Danaparoid (Systemic)


VA CLASSIFICATION
Primary: BL112

Another commonly used name is
ORG 10172 .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antithrombotic—
Note: Danaparoid has been categorized as one of a group of substances known as low molecular weight heparins (LMWHs), although it is technically a heparinoid.



Indications

Accepted

Thromboembolism, pulmonary (prophylaxis) and
Thrombosis, deep venous (prophylaxis)—Danaparoid is indicated for the prevention of postoperative deep venous thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients undergoing elective hip replacement surgery. {01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Isolated from porcine intestinal mucosa {01}.


Composition
    Depolymerized mixture of low molecular weight sulfated glycosaminoglycans, consisting of approximately 84% heparan sulfate, approximately 12% dermatan sulfate, and approximately 4% chondroitin sulfates. {01}
Molecular weight—
    Approximately 5500 daltons (average) {01}

Mechanism of action/Effect:

Danaparoid prevents fibrin formation in the coagulation pathway by inhibiting thrombin generation through the inhibition of coagulation factor Xa and thrombin (factor IIa). Unlike heparin, however, danaparoid preferentially potentiates the inhibition of coagulation factor Xa, with a ratio of anti-factor Xa activity to anti-factor IIa activity greater than 22:1. Danaparoid has little effect on clotting assays such as prothrombin time (PT), partial thromboplastin time (PTT), and bleeding time. {01}


Other actions/effects:

Danaparoid has only minor effects on platelet function, platelet aggregability, and fibrinolytic activity. {01}

Absorption:

Approximately 100% bioavailable following subcutaneous injection, measured as anti-factor Xa activity. {01}

Half-life:

Elimination—approximately 24 hours (average). {01}

Time to peak concentration:

Approximately 2 to 5 hours following subcutaneous injection. {01}

Peak serum concentration:

Dose-related. After single subcutaneous doses of 750, 1500, 2250, and 3250 anti-factor Xa units, peak concentrations of plasma anti-factor Xa activity were 102.4, 206.1, 283.9, and 403.4 microunits per mL, respectively. {01}

Elimination:
    Renal. In patients with severely impaired renal function, the elimination half-life of plasma anti-factor Xa activity may be prolonged. {01}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients hypersensitive to heparin or to pork products may be sensitive to danaparoid also. {01}

Carcinogenicity

No long-term animal studies have been performed with danaparoid to determine its carcinogenic potential. {01}

Mutagenicity

Danaparoid was not mutagenic in the Ames test, the in vitro CHL/HGPRT forward gene mutation assay, the in vitro CHO cell chromosome aberration test, the in vitro HeLa cell unscheduled DNA synthesis (UDS) test or the in vivo mouse micronucleus test. {01}

Pregnancy/Reproduction
Fertility—
In studies in rats, intravenous doses of up to 1090 anti-factor Xa units per kg of body weight (units/kg) per day (up to 5.9 times the human subcutaneous dose on a body surface area basis) did not affect fertility or reproductive performance. {01}

Pregnancy—
Adequate and well-controlled studies in humans have not been done. {01}

Studies in pregnant rats and rabbits given intravenous doses of danaparoid up to 1600 units/kg per day (up to 8.7 times the human dose on a body surface area basis) and up to 780 units/kg per day (up to 6 times the human dose on a body surface area basis), respectively, showed no evidence of harm to the fetus. {01}

FDA Pregnancy Category B. {01}

Breast-feeding

It is not known whether danaparoid is distributed into breast milk. However, problems in humans have not been documented. {01}

Pediatrics

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


Geriatrics


No information is available on the relationship of age to the effects of danaparoid in geriatric patients. {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.

Anticoagulants, coumarin- or indandione-derivative or
Platelet aggregation inhibitors    (increased risk of bleeding must be considered; the results of the prothrombin time [PT] and Thrombotest™, used for monitoring oral anticoagulant activity, are unreliable within 5 hours following danaparoid administration)

{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 problems exist:
» Bleeding, major, active    (may be exacerbated)

{01}
» Hypertension, severe, uncontrolled    (increased risk of cerebral hemorrhage)

{01}
» Stroke, hemorrhagic    (increased risk of uncontrollable hemorrhage)

{01}
» Thrombocytopenia associated with positive in vitro tests for antiplatelet antibody in the presence of danaparoid    (risk of recurrence)

{01}
Note: Danaparoid exhibits a low cross-reactivity with antiplatelet antibodies in individuals with Type II heparin-induced thrombocytopenia (HIT). {01}


Risk-benefit should be considered when the following medical problems exist
Any medical procedure or condition in which the risk of bleeding or hemorrhage is present, such as:{01}
» Anesthesia, epidural or spinal(risk of epidural or spinal hematoma, which can result in long-term or permanent paralysis; this risk is increased with the use of indwelling epidural catheters or by the concomitant use of medications that affect hemostasis, such as nonsteroidal anti-inflammatory drugs, platelet inhibitors, or other anticoagulants; the risk may also be increased by traumatic or repeated epidural or spinal puncture)
» Blood dyscrasias, hemorrhagic, congenital or acquired
» Endocarditis, bacterial
» Renal function impairment, severe
» Stroke, nonhemorrhagic
» Surgery, especially brain, spinal, or ophthalmologic
» Ulceration, other lesions, or recent bleeding of the gastrointestinal tract, active
Sensitivity to danaparoid, heparin, pork products, or sulfites    (patients sensitive to sulfites may be sensitive to danaparoid injection because it contains sodium sulfite; sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic patients, and may result in allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes)

{01}

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: Since danaparoid has only a small effect on factor IIa activity, routine coagulation tests such as prothrombin time (PT), activated partial thromboplastin time (APTT), kaolin cephalin clotting time (KCCT), whole blood clotting time (WBCT), and thrombin time (TT) are unsuitable for monitoring danaparoid activity at recommended doses. {01}
Patients with a serum creatinine ³ 2 mg per deciliter should be carefully monitored, since danaparoid's activity may be prolonged in these patients. {01}

» Blood counts, complete (CBC), including
Hematocrit
Platelet count    (recommended during treatment to detect occult bleeding or any degree of thrombocytopenia)

{01}
Blood pressure measurement    (recommended periodically during therapy; an unexplained drop in blood pressure may signal occult bleeding)

{01}
» Neurologic status    (frequent monitoring for signs and symptoms of neurological impairment is recommended; if neurologic compromise is noted, urgent treatment is necessary {01})


Stool tests for occult blood    (should be performed at regular intervals during therapy)

{01}


Side/Adverse Effects
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:

Note: No cases of white clot syndrome or Type II thrombocytopenia have been reported in clinical studies for the prophylaxis of deep venous thrombosis in patients receiving multiple doses of danaparoid for up to 14 days. {01}


Those indicating need for medical attention
Incidence less frequent
    
Fever {01}
    
hemorrhage (bleeding gums; coughing up blood; difficulty in breathing or swallowing; dizziness; headache; increased menstrual flow or vaginal bleeding; nosebleeds; paralysis; prolonged bleeding from cuts; red or dark brown urine; red or black, tarry stools; shortness of breath; unexplained pain, swelling, or discomfort, especially in the chest, abdomen, joints, or muscles; unusual bruising; vomiting of blood or coffee ground–like material; weakness){01}

Incidence rare
    
Epidural or spinal hematoma {01}(back pain; bowel/bladder dysfunction; leg weakness; numbness; paralysis; paresthesias)—back pain is not a typical presentation but some patients may experience this symptom
    
skin rash {01}

Note: If an epidural or spinal hematoma is suspected, urgent intervention is necessary {01}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Pain at injection site {01}

Incidence less frequent
    
Constipation {01}
    
nausea {01}





Overdose
For specific information on the agents used in the management of danaparoid overdose, see the Protamine (Systemic) monograph.

For more information on the management of overdose, 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:
Acute
    
Bleeding complications, which may include blood in urine
bloody or black, tarry stools
bruising
coughing up blood
ecchymosis (large, non-elevated blue or purplish patches in the skin), hematoma
hypochromic anemia (fatigue; headache; irritability; lightheadedness), nosebleed
persistent bleeding or oozing from mucous membranes or surgical wound
shortness of breath
vomiting of blood or material that looks like coffee grounds {01}


Treatment of overdose
The effects of danaparoid on anti-factor Xa activity cannot be antagonized with any known agent at this time. Although protamine sulfate partially neutralizes the anti-factor Xa activity of danaparoid and can be safely coadministered, there is no evidence that protamine sulfate can reduce severe, nonsurgical bleeding during treatment with danaparoid. {01}

Specific treatment—In the event of serious bleeding, danaparoid should be stopped and blood or blood product transfusions should be administered as needed. {01}


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Danaparoid (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to danaparoid, heparin, pork products, or sulfites
Other medical problems, especially bacterial endocarditis; bleeding; hemorrhagic blood dyscrasias; severe renal function impairment; severe, uncontrolled hypertension; stroke; surgery; thrombocytopenia; and ulcers or other lesions of the gastrointestinal tract

Proper use of this medication

» Proper dosing

Precautions while using this medication
» Need to inform all health care providers of use of medication

» Notifying physician immediately if signs and symptoms of bleeding or epidural/spinal hematoma occur


Side/adverse effects
Signs of potential side effects, especially fever, hemorrhage, epidural or spinal hematoma, and skin rash


General Dosing Information
The anti-factor Xa unit activity of danaparoid is not equivalent to that of heparin or low molecular weight heparins. Therefore, danaparoid cannot be used interchangeably (unit for unit) with unfractionated heparin or any low molecular weight heparin. {01}

Danaparoid is administered by deep subcutaneous injection. It must not be injected intramuscularly. {01}

Injection technique: The patient should be lying down during injection. A 25- to 26-gauge needle should be used to minimize tissue trauma. Administration should be alternated between the left and right anterolateral and left and right posterolateral abdominal wall. A fold of skin must be lifted up with thumb and forefinger, and the entire length of the needle should be inserted. The skin fold should be held throughout the injection and should not be pinched or rubbed afterwards. {01}


Parenteral Dosage Forms

DANAPAROID SODIUM INJECTION

Usual adult dose
Thromboembolism, pulmonary (prophylaxis) and
Thrombosis, deep venous (prophylaxis)
Subcutaneous, 750 anti-factor Xa units two times a day, beginning one to four hours prior to hip replacement surgery, and then no sooner than two hours after surgery. Treatment should be continued until the risk of deep venous thrombosis has diminished, usually within seven to ten days, but may be continued for up to fourteen days. {01}


Usual pediatric dose
Safety and efficacy have not been established. {01}

Strength(s) usually available
U.S.—


750 anti-factor Xa units per 0.6 mL (Rx) [Orgaran (in single unit-dose syringes) (sodium sulfite 0.15% [to prevent discoloration])]{01}


750 anti-factor Xa units per 0.6 mL (Rx) [Orgaran (in 0.6-mL ampuls) (sodium sulfite 0.15% [to prevent discoloration])]{01}

Packaging and storage:
Ampuls should be stored between 2 and 30 °C (36 and 86 °F). Syringes should be stored between 2 and 8 °C (36 and 46 °F). Protect from light. {01}



Developed: 04/28/1997
Revised: 07/10/1998



References
  1. Orgaran package insert (Organon—US), Rev 1/97, Rec 2/97; Rev 1/98, Rec 6/98.
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