WARNING: 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 spinal hematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the use of indwelling spinal catheters for administration of analgesia or by the concomitant use of drugs affecting hemostasis such as non- steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants. Likewise with such agents, the risk appears to be increased by traumatic or 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 Warnings and Precautions ( 5.1 ) ] . WARNING: SPINAL/EPIDURAL HEMATOMAS See Full Prescribing Information for complete boxed warning. 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 spinal hematoma which can result in long-term or permanent paralysis ( 5.1 ).
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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Hemorrhage: Bleeding can occur at any site during therapy with Iprivask. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site. Avoid intramuscular injection as local bleeding and hematoma formation may result. ( 5.3 ). • Increased Risk of bleeding with Renal Impairment: Dose reductions by factors of three and nine are recommended for patients with moderate and severe renal impairment respectively ( 2.2 ). In addition, daily aPTT and serum creatinine monitoring are recommended for patients with moderate or severe renal impairment ( 5.2 ). 5.1 Spinal/Epidural Hematoma There is a risk of neuraxial hematoma 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-Steroidal Anti-Inflammatory Drugs), platelet inhibitors or other anticoagulants [ see Drug Interactions (7.1) ] . The risk may also be increased by traumatic or repeated neuraxial puncture. To reduce the potential risk of bleeding associated with the concurrent use of desirudin and epidural or spinal anesthesia/analgesia, the pharmacokinetic profile of the drug should be considered [ see Clinical Pharmacology (12.3) ] 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 anticoagulant effect of desirudin is low [ see Dosage and Administration (2.1) ] . 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 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. 5.2 Hemorrhagic Events Avoid intramuscular injection of Iprivask as bleeding and local hematoma formation can occur. Iprivask increases the risks of hemorrhage in patients with 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, e.g. hemophilia, liver disease) or a history of gastrointestinal or pulmonary bleeding within the past 3 months. Bleeding can occur at any site during therapy with Iprivask. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site. In post marketing experience reports of fatal and serious bleeding events have occurred in patients treated with Iprivask. Sources of hemorrhage included bleeding from the brain, gastrointestinal tract, spleen, rectum, and vagina [ see Adverse Reactions (6.2) ]. Avoid use with other drugs that inhibit or modify platelet function or affect blood clotting (e.g., anticoagulants, antiplatelet agents, NSAIDs, SSRIs) as coadministration with Iprivask may potentiate bleeding. If these concomitant medications cannot be avoided, patients should be monitored for bleeding [ see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]. 5.3 Increased Risk of Bleeding with Renal Impairment Iprivask must be used with caution in patients with renal impairment due to an increased risk for bleeding, particularly in those with moderate and severe renal impairment (creatinine clearance ≤60 mL/min) [ see Clinical Pharmacology (12.3) ]. Reduce dose and monitor daily aPTT and serum creatinine in patients with moderate and severe renal impairment [ see Dosage and Administration ( 2.2 , 2.3 ) ]. 5.4 Antibodies/Re-exposure Antibodies have been reported in patients treated with hirudins. Potential for cross-sensitivity to hirudin products cannot be excluded. Irritative skin reactions were observed in 9/322 volunteers exposed to Iprivask by subcutaneous injection or intravenous bolus or infusion in single or multiple administrations of the drug. The allergic reaction in volunteers consisted of arthralgia, erythema, pruritus, or uticaria. Allergic events were reported in <2% of patients who were administered desirudin in Phase III clinical trials. Allergic events were reported in 1% of patients receiving unfractionated heparin and 1% of patients receiving enoxaparin. Hirudin-specific IgE evaluations may not be indicative of sensitivity to Iprivask as this test was not always positive in the presence of symptoms., Anti-hirudin antibodies have been detected upon re-exposure to desirudin. [ see Adverse Reactions (6.1) ] . Fatal anaphylactic reactions have been reported during hirudin therapy.
6 ADVERSE REACTIONS The following serious reactions are described further in other sections of the prescribing information • Spinal/Epidural Hematoma [ see Warnings and Precautions (5.1) ] • Hemorrhagic Events [ see Warnings and Precautions (5.2) ] • Increased Risk of Bleeding with Renal Impairment [ see Warnings and Precautions (5.3) ] • Antibodies/Re-exposure [ see Warnings and Precautions (5.4) ] Most common adverse reaction was hemorrhage (33%). Other adverse reactions (incidence ≥2%) injection site mass, wound secretion, anemia, deep thrombophlebitis and nausea ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Marathon Pharmaceuticals, LLC at 1-866-562-4620 or drugsafety@prosarcorp.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In 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. Hemorrhagic Events [ see Warnings and Precautions (5.2) ] : The following rates of hemorrhagic events have been reported during clinical trials. Hemorrhage in Patients Undergoing Hip Replacement Surgery Dosing Regimen Iprivask Heparin Enoxaparin 15 mg q12h SC N=1561 n (%) 5000 IU q8h SC N=501 n (%) 40 mg QD SC N=1036 n (%) 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 (<1) 0 (0) 2 (<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 [ see Warnings and Precautions (5.1) ]. 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 ≥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 ≥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=501 n (%) 40 mg QD SC N=1036 n (%) Injection Site Mass 56 (4) 32 (6) 7 (<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 (<1) 10 (<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 <2% and >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 <2% overall and in 2% of patients who were administered 15 mg desirudin. [ see Warnings and Precautions (5.4) ] . 6.2 Post Marketing Experience 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: reports of major hemorrhages [ see Warnings and Precautions (5.2) ], some of which were fatal, and anaphylactic/anaphylactoid reactions [ see Warnings and Precautions (5.4) ].