Does the FDA have a clue about the safe prescribing of opioids? Based on their September 10 press release we are about to find out. If you go to the FDA web page this appears to be the most relevant document. It contains the following warnings:
BOXED WARNING
In the boxed warning in Highlights, include the following text:
• Tradename exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. (5.1)
• Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow Tradename (formulation) whole to avoid exposure to a potentially fatal dose of (active opioid). (5.2)
• Accidental consumption of Tradename, especially in children, can result in fatal overdose of (active opioid). (5.2)
• For patients who require opioid therapy while pregnant, be aware that infants may require treatment for neonatal opioid withdrawal syndrome. Prolonged use during pregnancy can result in life-threatening neonatal opioid withdrawal syndrome. (5.3)
For products with an interaction with alcohol, also include the following:
• Instruct patients not to consume alcohol or any products containing alcohol while taking Tradename because co-ingestion can result in fatal plasma (active opioid) levels. (5.4)
As I read through these warnings I have several associations. First off, physicians were told 12 years ago in JAMA that they were undertreating pain, misunderstood pain, and that pain treatment needed to change. That was a naive document that depended on an assumption that pain could be "quantitated" on a 10 point scale. Over a decade and 100,000 opioid overdose deaths later we are not told that providing this information on drug labels will make a difference. That leads me to my second association, there is nothing in the above warning that I didn't learn in medical school 30 years ago, including the risk of neonatal withdrawal. The third association is that this definition and intervention is almost completely naive about addiction. A person with an addiction does not care about dire warnings. They don't care about their pain ratings. They care about acquiring and using addictive drugs. It is the nature of addiction. Their entire conscious state has changed. The tendency toward opiate addiction or not is probably biologically determined and a doctor cannot predict who is at risk. If you take an initial dose of opiate and experience intense euphoria, high energy and productivity, and intense sense of well being or feel like you finally have become the person you always wanted to be - you may be a person at high risk for opiate addiction. It doesn't really matter if they have a chronic pain disorder.
What needs to be done? What should the FDA being doing immediately. The four most important misconceptions driving both the epidemic of opioid dependence and the accidental overdose trend are:
1. Opioids are a silver bullet and will eliminate chronic pain if the dose is high enough.
2. Once a maintenance dose is achieved the level of pain relief should be constant.
3. Opioids are only taken for primary gain - the analgesic effect or the elimination of pain.
4. Opiates - prescribed by a doctor will not lead to reactivation of a previous addiction.
What do people need to know now? Probably not the new package insert for opioids. Most physicians don't read it. Every person taking an opioid need to know that it can affect their subjective state in such a way that it will place them at risk for addiction. They need to know at that time that they need to contact their physician and discuss it and the possibility of alternate or more closely monitored treatment. They need to know that there is no medicine that will treat chronic pain into remission. Physicians need to know a number of things including the fact that there is no medication that will eliminate chronic pain. They also need to know that it takes time and detailed evaluations (calls to pharmacy, tox screens, limited prescriptions, assessment of functional capacity) to optimize treatment and prevent addiction.
The warning on a package insert from the FDA containing seriously dated information will not do it. Dire warnings about an epidemic won't do it.
George Dawson, MD, DFAPA
Showing posts with label FDA. Show all posts
Showing posts with label FDA. Show all posts
Monday, September 16, 2013
Saturday, July 20, 2013
Is the FDA objective enough to assess treatments in psychiatry - or is this just politics as usual?
The American Psychiatric Association (APA) feed posted a link to this FDA news release regarding a new biological test for Attention Deficit Hyperactivity disorder. The device is essentially a quantitative EEG (QEEG) machine. The QEEG heyday was back in the mid 1980s to 1990's. Devices were designed that could take the standard output of an EEG montage and look at the frequency bands and how that activity fluctuated topographically within the individual. There were two major manufacturers at the time and both of those technologies allowed for a comparison of the subjects QEEG with a standardized groups. The difference could be determined as a t or z score and that was plotted relative to the electrode placements. The final analysis would yield maps consisting of frequencies and mathematical operations on those frequencies.
There were several articles on this methodology including an impressive article in Science on the diagnostic capabilities of these instruments. One manufacturer provided an algorithm of clinical features and EEG features that purported to diagnose major psychiatric disorders. You could actually analyze the data both ways - with or without the clinical features. There was enthusiasm to the point that a new psychiatric subspecialty in electrophysiology was made to meet the requirements of psychiatrists who wanted to use QEEG technology.
In 1988, I was so impressed with the technology that I approached a potential employer and struck a bargain that I would take a salary cut if they would buy me the machine and the deal was struck. I was fortunate enough to be affiliated with a certified electrophysiology lab with an outstanding electrophysiologist and EEG technologists. This was critical in order to collect standardized data and select numerous 2 second epochs of EEG data for computerized analysis. The epochs had to be completely free of artifact in order to provide valid data for analysis and anywhere from 30 to 60 of these epochs needed to be selected per patient.
If you think about it for more than a few minutes, what is wrong with the idea that EEG frequencies should point to a specific psychiatric diagnosis? The short answer is a lack of specificity. There are literally hundreds of conditions that can lead to fast or slow frequencies including normal fluctuations of conscious states. During my QEEG work we had to collect EEG epochs for analysis in the "eyes closed but alert" state. Quantitative EEGs can demonstrate significant fluctuation in that state.
After several hundred QEEGs with and without the computerized algorithm, it was apparent that the diagnostic abilities of QEEG were low. There were literally a handful of analyses that seemed to match the clinical diagnosis and at that point we shut down the project. As far as I can tell from their web site, that company no longer sells a QEEG machine claiming to make psychiatric diagnoses.
I have not been able to locate the specific reference for this FDA approval. The FDA press release states:
"In support of the de novo petition, the manufacturer submitted data including a clinical study that evaluated 275 children and adolescents ranging from 6 to 17 years old with attention or behavioral concerns. Clinicians evaluated all 275 patients using the NEBA System and using standard diagnostic protocols, including the Diagnostic and Statistical Manual of Mental Disorders IV Text Revision(DSM-IV-TR) criteria, behavioral questionnaires, behavioral and IQ testing, and physical exams to determine if the patient had ADHD. An independent group of ADHD experts reviewed these data and arrived at a consensus diagnosis regarding whether the research subject met clinical criteria for ADHD or another condition. The study results showed that the use of the NEBA System aided clinicians in making a more accurate diagnosis of ADHD when used in conjunction with a clinical assessment for ADHD, compared with doing the clinical assessment alone."
From ClinicalTrials.gov that appears to be this registered clinical trial. No results are reported and there are no publications in peer reviewed journals that I can find. The concerns about this technology should be apparent from the history outlined in the above narrative and the same application suggested by the FDA. This is not a diagnostic procedure but one that is a supplement to the clinical evaluation for ADHD. It reminds me what Russell Barkley - noted ADHD expert and scholar said in a seminar I attended last fall. There are no gold standard tests for ADHD any more than there are for any other problems of executive function. He pointed out that hours of neuropsychological testing (he is a neuropsychologist) is no more accurate than standard ADHD checklists. Neuropsychological testing is important because of the high prevalence of learning disorders in ADHD.
My prediction at this point (pending an actual published research paper) is that this QEEG machine will not be that clinically useful and if it is a question of neuropsychological testing versus the QEEG, neuropsych testing should be the the option because it can detect and allow for treatment planning for any associated learning disorders and QEEG cannot. One of the risks here in an age where insurance companies deny diagnostic costs is that neuropsychological testing is denied and the QEEG substituted depending on cost. That would not allow for the recognition or treatment planning for a learning disorder.
The larger question is how competent the FDA is to make decisions on devices for psychiatric disorders? The FDA came out with a notice in 2011 that electroconvulsive therapy devices may need to be reclassified (Class II to Class III) resulting in the need for additional testing, clinical trials, and regulation. That occurred after two generations of psychiatrists were trained on the current devices and have clinically demonstrated that it is a safe, effective and in many cases life saving therapy. They completed their own study and meta-analyses and it is unclear to me what they concluded. I consider the FDA web site to essentially be unnavigable. Available information in the psychiatric literature suggests that they are still is the process of coming up with a formula for reclassification of ECT devices to a more restrictive category and that their analysis of the efficacy of ECT may have been seriously underestimated. The concern of the authors is that reclassification will restrict availability of ECT to patients who have clear indications for its use much in the same way that poor Medicare reimbursement restricts the availability in some hospitals now.
The even larger question is there some kind of systematic bias operating here? Both the ECT and QEEG decisions seem mismatched with the available science and clinical experience. The FDA has the appearance of transparency, but you can never find what you need in the thousands of web pages that are linked to the agency. In the ECT example, I could not find a clear statement, vote or conclusion about the ECT decision until I read the article by Weiner, at al. In the case of the QEEG device there is no publication of the study supporting its use. Independent review suggests that there have been no advances in the past 16 years.
George Dawson, MD, DFAPA
FDA Executive Summary. Meeting to Discuss the Classification of Electroconvulsive Therapy (ECT) Devices. January 27-28, 2011.
Weiner R, Lisanby SH, Husain MM, Morales OG, Maixner DF, Hall SE, Beeghly J,Greden JF; National Network of Depression Centers. Electroconvulsive therapy device classification: response to FDA advisory panel hearing and recommendations. J Clin Psychiatry. 2013 Jan;74(1):38-42. doi:10.4088/JCP.12cs08260. PubMed PMID: 23419224.
Sand T, Bjørk MH, Vaaler AE. Is EEG a useful test in adult psychiatry? Tidsskr Nor Laegeforen. 2013 Jun 11;133(11):1200-1204. English, Norwegian. PubMed PMID: 23759782.
Nuwer M. Assessment of digital EEG, quantitative EEG, and EEG brain mapping: report of the American Academy of Neurology and the American Clinical Neurophysiology Society. Neurology. 1997 Jul;49(1):277-92. Review. PubMed PMID: 9222209.
"E. On the basis of current clinical literature, opinions of most experts, and proposed rationales for their use,QEEG remains investigational for clinical use in postconcussion syndrome, mild or moderate head injury, learning disability, attention disorders, schizophrenia, depression, alcoholism, and drug abuse." (from Nuwer 1997)
There were several articles on this methodology including an impressive article in Science on the diagnostic capabilities of these instruments. One manufacturer provided an algorithm of clinical features and EEG features that purported to diagnose major psychiatric disorders. You could actually analyze the data both ways - with or without the clinical features. There was enthusiasm to the point that a new psychiatric subspecialty in electrophysiology was made to meet the requirements of psychiatrists who wanted to use QEEG technology.
In 1988, I was so impressed with the technology that I approached a potential employer and struck a bargain that I would take a salary cut if they would buy me the machine and the deal was struck. I was fortunate enough to be affiliated with a certified electrophysiology lab with an outstanding electrophysiologist and EEG technologists. This was critical in order to collect standardized data and select numerous 2 second epochs of EEG data for computerized analysis. The epochs had to be completely free of artifact in order to provide valid data for analysis and anywhere from 30 to 60 of these epochs needed to be selected per patient.
If you think about it for more than a few minutes, what is wrong with the idea that EEG frequencies should point to a specific psychiatric diagnosis? The short answer is a lack of specificity. There are literally hundreds of conditions that can lead to fast or slow frequencies including normal fluctuations of conscious states. During my QEEG work we had to collect EEG epochs for analysis in the "eyes closed but alert" state. Quantitative EEGs can demonstrate significant fluctuation in that state.
After several hundred QEEGs with and without the computerized algorithm, it was apparent that the diagnostic abilities of QEEG were low. There were literally a handful of analyses that seemed to match the clinical diagnosis and at that point we shut down the project. As far as I can tell from their web site, that company no longer sells a QEEG machine claiming to make psychiatric diagnoses.
I have not been able to locate the specific reference for this FDA approval. The FDA press release states:
"In support of the de novo petition, the manufacturer submitted data including a clinical study that evaluated 275 children and adolescents ranging from 6 to 17 years old with attention or behavioral concerns. Clinicians evaluated all 275 patients using the NEBA System and using standard diagnostic protocols, including the Diagnostic and Statistical Manual of Mental Disorders IV Text Revision(DSM-IV-TR) criteria, behavioral questionnaires, behavioral and IQ testing, and physical exams to determine if the patient had ADHD. An independent group of ADHD experts reviewed these data and arrived at a consensus diagnosis regarding whether the research subject met clinical criteria for ADHD or another condition. The study results showed that the use of the NEBA System aided clinicians in making a more accurate diagnosis of ADHD when used in conjunction with a clinical assessment for ADHD, compared with doing the clinical assessment alone."
From ClinicalTrials.gov that appears to be this registered clinical trial. No results are reported and there are no publications in peer reviewed journals that I can find. The concerns about this technology should be apparent from the history outlined in the above narrative and the same application suggested by the FDA. This is not a diagnostic procedure but one that is a supplement to the clinical evaluation for ADHD. It reminds me what Russell Barkley - noted ADHD expert and scholar said in a seminar I attended last fall. There are no gold standard tests for ADHD any more than there are for any other problems of executive function. He pointed out that hours of neuropsychological testing (he is a neuropsychologist) is no more accurate than standard ADHD checklists. Neuropsychological testing is important because of the high prevalence of learning disorders in ADHD.
My prediction at this point (pending an actual published research paper) is that this QEEG machine will not be that clinically useful and if it is a question of neuropsychological testing versus the QEEG, neuropsych testing should be the the option because it can detect and allow for treatment planning for any associated learning disorders and QEEG cannot. One of the risks here in an age where insurance companies deny diagnostic costs is that neuropsychological testing is denied and the QEEG substituted depending on cost. That would not allow for the recognition or treatment planning for a learning disorder.
The larger question is how competent the FDA is to make decisions on devices for psychiatric disorders? The FDA came out with a notice in 2011 that electroconvulsive therapy devices may need to be reclassified (Class II to Class III) resulting in the need for additional testing, clinical trials, and regulation. That occurred after two generations of psychiatrists were trained on the current devices and have clinically demonstrated that it is a safe, effective and in many cases life saving therapy. They completed their own study and meta-analyses and it is unclear to me what they concluded. I consider the FDA web site to essentially be unnavigable. Available information in the psychiatric literature suggests that they are still is the process of coming up with a formula for reclassification of ECT devices to a more restrictive category and that their analysis of the efficacy of ECT may have been seriously underestimated. The concern of the authors is that reclassification will restrict availability of ECT to patients who have clear indications for its use much in the same way that poor Medicare reimbursement restricts the availability in some hospitals now.
The even larger question is there some kind of systematic bias operating here? Both the ECT and QEEG decisions seem mismatched with the available science and clinical experience. The FDA has the appearance of transparency, but you can never find what you need in the thousands of web pages that are linked to the agency. In the ECT example, I could not find a clear statement, vote or conclusion about the ECT decision until I read the article by Weiner, at al. In the case of the QEEG device there is no publication of the study supporting its use. Independent review suggests that there have been no advances in the past 16 years.
George Dawson, MD, DFAPA
FDA Executive Summary. Meeting to Discuss the Classification of Electroconvulsive Therapy (ECT) Devices. January 27-28, 2011.
Weiner R, Lisanby SH, Husain MM, Morales OG, Maixner DF, Hall SE, Beeghly J,Greden JF; National Network of Depression Centers. Electroconvulsive therapy device classification: response to FDA advisory panel hearing and recommendations. J Clin Psychiatry. 2013 Jan;74(1):38-42. doi:10.4088/JCP.12cs08260. PubMed PMID: 23419224.
Sand T, Bjørk MH, Vaaler AE. Is EEG a useful test in adult psychiatry? Tidsskr Nor Laegeforen. 2013 Jun 11;133(11):1200-1204. English, Norwegian. PubMed PMID: 23759782.
Nuwer M. Assessment of digital EEG, quantitative EEG, and EEG brain mapping: report of the American Academy of Neurology and the American Clinical Neurophysiology Society. Neurology. 1997 Jul;49(1):277-92. Review. PubMed PMID: 9222209.
"E. On the basis of current clinical literature, opinions of most experts, and proposed rationales for their use,QEEG remains investigational for clinical use in postconcussion syndrome, mild or moderate head injury, learning disability, attention disorders, schizophrenia, depression, alcoholism, and drug abuse." (from Nuwer 1997)
Friday, November 23, 2012
Mayo Clinic Counterpoint to FDA on Citalopram
The Mayo Clinic came out with their recommendations on what to do about the FDA's warning about citalopram. By their own description they are more liberal with regard to their citalopram recommendations and more conservative regarding escitalopram. I have previously reviewed the problem here and concluded that there is really a lack of data available on the likelihood of electrocardiogram abnormalities during normal clinical use and if citalopram is as cardiotoxic as the FDA is describing it - we should treat it more like a standard antiarrhythmic drug and used flecanide as an example.
For all practical purposes that would include baseline ECGs, ECGs at the max dose and taking it up one more level from either the Mayo Clinic or the FDA - a stress test looking for QTc prolongation at higher heart rates. The other elements in the Mayo recommendations based on history and physical examination and expecting some physician knowledge of drug metabolism are fairly standard. I thought it was interesting that they did not mention checking plasma levels of the drug especially in complex cases (eg. a patient with cirrhosis) who only responds to higher than recommended doses of the drug. Regarding the statements: "Selective serotonin reuptake inhibitors cannot simply be substituted for one another, not even escitalopram for citalopram." That is generally true and where are these guys in the battle against PBMs saying that these drugs are all equivalent? I have not found any patient that responded selectively to citalopram and not escitalopram. I have generally been able to convert patients to an equivalent amount of escitalopram the next day.
Both the Mayo Clinic and the FDA are silent on molecular approaches to solving this problem and screening patient for potential risk before they are started on either drug. The Mayo Clinic offers testing for cytochrome P450 genotypes. The genetic basis for hereditary prolonged QTc intervals has been a hot topic of research over the past decade. It is probably time to expand the search for additional genotypes that place people at risk during specific drug therapies. Until then we have only very approximate methods of determining the at - risk population and keeping them safe and the Mayo recommendations are more reality based than the FDA.
I think it would also be possible to estimate the risk associated with taking citalopram across the entire population. In fact, at this point the FDA seems to have the data to estimate the risk of any QTc effect at all to the risk of torsade de pointes - the most significant arrhythmia. I think it is very important for patients making the decision to have this number and if I can provide numbers on rare but serious antidepressant complications like serotonin syndrome, a federal agency with more perfect information and no patient care responsibility can do better.
George Dawson, MD, DFAPA
Sheeler RD, Ackerman MJ, Richelson E, Nelson TK, Staab JP, Tangalos EG, Dieser LM, Cunningham JL. Considerations on safety concerns about citalopram prescribing. Mayo Clin Proc. 2012 Nov;87(11):1042-5.
FDA Drug Safety Communication: Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses.
For all practical purposes that would include baseline ECGs, ECGs at the max dose and taking it up one more level from either the Mayo Clinic or the FDA - a stress test looking for QTc prolongation at higher heart rates. The other elements in the Mayo recommendations based on history and physical examination and expecting some physician knowledge of drug metabolism are fairly standard. I thought it was interesting that they did not mention checking plasma levels of the drug especially in complex cases (eg. a patient with cirrhosis) who only responds to higher than recommended doses of the drug. Regarding the statements: "Selective serotonin reuptake inhibitors cannot simply be substituted for one another, not even escitalopram for citalopram." That is generally true and where are these guys in the battle against PBMs saying that these drugs are all equivalent? I have not found any patient that responded selectively to citalopram and not escitalopram. I have generally been able to convert patients to an equivalent amount of escitalopram the next day.
Both the Mayo Clinic and the FDA are silent on molecular approaches to solving this problem and screening patient for potential risk before they are started on either drug. The Mayo Clinic offers testing for cytochrome P450 genotypes. The genetic basis for hereditary prolonged QTc intervals has been a hot topic of research over the past decade. It is probably time to expand the search for additional genotypes that place people at risk during specific drug therapies. Until then we have only very approximate methods of determining the at - risk population and keeping them safe and the Mayo recommendations are more reality based than the FDA.
I think it would also be possible to estimate the risk associated with taking citalopram across the entire population. In fact, at this point the FDA seems to have the data to estimate the risk of any QTc effect at all to the risk of torsade de pointes - the most significant arrhythmia. I think it is very important for patients making the decision to have this number and if I can provide numbers on rare but serious antidepressant complications like serotonin syndrome, a federal agency with more perfect information and no patient care responsibility can do better.
George Dawson, MD, DFAPA
Sheeler RD, Ackerman MJ, Richelson E, Nelson TK, Staab JP, Tangalos EG, Dieser LM, Cunningham JL. Considerations on safety concerns about citalopram prescribing. Mayo Clin Proc. 2012 Nov;87(11):1042-5.
FDA Drug Safety Communication: Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses.
Sunday, April 29, 2012
Does the FDA discriminate against antidepressants?
The FDA came out with a new warning on citalopram on 3/28/2012. The main point of the warning is that citalopram may lead to electrocardiogram changes that can be associated with an abnormal heart rhythm or arrhythmia that is potentially fatal. The specific change is prolongation of the QTc interval or the interval that correlates with the total duration of ventricular activation and recovery.
Citalopram is a widely used antidepressant medication and it widely used for three reasons. It is not likely to have a lot of interactions with other drugs. Citalopram figured prominently in the STAR*D algorithm from the largest study done on enhancing antidepressant effectiveness. A third reason is that it is a generic medication and it is very inexpensive. Psychiatrists have broad experience with the drug and the general experience is that it is well tolerated with little toxicity.
Flecainide is a Type IC antiarrhythmic agent indicated for the prevention of paroxysmal atrial fibrillation (AF), paroxysmal supraventricular tachycardia (PSVT), and the prevention of life-threatening ventricular arrhythmias like sustained ventricular tachycardia. The FDA warnings on the drug include proarrhytmic effects and excess mortality. The excess mortality was directly observed in a clinical trial done to suppress ventricular arrhythmias.
The black box warnings for each drug listed below are directly from Medline:
Looking at the safety concerns for both medications - important differences emerge. First, the FDA recommends maximum doses for the citalopram not just for the a maximum dose for adults but in specific conditions including aging. Searching the FDA web site shows exactly 25 references for safety concerns of flecainide and none of them contain that level of information. Second, the citalopram warning shows a table of QTc interval changes by dose for both citalopram and escitalopram. There is no information in FDA documents (that I could find) for flecainide even though it is widely accepted that flecainide causes dose related changes in not just the QTc interval but also the QRS and PR intervals along with a host of additional effects on cardiac pacemakers and conduction. The overall tone of the release is that citalopram is a potentially cardiotoxic drug. Third, the ECG monitoring recommendations are not internally consistent. The absolute cut off of a QTc interval of 500 ms is highly unlikely - even in cases where the patient is taking 60 mg per day or more of citalopram. It is also unlikely that the QTc intervals in the citalopram warning will lead to a QTc interval of greater than 500 ms. This will result in tens of thousands of ECGs done because that is the only way that the QTc interval can be determined.
The black box warnings and the recently issued warning all considered, serious questions are raised relative to drugs with known cardiotoxicity and the whole issue of QTc warnings in all psychiatric drugs. Certainly nobody wants a rare severe complication as a result of a prescription medication but can it really be avoided? What good would ECG screening do? There have not been any trials to address that issue of whether all patients taking citalopram need baseline ECGs. All the patients taking flecainide have probably had multiple ECGs done that indicate a possible need for treatment but there is little guidance on the ECG issue. In many patients taking flecainide, patients get serial ECGs and they do exercise stress tests to rule out proarrhythmic effects. Are the same precautions needed for patients on citalopram?
Are the thresholds for treatment different given the fact that flecainide caused increased mortality during clinical trials and citalopram did not? There would be an argument that flecainide is used to treat life-threatening arrhythmias, but the other indication is for prevention of atrial fibrillation and atrial fibrillation is not a life threatening arrhythmia. With regard to the seriousness of the diagnosis, major depression carries a lifetime mortality of 10%. Finally, where is the table on the relationship between flecainide dose and QTc prolongation like we see for both citalopram and escitalopram? Is it possible that flecainide has more of an effect throughout the dosage range than citalopram?
These are serious questions given that I have already established that there is a significant bias in the media against psychiatry, psychiatrists and psychiatric medications. The most recent FDA warning has created a lot of anxiety for psychiatrists and any patient taking citalopram. The majority of those patients are being seen by primary care physicians.
If citalopram is that cardiotoxic, let's see the evidence and let's see how it compares to a medication with known cardiotoxicity. Let's have the same level of warning for both medications and some concrete ideas about what needs to be done to manage that risk.
George Dawson, MD, DFAPA
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