Dosage And Administration

All patients should be evaluated for a bleeding disorder before administration of VenoxTaj, unless the medication is needed urgently. Since coagulation parameters are unsuitable for monitoring VenoxTaj activity, routine monitoring of coagulation parameters is not required

For subcutaneous use, VenoxTaj should not be mixed with other injections or infusions. For intravenous use (i.e., for treatment of acute STEMI), VenoxTaj can be mixed with normal saline solution (0.9%) or 5% dextrose in water.

VenoxTaj is not intended for intramuscular administration.

Adult Dosage

Abdominal Surgery: In patients undergoing abdominal surgery who are at risk for thromboembolic complications, the recommended dose of VenoxTaj is 40 mg once a day administered by SC injection with the initial dose given 2 hours prior to surgery. The usual duration of administration is 7 to 10 days; up to 12 days administration has been administered in clinical trials.

Hip or Knee Replacement Surgery: In patients undergoing hip or knee replacement surgery, the recommended dose of VenoxTaj is 30 mg every 12 hours administered by SC injection. Provided that hemostasis has been established, the initial dose should be given 12 to 24 hours after surgery. For hip replacement surgery, a dose of 40 mg once a day SC, given initially 12 (±3) hours prior to surgery, may be considered. Following the initial phase of thromboprophylaxis in hip replacement surgery patients, it is recommended that continued prophylaxis with VenoxTaj 40 mg once a day be administered by SC injection for 3 weeks. The usual duration of administration is 7 to 10 days; up to 14 days administration has been administered in clinical trials.

Medical Patients During Acute Illness: In medical patients at risk for thromboembolic complications due to severely restricted mobility during acute illness, the recommended dose of VenoxTaj is 40 mg once a day administered by SC injection. The usual duration of administration is 6 to 11 days; up to 14 days of VenoxTaj has been administered in the controlled clinical trial.

Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism: In outpatient treatment, patients with acute deep vein thrombosis without pulmonary embolism who can be treated at home, the recommended dose of VenoxTaj is 1 mg/kg every 12 hours administered SC. In inpatient (hospital) treatment, patients with acute deep vein thrombosis with pulmonary embolism or patients with acute deep vein thrombosis without pulmonary embolism (who are not candidates for outpatient treatment), the recommended dose of VenoxTaj is 1 mg/kg every 12 hours administered SC or 1.5 mg/kg once a day administered SC at the same time every day. In both outpatient and inpatient (hospital) treatments, warfarin sodium therapy should be initiated when appropriate (usually within 72 hours of VenoxTaj). VenoxTaj should be continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (International Normalization Ratio 2.0 to 3.0). The average duration of administration is 7 days; up to 17 days of VenoxTaj administration has been administered in controlled clinical trials.

Unstable Angina and Non-Q-Wave Myocardial Infarction: In patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of VenoxTaj is 1 mg/kg administered SC every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily). Treatment with VenoxTaj should be prescribed for a minimum of 2 days and continued until clinical stabilization. The usual duration of treatment is 2 to 8 days; up to 12.5 days of VenoxTaj has been administered in clinical trials.

Treatment of Acute ST-Segment Elevation Myocardial Infarction: In patients with acute ST-segment elevation myocardial infarction, the recommended dose of VenoxTaj 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 the first two doses only, followed by 1 mg/kg dosing for the remaining doses). Dosage adjustments are recommended in patients ≥75 years of age [see Dosage and Administration (2.3)]. All patients should receive aspirin as soon as they are identified as having STEMI and maintained with 75 to 325 mg once daily unless contraindicated.

When administered in conjunction with a thrombolytic (fibrin-specific or non-fibrin specific), VenoxTaj should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. In the pivotal clinical study, the VenoxTaj treatment duration was 8 days or until hospital discharge, whichever came first. An optimal duration of treatment is not known, but it is likely to be longer than 8 days.

For patients managed with percutaneous coronary intervention (PCI): If the last VenoxTaj SC administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last VenoxTaj SC administration was given more than 8 hours before balloon inflation, an IV bolus of 0.3 mg/kg of VenoxTaj should be administered

Administration

VenoxTaj is a clear, colorless to pale yellow sterile solution, and as with other parenteral drug products, should be inspected visually for particulate matter and discoloration prior to administration.

The use of a tuberculin syringe or equivalent is recommended when using VenoxTaj multiple-dose vials to assure withdrawal of the appropriate volume of drug.

VenoxTaj must not be administered by intramuscular injection. VenoxTaj is intended for use under the guidance of a physician.

For subcutaneous administration, patients may self-inject only if their physicians determine that it is appropriate and with medical follow-up, as necessary. Proper training in subcutaneous injection technique (with or without the assistance of an injection device) should be provided.

Contraindications

• Active major bleeding

• Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of enoxaparin sodium

• Known hypersensitivity to enoxaparin sodium (e.g., pruritus, urticaria, anaphylactic/anaphylactoid reactions)

• Known hypersensitivity to heparin or pork products

• Known hypersensitivity to benzyl alcohol (which is in only the multi-dose formulation of VenoxTaj)

Warnings And Precautions

Increased Risk of Hemorrhage

Cases of epidural or spinal hematomas have been reported with the associated use of VenoxTaj and spinal/epidural anesthesia or spinal puncture resulting in long-term or permanent paralysis. The risk of these events is higher with the use of post-operative indwelling epidural catheters or by the concomitant use of additional drugs affecting hemostasis such as NSAIDs

VenoxTaj should be used with extreme caution in conditions with increased risk of hemorrhage, 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 hemorrhages including retroperitoneal and intracranial bleeding have been reported. Some of these cases have been fatal.

Bleeding can occur at any site during therapy with VenoxTaj. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site.

Percutaneous Coronary Revascularization Procedures

To minimize the risk of bleeding following the vascular instrumentation during the treatment of unstable angina, non-Q-wave myocardial infarction and acute ST-segment elevation myocardial infarction, adhere precisely to the intervals recommended between VenoxTaj doses. It is important to achieve hemostasis 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, sheath should be removed 6 hours after the last IV/SC VenoxTaj. 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 hematoma formation

Use of VenoxTaj with Concomitant Medical Conditions

VenoxTaj should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction and hemorrhage.

History of Heparin-Induced Thrombocytopenia

VenoxTaj should be used with extreme caution in patients with a history of heparin-induced thrombocytopenia.

Thrombocytopenia

Thrombocytopenia can occur with the administration of VenoxTaj.

Moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) occurred at a rate of 1.3% in patients given VenoxTaj, 1.2% in patients given heparin, and 0.7% in patients given placebo in clinical trials.

Platelet counts less than 50,000/mm3 occurred at a rate of 0.1% in patients given VenoxTaj, 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/mm3, VenoxTaj 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

Interchangeability with Other Heparins

VenoxTaj cannot be used interchangeably (unit for unit) with heparin or other low molecular weight heparins as they differ in manufacturing process, molecular weight distribution, anti -Xa and anti-IIa activities, units, and dosage. Each of these medicines has its own instructions for use.

Pregnant Women with Mechanical Prosthetic Heart Valves

The use of VenoxTaj 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 enoxaparin (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 fetal death. Although a causal relationship has not been established these deaths may have been due to therapeutic failure or inadequate anticoagulation. No patients in the heparin/warfarin group (0 of 4 women) died. There also have been isolated postmarketing reports of valve thrombosis in pregnant women with mechanical prosthetic heart valves while receiving enoxaparin for thromboprophylaxis. Women with mechanical prosthetic heart valves may be at higher risk for thromboembolism during pregnancy, and, when pregnant, have a higher rate of fetal loss from stillbirth, spontaneous abortion and premature delivery. Therefore, frequent monitoring of peak and trough anti-Factor Xa levels, and adjusting of dosage may be needed

Benzyl Alcohol

VenoxTaj multiple-dose vials contain benzyl alcohol as a preservative. The administration of medications containing benzyl alcohol as a preservative to premature neonates has been associated with a fatal “gasping syndrome”. Because benzyl alcohol may cross the placenta, VenoxTaj multiple-dose vials, preserved with benzyl alcohol, should be used with caution in pregnant women and only if clearly needed

Laboratory Tests

Periodic complete blood counts, including platelet count, and stool occult blood tests are recommended during the course of treatment with VenoxTaj. When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of VenoxTaj activity and, therefore, unsuitable for monitoring. Anti-Factor Xa may be used to monitor the anticoagulant effect of VenoxTaj in patients with significant renal impairment. If during VenoxTaj therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa levels may be used to monitor the anticoagulant effects of VenoxTaj

Adverse Reactions

Clinical Trials Experience

The following serious adverse reactions are also discussed in other sections of the labeling:

• Spinal/epidural hematoma [see Boxed Warning]

• Increased Risk of Hemorrhage

• Thrombocytopenia

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

During clinical development for the approved indications, 15,918 patients were exposed to enoxaparin sodium. These included 1,228 for prophylaxis of deep vein thrombosis following abdominal surgery in patients at risk for thromboembolic complications, 1,368 for prophylaxis of deep vein thrombosis following hip or knee replacement surgery, 711 for prophylaxis of deep vein thrombosis in medical patients with severely restricted mobility during acute illness, 1,578 for prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial infarction, 10,176 for treatment of acute ST-elevation myocardial infarction, and 857 for treatment of deep vein thrombosis with or without pulmonary embolism. Enoxaparin sodium doses in the clinical trials for prophylaxis of deep vein thrombosis following abdominal or hip or knee replacement surgery or in medical patients with severely restricted mobility during acute illness ranged from 40 mg SC once daily to 30 mg SC twice daily. In the clinical studies for prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction doses were 1 mg/kg every 12 hours and in the clinical studies for treatment of acute ST-segment elevation myocardial infarction enoxaparin sodium doses were a 30 mg IV bolus followed by 1 mg/kg every 12 hours SC.

Elevations of Serum Aminotransferases

Asymptomatic increases in aspartate (AST [SGOT]) and alanine (ALT [SGPT]) aminotransferase levels greater than three times the upper limit of normal of the laboratory reference range have been reported in up to 6.1% and 5.9% of patients, respectively, during treatment with VenoxTaj. Similar significant increases in aminotransferase levels have also been observed in patients and healthy volunteers treated with heparin and other low molecular weight heparins. Such elevations are fully reversible and are rarely associated with increases in bilirubin.

Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like VenoxTaj should be interpreted with caution.

Local Reactions

Mild local irritation, pain, hematoma, ecchymosis, and erythema may follow SC injection of VenoxTaj.

Drug Interactions

Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued prior to initiation of VenoxTaj therapy. These agents include medications such as: anticoagulants, platelet inhibitors including acetylsalicylic acid, salicylates, NSAIDs (including ketorolac tromethamine), dipyridamole, or sulfinpyrazone. If co-administration is essential, conduct close clinical and laboratory monitoring

Use In Specific Populations

Pregnancy

Pregnancy Category B

All pregnancies have a background risk of birth defect, loss, or other adverse outcome regardless of drug exposure. The fetal risk summary below describes the potential of VenoxTaj to increase the risk of developmental abnormalities above the background risk.

Fetal Risk Summary

VenoxTaj does not cross the placenta, and is not expected to result in fetal exposure to the drug. Human data from a retrospective cohort study, which included 693 live births, suggest that VenoxTaj does not increase the risk of major developmental abnormalities. Based on animal data, enoxaparin is not predicted to increase the risk of major developmental abnormalities

Clinical Considerations

Pregnancy alone confers an increased risk for thromboembolism that is even higher for women with thromboembolic disease and certain high risk pregnancy conditions. While not adequately studied, pregnant women with mechanical prosthetic heart valves may be at even higher risk for thrombosis [see Warnings and Precautions (5.7) and Use in Specific Populations (8.6) ]. Pregnant women with thromboembolic disease, including those with mechanical prosthetic heart valves and those with inherited or acquired thrombophilias, have an increased risk of other maternal complications and fetal loss regardless of the type of anticoagulant used.

All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. Pregnant women receiving enoxaparin should be carefully monitored for evidence of bleeding or excessive anticoagulation. Consideration for use of a shorter acting anticoagulant should be specifically addressed as delivery approaches [see Boxed Warning ]. Hemorrhage can occur at any site and may lead to death of mother and/or fetus. Pregnant women should be apprised of the potential hazard to the fetus and the mother if enoxaparin is administered during pregnancy.

It is not known if monitoring of anti-Factor Xa activity and dose adjustment (by weight or anti-Factor Xa activity) of VenoxTaj affect the safety and the efficacy of the drug during pregnancy. Cases of “gasping syndrome” have occurred in premature infants when large amounts of benzyl alcohol have been administered (99 -405 mg/kg/day). The multiple-dose vial of VenoxTaj contains 15 mg benzyl alcohol per 1 mL as a preservative

Nursing Mothers

It is not known whether VenoxTaj is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VenoxTaj, a decision should be made whether to discontinue nursing or discontinue VenoxTaj, taking into account the importance of VenoxTaj to the mother and the known benefits of nursing.

Pediatric Use

Safety and effectiveness of VenoxTaj in pediatric patients have not been established.

Geriatric use

Prevention of Deep Vein Thrombosis in Hip, Knee and Abdominal Surgery; Treatment of Deep Vein Thrombosis, Prevention of Ischemic Complications of Unstable Angina and Non-Q-wave Myocardial Infarction Over 2800 patients, 65 years and older, have received VenoxTaj in pivotal clinical trials. The efficacy of VenoxTaj in the geriatric (65 years) was similar to that seen in younger patients years). The incidence of bleeding complications was similar between geriatric and younger patients when 30 mg every 12 hours or 40 mg once a day doses of VenoxTaj were employed. The incidence of bleeding complications was higher in geriatric patients as compared to younger patients when VenoxTaj was administered at doses of 1.5 mg/kg once a day or 1 mg/kg every 12 hours. The risk of VenoxTaj-associated bleeding increased with age. Serious adverse events increased with age for patients receiving VenoxTaj. Other clinical experience (including postmarketing surveillance and literature reports) has not revealed additional differences in the safety of VenoxTaj between geriatric and younger patients. Careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) is advised. VenoxTaj should be used with care in geriatric patients who may show delayed elimination of enoxaparin. Monitoring of geriatric patients with low body weight (45 kg) and those predisposed to decreased renal function should be considered [see Warnings and Precautions

Treatment of Acute ST-Segment Elevation Myocardial Infarction

In the clinical study for treatment of acute ST-segment elevation myocardial infarction, there was no evidence of difference in efficacy between patients  years of age (n = 1241) and patients less than 75 years of age (n=9015). Patients  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 Dosage and Administration (2.3)]. The incidence of bleeding complications was higher in patients 65 years of age as compared to younger patients (65 years).

Patients with Mechanical Prosthetic Heart Valves

The use of VenoxTaj has not been adequately studied for thromboprophylaxis in patients with mechanical prosthetic heart valves and has not been adequately studied for long-term use in this patient population. Isolated cases of prosthetic heart valve thrombosis have been reported in patients with mechanical prosthetic heart valves who have received enoxaparin for thromboprophylaxis. Some of these cases were pregnant women in whom thrombosis led to maternal and fetal deaths. Insufficient data, the underlying disease and the possibility of inadequate anticoagulation complicate the evaluation of these cases. Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism

Renal Impairment

In patients with renal impairment, there is an increase in exposure of enoxaparin sodium. All such patients should be observed carefully for signs and symptoms of bleeding. Because exposure of enoxaparin sodium 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. No dosage adjustment is recommended in patients with moderate (creatinine clearance 30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. In patients with renal failure, treatment with enoxaparin has been associated with the development of hyperkalemia

Hepatic Impairment

The impact of hepatic impairment on enoxaparin’s exposure and antithrombotic effect has not been investigated. Caution should be exercised when administering enoxaparin to patients with hepatic impairment.

Low-Weight Patients

An increase in exposure of enoxaparin sodium with prophylactic dosages (non-weight adjusted) has been observed in low-weight women (45 kg) and low-weight men (57 kg). All such patients should be observed carefully for signs and symptoms of bleeding