Off-label Use of Drugs in the Neuroendovascular Suite

SUMMARY: The off-label use of drugs and devices in neuroendovascular procedures is common. Neurointerventionalists should be well aware of the level of evidence available in support of the off-label use of drugs and devices in their practice and some of the potential adverse events associated with them. These uses are categorized as I or II if they have been evaluated as primary or ancillary interventions in prospective trials/registries of neuroendovascular procedures and III if they were evaluated in case series. Category IV use is based on evaluation as primary or ancillary interventions in prospective trials/registries of non-neuroendovascular procedures. Physicians are allowed to use off-label drugs and procedures if there is strong evidence that they are beneficial for the patient. The neurointerventional professional societies agree that off-label use of drugs and devices is an important part of the specialty, but practicing providers should base their decisions on sound evidence when using such drugs and devices. ABBREVIATIONS: GDC Guglielmi detachable coil; IA intra-arterial; ICH intracerebral hemorrhage; PROACT Prolyse in Acute Cerebral Thromboembolism; UK urokinase Off-label1 use for prescription drugs, biologics, and approved medical devices is any use that is not specified in the labeling approved by the US Food and Drug Administration. Labeling includes any written material that accompanies, supplements, or explains the product. In neuroendovascular procedures practice, this use is relatively common. However, the knowledge among practicing neuroradiologists, endovascular neurosurgeons, and interventional neurologists regarding the principles and consequences of using off-label products in their practice is lacking. If physicians use a product for an indication not in the approved or cleared labeling, they have the responsibility to be wellinformed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain awareness of the use and effects of the product. FDA regulations allow the exchange and dissemination of scientific information on the unapproved uses of a product in response to unsolicited requests from physicians, continuing medical education programs, and peer-reviewed scientific and medical journals. This Review Article provides data with the following objectives: 1) allowing physicians to recognize off-label use of products within the scope of their practice, 2) identifying instances when the off-label use of medical products is recognized as a generally accepted medical standard within the physician community, 3) summarizing our experience using off-label products in our practice, and 4) providing recommendations from professional organizations on off-label use of drugs and medical devices. OFF-LABEL USE OF DRUGS IN THE NEUROENDOVASCULAR SUITE The following summarizes the most common drugs used off-label within the neuroendovascular suite. Intra-Arterial Use of Thrombolytics Approved Use of Thrombolytics. For acute ischemic stroke, intravenous administration within 3 hours of symptom onset; massive pulmonary embolus; and acute myocardial infarction. Off-Label Use. Intra-arterial administration for acute ischemic stroke up to 9 hours after symptom onset (category I). The only FDA-approved thrombolytic for acute ischemic stroke treatment is IV alteplase (Activase; Genentech, South San Francisco, California). Treatment should only be initiated within 3 hours after the onset of stroke symptoms and after exclusion of intracranial hemorrhage by a cranial CT scan. A subgroup of patients with ischemic stroke is treated by using intra-arterial thrombolytics with various criteria either alone or in combination with IV From the Zeenat Qureshi Stroke Research Center (M.M.A., A.E.H., A.I.Q.) and Department of Radiology (M.M.A.), University of Minnesota, Minneapolis, Minnesota. Please address correspondence to Mohamed Abdilhalim, MD, Department of Radiology, University of Minnesota, Diagnostic Radiology MMC 292, 420 Delaware St SE, Minneapolis, MN 55455; e-mail: [email protected] Indicates open access to non-subscribers at www.ajnr.org Indicates article with supplemental on-line table http://dx.doi.org/10.3174/ajnr.A3447 2054 Abdihalim Nov 2013 www.ajnr.org thrombolytics and/or mechanical thrombectomy. Intra-arterial urokinase (Abbokinase; Abbott Laboratories, Chicago, Illinois) was the most commonly used intra-arterial thrombolytic for acute ischemic stroke before 1999. However, an FDA action resulted in withdrawal of urokinase from the market for 4 years. FDA inspectors found that Abbott was not taking adequate steps to test for infection in or prevent contamination of the kidney cells used to manufacture the drug. This withdrawal led to use of other thrombolytic medications including prourokinase, reteplase, tenecteplase, and alteplase as part of endovascular treatment for acute ischemic stroke. Prourokinase was the only thrombolytic that was considered for FDA approval on the basis of the results of PROACT I and II trials. In both of those trials, patients were given intra-arterial (IA) prourokinase within 6 hours of symptoms onset. These trials demonstrated an increased rate of recanalization, 57.7% and 67% (treatment group) versus 14.3% and 18% (controls). Moreover, a recent meta-analysis of 5 randomized controlled trials of IA thrombolysis of acute ischemic stroke with 395 participants showed IA thrombolysis by using pro-UK, UK, or recombinant tissue plasminogen activator substantially increased the rates of recanalization and had excellent clinical outcomes. The increased hemorrhage frequencies were not associated with any increase in mortality. The off-label use of thrombolytics is recognized as a generally accepted medical standard within the physician community (category I). The formulation of thrombolytics (more concentrated compared with IV-use formulation) and the maximum dose used require sound principles or previous studies that have reported on these issues. Third-generation thrombolytics, tenecteplase (17 7 minutes), and reteplase (15–18 minutes), have longer half-lives and greater penetration in the thrombus matrix than alteplase (5 minutes). Platelet Glycoprotein IIb/IIIa Inhibitors Approved Use. Patients with acute coronary syndrome who are treated medically only and those undergoing percutaneous coronary intervention; and patients undergoing percutaneous coronary intervention including stent placement. Off-Label Use. Intraprocedural thrombosis and ischemic events following endovascular procedures (category III). The experience of using platelet glycoprotein IIb/IIIa inhibitors abciximab (Reopro; Johnson and Johnson, Malvern, Pennsylvania), eptifibatide (Integrillin; Merck, Whitehouse Station, New Jersey), and tirofiban (Aggrasat; Merck, West Point, Pennsylvania) in neurointerventional procedures is limited. These agents are effective in reducing ischemic complications of acute myocardial infarctions and thrombotic complications associated with percutaneous coronary interventions. The FDA-approved indications of glycoprotein IIb/IIIa inhibitors are in acute coronary syndromes and as an adjunct to percutaneous coronary interventions. The offlabel use of glycoprotein IIb/IIIa inhibitors was evaluated in several case series and clinical trials focusing on patients undergoing endovascular treatment for acute ischemic stroke or those undergoing carotid artery stent placement. The use of platelet glycoprotein IIb/IIIa inhibitors in both of these applications was discontinued for the most part. The premature discontinuation of the Abciximab in Emergency Treatment of Stroke Trial II after 808 patients with acute ischemia were enrolled due to high rates of intracranial hemorrhage associated with IV abciximab (IV bolus followed by IV infusion) limited the enthusiasm for further evaluation in ischemic stroke. The routine use in carotid artery stent placement was discontinued after a randomized trial, and 2 single-center comparisons with historical controls did not demonstrate any reduction in periprocedural ischemic events. The relatively high rate of fatal intracerebral hemorrhages (ICHs) observed in studies also reduced the enthusiasm for using these agents. Some local institutional review boards may require that planned use of these agents involve informing patients or relatives regarding such complications. The current use in neuroendovascular procedures is limited to intraprocedural thrombosis and ischemic events (category III). Glycoprotein IIb/IIIa inhibitors are approved only for IV administration but are usually administered by IV infusion, IA bolus followed by IV infusion, or IV bolus followed by IV infusion. Physicians administering these agents should be well aware of the principle of dose conversion of any agent requiring special formulation, reversal half-lives, and monitoring for thrombocytopenia. Abciximab requires filtration, while eptifibatide and tirofiban do not, before administration. Dosing of both eptifibatide and tirofiban should be adjusted in patients with renal failure (renal elimination) but this is not necessary with abciximab (eliminated by the reticuloendothelial system). Although rare, thrombocytopenia can occur within 1–24 hours after infusion. When these agents are infused, platelets should be monitored 1–2 hours after infusion and again 24 hours after infusion. Platelets should recover rapidly after discontinuation. The off-label use of platelet glycoprotein IIb/IIIa inhibitors is recognized as a generally accepted medical standard within the physician community in certain situations such as intraprocedural thrombosis. Calcium Channel Blockers ApprovedUse. Cerebral vasospasm (nimodipine), hypertension, angina, atrial arrhythmia, and paroxysmal supraventricular tachycardia. Off-Label Use. Intra-arterial administration for improving arterial luminal narrowing in patients with symptomatic cerebral vasospasm due to subarachnoid hemorrhage in native intracranial arteries (category III). Randomized controlled trials have shown that oral nimodipine (Nimotop; Bayer, West Haven, Connecticut) is effective in reducing delayed ischemic neurologic deficits caused by cerebral vasospasm following subarachnoid hemorrhage. Nimodipine, 60 mg orally every 4 hours for 21 consecutive days started within 96 hours of subarachnoid hemorrhage, is FDA-approved to prevent cerebral vasospasm. Intra-arterial or intravenous use of verapamil, nimodipine (Nimotop), and nicardipine (Cardene; Baxter Healthcare, Deerfield, Illinois) have all been reported to be effective and safe in the treatment of cerebral vasospasm (category III). The offlabel use of calcium channel blockers in treating cerebral vasospasm is recognized as a generally accepted medical practice within the physician community; however, the treating physician AJNR Am J Neuroradiol 34:2054–63 Nov 2013 www.ajnr.org 2055 must ensure that adequate hemodynamic monitoring is performed on patients receiving these agents. Low doses of intraarterial calcium channel blockers were not associated with significant hemodynamic changes, but high-dose nicardipine was associated with hypotension. The duration of monitoring must be adequate on the basis of the half-life of the agent: verapamil (4 minutes), nimodipine (7 minutes), and nicardipine (3 minutes). Physicians must also be familiar with and prepared to address commonly observed adverse events of hypotension and bradycardia. These agents are all category C medications during