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Lovenox (Enoxaparin Sodium) - Side Effects and Adverse Reactions

 
 



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 [see Warnings and Precautions ]
  • Thrombocytopenia [see Warnings and Precautions ]

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 SurgeryBleeding 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.
Dosing Regimen
Indications Lovenox
40 mg q.d. SC
Heparin
5000 U q8h SC
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 SurgeryBleeding 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.
Indications Dosing Regimen
Lovenox
40 mg q.d. SC
Lovenox
30 mg q12h SC
Heparin
15,000 U/24h SC
Hip Replacement Surgery without Extended Prophylaxis 1 n = 786
31 (4%)
n = 541
32 (6%)
Hip Replacement Surgery with Extended Prophylaxis
Peri-operative PeriodLovenox 40 mg SC once a day initiated up to 12 hours prior to surgery and continued for up to 7 days after surgery n = 288
4 (2%)
Extended Prophylaxis PeriodLovenox 40 mg SC once a day for up to 21 days after discharge n = 221
0 (0%)
Knee Replacement Surgery without Extended Prophylaxis n = 294
3 (1%)
n = 225
3 (1%)

1 Lovenox 30 mg every 12 hours SC initiated 12 to 24 hours after surgery and continued for up to 14 days after surgery

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 IllnessBleeding 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.
Indications Dosing Regimen
Lovenox 1
20 mg q.d. SC
Lovenox
40 mg q.d. SC
Placebo
Medical Patients During Acute Illness n = 351
1 (<1%)
n = 360
3 (<1%)
n = 362
2 (<1%)

1 The rates represent major bleeding on study medication up to 24 hours after last dose.

Table 5 Major Bleeding Episodes in Deep Vein Thrombosis with or without Pulmonary Embolism Treatment 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.
Dosing RegimenAll 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.
Indication Lovenox
1.5 mg/kg q.d. SC
Lovenox
1 mg/kg q12h SC
Heparin
aPTT Adjusted IV Therapy
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
1 mg/kg q12h SC
Heparin
aPTT Adjusted IV Therapy
Unstable Angina and Non-Q-Wave MIAspirin 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. n = 1578
17 (1%)
n = 1529
18 (1%)
1 The rates represent major bleeding on study medication up to 12 hours after dose.

Table 7 Major Bleeding Episodes in Acute ST-Segment Elevation Myocardial Infarction
Dosing Regimen
Indication Lovenox 1
Initial 30 mg IV bolus followed by 1 mg/kg q12h SC
Heparin
aPTT Adjusted IV Therapy
Acute ST-Segment Elevation Myocardial Infarction, n = 10176
n (%)
n = 10151
n (%)
- Major bleeding (including ICH) 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. 211 138 (1.4)
- Intracranial hemorrhages (ICH) 84 (0.8) 66 (0.7)
1 The rates represent major bleeding (including ICH) up to 30 days

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 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.
%
Extended Prophylaxis Period
n = 131 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.
%
n = 1080
%
n = 766
%
n = 115
%
Severe Total Severe Total Severe Total Severe Total Severe 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 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 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 ] 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.



REPORTS OF SUSPECTED LOVENOX SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Lovenox. The information is not vetted and should not be considered as verified clinical evidence.

Possible Lovenox side effects / adverse reactions in 59 year old male

Reported by a pharmacist from United States on 2011-10-03

Patient: 59 year old male

Reactions: Retroperitoneal Haemorrhage

Suspect drug(s):
Lovenox



Possible Lovenox side effects / adverse reactions in 56 year old female

Reported by a health professional (non-physician/pharmacist) from France on 2011-10-04

Patient: 56 year old female

Reactions: Haematuria, Hypoprothrombinaemia

Adverse event resulted in: hospitalization

Suspect drug(s):
Lovenox
    Indication: Deep Vein Thrombosis
    Start date: 2011-06-09

Previscan
    Administration route: Oral
    Indication: Deep Vein Thrombosis
    Start date: 2011-06-01
    End date: 2011-06-19



Possible Lovenox side effects / adverse reactions in 56 year old female

Reported by a health professional (non-physician/pharmacist) from France on 2011-10-04

Patient: 56 year old female

Reactions: Agranulocytosis

Adverse event resulted in: life threatening event

Suspect drug(s):
Lovenox
    Start date: 2011-03-11
    End date: 2011-03-24

Keppra
    Dosage: dose:100 milligram(s)/millilitre
    Start date: 2011-03-18
    End date: 2011-03-24

Lasix
    Dosage: dose:20 milligram(s)/millilitre
    Start date: 2011-03-19
    End date: 2011-03-24



See index of all Lovenox side effect reports >>

Drug label data at the top of this Page last updated: 2009-08-13

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