Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

- Rogue Medic

FDA Warning of Zyprexa Deaths – NOT With the Drug used by EMS or in the Emergency Department


Today the FDA (Food and Drug Administration) sent out a safety announcement about long-acting olanzapine (Zyprexa Relprevv).

This is not the form of olanzapine (Zyprexa) used by EMS or used in the ED (Emergency Department).

Post-injection Delirium Sedation Syndrome (PDSS): Patients are at risk for severe drowsiness (including unconsciousness or coma) and/or confusion and disorientation after each injection and must stay at the doctor’s office or clinic for at least 3 hours after the injection is given. ZYPREXA RELPREVV is only prescribed by doctors who are enrolled in the ZYPREXA RELPREVV Patient Care Program to patients who are also enrolled.[1]


The affected medication is packaged as Zyprexa Relprevv, the long-acting version of olanzepine.

Image credit.[2]

We would use olanzapine in its regular formulation, which has been available as a generic since 2011, when Eli lilly’s patent expired.

The patent on Zyprexa Relprevv does not expire until September 30, 2018, so it is only available as an expensive version from Eli Lilly.[3]

What happened?

FDA is investigating two unexplained deaths in patients who received an intramuscular injection of the antipsychotic drug Zyprexa Relprevv (olanzapine pamoate). The patients died 3-4 days after receiving an appropriate dose of the drug, well after the 3-hour post-injection monitoring period required under the Zyprexa Relprevv Risk Evaluation and Mitigation Strategy (REMS). Both patients were found to have very high olanzapine blood levels after death.[4]


Why 3 hours?

Click on images to make them larger.

Post-injection delirium/sedation syndrome events and time to initial onset, incapacitation, and hospitalization. The middle line inside the box is the median 50th percentile; left border of the box is the 25th percentile and right borders of the box is the 75th percentile; left whisker is the 10th percentile and right whisker is the 90th percentile.[5]


All patients demonstrated symptoms within 5 hours of injection, so onset 3 to 4 days after injection seems unlikely. This medication can only be given in the clinic or doctor’s office, so an extra dose is improbable.

How likely is it that the cause of death is the medication?

It would seem unlikely, except that Both patients were found to have very high olanzapine blood levels after death.

The FDA will investigate this and may find out the cause(s) of death, or may nor find out the cause(s) of death, but it does not appear to be something that affects emergency patients.

These patients may present to EMS, or the ED, from a doctor’s office or clinic and we should be familiar with treatment.

Symptoms appear to be less severe than with an overdose of olanzapine, so management should be just supportive care (assess blood sugar, vital signs, level of consciousness, . . .), only treating what truly needs to be treated (seizures, airway compromise, . . .).

As discussed by McDonnell et al. [5], the probable mechanism most likely involves accidental entry of the medication into the blood stream following blood vessel injury during the injection process. The similarity in incidence of olanzapine LAI PDSS (0.07% of injections) to that of Hoigne’s syndrome following accidental intravascular injection of penicillin procaine G (0.08% of injections) [6] suggests that these findings may be approximating the naturally occurring background rate for accidental direct or indirect intravascular injection during any intramuscular injection process.[5]


Accidental intravenous, or intra-arterial, injection does not seem to be a possible cause of deaths that happen several days later.

We do not have other information on the patients, such as when they were last seen without any symptoms, what other medications they were taking, what other medical conditions were present, whether there were signs of trauma, . . . , so the only thing to do is wait for more information.

If you carry olanzapine, there is no reason not to keep using it as before.

If this encourages you to switch to ketamine, I do not see any problem with that decision.


[1] Important Safety Information about ZYPREXA® RELPREVV™ (olanzapine) For Extended Release Injectable Suspension
Eli Lilly
Home page.

[2] ZYPREXA RELPREVV (olanzapine pamoate) kit
[Eli Lilly and Company]

FDA Label

[3] Generic Zyprexa Relprevv Availability
Information page.

[4] Zyprexa Relprevv (Olanzapine Pamoate): Drug Safety Communication – FDA Investigating Two Deaths Following Injection
Posted 06/18/2013
FDA Drug Safety Communication

[5] Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, I: analysis of cases.
Detke HC, McDonnell DP, Brunner E, Zhao F, Sorsaburu S, Stefaniak VJ, Corya SA.
BMC Psychiatry. 2010 Jun 10;10:43. doi: 10.1186/1471-244X-10-43.
PMID: 20537128 [PubMed – indexed for MEDLINE]

Free Full Text from BMC Psychiatry.


Comment on With Conflicting Evidence, What Should We Do? – Oxygen


In the comments to With Conflicting Evidence, What Should We Do? – Oxygen is the following from Dr. Brooks Walsh.

The importance of this study is that it may suggest that hyperoxia may be beneficial at different points in critical illness, and that we need to be careful before acting too broadly.


The way to find out what works is with prospective studies.

We do not have any shortage of cardiac arrests to study. We only have a shortage of research and therefore a shortage of understanding.

We should not attempt to make up for that ignorance with wishful thinking.

Homeopathy, epinephrine, chiropractic, oxygen, Reiki, amiodarone, prayer, lidocaine, acupuncture, vasopressin, et cetera. There is no shortage of possible treatments that lack evidence of benefit.

Where do we start?

Homeopathy probably has more research than all of the other treatments combined.

Howevere, homeopathy is just playing the numbers. There is no real treatment, but if we study a placebo enough times, there will be some statistically significant results.

This is just the same as flipping a coin. If we flip a coin enough times, we will produce a series of heads that is so long that it will have a p value that has an impressive bunch of zeroes in it.

Image credit. Click on image to make it larger. Below is the mouse-over text from this – xkcd 882.

So, uh, we did the green study again and got no link. It was probably a–‘ ‘RESEARCH CONFLICTED ON GREEN JELLY BEAN/ACNE LINK; MORE STUDY RECOMMENDED!


The important point is to pretend that the other studies do not matter. Except that the other studies do matter. All that is being done is throwing feces at a wall and hoping that something sticks.

We have been pretending that, with our understanding of physiology, we are too smart to have too study oxygen.

We have been very arrogant and very stupid.

We haven’t even bothered to find out how dangerous our treatments are.

Perhaps there is an analog to the past studies that looked at the treatment of sepsis. Initial studies of sepsis therapy, using aggressive fluid resus and pressors, were conducted in the ICU, hours after admission. Although these studies were based on strong physiologic evidence, the clinical studies were negative. However, when these same interventions were started in the ED, minutes after arrival, we found a huge drop in mortality. Timing matters.


I should have linked to an mp3 recording of Dr. Mervyn Singer pointing out that hypoxemia is probably not as dangerous as we have been told.[1]

Dr. Singer also has a presentation pointing out the problems with catecholamines in sepsis and questioning the research showing benefit from dopamine.[2]

Dr. Singer raises some interesting questions. the only way to find out the answers is to do the research, not to claim that a lack of proof of harm is evidence of benefit.

Very few treatments have been proven to be harmful, so we could use anything. If enough people follow suit, we have a standard of care that probably is much more harmful than we image and probably not helpful at all.

And so it may be with oxygen. It doesn’t help that most of the studies out there are retrospective, and so are suggestive, but they require confirmation with prospective trials. Some “common-sense” changes in practice have already been implemented, but we need to be careful before extending this reasoning to all clinical situations.


We do not have any high-quality data of benefit. We have a lot of anecdotes of kitchen sink treatment.

When we throw the kitchen sink at the patient, sometimes the patient dies and sometimes the patient lives. We cannot tell if there is any benefit from the kitchen sink, or from any element of the kitchen sink, but we don’t let that stop us.

Our ignorance is unstoppable.

We already have an avalanche of excuses for continuing to harm patients.

We need to stop making excuses and figure out what we are doing.


[1] Permissive hypoxaemia – the way forward
2011, Critical Care, Manchester Critical Care Conference
2011-04-28 at 09:30
Dr. Mervyn Singer
Free Emergency Medicine Talks
Free page with link to free mp3 of presentation.

[2] Catecholamines Should Be Banned
2009, Critical Care, Manchester Critical Care Conference
2009-04-24 at 15:45
Dr. Mervyn Singer
Free Emergency Medicine Talks
Free page with link to free mp3 of presentation.


Does an Oxygen Saturation of 100% Mean an Overdose?


Are we harming patients with oxygen?[1]

This will offend many in the oxygen religion, but we should start thinking of oxygen overdose.

What is our use of oxygen for everything based on?

Received wisdom from authority figures. We need to stop using authority and tradition as excuses to harm people.

Tom Bouthillet, Kelly Arashin, and Mike McEvoy discuss the harms of oxygen and the evidence of harm.

Go listen to the podcast, or watch the video.

Then reconsider your answer to my question.

Are we overdosing our patients, when we raise their oxygen saturation to 100%?

What if the original oxygen saturation was 94%?

What if the original oxygen saturation was 74%?

What if the original oxygen saturation was 54%?

Does the original oxygen saturation matter?

Would we have the same worries if the drug (oxygen is a drug) is morphine, NTG, midazolam, or even amiodarone?

Why do we grant the beliefs of the religion of oxygen such immunity from examination?


According to Mike McEvoy, the goal is 92% to 96%.

Not 97%.

98% is worse.

99% is much worse.

100% is as bad as it can get – even worse than hypoxia.


Go listen to the podcast, or watch the video.

A couple of points. Mike McEvoy states that the intensive care community has been familiar with this since the 1990s. This has been studied, and there has been evidence of harm since at least as early as 1950.

The administration of 100 per cent oxygen may actually be contraindicated in patients in whom oxygen saturation of arterial blood is normal.[2]


This was a decade before we found out that internal mammary artery ligation is nothing more than a placebo surgery.[3] That extremely popular procedure was done away with so quickly, that few people even remember the use of internal mammary artery ligation as a treatment for angina?

Oxygen has tradition behind it encouraging us to keep killing patients.

We should have been smart enough to reconsider our devotion to received wisdom and authority in 1950.

Many of us still refuse to learn.

This is why we need evidence before applying treatments to everyone.

How many hundreds of thousands of patient have we killed with oxygen and our refusal to require evidence of improved outcomes?


Go listen to the podcast, or watch the video.


[1] EMS 12-Lead podcast – Episode #11 – Are we harming patients with oxygen?
EMS 12 Lead Podcast
EMS 12 Lead
Page with podcast and video podcast.

[2] One hundred percent oxygen in the treatment of acute myocardial infarction and severe angina pectoris.
J Am Med Assoc. 1950 Sep 30;144(5):373-5. No abstract available.
PMID: 14774103 [PubMed – indexed for MEDLINE]

In five patients with angina pectoris the administration of 100 per cent oxygen did not favorably influence the onset or duration of pain or the electrocardiographic alterations induced by standard exercise. On the contrary, oxygen therapy actually appeared responsible for more pronounced and persistent electrocardiographic changes in several patients.

[3] An evaluation of internal-mammary-artery ligation by a double-blind technic.
N Engl J Med. 1959 May 28;260(22):1115-8. No abstract available.
PMID: 13657350 [PubMed – indexed for MEDLINE]