SPINAL/EPIDURAL HEMATOMAS When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with selective inhibitors of thrombin such as Iprivask may be at risk of developing an epidural or spina lhematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the use of indwelling spinal catheters foradministration of analgesia or by the concomitant use of drugs affecting hemostasis suchas non- steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants. Likewise with such agents, the risk appears to be increased by traumaticor repeated epidural or spinal puncture. Patients should be frequently monitored for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. The physician should consider the potential benefit versus risk before neuraxial intervention, in patients anticoagulated or to be anticoagulated for thromboprophylaxis (see also WARNINGS).
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warnings
WARNINGS Renal Insufficiency: Iprivask must be used with caution in patients with renal impairment, particularly in those with moderate and severe renal impairment (creatinine clearance ≤60 mL/min/1.73 m2 body surface area) (see CLINICAL PHARMACOLOGY, Special Populations, Renal Insufficiency). Dose reductions by factors of three and nine are recommended for pat ients wi thmoderate and severe renal impairment respectively (see DOSAGE AND ADMINISTRATION). In addition, daily aPTT and serum creatinine monitoringare recommended for patients with moderate or severe renal impairment (see PRECAUTIONS, Laboratory Tests). Hemorrhagic Events: Iprivask is not intended for intramuscular injection as local hematoma formation may result. Iprivask, like other anticoagulants, should be used with caution in patients with increased risks of hemorrhage such as those with recent major surgery, organ biopsy orpuncture 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 oracquired, e.g. hemophilia, liver disease) or a history of gastrointestinal orpulmonary bleeding within the past 3 months. Bleeding can occur at any site during therapy with Iprivask. An unexplained fall inhematocrit or blood pressure should lead to a search for a bleeding site. Spinal/Epidural Anesthesia: As with other anticoagulants, there is a risk of neuraxialhematoma formation with the concurrent use of desirudin and spinal/epidural anesthesia,which has the potential to result in long term or permanent paralysis. The risk may be greater with the use of post-operative indwelling catheters or the concomitant use of additional drugs affecting hemostasis such as NSAIDs (Non-SteroidalAnti-Inflammatory Drugs), platelet inhibitors or other anticoagulants (see BoxedWARNING and PRECAUTIONS, Drug Interactions). The risk may also be increasedby traumatic or repeated neuraxial puncture. To reduce the potential risk of bleeding associated with the concurrent use of desirudinand epidural or spinal anesthesia/analgesia, the pharmacokinetic profile of the drug should be considered (see CLINICAL PHARMACOLOGY, Pharmacokinetic properties) when scheduling or using epidural or spinal anesthesia in proximity to desirudin administration. The physician should consider placement of the catheter prior to initiating desirudin and removal of the catheter when the anticoagulanteffect of desirudin is low (see DOSAGE and ADMINISTRATION). Should the physician decide to administer anticoagulation in the context of epidural/spinal anesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. Patients should be instructed to inform their physician immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated. The physician should consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis (see also WARNINGS, Hemorrhage, and PRECAUTIONS, Drug Interactions). Iprivask cannot be used interchangeably with other hirudins as they differ in manufacturing process and specific biological activity (ATUs). Each of these medicines has its own instructions for use.
ADVERSE REACTIONSIn the Phase II and III clinical studies, desirudin was administered to 2159 patients undergoing elective hip replacement surgery to determine the safety and efficacy of Iprivask in preventing VTE in this population. Below is the safety profile of the Iprivask 15 mg (q12h) regimen from these 5 multicenter clinical trials. Hemorrhagic Events: The following rates of hemorrhagic events have been reported during clinical trials. Hemorrhage in Patients Undergoing Hip Replacement Surgery Dosing Regimen Dosing Regimen Dosing Regimen Iprivask Heparin Enoxaparin 15 mg q12h SC N=1561 n (%) 5000 IU q8h SCN=501 n (%) 40 mg QD SCN=1036n (%) Patients with Any Hemorrhage a 464 (30) 111 (22) 341 (33) Patients with Serious Hemorrhage b 41 (3) 15 (3) 21 (2) Patients with Major Hemorrhage c 13 (less than 1) 0 (0) 2 (less than 1) a. Includes hematomas which occurred at an incidence of 6% in the Iprivask and enoxaparin treatment groups and 5% in the heparin treatment group. b. Bleeding complications were considered serious if perioperative transfusion requirements exceeded 5 units of whole blood or packed red cells, or if total transfusion requirements up to postoperative Day 6 inclusive exceeded 7 units of whole blood or packed red cells, or total blood loss up to postoperative Day 6 inclusive exceeded 3500 mL. c. Bleeding complications were considered major if the hemorrhage was: (1) overt and it produced a fall in hemoglobin of greater than or equal to 2g/dL or if it lead to a transfusion of 2 or more units of whole or packed cells outside the perioperative period (the time from start of surgery until up to 12 hours after); (2) Retroperitoneal, intracranial, intraocular, intraspinal, or occurred in a major prosthetic joint Non-hemorrhagic Events: Non-hemorrhagic adverse events occurring at greater than or equal to 2% incidence in patients treated with Iprivask 15 mg (q 12h) during elective hip replacement surgery and considered to be remotely, possibly, or probably related to desirudin are provided below. Adverse Events Occurring at ≥2% in Iprivask Treated Patients Undergoing Hip Replacement Surgery a,b Iprivask Heparin Enoxaparin Body System (Preferred Term) 15 mg q12h SC N=1561 n (%) 5000 IU q8h SC N=501n (%) 40 mg QD SCN=1036n (%) Injection Site Mass 56 (4) 32 (6) 7 (less than 1) Wound Secretion 59 (4) 23 (5) 34 (3) Anemia 51 (3) 11 (2) 37 (4) Deep Thrombophlebitis 24 (2) 41 (8) 22 (2) Nausea 24 (2) 5 (less than 1) 10 (less than 1) a Represents events reported while on treatment, excluding unrelated adverse events b All hemorrhages that occurred are included in ADVERSE REACTIONS, Hemorrhagic Events. Related Adverse Events with a Frequency of less than 2% and greater than 0.2% (in decreasing order of frequency): thrombosis, hypotension, leg edema, fever, decreased hemoglobin, hematuria, dizziness, epistaxis, vomiting, impaired healing, cerebrovascular disorder, leg pain, hematemesis. Allergic Reactions. In clinical studies, allergic events were reported less than 2% overall and in 2% of patients who were administered 15 mg desi rudin. (See PRECAUTIONS, General , Ant ibodies/ Re-exposure). Post Marketing: In addition to adverse events reported from clinical trials the following adverse events have been identified during post approval use of Iprivask. These events were reported voluntarily from a population of unknown size and the frequency of occurrence cannot be determined precisely: rare reports of major hemorrhages , some of which were fatal , and anaphylactic/anaphylactoid reactions.
adverse reactions table
<table width="100%" border="4" ID="i7e932e41-65f6-4a87-8257-7298380a7cb2"> <caption>Hemorrhage in Patients Undergoing Hip Replacement Surgery</caption> <tbody> <tr> <td/> <td> <content styleCode="bold">Dosing Regimen</content> </td> <td> <content styleCode="bold">Dosing Regimen</content> </td> <td> <content styleCode="bold">Dosing Regimen</content> </td> </tr> <tr> <td/> <td> <content styleCode="bold">Iprivask </content> </td> <td> <content styleCode="bold">Heparin</content> </td> <td> <content styleCode="bold">Enoxaparin</content> </td> </tr> <tr> <td/> <td>15 mg q12h SC N=1561 n (%)</td> <td>5000 IU q8h SCN=501 n (%)</td> <td>40 mg QD SCN=1036n (%)</td> </tr> <tr> <td>Patients with Any Hemorrhage a</td> <td>464 (30)</td> <td>111 (22)</td> <td>341 (33)</td> </tr> <tr> <td>Patients with Serious Hemorrhage b</td> <td>41 (3)</td> <td>15 (3)</td> <td>21 (2)</td> </tr> <tr> <td>Patients with Major Hemorrhage c</td> <td>13 (less than 1)</td> <td>0 (0)</td> <td>2 (less than 1)</td> </tr> </tbody> </table>