Volume 9, Number 3 July 1999
Alteplase is a serine protease that binds to fibrin in a thrombus or blood clot resulting in conversion of plasminogen to plasmin and initiation of local fibrinolysis. Alteplase has been approved in Canada since 1987 for the management of acute myocardial infarction.
On Feb. 16, 1999, the Therapeutic Products Programme (TPP) approved the drug Activase [registered sign] rt-PA (alteplase) in accordance with the Notice of Compliance with Conditions policy, which was issued on May 28, 1998, for the management of acute ischemic stroke in adults to improve neurological recovery and reduce the incidence of disability. The purpose of the Notice of Compliance with Conditions Policy is to provide earlier access to promising new drugs to patients suffering from serious, life-threatening or severely debilitating diseases or conditions and to create a mechanism to ensure that the manufacturer conducts confirmatory studies to establish the link between anticipated and real benefit.
Under the conditions specifically associated with the approval of Activase [registered sign] rt-PA, the Canadian sponsor Hoffmann-La Roche Limited has committed to the following:
- To develop and implement a physician education plan concerning proper use of the drug in the treatment of stroke.
- To conduct a general mailing to all Canadian Board-certified neurologists and heads of emergency medicine departments reinforcing the key conditions for drug administration in the management of stroke.
- To report the results of safety monitoring and post-marketing studies at specified times to the TPP.
- To support a study to try to identify stroke patients who would benefit most from treatment with alteplase.
The use of alteplase in acute ischemic stroke increases the risk of intracranial hemorrhage. [1] Data from the most favourable clinical study showed that the incidence of intracranial hemorrhage in patients with acute ischemic stroke was higher in the alteplase group than in the placebo group (6.4% v. 0.6% within 36 hours of administration). [1, 2] There was, however, no difference in the overall rate of death at day 90 between the 2 groups, although there was a trend toward a higher death rate among patients with severe stroke in the alteplase group than among those in the placebo group. [1] Doses greater than 0.9 mg/kg may be associated with an increased risk of intracranial hemorrhage. Therefore, a dose of 0.9 mg/kg (maximum 90 mg) should not be exceeded when used in stroke treatment. [1]
The use of alteplase in the treatment of stroke is limited to the following situations:
- Physicians must be experienced in acute stroke management, and be treating patients in a hospital setting equipped with appropriate laboratory facilities to follow the neurological and hematological status of the patient. [1]
- Treatment should be started only within the first 3 hours after the onset of stroke symptoms, and only after exclusion of intracranial hemorrhage by a cranial CT scan or other diagnostic imaging method sensitive for the presence of hemorrhage. [1] Treatment started more than 3 hours after the onset of symptoms is not recommended. Few patients (< 10%) present to hospital emergency departments within 3 hours after onset of stroke symptoms. [3]
- Treatment is contraindicated in situations where the risk of bleeding is increased, including recent surgery, head trauma or previous stroke, active internal bleeding, anticoagulant use, low platelet count (less than 100 x 109/L) or uncontrolled hypertension (e.g., systolic pressure greater than 185 mm Hg or diastolic pressure greater than 110 mm Hg). [1, 2]
A separate, comprehensive product monograph pertaining only to the use of alteplase in the treatment of stroke has been prepared. [1]
This notice of Compliance with Conditions is subject to revocation if the above-mentioned conditions are not met, or result in data indicating that the risks of treatment outweigh the benefits in stroke patients.
Written by: Catherine Parker, BSc, and Harold Rode, PhD, Bureau of Biologics and Radiopharmaceuticals.