Professional Information
Lepirudin (Systemic)
VA CLASSIFICATION
Primary: BL113
Commonly used brand name(s): Refludan.
Another commonly used name is
hirudin, recombinant .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Anticoagulant—
Indications
Accepted
Thromboembolism, heparin-induced (treatment)—Lepirudin is indicated for anticoagulation in patients with heparin-induced thrombocytopenia and associated thromboembolic disease in order to prevent further thromboembolic complications {01}.
Pharmacology/Pharmacokinetics
Note: Pharmacokinetic behavior follows a two-compartment model {01}.
Physicochemical characteristics:
Source—
Synthetic. Recombinant form of hirudin (a naturally occurring family of highly homologous isopolypeptides produced by the leech Hirudo medicinalis ) that is produced by a recombinant DNA process involving yeast cells. A polypeptide composed of 65 amino acids, which differs from naturally occurring hirudin by substitution of leucine for isoleucine at the N-terminal end of the molecule and by absence of a sulfate group on the tyrosine at position 63. {01}
Molecular weight—
6979.5 daltons {01}
pH
Approximately 7 {01}.
Solubility
Freely soluble in water for injection or 0.9% sodium chloride injection {01}.
Mechanism of action/Effect:
A highly specific inhibitor of the thrombogenic activity of thrombin; one molecule of lepirudin binds to one molecule of thrombin. Produces dose-dependent increases in activated partial thromboplastin time (aPTT). Its action is independent of antithrombin III and it is not inhibited by platelet factor 4. {01}
The pharmacodynamic response is directly related to lepirudin concentrations {01}. No saturable effect has been observed at intravenous doses up to 500 mcg (0.5 mg) per kg of body weight {01}.
Distribution:
Essentially confined to extracellular fluids {01}.
Biotransformation:
Although conclusive data are not available, biotransformation is thought to involve release of amino acids via catabolic hydrolysis of the parent drug {01}.
Half-life:
Distribution:
10 minutes {01}.
Elimination:
Young healthy volunteers: About 1.3 hours {01}.
Renal function impairment, severe (creatinine clearance less than 15 mL per minute): Up to 2 days {01}.
Hemodialysis: Up to 2 days {01}.
Note: Elimination follows a first-order kinetics process {01}.
Elimination:
Renal, about 48% (35% unchanged) {01}.
In dialysis—
May be removable by hemofiltration or hemodialysis {01}.
Note: Systemic clearance of lepirudin is proportional to the glomerular filtration rate (GFR) or creatinine clearance {01}. Systemic clearance is about 25% lower in women than in men and about 20% lower in the elderly than in younger patients {01}.
Precautions to Consider
Cross-sensitivity and/or related problems
Patients sensitive to other hirudins may also be sensitive to lepirudin {01}.
Carcinogenicity
Long-term studies in animals have not been done {01}.
Mutagenicity
Lepirudin was not found to be genotoxic in the Ames test, the Chinese hamster cell (V79/HGPRT) forward mutation test, the A549 human cell line unscheduled DNA synthesis (UDS) test, the Chinese hamster V79 cell chromosome aberration test, or the mouse micronucleus test {01}.
Pregnancy/Reproduction
Fertility—
Studies in male and female rats given intravenous doses up to 30 mg per kg of body weight (mg/kg) per day (180 mg per square meter of body surface area [mg/m 2] per day or 1.2 times the recommended maximum human total daily dose based on body surface area of 1.45 m 2 for a 50-kg subject) found no effect on fertility or reproductive performance {01}.
Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.
Lepirudin has been found to cross the placenta after intravenous administration to pregnant rats. It is not known whether lepirudin crosses the placenta in humans. {01}
Studies in rats and rabbits at intravenous doses up to 30 mg/kg per day (180 and 360 mg/m 2 per day or 1.2 and 2.4 times, respectively, the maximum recommended human total daily dose based on body surface area) found no evidence of fetal toxicity. However, an increase in maternal mortality due to undetermined causes was found in pregnant rats given 30 mg/kg per day during organogenesis and perinatal-postnatal periods. {01}
FDA Pregnancy Category B {01}.
Breast-feeding
It is not known whether lepirudin is distributed into human breast milk. However, risk-benefit should be considered. {01}
Pediatrics
Safety and efficacy in pediatric patients have not been established {01}. However, two children (11 and 12 years of age) were treated with lepirudin at doses ranging from 0.15 to 0.22 mg/kg per hour for 8 days, and 0.1 to 0.7 mg/kg per hour for 58 days, respectively, without serious adverse events {01}.
Geriatrics
Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of lepirudin 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 lepirudin.
Systemic clearance in elderly patients is about 20% lower than in younger 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{01} or
» Platelet aggregation inhibitors{01} (concurrent use may increase the risk of bleeding; gradual reduction in dose/rate of lepirudin is recommended prior to switching to an oral anticoagulant {01})
» Thrombolytics, such as:
Alteplase, recombinant{01}
Anistreplase
Reteplase
Streptokinase{01}
Urokinase (concurrent use may considerably increase the effect of lepirudin on activated partial thromboplastin time [aPTT] prolongation and increase the risk of bleeding complications such as intracranial 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
Activated partial thromboplastin time (aPTT) (lepirudin dose–related increases occur {01})
Thrombin time (TT) (increased even at low doses of lepirudin {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).
Risk-benefit should be considered when the following medical problems exist
» Conditions associated with a possible increased risk of bleeding, including
Anomaly of vessels or organs{01}
Bacterial endocarditis{01}
Bleeding, recent major (e.g., intracranial, gastrointestinal, intraocular, or pulmonary bleeding){01}
Cerebrovascular accident, stroke, intracerebral surgery, or other neuraxial procedures, recent{01}
Hemorrhagic diathesis{01}
Hypertension, severe uncontrolled{01}
Puncture of large vessels or organ biopsy, recent{01}
Renal function impairment, severe{01}
Surgery, recent major{01} (careful assessment of risk-benefit is recommended before initiation of treatment with lepirudin, because of the risk of life-threatening intracranial bleeding {01})
» Hepatic function impairment, severe, including cirrhosis{01} (may increase the anticoagulant effect of lepirudin as a result of reduced generation of vitamin K–dependent coagulation factors {01})
» Renal function impairment, known or suspected (creatinine clearance less than 60 mL per minute or serum creatinine greater than 1.5 mg per deciliter) (dosage reduction of both the bolus intravenous injection and the intravenous infusion rate is recommended to prevent possible overdosage that may occur even with the standard dosing regimen {01})
» Sensitivity to lepirudin or other hirudins{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):
» Activated partial thromboplastin time (aPTT){01} (recommended prior to initiation of therapy, 4 hours after the start of the lepirudin infusion, and at least once a day during treatment; it is recommended that frequency of monitoring be increased in patients with renal function impairment, severe hepatic injury, or an increased risk of bleeding; the goal is to maintain the aPTT ratio [the patient's aPTT at a given time over an aPTT reference value, usually the median of the laboratory normal range for aPTT] between 1.5 and 2.5; it is recommended that lepirudin treatment not be initiated in patients with an aPTT ratio over 2.5 to avoid initial overdosing {01})
Note: At plasma lepirudin concentrations of 1500 nanograms per mL, the following aPTT ratios have been observed: nearly 3 for healthy volunteers, 2.3 for patients with heparin-induced thrombocytopenia, and 2.1 for patients with deep venous thrombosis {01}.
Thrombin time (TT) is not suitable for routine monitoring of lepirudin therapy because TT has been found to exceed 200 seconds even at low plasma concentrations of lepirudin {01}.
Side/Adverse Effects
Note: Formation of antihirudin antibodies has been observed in about 40% of heparin-induced thrombocytopenia patients treated with lepirudin, which may increase the anticoagulant effect of lepirudin as a result of delayed renal elimination of active lepirudin-antihirudin complexes. Strict monitoring of aPTT is recommended during prolonged therapy. However, neither neutralization of lepirudin's effects nor allergic reactions associated with positive antibody test results have been observed. {01}
Intracranial bleeding has been reported, but only in patients with acute myocardial infarction who were treated with both lepirudin and thrombolytic therapy (rt-PA or streptokinase) {01}. It has not been reported in patients treated with lepirudin alone {01}.
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
Bleeding complications
including bleeding from puncture sites and wounds{01}
and hematoma{01} (collection of blood under the skin)
Incidence less frequent
Allergic reaction{01} (skin rash or itching)
bleeding complications
including anemia{01} (unusual tiredness), hematuria{01} (blood in urine), gastrointestinal and rectal bleeding{01} (black, tarry stools; blood in stools; vomiting of blood or material that looks like coffee grounds), coughing up blood{01}
nosebleed{01}
and vaginal bleeding{01}
fever{01}
heart failure{01} (swelling of feet or lower legs)
pneumonia{01} (fever or chills; cough; shortness of breath)
Overdose
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
Bleeding complications {01}
Treatment of overdose
There is no specific antidote to lepirudin. If life threatening bleeding occurs and excessive plasma levels of lepirudin are suspected the following steps should be taken:{02}{03}
Discontinue lepirudin immediately {01}.
Determine aPTT and other coagulation factor levels as appropriate {01}.
Determine hemoglobin and prepare for blood transfusion if necessary {01}.
Treat patient for shock as necessary and appropriate {01}.
There is some evidence that hemofiltration or hemodialysis (using high-flux dialysis membranes with a cutoff point of 50,000 daltons, e.g., AN/69) may be effective {01}.
General Dosing Information
In general, the dosage or infusion rate is adjusted according to the activated partial thromboplastin time (aPTT) ratio, which is the patient's aPTT at a given time over an aPTT reference value (usually the median of the laboratory normal range for aPTT). The target range for the aPTT ratio during treatment is 1.5 to 2.5, above which the risk of bleeding increases without an incremental increase in clinical efficacy. {01}
It is recommended that lepirudin treatment not be initiated in patients with an aPTT ratio of over 2.5, to avoid initial overdosing {01}.
Unless there is a clinical need to react immediately, it is recommended that any aPTT ratio that is out of the target range be confirmed at least once before altering the dose of lepirudin {01}.
If the aPTT ratio is confirmed to be above 2.5, it is recommended that the lepirudin infusion be discontinued for 2 hours and the rate decreased by 50% when it is reinstituted (without repeating the initial bolus injection), followed by another determination of aPTT ratio 4 hours later {01}.
If the aPTT ratio is confirmed to be below 1.5, it is recommended that the infusion rate be increased in increments of 20%, with determination of the aPTT ratio 4 hours after each increase {01}.
When switching to oral anticoagulation, it is recommended that the dose of lepirudin be gradually reduced to produce an aPTT ratio just above 1.5 before initiation of oral anticoagulant therapy. Lepirudin may be discontinued as soon as the international normalized ratio (INR) reaches 2. {01}
Lepirudin is almost exclusively excreted in the kidneys; therefore, the patient's renal function should be considered prior to administration. The initial intravenous injection and the continuous infusion rate must be reduced in case of known or suspected renal function impairment. Dosage adjustments should be based on creatinine clearance values, whenever available, as obtained from a reliable method (24-hour urine sampling). If creatinine clearance is not available, dosage adjustments should be based on serum creatinine values. {01}
Dosage adjustment in renal function impairment {01}
The initial intravenous injection should be reduced to 0.2 mg per kg of body weight.
Adjustment of infusion rate:
•
| Creatinine clearance (mL/min) | Serum creatinine (mg/dL) | % of standard initial infusion rate | Infusion rate (mg/kg/hour) |
| 45 - 60 | 1.6 - 2 | 50% | 0.075 |
| 30 - 44 | 2.1 - 3 | 30% | 0.045 |
| 15 - 29 | 3.1 - 6 | 15% | 0.0225 |
| < 15 | > 6 | avoid or stop infusion | |
In hemodialysis patients or in case of acute renal failure, the lepirudin infusion should be avoided or stopped. Additional intravenous bolus injections at a dose of 0.1 mg per kg of body weight may be considered every other day, only if the aPTT ratio falls below the lower therapeutic limit of 1.5.
Concomitant use with thrombolytic therapy {01}
There is limited information on the combined use of lepirudin and thrombolytic agents. The following dosage regimen of lepirudin was used in nine patients with heparin-induced thrombocytopenia who presented with thromboembolic complications at baseline and were started on both lepirudin and thrombolytic therapy:
• Initial intravenous injection: 0.2 mg per kg of body weight
• Continuous intravenous infusion: 0.1 mg per kg of body weight per hour.
Concomitant treatment with thrombolytic agents may increase the risk of bleeding complications, including potentially life-threatening intracranial bleeding, and considerably enhance the effect of lepirudin on aPTT prolongation {01}.
Parenteral Dosage Forms
LEPIRUDIN FOR INJECTION
Usual adult dose
Thromboembolism, heparin-induced (treatment)
Initial: Intravenous (slowly, for example over fifteen to twenty seconds), 400 mcg (0.4 mg) per kg of body weight (up to 44 mg), {01} followed by—
Intravenous infusion, at a rate of 150 mcg (0.15 mg) per kg of body weight per hour (up to 16.5 mg per hour, initially) for two to ten days or longer {01}.
Note: Basing the initial dosage on the patient"s body weight is valid for patients weighing up to 110 kg. However, for patients weighing more than 110 kg, the initial dosage should not be increased above 44 mg or the maximum infusion rate above 16.5 mg per hour. {01}
Dosage is adjusted according to activated partial thromboplastin time (aPTT) ratio determinations {01}.
Dosage adjustment in renal function impairment is recommended {01}. See General Dosing Information .
Although lepirudin has been used in a few patients in combination with thrombolytic therapy, the dosage in such combination has not been established {01}. See General Dosing Information .
Usual adult prescribing limits
In general, it is recommended that the infusion rate not exceed 0.21 mg per kg of body weight per hour without checking for coagulation abnormalities that might prevent an appropriate aPTT response {01}.
Usual pediatric dose
Safety and efficacy have not been established {01}.
Note: Two children (11 and 12 years of age) were treated with lepirudin at doses ranging from 150 to 220 mcg (0.15 to 0.22 mg) per kg of body weight per hour for eight days and 100 to 700 mcg (0.1 to 0.7 mg) per kg of body weight per hour for fifty-eight days, respectively, without serious adverse events {01}.
Size(s) usually available:
U.S.—
50 mg (Rx) [Refludan (mannitol 40 mg) (sodium hydroxide)]
Canada—
50 mg (Rx) [Refludan (mannitol 40 mg) (sodium hydroxide)]
{02}
Packaging and storage:
Store unopened vials between 2 and 25 °C (36 and 77 °F) {01}.
Preparation of dosage form:
For rapid, complete reconstitution, inject 1 mL of diluent into the vial and shake gently.{03}
Lepirudin for injection is reconstituted by adding 1 mL of water for injection or 0.9% sodium chloride injection to the 50-mg vial and shaking gently, producing a clear, colorless solution within a few seconds to less than 3 minutesand should be warmed to room temperature before using{03}{02} {01}.
For further dilution, 0.9% sodium chloride injection or 5% dextrose injection are suitable.{03}
Parenteral drug products should be inspected visually for particulate matter and discoloration before use. Do not use solutions that are cloudy or contian particles.{03}{02}
For administration by intravenous injection (bolus)(concentration of 5mg/mL), the reconstituted solution is further diluted by transferring the solution to a sterile, single-use syringe (of at least 10 mL capacity) and adding sufficient water for injection, 0.9% sodium chloride injection, or 5% dextrose injection to produce a total volume of 10 mL of a solution containing 5 mg of lepirudin per mL {02}{03}{01}.
For administration by continuous intravenous infusion(concentrations of 0.2 or 0.4 mg/ml), the contents of two vials of reconstituted solution (total of 100 mg of lepirudin) are transferred into an infusion bag containing 500 mL or 250 mL of 0.9% sodium chloride injection or 5% dextrose injection, producing a solution containing 0.2 or 0.4 mg of lepirudin per mL, respectively {01}.{02}{03}
Stability:
It is recommended that any unused portion of a vial be discarded and that the reconstituted solution be used immediately {01}. For administration by intravenous infusion, the reconstituted solution is stable for up to 24 hours at room temperature {01}.
Incompatibilities:
Mixing with other drugs is not recommended {01}.
Developed: 08/07/1998
Revised: 01/22/2001
References
- Refludan package insert (Hoechst Marion Roussel—U.S.), Rev 3/98, Rec 3/98.
- Product Information: Refludan™, lepirudin. Aventis Pharma Inc., Laval, Quebec, (PI issued 01/2000) PI reviewed (01/2001).
- Product Information: Refludan®, lepirudin. Hoescht Marion Roussel, Inc., Kansan City, MO, (PI issued 10/1998) PI reviewed (01/2001).
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