Lovenox Drug Information

Pretreatment Evaluation

Evaluate all patients for a bleeding disorder before starting Lovenox treatment, unless treatment is urgently needed.

Adult Dosage Abdominal Surgery

The recommended dose of Lovenox is 40 mg by subcutaneous injection once a day (with the initial dose given 2 hours prior to surgery) in patients undergoing abdominal surgery who are at risk for thromboembolic complications. The usual duration of administration is 7 to 10 days. Hip or Knee Replacement Surgery The recommended dose of Lovenox is 30 mg every 12 hours administered by subcutaneous injection in patients undergoing hip or knee replacement surgery.

Administer the initial dose 12 to 24 hours after surgery, provided that hemostasis has been established. A dose of Lovenox of 40 mg once a day subcutaneously may be considered for hip replacement surgery for up to 3 weeks. Administer the initial dose 12 (±3) hours prior to surgery.

Medical Patients during Acute Illness The recommended dose of Lovenox is 40 mg once a day administered by subcutaneous injection for medical patients at risk for thromboembolic complications due to severely restricted mobility during acute illness. The usual duration of administration is 6 to 11 days. Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism The recommended dose of Lovenox is 1 mg/kg every 12 hours administered subcutaneously in patients with acute deep vein thrombosis without pulmonary embolism, who can be treated at home in an outpatient setting.

The recommended dose of Lovenox is 1 mg/kg every 12 hours administered subcutaneously or 1.5 mg/kg once a day administered subcutaneously at the same time every day for inpatient (hospital) treatment of 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). In both outpatient and inpatient (hospital) treatments, initiate warfarin sodium therapy when appropriate (usually within 72 hours of Lovenox). Continue Lovenox for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (International Normalization Ratio 2 to 3).

The average duration of administration is 7 days. Unstable Angina and Non–Q-Wave Myocardial Infarction The recommended dose of Lovenox is 1 mg/kg administered subcutaneously every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily) in patients with unstable angina or non–Q-wave myocardial infarction. Treat with Lovenox for a minimum of 2 days and continue until clinical stabilization.

The usual duration of treatment is 2 to 8 days. Treatment of Acute ST-Segment Elevation Myocardial Infarction The recommended dose of Lovenox is a single intravenous bolus of 30 mg plus a 1 mg/kg subcutaneous dose followed by 1 mg/kg administered subcutaneously every 12 hours (maximum 100 mg for the first two doses only, followed by 1 mg/kg dosing for the remaining doses) in patients with acute ST-segment elevation myocardial infarction. Reduce the dosage in patients ≥75 years of age.

Unless contraindicated, administer aspirin to all patients as soon as they are identified as having STEMI and continue dosing with 75 to 325 mg once daily. When administered in conjunction with a thrombolytic (fibrin specific or non–fibrin specific), administer Lovenox between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. The usual duration of Lovenox therapy is 8 days or until hospital discharge.

For patients managed with percutaneous coronary intervention (PCI), if the last Lovenox subcutaneous administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last Lovenox subcutaneous administration was given more than 8 hours before balloon inflation, administer an intravenous bolus of 0.3 mg/kg of Lovenox.

Dose Reduction for Patients with Severe Renal Impairment

The recommended prophylaxis and treatment dosage regimens for patients with severe renal impairment (creatinine clearance <30 mL/min) are described in Table 1. Table 1: Dosage Regimens for Patients with Severe Renal Impairment (creatinine clearance <30 mL/minute) Although no dose adjustment is recommended in patients with creatinine clearance 30 to 50 mL/min and creatinine clearance 50 to 80 mL/min, observe these patients frequently for signs and symptoms of bleeding.

Recommended Dosage for Geriatric Patients with Acute ST-Segment Elevation Myocardial Infarction For treatment of acute ST-segment elevation myocardial infarction in geriatric patients ≥75 years of age, do not use an initial intravenous bolus. No dose adjustment is necessary for other indications in geriatric patients unless kidney function is impaired.

Administration

Do not administer Lovenox by intramuscular injection. Administer Lovenox by intravenous or subcutaneous injection only. Lovenox 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.

Use a tuberculin syringe or equivalent when using Lovenox multiple-dose vials to assure withdrawal of the appropriate volume of drug. Patients may self-inject by the subcutaneous route of administration only after their physicians determine that it is appropriate and with medical follow-up, as necessary. Provide proper training in subcutaneous injection technique before allowing self-injection (with or without the assistance of an injection device).

Subcutaneous Injection Technique • Position patients in a supine position for Lovenox administration by deep subcutaneous injection. • Do not expel the air bubble from the prefilled syringes before the injection, to avoid the loss of drug. • Do not inject into skin that has bruises or scars. Do not inject through clothes. • Alternate injection sites between the left and right anterolateral and left and right posterolateral abdominal wall. • Introduce the whole length of the needle into a skin fold held between the thumb and forefinger; hold the skin fold throughout the injection. To minimize bruising, do not rub the injection site after completion of the injection.

Lovenox prefilled syringes and graduated prefilled syringes are for single, one-time use only and are available with a system that shields the needle after injection. Remove the prefilled syringe from the packaging by peeling at the arrow as directed on the lid. Do not remove by pulling on the plunger as this may damage the syringe. 1.

Remove the needle shield by pulling it straight off the syringe (see Figure A ). If less than the full syringe volume is needed to administer the prescribed dose, eject syringe contents until the prescribed dose is left in the syringe. Figure A 2. 3.

Inject using standard technique, pushing the plunger to the bottom of the syringe (see Figure B ). Figure B 4. 5. Remove the syringe from the injection site keeping your finger on the plunger rod (see Figure C ).

Figure C 6. 7. Orient the needle away from you and others, and activate the safety system by firmly pushing the plunger rod. The protective sleeve will automatically cover the needle and an audible "click" will be heard to confirm shield activation (see Figure D ).

Figure D 8. 9. Immediately dispose of the syringe in the nearest sharps container (see Figure E ). Figure E 10.

NOTE: • The safety system can only be activated once the syringe has been emptied. • Activation of the safety system must be done only after removing the needle from the patient's skin. • Do not replace the needle shield after injection. • The safety system should not be sterilized. Activation of the safety system may cause minimal splatter of fluid. For optimal safety, activate the system while orienting it downwards away from yourself and others.

Figure A Figure B Figure C Figure D Figure E Intravenous (Bolus) Injection Technique Use the multiple-dose vial for intravenous injections. Administer Lovenox through an intravenous line. Do not mix or coadminister Lovenox with other medications.

Flush the intravenous access device with a sufficient volume of saline or dextrose solution prior to and following the intravenous bolus administration of Lovenox, to prevent mixing of drugs. Lovenox is compatible with normal saline solution (0.9%) or 5% dextrose in water.

Monitoring for Safety

During therapy monitor complete blood counts including platelets and stool occult blood. Assess for signs and symptoms of bleeding. In patients with renal impairment anti-Factor Xa levels may be used to monitor the anticoagulant effects of Lovenox.

If during Lovenox therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa levels may be used to monitor the anticoagulant effects of Lovenox. Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are not adequate for monitoring the anticoagulant effects of Lovenox.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. During clinical development for the approved indications, 15,918 patients were exposed to Lovenox. 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.

Lovenox 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 subcutaneously once daily to 30 mg subcutaneously 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 Lovenox doses were a 30 mg intravenous bolus followed by 1 mg/kg every 12 hours subcutaneously. Hemorrhage The following rates of major bleeding events have been reported during clinical trials with Lovenox (see Tables 2 to 7).

Table 2: Major Bleeding Episodes following Abdominal and Colorectal Surgery Bleeding complications were considered major: if the hemorrhage caused a significant clinical event, or if accompanied by a hemoglobin decrease ≥2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal, intraocular, and intracranial hemorrhages were always considered major. In the knee replacement surgery trials, intraocular hemorrhages were also considered major hemorrhages.

NOTE: At no time point were the 40 mg once a day pre-operative and the 30 mg every 12 hours postoperative hip replacement surgery prophylactic regimens compared in clinical trials. Injection site hematomas during the extended prophylaxis period after hip replacement surgery occurred in 9% of the Lovenox patients versus 1.8% of the placebo patients. Table 4: Major Bleeding Episodes in Medical Patients with Severely Restricted Mobility during Acute Illness Bleeding complications were considered major: if the hemorrhage caused a significant clinical event, if the hemorrhage caused a decrease in hemoglobin of ≥2 g/dL or transfusion of 2 or more units of blood products.

Retroperitoneal and intracranial hemorrhages were always considered major although none were reported during the trial. Table 5: Major Bleeding Episodes in Deep Vein Thrombosis with or without Pulmonary Embolism Treatment Bleeding complications were considered major: if the hemorrhage caused a significant clinical event, or if accompanied by a hemoglobin decrease ≥2 g/dL or transfusion of 2 or more units of blood products. Table 6: Major Bleeding Episodes in Unstable Angina and Non–Q-Wave Myocardial Infarction Dosing Regimen Indication Lovenox The rates represent major bleeding on study medication up to 12 hours after dose. 1 mg/kg q12h subcutaneously Heparin aPTT Adjusted Intravenous Therapy Unstable Angina and Non–Q-Wave MI Aspirin therapy was administered concurrently (100 to 325 mg per day)., Bleeding complications were considered major: if the hemorrhage caused a significant clinical event, or if accompanied by a hemoglobin decrease by ≥3 g/dL or transfusion of 2 or more units of blood products.

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 Lovenox should be interpreted with caution. Local Reactions Local irritation, pain, hematoma, ecchymosis, and erythema may follow subcutaneous injection of Lovenox. Adverse Reactions in Patients Receiving Lovenox for Prophylaxis or Treatment of DVT, PE Other adverse reactions that were thought to be possibly or probably related to treatment with Lovenox, heparin, or placebo in clinical trials with patients undergoing hip or knee replacement surgery, abdominal or colorectal surgery, or treatment for DVT and that occurred at a rate of at least 2% in the Lovenox group, are provided below (see Tables 8 to 11).

Table 8: Adverse Reactions Occurring at ≥2% Incidence in Lovenox-Treated Patients Undergoing Abdominal or s Occurring at ≥2% Incidence in Lovenox-Treated Patients Undergoing Hip or Knee Replacement Surgery s Occurring at ≥2% Incidence in Lovenox-Treated Medical Patients with Severely Restricted Mobility during Acute Illness s Occurring at ≥2% Incidence in Lovenox-Treated Patients Undergoing Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism s in Lovenox-Treated Patients with Unstable Angina or Non–Q-Wave Myocardial Infarction Non-hemorrhagic clinical events reported to be related to Lovenox therapy occurred at an incidence of ≤1%. Non-major hemorrhagic events, primarily injection site ecchymosis and hematomas, were more frequently reported in patients treated with subcutaneous Lovenox than in patients treated with intravenous heparin. Serious adverse events with Lovenox or heparin in a clinical trial in patients with unstable angina or non–Q-wave myocardial infarction that occurred at a rate of at least 0.5% in the Lovenox group are provided below (see Table 12 ).

Table 12: Serious Adverse Events Occurring at ≥0.5% Incidence in Lovenox-Treated Patients with Unstable Angina or Non–Q-Wave Myocardial Infarction In a clinical trial in patients with acute ST-segment elevation myocardial infarction, thrombocytopenia occurred at a rate of 1.5%.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Lovenox. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. There have been reports of epidural or spinal hematoma formation with concurrent use of Lovenox and spinal/epidural anesthesia or spinal puncture.

The majority of patients had a postoperative indwelling epidural catheter placed for analgesia or received additional drugs affecting hemostasis such as NSAIDs. Many of the epidural or spinal hematomas caused neurologic injury, including long-term or permanent paralysis. Local reactions at the injection site (e.g. nodules, inflammation, oozing), systemic allergic reactions (e.g. pruritus, urticaria, anaphylactic/anaphylactoid reactions including shock), vesiculobullous rash, cases of hypersensitivity cutaneous vasculitis, purpura, skin necrosis (occurring at either the injection site or distant from the injection site), thrombocytosis, and thrombocytopenia with thrombosis have been reported.

Cases of hyperkalemia have been reported. Most of these reports occurred in patients who also had conditions that tend toward the development of hyperkalemia (e.g., renal dysfunction, concomitant potassium-sparing drugs, administration of potassium, hematoma in body tissues). Very rare cases of hyperlipidemia have also been reported, with one case of hyperlipidemia, with marked hypertriglyceridemia, reported in a diabetic pregnant woman; causality has not been determined.

Cases of headache, hemorrhagic anemia, eosinophilia, alopecia, hepatocellular and cholestatic liver injury have been reported. Osteoporosis has also been reported following long-term therapy.

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

Discontinue agents which may enhance hemorrhage risk prior to initiation of Lovenox or conduct close clinical and laboratory monitoring.

Pregnancy Risk Summary Placental transfer of enoxaparin was observed in the animal studies. Human data from a retrospective cohort study, which included 693 live births, suggest that enoxaparin does not increase the risk of major developmental abnormalities (see Data ). Based on animal data, Lovenox is not predicted to increase the risk of major developmental abnormalities (see Data ).

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.

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. 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 Lovenox 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.

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 Lovenox 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 Lovenox 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 Lovenox contains 15 mg benzyl alcohol per 1 mL as a preservative. Data Human data There are no adequate and well-controlled studies in pregnant women.

A retrospective study reviewed the records of 604 women who used Lovenox during pregnancy. A total of 624 pregnancies resulted in 693 live births. There were 72 hemorrhagic events (11 serious) in 63 women.

There were 14 cases of neonatal hemorrhage. Major congenital anomalies in live births occurred at rates (2.5%) similar to background rates. There have been postmarketing reports of fetal death when pregnant women received Lovenox.

Causality for these cases has not been determined. Insufficient data, the underlying disease, and the possibility of inadequate anticoagulation complicate the evaluation of these cases. A clinical study using Lovenox in pregnant women with mechanical prosthetic heart valves has been conducted.

Animal data Teratology studies have been conducted in pregnant rats and rabbits at subcutaneous doses of enoxaparin up to 15 times the recommended human dose (by comparison with 2 mg/kg as the maximum recommended daily dose). There was no evidence of teratogenic effects or fetotoxicity due to enoxaparin. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Pediatric Use Safety and effectiveness of Lovenox in pediatric patients have not been established. Lovenox is not approved for use in neonates or infants. Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and low-birth-weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative.

In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth-weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.

The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Lovenox multiple-dose vials contain 15 mg/mL of benzyl alcohol (at the dose of 1.5 mg/kg twice a day, benzyl alcohol exposure in patients is 0.45 mg/kg daily).

• Lovenox is contraindicated in patients with:
• Active major bleeding
• History of immune-mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies
• 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 multiple-dose formulation of Lovenox)
• Active major bleeding
• Hypersensitivity to enoxaparin sodium
• Hypersensitivity to benzyl alcohol (for multiple-dose formulation only)

Accidental overdosage following administration of Lovenox may lead to hemorrhagic complications. Injected Lovenox may be largely neutralized by the slow intravenous injection of protamine sulfate (1% solution). The dose of protamine sulfate should be equal to the dose of Lovenox injected: 1 mg protamine sulfate should be administered to neutralize 1 mg Lovenox, if Lovenox was administered in the previous 8 hours.

An infusion of 0.5 mg protamine per 1 mg of Lovenox may be administered if Lovenox was administered greater than 8 hours previous to the protamine administration, or if it has been determined that a second dose of protamine is required. If at least 12 hours have elapsed since the last Lovenox injection, protamine administration may not be required; however, even with higher doses of protamine, the aPTT may remain more prolonged than following administration of heparin. In all cases, the anti-Factor Xa activity is never completely neutralized (maximum about 60%).

Particular care should be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, it should be given only when resuscitation techniques and treatment of anaphylactic shock are readily available.

For additional information consult the labeling of protamine sulfate injection products.