Lovenox Side Effects

Please note - some side effects for Lovenox may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Lovenox - for the Consumer

Lovenox

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Lovenox:

Diarrhea; mild pain, irritation, swelling, redness, bleeding, or bruising at the injection site; nausea.

Seek medical attention right away if any of these SEVERE side effects occur when using Lovenox:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bloody, black, or tarry stools; confusion; difficulty walking; fainting; fever; pale skin; pink or red urine; severe or persistent dizziness, tiredness, or weakness; swelling; tingling, numbness (especially in the legs and feet), and muscle weakness; unusual bleeding or bruising; vomit that looks like coffee grounds.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Lovenox Side Effects - for the Professional

Lovenox

Clinical Trials Experience

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

• Spinal/epidural hematoma [see Boxed Warning and Warnings and Precautions (5.1)]
• Increased Risk of Hemorrhage [see Warnings and Precautions (5.1)]
• Thrombocytopenia [see Warnings and Precautions (5.5)]

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.

Hemorrhage

The incidence of major hemorrhagic complications during Lovenox treatment has been low.

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*

	Dosing Regimen
Indications	Lovenox 40 mg q.d. SC	Heparin 5000 U q8h SC
* Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) 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.
Abdominal Surgery	n = 555 23 (4%)	n = 560 16 (3%)
Colorectal Surgery	n = 673 28 (4%)	n = 674 21 (3%)

Table 3 Major Bleeding Episodes Following Hip or Knee Replacement Surgery*

Indications	Dosing Regimen
	Lovenox 40 mg q.d. SC	Lovenox 30 mg q12h SC	Heparin 15,000 U/24h SC
* Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if accompanied by a hemoglobin decrease ≥ 2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal and intracranial hemorrhages were always considered major. In the knee replacement surgery trials, intraocular hemorrhages were also considered major hemorrhages. † Lovenox 30 mg every 12 hours SC initiated 12 to 24 hours after surgery and continued for up to 14 days after surgery ‡ Lovenox 40 mg SC once a day initiated up to 12 hours prior to surgery and continued for up to 7 days after surgery § Lovenox 40 mg SC once a day for up to 21 days after discharge
Hip Replacement Surgery without Extended Prophylaxis†		n = 786 31 (4%)	n = 541 32 (6%)
Hip Replacement Surgery with Extended Prophylaxis
Peri-operative Period‡	n = 288 4 (2%)
Extended Prophylaxis Period§	n = 221 0 (0%)
Knee Replacement Surgery without Extended Prophylaxis†		n = 294 3 (1%)	n = 225 3 (1%)

NOTE: At no time point were the 40 mg once a day pre-operative and the 30 mg every 12 hours post-operative 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*

Indications	Dosing Regimen
	Lovenox† 20 mg q.d. SC	Lovenox† 40 mg q.d. SC	Placebo†
* Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, (2) 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. † The rates represent major bleeding on study medication up to 24 hours after last dose.
Medical Patients During Acute Illness	n = 351 1 (<1%)	n = 360 3 (<1%)	n = 362 2 (<1%)

Table 5 Major Bleeding Episodes in Deep Vein Thrombosis with or without Pulmonary Embolism Treatment *

	Dosing Regimen†
Indication	Lovenox 1.5 mg/kg q.d. SC	Lovenox 1 mg/kg q12h SC	Heparin aPTT Adjusted IV Therapy
* Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) 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. † All patients also received warfarin sodium (dose-adjusted according to PT to achieve an INR of 2.0 to 3.0) commencing within 72 hours of Lovenox or standard heparin therapy and continuing for up to 90 days.
Treatment of DVT and PE	n = 298 5 (2%)	n = 559 9 (2%)	n = 554 9 (2%)

Table 6 Major Bleeding Episodes in Unstable Angina and Non-Q-Wave Myocardial Infarction

Indication	Dosing Regimen
	Lovenox* 1 mg/kg q12h SC	Heparin* aPTT Adjusted IV Therapy
* The rates represent major bleeding on study medication up to 12 hours after dose. † Aspirin therapy was administered concurrently (100 to 325 mg per day). ‡ Bleeding complications were considered major: (1) if the hemorrhage caused a significant clinical event, or (2) if accompanied by a hemoglobin decrease by ≥ 3 g/dL or transfusion of 2 or more units of blood products. Intraocular, retroperitoneal, and intracranial hemorrhages were always considered major.
Unstable Angina and Non-Q-Wave MI†,‡	n = 1578 17 (1%)	n = 1529 18 (1%)

Table 7 Major Bleeding Episodes in Acute ST-Segment Elevation Myocardial Infarction

	Dosing Regimen
Indication	Lovenox* Initial 30 mg IV bolus followed by 1 mg/kg q12h SC	Heparin* aPTT Adjusted IV Therapy
* The rates represent major bleeding (including ICH) up to 30 days † Bleedings were considered major if the hemorrhage caused a significant clinical event associated with a hemoglobin decrease by ≥ 5 g/dL. ICH were always considered major.
Acute ST-Segment Elevation Myocardial Infarction	n = 10176 n (%)	n = 10151 n (%)
- Major bleeding (including ICH) †	211 (2.1)	138 (1.4)
- Intracranial hemorrhages (ICH)	84 (0.8)	66 (0.7)

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 Lovenox. 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 Lovenox should be interpreted with caution.

Local Reactions

Mild local irritation, pain, hematoma, ecchymosis, and erythema may follow SC 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 Colorectal Surgery

Adverse Reaction	Dosing Regimen
	Lovenox 40 mg q.d. SC n = 1228 %		Heparin 5000 U q8h SC n = 1234 %
	Severe	Total	Severe	Total
Hemorrhage	<1	7	<1	6
Anemia	<1	3	<1	3
Ecchymosis	0	3	0	3

Table 9 Adverse Reactions Occurring at ≥2% Incidence in Lovenox-Treated Patients Undergoing Hip or Knee Replacement Surgery

Adverse Reaction	Dosing Regimen
	Lovenox 40 mg q.d. SC				Lovenox 30 mg q12h SC		Heparin 15,000 U/24h SC		Placebo q12h SC
	Peri-operative Period n = 288 * %		Extended Prophylaxis Period n = 131 † %		n = 1080 %		n = 766 %		n = 115 %
	Severe Total		Severe Total		Severe Total		Severe Total		Severe Total
* Data represent 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. † Data represent 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.
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 edema	0	6	0	0	<1	3	<1	4	0	3

Table 10 Adverse Reactions Occurring at ≥2% Incidence in Lovenox-Treated Medical Patients with Severely Restricted Mobility During Acute Illness

Adverse Reaction	Dosing Regimen
	Lovenox 40 mg q.d. SC n = 360 %	Placebo q.d. SC n = 362 %
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

Table 11 Adverse Reactions Occurring at ≥2% Incidence in Lovenox-Treated Patients Undergoing Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism

Adverse Reaction	Dosing Regimen
	Lovenox 1.5 mg/kg q.d. SC n = 298 %		Lovenox 1 mg/kg q12h SC n = 559 %		Heparin aPTT Adjusted IV Therapy n = 544 %
	Severe	Total	Severe	Total	Severe	Total
Injection Site Hemorrhage	0	5	0	3	<1	<1
Injection Site Pain	0	2	0	2	0	0
Hematuria	0	2	0	<1	<1	2

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 events, 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 [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

Adverse Event	Dosing Regimen
	Lovenox 1 mg/kg q12h SC n = 1578 n (%)	Heparin aPTT Adjusted IV 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 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 adverse reaction that occurred at a rate of at least 0.5% in the Lovenox group was thrombocytopenia (1.5%).

Postmarketing 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, purpura, skin necrosis (occurring at either the injection site or distant from the injection site), thrombocytosis, and thrombocytopenia with thrombosis [see Warnings 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.

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.

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Side Effects by Body System - for Healthcare Professionals

Hematologic

Hematologic side effects including wound hematoma (11%), anemia (3%), ecchymosis (3%), thrombocytopenia (1.5%), thrombocytosis, hemarthrosis, thrombosis, hypochromic anemia, and retroperitoneal hematoma have been reported. Clinical trials experience included reports of spinal/epidural hematoma and increased risk of hemorrhage.

Patients undergoing spinal/epidural anesthesia or puncture and anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids are at risk for long-term or permanent paralysis due to epidural or spinal hematoma. The risk of these events is increased by the use of indwelling epidural catheters or by concomitant use of platelet inhibitors, other anticoagulants, or drugs that affect hemostasis.

In one clinical study, compared with younger patients, the incidence of bleeding complications was higher in patients greater than or equal to 65-years-old.

Patients previously exposed to unfractionated heparin or a low-molecular-weight heparin appear to be more susceptible to developing heparin-induced thrombocytopenia (HIT) and HIT-related thromboembolic complications (e.g., transient ischemic attack, stroke) than those who were never exposed.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated, prothrombotic reaction that occurs in 0.5% to 5% of patients treated with unfractionated heparin and in less than 1% of patients treated with a low molecular weight heparin (LMWH). The decrease in platelet count associated with HIT usually begins 5 to 14 days after starting heparin. However, patients with a previous exposure to heparin may have an abrupt decrease in platelets upon restarting heparin. Patients with LMWH-induced HIT exhibit a longer delay in the onset of symptoms compared with those who develop it from unfractionated heparin. Following discontinuation, platelet counts begin to recover within 4 days, but may take more than 2 weeks in patients with high-titer HIT antibodies. Thrombocytopenia is caused by heparin-dependent IgG antibodies that bind to a specific platelet protein, platelet factor 4 (PF4). The heparin-PF4-IgG immune complex binds to platelets causing platelet activation. The activated platelets cause release of platelet-derived procoagulant microparticles, which accelerate coagulation reactions and generate thrombin. LMWHs have a high cross-reactivity with circulating heparin-PF4-IgG immune complex. Factors associated with a higher risk for developing HIT-associated thrombosis include women, nonwhites, severity of thrombocytopenia, and lower body weight. Complications associated with HIT include exacerbation of venous thromboembolism, arterial or venous thrombosis, limb gangrene, stroke, and skin necrosis. The antibodies that cause HIT will usually disappear after approximately 3 months; therefore, use of unfractionated heparin or LMWH may be considered in a patient with a history of HIT if the antibody test is negative.

Factors associated with an increased risk of bleeding include high doses, advanced age, renal dysfunction, and concomitant use of other drugs that affect hemostasis.

Hepatic

Hepatic side effects have included transient elevations in liver function tests.

Local

Local side effects have included pain, erythema, ecchymosis, and hematoma. Rarely, painful, red induration and necrotic ulcerations at the injection site have been reported. Skin necrosis distant from the injection site has also been reported.

Skin necrosis occasionally accompanies heparin-associated thrombocytopenia and thrombosis syndrome. This complication is thought to occur less with enoxaparin than with unfractionated heparin. However, a recent report noted the occurrence of skin necrosis and associated thrombocytopenia with low molecular weight heparin use. If late-onset skin necrosis, thrombocytopenia, and/or thromboembolism occur during use, immediate discontinuation of low-molecular weight heparin is mandatory in order to avoid potentially fatal thromboembolic complications.

Hypersensitivity

Hypersensitivity side effects including systemic allergic reactions, pruritus, urticaria, and anaphylactoid reactions have been reported in postmarketing experience. A case of angioedema has been reported.

Dermatologic

Dermatologic side effects have included vesiculobullous rash, purpura, and cutaneous vasculitis. At least two cases of bullous pemphigoid-like eruption and one rare case of enoxaparin-induced ischemic skin necrosis have been reported.

Respiratory

Respiratory side effects have included lung edema, pneumonia, and dyspnea.

Cardiovascular

Cardiovascular side effects have included atrial fibrillation, heart failure, edema, and peripheral edema.

Gastrointestinal

Gastrointestinal side effects have included nausea and diarrhea.

Metabolic

One case of hyperlipidemia with marked hypertriglyceridemia was reported in a diabetic pregnant woman, although causality has not been determined.

Metabolic side effects have rarely included hyperlipidemia. Postmarketing reports have included cases of hyperkalemia. 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, and hematoma in body tissues).

Genitourinary

Genitourinary side effects have included hematuria.

Nervous system

Nervous system side effects have included confusion.

Other

Other side effects have included fever.

General

Any unexplained decrease in blood pressure and/or hematocrit as well as unexplained symptoms should prompt consideration of a possible hemorrhagic event.

In general, hemorrhagic side effects have occurred in 3% to 7% of patients. A meta-analysis of published studies reported an overall incidence of major bleeding with low molecular weight heparins of 0.7% to 1.4%. Hemorrhage may occur at any site in the body.

Musculoskeletal

In a study involving pregnant women (n=120) requiring thromboprophylaxis, clinically significant bone loss (i.e., 10% or greater) in the femur occurred in approximately 2% to 2.5% of patients regardless if they received enoxaparin (68.4 mg/day) or unfractionated heparin (17,380 units/day) for approximately 26 to 27 weeks.

Musculoskeletal side effects have included osteoporosis.

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