Enoxaparin Sodium (Page 6 of 16)

Adverse Events in Enoxaparin Sodium Injection-Treated Patients with Unstable Angina or Non-Q-Wave Myocardial Infarction:

Non-hemorrhagic clinical events reported to be related to enoxaparin sodium injection 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 enoxaparin sodium injection than in patients treated with intravenous heparin.

Serious adverse events with enoxaparin sodium injection 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 enoxaparin sodium injection group are provided below (see Table 12).

Table 12: Serious Adverse Events Occurring at ≥0.5% Incidence in Enoxaparin Sodium Injection-Treated Patients with Unstable Angina or Non-Q-Wave Myocardial Infarction
Dosing Regimen
Adverse Event Enoxaparin Sodium Injection 1 mg/kg q12h subcutaneously n = 1578 n (%) Heparin aPTT Adjusted Intravenous Therapy n = 1529 n (%)

Atrial fibrillation

11 (0.70)

3 (0.20)

Heart failure

15 (0.95)

11 (0.72)

Lung edema

11 (0.70)

11 (0.72)

Pneumonia

13 (0.82)

9 (0.59)

Adverse Reactions in Enoxaparin Sodium Injection-Treated Patients with Acute ST-Segment Elevation Myocardial Infarction

In a clinical trial in patients with acute ST-segment elevation myocardial infarction, thrombocytopenia occurred at a rate of 1.5%.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of enoxaparin sodium injection. 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 enoxaparin sodium injection 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 [seeWarnings and Precautions (5.5) ] 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.

7 DRUG INTERACTIONS

Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued prior to initiation of enoxaparin sodium injection 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 [see Warnings and Precautions (5.1)].

8 USE IN SPECIFIC POPULATIONS

8.1 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 sodium does not increase the risk of major developmental abnormalities (see Data). Based on animal data, enoxaparin sodium 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 2% to 4% and 15% to 20%, 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 [seeWarnings and Precautions (5.7)andUse 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 sodium 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 sodium 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 enoxaparin sodium injection affect the safety and the efficacy of the drug during pregnancy.

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 enoxaparin sodium 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 enoxaparin sodium injection. 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 enoxaparin sodium in pregnant women with mechanical prosthetic heart valves has been conducted [seeWarnings and Precautions (5.7) ].

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.

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