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May 6, 1998
In response to your questions and concerns, the FDA is providing updated information with respect to this important safety-related issue.
The purpose of the Public Health Advisory was to call attention to postmarketing reports of patients who have developed epidural or spinal hematomas with the concurrent use of LMWHs/heparinoids and spinal/epidural anesthesia or spinal puncture.
Many of the hematomas caused neurologic injury, including long-term or permanent paralysis. Given the potential seriousness of this complication, the Public Health Advisory was released in the belief that patients and healthcare professionals should be notified.
The four currently approved drug products are Fragmin (dalteparin sodium) Injection, Lovenox (enoxaparin sodium) Injection, Normiflo (ardeparin sodium) Injection, and Orgaran (danaparoid sodium) Injection. The postmarketing reports received at the time of the Public Health Advisory involved patients who were treated with Lovenox .
However, the adverse event would be expected to occur with drugs with similar pharmacological activity used in the same manner. Therefore, the FDA asked all manufacturers of LMWHs and heparinoids to revise their package inserts to provide further information for the safe and effective use of these drugs.
Since the Public Health Advisory, two Norwegian patients administered Fragmin have been reported in the literature to have developed epidural hematomas.
As of April 1998, there have been more than 50 spontaneous safety reports describing patients who have developed epidural or spinal hematomas with concurrent use of enoxaparin sodium and spinal/epidural anesthesia or spinal puncture.
No, the FDA is NOT contraindicating or eliminating the use of spinal/epidural anesthesia with LMWHs/heparinoids.
The purpose of the December 15, 1997 FDA Public Health Advisory was to inform healthcare professionals about the reporting of these serious adverse events. Further, the FDA does not regulate the practice of medicine.
The limitations of spontaneous reports data, particularly underreporting, make it impossible to say how frequently these specific adverse events occur. Because these reports are made voluntarily, only those cases that are reported are known, and there is no definitive information as to the size of the potential patient population exposed to the agents in question.
With respect to Lovenox Injection, millions of syringes have been distributed since its market introduction.
Yes. Approximately 75% of the patients were women. The overall patient median age was about 75 years. The majority of patients had either knee or hip replacement surgery, and a minority had spinal surgery.
The majority of the patients had spinal/epidural anesthesia with or without catheter placement. Five reports were for patients who had no surgery. Of these five case reports, three patients had spinal injections and two patients had no known spinal puncture/trauma.
The reported signs and symptoms were sensory deficits including numbness and/or paresthesias; motor deficits including leg weakness and/or paralysis; and bowel/bladder dysfunction. Back pain was NOT the typical presentation, although some patients also experienced this symptom.
Patients with spinal/epidural hematomas may initially present with a single sign/symptom, or a combination of signs and symptoms.
The onset of signs/symptoms was generally about 2-3 days after initiation of Lovenox therapy.
Overall, the reports did not provide sufficient information to correlate the timing of epidural/ spinal catheter removal and the onset of neurological signs/symptoms associated with spinal/ epidural hematomas.
The available clinical data for the reported cases of spinal/epidural hematomas do not provide adequate information to determine the optimal time for performing spinal/epidural procedures in patients anticoagulated or scheduled to be anticoagulated with LMWHs or heparinoids.
However, when performing procedures in patients anticoagulated or scheduled to be anticoagulated with LMWHs or heparinoids, including: 1) spinal anesthesia, 2) placing or removing spinal/epidural catheters, or 3) any procedure involving epidural or dural puncture, the following should be considered:
Regarding specific evidence and scientific documentation of spinal/epidural hematomas/bleeds associated with the use of LMWHs and spinal/epidural anesthesia, you can obtain the tabulation of reports in Lovenox users made to FDA through January 7, 1998 by calling either:
In addition, the following literature review articles are recommended:
At this time, as stated in the Public Health Advisory, FDA believes practitioners should be aware of the following:
If neurologic compromise is noted, urgent intervention is necessary.
Yes. The package inserts of Fragmin , Lovenox , Normiflo , and Orgaran Injections were revised in January 1998 to include additional safety information and recommendations in a Boxed Warning, with related revisions in the Warnings, Precautions, and Adverse Reactions sections. These revisions were addressed in the Public Health Advisory, and are outlined in the answer immediately above.
To further review these labeling changes, go to the MedWatch Web Site at www.fda.gov/ medwatch/safety/1998/jan98.htm, or contact the following individual manufacturers for a copy of their specific revised label/package insert:
The committee concluded that the current amount of data is too sparse to determine specific time intervals between the insertion and removal of the spinal/epidural catheters and the development of spinal/epidural hematomas.
Further, the committee agreed that physicians should be given sufficient information to make an educated decision about the relative risks of different types of anesthesia, and balance the risks of perioperative thromboembolic complications and spinal or epidural hematomas.
A transcript (300+ pages) of the February 5, 1998 meeting can be easily accessed via internet at www.fda.gov/ohrms/dockets/ac/98/transcpt/3380t1.pdf .
All healthcare professionals are strongly encouraged to report any serious adverse events, including cases of epidural or spinal hematomas, occurring with the use of LMWHs, heparinoids, or other anticoagulants to either FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178) or mail (using postage-paid form) to FDA, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787, or to the respective pharmaceutical manufacturers:
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