Criteria for Outpatient Use Guidelines

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[Dalteparin (Fragmin®); Enoxaparin (Lovenox®)]

[Developed, August 1999; Revised, August 2000; July 2001; July 2002; August 2003; January 2009]

Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with [*].

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1.* Dosage

Adults
Low-molecular-weight heparins (LMWH) are FDA-approved in adults to treat  inpatient deep vein thrombosis (DVT) with or without pulmonary embolism (PE), prevent DVT in patients undergoing abdominal surgery, hip replacement surgery, or knee replacement surgery, as well as those medical patients with acute illness and severely limited mobility, treat outpatient acute DVT without PE, treat acute ST-segment elevation myocardial infarction (STEMI) in patients managed medically, prevent ischemic complications of unstable angina and non-Q-wave myocardial infarction, and treat venous thromboembolism (VTE) to reduce recurrence in cancer patients.1, 2 Adult dosages are dependent upon therapeutic diagnosis, body weight, and renal function and are summarized in Table 1.   In some circumstances (e.g., weight-based dosages), maximum daily dosages are not readily identifiable. 

^1-6
Adult LMWH Recommended Dosages

TREATMENT INDICATION	DRUG	MAXIMUM RECOMMENDED DOSAGE -- Standard	MAXIMUM RECOMMENDED DOSAGE -- Severe Renal Impairment (CrCl < 30 ml/min)
Deep vein thrombosis (DVT)/pulmonary embolus (PE) prophylaxis for hip replacement surgery	enoxaparin (Lovenox®) dalteparin (Fragmin®)	30 mg SC every 12 hours or 40 mg subcutaneously (SC) once daily 5000 IU SC once daily	30 mg SC once daily ---*
DVT/PE prophylaxis for knee replacement surgery	enoxaparin	30 mg SC every 12 hours	30 mg SC once daily
DVT/PE prophylaxis for abdominal surgery	enoxaparin dalteparin	40 mg SC once daily moderate risk: 2500 IU SC once daily high risk: 5000 IU SC once daily	30 mg SC once daily ---*
DVT prophylaxis for acute illness and significantly limited mobility	enoxaparin dalteparin	40 mg SC once daily 5000 IU SC once daily	30 mg SC once daily ---*
Outpatient DVT treatment without PE, co-administered with warfarin	enoxaparin	1 mg/kg SC every 12 hours	1 mg/kg SC once daily
DVT/PE treatment in cancer patients	dalteparin	month 1: 200 IU/kg SC once daily month 2-6: 150 IU/kg SC once daily (maximum total daily dose = 18,000 IU)	---*
Inpatient DVT treatment with or without PE, co-administered with warfarin	enoxaparin	1 mg/kg SC every 12 hours or 1.5 mg/kg SC daily	1 mg/kg SC once daily
Unstable angina/non-Q-wave myocardial infarction (MI), when co-administered with aspirin	enoxaparin dalteparin	1 mg/kg SC every 12 hours 120 IU/kg SC every 12 hours (maximum single dose = 10,000 units)	1 mg/kg SC once daily ---*
Acute STEMI	enoxaparin	< 75 years: 30 mg IV bolus x1 + 1mg/kg SC, followed by 1 mg/kg SC every 12 hours with aspirin > 75 years: 0.75 mg/kg SC every 12 hours with aspirin (no bolus)	30 mg IV bolus x1 + 1mg/kg SC, followed by 1 mg/kg SC once daily with aspirin 1 mg/kg SC once daily with aspirin

*Monitor anti-Xa levels to determine dalteparin dose necessary to achieve anti-Xa levels in the range of 0.5 to 1.5 IU/ml.

Pediatrics

Safety and efficacy of LMWH for use in children younger than 18 years of age have not been established.^{1, 2}

2. Duration of Therapy ^1-18

When prescribed as preventive therapy, LMWH should be administered until the risk of deep venous thrombosis has diminished.  When utilized in the management of DVT and pulmonary embolism, warfarin therapy is typically initiated within 72 hours of enoxaparin therapy.  Enoxaparin is continued until a therapeutic anticoagulant effect with warfarin has been achieved.   Recent studies suggest that LMWH are effective as monotherapy in preventing VTE when utilized for certain postsurgical conditions (e.g., total knee replacement) or in patients requiring continued anticoagulant therapy for management of venous thromboembolism on an outpatient basis in place of warfarin.  Advantages include shortened hospital stays and reduced need for laboratory monitoring.  Long-term treatment of VTE in cancer patients is managed with dalteparin rather than warfarin for three to six months.

Enoxaparin has been determined to be more effective than heparin in limiting coronary ischemic complications associated with unstable angina or non-Q-wave myocardial infarction (MI).  Dalteparin has been shown to be more effective than placebo and comparable to heparin therapy in reducing mortality and MI in patients with unstable angina or non-Q-wave MI.  Dalteparin or enoxaparin treatment is administered in conjunction with aspirin therapy and should be continued until clinical stabilization is achieved in these patients (a minimum of 2 days for enoxaparin therapy).  Compared to unfractionated heparin, enoxaparin has been shown to significantly reduce MI recurrence in patients with acute STEMI receiving concurrent aspirin therapy when administered for a maximum of 8 days or hospital discharge, whichever came first.  LMWH treatment duration varies with respect to therapeutic indication and is summarized in Table 2.

^1-6
LMWH Recommended Treatment Duration (Adults)

TREATMENT INDICATION	DRUG	TREATMENT DURATION RANGE	MAXIMUM TREATMENT DURATION
DVT/PE prophylaxis for hip replacement surgery#	enoxaparin dalteparin	7 to 10 days 5 to 10 days	14 days+ 14 days+
DVT/PE prophylaxis for knee replacement surgery	enoxaparin	7 to 10 days	14 days
DVT/PE prophylaxis for abdominal surgery	enoxaparin dalteparin	7 to 10 days 5 to 10 days	12 days 10 days*
DVT/PE prophylaxis for acute illness and significantly limited mobility	enoxaparin dalteparin	6 to 11 days 12 to 14 days	14 days 14 days
DVT/PE treatment in cancer patients	dalteparin	6 months	6 months
Outpatient DVT treatment without pulmonary embolus (PE)	enoxaparin	7 days^	17 days
Inpatient DVT treatment with or without PE	enoxaparin	7 days^	17 days
Unstable angina/non-Q-wave myocardial infarction (MI)	enoxaparin dalteparin	2 to 8 days 5 to 8 days	12.5 days 8 days
Acute STEMI	enoxaparin	up to 8 days or hospital discharge, whichever is first	not determined

#Although not FDA-approved, LMWH also recommended for prevention of venous thromboembolism in hip fracture surgery.⁷
+In hip replacement surgery patients with high thromboembolic risk, dalteparin and enoxaparin may be continued for 28 to 35 days.⁷
*In select high-risk general surgery patients, including cancer surgery patients, dalteparin may be continued for 2-3 weeks.⁷
^ To treat inpatient or outpatient DVT, enoxaparin therapy should be continued for a minimum of 5 days and until a therapeutic International Normalized Ratio (INR) of 2.0 to 3.0 is achieved.¹

3.* Duplicative Therapy

Concurrent administration of multiple low molecular weight heparin products does not provide additional therapeutic benefit and is not recommended.  Patient profiles containing concomitant prescriptions for two or more low molecular weight heparin products will be reviewed.

4.* Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions.

The following drug-drug interactions are considered clinically relevant for LMWH.  Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed:

a. Drugs Affecting Hemostasis (e.g., Anticoagulants, NSAIDs) [clinical significance level- major (DrugReax); anticoagulants: 1-severe, NSAIDs, platelet inhibitors: 2-major (CP); 2 (DIF)]

The combined use of LMWH and drugs that affect hemostasis may produce an additive prolongation of bleeding time and an increased risk of bleeding, including gastrointestinal bleeding.  The prolonged bleeding risk may persist for several days following discontinuation of platelet inhibitors.   Several cases of spinal and epidural hematomas have been reported with enoxaparin use in patients receiving spinal or epidural anesthesia, many of whom were also receiving drugs that affect hemostasis like NSAIDs.  Drugs that affect hemostasis should be discontinued prior to initiating therapy with LMWH.  A non-acetylated salicylate may be administered in conjunction with LMWH to avoid antiplatelet activity.  Acetaminophen or narcotic analgesics are additional alternative analgesics for use in patients without inflammatory pain requiring LMWH therapy.  If coadministration of LMWH and drugs that affect hemostasis cannot be avoided, patients should be monitored closely for bleeding complications.  Concomitant administration of drugs that affect hemostasis and LMWH should be avoided, if possible.  If combined therapy is necessary, closely monitor patients for clinical and laboratory signs of bleeding.

b. Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) [clinical significance level – major (DrugReax); 4 (DIF)]

Hemostasis is maintained by several factors, including serotonin release from platelets.  Concurrent administration of LMWH with SSRIs may increase the risk of bleeding events, including ecchymosis, epistaxis, hematoma, petechiae, and life-threatening hemorrhages, as SSRIs and SNRIs may mechanistically interfere with platelet function.  Patients requiring adjunctive therapy with LMWH and SSRIs/SNRIs should be closely monitored for bleeding, with treatment adjustments as necessary, when doses are modified or therapy is initiated/discontinued.

References

1. Enoxaparin (Lovenox®) Package Insert.  Sanofi-Aventis, December 2009.
2. Dalteparin (Fragmin®) Package Insert.  Pfizer, Inc., April 2007.
3. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2011. Available at: http://www.clinicalpharmacology.com. Accessed June 9th, 2011.
4. DRUGDEX® System (electronic version). Thomson Reuters (Healthcare) Inc., Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com.libproxy.uthscsa.edu.   Accessed June 10th, 2011.
5. Drug Facts and Comparisons.  Clin-eguide [database online].  St. Louis, MO:  Wolters Kluwer Health, Inc; 2011.  Available at:  http://clineguide.ovid.com.ezproxy.lib.utexas.edu. Accessed June 10th, 2011.
6. AHFS Drug Information 2011.  Jackson, WY:  Teton Data Systems, Version 7.2.4, 2011.  Stat!Ref Electronic Medical Library.  Available at:  http://online.statref.com.libproxy.uthscsa.edu/.  Accessed June 10th, 2011.
7. American College of Chest Physicians.  Antithrombotic and thrombolytic therapy, 8th ed.  ACCP guidelines.  Chest. 2008;133(6 Suppl):67S-968S.
8. Practice Guideline.  2011 ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction.  (updating the 2007 guideline).  A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.  J Am Coll Cardiol. 2011;57:1920-59.
9. American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction.  J Am Coll Cardiol.2008;51;210-247.
10. Haines ST, Witt DM, Nutescu EA.  Venous thromboembolism.  In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds.  Pharmacotherapy: a pathophysiologic approach.  7th ed. New York: McGraw-Hill; 2008: 331-71.
11. Nutescu EA, Haines ST.  Venous thromboembolism. In:  Chisholm-Burns MA, Schwinghammer TL, Wells BG, et al, eds.  Pharmacotherapy: principles and practice. 2nd ed. New York:  McGraw-Hill; 2010:185-213.
12. Goodman SG, Barr A, Sobtchouk A, et al, for the Canadian Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) ST Segment Monitoring Substudy Group.  Low molecular weight heparin decreases rebound ischemia in unstable angina or non-Q-wave myocardial infarction: the Canadian ESSENCE ST segment monitoring substudy.  J Am Coll Cardiol. 2000;36:1507-13.
13. Fitzgerald RH Jr, Spiro TE, Trowbridge AA, Gardiner GA Jr, Whitsett TL, O’Connell MB, et al. and the Enoxaparin Clinical Trial Group.  Prevention of venous thromboembolic disease following primary total knee arthroplasty.  A randomized, multicenter, open-label, parallel-group comparison of enoxaparin and warfarin.  J Bone Joint Surg. 2001;83-A:900-6.
14. Merli G, Spiro TE, Olsson CG, Abildgaard U, Davidson BL, Eldor A, et al., and the Enoxaparin Clinical Trial Group.  Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease.  Ann Intern Med. 2001;134:191-202.
15. Colwell CW Jr., Collis DK, Paulson R, McCutchen JW, Bigler GT, Lutz S, Hardwick ME.  Comparison of enoxaparin and warfarin for the prevention of venous thromboembolic disease after total hip arthroplasty.  Evaluation during hospitalization and three months after discharge.  J Bone Joint Surg. 1999;81:932-40.
16. Francis CW, Pellegrini VD Jr., Totterman S, Boyd AD Jr., Marder VJ, Liebert KM, et al.  Prevention of deep-vein thrombosis after total hip arthroplasty.  Comparison of warfarin and dalteparin.  J Bone Joint Surg.1997;79:1365-72.
17. Simonneau G, Sors H, Charbonnier B, Page Y, Laaban JP, Azarian R, et al.   A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism.  The THESEE Study Group.  N Engl J Med. 1997;337:663-9.
18. Bergqvist D, Benoni G, Bjorgell O, Fredin H, Hedlundh U, Nicolas S, et al.  Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement.  N Engl J Med. 1996;335:696-700.
19. Drug interaction facts.  Clin-eguide [database online].  St. Louis, MO:  Wolters Kluwer Health, Inc; 2011.  Available at:  http://clineguide.ovid.com.ezproxy.lib.utexas.edu. Accessed June 10th, 2011.
20. DRUG-REAX® System (electronic version). Thomson Reuters (Healthcare) Inc., Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com.libproxy.uthscsa.edu.  Accessed June 10th, 2011.

Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and the College of Pharmacy, The University of Texas at Austin.  (Criteria 41)