Parin-E

Parin-E

enoxaparin sodium

Manufacturer:

Venus Remedies

Distributor:

Ni Lay Naing
Full Prescribing Info
Contents
Enoxaparin sodium.
Description
Parin-E contains Enoxaparin Sodium BP 40 mg or 60 mg (equivalent to 4,000 or 6,000 IU anti-Xa activity) as Active Pharmaceutical Ingredient.
The name of the medicine is PARIN-E 40 mg/PARIN-E 60 mg Pre-filled Syringe (called Parin E). PARIN-E contains a medicine called enoxaparin sodium. This belongs to a group of medicines called Low Molecular Weight Heparins.
Drug Substances: INN: Enoxaparin Sodium. Chemical Name: 6-[5-acetylamino-4,6-dihydroxy-2-(sulfooxymethyl)tetrahydropyran-3-yl] oxy-3-[5-(6-carboxy-4,5-dihydroxy-3-sulfooxy-tetrahydropyran-2-yl)oxy-6-(hydroxymethyl)-3-sulfoamino-4-sulfooxy-tetrahydropyran-2-yl]oxy-4-hydroxy-5-sulfooxy-tetrahydropyran-2-carboxylic acid.
Molecular Formula: (C26H40N2O36S5)n. Molecular Weight: 4500 daltons (average). Description: White or almost white powder. Solubility: Soluble in water, slightly soluble in methanol, practically insoluble in acetone.
Excipients/Inactive Ingredients: Sodium Hydroxide USP and Hydrochloric Acid USP as pH Adjusting Agent, Water for Injection BP as Diluent.
Action
Pharmacotherapeutic group: Antithrombotic agent, heparin group. ATC code: B01A B05.
Pharmacology: Pharmacodynamics: Enoxaparin is a low molecular weight heparin with a mean molecular weight of approximately 4,500 daltons. The drug substance is the sodium salt. The molecular weight distribution is: <2000 daltons ≤20%; 2000 to 8000 daltons ≥68%; >8000 daltons ≤18%.
Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic acid group at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of the chain. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains an 1,6 anhydro derivative on the reducing end of the polysaccharide chain.
Enoxaparin sodium is characterised by a higher ratio of antithrombotic activity to anticoagulant activity than unfractionated heparin. At recommended doses, it does not significantly influence platelet aggregation, binding of fibrinogen to platelets or global blood clotting tests such as APTT and prothrombin time.
Enoxaparin binds to anti-thrombin III leading to inhibition of coagulation factors IIa and Xa.
Enoxaparin has been shown to increase the blood concentration of Tissue Factor Pathway Inhibitor in healthy volunteers.
Mechanism of Action: The prophylaxis of thromboembolic disorders of venous origin, in particular those which may be associated with orthopaedic or general surgery.
The prophylaxis of venous thromboembolism in medical patients bedridden due to acute illness.
The treatment of venous thromboembolic disease presenting with deep vein thrombosis, pulmonary embolism or both.
The treatment of unstable angina and non-Q-wave myocardial infarction, administered concurrently with aspirin.
Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI) including patients to be managed medically or with subsequent Percutaneous Coronary Intervention (PCI) in conjunction with thrombolytic drugs (fibrin or non-fibrin specific).
The prevention of thrombus formation in the extracorporeal circulation during haemodialysis.
Pharmacokinetics: Enoxaparin is rapidly and completely absorbed following subcutaneous injection. The maximum plasma anti-Xa activity occurs 1 to 4 hours after injection with peak activities in the order of 0.16 IU/ml and 0.38 IU/ml after doses of 40 mg or 60 mg (for Parin-E 40 mg) and 20 mg or 40 mg (for Parin-E 60 mg) respectively. The anti-Xa activity generated is localised within the vascular compartments and elimination is characterised by a half-life of 4 to 5 hours. Following a 40 mg dose, anti-Xa activity may persist in the plasma for 24 hours.
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.
A linear relationship between anti-Xa plasma clearance and creatinine clearance at steady-state has been observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function. In patients with severe renal impairment (creatinine clearance < 30 ml/min), the AUC at steady state is significantly increased by an average of 65% after repeated, once daily subcutaneous doses of 40 or 60 mg.
Hepatic metabolism by desulphation and depolymerisation also contributes to elimination. The elimination half-life may be prolonged in elderly patients although no dosage adjustment is necessary.
A study of repeated, once daily subcutaneous doses of 1.5 mg/kg in healthy volunteers suggests that no dosage adjustment is necessary in obese subjects (BMI 30-48 kg/m2) compared to non-obese subjects.
Enoxaparin, as detected by anti-Xa activity, does not cross the placental barrier during the second trimester of pregnancy.
Low Body Weight: When non-weight adjusted dosing was administered, it was found after a single-subcutaneous 40 or 60 mg dose, that anti-Xa exposure is 52% higher in low-weight women (<45 kg) and 27% higher in low- weight men (<57 kg) when compared to normal weight control subjects.
Pharmacokinetic interactions: No pharmacokinetic interactions were observed between enoxaparin and thrombolytics when administered concomitantly.
Clinical Trial: The clinical overview is intended to provide an overall clinical finding of the clinical data in the application dossier for the regulatory agencies. This clinical overview (1) presents the strengths and limitations of the development program and study results, (2) analyze the benefits and risks of the medicinal product in its intended use, and (3) describe how the study results/reported literature supports critical parts of prescribing information. The overview of clinical testing strategy is based on the information available in the published literature and Indexed, peer reviewed journals.
This Medicinal product is a parental preparation; therefore the submission of a bioequivalence study is not applicable according to chapter 5.1.6 of the “note for guidance on the investigation of bioavailability and bioequivalence” ( CPMP/EWP/QWP/1401/98).
Both UFH and LMWH exert their anticoagulant activity by activating antithrombin and inhibiting factor Xa. Unlike UFH, LMWH yields a greater selective activity against factor Xa and has a lower affinity for antithrombin. As a result, LMWHs do not significantly alter the activated partial thromboplastin time, and this test is not useful to monitor their effect. LMWH produces a more predictable anticoagulant response, has a better bioavailability, has a longer half-life, and has a dose-independent clearance mechanism compared with UFH. In addition, LMWH has been demonstrated to cause less bleeding than UFH, because it binds less avidly to platelets, does not increase microvascular permeability, and is less likely to interfere with the interaction between platelets and the vessel wall. LWMH does not appear to have as high a risk for the development of thrombocytopenia as UFH.
The duration of action of the LMWHs varies, but antifactor Xa activity may persist up to 12 hours after a single subcutaneous injection. LMWHs are either given in standard doses or in weight-adjusted doses, depending on the agent and the indication. The proper dose for patients at the extremes of body weight has not been studied. The best test to monitor activity is an antifactor Xa assay, but assays may differ and may take time to process. In the event of an overdose, intravenous protamine sulfate can be used to reverse the effects of LMWH, as has been used with reversal of UFH. The specific dose varies for each LMWH, and the package insert should be consulted for proper use.
Pharmacodynamics: Enoxaparin is a low molecular weight heparin with a mean molecular weight of approximately 4,500 daltons. The drug substance is the sodium salt. The molecular weight distribution is: <2000 daltons ≤20%; 2000 to 8000 daltons ≥68%; >8000 daltons ≤18%.
Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic acid group at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of the chain. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains an 1,6 anhydro derivative on the reducing end of the polysaccharide chain.
Enoxaparin sodium is characterised by a higher ratio of antithrombotic activity to anticoagulant activity than unfractionated heparin. At recommended doses, it does not significantly influence platelet aggregation, binding of fibrinogen to platelets or global blood clotting tests such as APTT and prothrombin time.
Enoxaparin binds to anti-thrombin III leading to inhibition of coagulation factors IIa and Xa. Enoxaparin has been shown to increase the blood concentration of Tissue Factor Pathway Inhibitor in healthy volunteers.
Mechanism of Action: Enoxaparin is a low molecular weight heparin which has antithrombotic properties.
Pharmacokinetics: Absorption: Pharmacokinetic trials were conducted using the 100 mg/mL formulation. Maximum anti-Factor Xa and anti-thrombin (anti-Factor IIa) activities occur 3 to 5 hours after SC injection of enoxaparin. Mean peak anti-Factor Xa activity was 0.16 IU/mL (1.58 mcg/mL) and 0.38 IU/mL (3.83 mcg/mL) after the 40 mg and the 60 mg clinically tested SC doses, respectively. Mean (n=46) peak anti-Factor Xa activity was 1.1 IU/mL at steady state in patients with unstable angina receiving 1 mg/kg SC every 12 hours for 14 days. Mean absolute bioavailability of enoxaparin, after 1.5 mg/kg given SC, based on anti-Factor Xa activity is approximately 100% in healthy subjects.
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 84% of steady-state levels. Steady state is achieved on the second day of treatment.
Enoxaparin pharmacokinetics appear to be linear over the recommended dosage ranges. 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 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.
Metabolism: Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or depolymerization to lower molecular weight species with much reduced biological potency.
Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion of active and non-active fragments 40% of the dose.
Enoxaparin binds to and accelerates the activity of antithrombin III. By activating antithrombin III, enoxaparin preferentially potentiates the inhibition of coagulation factors Xa and IIa. The anticoagulant effect of enoxaparin can be directly correlated to its ability to inhibit factor Xa. Factor Xa catalyzes the conversion of prothrombin to thrombin, so enoxaparin’s inhibition of this process results in decreased thrombin and ultimately the prevention of fibrin clot formation.
In a double blind multicenter, parallel group study, Enoxaparin once a day SC was compared to placebo in the prophylaxis of deep vein thrombosis (DVT) in medical patients with severely restricted mobility during acute illness (defined as walking distance of < 10 meters for ≤ 3 days). This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or complicated chronic respiratory insufficiency (not requiring ventilatory support): acute infection (excluding septic shock); or acute rheumatic disorder [acute lumbar or sciatic pain, vertebral compression, acute arthritic episodes of the lower extremities]. A total of 1102 patients were enrolled in the study, and 1073 patients were treated. Patients ranged in age from 40 to 97 years (mean age 73 years) with equal proportions of men and women. Treatment continued for a maximum of 14 days (median duration 7 days). When given at a dose of 40 or 60 mg once a day SC, Enoxaparin significantly reduced the incidence of DVT as compared to placebo.
Similarly, in a multicenter, open-label, parallel group study, patients with acute proximal DVT were randomized to Enoxaparin or heparin. Patients who could not receive outpatient therapy were excluded from entering the study. Outpatient exclusion criteria included the following: inability to receive outpatient heparin therapy because of associated co-morbid conditions or potential for non-compliance and inability to attend follow-up visits as an outpatient because of geographic inaccessibility. Eligible patients could be treated in the hospital, but only Enoxaparin patients were permitted to go home on therapy (72%). A total of 501 patients were randomized in the study and all patients were treated. Patients ranged in age from 19 to 96 years (mean age 57.8 years) with 60.5% men and 39.5% women. Patients were randomized to either Enoxaparin 1 mg/kg every 12 hours SC or heparin IV bolus (5000 IU) followed by a continuous infusion administered to achieve an aPTT of 60 to 85 seconds (in-patient treatment). All patients also received warfarin sodium as described in the previous study. Enoxaparin or standard heparin therapy was administered for a minimum of 5 days. Enoxaparin was equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism.
To assess the safety and efficacy of low- molecular-weight heparins (LMWHs) for thromboprophylaxis and treatment of venous thromboembolism (VTE) in pregnancy, a systematic review of studies to the end of 2003 was undertaken. Data of VTE recurrence and side effects were extracted and cumulative incidences of VTE and adverse effects calculated. Of 81 reports identified, 64 reporting 2777 pregnancies were included. In 15 studies (174 patients) the indication for LMWH was treatment of acute VTE, and in 61 studies (2603 pregnancies) it was thromboprophylaxis or adverse pregnancy outcome. There were no maternal deaths. VTE and arterial thrombosis (associated with anti-phospholipid syndrome) were reported in 0.86% (95% confidence interval [CI], 0.55%-1.28%) and 0.50% (95% CI, 0.28%-0.84%) of pregnancies, respectively. Significant bleeding, generally associated with primary obstetric causes, occurred in 1.98% (95% CI, 1.50%-2.57%), allergic skin reactions in 1.80% (95% CI, 1.34%-2.37%), heparin-induced thrombocytopenia in 0%, thrombocytopenia (unrelated to LMWH) in 0.11% (95% CI, 0.02%-0.32%), and osteoporotic fracture in 0.04% (95% CI, < 0.01%-0.20%) of pregnancies. Overall, live births were reported in 94.7% of pregnancies, including 85.4% in those receiving LMWH for recurrent pregnancy loss. LMWH is both safe and effective to prevent or treat VTE in pregnancy. (Blood. 2005;106:401-407)
In many countries low-molecular-weight heparins (LMWHs) are increasingly used for hemodialysis (HD). Low-range activated clotting time (ACT-LR) values and anti-Xa activity had been used to monitor the degree of anticoagulation caused by LMWH. However, the facilities are not easily available at most hospitals. Such data are limited in Taiwan. Methods: A total of 76 patients receiving maintenance HD were prospectively enrolled. The HD patients were randomized to receive either nadroparin or enoxaparin and checked the ACT-LR values and anti-Xa activity. We aimed to analyze ACT-LR values and anti-Xa activity along with the clotting of the dialyzer or bleeding events associated with two LMWHs after they were administered. We also aimed to determine the dose necessary to reach maximum safety and efficacy. Results: We found no significant differences in LMWH dosage, ACT-LR values, and anti-Xa activity between the two groups. There were no significant differences in bleeding/adverse events and extracorporeal circuit thrombosis between the two groups. Most of the bleeding and adverse events were subcutaneous minor bleeding. No major bleeding or mortality was found. We found significant differences in mean dosage, cost, bleeding/adverse effect, and extracorporeal circuit thrombosis between excessive and reduced nadroparin dosage groups. Conclusion: LMWH is not still routinely used due to its high cost in Taiwan. In our clinical experience, nadroparin and enoxaparin exhibited high levels of safety and efficacy in chronic HD patients. Reduced LMWHs dosage could promote patient's safety and decreased HD cost in HD patients with excessive dosage of LMWHs.
A total of 1224 patients were enrolled in 91 centers in 14 countries between July 1999 and July 2002. Patients with STEMI ineligible for reperfusion were randomized to enoxaparin, enoxaparin plus tirofiban, UFH, or UFH plus tirofiban. All patients received oral aspirin. The primary efficacy end point was the 30-day combined incidence of death, reinfarction, or recurrent angina; the primary analysis was the comparison of the pooled enoxaparin and UFH groups. RESULTS: The incidence of the primary efficacy end point was 15.7% enoxaparin versus 17.3% for UFH (odds ratio 0.89 [95% confidence interval CI=0.66 to 1.21]) and 16.6% for tirofiban versus 16.4% for placebo (odds ratio 1.02 [95% CI 0.75 to 1.38]). The Thrombolysis In Myocardial Infarction (TIMI) major hemorrhage rate was 1.5% for enoxaparin versus 1.3% for UFH (odds ratio 1.16 [95% CI 0.44 to 3.02]) and 1.8% versus 1% for tirofiban versus placebo (odds ratio 1.82 [95% CI 0.67 to 4.95]). Enoxaparin appears to have a similar safety and efficacy profile to UFH and may be an alternative treatment.
In humans, enoxaparin given at a dose of 1.5 mg/kg subcutaneously (SC) is characterized by a higher ratio of anti-Factor Xa to anti-Factor IIa activity (mean ± SD, 14.0 ± 3.1) (based on areas under anti-Factor activity versus time curves) compared to the ratios observed for heparin (mean ± SD, 1.22 ± 0.13). Increases of up to 1.8 times the control values were seen in the thrombin time (TT) and the activated partial thromboplastin time (aPTT). Enoxaparin at a 1mg/kg dose (100 mg/mL concentration), administered SC every 12 hours to patients in a large clinical trial resulted in aPTT values of 45 seconds or less in the majority of patients (n=1607). A 30 mg IV bolus immediately followed by a 1 mg/kg SC administration resulted in aPTT post-injection values of 50 seconds. The average aPTT prolongation value on Day 1 was about 16% higher than on Day 4.
Heparin and its derivative, low-molecular-weight heparin (LMWH), are the anticoagulants of choice when a rapid anticoagulant effect is required, because their onset of action is immediate when administered by IV injection. Both types of heparins are administered in lower doses for primary prophylaxis than for treatment of venous thrombosis or acute myocardial ischemia. Heparin has pharmacokinetic limitations1 not shared by LMWHs. Based on these pharmacokinetic limitations, heparin therapy is usually restricted to the hospital setting, where its effect can be monitored and its dosage adjusted frequently. In contrast, LMWH preparations can be administered in either the in-hospital or out-of-hospital setting because they can be administered subcutaneously (sc) without the need for laboratory monitoring. When long-term anticoagulant therapy is indicated, heparin or LMWH administration is usually followed by treatment with oral anticoagulants. However, long-term out-of-hospital treatment with heparin or LMWH is used when anticoagulant therapy is indicated in pregnancy and in patients who develop recurrent venous thromboembolism while treated with appropriate doses of oral anticoagulant.
Anticoagulation studies in cancer patients with venous thromboembolism (VTE) have compared varying doses of different low molecular weight heparins (LMWH) to warfarin or unfractionated heparin (UFH) regimens, and most guidelines recommend LMWH as the preferred agent over vitamin K antagonists. However, very few studies compare different dosing regimens of the LMWH itself. As a result, practitioners attempt to extrapolate results from studies done in the general medicine population and apply them to cancer patients with VTE. Considering the differences in risk factors and hypercoagulability between these populations, such generalizations may compromise outcomes or safety for cancer patients. Currently, no study to date has compared the safety and efficacy of enoxaparin 1.5 mg/kg subcutaneously (SC) once daily vs. 1mg/kg SC twice daily in a prospective, randomized fashion, for the longterm treatment of VTE in patients with cancer. The purpose of this article is to review currently available literature utilizing these dosing schemes in order to risk-stratify cancer patients who may better qualify for one dosing regimen as compared to the other. Our analysis suggests that enoxaparin dosed at 1.5 mg/kg SC once daily may be a safe and effective alternative for the treatment of VTE in cancer patients with both a low risk of recurrent VTE and bleeding. In the absence of additional studies, the dosing of enoxaparin for cancer patients should be based on patient-specific risk factors.
Detailed Pharmacology: Pharmacodynamics: Enoxaparin is a low molecular weight heparin with a mean molecular weight of approximately 4,500 daltons. The drug substance is the sodium salt. The molecular weight distribution is: <2000 daltons ≤20%; 2000 to 8000 daltons ≥68%; >8000 daltons ≤18%.
Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic acid group at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of the chain. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains an 1,6 anhydro derivative on the reducing end of the polysaccharide chain.
Enoxaparin sodium is characterised by a higher ratio of antithrombotic activity to anticoagulant activity than unfractionated heparin. At recommended doses, it does not significantly influence platelet aggregation, binding of fibrinogen to platelets or global blood clotting tests such as APTT and prothrombin time.
Enoxaparin binds to anti-thrombin III leading to inhibition of coagulation factors IIa and Xa.
Enoxaparin has been shown to increase the blood concentration of Tissue Factor Pathway Inhibitor in healthy volunteers.
Pharmacokinetics:
Pharmacokinetic trials were conducted using the 100 mg/mL formulation. Maximum anti-Factor Xa and anti-thrombin (anti-Factor IIa) activities occur 3 to 5 hours after SC injection of enoxaparin. Mean peak anti-Factor Xa activity was 0.16 IU/mL (1.58 mcg/mL) and 0.38 IU/mL (3.83 mcg/mL) after the 20 mg and the 40 mg (for Parin-E 40 mg), and 40 mg and the 60 mg (for Parin-E 60 mg) clinically tested SC doses, respectively. Mean (n = 46) peak anti-Factor Xa activity was 1.1 IU/mL at steady state in patients with unstable angina receiving 1mg/kg SC every 12 hours for 14 days. Mean absolute bioavailability of enoxaparin, after 1.5 mg/kg given SC, based on anti-Factor Xa activity is approximately 100% in healthy subjects.
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 84% of steady-state levels. Steady state is achieved on the second day of treatment.
Enoxaparin pharmacokinetics appear to be linear over the recommended dosage ranges 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 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.
Toxicology: Preclinical Studies: No long-term studies in animals have been performed to evaluate the carcinogenic potential of enoxaparin.
Enoxaparin was not mutagenic in in vitro tests, including the Ames test, mouse lymphoma cell forward mutation test, and human lymphocyte chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test.
Enoxaparin was found to have no effect on fertility or reproductive performance of male and female rats at SC doses up to 20 mg/kg/day. Teratology studies have been conducted in pregnant rats and rabbits at SC doses of enoxaparin up to 30 mg/kg/day. There was no evidence of teratogenic effects or fetotoxicity due to enoxaparin.
Besides, the anticoagulant effects of enoxaparin, there was no evidence of adverse effects at 15 mg/kg/day in the 13-week subcutaneous toxicity studies both in rats and dogs and at 10mg/kg/day in the 26-week subcutaneous and intravenous toxicity studies both in rats and monkeys.
Clinical Studies: Both UFH and LMWH exert their anticoagulant activity by activating antithrombin and inhibiting factor Xa. Unlike UFH, LMWH yields a greater selective activity against factor Xa and has a lower affinity for antithrombin. As a result, LMWHs do not significantly alter the activated partial thromboplastin time, and this test is not useful to monitor their effect. LMWH produces a more predictable anticoagulant response, has a better bioavailability, has a longer half-life, and has a dose-independent clearance mechanism compared with UFH. In addition, LMWH has been demonstrated to cause less bleeding than UFH, because it binds less avidly to platelets, does not increase microvascular permeability, and is less likely to interfere with the interaction between platelets and the vessel wall.
LMWH does not appear to have as high a risk for the development of thrombocytopenia as UFH. The duration of action of the LMWHs varies, but antifactor Xa activity may persist up to 12 hours after a single subcutaneous injection. LMWHs are either given in standard doses or in weight-adjusted doses, depending on the agent and the indication. The proper dose for patients at the extremes of body weight has not been studied. The best test to monitor activity is an antifactor Xa assay, but assays may differ and may take time to process. In the event of an overdose, intravenous protamine sulfate can be used to reverse the effects of LMWH, as has been used with reversal of UFH. The specific dose varies for each LMWH, and the package insert should be consulted for proper use.
Pharmacodynamics: Enoxaparin is a low molecular weight heparin with a mean molecular weight of approximately 4,500 daltons. The drug substance is the sodium salt. The molecular weight distribution is: <2000 daltons ≤20%; 2000 to 8000 daltons ≥68%; >8000 daltons ≤18%.
Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic acid group at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of the chain. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains an 1,6 anhydro derivative on the reducing end of the polysaccharide chain.
Enoxaparin sodium is characterised by a higher ratio of antithrombotic activity to anticoagulant activity than unfractionated heparin. At recommended doses, it does not significantly influence platelet aggregation, binding of fibrinogen to platelets or global blood clotting tests such as APTT and prothrombin time.
Enoxaparin binds to anti-thrombin III leading to inhibition of coagulation factors IIa and Xa.
Enoxaparin has been shown to increase the blood concentration of Tissue Factor Pathway Inhibitor in healthy volunteers.
Pharmacokinetics: Absorption: Pharmacokinetic trials were conducted using the 100 mg/mL formulation. Maximum anti-Factor Xa and anti-thrombin (anti-Factor IIa) activities occur 3 to 5 hours after SC injection of enoxaparin. Mean peak anti-Factor Xa activity was 0.16 IU/mL (1.58 mcg/mL) and 0.38 IU/mL (3.83 mcg/mL) after the 20 mg and 40 mg (for Parin-E 40 mg) and 40 mg and the 60 mg (Parin-E 60 mg) clinically tested SC doses, respectively. Mean (n=46) peak anti-Factor Xa activity was 1.1 IU/mL at steady state in patients with unstable angina receiving 1 mg/kg SC every 12 hours for 14 days. Mean absolute bioavailability of enoxaparin, after 1.5 mg/kg given SC, based on anti-Factor Xa activity is approximately 100% in healthy subjects.
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 84% of steady-state levels. Steady state is achieved on the second day of treatment.
Enoxaparin pharmacokinetics appear to be linear over the recommended dosage ranges. After repeated subcutaneous administration of 40 or 60 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 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.
Metabolism: Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or depolymerization to lower molecular weight species with much reduced biological potency.
Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion of active and non-active fragments 40% of the dose.
Enoxaparin binds to and accelerates the activity of antithrombin III. By activating antithrombin III, enoxaparin preferentially potentiates the inhibition of coagulation factors Xa and IIa. The anticoagulant effect of enoxaparin can be directly correlated to its ability to inhibit factor Xa. Factor Xa catalyzes the conversion of prothrombin to thrombin, so enoxaparin’s inhibition of this process results in decreased thrombin and ultimately the prevention of fibrin clot formation.
Toxicology: Enoxaparin is one of the most commonly used low-molecular-weight heparins in a wide variety of thromboembolic disorders and has several advantages over unfractionated heparin. An analysis of its biophysical profile, with special emphasis on pharmacokinetic and pharmacodynamic properties, is undertaken in. In addition, most recent major clinical studies elucidating its role in common thromboembolic conditions are discussed, while keeping the historical perspective at hand. Readers will be able to understand the pharmacologic properties of enoxaparin with their clinical relevance for day-to-day use and critically analyze the amount and weight of scientific evidence behind its use in various disorders. In summary, enoxaparin has been shown, by a vast amount of scientific data, to be a safe and effective agent in the treatment of a whole spectrum of acute coronary syndromes, with similar efficacy and safety in the prevention and treatment of venous thromboembolism.
Low molecular weight heparins (LMWHs) have significantly reduced infarct size in animal studies but they have not been effective in clinical trials, probably because they were administered after ischemic injury had become irreversible. The present study was designed to explore the temporal characteristics of the LMWH enoxaparin with the objective of determining the duration of the treatment window in a rat model of temporary focal ischemia. Focal cerebral ischemia was induced by the intraluminal suture, middle cerebral artery occlusion (MCAO) method. Enoxaparin (10 mg/kg) was administered subcutaneously twice; the first dose was administered to different groups of animals either 1 h before or 1.5, 3, or 5 h after MCAO, and the second 4, 6, 9, or 25 h after the first dose. At 48 h animals were tested for motor coordination and brains were removed for determination of infarct size. Results showed that infarct size and degree of motor impairment were a function of time of the first and the second treatments. If the first treatment was given 1 h prior to MCAO, significant reductions in infarct size were obtained when the second treatment was given up to 6 h after the first (5 h after MCAO), but not when the second dose was given at longer intervals. If the first treatment was given 1.5 h after stroke onset, reduced infarct size was observed only in the group treated for the second time 4 h after the first injection. If the first treatment was given 3 h after MCAO, infarct size was not reduced in any group. However, if enoxaparin was administered intravenously rather than subcutaneously, significant reductions in infarct size were obtained when the first dose was given as long as 5 h after MCAO. These findings indicate that enoxaparin can reduce infarct size in rats when administered prior to stroke onset and suggest that the drug might be considered for prophylactic treatment in a phase 3 clinical trial. (See Figures 1 and 2).

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The antithrombotic effects of i.v. aspirin (4-30 mg/kg), heparin (100-500 U/kg), enoxaparin (4-30mg/kg) and clopidogrel (10-20 mg/kg) were studied in a rat Folts-like preparation of carotid arterial thrombosis. The frequency of cyclic flow reductions (CFRs; indicating occlusive thrombus formation) and bleeding time were measured. Drug doses that were singly ineffective at preventing occlusive thrombus formation were tested in the following combinations: aspirin (10 mg/kg) with heparin (250 U/kg); aspirin (4 mg/kg) with enoxaparin (4 mg/kg); and aspirin (10 mg/kg) with clopidogrel (10 mg/kg). Control period (pretreatment) CFRs were not significantly different between groups; average 7.0±0.3 CFRs/30 min (n=64). Tail bleeding time before drug(s) was 3.1±0.1 min (n=86).
When administered alone, aspirin (4-30mg/kg), heparin (250 U/kg) or enoxaparin (4 mg/kg) had no effect on CFRs or bleeding time. Heparin (500 U/kg), enoxaparin (10 and 30 mg/kg) and clopidogrel (20 or 40 mg/kg) significantly decreased CFRs. Single administration of heparin (500 U/kg) or enoxaparin (30 or 60 mg/kg) increased bleeding time by 4- or 11-fold. When co-administered, aspirin 10 mg/kg and heparin 250 U/kg decreased CFRs, but also increased bleeding time by 11-fold. However, combination of aspirin and enoxaparin (4 mg/kg each), or aspirin and clopidogrel (10 mg/kg each), decreased CFRs with no effect on bleeding. In a preparation of arterial thrombosis in the rat, combinations of sub- efficacious (low) doses of aspirin with enoxaparin or clopidogrel inhibited thrombus formation without augmenting bleeding time. However, low-dose aspirin combined with heparin, whilst inhibiting thrombus formation, exacerbated bleeding time. If these findings translate into the clinic, the use of effective low-dose combinations may have therapeutic advantages.
Indications/Uses
Prophylaxis of Deep Vein Thrombosis: PARIN-E is indicated for the Prophylaxis of Deep Vein Thrombosis, which may lead to pulmonary embolism (PE): in patients undergoing abdominal surgery who are at risk for thromboembolic complications [see Clinical Studies under Actions]; in patients undergoing hip replacement surgery, during and following hospitalization; in patients undergoing knee replacement surgery; in medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness.
Treatment of Acute Deep Vein Thrombosis: PARIN-E is indicated for: the inpatient treatment of acute deep vein thrombosis with or without pulmonary embolism, when administered in conjunction with warfarin sodium; the outpatient treatment of acute deep vein thrombosis without pulmonary embolism when administered in conjunction with warfarin sodium.
Prophylaxis of Ischemic Complications of Unstable Angina and Non-Q-Wave Myocardial Infarction: Parin-E is indicated for the prophylaxis of ischemic complications of unstable angina and non Q-wave myocardial infarction, when concurrently administered with aspirin.
Treatment of Acute ST-Segment Elevation Myocardial Infarction: Parin-E, when administered concurrently with aspirin, has been shown to reduce the rate of the combined endpoint of recurrent myocardial infarction or death in patients with acute ST-segment elevation myocardial infarction (STEMI) receiving thrombolysis and being managed medically or with percutaneous coronary intervention (PCI).
Dosage/Direction for Use
Dosing Considerations: See Tables 1 and 2.

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The recommended dosage adjustments do not apply to the haemodialysis indication.
Moderate and mild renal impairment: Although no dosage adjustments are recommended in patients with moderate renal impairment (creatinine clearance 30-50 ml/min) or mild renal impairment (creatinine clearance 50-80 ml/min), careful clinical monitoring is advised.
Dosage Adjustment: Hepatic dysfunction: In the absence of clinical studies, caution should be exercised.
Body weight: No dosage adjustments are recommended in obesity or low body weight PARIN-E is administered by subcutaneous injection for the prevention of venous thromboembolic disease, treatment of deep vein thrombosis or for the treatment of unstable angina, non-Q-wave myocardial infarction and acute ST elevation myocardial infarction (STEMI); through the arterial line of a dialysis circuit for the prevention of thrombus formation in the extra-corporeal circulation during haemodialysis; and via intravenous (bolus) injection through an intravenous line only for the initial dose of acute STEMI indication and before PCI when needed. It must not be administered by the intramuscular route.
To avoid accidental needle stick after injection, the prefilled syringes are fitted with an automatic safety device.
Subcutaneous injection technique: The prefilled disposable syringe is ready for immediate use. PARIN-E should be administered when the patient is lying down by deep subcutaneous injection. The administration should be alternated between the left and right anterolateral or posterolateral abdominal wall. The whole length of the needle should be introduced vertically into a skin fold held between the thumb and index finger. The skin fold should not be released until the injection is complete.
Once the plunger is fully pressed down the safety device is activated automatically. This protects the used needle.
Note: The plunger has to be pressed down all the way for the safety device to be activated.
Do not rub the injection site after administration.
Intravenous (Bolus) Injection Technique (for acute STEMI indication only): For intravenous injection, either the Multidose Vial or 60 mg, 80 mg or 100 mg prefilled syringes can be used. Enoxaparin sodium should be administered through an intravenous line. It should not be mixed or co-administered with other medications. To avoid the possible mixture of enoxaparin sodium with all 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 enoxaparin sodium to clear the port of drug. Enoxaparin sodium may be safely administered with normal saline solution (0.9%) or 5% dextrose in water.
Additional bolus for PCI when last SC administration was given more than 8 hours before balloon insertion: For patients being managed with Percutaneous Coronary Intervention (PCI), an additional IV bolus of 0.3 mg/kg is to be administered if last SC administration was given more than 8 hours before balloon inflation.
In order to assure the accuracy of the small volume to be injected, it is recommended to dilute the drug to 3 mg/ml.
To obtain a 3 mg/ml solution, using a 60 mg enoxaparin sodium prefilled syringe, it is recommended to use a 50 ml infusion bag (i.e. using either normal saline solution (0.9%) or 5% dextrose in water) as follows: Withdraw 30 ml from the infusion bag with a syringe and discard the liquid. Inject the complete contents of the 60 mg enoxaparin sodium prefilled syringe into the 20 ml remaining in the bag. Gently mix the contents of the bag. Withdraw the required volume of diluted solution with a syringe for administration into the intravenous line (using an appropriate injection site or port).
After dilution is completed, the volume to be injected can be calculated using the following formula: [Volume of diluted solution (ml) = Patient weight (kg) x 0.1] or using Table 3. It is recommended to prepare the dilution immediately before use and to discard any remaining solution immediately after use. (See Table 3.)

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Special Patient Groups: Elderly: For treatment of acute ST-segment Elevation Myocardial Infarction in elderly patients ≥75 years of age, do not use an initial IV bolus. Initiate dosing with 0.75 mg/kg SC every 12 hours (maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the remaining doses).
For other indications, no dosage adjustments are necessary in the elderly, unless kidney function is impaired.
Children: Not recommended, as dosage not established.
Renal impairment: In patients with renal impairment, there is an increase in enoxaparin exposure which increases the risk of bleeding. Since enoxaparin exposure is significantly increased in patients with severe renal impairment (creatinine clearance < 30 ml/min) dosage adjustments are recommended in therapeutic and prophylactic dosage ranges. Although no dosage adjustments are recommended in patients with moderate (creatinine clearance 30-50 ml/min) and mild (creatinine clearance 50-80 ml/min) renal impairment, careful clinical monitoring is advised. In the treatment of acute ST-segment Elevation Myocardial Infarction (STEMI), the data are limited in patients with creatinine levels above 220 and 175 μmol/L for males and females respectively.
Severe renal impairment: A dosage adjustment is required for patients with severe renal impairment (creatinine clearance < 30 ml/min), according to the following tables, since enoxaparin sodium exposure is significantly increased in this patient population.
Missed Dose: One should not administer a double dose to make up for a missed one.
Administration: PARIN-E should be administered subcutaneously as a single daily injection of 1.5 mg/kg (150 IU/kg).
PARIN-E treatment is usually prescribed for at least 5 days and until adequate oral anticoagulation is established.
Overdosage
Orally administered enoxaparin is poorly absorbed and even large oral doses should not lead to any serious consequences. This may be checked by plasma assays of anti-Xa and anti-IIa activities. Accidental overdose following parenteral administration may produce haemorrhagic complications. The anticoagulant effects can be largely neutralised by the slow intravenous injection of Protamine, but even with high doses of Protamine, the anti-Xa activity of enoxaparin sodium is never completely neutralised (maximum about 60%). The initial dose of Protamine depends on the dose of enoxaparin given and also consideration of the maximum recommended Protamine dose (50 mg). Data on Protamine dosing in humans for enoxaparin overdose is extremely limited. The available data suggest that in the first 8 hours after enoxaparin administration, 1 mg Protamine should neutralise the effects of 1 mg of enoxaparin. Where the dose of enoxaparin has exceeded 50 mg, an initial dose of 50 mg Protamine would be appropriate, based on the maximum recommended single protamine dose. Decisions regarding the necessity and dose of subsequent Protamine injections should be based on clinical response rather than measurement of anti Xa or anti XIIa results. The physician should also consider that the amount of enoxaparin in the body drops to 50% after 8 hours and 33% or less after 12 hours. The dose of Protamine should be adjusted depending on the length of time since enoxaparin was administered.
Contraindications
Contraindicated in patients with acute bacterial endocarditis, active major bleeding and conditions with a high risk of uncontrolled haemorrhage, including recent haemorrhagic stroke, thrombocytopenia in patients with a positive in-vitro aggregation test in the presence of enoxaparin; active gastric or duodenal ulceration; hypersensitivity to either enoxaparin sodium, heparin or its derivatives including other Low Molecular Weight Heparins; in patients receiving heparin for treatment rather than prophylaxis, locoregional anaesthesia in elective surgical procedures is contraindicated.
Special Precautions
Low Molecular Weight Heparins should not be used interchangeably since they differ in their manufacturing process, molecular weights, specific anti Xa activities, units and dosage. This results in differences in pharmacokinetics and associated biological activities (e.g. Anti-IIa activity, and platelet interactions). Special attention and compliance with the instructions for use specific to each proprietary medicinal product are therefore required.
Enoxaparin is to be used with extreme caution in patients with a history of heparin-induced thrombocytopenia with or without thrombosis.
As there is a risk of antibody-mediated heparin-induced thrombocytopenia also occurring with low molecular weight heparins, regular platelet count monitoring should be considered prior to and during therapy with these agents. Thrombocytopenia, should it occur, usually appears between the 5th and the 21st day following the beginning of therapy. Therefore, it is recommended that the platelet counts be measured before the initiation of therapy with enoxaparin sodium and then regularly thereafter during the treatment. In practice, if a confirmed significant decrease of the platelet count is observed (30 to 50 % of the initial value), enoxaparin sodium treatment must be immediately discontinued and the patient switched to another therapy.
Enoxaparin injection, as with any other anticoagulant therapy, should be used with caution in conditions with increased potential for bleeding, such as: impaired haemostasis, history of peptic ulcer, recent ischaemic stroke, uncontrolled severe arterial hypertension, diabetic retinopathy, recent neuro- or ophthalmologic surgery.
As with other anticoagulants, bleeding may occur at any site. If bleeding occurs, the origin of the haemorrhage should be investigated and appropriate treatment instituted. Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium level or taking potassium sparing drugs. The risk of hyperkalaemia appears to increase with duration of therapy but is usually reversible. Plasma potassium should be measured in patients at risk before starting heparin therapy and monitored regularly thereafter particularly if treatment is prolonged beyond about 7 days.
As with other anti-coagulants, there have been cases of intra-spinal haematomas reported with the concurrent use of enoxaparin sodium and spinal/epidural anaesthesia or spinal puncture resulting in long term or permanent paralysis. These events are rare with enoxaparin sodium dosage regimens 40 mg od or lower. The risk is greater with higher enoxaparin sodium dosage regimens, use of post- operative indwelling catheters or the concomitant use of additional drugs affecting haemostasis such as NSAIDs. The risk also appears to be increased by traumatic or repeated neuraxial puncture or in patients with a history of spinal surgery or spinal deformity.
To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium and epidural anaesthesia/analgesia, the pharmacokinetic profile of the drug should be considered. Placement and removal of the catheter is best performed when the anticoagulation effect of enoxaparin is low.
Placement or removal of a catheter should be delayed for 10-12 hours after administration of DVT prophylactic doses of enoxaparin sodium, whereas patients receiving higher doses of enoxaparin sodium (1.5 mg/kg once daily) will require longer delays (24 hours). The subsequent enoxaparin sodium dose should be given no sooner than 4 hours after catheter removal.
Should the physician decide to administer anticoagulation in the context of epidural/spinal anaesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment 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 nurse or 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.
Percutaneous coronary revascularisation procedures: To minimise the risk of bleeding following vascular instrumentation during the treatment of unstable angina, non-Q-wave myocardial infarction and acute ST-elevation myocardial infarction, adhere precisely to the intervals recommended between enoxaparin sodium doses. It is important to achieve homeostasis at the puncture site after PCI. If a closure device is used, the sheath can be removed immediately. If a manual compression method is used, sheath should be removed 6 hours after the last IV/SC enoxaparin sodium injection. If treatment 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.
For some patients with pulmonary embolism (e.g. those with severe haemodynamic instability) alternative treatment such as thrombolysis or surgery may be indicated.
Prosthetic Heart Valves:
There have been no adequate studies to assess the safe and effective use of enoxaparin sodium in preventing valve thrombosis in patients with prosthetic heart valves. Prophylactic doses of enoxaparin are not sufficient to prevent valve thrombosis in patients with prosthetic heart valves. Confounding factors, including underlying diseases and insufficient clinical data, limit the evaluation of these cases. Therapeutic failures have been reported in pregnant women with prosthetic heart valves on full anti-coagulant doses. The use of enoxaparin sodium cannot be recommended for this purpose.
Haemorrhage in the elderly: No increased bleeding tendency is observed in the elderly within the prophylactic dosage ranges. Elderly patients (especially patients aged eighty years and above) may be at an increased risk for bleeding complications within the therapeutic dosage ranges. In the treatment of acute ST-segment Elevation Myocardial Infarction (STEMI), an increase in bleeding events was observed in patients aged 65-75 years suggesting these patients might be at particular risk of bleeding. Careful clinical monitoring is advised.
Renal impairment: In patients with renal impairment, there is an increase in enoxaparin exposure which increases the risk of bleeding. Since enoxaparin exposure is significantly increased in patients with severe renal impairment (creatinine clearance <30 ml/min) dosage adjustments are recommended in therapeutic and prophylactic dosage ranges. Although no dosage adjustments are recommended in patients with moderate (creatinine clearance 30-50 ml/min) and mild (creatinine clearance 50-80 ml/min) renal impairment, careful clinical monitoring is advised. In the treatment of acute ST-segment Elevation Myocardial Infarction (STEMI), the data are limited in patients with creatinine levels above 220 and 175 μmol/L for males and females respectively.
Low body weight: In low-weight women (< 45 kg) and low-weight men (< 57 kg), an increase in enoxaparin exposure has been observed within the prophylactic dosage ranges (non-weight adjusted), which may lead to a higher risk of bleeding. Therefore, careful clinical monitoring is advised in these patients.
Monitoring: Risk assessment and clinical monitoring are the best predictors of the risk of potential bleeding. Routine anti-Xa activity monitoring is usually not required. However, anti-Xa activity monitoring might be considered in those patients treated with LMWH who also have either an increased risk of bleeding (such as those with renal impairment, elderly and extremes of weight) or are actively bleeding.
Laboratory tests: At doses used for prophylaxis of venous thromboembolism, enoxaparin sodium does not influence bleeding time and global blood coagulation tests significantly, nor does it affect platelet aggregation or binding of fibrinogen to platelets. At higher doses, increases in APTT (activated partial thromboplastin time) and ACT (activated clotting time) may occur. Increases in APTT and ACT are not linearly correlated with increasing enoxaparin sodium antithrombotic activity and therefore are unsuitable and unreliable for monitoring enoxaparin sodium activity.
Use In Pregnancy & Lactation
Do not use in pregnant women with mechanical heart valve as the patient may be at increased risk of developing blood clots.
Do not use during breastfeeding.
Adverse Reactions
Adverse Drug Reaction Overview: The adverse reactions observed in clinical studies and reported in post-marketing experience are detailed as follows.
Frequencies are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1,000); and very rare (<1/10,000) or not known (cannot be estimated from available data). Post-marketing adverse reactions are designated with a frequency "not known".
Haemorrhages: In clinical studies, haemorrhages were the most commonly reported reaction. These included major haemorrhages, reported at most in 4.2 % of the patients (surgical patients1). Some of these cases have been fatal.
As with other anticoagulants, haemorrhage may occur during enoxaparin therapy in the presence of associated risk factors such as: organic lesions liable to bleed, invasive procedures or the concomitant use of medications affecting haemostasis. The origin of the bleeding should be investigated and appropriate treatment instituted. (See Table 4.)

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Thrombocytopenia and thrombocytosis: See Table 5.

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Clinical Trial Adverse Drug Reactions: These reactions are presented as follows, whatever the indications, by system organ class, frequency grouping and decreasing order of seriousness. (See Table 6.)

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Post-Market Adverse Drug Reactions: The following adverse reactions have been identified during post-approval use of PARIN-E. The adverse reactions are derived from spontaneous reports and therefore, the frequency is “not known” (cannot be estimated from the available data).
Immune System Disorders: Anaphylactic/anaphylactoid reaction including shock.
Nervous System Disorders: Headache.
Vascular Disorders: Cases of spinal haematoma (or neuraxial haematoma) have been reported with the concurrent use of enoxaparin sodium as well as spinal/epidural anaesthesia or spinal puncture and post operative indwelling catheters. These reactions have resulted in varying degrees of neurologic injuries including long-term or permanent paralysis.
Blood and Lymphatic System Disorders: Haemorrhagic anaemia. Cases of immuno-allergic thrombocytopenia with thrombosis; in some of them thrombosis was complicated by organ infarction or limb ischaemia. Eosinophilia.
Skin and subcutaneous disorders: Cutaneous vasculitis, skin necrosis usually occurring at the injection site (these phenomena have been usually preceded by purpura or erythematous plaques, infiltrated and painful). Treatment with enoxaparin sodium must be discontinued. Injection site nodules (inflammatory nodules, which were not cystic enclosure of enoxaparin). They resolve after a few days and should not cause treatment discontinuation. Alopecia.
Hepatobiliary disorders: Hepatocellular liver injury. Cholestatic liver injury.
Musculoskeletal and connective tissue disorders: Osteoporosis following long-term therapy (greater than 3 months).
Valve thrombosis in patients with prosthetic heart valves have been reported rarely, usually associated with inadequate dosing.
Heparin products can cause hypoaldosteronism which may result in an increase in plasma potassium.
Rarely, clinically significant hyperkalaemia may occur particularly in patients with chronic renal failure and diabetes mellitus.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Drug Interactions
It is recommended that agents which affect haemostasis should be discontinued prior to enoxaparin therapy unless their use is essential, such as: systemic salicylates, acetylsalicylic acid, NSAIDs including ketorolac, dextran, and clopidogrel, systemic glucocorticoids, thrombolytics and anticoagulants. If the combination cannot be avoided, enoxaparin should be used with careful clinical and laboratory monitoring.
Caution For Usage
Special Handling Instructions: This medicine should not be used after the expiry date (EXP) shown on the pack.
Do not use medicine if particulate matter appears in reconstituted solution.
Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via waste water, and disposal through household waste should be avoided. Established 'collection systems' if available in your location should be used.
Storage
Do not store above 25°C. Do not refrigerate or freeze.
PARIN-E pre-filled syringes are single dose containers-discard any unused product.
Stability of PARIN-E is 24 months.
Patient Counseling Information
1. What is PARIN-E is and what is it used for: The name of the medicine is PARIN-E 40 mg/PARIN-E 60 mg Pre-filled Syringe (called PARIN-E). PARIN-E contains a medicine called enoxaparin sodium. This belongs to a group of medicines called Low Molecular Weight Heparins.
PARIN E works in two ways:1) Stopping existing blood clots from getting any bigger. This helps the body to break them down and stop them causing harm. 2) Stopping blood clots forming in the blood.
What PARIN-E is used for: PARIN-E is used to treat blood clots that are in the blood; stop blood clots forming in the blood in the following situations: unstable angina (where not enough blood gets to the heart), after an operation or long periods of bed rest due to illness, after a heart attack; stop blood clots forming in the tubes of dialysis machine (used for people with kidney problems).
2. Before using PARIN E: Do not take this medicine and tell a doctor, pharmacist or nurse if: The patient is allergic (hypersensitive) to enoxaparin sodium or any of the other ingredients of PARIN-E.
Signs of an allergic reaction include: a rash, swallowing or breathing problems, swelling of the lips, face, throat or tongue.
The patient is allergic to heparin or other Low Molecular Weight Heparins such as tinzaparin or dalteparin. The patient has a problem with bruising or bleeding too easily.
The patient has an ulcer in the stomach or gut (intestine).
The patient has had a stroke caused by bleeding in the brain.
The patient has an infection in the heart.
The patient is using the medicine called heparin to treat blood clots.
Do not take this medicine if any of the above applies to the patient. If the patient is not sure, talk to a doctor, pharmacist or nurse before taking PARIN-E.
Take special care with PARIN-E: Check with a doctor or pharmacist or nurse before using this medicine if: the patient has high blood pressure; the patient has kidney problems; the patient has had a heart valve fitted; the patient has ever had bruising and bleeding caused by the medicine 'heparin'; the patient has ever had a stroke; the patient has ever had a stomach ulcer; the patient has recently had an operation on the eyes or brain; the patient is a diabetic or has an illness known as 'diabetic retinopathy' (problems with the blood vessels in the eye caused by diabetes); the patient has any problems with the blood; the patient is underweight or overweight; the patient is an elderly (over 65 years old) and especially if the patient is aged over 75 years old.
If the patient is not sure if any of the above applies to him/her, he/she should talk to a doctor or pharmacist or nurse before using PARIN-E.
Taking or using other medicines: Please tell a doctor, pharmacist or nurse if the patient is taking or have recently taken any other medicines. This includes medicines the patient buys without a prescription, including herbal medicines. This is because PARIN-E can affect the way some other medicines work. Also some medicines can affect the way PARIN-E works.
In particular, the patient should not take this medicine and tell a doctor if: he/she is using the medicine called heparin to treat blood clots.
The patient should tell a doctor if he/she is taking any of the following medicines: Warfarin-used for thinning the blood. Aspirin, dipyridamole, clopidogrel or other medicines-used to stop blood clots forming. Dextran injection-used as a blood replacer. Ibuprofen, diclofenac, ketorolac or other medicines-used to treat pain and swelling in arthritis and other illnesses. Prednisolone, dexamethasone or other medicines-used to treat asthma, rheumatoid arthritis and other conditions. Water tablets (diuretics) such as spironolactone, triamterene or amiloride. These may increase the levels of potassium in the blood when taken with PARIN-E.
The doctor may change one of the patient's medicines or take regular blood tests to check that taking these medicines with PARIN-E is not causing the patient any harm.
Operations and anaesthetics: If the patient is going to have a spinal puncture or an operation where an epidural or spinal anaesthetic is used, patient should tell a doctor that he/she is using PARIN-E. The patient should also tell a doctor if he/she has any problem with the spine or if he/she has ever had spinal surgery.
Pregnancy and breast-feeding: The patient should talk to a doctor before using this medicine if she is pregnant, might become pregnant, or thinks she may be pregnant.
The patient should not use this medicine if she is pregnant and has a mechanical heart valve as the patient may be at increased risk of developing blood clots. The doctor should discuss this with the patient.
The patient should not breast-feed whilst using PARIN-E. If the patient is planning to breast-feed, she should talk to a doctor, pharmacist or nurse.
The patient should ask a doctor or pharmacist for advice before taking any medicine if she is pregnant or breast- feeding.
3. How to Use Parin-E: Having this medicine: Before the patient uses PARIN-E a doctor or nurse may carry out a blood test.
While the patient is in the hospital, a doctor or nurse will normally give the patient PARIN-E. This is because it needs to be given as an injection.
When the patient goes home, the patient may need to continue to use PARIN-E and give it to himself (see instructions as follows on how to do this).
PARIN-E is usually given by injection underneath the skin (subcutaneous).
If the patient is not sure why he/she is receiving PARIN-E or has any questions about how much PARIN-E is being given to him/her, the patient should speak to a doctor, pharmacist or nurse.
How much will be given to the patient: A doctor will decide how much to give the patient. The amount of PARIN-E given to the patient will depend on the reason it is being used.
If the patient has problems with his/her kidneys, the patient may be given a smaller amount of PARIN-E.
1)Treating blood clots that are in the blood: The usual dose is 1.5 mg for every kilogram of the patient's weight, each day. PARIN-E will usually be given for at least 5 days.
2) Stopping blood clots forming in the blood in the following situations: a) Unstable angina: The usual amount is 1mg for every kilogram of weight, every 12 hours. PARIN-E will usually be given for 2 to 8 days. The doctor will normally ask the patient to take aspirin as well.
b) After an operation or long periods of bed rest due to illness: The usual dose is 40 mg or 60 mg each day. The dose will depend on how likely the patient is to develop a clot: If the patient has a low to medium risk of getting a clot, the patient will be given 40 mg or 60 mg of PARIN-E each day. If the patient is going to have an operation, the patient's first injection will usually be given 2 hours before the operation.
If the patient has a higher risk of getting a clot, the patient will be given 40 mg or 60 mg each day. If the patient is going to have an operation, the patient's first injection will usually be given 12 hours before the operation.
If the patient is bedridden due to illness, the patient will be normally be given 40 mg of PARIN-E each day for 6 to 14 days.
c) After the patient has had a heart attack: PARIN-E can be used for two different types of heart attack called NSTEMI or STEMI. The amount of PARIN E given to the will depend on your age and the kind of heart attack the patient had.
i) NSTEMI type of heart attack: The usual amount is 1 mg for every kilogram of weight, every 12 hours. PARIN-E will usually be given for 2 to 8 days. The doctor will normally ask the patient to take aspirin as well.
ii) STEMI type of heart attack: If the patient is under 75 years old: 30 mg or 40 mg of PARIN-E will be given as an injection into the patient's vein (intravenous injection using PARIN-E Multidose Vial or 60, 80 or 100 mg Pre-filled syringes). At the same time, the patient will also be given PARIN-E as an injection under the skin (subcutaneous injection). The usual dose is 1 mg for every kilogram of the patient's weight. Then the patient will be given 1 mg for every kilogram of his/her weight every 12 hours after that. The maximum amount of PARIN-E given for the first two injections is 100 mg. The injections will normally be given for up to 8 days.
If the patient is aged 75 years or older: The doctor or nurse will give injections of PARIN-E under the patient's skin (subcutaneous injection). The usual dose is 0.75 mg for every kilogram of the patient's weight, every 12 hours. The maximum amount of PARIN-E given for the first two injections is 75 mg.
For patients having an operation called Percutaneous Coronary Intervention (PCI): Depending on when the patient was last given PARIN-E, a doctor may decide to give an additional dose of PARIN-E before a PCI operation. This is by injection into the patient's vein (intravenous using PARIN-E Multidose Vial or 60, 80 or 100 mg Pre-filled syringes).
3) Stop blood clots forming in the tubes of the patient's dialysis machine: The usual dose is 1 mg for every kilogram of the patient's weight.
PARIN-E is added to the tube leaving the body (arterial line) at the start of the dialysis session.
This amount is usually enough for a 4 hour session. However, a doctor may give the patient a further dose of 0.5 to 1 mg for every kilogram of the patient's weight if necessary.
If the patient has more PARIN-E than he/she should: If the patient thinks that he/she has used too much or too little PARIN-E, the patient should tell a doctor, nurse or pharmacist immediately, even if the patient has no signs of a problem. If a child accidentally injects or swallows PARIN-E, take them to a hospital casualty department straight away.
If the patient forgets to use PARIN-E: If the patient forgets to give himself a dose, the patient should have it as soon as he/she remembers. The patient should not give himself a double dose on the same day to make up for a forgotten dose. Keeping a diary will help to make sure the patient does not miss a dose.
If the patient stops using PARIN-E: It is important for the patient to keep having PARIN-E injections until a doctor decides to stop them. If the patient stops, the patient could get a blood clot which can be very dangerous.
Blood Tests: Using PARIN-E may affect the results of some blood tests. If the patient is going to have a blood test, it is important to tell a doctor that the patient is having PARIN-E.
4. Possible side-effects: Like all medicines, PARIN-E can cause side-effects, although not everybody gets them.
The patient should tell a nurse or doctor or go to hospital straight away if the he/she notices any of the following side-effects: Very common (affects more than 1 in 10 people): Bleeding a lot from a wound.
Common (affects 1 to 10 people in a 100): A painful rash of dark red spots under the skin which do not go away when the patient puts pressure on them. The patient may also notice pink patches on the skin. These are more likely to appear in the area the patient has been injected with PARIN-E.
Uncommon (affects 1 to 10 people in a 1,000): Sudden severe headache. This could be a sign of bleeding in the brain. A feeling of tenderness and swelling in the stomach. The patient may have bleeding inside the stomach.
Rare (affects less than 1 in a 1000 people): If the patient has an allergic reaction. The signs may include: a rash, swallowing or breathing problems, swelling of the patient's lips, face, throat or tongue.
If the patient has had a spinal puncture or a spinal anaesthetic and notice tingling, numbness and muscular weakness, particularly in the lower part of his/her body. Also if the patient loses control over his/her bladder or bowel (so the patient cannot control when he/she goes to the toilet).
The patient should tell a nurse or doctor as soon as possible if he/she notices any of the following side effects: Common (affects 1 to 10 people in a 100): The patient bruises more easily than usual. This could be because of a blood problem (thrombocytopenia).
The patient has pain, swelling or irritation in the area he/she has been injected with PARIN-E. This normally gets better after a few days.
Rare (affects less than 1 in a 1000 people): If the patient has a mechanical heart valve, treatment with PARIN-E might not be sufficient to prevent blood clots. The patient may notice that he/she has difficulty breathing, tiredness or difficulty exercising, chest pain, numbness, feeling sick or loss of consciousness. This could be due to a blood clot on the heart valve.
Other side effects that the patient should discuss with a nurse or doctor if he/she is concerned about them: Very common (affects more than 1 in 10 people): Changes in the results of blood tests done to check how the patient's liver is working. These usually go back to normal after the patients stop having PARIN-E.
Rare (affects less than 1 in a 1000 people): Changes in the potassium levels in the patient's blood. This is more likely to happen in people with kidney problems or diabetes. The doctor will be able to check this by carrying out a blood test.
Frequency unknown: If PARIN-E is used for a long period of time, it may increase the risk of the patient getting a condition called ‘osteoporosis’. This is when the patient's bones are more likely to break
5. How to dispose of PARIN-E: Do not store above 25°C. Do not store in a refrigerator or freezer.
Medicines should not be disposed of via wastewater or household waste. If the patient is using this medicine at home, he/she will be given a container (a sharps bin) to use for disposal. The patient should return the sharps bin or any used or unused syringes to a doctor or nurse or pharmacist for disposal. These measures will help to protect the environment.
6. Further Information: What PARIN E contains: Parin-E 40 mg: Each 40 mg pre-filled syringe contains 40 mg (4,000 IU anti-Xa activity) of the active substance, enoxaparin sodium in 0.4 ml. The other ingredient is water for injection.
Parin-E 60 mg: Each 60 mg pre-filled syringe contains 60 mg (6,000 IU anti-Xa activity) of the active substance, enoxaparin sodium in 0.6 ml. The other ingredient is water for injection.
ATC Classification
B01AB05 - enoxaparin ; Belongs to the class of heparin group. Used in the treatment of thrombosis.
Presentation/Packing
Soln for inj (pre-filled syringe) (clear) 40 mg/0.4 mL x 2's. 60 mg/0.6 mL x 2's.
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