Nadroparin (Systemic)


VA CLASSIFICATION
Primary: BL111

Commonly used brand name(s): Fraxiparine; Fraxiparine Forte.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.



Category:


Anticoagulant—

Antithrombotic—
Note: Nadroparin is one of a group of substances known as low molecular weight heparins (LMWHs).



Indications

Accepted

Angina, unstable (treatment) and
Myocardial infarction, non-Q wave (treatment)— Nadroparin is indicated in the treatment of unstable angina and non-Q wave myocardial infarction.{02}

Thromboembolism, pulmonary (prophylaxis); and
Thrombosis, deep venous (prophylaxis)—Nadroparin is indicated in the prevention of thromboembolic disorders, primarily deep vein thrombosis and pulmonary embolism, in general and orthopedic surgery{01}

Thrombosis, deep venous (treatment)—Nadroparin is indicated for the treatment of deep vein thrombosis{01}

Thrombosis during hemodialysis (prophylaxis)—Nadroparin is indicated for the prevention of clotting during hemodialysis{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Obtained by depolymerization of sodium heparin from porcine intestinal mucosa.{02}
Molecular weight—
    Mean 4300 daltons;{01} 75 to 95% of the glycosaminoglycan chains have molecular weights between 2000 and 8000 daltons{02}

Solubility
    Very soluble in water, 0.1 N hydrochloric acid.{01}
    Practically insoluble in methanol, methylene chloride, ethanol, dimethylformamide, acetone and ethyl acetate.{01}


pH
    5.5 — 8 (1 % aqueous solution).{01}

Mechanism of action/Effect:

Nadroparin binds to the plasma protein antithrombin III (ATIII). Inhibition of factor Xa and a subsequent antithrombotic effect are the major results of this binding.{01}{02}


Other actions/effects:

Other properties that are not dependent upon ATIII may contribute to antithrombotic activity. These include stimulation of the tissue factor pathway TFPI, activation of fibrolysis via direct release of tissue plasminogen activator from endothelial cells, and modification of hemorrological parameters (decreased blood viscosity and increased platelet and granulocyte membrane fluidity).{01}

Absorption:

Almost completely absorbed following subcutaneous injection with at least 89% bioavailability.{02}

Elimination

Normal renal function: 3.5 hours{01}

Severe renal function impaiment: 6 hours{01}

Time to peak plasma concentration:

Anti-factor Xa—Approximately 4 hours after a subcutaneous injection.{02}

Peak plasma concentration:

Anti-factor Xa—1.2 to 1.8 International Units (IU) per mL (IU/mL) following a subcutaneous dose of 171 anti-factor Xa IU per kg of body weight (anti-factor Xa IU/kg) and 0.5 to 1.1 IU/mL following a subcutaneous dose of 86 anti-factor Xa IU/kg.{02}

Time to peak effect:

Anti-Xa activity: 3-5 hours.{01}

Prolongation of APTT and thrombin: 4 hours.{01}

Duration of action:

Anti-factor Xa activity—18 hours.{02}

Elimination:
    Renally eliminated.{01}


Precautions to Consider

Pregnancy/Reproduction
Fertility—
Studies in rats given doses of 2.5, 10 and 40 mg per kg per day found no effect on fertility. Some reduced weight gain and delay in some developmental tests in offspring of the rats treated with 40 mg/kg per day were noted.{01}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done.

Animal studies and human clinical reports have not shown teratogenic or fetotoxic effects. However, potential risks should be weighed against potential benefits to the patient in determining whether to administer nadroparin in pregnancy.{01}

Breast-feeding

It is not known whether nadroparin is distributed in human breast milk. However, mothers receiving nadroparin should avoid breast-feeding{01}.

Pediatrics

No information is available on the relationship of age to the effects of nadroparin in the pediatric population. Safety and efficacy have not been established.{01}


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of nadroparin in the elderly. However, elderly patients are more likely to have age-related renal function impairment, which may require adjustment of dosage in patients receiving nadroparin.{01}{02}

Surgical

Knee surgery: The risk of bleeding in knee surgery patients receiving low molecular weight (LMW) heparins is higher than in other orthopedic surgical procedures. Furthermore, hemarthrosis is a serious complication of knee surgery. Prior to nadroparin administration during knee surgery, potential risk and benefit to the patient should be considered{01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Anesthesia, epidural or spinal{02}    (intraspinal hematomas resulting in long-term or permanent paralysis have been observed during concurrent use of low molecular weight (LMW) heparin and epidural or spinal anesthesia;{02} the risk is increased with the use of postoperative indwelling catheters and in traumatic or repeated epidural or spinal procedures;{02} although concurrent use is recommended only when the benefit to the patient outweighs the risk, if both are used, the following precautions are recommended: spinal invasion or withdrawal or manipulation of the catheter should be delayed for at least 12 hours after the last dose of nadroparin, subsequent dosing of nadroparin should not occur for at least 2 hours after the anesthetic procedure, and the patient should be carefully monitored for neurological signs with immediate diagnosis and treatment should these signs appear{02})


» Nonsteroidal anti-inflammatory drugs (NSAIDS){02} or
» Platelet aggregation inhibitors, other{02} or
» Salicylates{02}    (risk of bleeding is increased;{02} with the exception of aspirin used in the treatment of non–Q wave myocardial infarction or unstable angina, concurrent use of these agents with nadroparin is not recommended{02})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT[SGPT]), serum and
Aspartate aminotransferase (AST[SGOT]), serum    (values may be increased during therapy)

{01}
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Diabetic retinopathy or{01}
» Hemorrhagic retinopathy{01}    (risk of bleeding is increased; use is contraindicated)


» Endocarditis, acute infective{01}
» Hemorrhagic cerebrovascular event{01}    (risk of bleeding is increased; except in cases in which there are systemic emboli,{02} use is contraindicated)


» Hemostasis disorder{01}     (risk of bleeding is increased; except in cases of disseminated intravascular coagulation not induced by heparin,{02} use is contraindicated )


» Hypersensitivity to nadroparin{01}
» Hypertension, severe uncontrolled{01}
» Injury or surgery, central nervous system–related, ocular, or otic{01}    (risk of bleeding is increased; use is contraindicated)


» Organic lesions that are likely to bleed{02}    (risk of bleeding is increased; use is contraindicated)


» Thrombocytopenia, history of, induced by unfractionated or LMW heparin{02}    (risk of bleeding is increased; use is contraindicated)


Risk-benefit should be considered when the following medical problems exist
» Abortion, imminent or threatened{02}    (use is not recommended except when it is determined that the risk of thromboembolism or thrombosis outweighs the increased risk of bleeding{02})


» Gastrointestinal ulceration, history of{02}    (risk of bleeding is increased)


Hepatic function impairment{02}    (caution is recommended{02})


» Platelet defects{02} or
» Thrombocytopenia, congenital or drug-induced (by other than unfractionated or LMW heparin){02}    (caution if recommended{02})


» Renal insufficiency{01}    (nadroparin effects are longer lasting in patients with renal insufficiency; dosage reduction should be considered in patients with moderate or severe insufficiency{02})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


Note: Routine clotting assays such as activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) are unsuitable for monitoring nadroparin's anticoagulant activity because nadroparin does not significantly affect these tests.{02} Increased doses intended to prolong the APTT could cause overdose and bleeding.{02} Prolongation of the APTT should be used only as a criterion of overdose.{02}

» Anti-factor Xa concentration, plasma and{01}
» Hemoglobin concentration{01}    (regular monitoring is recommended to detect bleeding complications;{02} bleeding complications should be considered major if the hemoglobin concentration is decreased by 2 grams per dL or if a transfusion of two or more units is required{02})

    (monitoring also is recommended to assess therapeutic efficacy; the expected anti-factor Xa concentrations before treatment of deep venous thrombosis and treatment of unstable angina or non–Q wave myocardial infarction are < 0.2 anti-factor Xa IU/mL [0.2 to 0.4 anti-factor Xa IU/mL for patients with an increased risk of bleeding] and < 0.4 anti-factor Xa IU/mL, respectively;{02} 3 to 4 hours after nadroparin injection, the expected concentrations are 1.2 to 1.8 anti-factor Xa IU/mL [0.5 to 1.1 anti-factor Xa IU/mL for patients with an increased risk of bleeding] and < 1.2 anti-factor Xa IU/mL, respectively;{02} the expected anti-factor Xa concentration produced by nadroparin given during hemodialysis to prevent thrombosis is 0.5 to 1 anti-factor Xa IU/mL{02})


» International Normalized Ratio (INR){02}    (monitoring is recommended during treatment of deep venous thrombosis to determine the duration of nadroparin therapy{02})


Platelet counts{01}    (should be determined prior to the commencement of therapy and twice a week for the duration of therapy)




Side/Adverse Effects

Note: Osteoporosis is associated with the use of high doses of unfractionated heparin over a long period of time.{02} Osteoporosis has not been observed with the use of nadroparin, possibly because it has not been used in many patients long-term.{02} However, the risk cannot be excluded.{02}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Injection site hematoma {02}(deep, dark purple bruise, pain, or swelling at place of injection)

Incidence rare
    
Allergic reaction {02}(fever; hives; itching; skin rash)
    
anaphylactoid reaction {02}(bluish discoloration, flushing, or redness of skin; coughing; difficulty in swallowing; dizziness or feeling faint ; skin rash, hives, or itching; swelling of eyelids, face, or lips; tightness in chest, troubled breathing, and/or wheezing)
    
bleeding {02}— may range from mild local hematomas to major hemorrhagic events{02}
    
bruising, unexpected {02}
    
cutaneous necrosis {02}(blue-green to black skin discoloration; pain, redness, or sloughing of skin at place of injection)
    
epistaxis {02}(nosebleed)
    
hematuria {02}(blood in the urine)
    
intraspinal hematoma {02}(back pain; bladder or bowel dysfunction; leg weakness; numbness; paralysis; paresthesias)—observed during concurrent use of low molecular weight heparin and epidural or spinal anesthesia{02}
    
melena {02}( black, tarry stools; vomiting of blood or coffee ground–like material)
    
purpura {02}(small purple or red spots on mucous membranes or skin)
    
skin rash {02}
    
thrombocytopenia {02}(bleeding from mucous membranes; rash consisting of pinpoint, purple-red spots, often beginning on the legs; unusual bruising)

Note: Risk factors for bleeding include advanced age; chronic, heavy alcohol consumption; concurrent use of platelet inhibiting medications; plasma anti-factor Xa activity of 2 International Units (IU) per mL or more; renal failure; or serious, concurrent illness.{02}
If thrombocytopenia develops, nadroparin therapy should be discontinued immediately.{02}






Overdose
For specific information on the agents used in the management of nadroparin overdose, see the Protamine (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Hemorrhage{01}


Treatment of overdose


Specific treatment:
Minor bleeding: Reducing or delaying subsequent doses of nadroparin will usually suffice in minor instances of overdosage{01}

Serious cases: Use protamine sulfate to neutralize the anticoagulant activity of nadroparin. A dose of 0.6 mL of protamine (6 mg, 625 A.H.U.) neutralizes approximately 950 anti-Xa IU. In order to avoid severe hypotensive and anaphylactoid reactions, the rate of protamine administration should not exceed 20 mg per minute.{01}



Monitoring:
Platelet count and other coagulation parameters should be monitored{01}



Supportive care:
Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Nadroparin (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to nadroparin





Breast-feeding— Mothers receiving nadroparin should avoid breast-feeding

Surgical
Knee surgery: The risk of bleeding in knee surgery patients receiving low molecular weight (LMW) heparins is higher than in other orthopedic surgical procedures. Furthermore, hemarthosis is a serious complication of knee surgery. Prior to nadroparin administration during knee surgery, potential risk and benefit to the patient should be considered
Other medications, especially epidural or spinal anesthesia, nonsteroidal anti-inflammatory drugs, other platelet aggregation inhibitors, or salicylates
Other medical problems, especially acute, infective endocarditis; central nervous system–related, ocular, or otic injury or surgery; diabetic retinopathy; hemorrhagic cerebrovascular event; hemorrhagic retinopathy; hemostasis disorder; history of gastrointestinal ulceration; imminent or threatened abortion; organic lesions that are likely to bleed; platelet defects; renal insufficiency; severe, uncontrolled hypertension; or thrombocytopenia

Proper use of this medication
» Proper injection technique

» Safe handling and disposal of syringes

» Proper dosing

Proper storage


Side/adverse effects
Signs of potential side effects especially injection site hematoma, allergic reaction, anaphylactoid reaction, bleeding, unexpected bruising, cutaneous necrosis, epistaxis, hematuria, intraspinal hematoma, melena, purpura, skin rash, and thrombocytopenia


General Dosing Information
Nadroparin is administered by subcutaneous injection into the anterolateral abdominal wall or the thigh.{02} It must not be administered intramuscularly.{02}

Nadroparin differs from unfractionated heparin and other low molecular weight heparins in anti-factor Xa and anti-factor IIa activity, molecular weight, units, and manufacturing processes.{02} Therefore, unit for unit, they cannot be used interchangeably.{02}

For treatment of non–Q wave myocardial infarction or unstable angina
In addition to nadroparin, patients should receive up to 325 mg of aspirin per day.{02}

For treatment of deep venous thrombosis
Concurrent use of a vitamin K antagonist is recommended.{02}

Nadroparin therapy should continue until the International Normalized Ratio (INR) is within the therapeutic range.{02} This usually takes at least 5 days.{02}


Parenteral Dosage Forms

NADROPARIN CALCIUM INJECTION

Usual Adult Dose
Angina, unstable (treatment) and
Myocardial infarction, non–Q wave (treatment)
Subcutaneous, initially 86 anti-factor Xa International Units (IU) per kg of body weight followed by 86 anti-factor Xa IU per kg of body weight every twelve hours for six days.{02}

Thromboembolism, pulmonary (prophylaxis) and
Thrombosis, deep venous (prophylaxis)
General surgery: Subcutaneous, 2850 anti-factor Xa IU per day beginning two to four hours before surgery and continuing for at least seven days and until the patient is actively ambulant.{02}

Hip replacement surgery: Subcutaneous, 38 anti-factor Xa IU per kg of body weight twelve hours before surgery, twelve hours after surgery, and once a day for the first three postoperative days.{02} Then, 57 anti-factor Xa IU per kg of body weight beginning on postoperative day 4 and continuing at least through postoperative day 10 and until the patient is actively ambulant.{02}

Thrombosis, deep venous (treatment)
Patients weighing less than 40 kg or more than 100 kg: Specific dosing guidelines have not been established.{02} Dosing must be individualized based upon clinical and laboratory parameters.{02}

Patients weighing 40 to 100 kg: Subcutaneous, 171 anti-factor Xa IU per kg of body weight once a day;{02} or, 86 anti-factor Xa IU per kg of body weight two times a day in patients who have an increased risk of bleeding.{02} Therapy should continue until the International Normalized Ratio (INR) is within the therapeutic range, which usually occurs after five days.{02}

Thrombosis during hemodialysis (prophylaxis)
Intra-arterial, 65 anti-factor Xa IU per kg of body weight beginning at the start of each session that is expected to last four hours or less.{02} An additional, smaller dose may be given during sessions lasting longer than four hours.{02} The dose should be halved in patients who have an increased risk of bleeding.{02}


Usual adult prescribing limits
17,100 IU per day{01}

Usual Pediatric Dose
Safety and efficacy have not been established.

Usual Geriatric Dose
See Usual adult dose.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


9,500 anti-Xa IU per 1 mL [Fraxiparine (Rx)]{01}


19,000 anti-Xa IU per 1 mL [Fraxiparine Forte (Rx)]{01}

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F). Do not freeze or refrigerate{01}.

Incompatibilities:
Do not mix with other preparations{01}

Auxiliary labeling:
   • Discard unused portion of each syringe{01}
   • Syringes are intended for single use only{01}
   • Keep out of the reach of children{01}



Developed: 03/21/01



References
  1. Product Information: Fraxiparine™, nadroparin. Sanofi Canada, Markham, Ontario, (PI revised 05/1999) reviewed 01/2001.
  1. Product Information: Fraxiparine™, nadroparin. Sanofi-Synthélabo Canada, Markham, Ontario, (PI revised 02/2000) reviewed 03/2001.
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