Desirudin, a biosynthetic form of hirudin, is an anticoagulant.1, 2, 3
Thromboprophylaxis in Hip-Replacement Surgery
Desirudin is used for the prevention of postoperative deep-vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients undergoing elective hip-replacement surgery.1, 2, 3, 4
Efficacy and safety of desirudin for the prevention of venous thromboembolic events (VTE) in patients undergoing elective total hip-replacement surgery are based principally on the results of 2 randomized, double-blind, multicenter trials and one double-blind, dose-finding trial demonstrating a reduction in the incidence of VTE compared with either unfractionated heparin or low-molecular weight heparin.1, 2, 3 In the first multicenter study, patients received either desirudin 15 mg every 12 hours or heparin sodium 5000 units every 8 hours, beginning preoperatively and continuing for a median of 9 days; both drugs were administered subcutaneously.1, 2 Treatment with desirudin was initiated after induction of regional anesthesia (when used) and within 30 minutes prior to surgery; the initial dose of heparin sodium was administered 2 hours prior to surgery.2 Based on results in 351 evaluable patients, a lower overall incidence of confirmed DVT was reported in patients receiving desirudin versus heparin (approximately 7% versus 23%, respectively), corresponding to a relative risk reduction of 68% with desirudin prophylaxis.2 In addition, rates of proximal DVT were lower in patients receiving desirudin versus heparin (approximately 3% versus 16%, respectively), corresponding to a relative risk reduction of 79%.1 No cases of PE or death occurred during the period of VTE prophylaxis in either treatment group.2 During a mean follow-up period of 44 days following surgery, between termination of anticoagulant prophylaxis and the follow-up evaluation, PE occurred in 4 patients who had received heparin and in none who had received desirudin.2 The rates of bleeding complications (including serious hemorrhage) and use of supportive measures (e.g., blood transfusions, plasma expanders) were similar in both treatment groups.2 Postoperative complications, including thigh swelling, wound hematoma, and superficial wound infection or dehiscence, were reported in 5 or 6% of patients receiving heparin or desirudin, respectively.2
In the second multicenter study, patients received either desirudin 15 mg every 12 hours or enoxaparin sodium 40 mg every 24 hours; both drugs were administered subcutaneously for 8-12 days (mean duration 9.8 or 9.7 days with desirudin or enoxaparin, respectively).1, 3 Treatment with desirudin was initiated after induction of anesthesia (when regional block anesthesia was used) and within 30 minutes prior to surgery; the initial dose of enoxaparin sodium was administered the evening prior to surgery.3 Based on results in 1587 evaluable patients, the overall incidence of major VTE (i.e., proximal DVT, fatal or nonfatal PE, or unexplained death) was reduced in patients receiving desirudin compared with those receiving enoxaparin (4.9% versus 7.6%, respectively), corresponding to a relative risk reduction of approximately 36%.3 In addition, lower rates of overall DVT (18.4% versus 25.5% with desirudin versus enoxaparin, respectively) and proximal DVT (4.5% versus 7.5% with desirudin versus enoxaparin, respectively) were reported, corresponding to relative risk reductions of 28 and approximately 40%, respectively.3 PE was confirmed in 2 patients in each treatment group, and one patient receiving desirudin died following cardiac arrest during hip-replacement surgery.3 The rates of bleeding complications (including serious hemorrhage) and the use of supportive measures (e.g., blood transfusions, plasma expanders) were similar between the two groups.3 Injection site hematoma (or mass) was reported more frequently with desirudin compared with enoxaparin (2.8% versus 0.6%).3
In a multicenter, double-blind, dose-finding study evaluating the safety and efficacy of various doses of desirudin (10, 15, and 20 mg) given every 12 hours and heparin sodium 5000 units every 8 hours, both administered subcutaneously,1 a lower VTE incidence was reported with all desirudin dosages compared with heparin.4, 17 The use of a higher dosage (i.e., 40 mg every 12 hours) of desirudin was associated with excessive hemorrhage in a separate open-label, dose-finding study.1, 12
All patients should be evaluated for bleeding disorder risk prior to initiation of prophylaxis with desirudin.1
The manufacturer states that desirudin is not interchangeable with other hirudin agents due to differences in manufacturing processes and biological activity.1
Reconstitution and Administration
Desirudin is administered by subcutaneous injection, preferably in the abdomen or thigh.1 The drug should not be administered IM because of the risk of local hematoma formation.1
Desirudin lyophilized powder for injection should be stored at a controlled room temperature of 25°C, but may be exposed to temperatures ranging from 15-30°C.1
Commercially available desirudin powder for injection must be reconstituted before administration.1 Desirudin lyophilized powder is reconstituted by adding the entire contents of the manufacturer-provided diluent syringe (containing 0.6 mL of mannitol 3% in water for injection) to a vial labeled as containing 15.75 mg of desirudin.1 Using the vial adapter provided by the manufacturer, the adapter should be pushed down into the vial containing desirudin lyophilized powder until the spike pierces the rubber stopper and snaps into place.1 After removal of the syringe cap from the syringe containing the diluent, the syringe should be attached to the vial adapter and secured onto the vial using a twisting motion.1 The plunger of the diluent syringe should then be pushed down to complete the transfer of the entire amount of diluent solution into the desirudin vial.1 While the syringe is still attached to the vial adapter, the vial should be gently swirled to aid reconstitution; the powder, in the form of a round tablet, should dissolve within 10 seconds.1 With the syringe still attached to the vial adapter, the vial should be inverted and the entire contents of the vial withdrawn into the syringe.1 Although the vial contains desirudin 15.75 mg in 0.6 mL of solution, some volume loss and contraction occurs as a result of dead space in the needle and syringe during the transfer process; therefore, the final volume withdrawn back into the syringe for subcutaneous administration is 0.5 mL, which provides 15 mg of desirudin.1, 14 Once all the solution has been withdrawn from the vial, the syringe should be removed from the vial adapter.1 Before injection, an Eclipse® needle (provided by the manufacturer) should be attached to the syringe containing the desirudin solution.1 The manufacturer's labeling should be consulted for additional details regarding reconstitution of desirudin.1
The reconstituted solution should be used immediately; however, the manufacturer states that desirudin solutions, when prepared as directed and protected from light, are stable at room temperature for up to 24 hours.1 Any unused reconstituted solution remaining in the vial should be discarded.1 Desirudin should not be mixed with any other injections, solvents, or infusions.1
Prevention of Venous Thromboembolism in Hip-Replacement Surgery
For prevention of venous thromboembolic events in patients undergoing total hip-replacement surgery, the recommended adult dosage of desirudin in patients with normal renal function is 15 mg subcutaneously every 12 hours.1, 2, 3 The initial dose is administered up to 5-15 minutes prior to surgery.1 If spinal/epidural anesthesia is used, the first dose of desirudin should be administered after induction of regional block anesthesia, when applicable.1 (See Warnings: Neurologic Effects, under Warnings/Precautions in Cautions.)
In clinical trials, treatment continued on average for 9-12 days.1, 2, 3 There is no clinical experience with the use of desirudin beyond 12 days.6
While information in US Food and Drug Administration (FDA)-approved labeling for desirudin dated January 2010 recommends a reduction in dosage for patients with moderate or severe renal impairment, the manufacturer has submitted a request to FDA for a change to desirudin labeling and currently15 recommends no dosage adjustment in patients with moderate renal impairment (i.e., patients with moderate renal impairment should receive the same dosage as patients with normal renal function) and modification of the dosage regimen for patients with severe renal impairment†.14, 15 The manufacturer also has proposed alternative instructions for aPTT monitoring of desirudin therapy in patients with severe renal impairment†.14, 15 The manufacturer states that based on current data, use of dosing information in FDA-approved labeling dated January 2010 is likely to result in subtherapeutic concentrations of desirudin, which may lead to treatment failure.15
Information in FDA-approved labeling for desirudin dated January 2010 regarding dosage reductions in patients with moderate or severe renal impairment was based empirically on results of a study indicating an increase in area under plasma concentration-time curve (AUC) in patients with impaired renal function who received single IV doses of desirudin.15 However, some evidence suggests that data based on IV dosing do not adequately reflect the pharmacokinetic parameters and pharmacodynamic activity of the drug when administered subcutaneously.1, 15, 16 In addition, some experts contend that dosage modifications in patients with impaired renal function should be based on reducing peak plasma concentrations of desirudin rather than reducing AUC since higher peak plasma concentrations (not increased AUC) are correlated with an increased risk of bleeding.15, 16 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer recommends caution in using desirudin in patients with renal impairment since elimination of the drug may be delayed in such patients, resulting in prolongation of aPTT.1 Monitoring of aPTT and serum creatinine concentration at least daily is recommended when desirudin in used in patients with moderate to severe renal impairment.1 Patients with renal impairment should be carefully monitored for signs and symptoms of bleeding.1
For the prevention of postoperative venous thromboembolic events in patients undergoing total hip-replacement surgery who have moderate renal impairment (creatinine clearance of 31-60 mL/minute or greater [corrected to 1.73 m2 of body surface area]), the manufacturer currently recommends a desirudin dosage of 15 mg subcutaneously every 12 hours† (i.e., the same dosage as that recommended for patients with normal renal function); this recommendation is based on pharmacokinetic data indicating that the dosage for moderate renal impairment recommended in FDA-approved labeling dated January 2010 results in a subtherapeutic plasma concentration, a diminished anticoagulant effect, and possible treatment failure.15 The dosage of desirudin for patients with moderate renal impairment included in FDA-approved labeling dated January 2010, which the manufacturer does not currently recommend, is 5 mg every 12 hours subcutaneously; this labeling also includes instructions for further reducing the dosage (i.e., to less than 5 mg) after consideration of the magnitude of the initial coagulopathy (i.e., aPTT abnormality).1, 15
The aPTT and serum creatinine concentration should be monitored at least daily in patients with renal impairment.1 The manufacturer states that the target peak aPTT ratio (i.e., obtained 1.5-2 hours after a subcutaneous dose) should average about 1.3-1.4 times the baseline value in patients receiving a 15-mg dose of desirudin.14 If the peak aPTT ratio exceeds 2 times the baseline value, this may indicate drug accumulation and desirudin therapy should be temporarily interrupted until the trough aPTT ratio (i.e., obtained just before a subcutaneous dose) is less than 1.4.1, 14, 15
For the prevention of postoperative venous thromboembolic events in patients undergoing total hip-replacement surgery who have severe renal impairment (creatinine clearance 11-30 mL/minute [corrected to 1.73 m2 of body surface area]), the manufacturer currently recommends a desirudin dosage of 7.5 mg subcutaneously every 24 hours† based on pharmacokinetic data in patients with severe renal impairment receiving subcutaneous rather than IV desirudin.15 The dosage of desirudin for patients with severe renal impairment included in FDA-approved labeling dated January 2010, which the manufacturer does not currently recommend, is 1.7 mg every 12 hours subcutaneously; this labeling also includes instructions for further reducing the dosage (i.e., to less than 1.7 mg) after consideration of the magnitude of the initial coagulopathy (i.e., aPTT abnormality).1, 15
Due to a lack of clinical and pharmacokinetic data in patients with very severe renal impairment (creatinine clearance of 10 mL/minute or less), the manufacturer currently recommends that desirudin be avoided in such patients.15
The manufacturer states that aPTT and serum creatinine concentration should be monitored at least daily in patients with renal impairment.1 Currently, the manufacturer recommends an alternative monitoring protocol for patients with severe renal impairment † that differs from that in FDA-approved labeling dated January 2010.14, 15 In this alternative monitoring protocol, the manufacturer states that desirudin therapy should be temporarily interrupted if the trough (i.e., obtained just before the dose) aPTT ratio is 1.4 or greater and that such therapy should be resumed only when the trough aPTT ratio is less than 1.4†.14 If aPTT monitoring is performed using peak aPTT (i.e., obtained 1.5-2 hours after a subcutaneous dose), desirudin treatment should be interrupted if the peak aPTT ratio exceeds 2 and should only be resumed when the trough aPTT is less than 1.4†.14, 15 Information on aPTT monitoring in patients with severe renal impairment in FDA-approved labeling dated January 2010,1 which the manufacturer does not currently recommend,15 states that desirudin therapy should be temporarily interrupted if the aPTT ratio exceeds 2 and should be resumed at a reduced dosage only when the aPTT ratio is less than 2.1, 15
Known hypersensitivity to natural or recombinant hirudins.1 Active bleeding and/or irreversible coagulation disorders.1
As with other anticoagulants, desirudin should be used with caution in patients with an increased risk of hemorrhage, such as those who have had recent major surgery, organ biopsy, or puncture of a non-compressible vessel within the last month; a history of hemorrhagic stroke, intracranial or intraocular bleeding (including diabetic [hemorrhagic] retinopathy); recent ischemic stroke; severe uncontrolled hypertension; bacterial endocarditis; a known hemostatic disorder (congenital or acquired such as hemophilia or liver disease); or a history of a GI or pulmonary bleeding event within the past 3 months.1
In the event of overdose or excessive anticoagulation, desirudin should be discontinued, monitoring of aPTT and other coagulation factors should be performed, and symptomatic and supportive treatment (i.e., transfusions or plasma expanders) should be used as needed.1 No specific antidote to desirudin is currently available.1 However, the anticoagulant effects may be partially reversed using activated protein plasma concentrates (i.e., thrombin-rich plasma concentrates).1 Limited data from a small study in healthy men receiving a 4-hour continuous IV infusion of desirudin followed by a rapid IV infusion of desmopressin (i.e., 0.3 mcg/kg over 15 minutes) demonstrated a partial reversal of the desirudin-induced coagulopathy (as indicated by a reduction in the aPTT).1, 7 In addition, a sixfold to sevenfold or greater increase (over baseline) in plasma factor VIII:C concentrations was observed approximately 1 hour after the start of the desmopressin infusion.7 Although limited data suggest a partial benefit in the use of desmopressin to reduce aPTT, no formal studies have been conducted establishing the clinical effectiveness of desmopressin in the management of bleeding resulting from a desirudin overdose.1
As with other anticoagulants, caution should be used when desirudin is administered concomitantly with drugs that affect platelet function, including systemic salicylates, nonsteroidal anti-inflammatory agents (NSAIAs), ticlopidine, dipyridamole, sulfinpyrazone, clopidogrel, and abciximab or other glycoprotein IIb/IIIa receptor antagonists.1, 6
Bleeding can occur at any site during treatment with desirudin; if an unexplained drop in hematocrit or blood pressure occurs during treatment, the patient should be evaluated to identify a potential bleeding site.1
Concurrent use of anticoagulants, including desirudin, with neuraxial (spinal/epidural) anesthesia or spinal puncture may increase the risk of developing epidural or spinal hematomas and neurologic injury, including long-term or permanent paralysis.1 The risk of these adverse events is increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs that affect hemostasis, such as NSAIAs, platelet aggregation inhibitors, or anticoagulants.1 The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.1
To reduce risk of bleeding, the use of neuraxial anesthesia, specifically the insertion and removal of the epidural catheter, should be undertaken with consideration of the pharmacokinetic properties of the drug (i.e., onset of effect and half life).1, 2 Placement of the epidural catheter should take place prior to initiation of desirudin treatment; removal of the epidural catheter should take place when anticoagulant effects are at a minimum.1 In clinical trials, desirudin was administered within 30 minutes prior to start of the operation.2, 3 Since 90% of the maximum concentration of desirudin in achieved within 30 minutes, the antithrombotic effects of desirudin can be expected to be adequate during and after the surgical procedure.2 Frequent monitoring is recommended for patients receiving anticoagulation in the context of epidural/spinal anesthesia.1 Patients should be monitored for manifestations of neurologic impairment (midline back pain, sensory or motor deficits [numbness or weakness in lower limbs], bowel and/or bladder dysfunction).1 Clinicians should fully consider the potential benefits versus risks of spinal or epidural anesthesia or spinal puncture in patients receiving or who are being considered for thromboprophylaxis with anticoagulants.1
In a practice advisory issued by the American Society of Regional Anesthesia and Pain Medicine (ASRA) addressing the use of regional anesthesia in patients receiving antithrombotic or thrombolytic therapy, experts recommended that neuraxial anesthesia not be used in patients receiving direct thrombin inhibitors.8 Although no cases of spinal hematoma related to neuraxial anesthesia have been reported in patients receiving a direct thrombin inhibitor, cases of spontaneous intracranial bleeding have been reported.8 Due to the lack of available information and potential use of hirudin drugs in other conditions (heparin-induced thrombocytopenia [HIT], adjunct to angioplasty), a full risk assessment, according to the ASRA experts, cannot be made for the use of desirudin (or any hirudin agent) as thromboprophylaxis in patients undergoing a surgical procedure requiring neuraxial blockade.8
Allergic reactions have been reported in 2% of patients during controlled clinical trials.1 Fatal anaphylactoid reactions have been reported during hirudin therapy.1
Irritative skin reactions in response to a skin-prick or intradermal antigen challenge have been reported in approximately 3% of immunocompetent volunteers at 1-2 months after receiving a single dose of desirudin administered either subcutaneously or IV.13, 14 In 200 individuals who received a second dose of the drug, 3 experienced manifestations of an allergic reaction that was ruled unrelated to the drug in 2 individuals; an additional 3 individuals had a positive skin test but no other manifestations of an allergic reaction.13
Antihirudin antibodies were detected in approximately 10% of patients receiving a single course of desirudin as prophylaxis in total hip-replacement surgery during a dose-finding clinical trial.9 Seroconversion occurred after 8 days of therapy.9 The detected antibodies, as confirmed by ELISA assay methods, were fully cross-reactive with lepirudin, another recombinant hirudin; no inhibitory antibodies were detected.9 Mean plasma concentrations of desirudin and clinical outcomes (e.g., rates of VTE, allergic reactions, hemorrhage) were similar in both antibody-positive and antibody-negative patients after a single course of desirudin.9 Rarely, anti-hirudin antibodies have been detected in patients upon re-exposure to desirudin.1
Concomitant administration of warfarin has no substantial effect on the pharmacokinetics of desirudin.1 Enhanced anticoagulant effects have been observed in a small number of healthy individuals receiving a fixed dose of oral warfarin 10 mg concomitantly with subcutaneous desirudin 0.3 mg/kg every 12 hours for 3 days.10 An additive anticoagulant effect, reflected by an 18-second prolongation of the aPTT and a median increase of INR by 1.1, has been reported with this combination.10 The investigators of this study concluded, however, that the observed effects on aPTT and INR in this small sample were not clinically important.10
If a patient is switched from an oral anticoagulant to desirudin or vice versa, close monitoring of anticoagulant activity is recommended, taking into account the overall coagulation status of the patient at the time that a change in therapy occurs.1 Close monitoring of aPTT is recommended if desirudin is administered concomitantly with an oral anticoagulant.4
Patient Monitoring and Evaluation
While all thrombin-dependent coagulation assays are affected by desirudin administration, daily monitoring of the aPTT ratio generally should be used to assess anticoagulant activity in patients with increased risk of bleeding and/or renal or hepatic impairment.1, 6
The manufacturer also recommends at least daily monitoring of serum creatinine concentration in patients with renal impairment receiving desirudin.1
The manufacturer states that thrombin time (TT) is not a useful monitoring parameter for desirudin.1
Category C.1 (See Users Guide)
It is not known whether desirudin is distributed into milk in humans; the manufacturer recommends caution if used in nursing women.1 ACCP recommends that the drug be continued in nursing women who are already receiving such therapy.1012
Safety and efficacy not established in children.1
The mean plasma clearance of desirudin was reduced by 28% in patients 65 years or older compared with younger patients.1 However, population pharmacokinetic studies conducted in patients receiving the drug for elective total hip-replacement surgery indicate that age does not affect clearance of desirudin when renal function is taken into consideration (i.e., use of renally adjusted dosages).1 Because geriatric patients may have decreased renal function and because patients with renal impairment may be at risk for desirudin-induced toxicity, geriatric patients receiving the drug should be monitored closely.1
A similar reduction in VTE rates was observed in geriatric and younger patients receiving desirudin and undergoing total hip-replacement surgery.1 The incidence of hemorrhage also was similar in patients older or younger than 65 years of a however, serious adverse events were reported more frequently in the subpopulation of patients 75 years or older compared with patients 65 years of age or younger.1
Desirudin has not been studied in patients with hepatic impairment.1 Serious injury to the liver (e.g., cirrhosis) may result in enhancement of the anticoagulant effect of desirudin due to impaired production of vitamin K-dependent coagulation factors.1
Dosage adjustment is recommended for patients with severe renal impairment.1 (See Renal Impairment, under Dosage and Administration: Special Populations.)
In a pharmacokinetic study, healthy individuals with normal renal function and patients with renal impairment received IV desirudin in a dosage adjusted for baseline renal function.1 AUC was increased approximately threefold or ninefold in patients with moderate (creatinine clearance of 31-60 mL/minute or greater) or severe (creatinine clearance less than 31 mL/minute) renal impairment, respectively; no difference in AUC was observed in patients with mild renal impairment (creatinine clearance 61-90 mL/minute) compared with healthy individuals.1 Prolongation of the terminal elimination half-life to up to 12 hours has been reported in patients with severe renal impairment; the reported terminal half life of desirudin is 2-4 hours in patients with mild to moderate renal impairment.1, 11 In patients with normal renal function and those with mild to moderate renal impairment, the anticoagulant effects of desirudin returned to baseline with 24 hours after treatment; however, the anticoagulant effects were sustained for at least 60 hours in patients with severe renal impairment despite a fourfold reduction in initial dosage.11 Based on these data, an empiric dosage reduction corresponding to one-third or one-ninth of the normal dosage in patients with moderate or severe renal impairment, respectively, was included in FDA-approved labeling.1, 16
However, some evidence suggests that data based on IV administration of desirudin do not adequately reflect the pharmacokinetic parameters and pharmacodynamic activity of the drug when administered subcutaneously.15, 16 Pooled pharmacokinetic and pharmacodynamic data (i.e., anticoagulant effects) from 6 studies in patients with normal renal function or moderate renal impairment (i.e., creatinine clearance 31-60 mL/minute) receiving various doses of subcutaneous or IV desirudin suggested a similar pharmacodynamic response (i.e., desirudin concentration versus change in aPTT) in patients receiving the standard FDA-labeled dosage (15 mg subcutaneously every 12 hours) regardless of renal function.16 Patients with severe renal impairment (creatinine clearance less than 30 mL/minute) were not included in this analysis.16 In the pooled analysis, in which data on desirudin plasma concentrations and aPTT were extracted and used to generate pharmacokinetic simulations, a 34% increase in steady-state (i.e., after 5 doses) peak plasma desirudin concentrations was observed in patients with moderate renal impairment compared with those values in patients with normal renal function; AUC was increased by 76% in patients with moderate renal impairment.16 A subsequent modeling simulation predicted similar median desirudin concentrations (i.e., 2-hour post-dose concentration) in patients with normal and moderately impaired renal function using the FDA-labeled dosage (January 2010 labeling) for patients with normal renal function (15 mg subcutaneously every 12 hours) to yield plasma concentrations of 51.7 and 52.4 nmol/L, respectively.16 Based on data generated from this model, the use of the FDA-labeled dosage (January 2010 labeling) in patients with moderate renal impairment (i.e., 5 mg every 12 hours) was projected to yield a subtherapeutic desirudin concentration of 17.5 nmol/L, corresponding to an aPTT ratio of 1.3.15 Based on data from animal studies, therapeutic desirudin concentrations are reported to range from 72 to 215 nmol/L.15 Based on these data, the manufacturer has submitted a labeling supplement to FDA recommending alternative desirudin dosage regimens for patients with moderate renal impairment.15 These alternative regimens take into consideration the importance of achieving a therapeutic peak plasma concentration that is likely to produce a desired anticoagulant effect in patients with varying degrees of renal function receiving the drug.15 (See Renal Impairment, under Dosage and Administration: Special Populations.)
The manufacturer recommends monitoring of aPTT and serum creatinine concentration at least daily in patients with moderate or severe renal impairment.1
Hemorrhage, including hematoma, was the most common adverse effect observed in clinical studies of desirudin in patients undergoing hip-replacement surgery.1, 3 Other adverse events reported in at least 2% of patients receiving desirudin in clinical studies and considered remotely, possibly, or probably related to the drug include injection site mass, 1, 2, 3 wound secretion (dehiscence),1, 3 anemia, 1 deep thrombophlebitis,1 and nausea.1
Potential pharmacologic interaction (increased risk of hemorrhage) when desirudin is administered concomitantly with thrombolytic and anticoagulant therapy.1 Any agent that may enhance the risk of hemorrhage should be discontinued prior to initiation of desirudin therapy.1 If concomitant administration of desirudin with a thrombolytic or anticoagulant cannot be avoided, close monitoring of the clinical status of the patient and laboratory parameters should be performed.1
During prophylaxis of VTE in patients undergoing total hip-replacement surgery, concomitant use of desirudin with heparin (unfractionated and low-molecular weight heparins) or dextrans is not recommended; unfractionated heparin and desirudin have additive effects on aPTT prolongation.1
Drugs Affecting Platelet Function
As with other anticoagulants, caution should be used when desirudin is administered concomitantly with drugs that affect platelet function, including systemic salicylates, NSAIAs, ticlopidine, dipyridamole, sulfinpyrazone, clopidogrel, and abciximab or other glycoprotein IIb/IIIa receptor antagonists.1
Desirudin, a biosynthetic (recombinant DNA) 65-amino acid peptide analog of naturally occurring hirudin, is an anticoagulant.1, 4 Hirudin is the polypeptide that is responsible for the anticoagulant properties of the saliva of the medicinal leech ( Hirudo medicinalis) .1, 4 Desirudin is identical to natural hirudin except for the absence of a sulfate group on tyrosine at position 63.1, 4
Desirudin is a specific, direct thrombin inhibitor that binds to the active catalytic and substrate-recognition (exosite) of circulating and clot-bond thrombin.1, 4 Inhibition of thrombin prevents various steps in the coagulation process (e.g., activation of factors V, VIII, and XIII; conversion of fibrinogen to fibrin; platelet activation and aggregation).1, 4 Desirudin affects all coagulation assays that are dependent on thrombin, including activated partial thromboplastin time (aPTT), which increases in a dose-dependent manner with desirudin administration.1, 4 (See Patient Monitoring and Evaluation under Warnings/Precautions: General Precautions, in Cautions.)
The biological activity of desirudin is determined through a chromogenic assay that measures the ability of the drug to inhibit the hydrolysis of a chromogenic peptidic substrate by thrombin compared with a desirudin standard.1 Each single-dose vial of commercially available desirudin contains 15.75 mg of the drug, corresponding to approximately 315,000 antithrombin units (20,000 antithrombin units per mg) with reference to the WHO international standard (1991) for alphathrombin.1
Peak plasma desirudin concentrations are reached 1-3 hours after a subcutaneous dose.1, 4 The drug is distributed into the extracellular space with an apparent volume of distribution of 0.25 L/kg.1 The pharmacologic effects of desirudin are not altered by co-administration of highly protein bound drugs (i.e., those with greater than 99% plasma protein binding).1
Desirudin is eliminated principally by the kidneys with 40-50% of a dose being excreted in urine as unchanged drug;1, 11 metabolites of the parent drug excreted in urine comprise less than 7% of the dose.1 The elimination half-life of desirudin is approximately 2-3 hours.1 4, 11 In patients with severe renal impairment, the elimination half-life may be prolonged up to 12 hours.1, 4, 11 (See Renal Impairment, under Warnings/Precautions in Cautions: Specific Populations.)
Importance of patients informing clinician if they have previously received treatment with desirudin or any other hirudin preparation.1, 6
Importance of reporting any signs of bleeding to clinicians immediately.1 Importance of informing clinician of any history of bleeding disorders or impaired renal function.1
Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs.1
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for subcutaneous use only | 15 mg |
1. Canyon Pharmaceuticals. Iprivask® (desirudin for injection) prescribing information. Hunt Valley, MD; 2010 Jan.
2. Eriksson BI, Ekman S, Kalebo P et al. Prevention of deep-vein thrombosis after total hip replacement: direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet . 1996; 347:635-9. [PubMed 8596376]
3. Eriksson BI, Wille-Jørgensen P, Kälebo P et al. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med . 1997; 337:1329-35. [PubMed 9358126]
4. Matheson AJ, Goa KL. Desirudin: a review of its use in the management of thrombotic disorders. Drugs . 2000; 60:679-700. [PubMed 11030473]
6. Revasc® (desirudin) 15 mg injection summary of product characteristics. From the EMEA web site. Accessed 2010 Jun 10. [Web]
7. Aminute DM, Mant TG, Walker SM et al. Effect of a 15-minute infusion of DDAVP on the pharmacokinetics and pharmacodynamics of REVASC during a four-hour intravenous infusion in healthy male volunteers. Thromb Haemost . 1997; 77:127-32. [PubMed 9031462]
8. Horlocker TT, Wedel DJ, Rowlingson JC et al. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med . 2010 Jan-Feb; 35:64-101.
9. Greinacher A, Eichler P, Albrecht D et al. Antihirudin antibodies following low-dose subcutaneous treatment with desirudin for thrombosis prophylaxis after hip-replacement surgery: incidence and clinical relevance. Blood . 2003; 101:2617-9. [PubMed 12393696]
10. Levy J, Kurz M, Whelton A. Lack of clinically significant interactions between the subcutaneously administered direct thrombin inhibitor desirudin and orally administered warfarin upon the international normalized ratio. Blood . 2009; (American Society of Hematology Annual Meeting Abstracts): Abstract No. 3131.
11. Lefèvre G, Duval M, Gauron S et al. Effect of renal impairment on the pharmacokinetics and pharmacodynamics of desirudin. Clin Pharmacol Ther . 1997; 62:50-9. [PubMed 9246019]
12. Eriksson BI, Kälebo P, Ekman S et al. Direct thrombin inhibition with Rec-hirudin CGP 39393 as prophylaxis of thromboembolic complications after total hip replacement. Thromb Haemost . 1994; 72:227-31. [PubMed 7831657]
13. Close P, Bichler J, Kerry R et al. Weak allergenicity of recombinant hirudin CGP 39393 (REVASC) in immunocompetent volunteers. The European Hirudin in Thrombosis Group (HIT Group). Coron Artery Dis . 1994; 5:943-9. [PubMed 7719527]
14. Canyon Pharmaceuticals, Hunt Valley, MD: Personal communication.
15. Canyon Pharmaceuticals: Use of Iprivask in patients with renal insufficiency. Parsipanny NJ: 2010 Jun.
16. Nafziger AN, Bertino JS. Desirudin dosing and monitoring in moderate renal impairment. J Clin Pharmacol . 2010; 50:614-22. [PubMed 19915180]
17. Eriksson BI, Ekman S, Kalebo P et al. Prevention of deep-vein thrombosis after total hip replacement: direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet . 1996; 347:635-9. [PubMed 8596376]
1012. Bates SM, Greer IA, Middeldorp S et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest . 2012; 141(2 Suppl):e691S-736S. [PubMed 22315276][PubMedCentral]