duration of treatment is from 7 to 14 days.

Prophylaxis in Conjunction with Abdominal or Colorectal Surgery: Enoxaparin should be administered between 2 hours prior to surgery. When using enoxaparin supplied in prefilled syringes of 0.4 mL, administer 40 mg (4 000 IU) enoxaparin, the contents of 1 syringe, every 24 hours, by the s.c. route in the abdomen. When using the multiple-dose vial, which also contains 10 mg/0.1 mL enoxaparin sterile solution, a tuberculin syringe or the equivalent is recommended to assure accurate withdrawal of the appropriate volume of drug. The usual duration of treatment is from 7 to 10 days for a maximum of 12 days.

Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism: Enoxaparin can be administered s.c. either as a single injection of 1.5 mg/kg or as twice daily injections of 1 mg/kg.

The 1.5 mg/kg body weight daily dose is the equivalent of 150 IU/kg and should be given once daily at the same time every day. The single daily dose should not exceed 18 000 IU.

In patients with complicated thromboembolic disorders, a dose of 1 mg/kg administered twice daily is recommended. This is the equivalent of 100 IU/kg.

Oral anticoagulant therapy should be initiated as soon as possible and enoxaparin should be continued until a therapeutic anticoagulant effect has been achieved (INR: 2 to 3), in general for approximately 7 days.

An investigator-driven study in patients with chronic renal insufficiency at 0.5 mk/kg s.c. showed that the elimination of enoxaparin is delayed in patients with renal failure compared to young healthy volunteers (t 1/2=5.12 vs 2.94 h). Based on these results and in the absence of multiple dose kinetic data at higher doses, enoxaparin dosage should be carefully monitored when treating patients with severely impaired renal function particularly when using high doses.

Treatment of Unstable Angina and non-Q-wave Myocardial Infarction: The recommended dose of enoxaparin is 1 mg/kg every 12 hours by s.c. injection. This is the equivalent of 100 IU/kg. The maximum dose should not exceed 10 000 IU/12 hours. The expected plasma anti-Xa levels during s.c. treatment would be
Important: The prefilled syringes are ready for use and no attempt should be made to expel air prior to giving the injection.

Under normal conditions of use, enoxaparin does not 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. The plasma levels of the drug can be verified by measuring anti-Xa and anti-IIa activities.

Availability And Storage: Prefilled Syringes: 30 mg/0.3 mL: Each syringe contains: enoxaparin sodium 30 mg in 0.3 mL water for injection. The solution is preservative-free and intended for use as a single-dose injection. Prefilled syringes of 0.3 mL, cartons of 10, each in individual blister pack.

40 mg/0.4 mL: Each syringe contains: enoxaparin sodium 40 mg in 0.4 mL water for injection. The solution is preservative-free and intended for use as a single-dose injection. Prefilled syringes of 0.4 mL, cartons of 10, each in individual blister pack.

60 mg/0.6 mL: Each syringe contains: enoxaparin sodium 60 mg in 0.6 mL water for injection. The solution is preservative-free and intended for use as a single-dose injection. Prefilled syringes of 0.6 mL, cartons of 10, each in individual blister pack.

80 mg/0.8 mL: Each syringe contains: enoxaparin sodium 80 mg in 0.8 mL water for injection. The solution is preservative-free and intended for use as a single-dose injection. Prefilled syringes of 0.8 mL, cartons of 10, each in individual blister pack.

100 mg/1.0 mL: Each syringe contains: enoxaparin sodium 100 mg in 1.0 mL water for injection. The solution is preservative-free and intended for use as a single-dose injection. Prefilled syringes of 1.0 mL, cartons of 10, each in individual blister pack.

Multiple-dose Vials: Each multiple-dose vial contains: enoxaparin sodium 300 mg in 3 mL water for injection (concentration 10 mg/0.1 mL) and 1.5% (m/v) benzyl alcohol as a preservative.

The pH of the syringe and multiple-dose solution is 5.5 to 7.5 with an approximate anti-factor Xa activity of 100 IU/1 mg of drug (with reference to the WHO First International Low Molecular Weight Heparin Reference Standard). Nitrogen is used in the headspace to inhibit oxidation. Store at room temperature (15 to 25°C). Protect from heat.

LOVENOX® Rhône-Poulenc Rorer Enoxaparin Sodium Anticoagulant – Antithrombotic

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