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SILVER SPRING, MD. – A Food and Drug Administration advisory panel recommended that a contraindication or warning be added to the labels of injectable corticosteroids, specifically pertaining to transforaminal administration of particulate steroid formulations administered into the cervical spine, at a meeting held to address serious neurologic events associated with epidural steroid injections.
The FDA convened the Nov. 24-25 meeting of its Anesthetic and Analgesic Drug Products Advisory Committee to discuss the available evidence of the benefits of epidural steroid injections (ESIs), widely used off label to treat back pain, and the serious neurologic adverse events associated with ESIs. These events include strokes, paraplegia, quadriplegia, spinal cord infarction, and deaths, and they are the basis of the class warning added to the labels of these products this year.
In April 2014, the FDA issued a safety communication about these reports, warning that “injection of corticosteroids into the epidural space of the spine may result in rare but serious adverse events, including loss of vision, stroke, paralysis, and death.” An estimated 9 million ESIs are administered each year in the United States.
The panel voted 15-7, with one abstention, in favor of a contraindication, while those voting no supported a warning as more appropriate. The original voting question on the agenda was whether all epidural steroid injections should be contraindicated, but the FDA reworded the question because the panelists felt it was too broad.
Dr. Michael Weisman, director of the division of rheumatology at Cedars-Sinai Medical Center and professor of medicine at the University of California, Los Angeles, said that, considering the wide variety of conditions treated with ESIs and the complicated anatomy of the spine, the benefits of depot formulations, particularly in the cervical spine, do not outweigh the significant risks. The risk is small, “but when it happens, it is very significant,” he said.
Dr. Jeffrey Kirsch, professor and chair of the department of anesthesiology and perioperative medicine at Oregon Health and Science University, Portland, supported the contraindication because “it’s too risky to administer the particulate medication in the cervical region, because of the risk of intravascular and intraarterial injection.”
In the medical literature, corticosteroids are classified as particulate or nonparticulate formulations, but the FDA uses the terms suspension or solution to classify steroids. Some studies have suggested that the risks and benefits of the two formulations may be different, and the agency has been criticized for not distinguishing between particulate and nonparticulate products in the warning statement.
Based on the available data, which had substantial limitations, the panelists were most concerned with the risks of epidural injections of particulate steroid products administered into the cervical spine with a transforaminal (TFA) approach because of a greater risk of accidental injection into the vasculature. They also noted that the risks were not limited to TFA cervical administration or to particulate products. As one panelist put it, “Why would anybody want sludge injected into their artery that goes to the brain?”
Based on the available evidence, the panel generally agreed that ESIs can have moderate beneficial effects in treating back pain, with substantial variations between patients, and that these benefits should be considered in the context of the risks and benefits of alternative therapies. They also said that there was not enough evidence to support a particular injection method or location or steroid formulation as superior. As one panelist pointed out, depot formulations may be more effective than nondepot formulations, but the differences are marginal and the risks are greater. One panelist supported a contraindication for all particulate injections for epidural use.
The FDA has been evaluating serious neurologic events associated with ESIs since 2009, after being contacted by an anesthesiologist about the risk of catastrophic neurologic injuries associated with TFA epidural injections of depot steroid formulations.
A review of events reported to the FDA’s Adverse Event Reporting System (FAERS) between November 1997 and April 2014 identified 90 cases of serious neurologic events associated with ESIs, including quadriplegia in a 53-year-old man who developed weakness in the left arm and both legs shortly after a triamcinolone injection – an MRI showed a diffuse vascular infarct to the cervical cord. As of April 2014, the FDA also received 41 reports of arachnoiditis in patients being treated for a variety of indications, most often unspecified back pain.
As with the FAERS data, cases identified in a medical literature review of studies between August 2012 and August 2014, also presented by the FDA at the meeting, were diverse. Cases were reported with cervical and lumbar TFA and interlaminar injections. No catastrophic cases associated with nonparticulate (solution) formulations were reported, but it is unclear whether that is related to the safety profile or lower use of nonparticulate formulations, according to the agency.
One of the panelists, Dr. Michael Sprintz, chief medical officer of the Sprintz Center for Pain and Dependency, The Woodlands, Tex., cautioned that the consequences of not having ESIs available should be considered. “By limiting patient access to these procedures, most pain docs are left with very little” to help these patients, which could result in a “massive increase” in opioid prescriptions, he said.
There are five injectable corticosteroids marketed in the United States: betamethasone, dexamethasone, hydrocortisone, methylprednisolone, and triamcinolone. In 2011, a statement was added to the labeling of injectable triamcinolone (Kenalog-10 and -40), manufactured by Bristol-Myers Squibb, that it was “not for epidural or intrathecal use.”
In 2013, about 420,000 people aged 65 years and older received ESIs, based on Medicare data, and about 604,000 people younger than 65 years in a national database of commercially insured patients also received ESIs. Both figures represent increases since 2009, according to the FDA. In both groups, almost half were TFA injections, most steroids used were suspensions, and more than one-third of the ESIs used were steroid suspensions administered by the TFA route.
The panelists had no conflicts to disclose. The FDA usually follows the recommendations of its advisory panels.
Serious adverse events associated with the use of epidural steroid injections should be reported to the FDA’s MedWatch program at http://www.fda.gov/Safety/MedWatch/ or 800-332-1088.
SILVER SPRING, MD. – A Food and Drug Administration advisory panel recommended that a contraindication or warning be added to the labels of injectable corticosteroids, specifically pertaining to transforaminal administration of particulate steroid formulations administered into the cervical spine, at a meeting held to address serious neurologic events associated with epidural steroid injections.
The FDA convened the Nov. 24-25 meeting of its Anesthetic and Analgesic Drug Products Advisory Committee to discuss the available evidence of the benefits of epidural steroid injections (ESIs), widely used off label to treat back pain, and the serious neurologic adverse events associated with ESIs. These events include strokes, paraplegia, quadriplegia, spinal cord infarction, and deaths, and they are the basis of the class warning added to the labels of these products this year.
In April 2014, the FDA issued a safety communication about these reports, warning that “injection of corticosteroids into the epidural space of the spine may result in rare but serious adverse events, including loss of vision, stroke, paralysis, and death.” An estimated 9 million ESIs are administered each year in the United States.
The panel voted 15-7, with one abstention, in favor of a contraindication, while those voting no supported a warning as more appropriate. The original voting question on the agenda was whether all epidural steroid injections should be contraindicated, but the FDA reworded the question because the panelists felt it was too broad.
Dr. Michael Weisman, director of the division of rheumatology at Cedars-Sinai Medical Center and professor of medicine at the University of California, Los Angeles, said that, considering the wide variety of conditions treated with ESIs and the complicated anatomy of the spine, the benefits of depot formulations, particularly in the cervical spine, do not outweigh the significant risks. The risk is small, “but when it happens, it is very significant,” he said.
Dr. Jeffrey Kirsch, professor and chair of the department of anesthesiology and perioperative medicine at Oregon Health and Science University, Portland, supported the contraindication because “it’s too risky to administer the particulate medication in the cervical region, because of the risk of intravascular and intraarterial injection.”
In the medical literature, corticosteroids are classified as particulate or nonparticulate formulations, but the FDA uses the terms suspension or solution to classify steroids. Some studies have suggested that the risks and benefits of the two formulations may be different, and the agency has been criticized for not distinguishing between particulate and nonparticulate products in the warning statement.
Based on the available data, which had substantial limitations, the panelists were most concerned with the risks of epidural injections of particulate steroid products administered into the cervical spine with a transforaminal (TFA) approach because of a greater risk of accidental injection into the vasculature. They also noted that the risks were not limited to TFA cervical administration or to particulate products. As one panelist put it, “Why would anybody want sludge injected into their artery that goes to the brain?”
Based on the available evidence, the panel generally agreed that ESIs can have moderate beneficial effects in treating back pain, with substantial variations between patients, and that these benefits should be considered in the context of the risks and benefits of alternative therapies. They also said that there was not enough evidence to support a particular injection method or location or steroid formulation as superior. As one panelist pointed out, depot formulations may be more effective than nondepot formulations, but the differences are marginal and the risks are greater. One panelist supported a contraindication for all particulate injections for epidural use.
The FDA has been evaluating serious neurologic events associated with ESIs since 2009, after being contacted by an anesthesiologist about the risk of catastrophic neurologic injuries associated with TFA epidural injections of depot steroid formulations.
A review of events reported to the FDA’s Adverse Event Reporting System (FAERS) between November 1997 and April 2014 identified 90 cases of serious neurologic events associated with ESIs, including quadriplegia in a 53-year-old man who developed weakness in the left arm and both legs shortly after a triamcinolone injection – an MRI showed a diffuse vascular infarct to the cervical cord. As of April 2014, the FDA also received 41 reports of arachnoiditis in patients being treated for a variety of indications, most often unspecified back pain.
As with the FAERS data, cases identified in a medical literature review of studies between August 2012 and August 2014, also presented by the FDA at the meeting, were diverse. Cases were reported with cervical and lumbar TFA and interlaminar injections. No catastrophic cases associated with nonparticulate (solution) formulations were reported, but it is unclear whether that is related to the safety profile or lower use of nonparticulate formulations, according to the agency.
One of the panelists, Dr. Michael Sprintz, chief medical officer of the Sprintz Center for Pain and Dependency, The Woodlands, Tex., cautioned that the consequences of not having ESIs available should be considered. “By limiting patient access to these procedures, most pain docs are left with very little” to help these patients, which could result in a “massive increase” in opioid prescriptions, he said.
There are five injectable corticosteroids marketed in the United States: betamethasone, dexamethasone, hydrocortisone, methylprednisolone, and triamcinolone. In 2011, a statement was added to the labeling of injectable triamcinolone (Kenalog-10 and -40), manufactured by Bristol-Myers Squibb, that it was “not for epidural or intrathecal use.”
In 2013, about 420,000 people aged 65 years and older received ESIs, based on Medicare data, and about 604,000 people younger than 65 years in a national database of commercially insured patients also received ESIs. Both figures represent increases since 2009, according to the FDA. In both groups, almost half were TFA injections, most steroids used were suspensions, and more than one-third of the ESIs used were steroid suspensions administered by the TFA route.
The panelists had no conflicts to disclose. The FDA usually follows the recommendations of its advisory panels.
Serious adverse events associated with the use of epidural steroid injections should be reported to the FDA’s MedWatch program at http://www.fda.gov/Safety/MedWatch/ or 800-332-1088.
SILVER SPRING, MD. – A Food and Drug Administration advisory panel recommended that a contraindication or warning be added to the labels of injectable corticosteroids, specifically pertaining to transforaminal administration of particulate steroid formulations administered into the cervical spine, at a meeting held to address serious neurologic events associated with epidural steroid injections.
The FDA convened the Nov. 24-25 meeting of its Anesthetic and Analgesic Drug Products Advisory Committee to discuss the available evidence of the benefits of epidural steroid injections (ESIs), widely used off label to treat back pain, and the serious neurologic adverse events associated with ESIs. These events include strokes, paraplegia, quadriplegia, spinal cord infarction, and deaths, and they are the basis of the class warning added to the labels of these products this year.
In April 2014, the FDA issued a safety communication about these reports, warning that “injection of corticosteroids into the epidural space of the spine may result in rare but serious adverse events, including loss of vision, stroke, paralysis, and death.” An estimated 9 million ESIs are administered each year in the United States.
The panel voted 15-7, with one abstention, in favor of a contraindication, while those voting no supported a warning as more appropriate. The original voting question on the agenda was whether all epidural steroid injections should be contraindicated, but the FDA reworded the question because the panelists felt it was too broad.
Dr. Michael Weisman, director of the division of rheumatology at Cedars-Sinai Medical Center and professor of medicine at the University of California, Los Angeles, said that, considering the wide variety of conditions treated with ESIs and the complicated anatomy of the spine, the benefits of depot formulations, particularly in the cervical spine, do not outweigh the significant risks. The risk is small, “but when it happens, it is very significant,” he said.
Dr. Jeffrey Kirsch, professor and chair of the department of anesthesiology and perioperative medicine at Oregon Health and Science University, Portland, supported the contraindication because “it’s too risky to administer the particulate medication in the cervical region, because of the risk of intravascular and intraarterial injection.”
In the medical literature, corticosteroids are classified as particulate or nonparticulate formulations, but the FDA uses the terms suspension or solution to classify steroids. Some studies have suggested that the risks and benefits of the two formulations may be different, and the agency has been criticized for not distinguishing between particulate and nonparticulate products in the warning statement.
Based on the available data, which had substantial limitations, the panelists were most concerned with the risks of epidural injections of particulate steroid products administered into the cervical spine with a transforaminal (TFA) approach because of a greater risk of accidental injection into the vasculature. They also noted that the risks were not limited to TFA cervical administration or to particulate products. As one panelist put it, “Why would anybody want sludge injected into their artery that goes to the brain?”
Based on the available evidence, the panel generally agreed that ESIs can have moderate beneficial effects in treating back pain, with substantial variations between patients, and that these benefits should be considered in the context of the risks and benefits of alternative therapies. They also said that there was not enough evidence to support a particular injection method or location or steroid formulation as superior. As one panelist pointed out, depot formulations may be more effective than nondepot formulations, but the differences are marginal and the risks are greater. One panelist supported a contraindication for all particulate injections for epidural use.
The FDA has been evaluating serious neurologic events associated with ESIs since 2009, after being contacted by an anesthesiologist about the risk of catastrophic neurologic injuries associated with TFA epidural injections of depot steroid formulations.
A review of events reported to the FDA’s Adverse Event Reporting System (FAERS) between November 1997 and April 2014 identified 90 cases of serious neurologic events associated with ESIs, including quadriplegia in a 53-year-old man who developed weakness in the left arm and both legs shortly after a triamcinolone injection – an MRI showed a diffuse vascular infarct to the cervical cord. As of April 2014, the FDA also received 41 reports of arachnoiditis in patients being treated for a variety of indications, most often unspecified back pain.
As with the FAERS data, cases identified in a medical literature review of studies between August 2012 and August 2014, also presented by the FDA at the meeting, were diverse. Cases were reported with cervical and lumbar TFA and interlaminar injections. No catastrophic cases associated with nonparticulate (solution) formulations were reported, but it is unclear whether that is related to the safety profile or lower use of nonparticulate formulations, according to the agency.
One of the panelists, Dr. Michael Sprintz, chief medical officer of the Sprintz Center for Pain and Dependency, The Woodlands, Tex., cautioned that the consequences of not having ESIs available should be considered. “By limiting patient access to these procedures, most pain docs are left with very little” to help these patients, which could result in a “massive increase” in opioid prescriptions, he said.
There are five injectable corticosteroids marketed in the United States: betamethasone, dexamethasone, hydrocortisone, methylprednisolone, and triamcinolone. In 2011, a statement was added to the labeling of injectable triamcinolone (Kenalog-10 and -40), manufactured by Bristol-Myers Squibb, that it was “not for epidural or intrathecal use.”
In 2013, about 420,000 people aged 65 years and older received ESIs, based on Medicare data, and about 604,000 people younger than 65 years in a national database of commercially insured patients also received ESIs. Both figures represent increases since 2009, according to the FDA. In both groups, almost half were TFA injections, most steroids used were suspensions, and more than one-third of the ESIs used were steroid suspensions administered by the TFA route.
The panelists had no conflicts to disclose. The FDA usually follows the recommendations of its advisory panels.
Serious adverse events associated with the use of epidural steroid injections should be reported to the FDA’s MedWatch program at http://www.fda.gov/Safety/MedWatch/ or 800-332-1088.
AT AN FDA ADVISORY COMMITTEE MEETING
