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DATA SHEET
1 CLEXANE®^ AND CLEXANE®^ FORTE*
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
CLEXANE^ SYRINGES
Pre-filled syringes, ready-to-use:
20 mg injection enoxaparin sodium 20mg (equivalent to 2,000 IU anti-Xa activity) in 0.2 mL
40 mg injection enoxaparin sodium 40mg (equivalent to 4,000 IU anti-Xa activity) in 0.4 mL
Pre-filled graduated syringes with graduated markings, ready-to-use:
60 mg injection enoxaparin sodium 60mg (equivalent to 6,000 IU anti-Xa activity) in 0.6 mL
80 mg injection enoxaparin sodium 80mg (equivalent to 8,000 IU anti-Xa activity) in 0.8 mL
100 mg injection enoxaparin sodium 100mg (equivalent to 10,000 IU anti-Xa activity) in 1. mL
CLEXANE^ (with safety lock system)
Pre-filled syringes, ready-to-use:
20 mg injection enoxaparin sodium 20mg (equivalent to 2,000 IU anti-Xa activity) in 0.2 mL
40 mg injection enoxaparin sodium 40mg (equivalent to 4,000 IU anti-Xa activity) in 0.4 mL
Pre-filled graduated syringes with graduated markings, ready-to-use:
60 mg injection enoxaparin sodium 60mg (equivalent to 6,000 IU anti-Xa activity) in 0.6 mL
80 mg injection enoxaparin sodium 80mg (equivalent to 8,000 IU anti-Xa activity) in 0.8 mL
100 mg injection enoxaparin sodium 100mg (equivalent to 10,000 IU anti-Xa activity) in 1. mL
CLEXANE^ FORTE SYRINGES #
Pre-filled graduated syringes with the double graduated markings, ready-to-use:
120 mg injection enoxaparin sodium 120mg (equivalent to 12,000 IU anti-Xa activity) in 0. mL
150 mg injection enoxaparin sodium 150mg (equivalent to 15,000 IU anti-Xa activity) in 1. mL
CLEXANE^ FORTE SYRINGES (with safety lock system)
Pre-filled graduated syringes with the double graduated markings, ready-to-use:
120 mg injection enoxaparin sodium 120mg (equivalent to 12,000 IU anti-Xa activity) in 0. mL
150 mg injection enoxaparin sodium 150mg (equivalent to 15,000 IU anti-Xa activity) in 1. mL
(^) Not marketed
* (^) Subsequent references to “CLEXANE” refer to both CLEXANE and CLEXANE FORTE
For full list of excipients, see section 6.
3 PHARMACEUTICAL FORM
Solution for injection.
Clear, colourless to pale yellow solution.
4 CLINICAL PARTICULARS
4.1 THERAPEUTIC INDICATIONS
CLEXANE is indicated for:
Prophylaxis of venous thromboembolic disease, in particular those which may be associated with orthopaedic, general, major colorectal or cancer surgery.
Prophylaxis of venous thromboembolism in general medical patients bedridden due to acute illnesses including acute heart failure, respiratory failure, severe infections, rheumatic disease.
Treatment of venous thromboembolic disease.
In patients with a moderate risk of thromboembolism, the recommended CLEXANE dosage is 20 mg (0.2 mL; anti-Xa: 2000 IU) subcutaneously once daily. In moderate risk patients undergoing surgery, the initial dose should be given approximately 2 hours preoperatively. The timing of the first dose may need to be modified if spinal/epidural anaesthesia is to be performed (see section 4.4 – Spinal/Epidural Anaesthesia).
Duration of therapy
High to Moderate Risk: Prophylaxis should be continued at 20 mg once daily for 7 to 10 days or until the risk of thromboembolism has diminished.
Prolonged Thromboprophylaxis
Patients at high risk for thromboembolic complications who undergo abdominal or pelvic surgery for cancer may benefit from an extended prophylaxis up to 4 weeks.
Therapy with 40 mg once daily for 30 post-operative days has been proven to be beneficial in total hip replacement surgery.
Under normal conditions of use, CLEXANE does not modify global clotting tests and therefore there is no need to perform these tests in order to monitor therapy.
Prophylaxis of Venous Thromboembolism in Medical Patients
The recommended dose of CLEXANE is 40 mg once daily by subcutaneous injection.
Treatment with CLEXANE is prescribed for a minimum of 6 days and continued until the return to full ambulation, for a maximum of 14 days.
Treatment of Venous Thrombosis
The initial clinical trials which established the efficacy of CLEXANE in the treatment of deep venous thrombosis were conducted on patients who were initially treated with heparin and then changed to CLEXANE when a definitive diagnosis was established. However, the use of heparin prior to CLEXANE is not currently recommended. The average duration of therapy in the clinical trials was 10 days. No data are available on the safety of long term treatment. Data on use in patients over 65 years of age in these trials were limited.
The recommended dosage for treatment of established deep vein thrombosis with CLEXANE is 1.5 mg/kg body weight once daily (150 IU anti-Xa activity/kg body weight) or 1 mg/kg body weight (100 IU anti-Xa activity/kg bodyweight) twice daily subcutaneously. In high risk patients, eg, the obese or patients with baseline iliac vein thrombosis or cancer, a dose of 1 mg/kg body weight administered twice daily may be more beneficial.
Warfarin sodium therapy should be initiated when appropriate (usually within 72 hours of commencing CLEXANE initiation). CLEXANE should be continued for a minimum of 5 days and until a therapeutic anticoagulant effect has been achieved (International Normalisation Ratio 2.0 to 3.0).
Treatment of Unstable Angina and Non-Q-Wave Myocardial Infarction
The recommended dose of CLEXANE is 1 mg/kg (100 IU anti-Xa activity/kg) every 12 hours by subcutaneous injection, administered concurrently with oral aspirin (100 to 300 mg once daily).
Treatment with CLEXANE in these patients should be prescribed for a minimum of 2 days and continued until clinical stabilisation. The usual duration of treatment is 2 to 8 days.
Treatment of Acute ST-segment Elevation Myocardial Infarction
In patients with acute ST-segment elevation myocardial infarction, administered in conjunction with a fibrinolytic (fibrin-specific or non-fibrin specific), the recommended dose of CLEXANE is a single IV bolus of 30 mg plus a 1 mg/kg SC dose, followed by 1 mg/kg administered SC every 12 hours (maximum 100 mg for each of the first two SC doses only, followed by 1 mg/kg dosing for the remaining doses). For dosage in patients ≥75 years of age, see section 4.2: Renal Impairment and Elderly.
When administered in conjunction with a thrombolytic (fibrin-specific or non-fibrin specific), CLEXANE should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. All patients should receive aspirin as soon as they are identified as having STEMI (100 to 300 mg once daily, unless contraindicated). The recommended duration of CLEXANE treatment is 8 days or until hospital discharge, whichever comes first.
For patients managed with Percutaneous Coronary Intervention (PCI): If the last CLEXANE SC administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last CLEXANE SC administration was given more than 8 hours before balloon inflation, an IV bolus of 0.3 mg/kg of CLEXANE should be administered (see section 4.4: Percutaneous Coronary Revascularisation Procedures).
Haemodialysis
In patients undergoing repeated sessions of haemodialysis, the prevention of thrombosis in the extracorporeal blood circuit is obtained by injection of a dose of 1 mg/kg (100 IU anti-Xa activity/kg) into the arterial line of the dialysis circuit at the start of the session. The dose is usually sufficient for a 4 hour haemodialysis session. If fibrin rings are formed, a further dose of 0.5 to 1 mg/kg (50 to 100 IU anti-Xa activity/kg) should be made depending on the time before the end of the dialysis.
In haemodialysed patients with a high risk of haemorrhage, (in particular, in pre or post-operative dialysed patients) or with a progressive haemorrhagic disorder, the dialysis sessions may be carried out by using a dose of 0.5 mg/kg (50 IU anti-Xa activity/kg) (double vascular access) or 0.75 mg/kg (75 IU anti-Xa activity/kg) (single vascular access).
Renal Impairment
Severe Renal Impairment
No dose reduction is necessary in the elderly for other indications, unless kidney function is impaired; however clinical observation is advised (see section 4.4: Elderly and Renal impairment).
Children
The safety and efficacy of CLEXANE in children has not been established.
Subcutaneous Injection Technique
Injection should be made preferably when the patient is reclining. CLEXANE is administered by deep subcutaneous injection. Injection of CLEXANE should be alternated between the left and right anterolateral abdominal wall using a different site for each injection. Do not expel the air bubble from the syringe before the injection to avoid the loss of drug. CLEXANE contains no antimicrobial agent and should be used only once and then discarded.
The needles on the pre-filled syringes of CLEXANE are covered in a silicon coating, to enable ease of penetration. Do not wipe the needle or allow CLEXANE solution to crystallise on the needle prior to use, as this will damage the silicon coating. A “dart” injection technique should be used to administer CLEXANE. Do not rub the injection site after administration.
Intravenous (Bolus) Injection Technique (for the treatment of acute STEMI)
For intravenous injection, the graduated pre-filled syringes should be used, see subsection below. CLEXANE should be administered through an intravenous line and should not be co-administered with other medications. To avoid the possible mixture of CLEXANE 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 CLEXANE to clear the port of drug. CLEXANE may be safely administered with normal saline solution (0.9%) or 5% dextrose in water.
Pre-filled Syringes
The pre-filled disposable syringe is ready for immediate use. The whole length of the needle should be introduced vertically (at a 90° angle to the skin) into a skin fold gently held between the thumb and forefinger. The skin fold should be held throughout the duration of the injection.
Graduated Pre-filled Syringes
When using the 60 mg, 80 mg, 100 mg, 120 mg and 150 mg graduated prefilled syringes, the volume to be injected should be measured precisely according to the dosage recommended, without expelling the air bubble while adjusting dosage. If the dose required is exactly 60, 80, 100, 120 or 150 mg inject the full contents of the syringe. The whole length of the needle should be introduced vertically (at a 90° angle to the skin) into a skin fold gently held between the thumb and forefinger. The skin fold should be held throughout the duration of the injection.
4.3 CONTRAINDICATION
- Allergy to CLEXANE or its derivatives including other LMWH’s.
- Acute bacterial endocarditis.
- Conditions with a high risk of uncontrolled haemorrhage including major bleeding disorders, focal lesions, haemorrhagic stroke, active ulcerative conditions showing a tendency to haemorrhage (e.g. peptic ulcer, ulcerative colitis).
- History of immune mediated heparin induced thrombocytopaenia (HIT) within the past 100 days or in the presence of circulating antibodies (see section 4.4).
4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE
LMWH products are not clinically interchangeable
They differ in their manufacturing process, molecular weights, specific anti-Xa activities, units and dosage. The biological activity of different LMWH’s cannot be expressed in a test allowing for a simple dose comparison. Different low molecular weight heparins may not be bioequivalent in terms of their labelled anti-Xa activities and alternative products should not be introduced nor interchanged during a course of treatment.
Not to be administered by the intramuscular route.
Risk of Haemorrhage
CLEXANE should be used with extreme caution in conditions with increased risk of haemorrhage, such as bacterial endocarditis, congenital or acquired bleeding disorders, active ulcerative and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal, or ophthalmological surgery, or in patients treated concomitantly with platelet inhibitors. Major haemorrhages including retroperitoneal and intracranial bleeding have been reported. Some of these cases have been fatal. As with other anticoagulants, bleeding can occur at any site during therapy with CLEXANE (see section 4.8). If bleeding occurs, the origin of the haemorrhage should be investigated and appropriate treatment instigated. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site and appropriate treatment instituted.
Concomitant Medical Conditions
CLEXANE should be used with caution in patients with the following conditions: hepatic insufficiency, a bleeding diathesis, uncontrolled arterial hypertension, a history of gastrointestinal ulceration, impaired haemostasis, recent ischaemic stroke, diabetic retinopathy, recent neuro- or ophthalmologic surgery and haemorrhage.
Heparin-Induced Thrombocytopenia
symptoms of spinal haematoma such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. Patients should be instructed to inform their physician immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal haematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated.
Thrombocytopenia
Thrombocytopenia can occur with the administration of CLEXANE. Moderate thrombocytopenia (platelet counts between 100,000/mm^3 and 50,000/mm 3 ) occurred at a rate of 1.3% in patients given CLEXANE, 1.2% in patients given heparin, and 0.7% in patients given placebo in clinical trials. Platelet counts less than 50,000/mm 3 occurred at a rate of 0.1% in patients given CLEXANE, in 0.2% of patients given heparin, and 0.4% of patients given placebo in the same trials. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm 3 , CLEXANE should be discontinued. Cases of heparin-induced thrombocytopenia with thrombosis have also been observed in clinical practice. Some of these cases were complicated by organ infarction, limb ischemia, or death.
Prosthetic Heart Valves
There have been no adequate studies to assess the safe and effective use of CLEXANE in preventing thromboembolism in patients with prosthetic heart valves. Cases of prosthetic heart valve thrombosis have been reported in patients with prosthetic heart valves who have received enoxaparin for thromboprophylaxis. Confounding factors, including underlying disease and insufficient clinical data, limit the evaluation of these cases. Some of these cases were pregnant women in whom thrombosis led to maternal and foetal death. Pregnant women with mechanical prosthetic heart valves may be at a higher risk for thromboembolism. The use of CLEXANE cannot be recommended for this purpose (see section 4.6).
Percutaneous Coronary Revascularisation Procedures
To minimise the risk of bleeding following the vascular instrumentation during the treatment of unstable angina, non Q-wave myocardial infarction and ST-segment elevation acute myocardial infarction, adhere precisely to the intervals recommended between CLEXANE doses. It is important to achieve haemostasis at the puncture site after PCI. In case a closure device is used, the sheath can be removed immediately. If a manual compression method is used, the sheath should be removed 6 hours after the last IV/SC CLEXANE injection. If the treatment with enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than 6 to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding or haematoma formation.
Renal Impairment
In patients with renal impairment, there is an increase in exposure of CLEXANE which increases the risk of bleeding. Since exposure of CLEXANE is significantly increased in patients with severe renal impairment (creatinine clearance <30 mL/min), a dosage adjustment is recommended for therapeutic and prophylactic dosage ranges. Although no dose adjustment is recommended in
patients with moderate (creatinine clearance 30-50 mL/min) and mild (creatinine clearance 50- mL/min) renal impairment, careful clinical observation is advised (see section 4.2: Renal Impairment).
Pharmacokinetics of enoxaparin are altered in renal impairment. The extent to which a defect in platelet function in severe renal failure might further contribute to bleeding risk is unknown.
Hepatic Impairment
See section 4.
Low Weight
An increase in exposure of CLEXANE with prophylactic dosages (non-weight adjusted) has been observed in low-weight women (<45 kg) and low-weight men (<57 kg), which may lead to a higher risk of bleeding. Therefore, careful clinical observation is advised in these patients.
Obese Patients
Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses in obese patients (BMI >30 kg/m 2 ) has not been fully determined and there is no consensus for dose adjustment. These patients should be observed carefully for signs and symptoms of thromboembolism.
Paediatric Use
The safety and efficacy of CLEXANE in children has not been established.
Use in the Elderly
No increased bleeding tendency is observed in the elderly with the prophylactic dosage ranges. Elderly patients (especially patients eighty years of age and older) may be at an increased risk for bleeding complications with the therapeutic dosage ranges. Careful clinical observation is advised. A dosage adjustment may be necessary in elderly patients due to age-related impairment of renal function (see section 4.2: Renal Impairment).
In the clinical study for treatment of acute STEMI, in patients ≥75 years of age (n = 2532) the rate of death or myocardial re-infarction was higher than in the global population but lower in the enoxaparin group (24.8%) than in the UFH group (26.3%, relative risk 0.94, p = 0.38). Patients ≥75 years of age did not receive a 30-mg IV bolus prior to the normal dosage regimen and had their SC dose adjusted to 0.75 mg/kg every 12 hours (see section 4.2).
In patients ≥75 years of age, the rate of TIMI major bleeding was higher than in the global population and was higher in the enoxaparin group (3.3%) for patients ≥75 years of age compared with the UFH group (2.9%, RR 1.15, p=0.57).
4.6 FERTILITY, PREGNANCY AND LACTATION
Fertility
Enoxaparin was found to have no effect on fertility or reproductive performance of male and female rats at subcutaneous doses up to 20 mg/kg/day.
Pregnancy
Category C.
In embryo-foetal development studies of enoxaparin there was no evidence of teratogenicity at 30 mg/kg/day SC or 160 mg/kg/day IV in either rats or rabbits. A reduction in rat pup weights occurred at 20 mg/kg/day enoxaparin SC only when administered during the late phase of gestation. An increase in post-implantation loss was noted at 160 mg/kg/day enoxaparin IV in rabbits, but not at 40 mg/kg/day IV, nor in rats at up to 160 mg/kg/day IV. Post-natal development in rats was not affected by doses tested up to a maximum of 20 mg/kg/day enoxaparin IV.
In humans, there is no evidence that enoxaparin sodium crosses the placental barrier during the second trimester of pregnancy. There is no information available concerning the use of CLEXANE during the first and the third trimesters. As there are no adequate and well-controlled studies in pregnant women and because animal studies are not always predictive of human response, this medicine should be used during pregnancy only if the physician has established a clear need.
There have been reports of congenital anomalies in infants born to women who received enoxaparin during pregnancy including cerebral anomalies, limb anomalies, hypospadias, peripheral vascular malformation, fibrotic dysplasia and cardiac defect. A cause and effect relationship has not been established nor has the incidence been shown to be higher than in the general population.
There have been post-marketing reports of foetal death when pregnant women received CLEXANE. Causality for these cases has not been determined. Pregnant women receiving anti- coagulants, including enoxaparin, are at increased risk of bleeding. Haemorrhage can occur at any site and may lead to death of mother and/or foetus. Pregnant women receiving enoxaparin should be carefully monitored. Pregnant women and women of child-bearing potential should be apprised of the potential hazard to the foetus and the mother if enoxaparin is administered during pregnancy.
The use of enoxaparin for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic heart valves given CLEXANE (1 mg/kg twice daily) to reduce the risk of thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal and foetal death. There have been isolated post-marketing reports of valve thrombosis in pregnant women with mechanical prosthetic heart valves while receiving enoxaparin for thromboprophylaxis. Pregnant women with mechanical prosthetic heart valves may be at a higher
risk for thromboembolism. In the absence of additional dosing, efficacy and safety information in this circumstance, CLEXANE is not recommended for use in pregnant women with mechanical prosthetic heart valves (see section 4.4: Prosthetic Heart Valves).
Lactation
It is unknown whether enoxaparin is excreted into the breast milk of humans. In lactating rats, the concentration of 35 S-enoxaparin sodium or its labelled metabolites in milk was similar to that in maternal plasma. Apart from lower birth weights and slightly delayed physical development, there were no significant adverse effects of 20 mg/kg/day enoxaparin SC in a peri- and post- natal study in rats. Effects of CLEXANE on lactating women have not been studied. As a precaution, women should be advised not to breast feed while using CLEXANE.
4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
CLEXANE has no effect on the ability to drive and operate machines.
4.8 UNDESIRABLE EFFECTS
Clinical Trial Data
Enoxaparin sodium has been evaluated in more than 15,000 patients. The following information relates to adverse events observed in controlled clinical trials with patients given CLEXANE prophylaxis of deep vein thrombosis following orthopaedic or abdominal surgery in patients at risk for thromboembolic complications (n = 1176), prophylaxis of deep vein thrombosis in acutely ill medical patients with severely restricted mobility (n = 1169) , treatment of deep vein thrombosis with or without pulmonary embolism (n = 669) or with patients given CLEXANE for the treatment of unstable angina or non-Q-wave myocardial infarction, administered concurrently with aspirin (n = 1578) or with patients given CLEXANE for the treatment of acute ST-segment elevation myocardial infarction (n = 10176).
Reported adverse events are presented at frequencies of:
very common > 1/10 (10%)
common ≥ 1/100 (1%) and < 1/10 (10%)
uncommon ≥ 1/1000 (0.1%) and < 1/100 (1%)
rare ≥ 1/10000 (0.01%) and < 1/1000 (0.1%)
very rare < 1/10000 (<0.01%)
Haematological
Common : Anaemia
Very common : Asymptomatic and reversible increases in liver enzymes levels (eg. transaminases) have been reported [NOTE: Liver enzymes were not assessed in the Unstable Angina Population].
Gastrointestinal
Common: Nausea, Diarrhoea
Other
Common: Peripheral oedema, Fever
Psychiatric Disorders
Common: Confusion
Immune System Disorders
Common : Allergic reaction
Rare: Anaphylactic/ anaphylactoid reaction (see also Post-Marketing Experience )
Skin and Subcutaneous Tissue Disorders
Common: Urticaria, pruritus, erythema
Uncommon: Bullous dermatitis
General Disorders and Administration Site Conditions
Common: Injection site haematoma, injection site pain, other injection site reaction (such as injection site oedema, haemorrhage, hypersensitivity, inflammation, mass, pain or reaction)
Uncommon: Local irritation, skin necrosis at injection site
Investigations
Rare: hyperkalaemia
Post-Marketing Experience
The following information relates to events observed following the marketing of CLEXANE. Voluntary reports of adverse events that have been received since market introduction (without causal relationship) that are not listed previously are cited below.
Immune System Disorders
Anaphylactic/ anaphylactoid reactions including shock have been reported.
Nervous System Disorders
Headaches have been reported.
Haematological
Rare : There have been rare reports of spinal or neuraxial haematomas with the concurrent use of CLEXANE and spinal/epidural anaesthesia, spinal puncture or post-operative indwelling catheters. These events have resulted in varying degrees of neurologic injuries including long- term or permanent paralysis (see section 4.4).
Blood Disorders
Rare cases of immuno-allergic thrombocytopenia with or without thrombosis have been reported. In some cases, thrombosis was complicated by organ infarction or limb ischaemia (see section 4.4).
Asymptomatic and reversible increases in platelet counts, haemorrhagic anaemia and eosinophilia have been reported.
Hypersensitivity and Skin - Injection site
Very rare : Pain, haematoma and mild local irritation may follow the subcutaneous injection of CLEXANE.
Hard inflammatory nodules, which are not cystic enclosures of CLEXANE, have been observed at the injection site. They resolve after a few days and should not cause treatment discontinuation.
Rare cases of skin necrosis, usually occurring at the injection site, have been reported with both unfractionated and low molecular weight heparins. These phenomena are usually preceded by purpura or erythematous plaques, infiltrated and painful. Treatment with CLEXANE must be discontinued immediately.
Alopecia has also been reported.
Systemic Allergic Reactions
Rare: Cutaneous (bullous) or systemic allergic reactions (such as pruritis, rash and urticaria), including anaphylactic/anaphylactoid reactions may occur. In some cases discontinuation of the treatment may be necessary.
Cases of hypersensitivity cutaneous vasculitis have been reported.
Metabolism Disorders
Cases of hyperkalaemia have been reported with heparins and low molecular weight heparins. Use of low molecular weight heparins over extended periods has been reported to be associated with development of osteopenia. Very rare cases of hyperlipidemia have also been reported.
Hepatobiliary Disorders
5 PHARMACOLOGICAL PROPERTIES
CHEMICAL STRUCTURE
R
X= 15 to
n= 0 to 20
100 - X H n =1 to 21
X = Percent of polysaccharide chain containing 1, 6 anhydro derivative on the reducing end
5.1 PHARMACODYNAMIC PROPERTIES
Enoxaparin sodium is a low molecular weight heparin, LMWH (mean molecular weight of approximately 4,500 daltons). The drug substance is the sodium salt.
The molecular weight distribution is:
< 2000 daltons 12 to 20%
2000 to 8000 daltons 68 to 82%
8000 daltons ≤ 18%
Enoxaparin sodium is obtained by alkaline depolymerisation of heparin benzyl ester derived from porcine intestinal mucosa. Its structure is characterised by a 4-enopyranose uronate group at the non-reducing end. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains a 1,6 anhydro derivative on the reducing end of the polysaccharide chain.
In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity (approximately 100 U/mg) and a low anti-IIa or anti-thrombin activity (approximately 28 IU/mg). Pharmacodynamic parameters studied in healthy volunteers at enoxaparin sodium concentration over the range 100 - 200 mg/ mL were comparable.
5.2 PHARMACOKINETIC PROPERTIES
The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time course of anti-Xa activity and also by anti-IIa activity, at the recommended dosage ranges after single and repeated subcutaneous administration and after single intravenous administration. The quantitative determination of anti-Xa and anti-IIa pharmacokinetic activities was conducted by validated amidolytic methods with specific substrates and an enoxaparin standard calibrated against the international standard for LMWH’s (NIBSC).
Bioavailability and Absorption
After subcutaneous (SC) injection of 20 to 80 mg and 1 or 2 mg/kg, enoxaparin sodium is rapidly and completely absorbed. The absorption is directly proportional to the dose administered indicating that, unlike unfractionated heparin, absorption of enoxaparin sodium is linear. The absolute bioavailability of enoxaparin sodium after subcutaneous injection, based on anti-Xa activity, is close to 100%. Injection volume and dose concentration over the range 100- mg/mL does not affect pharmacokinetic parameters in healthy volunteers.
The mean maximum plasma anti-Xa activity is observed 3 to 5 hours after subcutaneous injection and achieved approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/mL following single-subcutaneous administration of 20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg doses respectively.
A 30 mg IV bolus immediately followed by a 1 mg/kg SC every 12 hours provided initial peak anti-Factor Xa levels of 1.16 IU/mL (n=16) and average exposure corresponding to 88% of steady-state levels. Steady-state is achieved on the second day of treatment.
Enoxaparin pharmacokinetics appears to be linear over the recommended dosage ranges. Intra- patient and inter-patient variability is low. After repeated subcutaneous administration of 40 mg once daily and 1.5 mg/kg once daily regimens in healthy volunteers, the steady-state is reached on day 2 with an average exposure ratio about 15% higher than after a single dose. Steady-state enoxaparin activity levels are well predicted by single dose pharmacokinetics. After repeated subcutaneous administration of the 1 mg/kg twice daily regimen, the steady-state is reached from day 3 to 4 with mean exposure about 65% higher than after a single dose and mean peak and trough levels of about 1.2 and 0.52 IU/mL, respectively. Based on enoxaparin sodium pharmacokinetics, this difference in steady state is expected and within the therapeutic range.
Plasma anti-IIa activity after subcutaneous administration is approximately ten-fold lower than anti-Xa activity. The mean maximum plasma anti-IIa activity is observed approximately 3 to 4 hours following subcutaneous injection and reaches 0.13 IU/mL and 0.19 IU/mL following repeated administration of 1 mg/kg twice daily and 1.5 mg/kg once daily, respectively.
Distribution
The volume of distribution of enoxaparin sodium anti-Xa activity is about 5 litres and is close to the blood volume.
Elimination and Metabolism
