Ardeparin (Systemic)
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VA CLASSIFICATION
Primary: BL111
Commonly used brand name(s): Normiflo.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
†Not commercially available in Canada.
Category:
Anticoagulant—
antithrombotic—
Note: Ardeparin is one of a group of substances known as low molecular weight heparins (LMWHs) {01}.
Indications
Accepted
Thromboembolism, pulmonary (prophylaxis) and
Thrombosis, deep venous (prophylaxis)—Ardeparin is indicated for prevention of deep vein thrombosis, which may result in pulmonary embolism, following knee replacement surgery {01}.
Pharmacology/Pharmacokinetics
Note: Because plasma concentrations cannot be measured directly, the pharmacokinetic and pharmacodynamic properties of ardeparin are evaluated on the basis of changes in plasma serine protease activity that are considered important in hemostasis and are affected by ardeparin {01}.
Physicochemical characteristics:
Source—
Isolated from porcine intestinal mucosa {01}.
Molecular weight—
Average: 6000 daltons {01}
pH
4.5 to 7 {01}.
Mechanism of action/Effect:
Ardeparin acts at multiple sites in the normal coagulation system to inhibit reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo . Ardeparin inhibits thrombosis by binding to antithrombin III and accelerating its activity, thus inactivating factor Xa and thrombin. Ardeparin also inhibits thrombin by binding to heparin cofactor II. At recommended dosages, ardeparin has no effect on prothrombin time (PT) assays and may or may not prolong the activated partial thromboplastin time (APTT). {01}
Note: Ardeparin has a higher ratio of anti-factor Xa to anti-factor IIa activity (about 2:1) than does unfractionated heparin (about 1:1 or less) {01}.
Absorption:
Well-absorbed after subcutaneous administration, with a mean bioavailability of 92% based on anti-factor Xa activity {01}.
Note: Ardeparin pharmacokinetics fit a one-compartment pharmacokinetic model with apparent first-order absorption {01}. Dose proportionality is slightly nonlinear; each doubling of the dose produces an anti-factor Xa area under the plasma concentration–time curve (AUC) that is about 25% higher than would be expected with linear dose proportionality, although anti-factor IIa activity over the same dose range does exhibit linear dose proportionality {01}.
Half-life:
Elimination:
Anti-factor Xa activity: Average, 3.3 hours following a single intravenous dose {01}.
Anti-factor IIa activity: Average, 1.2 hours following a single intravenous dose {01}.
Time to peak concentration:
Mean peak plasma anti-factor Xa activity—2.7 hours after a single subcutaneous dose of 30 to 100 units per kg of body weight (units/kg) {01}.
Mean plasma anti-factor IIa activity—3 hours after a single subcutaneous dose of 100 units/kg {01}.
Peak plasma concentration
Mean peak plasma anti-factor Xa activity—0.09 to 0.32 units per mL (units/mL) after 30 to 100 anti-factor Xa units/kg single doses {01}.
Mean plasma anti-factor IIa activity—Barely detectable after 30 anti-factor Xa units/kg and 0.07 units/mL after 100 anti-factor Xa units/kg single doses {01}.
Note: Peak anti-factor Xa plasma concentrations of ardeparin after single subcutaneous doses of 60 mg (5400 anti-factor Xa units) were about twice as high as those after subcutaneous doses of 60 mg (9600 anti-factor Xa units) of heparin {01}.
Elimination:
Renal {01}.
In dialysis—
Ardeparin does not appear to be removable by hemodialysis {01}.
Precautions to Consider
Cross-sensitivity and/or related problems
Patients sensitive to heparin or to pork products may be sensitive to ardeparin also {01}.
Carcinogenicity
Long-term studies in animals have not been done {01}.
Mutagenicity
Ardeparin was not found to be mutagenic in in vitro tests including the Ames test, the Chinese hamster ovarian cell (CHO/HGPRT) forward mutation test, or in in vivo tests including the mouse micronucleus test and the rat bone marrow cell chromosome aberration test {01}.
Pregnancy/Reproduction
Fertility—
Studies in male rats at subcutaneous doses of up to 3180 anti-factor Xa units per kg of body weight (units/kg) per day (19,080 anti-factor Xa units per square meter of body surface area [units/m 2] per day, approximately five times the recommended human dose based on body surface area) and in female rats at subcutaneous doses of up to 1590 units/kg per day (9540 units/m 2 per day, approximately three times the recommended human dose based on body surface area) found no evidence of impairment of fertility or of reproductive performance {01}.
Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.
Studies in pregnant rats at subcutaneous doses of up to 1590 units/kg per day (9540 units/m 2 per day, approximately three times the recommended human dose based on body surface area) and in pregnant rabbits at subcutaneous doses of up to 3180 units/kg per day (34,980 units/m 2 per day, approximately 10 times the recommended human dose based on body surface area) found no evidence of teratogenicity {01}. However, ardeparin was found to be teratogenic (scoliosis) in rats at intravenous doses of 4240 units/kg per day (25,440 units/m 2 per day, approximately seven times the recommended human dose based on body surface area) and was also teratogenic (interventricular septal defects, stenosis of the aortic arch and pulmonary trunk, and fused sternebrae) in rabbits at intravenous doses of 3744 units/kg per day and above (41,184 units/m 2 per day, approximately 11 times the recommended human dose based on body surface area) {01}.
FDA Pregnancy Category C {01}.
Breast-feeding
It is not known whether ardeparin is distributed into breast milk {01}. However, problems in humans have not been documented.
Pediatrics
Appropriate studies on the relationship of age to the effects of ardeparin have not been performed in the pediatric population. Safety and efficacy have not been established {01}.
Geriatrics
Studies performed in patients up to 92 years of age have not demonstrated geriatrics-specific problems that would limit the usefulness of ardeparin in the elderly {01}.
Based on results of pharmacokinetic studies in 934 patients in two large-scale clinical trials, age and gender do not need to be considered in dosing ardeparin {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 such as:
Anti-inflammatory drugs, nonsteroidal (NSAIDs)
Aspirin (increased risk of bleeding {01})
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 (increases in values to as high as three times the upper limit of normal have been reported in both normal subjects and patients given ardeparin; these effects are similar to those seen with heparin and other low molecular weight heparins; these increases are usually fully reversible and are rarely associated with increases in serum bilirubin concentrations; however, because of the importance of aminotransferase determinations in the differential diagnosis of myocardial infarction, hepatic disease, and pulmonary embolism, elevations should be interpreted with caution {01})
Triglycerides (paradoxical increases in serum concentrations have been reported, even though ardeparin is known to increase lipoprotein lipase activity {01})
Note: At normal doses, ardeparin has no effect on prothrombin time (PT). There is no effect on, or only a slight prolongation (usually less than 50 seconds) of, activated partial thromboplastin time (APTT). {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 ardeparin or
» Thrombocytopenia, heparin-induced, history of (risk of recurrence {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 also may be increased by traumatic or repeated epidural or spinal puncture)
» Blood dyscrasias, hemorrhagic, congenital or acquired
» Endocarditis, bacterial
» Hepatic function impairment, severe
» Renal function impairment, severe
» Retinopathy, diabetic or hypertensive
» Surgery, especially brain, spinal, or ophthalmologic
» Ulceration, other lesions, or recent bleeding of the gastrointestinal tract, active
Sensitivity to ardeparin, heparin, methylparaben, pork products, propylparaben, or sulfites
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 monitoring of coagulation parameters (activated partial thromboplastin time [APTT]) is not necessary {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})
Urinalysis (recommended during treatment to detect occult bleeding {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:
Those indicating need for medical attention
Incidence less frequent
Anemia{01}
fever{01}
hematoma at injection site{01} (deep, dark purple bruise, pain, or swelling at place of injection)
hemorrhage{01} (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)
Incidence rare
Allergic reaction{01} (fever; skin rash, hives, or itching)
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
thrombocytopenia{01} (bleeding from mucous membranes; rash consisting of pinpoint, purple-red spots, often beginning on the legs; unusual bruising)
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 less frequent
Nausea{01}
pain at injection site{01}
vomiting{01}
Overdose
For specific information on the agent used in the management of ardeparin 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:
Acute
Hemorrhage{01}
Note: Bleeding at the surgical site or at venipuncture sites may be the first sign of bleeding complications. Other signs may include epistaxis, hematuria, or blood in stools. Easy bruising or petechiae may be seen before frank bleeding. {01}
Treatment of overdose
Most bleeding can be controlled by discontinuing ardeparin, applying pressure to the site, if possible, and replacing volume and hemostatic blood elements (e.g., fresh frozen plasma, platelets) as required {01}.
Specific treatment:
Protamine sulfate may be administered if the above is ineffective or if a known ardeparin overdosage has occurred in a bleeding patient. A dose of 1 mg of protamine sulfate neutralizes approximately 100 anti-factor Xa units of ardeparin. The anti-factor IIa activity of intravenously administered ardeparin is completely neutralized within 10 minutes following an intravenous infusion dose of equal weight protamine sulfate (about 1 mg protamine sulfate for each 100 anti-factor Xa units of administered ardeparin). The anti-factor Xa and clot-based anti-factor Xa assay activities of ardeparin are reduced by about 75% within 10 minutes and are almost completely neutralized within 30 minutes after protamine sulfate administration. If protamine sulfate is given and bleeding persists, approximately 2 hours after the dose of protamine, blood should be withdrawn and residual anti-factor Xa levels determined. Additional protamine sulfate may be administered if clinically important bleeding persists or if anti-factor Xa levels remain higher than desired. {01}
Protamine sulfate should be administered with great care to avoid an overdose. Severe hypotensive and anaphylactoid reactions, possibly fatal, may occur with protamine sulfate. It should be administered only when resuscitation techniques and treatment of anaphylactic shock are readily available. {01}
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Ardeparin (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Sensitivity to ardeparin, heparin, methlyparaben, pork products, propylparaben, or sulfites
Other medical problems, especially bacterial endocarditis; bleeding; diabetic or hypertensive retinopathy; hemorrhagic blood dyscrasias; severe hepatic function impairment; severe renal function impairment; severe, uncontrolled hypertension; stroke; surgery; thrombocytopenia; or 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 anemia, fever, hematoma at injection site, hemorrhage, allergic reaction, epidural or spinal hematoma, and thrombocytopenia
General Dosing Information
Ardeparin cannot be used interchangeably (unit for unit) with heparin sodium or other low molecular weight heparins {01}.
Ardeparin should be administered subcutaneously {01}. Intramuscular injection is not recommended because of the possibility of hematoma at the injection site {01}. Ardeparin is not intended for intravenous administration {01}.
Injection technique: The patient should be sitting or lying down during injection. It may be given by deep (intra-fat) injection into the abdomen (avoiding the navel), the anterior aspect of the thighs, or the outer aspect of the upper arms; the site should be rotated with each injection. A skin fold, held between the thumb and forefinger, must be lifted, and the entire length of the needle inserted into the fold at a 45- to 90-degree angle. The plunger of the needle should be drawn back before the medication is injected to ensure that the needle is not in the intravascular space. To reduce bruising, the injection site should not be rubbed after the injection is completed. {01}
Subcutaneous dosing is calculated according to body weight because, in early clinical trials, plasma anti-factor Xa activity after fixed doses was found to be lower in patients of greater body weight; dosing according to body weight produces relatively constant anti-factor Xa activity {01}.
Because of the lack of correlation between renal function and bleeding rates and because ardeparin clearance was not reduced to a greater extent in patients with severe renal function impairment than in those with mild to moderate impairment, dosage adjustment does not appear to be necessary in patients with renal disease {01}.
Close observation for possible bleeding is recommended if ardeparin is administered during or immediately after diagnostic lumbar puncture, epidural anesthesia, or spinal anesthesia {01}.
If thromboembolism develops in spite of ardeparin prophylactic therapy, it is recommended that ardeparin be withdrawn and appropriate therapy initiated {01}.
Parenteral Dosage Forms
ARDEPARIN SODIUM INJECTION
Usual adult dose
Thromboembolism, pulmonary (prophylaxis) and
Thrombosis, deep venous (prophylaxis)
Subcutaneous (by deep [intra-fat] injection), 50 anti-factor Xa units per kg of body weight every twelve hours following knee replacement surgery {01}. Treatment should be initiated in the evening of the day of surgery or the following morning, and should continue for up to fourteen days or until the patient is fully ambulatory, whichever is shorter {01}.
Usual pediatric dose
Safety and efficacy have not been established {01}.
Strength(s) usually available
U.S.—
5000 anti-factor Xa units per 0.5 mL (in a single-use sterile cartridge-needle unit) (Rx) [Normiflo (glycerin) (methylparaben) (sodium metabisulfite) (propylparaben) (sodium hydroxide [to adjust pH]) (water for injection)]
10,000 anti-factor Xa units per 0.5 mL (in a single-use sterile cartridge-needle unit) (Rx) [Normiflo (glycerin) (methylparaben) (sodium metabisulfite) (propylparaben) (sodium hydroxide [to adjust pH]) (water for injection)]
Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F) {01}.
Preparation of dosage form:
To calculate the volume (in mL) for a 50 anti-factor Xa units per kg (units/kg) subcutaneous dose, one of the following formulas may be used, depending on the strength used: • For patients weighing up to 100 kg (220 pounds) (using the 5000 anti-factor Xa units per 0.5 mL strength)—Patient's body weight (kg) x 0.005 mL per kg {01}.
• For patients weighing more than 100 kg (220 pounds) (using the 10,000 anti-factor Xa units per 0.5 mL strength)—Patient's body weight (kg) x 0.0025 mL per kg {01}.
Note: The manufacturer provides detailed information in the labeling in tabular form regarding the volume of ardeparin sodium injection to be administered for a range of patient weights {01}.
Incompatibilities:
Mixing of ardeparin sodium injection with other injections or infusions is not recommended {01}.
Developed: 07/10/1998
References
- Normiflo package insert (Wyeth Laboratories—US), Rev 5/23/97, Rec 6/97; Rev 1/98, Rec 6/98.
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