Archive for the ‘FDA’ Category
Wednesday, December 5th, 2012
It has been a few years, but the FDA’s war on antiemetics (medications for vomiting) continues.
To review …
Bendectin was the first antiemetic to be taken off the market after famous plaintiff attorney Melvin Belli sued Merrell Dow Pharmaceuticals. No credible evidence was ever found that Bendectin caused birth defects as the plaintiff attorneys alleged, yet Merrell Dow removed bendectin from the market to avoid further lawsuits.
Droperidol was another great nausea medicine that got the FDA’s dreaded “black box” because it allegedly caused QT prolongation. See commentary here.
Then the FDA went after Tigan suppositories. Remove them from the market, it demanded.
Compazine was next to get the dreaded “black box” kiss of death.
Then came Reglan, which joined the “black box” club due to a risk of tardive dyskinesia. Interesting that one of the medications that has been used to treat tardive dyskinesia is another antiemetic … Zofran.
Phenergan was next. In Wyeth v. Levine, a Vermont jury decided that drug labeling warning against intra-arterial use wasn’t strong enough. The resulting black box warning struck fear into the hearts of hospital risk managers everywhere. By the way, how many of you knew that Phenergan is an antihistamine and, like Benadryl, can be used as a local anesthetic?
It appears that not enough people were scared off by the previous FDA warning on Zofran, though.
Now, the FDA has decided the 32 mg IV dose of Zofran has the “potential for serious cardiac risks” and is demanding removal of all 32 mg IV Zofran doses from the market. Those same cardiac risks – QT prolongation – were used to get droperidol black boxed, so it is only a matter of time until Zofran gets its scarlet letter from the FDA.
Personally, I would like to see the FDA’s studies on Zofran … and all the other antiemetics for that matter. I seriously doubt many of the claims.
In the meantime there’s always Aprepitant. That’s only $100/dose (in 2004). Plus … the FDA won’t determine that it’s bad for your health for at least another 10 years – about the time it goes off patent.
Thursday, August 16th, 2012
Get ready for more governmental regulation of opioids and maybe even some black box warnings added to the prescribing information for c0deine-containing drugs … just for everyone’s safety, of course.
According to this FDA Special Bulletin on Safety Information, three pediatric deaths and one case of respiratory depression were documented in the medical literature after children took codeine-containing compounds. The etiology for the deaths was allegedly because the children had a variation in their cytochrome P450 enzyme that caused the codeine to break down faster into morphine, high levels of which, according to the FDA, “may be fatal.” If your child or your patient is an “ultra-rapid metabolizer” of codeine, he or she could DIE.
The FDA also published a “Drug Safety Communication” that disclosed the studies on which its recommendations were based.
One case cited by the FDA as “proof” that codeine can kill you involved a 2 year old child with sleep apnea who underwent tonsillectomy and adenoidectomy and who died three days after surgery. At autopsy, the child had elevated levels of codeine and morphine in his system, had aspirated food particles, and also had bilateral pneumonia. No mention of how much codeine the patient’s parents gave the child, only of the dose that was prescribed. No mention of how bilateral pneumonia or aspiration in a young child can be deadly. The researchers concluded that the elevated morphine levels “may” have contributed to the child’s death. The FDA wants you to believe that there was a causal connection there.
Another article cited by the FDA was from the same authors who now found three additional cases of children who died after having tonsillectomy/adenoidectomy and were prescribed codeine. I didn’t purchase the article, but I also am assuming that there were no controls for dosing of the medication, only for prescription of the medication. In other words, I doubt that the researchers would be able to tell whether the parents accidentally just gave the child too much medication as opposed to whether some genetic variant caused higher than normal blood levels of the medication at normal doses.
I also did a PubMed search for “children codeine p450” and also “pediatric codeine p450“.
There was one Canadian case report of a mother who was an “ultra rapid metabolism phenotype” whose breastfed child had fatal opioid intoxication after the mother used codeine.
There was another case report from Canada of a 5 year old girl who died from hydrocodone overdose when she was taking both clarithromycin for an ear infection and valproic acid for seizures. The medications decreased metabolism of the drug and she also had a genetic defect that decreased the metabolism of the drug.
None of the other articles that I found mentioned pediatric death due to an interaction between opioids and cytochrome P450.
Now, based on 4 deaths out of likely hundreds of millions of codeine prescriptions, the FDA is “currently conducting a safety review of codeine” and is recommending that doctors use low doses of codeine for patients in pain or that doctors just use another medication completely for children in pain. The FDA also recommends that caregivers monitor patients for signs of opioid toxicity. These recommendations are already in the prescribing information for Tylenol with Codeine.
Oh, and the FDA also notes that doctors can always perform “FDA approved” genetic testing to see if children have the gene responsible for rapid metabolism of codeine.
I can’t help wonder what motivation the FDA has to issue this warning about 4 deaths in tens or even hundreds of millions of prescriptions that were hypothesized to have been caused by this mechanism. It’s not like codeine is a new drug or that the cytochrome P450 pathway is a new discovery. Why now?
Trying to justify the FDA’s existence/budget? Getting a cut of the fees for approving the genetic testing? Getting fees for some new pain medication so that it can be approved for use in pediatric patients? Something just doesn’t make sense.
Of course, now if sometime in the future a young patient dies from an alleged codeine overdose, there will be some newspaper article published and some lawsuit for millions of dollars in damages filed alleging that if only the negligent doctor had paid attention to the FDA warnings and performed CYP2D6 genotyping, the patient would probably still be alive today.
And people wonder why doctors practice defensive medicine.
Congratulations to the Wall Street Journal, NY Times, Washington Post, ABC News, Bloomberg News, NPR, and the Boston Globe for feeding into the hysteria. Hat tip to EM Today from ACEP for the links.
Friday, September 16th, 2011
Get ready for a “black box” warning on Zofran.
The FDA has just issued a “safety alert” stating that Zofran may now be potentially deadly.
The FDA is now recommending ECG monitoring in patients who receive Zofran who have potential “electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias, or in patients taking other medications that can lead to QT prolongation.”
After all, Zofran has now gone generic like previous anti-nausea medications that have also received black box warnings. The FDA approved Zofran for use in 1991, meaning that Zofran has been on the market for twenty years.
Now, through diligent research, the FDA has decided that that Zofran may cause QT prolongation — just like most of the other anti-nausea medications. As a result, GlaxoSmithKline has been ordered to perform studies to determine whether Zofran could prolong QT intervals, and, if so, to what extent.
Since the FDA states that it has been performing “ongoing safety studies” … for the past twenty years … why doesn’t the FDA actually publish the results of those safety studies that led to the posting of its alarming “safety notice”?
Now we have one less medication in our armamentarium to treat nausea and vomiting. I suppose we can always give ginger root until that gets a black box warning, too. It’s only been around for a few centuries.
Whoa. I think that my heart just skipped a beat. Reading FDA safety notices may have caused me to have QT prolongation. I think that we need to put black box warnings on FDA safety notices and no one should read them without proper EKG monitoring.
Who do we get to study that?
Friday, May 1st, 2009
The FDA just issued a news release urging consumers to stop using HydroxyCut products, noting that some products were “associtated with” liver injuries. Iovate, the manufacturer, has agreed to recall all HydroxyCut products.
Out of millions of doses of HydroxyCut sold, there were 23 reports of “serious health problems” “associated with” the use of the product, ranging from jaundice to elevated liver enzymes to permanent liver damage resulting in a liver transplant. There was also one death from liver failure.
I keep putting the “associated with” in quotes because we have to be very careful about how we interpret the terms we use.
Almost all people who die from asthma have probably used an inhaler shortly before their death. That means that use of asthma inhalers is “associated with” deaths from asthma. Can we say that asthma inhalers caused death in those patients? If so, we need to take asthma inhalers off the market.
Many people who die in hospital emergency departments are brought by ambulances. Ambulance use is therefore “associated with” deaths in the hospital emergency department. Do ambulances cause death? Should we stop EMS transports immediately?
Paying taxes is associated with increased … aww nevermind. You get the picture.
So is this FDA warning a bunch of hooey or has Iovate been slipping the general public a Mickey all these years?
Thursday, March 5th, 2009
In less than 24 hours, Phenergan will no longer be available in one of the largest teaching hospitals in our area. Because of the decision of 6 appointed justices in our US Supreme Court, the hospital is removing all of the Phenergan in the hospital’s stock.
Thus continues the assault on many of the antiemetic stalwarts that we have been using for decades.
Bendectin was the first antiemetic to go the way of the dodo bird after famous plaintiff attorney Melvin Belli sued Merrell Dow Pharmaceuticals. No credible evidence was ever found that Bendectin caused birth defects as the plaintiff attorneys alleged.
Droperidol was another great nausea medicine that got the FDA’s dreaded “black box.”
Then the FDA went after Tigan suppositories.
Compazine was next to get the dreaded “black box” kiss of death.
Just last week, Reglan joined the “black box” club due to a risk of tardive dyskinesia.
Now Phenergan is going to take a hit. After the publicity, many doctors and hospitals will be afraid to use it.
It’s just amazing that the medical profession has been poisoning patients with all of these medications for decades and just now we’re finding out about it.
Luckily, we still have Zofran and other 5-HT3 receptor antagonists – if patients can afford it.
I wrote a prescription for 12 Zofran ODT tablets for a patient who was vomiting last week. The pharmacist called me and said that the prescription would cost $260 and it wasn’t covered on the patient’s insurance. Could I change it to something else?
I wasn’t willing to take the chance if the patient had a bad outcome.
Defensive medicine strikes again. Avoid the bad outcome.
I wrote about the Wyeth case here and here. I’m by no means a staunch drug manufacturer supporter, but pretend that you’re running a manufacturing company. What are you supposed to do with your drug labels now? Overlawyered.com has a summary of opinions about the Supreme Court’s decision as well as a link to the published opinion.
The product labeling for Phenergan had the following language in it:
I skimmed the 80 page US Supreme Court opinion and it appears that the majority believed that “Wyeth could have unilaterally added a stronger warning about IV-push administration.” Good thinking. Now you’ve just opened the legal floodgates to every Tom, Dick and Harry who has ever had a bad outcome from taking a medication. All they have to claim is that the warnings on the medication bottle “weren’t strong enough” and they’ve got the opinions of six Supreme Court justices to guide them on their quest for independent wealth at the expense of a drug manufacturer.
Extending the Supreme Court’s logic puts every pharmaceutical manufacturer on notice that they must discover each and every way someone could possibly misuse their product and specifically warn the public not to use the product in that manner.
Don’t pour Phenergan in electric sockets – it could start a fire and burn down your house
Don’t feed Phenergan to your goldfish – it could burn their scales off and give you emotional distress
Don’t gargle with Phenergan – it could cause caustic burns to your throat and you could get disfiguring burns and you could suffocate to death
Don’t mix Phenergan with Frosted Flakes – it could cause an exothermic reaction with the Frosted Flakes, resulting in nasal irritation if you breathe the fumes
Actually, I created a Supreme Court-approved label that all pharmaceutical companies could use when they decide to manufacture medications. I’ll bet that some companies will find it very helpful:
If this label makes you feel nauseous, be careful.
There aren’t that many antiemetics left that doctors will be willing to prescribe to you.
UPDATE MARCH 7, 2009
The ink wasn’t even dry on the opinion and firms are out looking for “mass tort” clients.
Tuesday, October 28th, 2008
There have been a lot of opinions rendered about the Wyeth v. Levine lawsuit. Want to read all the briefs? Click here. Including amicus briefs, there are about 30 of them. You can also read more about the case at this NY Times article.
The case has been fought out in Vermont’s trial court and in the Vermont Supreme Court.
Now the case is pending before the US Supreme Court.
It’s a little odd when a drug company writes me to solicit my opinion. Last week I was invited to a conference call with several bloggers including TK from ER Stories and Michael Miller from Health Policy and Communications Blog along with one of the Wyeth representatives and a Wyeth attorney. Why did they want bloggers on a conference call about a pending Supreme Court case? They want to bring the facts and the issues to the public eye. Not sure why they picked me. Must be my charm …
Before I start down this road, I’m a doctor, I’m not a legal scholar (but I did stay at a Holiday Inn Express). I’m not being paid by Wyeth or anyone else to discuss this. Just doing these posts because I think the issue is important. I’m also relying on Wyeth for some of the facts since the case is complex and I don’t have the time to read all of the briefs in this case. However, as far as I know, the “other” issues have been decided and the remaining issue before the US Supreme Court is one of “preemption.” I’ve tried to get the facts correct, but feel free to correct me if I have made a factual mistake.
Today, I’ll focus on the history of the case and tomorrow I’ll get out my soapbox.
The story began when a musician named Diana Levine went to the Northeast Washington County Community Health clinic with a migraine headache and vomiting. She received intramuscular injections of Demerol (meperidine) and Phenergan (promethazine) and was discharged. Her symptoms weren’t controlled. In fact, she began vomiting more and returned to the clinic. In order to improve her symptoms more quickly, the physician assistant gave Ms. Levine IV Demerol and IV Phenergan. Ms. Levine didn’t have an IV established, so the PA inserted a “butterfly” needle into the patient’s vein and injected the medication.
Before I tell you about the outcome, you have to know a little more about the drug Phenergan.
Phenergan is approved for use by the FDA. I have previously commented how the FDA doesn’t exactly do the best job investigating medications. Just think, the FDA approved all those cough and cold medications that the pediatricians are now decrying as a public health threat. Well, actually, the pediatricians are just saying that everyone is too dumb to take them correctly, but that’s another story. According to Wyeth’s brief, Wyeth had ongoing discussions over the years with the FDA to make sure that the FDA felt that the labeling was adequate. Even if we assume that the FDA had no idea what it was doing when it approved Phenergan for use, during the conference call the Wyeth rep stated that more than 220 million doses of Phenergan have been given around the world.
Phenergan is an irritant. If you’ve ever gotten shots before, you know that some shots hurt like heck and that you can hardly even feel other shots. I commented in one of my previous posts that Phenergan produced “burning” sensation when it is injected into someone’s buttocks. The FDA has also approved Phenergan for intravenous use, and, just like the muscles, Phenergan causes irritation when injected into a vein. Therefore, when Phenergan is administered into a vein, the manufacturer recommends that it be administered slowly and recommends that no more than 25 mg be given at one time. Injection of Phenergan into the skin or arteries can cause serious injuries including skin necrosis and gangrene.
Back to the story ….
Ms. Levine got the Phenergan as an IV injection … at least that is what the physician assistant thought happened. Shortly after starting to inject the Phenergan, the patient started having pain in her hand. Severe pain. Very severe. She described the pain as the worst pain she had ever experienced in her life. The PA finished the injection and then realized something terrible. She had mistakenly given Phenergan into Ms. Levine’s artery. The medication traveled to Ms. Levine’s hand and the irritation shut down the blood flow to her fingers. Within days, Ms. Levine had developed gangrene in her hand and required an amputation of her hand and arm at the forearm.
Ms. Levine justifiably filed a lawsuit.
Her lawsuit named the physician, the physician assistant, and the clinic. All of those parties settled the case before going to trial. The other party to the lawsuit was Wyeth, the company that manufactured the medication that caused Ms. Levine’s injuries.
I don’t think that the allegations against the other parties are pertinent to the case, but one thing that I think was pertinent was the reported testimony of the physician in the case. I haven’t read the testimony, but one of Wyeth’s attorneys stated that the physician testified that if the warning on the medication had been stronger, he would have never ordered the medication to be given IV. The story then becomes an “old lady who swallowed a fly” argument. If the warning was there, the medication wouldn’t have been ordered IV. Then the PA wouldn’t have tried to give the medication IV. If the PA hadn’t tried to give the medication IV, the medication wouldn’t have been injected into the artery. Then the patient wouldn’t have lost her hand.
Even though Phenergan is approved as being “safe and effective” for IV use by the FDA, Ms. Levine’s attorneys argued that the product labeling should state that “no” IV use is allowed so that patients will never get gangrene due to accidental arterial injections. The medication just isn’t safe when given that way. Wyeth’s Supreme Court brief quotes the plaintiff attorney as telling the jury “The FDA doesn’t make the [safety] decision, you do.”
Wyeth argues that its extensive discussions with the FDA and the labeling changes it made in response to those discussions are sufficient to put the users of Phenergan on notice of the potential adverse effects. It also notes that out of 220 million Phenergan doses, there are 4 confirmed and up to 20 possible cases of gangrene associated with its use.
Do the FDA-approved product inserts amount to a “minimum necessary” standard which drug companies should then be required to supplement as Ms. Levine argues? Or are the FDA-approved product inserts sufficient by themselves to adequately warn consumers of potential dangers when using the drug as Wyeth argues?
If you agree with Wyeth, then the rulings by the FDA prevent (i.e. “pre-empt”) any actions by the state courts and Wyeth wins.
That’s where the battle lines have been drawn.
Tune in tomorrow for the rants.
Friday, February 1st, 2008
In a post I put up last September, I asked “What Is Going On With The FDA??”
Thanks to a couple of articles I figured it out.
There’s a reason it takes so many years for the FDA to take action against “dangerous” drugs like children’s cold meds, Rocephin, and Haldol. These drugs have all been on the market for more than 15 years and in just the past six months, the FDA came to the conclusion that they were all a threat to American lives.
Enter the GAO.
In a New York Times article, government investigators have just reported that the FDA is woefully understaffed. The article stated that at the FDA’s current staffing level, it would take more than 13 years to check every foreign drug manufacturing plant, and more than 1900 years to check every foreign food manufacturing plant. No, I didn’t have a nervous twitch on the “0″ key. The article states “one thousand nine hundred” years to check all the foreign food manufacturing plants. In fact, the FDA computer systems are so bad that they can’t even create a list of which plants have been inspected and which have not.
A Wall Street Journal article reported that the FDA can’t even keep up with inspection of domestic manufacturers of medical devices (like defibrillators and contact lenses).
A former lawyer for the agency stated that “This is a fundamentally broken agency, and it needs to be repaired.”
So it isn’t like Big Pharma is paying off the FDA to approve drugs while they are on patent and then put danger labels on them when they are off patent (and no longer earn the drug
cartels companies any money). It’s just that the FDA is so overworked that 15 years is about how long it takes until they can review a drug’s safety profile.
Doesn’t that make you feel better?
Hat Tip to ACEP‘s Emergency Medicine Today
Monday, October 22nd, 2007
According to a front page article in the Washington Post, an FDA panel voted 13 to 9 to recommend against the use of over the counter cold medications in children less than age 6.
Is there some genetic transformation between the 2190th and 2191st day of life that makes someone less likely to have adverse effects from these medications? Or is the panel just drawing arbitrary lines in the sand at age 6?
I think the reason they made this arbitrary age is because everyone on the panel has kids that are older than age 6, so they don’t have to worry about treating colds in their kids any more.
Here’s an interesting factoid: According to the Washington Post article, Mary Tinetti, MD of the Yale School of Medicine is the doctor who chaired the FDA panel. Mary Tinetti is also Chief of the Division of GERIATRICS at Yale. She is the Director of the Claude D. Pepper Older Americans Independence Center. Her interests are in fall injury risk prevention and geriatric health problems. All of this is obviously germane to the effects of children’s cough and cold medications. In fact, she must have a lot of experience with 6 year olds — maybe when they come to their grandparent’s doctor’s appointments and are all strung out on cold medications.
If I were asked to be on a panel with Dr. Tinetti’s qualifications, I would decline because of a lack of experience with the subject matter. Why did she accept the appointment?
If your kids are sick this winter and you want to get an FDA expert’s opinion, you can contact Dr. Tinetti at the link above.
Sunday, September 23rd, 2007
No, I haven’t been watching the movie “Conspiracy Theory” too much.
No, I don’t believe that Big Pharma is coming to get me (yet).
But within the past week, I’ve received two warnings via e-mail about how I should stop using medications I’ve used all my career. Suddenly, they’re a threat to the life and well-being of my patients.
First, it’s an FDA ALERT about haloperidol (Haldol). After 18 years, now we must put all Haldol patients on an EKG monitor. I was thinking about that during one of my rant manic phases. Does that also mean that we can bill the government more for taking care of these patients since we are providing a higher level of care?
The latest warning is another FDA ALERT regarding ceftriaxone (Rocephin). If Rocephin is given within 48 hours of anything containing calcium, it can form a Rocephin-calcium complex in the lungs and could KILL YOU! There are case reports that prove this, you know. At least that’s what the FDA says. So I went to PubMed and looked for them.
One small study from 2004 stated that Rocephin may cause small sized asymptomatic renal stones when administered in children.
Another small study from 2000 stated that Rocephin can cause transient biliary stones in children that typically disappear in less than 2 months.
Another case report from 2000 showed a 5 year old girl that developed symptomatic pseudolithiasis during treatment with “Rocephalin” (maybe it was another medication – Rocephin’s evil isomer). The symptoms disappeared within a few days after changing antibiotics.
Several studies from 1990, 1992, and 1991 discuss how Rocephin can complex with calcium and cause biliary sludge. One patient allegedly developed pancreatitis from Rocephin.
But I’ll be darned if I can find one case of a patient developing the dreaded lung Rocephin complex. And no case reports I found had anyone dying from Rocephin – at least in any of the studies published on PubMed. Maybe these are top secret government studies that are off limits to the public. Secret Squirrel, we need your help.
But now, if your kid drinks milk, you better not give him Rocephalin for 48 hours because he could develop kidney stones in his lung and could die. And whatever you do, if you’re taking Rocephin, DON’T HYPERVENTILATE. You could increase the ionized calcium in your system, it could bind with Rocephin and you could kill yourself.
What’s my beef?
First, why did the FDA wait for 18 years to now suddenly declare this drug a threat to human life? If kids really did die from receiving Rocephin and calcium together, these rocket scientists at the FDA should be held responsible for delaying their FDA ALERT for so long.
Second, Rocephin went off patent in July 2005. Another FDA attack on a generic drug. Ceftazidime and cefotaxime are two other generic injectables in this class of antibiotics. I’m just waiting to see how long it takes before these medications get FDA ALERTS, too. Then physicians will be pushed into prescribing the high-priced but “safe” brand name injectable antibiotics.
Third, what’s so magical about 48 hours between calcium and Rocephin? Has the FDA not heard about protein binding? Or does that only occur with drugs that are off-patent?
I’m going to go take a couple of aspirin, now. But I’m only taking them with water. Filtered water. From a spring in a small town in northern France.
Friday, September 21st, 2007
The FDA just came out with an FDA ALERT warning healthcare providers about the use of Haldol.
Based on an Italian study in 2005, there may be a link between Haldol and Torsades de Pointes/QT prolongation. In addition, there were “at least 28 case reports” of Torsades and QT prolongation with Haldol use. Knock me over with a feather.
Now there is a recommendation that EKG monitoring be performed on anyone receiving IV Haldol.
Haldol was approved by the FDA in 1988. Nineteen years and probably tens of millions of doses later we are able to come up with a whole 28 case reports that may link Haldol to prolonged QT syndromes? Impressive.
Notice how the ALERT states
Based on case reports alone, we are unable to estimate the frequency with which QT prolongation or TdP occur following administration of these drugs.
Doesn’t matter. Just blast this medication the same way you blasted Droperidol with no scientific basis.
So now I have some questions.
If the FDA was so concerned for patient safety, why did it wait for two years before posting its FDA ALERT? The study which forms the basis for its ALERT was published in 2005.
Did anyone notice that the Italian study cited used Haldol decanoate – the long-acting version of the drug? No one gives that IV.
Did anyone notice that the study cited by the FDA was sponsored by Johnson & Johnson? Janssen Pharmaceuticals is one of Johnson & Johnson’s partners and makes a product named Zyprexa that competes with Haldol. Zyprexa has sales of more than $2 billion per year. Don’t suppose that sales of Zyprexa will be hurt by the FDA’s shock statement about Haldol usage.
Interesting NY Times article from 2003 showing how these antipsychotic drugs are a huge moneymaker for pharmaceutical companies. The article notes that
For the price of treating one person with Zyprexa at $303 for a month’s prescription, he said, or two on Risperdal, at $159 per month, the state could treat 8 or 10 people with Haldol at $35 per month.
Zyprexa and Risperdal have been linked to early onset diabetes and DEATH, but there is no “FDA ALERT” that we have to do Hemoglobin A1c levels or blood glucose levels before giving them. Risperdal is also linked to strokes, but there is no “FDA ALERT” that we have to do a CT scan on every patient before we give it. Why all the fuss about Haldol?
Want me to stop using Haldol? Here’s my proposal to patients:
Stop coming into my emergency department as an angry drunk or a combative drug abuser. Stop trying to assault me or my staff. Cooperate with us while we try to help you. Then I won’t have to use Haldol on you and everyone will be happy – except maybe Johnson & Johnson.