Vol. VI, No. I
  January/February 2003

  Jeff Ketz,
  Pharm. D., BCPS

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 Pharmacotherapy
 Update Index

Enoxaparin Clinical Pearl

FDA-Approved Dosing of Enoxaparin (Lovenox®)

Post-knee replacement surgery:
30 mg subcutaneously (SC) Q12 h (clot prevention)

Post-hip replacement surgery:
30 mg SC Q12 h or
40 mg SC once a day (clot prevention)

Post-abdominal surgery:
40 mg SC once a day (clot prevention)

Medical inpatients during acute illness:
40 mg SC once a day (clot prevention)

Inpatient treatment of deep vein thrombosis (DVT) with or without pulmonary embolism (PE):
1 mg/kg SC Q 12 h or 1.5 mg/kg SC once a day

Outpatient treatment of deep vein thrombosis (DVT)without pulmonary embolism (PE):
1 mg/kg SC Q 12 h

Unstable angina or Non-Q wave MI:
1 mg/kg SC Q12 h

Cautions and Notes About Enoxaparin
Enoxaparin should not be used in patients with a creatinine clearance (CrCl) less than 30 mL/min.
Renal impairment results in decreased elimination of enoxaparin and increased anticoagulant response.

Black Box Warning — When spinal puncture or epidural/spinal anesthesia is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.

Enoxaparin should not be used in patients with known or suspected heparin-induced thrombocytopenia.

The 30-, 40-, 60-, 80- and 100-mg syringes of enoxaparin are 100 mg/mL concentration. The 120- and 150-mg syringes of enoxaparin are 150 mg/mL concentration.

Pharmacology and Pharmacokinetics of Enoxaparin
Enoxaparin catalyzes the binding of antithrombin III with both factor Xa and factor IIa. Anti-factor Xa and anti-factor IIa activity results in anticoagulation. For enoxaparin, the ability to neutralize factor Xa and factor IIa is approximately a 4:1 ratio.

The bioavailability of enoxaparin given subcutaneously is 92%. The volume of distribution of enoxaparin, based on anti-factor Xa activity, is 6 liters (in an average patient).

The elimination half-life of enoxaparin administered subcutaneously, based on anti-factor Xa activity, is 4.5 hours and is primarily renal. The maximum anti-factor Xa and anti-factor IIa activity occurs 3 to 5 hours after injection. In addition, the anti-factor Xa activity persists in the plasma for about 12 hours after a 40 mg dose.

Monitoring of Enoxaparin Activity
In general, because response to enoxaparin at usual doses is consistent from patient to patient, the anticoagulant response to enoxaparin does not need to be monitored. However, anticoagulant activity of enoxaparin can be monitored by measuring factor Xa inhibition (anti-factor Xa activity).

For enoxaparin patients, this test is called the low molecular weight heparin assay. The therapeutic range for anticoagulation is 0.5 to 1 IU/mL. The low molecular weight heparin assay may be useful in patients who are at extremes of weight (less than 45 kg or greater than 130 or 150 kg) as well as in those patients with impaired renal function (ClCr 30 to 50 mL/min). This test should be ordered as the "low molecular weight heparin assay."

The draw time of the assay is generally 4 hours post-dose of enoxaparin. This measures the peak activity of enoxaparin. There are no recommended dose adjustments based on the results of the low molecular weight heparin assay. The dose can be adjusted empirically, and then, the assay should be repeated. Anticoagulant activity of enoxaparin cannot be accurately monitored by the PTT.

Antidote for Enoxaparin
Protamine 1 mg given by slow infusion should be administered to neutralize 1 mg of enoxaparin. If a PTT drawn 2 to 4 hours after the first dose of protamine remains prolonged, a second infusion of 0.5 mg protamine per 1 mg enoxaparin can be given. Anti-factor Xa activity is only partially neutralized by protamine (maximum 60%).

Enoxaparin for Obese or Underweight Patients
The volume of distribution of enoxaparin is approximately 6 liters, which is slightly greater than the plasma volume of the body. In obese patients, the plasma volume does not increase proportionally with weight.

Patients at extremes of weight should have the dose of enoxaparin adjusted and anticoagulation should be monitored using the low molecular weight heparin assay.

In clinical trials using enoxaparin for the treatment of DVT or PE, the 1 mg/kg Q 12 h dose was given to patients up to weights of approximately 150 kg. The maximum dose of enoxaparin should be 150 mg SC Q 12 h. For a patient receiving a dose of enoxaparin of 130 mg to 150 mg (i.e., patient weight 130 kg to 150 kg or greater), the low molecular weight heparin assay may be a useful monitoring tool.

Patients weighing < 45 kg were not included in clinical trials; therefore, these patients should also be monitored using the low molecular weight heparin assay.

Enoxaparin for Patients with Renal Dysfunction
The elimination of enoxaparin is impaired in patients with renal dysfunction, and anticoagulant effects may be increased in these patients. Enoxaparin should not be used in patients with a ClCr <30 mL/min. The low molecular weight heparin assay may be used to monitor patients with moderate renal dysfunction (ClCr 30 to 50 mL/min). There is no recommended renal dose adjustment for enoxaparin. Patients with serum creatinine values >2.0 were excluded from most clinical trials of enoxaparin. Patients on hemodialysis, peritoneal dialysis or CVVHD are not candidates for enoxaparin.

As a rough estimate of creatinine clearance, a serum creatinine as low as 2.0 may indicate severe renal dysfunction in a patient of average or greater than average weight, and a serum creatinine value of >1.6 may indicate severe renal dysfunction in underweight patient.

To estimate the creatinine clearance (CrCl), first calculate the patients ideal body weight (IBW) in kg:

Male: 50 kg + 2.3 (height in inches over 5 feet)
Female: 45 kg + 2.3 (height in inches over 5 feet)

Then, use the Cockroft-Gault equation to calculate the estimated creatinine clearance (CrCl):

Estimated ClCr (mL/min) for a Male=
(140 – Age)(IBW in kg)
(72)(SCr)
For a female patient, multiply result by 0.85

Enoxaparin in Patients Awaiting CABG Surgery
ACC/AHA guidelines recommend that patients awaiting CABG surgery should be converted to unfractionated heparin while awaiting surgery because of the long duration of action of enoxaparin, as well as the risk of bleeding if enoxaparin anticoagulation is not monitored.