Monday, March 31, 2008

Vytorin and Singulair: Problems for the Company, Confusion for the Public

Much has happened in health related news in the past week since I have been away. In my mind, most notably news about Singulair and Vytorin; ironically both Merck products.

FDA looks into Singulair, risks of suicidal thoughts
As reported by USAToday and other sources, last week, the FDA announced this early communication about reports about possible links with the popular asthma and allergy drug and suicidal thoughts. Similar to previous post about the Spiriva warning, and my initial post when the FDA decided to release these warnings, this is another example of information that is really helpful to no one, confusing to patients, and disastrous to physicians who will be bombarded with phone calls from concerned patients and parents. Though reports of possible suicidal though are very serious and should certainly be investigated, such a warning is premature. Singulair is extremely common, with millions of prescriptions sold, so if there really were a link to suicidal thought and this medication, we would probably know about it by now. There is no real biologically plausible explanation for the connection.
Bottom Line: Singulair is a very clean and safe drug, and this report is no reason to stop it.
What you will not hear elsewhere: Though Singulair is likely safe, it is ridiculously over prescribed. Singulair is indicated for the treatment of allergies and asthma. For allergies, It has not been shown to be more effective than Claritin (which is now generic and over-the-counter). In fact, when Merck-Schering were trying to add Singulair to Claritin, they found it no more effective than Claritin alone (sound familiar?). In this case, they decided not to manufacture this new pill. The most effective agents for allergic rhinitis are inhaled nasal corticosteroids. Flonase is now available as generic fluticasone, and is much more effective then Singulair (which is not generic), Claritin or the combination of the two. Regarding asthma, the updated 2007 NIH guidelines recommend inhaled corticosteroids for asthmatics of all ages. The data is overwhelming, clear and convincing. Singulair, which has much less of an effect is considered alternative therapy by the NIH. Yet, Singulair remains one of the most commonly prescribed drugs for asthma.

More on Vytorin
Despite all the "shocking" headlines, from CNN to ABC news, there really isn't anything new here. My favorite was the video from the Today Show on NBC that titled this a "health alert." However, this story clearly hits home for many. My post on the letter I received from Merck on this matter has thus far been my most viewed post. The results that were reported in the latest cardiology meeting and in the New England Journal simultaneously confirm what was announced in January. Vytorin (zetia plus zocor) did lower cholesterol more than Zocor alone, but there was no difference in its ability to prevent clogging of the arteries. This is important news because this means that there continuing evidence that there may be more to the cholesterol story than just lowering "bad" cholesterol or ldl.
Bottom Line: Though the news does reinforce not using Vytorin as initial therapy, it does not mean that Zetia is completely useless. Some patients have side effects from statin medications, and if they can not take a statin (or take it at a dose they need to lower their cholesterol), then Zetia currently the best option.
What you will not hear elsewhere: There will be multiple comments about how Merck promoted this drug (remember the ads with family members dressed to look very similar to cholesterol containing foods?). The New England Journal has a very interesting piece on the differences in use of Vytorin and Zetia between Canada and the US, which (correctly) suggests that much of this may be do to direct to consumer advertisement (which is not allowed in Canada). However, what is not discussed is that one major determining factor in what a physician prescribes for their patient is which drug happens to be preferred by their insurance company's prescription formulary. The only patients I wrote prescriptions for Vytorin for were my patients who had Aetna insurance. Until very recently, if you were an Aetna patient, the only cholesterol lowering options you had were Zocor and Vytorin. Thus, for those patients who needed a stronger statin the Zocor (such as Lipitor or Crestor-Crestor is now finally on Aetna's formulary), I had no choice but to go with Vytorin, despite limited data. Why would Aetna choose this over Lipitor (the most popular cholesterol drug) or Crestor (new kid on the block)? Merck had obviously given Aetna a much better price then the competition on their cholesterol lowering drugs.
Finally, don't throw out surrogate markers just yet. Even more evidence that LDL cholesterol may not be the only thing that is important, just announced in the Wall Street Journal today that Astra Zeneca was stopping a Crestor trial early because patients clearly benefited from the drug. The Jupiter trial (which we were involved in) took patients with relatively normal LDL cholesterol, but high CRP levels (which have also been associated with increased risk) and randomized them to placebo or Crestor 20mg. Though the results have not been published, clearly a significant amount of patients taking Crestor had fewer heart attacks or strokes.


MatthewCT1 said...

Dr. Mintz,
I think you may change your mind after reading some of these experiences.

While I keep hearing there is no "mechanism" for causing behaviorial issues this has become a HUGE problem for many, many individuals and parents. The next 9 months of the FDA's investigation will be interesting. I have corresponded directly with Leslie Hendeles, professor of Pharmacology and Pediactrics and the University of Florida and his direct quote to me was "I think the efficacy of Singulair is modest. If we took all of our patients off it right now we wouldn't see any issues".
Read some of the real accounts of the side effects of this drug. While it may work for some it has been a NIGHTMARE for many!!!

Dr. Matthew Mintz said...

I completely agree that the effects of Singulair are modest at best, so in this case it is possible that (if proven true) the side effects aren't worth the risk.
However, these reports need further investigation before serious action should be taken by patients and doctors. The link you have posted sites a small laboratory study that looks at receptors in the brain. Even though there are receptors in the brain, this does not mean that Singulair interacts with these brain receptors let alone causes side effects.
It will be interesting to see what the research shows. I have a feeling that this will not pan out to be true based on the fact that there are millions of people on Singulair and there are only a few reported cases which may not even be associated with the medication.

MatthewCT1 said...

You didn't read...there are 30 pages of reported only read the first entry. There are 30+ pages of real experiences so it is not just a "few" reported cases. Moreover, these are just the reported experiences of people who found this website and not a good representation of the entire population.
All I can tell you is that my son and many other children and individuals have experienced severe side effects. My 5 yr. old son would say things like "I don't want to be in this life anymore" and "I want to kill myself". 5 yr. olds don't even know what that means. As a parent I KNOW my child's normal behavior and he was on no other drugs and never has been so there is no confusion in my mind as to what caused his severe behavioral changes. I will leave it at that. After taking my son off this drug he recovered and his behavior is much, much better. Please take some time to read more of these experiences. It's odd how the medical community is blowing this off and it creeps me out.
Here is my experience:
My 5 year old son was diagnosed with mild asthma and put on Singulair. Within a few months he began having uncontrollable fits of rage, displayed self-loathing behavior, had night terrors, and was inconsolable during these episodes. He became very destructive and was a danger to himself and our family. He even talked about killing himself and would say things like "I don't want to be in this life anymore" and "I want to kill myself". He would threaten my wife and his siblings and told them he wanted to kill them. It was a truly terrifying experience. Our pediatrician was clueless to these side affects and recommended we have our child go through a psychological evaluation. I knew this was not my child's normal behavior so I searched the internet for Singulair side effects and found some message boards where parents just like me were telling their stories of their children's aggressive behavior. I immediately took my son off the drug and within a couple weeks he was back to his normal self. He told us that he no longer has "that feeling inside of him". Five year old children don't even know what suicide is and to see my son talk like this was extremely frightening. He is a sweet, intelligent, loving boy who had never exhibited behavior like this until he went on Singulair. We have not seen this behavior after taking him off the drug. Please use your best judgement and connect the dots for yourselves.

Dr. Mintz...there is meat to this situation.

Dr. Matthew Mintz said...

I am sorry for your son's suffering and glad he doing better. I also agree that there might possibly be a link between suicidality and singulair. I also agree with the FDA taking the matter very seriously. (I also think Singulair is prescribed WAY too often since it is considered alternative therapy for asthma and yet is one of the most commonly prescribed asthma drugs.)
The problem that I have is the way in which the FDA chooses to disclose their concerns and the way in which the media responds.
When you starting giving any drug to millions of patients, some of them are going to have side effects, even if the drug is generally safe. Even if there is a risk of suicidal thoughts in 1/100,000 patients, does this mean we shouldn't use the drug? In the case of Singulair maybe, since there are better alternatives, but these warnings have come out for other drugs that people rely on to function.
I would bet that every primary care physician, family practice doc, and pediatrician received at least a dozen phone calls from concerned patients. Since we are given virtually no information, other than that the FDA is looking into the matter, it is unclear what to tell patients.
There needs to be a balance between warning doctors and patients about potential serious side effects and unnecessarily scaring the masses. The current method does not accomplish this.

Anonymous said...

You missed the point when you griped about unnecessary phone calls to doctors. I have made over a hundred unnecessary visits to doctors who treated my kids emotional and behavior issues - all caused by Singulair, all solved by ceasing the medication. Tell me that the dozen phone calls you will get on this are more important than what those visits have cost me, my kids, and my health insurance company. My kids swallowed medicine that affected their mental health very seriously, and we - parents and doctors - made them take brain-altering medications to deal with the issues caused by Singulair. For every kid that has thought of suicide while taking Singulair, I suspect there are many more who are depressed, underperforming and demotivating. And those kids will cost all of us a LOT more than a few phone calls. Kids don't often know how to say "Gee, I'm depressed" or "I'm demotivated". Parents think the kid is acting out, or entering the teen years. And for the record - my most severely asthmatic child is still on Singulair, it works great for her. But if I had known about the potential side effects, I would have recognized the problems right away, rather than after four years of absolute frustration.

Dr. Matthew Mintz said...

Concerns from patients (especially parents of children) who are experiencing problems are never a burden. The issue here is when and how the FDA sends out a warning to the public (and the media picks up on this) when there is no clear evidence that there is in fact a problem. Per the FDA website,
"The FDA is investigating a possible association between the use of Singulair and behavior/mood changes, suicidality and suicide."
The FDA stated that their investigation would take 9 months. Until their is conclusive evidence of a problem, I think it would be more prudent to wait to announce this then scare and confuse the public. Alternatively, the FDA should do a better job communicating the level of risk (i.e. 30 reports in 3 million patients) and specific recommendations for patients and physicians until their more conclusive report (i.e. patients doing well on Singulair should continue to take it, but if you have any suspicion of a behavior change, you should discuss this with your physician). Currently, the information released is extremely limited, so that patients and physicians can not make informed decisions, which is extremely frustrating for everyone.

Anonymous said...

Dear Dr. Mintz - Thank you for taking the time to reply. It's probably not easy to face parental frustration over a problem you didn't cause!

Perhaps the conversation should be about why there isn't any "clear evidence" as you put it. Our family history is incredibly clear on Singulair; I have a pair of identical twins, one on 5mg and one on 10mg. The one on 10mg was extremely demotivated, argumentative and negative for 3 years and 8 months. The other one was moderately affected. Took the 10 mg kid off Singulair. Five days later, Mr. 5 mgs asks "Why is he always so happy these days?" (I didn't tell anyone he'd stopped taking it). Now no one is taking Singulair at my house.

So, I took this information to the doctor who prescribed it. He's fascinated. Riveted. Wants me to report it as an Adverse Event. Not him. I download the Adverse Event paperwork. Twelve pages of instructions - with a strong directive that it's preferred that the prescribing physician fill out this paperwork. But the prescribing physician doesn't want to. Agrees with me that we had an adverse event. Doesn't want to fill out the paperwork.

So I go to the psychiatrist who has been treating the kids. Wow, she sees a difference too. She doesn't want to fill out the paperwork - she did not prescribe the medicine. She suggests that I write a note directly to the drug company, complaining about the effects. Of course, now that the kids are doing better, we'll be seeing her a lot less.

I go back to the Adverse Event reporting forms. There's some interesting language on the forms. It seems that my right to privacy is protected in that the content of the form won't be released to "the public". It also seems that the FDA will be sharing my information with Merck. And it seems that Merck may or may not have access to my other health records, via the FDA investigation. And guess what - once they are in Merck's hands, they are no longer my private health records.

What do you think? Is there a part of this that I've misunderstood?

Anonymous said...

Dr. Mintz,

I am a mom of four. My 19 mon. old has allergies which he is slowly outgrowing. (outgrew wheat, peanut, and soy. Still has egg, milk and dog/cat).
We just came back from an appt. for his allergies and were set up with a (in my opinion) HUGE asthma treatment. This was because of a resent hospital stay we had with him because he was tight with asthma "symptoms". I was not thrilled when told I should give Singulair for the simple fact that I don't like an every day medication for a developing toddler, especially since he only had one fluke occation.
Then I went online and found ALL this info. on the dangers of Singulair and this new report.
I am not against drugs, but now believe it was irresponsible (if I may be bold) of the doctor to prescribe a medicine under "consideration" without informing me of this new info. I have not filled this prescription. He also prescribed the daily Flonase mentioned in your article. Do you agree that my son's risk to an asthma attack don't outway the benefits that Singulair would (or wouldn't) bring? I want to be an informed and responsible parent and am seeking advise! Thanks!
Mommy of 4

Dr. Matthew Mintz said...

You are really asking two questions:
1. Does your 19 month son with a history of allergies deserve a daily medication because of a hospitalization for wheezing?
2. Is Singulair the right choice?

There answer to #1 is clearly yes. He deserves HUGE asthma treatment because a hospitalization is HUGE deal. 11 people die from asthma each day. The 2002 NIH guidelines stated that even infants with risk for developings asthma (family history, eczema, allergic rhinitis) who have more than 2 wheezing episodes a year should be considered for daily medications. The 2007 went even further to suggest that a hospital stay is a warning sign that if severe enough, 1 visit would be all you need for daily med.

2. The answer to #2 is clearly no. There is limited data on infants, but the guidelines recommend inhaled corticosteroids as a first line agent for all asthmatics from 1 month to 100 years! I am not so much concerned about Singulair's side effects (it probably is pretty safe), but more concerned about Singulair's lack of efficacy. Singulair has not be proven to prevent hospitalizations. Inhaled steroids have.
A 19 month old post-hospitalization, in addition to allergen avoidance and looking for triggers, should be on a pulmicort respules (the only nebulized steroids in the US). The flonase is trickier, because on the one hand inhaled steroids are the most effective agents for allergic rhinitis, and if the allergies were sighificant enough to trigger the attack, then this would be warranted. On the other hand, they have not been studied in such a young population. Veramyst is indicated for as young as 24 months. I think this would be a reasonable option.

Anonymous said...

Dr. Mintz the reports are true. My brother went through hell with this drug. I don't need the FDA to tell me if it's true or not.

This drug has killed, and people are not being told of the risk.

Serious action should not take a year, people who are on this drug should be told now, so that they can monitor the person on Singulair.

"It will be interesting to see what the research shows"

Yeah well I'll tell you what it's going to show. NOTHING. Pushed under the rug.

curious said...

Depression is a risk factor for suicide and was seen in the clinical trials in connection with montelukast use:
(pdf pg 86).It was not a big number of patients, nor was it that many more than those taking placebo - the difference was 0.2%, but in the population now estimated to be taking Singulair, that 0.2% could add up to thousands and thousands of depressed patients.

Also, a patient taking montelukast dropped out due to depression. The investigator deemed it related to montelukast (pdf pg 84.)Seems to me like someone thought there was a connection over ten years ago. Interesting how this information has not been communicated to the public and depression wasn't added to the label until 2007. I guess all the people who took it during the interval were guinea pigs.

Leukotrienes have been found in the brain yet nobody knows exactly what their role is in the functioning of the brain. Nor do they know exactly what happens when these currently unknown functions are interrupted.

Also, many side effects of Singulair parallel symptoms of vasculitis. Published case reports and studies indicate montelukast may cause vasculitis. Vasculitis in the brain may cause mood/behavior changes. It isn't too far a stretch that depression and suicidal behavior are some of these changes!

Dr. Matthew Mintz said...

If there are two things that I have learned since starting medical school it's that the human body is extraordinarily complex and any agent or stressor introduced can cause a variety of problems AND the human body is extraordinarily resilient such that multiple threats (infection, toxins, medications, etc.) are compensated for pretty well. For example, the alcholic has to due substantial damage to his liver before major consequences ensue. Similarly, I tell my patients that any medication, drug, supplement, etc. can cause any side effect in one individual person.
Thus, there is probably some pathway (i.e. leukotrienes in the brain as you suggest) where in certain individuals Singulair might cause depression leading to suicide.
The issue is not really whether or not this can happen, but how often is it likely to occur, how serious are the ramifications, what is the risk of not taking the drug, and what is the benefit of taking the drug.
For Singulair, the risk is probably real enough and the harm potentially great enough to list this as a possible side effect so that doctors and patients are aware, but rare enough (if real at all) to be a substantial concern for most patients.
The problem I have with Singulair is that even though it is a pretty safe pill (likely safer than most medications currently prescribed today), it doesn't work all that well, especially compared to inhaled steroids for allergies and asthma. This is why I never prescribe the medication.