Pharmacy & Therapeutics - September 2008 - (Page CB11)

Table 9 Adverse Events Occurring at ≥2% Incidence in Lovenox-Treated Patients1 Undergoing Hip or Knee Replacement Surgery Dosing Regimen Lovenox Lovenox Heparin Placebo 40 mg q.d. SC 30 mg q12h 15,000 U/24h q12h SC SC SC PeriExtended operative Prophylaxis Period Period n = 288 2 n = 131 3 n = 1080 n = 766 n = 115 % % % % % Adverse Severe Severe Severe Severe Severe Event Total Total Total Total Total Fever 0 8 0 0 <1 5 <1 4 0 3 Hemorrhage <1 13 0 5 <1 4 1 4 0 3 Nausea <1 3 <1 2 0 2 Anemia 0 16 0 <2 <1 2 2 5 <1 7 Edema <1 2 <1 2 0 2 Peripheral 0 6 0 0 <1 3 <1 4 0 3 edema 1 Excluding unrelated adverse events. 2 Data represents Lovenox 40 mg SC once a day initiated up to 12 hours prior to surgery in 288 hip replacement surgery patients who received Lovenox peri-operatively in an unblinded fashion in one clinical trial. 3 Data represents Lovenox 40 mg SC once a day given in a blinded fashion as extended prophylaxis at the end of the peri-operative period in 131 of the original 288 hip replacement surgery patients for up to 21 days in one clinical trial. Table 10 Adverse Events Occurring at ≥2% Incidence in Lovenox-Treated Medical Patients1 With Severely Restricted Mobility During Acute Illness Dosing Regimen Lovenox Placebo 40 mg q.d. SC q.d. SC n = 360 n = 362 Adverse Event % % Dyspnea 3.3 5.2 Thrombocytopenia 2.8 2.8 Confusion 2.2 1.1 Diarrhea 2.2 1.7 Nausea 2.5 1.7 1 Excluding unrelated and unlikely adverse events. Table 11 Adverse Events Occurring at ≥2% Incidence in Lovenox-Treated Patients1 Undergoing Treatment of Deep Vein Thrombosis With or Without Pulmonary Embolism Lovenox 1.5 mg/kg q.d. SC n = 298 % Severe Total 0 5 Dosing Regimen Lovenox 1 mg/kg q12h SC n = 559 % Severe Total 0 3 0 0 2 <1 Heparin aPTT Adjusted IV Therapy n = 544 % Severe Total <1 <1 0 <1 0 2 Adverse Reactions in Lovenox-Treated Patients With acute ST-segment Elevation Myocardial Infarction: In a clinical trial in patients with acute ST-segment elevation myocardial infarction, the only additional possibly related adverse reaction that occurred at a rate of at least 0.5% in the Lovenox group was thrombocytopenia (1.5%). 6.2 Post-Marketing Experience 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 post-operative 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), vesiculobullous rash, rare cases of hypersensitivity cutaneous vasculitis, hyperkalemia, purpura, skin necrosis (usually occurring at injection site), thrombocytosis, and thrombocytopenia with thrombosis [see Warnings and Precautions (5.5)] have been reported. 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. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to estimate reliably their frequency or to establish a causal relationship to drug exposure. 7 DRUG INTERACTIONS Unless really needed, 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 co-administration is essential, conduct close clinical and laboratory monitoring [see Warnings and Precautions (5.9)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. The fetal risk summary below describes the potential of Lovenox to increase the risk of developmental abnormalities above background risk. Fetal Risk Summary Lovenox is not predicted to increase the risk of developmental abnormalities. Lovenox does not cross the placenta, based on human and animal studies, and shows no evidence of teratogenic effects or fetotoxicity. 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 [see Warnings and Precautions (5.8)]. Clinical Considerations It is not known if either dose adjustment or monitoring of anti-Xa activity of enoxaparin are necessary during pregnancy. 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 such as enoxaparin, 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. 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 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 enoxaparin in pregnant women with mechanical prosthetic heart valves has been conducted [see Warnings and Precautions (5.7)]. •Animal Data - Teratology studies have been conducted in pregnant rats and rabbits at SC doses of enoxaparin up to 30 mg/kg/day or 211 mg/m2/day and 410 mg/m2/day, respectively. 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. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Lovenox is administered to nursing women. 8.4 Pediatric Use Safety and effectiveness of Lovenox in pediatric patients have not been established. Adverse Event Injection Site Hemorrhage Injection Site Pain 0 2 Hematuria 0 2 1 Excluding unrelated adverse events. Adverse Events 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 episodes, primarily injection site ecchymoses and hematomas, were more frequently reported in patients treated with SC Lovenox than in patients treated with IV 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 (irrespective of relationship to drug therapy) [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 Dosing Regimen Lovenox Heparin 1 mg/kg q12h SC aPTT Adjusted IV Therapy n = 1578 n = 1529 Adverse Event n (%) 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)

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Pharmacy & Therapeutics - September 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Effect of Prescription Copays on Adherence and Treatment Failure with Oral Antidiabetic Medications Vaccine Declinations Present New Challenges for Public Health Universal Health Care in America Digestive Disease Week and American Diabetes Association Pharmaceutical Approval Update

Pharmacy & Therapeutics - September 2008

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