(Low Molecular Weight Heparins) LMWH's

dalteparin (Fragmin ®)	enoxaparin (Lovenox ®)
tinzaparin (Innohep ®)	fondaparinux (Arixtra ®)
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Thrombocytopenia incidence: LMWH's: 0.6% Unfractionated heparin: 3.5%
Protein binding: LMWH's: Low Unfractionated heparin: high

dalteparin (Fragmin ®):

INDICATIONS AND USAGE
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FRAGMIN Injection is indicated for the prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin therapy (as described in CLINICAL TRIALS, Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction).
FRAGMIN is also indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE):

In patients undergoing hip replacement surgery; In patients undergoing abdominal surgery who are at risk for thromboembolic complications; In medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness.

DOSAGE AND ADMINISTRATION
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UNSTABLE ANGINA AND NON-Q-WAVE MYOCARDIAL INFARCTION:
In patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of FRAGMIN Injection is 120 IU/kg of body weight, but not more than 10,000 IU, subcutaneously (s.c.) every 12 hours with concurrent oral aspirin (75 to 165 mg once daily) therapy. Treatment should be continued until the patient is clinically stabilized. The usual duration of administration is 5 to 8 days. Concurrent aspirin therapy is recommended except when contraindicated.
Table 11 lists the volume of FRAGMIN, based on the 9.5 mL multiple-dose vial (10,000 IU/mL), to be administered for a range of patient weights.

**Table 11 Volume of FRAGMIN to be Administered by Patient Weight, Based on 9.5 mL Vial (10,000 IU/mL)**
Patient weight (lb)	< 110	110 to 131	132 to 153	154 to 175	176 to 197	>/= 198
Patient weight (kg)	< 50	50 to 59	60 to 69	70 to 79	80 to 89	>/= 90
Volume of FRAGMIN (mL)	0.55	0.65	0.75	0.90	1.00	1.00

HIP REPLACEMENT SURGERY:
Table 12 presents the dosing options for patients undergoing hip replacement surgery. The usual duration of administration is 5 to 10 days after surgery; up to 14 days of treatment with FRAGMIN have been well tolerated in clinical trials.

**Table 12 Dosing Options for Patients Undergoing Hip Replacement Surgery**
Timing of First Dose of FRAGMIN	Dose of FRAGMIN to be Given Subcutaneously
Timing of First Dose of FRAGMIN	10 to 14 Hours Before Surgery	Within 2 Hours Before Surgery	4 to 8 Hours After Surgery ¹	Postoperative Period ²
Postoperative Start	--	--	2500 IU ³	5000 IU qd
Preoperative Start - Day of Surgery	--	2500 IU	2500 IU ³	5000 IU qd
Preoperative Start - Evening Before Surgery ⁴	5000 IU	--	5000 IU	5000 IU qd
¹ Or later, if hemostasis has not been achieved. ² Up to 14 days of treatment was well tolerated in controlled clinical trials, where the usual duration of treatment was 5 to 10 days postoperatively. ³ Allow a minimum of 6 hours between this dose and the dose to be given on Postoperative Day 1. Adjust the timing of the dose on Postoperative Day 1 accordingly. ⁴ Allow approximately 24 hours between doses.

ABDOMINAL SURGERY:
In patients undergoing abdominal surgery with a risk of thromboembolic complications, the recommended dose of FRAGMIN is 2500 IU administered by s.c. injection once daily, starting 1 to 2 hours prior to surgery and repeated once daily postoperatively. The usual duration of administration is 5 to 10 days.
In patients undergoing abdominal surgery associated with a high risk of thromboembolic complications, such as malignant disorder, the recommended dose of FRAGMIN is 5000 IU s.c. the evening before surgery, then once daily postoperatively. The usual duration of administration is 5 to 10 days. Alternatively, in patients with malignancy, 2500 IU of FRAGMIN can be administered s.c. 1 to 2 hours before surgery followed by 2500 IU s.c. 12 hours later, and then 5000 IU once daily postoperatively. The usual duration of administration is 5 to 10 days.
Dosage adjustment and routine monitoring of coagulation parameters are not required if the dosage and administration recommendations specified above are followed.

MEDICAL PATIENTS WITH SEVERELY RESTRICTED MOBILITY DURING ACUTE ILLNESS:
In medical patients with severely restricted mobility during acute illness, the recommended dose of FRAGMIN is 5000 IU administered by s.c. injection once daily. In clinical trials, the usual duration of administration was 12 to 14 days.

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Renal dosing:

In patients with severely impaired renal function (CrCl ≤ 30 mL/min), monitoring for anti-Xa levels is recommended to determine the appropriate FRAGMIN dose. Target anti-Xa range is 0.5-1.5 IU/mL. When monitoring anti-Xa in these patients, sampling should be performed 4-6 hrs after FRAGMIN dosing and only after the patient has received 3-4 doses.

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DVT prophylaxis, abdominal surgery: 2,500 units 1-2 hours preop and once daily postop x 5-10 days (High risk patients (e.g. malignancy): 5000 units SC 1-2 hrs prior to surgery and then qd x 5-10 days.)
Prophylaxis (hip replacement): 2500 units 4-8 hrs postop, then 5000 units qd x 5-10 days (up to 14 days). Start at least 6hr after postop dose. Alternatively: 5000 units 10-14hrs preop and 4-8hrs postop. Maint: 5000 units qd up to 14 days.

Unstable angina, non-Q-wave MI: 120 units/kg up to 10,000 units SC every 12 hours with aspirin (75-165mg) until stable.
DVT treatment (not FDA approved): Dosing: 200 IU/kg SC qd (Max: 18,000 units/day)

danaparoid (Orgaran ®):

Removed from the market

enoxaparin (Lovenox ®):

DOSAGE AND ADMINISTRATION
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All patients should be evaluated for a bleeding disorder before administration of Lovenox, unless the medication is needed urgently. Since coagulation parameters are unsuitable for monitoring Lovenox activity, routine monitoring of coagulation parameters is not required.

For subcutaneous use, Lovenox should not be mixed with other injections or infusions. For intravenous use (i.e., for treatment of acute STEMI), Lovenox can be mixed with normal saline solution (0.9%) or 5% dextrose in water.

Lovenox is not intended for intramuscular administration.

Adult Dosage
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Abdominal Surgery: In patients undergoing abdominal surgery who are at risk for thromboembolic complications, the recommended dose of Lovenox is 40 mg once a day administered by SC injection with the initial dose given 2 hours prior to surgery. The usual duration of administration is 7 to 10 days; up to 12 days administration has been administered in clinical trials.

Hip or Knee Replacement Surgery: In patients undergoing hip or knee replacement surgery, the recommended dose of Lovenox is 30 mg every 12 hours administered by SC injection. Provided that hemostasis has been established, the initial dose should be given 12 to 24 hours after surgery. For hip replacement surgery, a dose of 40 mg once a day SC, given initially 12 (±3) hours prior to surgery, may be considered. Following the initial phase of thromboprophylaxis in hip replacement surgery patients, it is recommended that continued prophylaxis with Lovenox 40 mg once a day is administered by SC injection for 3 weeks. The usual duration of administration is 7 to 10 days; up to 14 days administration has been administered in clinical trials.

Medical Patients During Acute Illness: In medical patients at risk for thromboembolic complications due to severely restricted mobility during acute illness, the recommended dose of Lovenox is 40 mg once a day administered by SC injection. The usual duration of administration is 6 to 11 days; up to 14 days of Lovenox has been administered in the controlled clinical trial.

Treatment of Deep Vein Thrombosis With or Without Pulmonary Embolism:
In outpatient treatment, patients with acute deep vein thrombosis without pulmonary embolism who can be treated at home, the recommended dose of Lovenox is 1 mg/kg every 12 hours administered SC.
In inpatient (hospital) treatment, patients with acute deep vein thrombosis with pulmonary embolism or patients with acute deep vein thrombosis without pulmonary embolism (who are not candidates for outpatient treatment), the recommended dose of Lovenox is 1 mg/kg every 12 hours administered SC or 1.5 mg/kg once a day administered SC at the same time every day. In both outpatient and inpatient (hospital) treatments, warfarin sodium therapy should be initiated when appropriate (usually within 72 hours of Lovenox). Lovenox should be continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (International Normalization Ratio 2.0 to 3.0). The average duration of administration is 7 days; up to 17 days of Lovenox administration has been administered in controlled clinical trials.

Unstable Angina and Non-Q-Wave Myocardial Infarction: In patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of Lovenox is 1 mg/kg administered SC every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily). Treatment with Lovenox should be prescribed for a minimum of 2 days and continued until clinical stabilization. The usual duration of treatment is 2 to 8 days; up to 12.5 days of Lovenox has been administered in clinical trials.

Treatment of acute ST-segment Elevation Myocardial Infarction: In patients with acute ST-segment Elevation Myocardial Infarction, the recommended dose of Lovenox is a single IV bolus of 30 mg plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC every 12 hours (maximum 100 mg for the first two doses only, followed by 1 mg/kg dosing for the remaining doses). Dosage adjustments are recommended in patients ≥75 years of age.

When administered in conjunction with a thrombolytic (fibrin-specific or non-fibrin specific), Lovenox should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. All patients should receive acetylsalicylic acid (ASA) as soon as they are identified as having STEMI and maintained with 75 to 325 mg once daily unless contraindicated. In the pivotal clinical study, the Lovenox treatment duration was 8 days or until hospital discharge, whichever came first. An optimal duration of treatment is not known, but it is likely to be longer than 8 days.

For patients managed with Percutaneous Coronary Intervention (PCI): If the last Lovenox SC administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last Lovenox SC administration was given more than 8 hours before balloon inflation, an IV bolus of 0.3 mg/kg of Lovenox should be administered.

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Renal Impairment
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Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30–50 mL/min) and mild (creatinine clearance 50–80 mL/min) renal impairment, all such patients should be observed carefully for signs and symptoms of bleeding.

The recommended prophylaxis and treatment dosage regimens for patients with severe renal impairment (creatinine clearance <30 mL/min) are described in Table below.

Dosage Regimens for Patients with Severe Renal Impairment (creatinine clearance <30mL/minute)
Indication	Dosage Regimen
Prophylaxis in abdominal surgery	30 mg administered SC once daily
Prophylaxis in hip or knee replacement surgery	30 mg administered SC once daily
Prophylaxis in medical patients during acute illness	30 mg administered SC once daily
Inpatient treatment of acute deep vein thrombosis with or without pulmonary embolism, when administered in conjunction with warfarin sodium	1 mg/kg administered SC once daily
Outpatient treatment of acute deep vein thrombosis without pulmonary embolism, when administered in conjunction with warfarin sodium	1 mg/kg administered SC once daily
Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin	1 mg/kg administered SC once daily
Treatment of acute ST-segment Elevation Myocardial Infarction in patients <75 years of age	30-mg single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC once daily.
Treatment of acute ST-segment Elevation Myocardial Infarction in geriatric patients ≥75 years of age	1 mg/kg administered SC once daily (no initial bolus)

Geriatric patients with acute ST-segment Elevation Myocardial Infarction
For treatment of acute ST-segment Elevation Myocardial Infarction in geriatric patients ≥75 years of age, do not use an initial IV bolus. Initiate dosing with 0.75 mg/kg SC every 12 hours (maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the remaining doses). No dose adjustment is necessary for other indications in geriatric patients unless kidney function is impaired.

tinzaparin (Innohep ®):

Prevention of deep vein thrombosis, general surgery: 3500 units anti-Xa SC qd x 5-10 days.
Prevention of deep vein thrombosis, orthopedic surgery: 50 units anti-Xa/kg SC qd.
Treatment of deep vein thrombosis / PE: 175 units anti-Xa/kg SC qd for at least 6 days and until the patient is adequately anticoagulated with warfarin (INR of 2 for at least 2 days)

Factor Xa Inhibitors

fondaparinux (Arixtra ®):

Synthetic pentasaccharide that causes an antithrombin III-mediated selective inhibition of factor Xa.
DVT prophylaxis: (patients > 50kg): 2.5 mg SC once daily (After hemostasis has been established, the initial dose should be given 6 to 8 hours after surgery. ) Usual duration: 5-9 days (up to 10 days following abdominal surgery or up to 11 days following hip replacement or knee replacement). Extended prophylaxis is recommended following hip fracture surgery.

Acute DVT/PE treatment:
<50 kg: 5 mg once daily
50-100 kg: 7.5 mg once daily
>100 kg: 10 mg once daily
Usual duration: 5-9 days (has been administered up to 26 days)

Renal Dosing:
[crcl 30 - 50 ml/min]: Use caution
[<30 ml/min]: Contraindicated
Supplied: Syringe: 2.5 mg/0.5 ml, 5 mg/0.4ml, 7.5 mg/0.6 ml, 10 mg/0.8 ml

Much more selective inhibitor of factor Xa

Agent	Anti-Xa/anti-IIa ratio
UFH	1:1
LMWH	2-4:1
Danaparoid	22:1
Fondaparinux	∞

Fragmin® versus Lovenox®

Fragmin® versus Lovenox®
DVT /PE Prophylaxis
Indication	Dalteparin (Fragmin)	Enoxaparin (Lovenox)
Knee replacement surgery prophylaxis	Not FDA-approved	30mg q12h x 7-10 days
Hip replacement surgery prophylaxis	5000 IU qd x 5-10 days	30mg q12h or 40mg qd x 7-10 days
General surgery prophylaxis	Moderate risk: 2500 IU qd x 5-10 days // high-risk patients: 5000 IU qd x 5-10 days	Moderate risk: 30 mg SC qd. high-risk patients: 40mg qd x 7-10 days or 30mg SC q12h.
Orthopedic surgery	2500 units 6-8 hours postop (omit if patient received spinal anesthesia), then 5000 units SC qd.	30mg q12h or 40mg qd x 7-10 days
Abdominal Surgery	5,000 IU SC the evening prior to surgery and then once daily for 5 to 10 days	40 mg SC qd (initial dose given 2 hours prior to surgery.) Usual duration of administration: 7 to 10 days
Acute trauma or spinal injury	2500 IU bid	30 mg SC qd
Prophylaxis in acute medically ill patients (high risk)	5000 IU SC qd.	40mg SC qd x 6-11 days
DVT / PE Treatment
Treatment of DVT (with or without PE)	Not FDA-approved. // Dosing: 200 IU/kg SC qd. Alternatively (patients with hypercoagulable states or with increased risk of bleeding): 100 IU/kg SC bid. (maximum of 18,000 IU qd or 9000 IU bid.)	1 mg/kg q12h or 1.5 mg/kg qd.
Acute coronary syndrome treatment
ACS (unstable angina / non-ST segment elevation MI)	120 IU/kg q12h x 5-8 days (maximum of 10,000 IU q12h)	1 mg/kg SC q12 x 2 to 8 days

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