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

- Rogue Medic

Drug shortages leading to better EMS protocols

MIEMSS (Maryland Institute for Emergency Medical Services Systems) has posted some changes to their protocols that are in response to the drug shortages affecting EMS.

This is good news, even though two of the three drugs being used as replacements are also subject to drug shortages. That is one of the problems with the drug shortage – the replacements end up suffering from increased demand to replace the original drugs.

Some of the drugs do not need any replacement, such as IV (IntraVenous) furosemide (Lasix) for CHF/ADHF (Congestive Heart Failure/Acute Decompensated Heart Failure) patients. The best thing we can do is to stop giving the drug and to stop giving any other diuretic for a medical condition that is not effectively treated with diuretics.[1]

Pain management drugs are important and availability is important.
 

The continuing medication shortage continues to affect Maryland EMS Operational Programs (EMSOPs). Morphine is among the medications that EMSOPs have had difficulty restocking.

Because of the importance of successfully managing pain in out-of-hospital medicine, the Protocol Review Committee has looked into alternatives to Morphine for Maryland EMS. MIEMSS has emergently included fentanyl in the 2012 Maryland Medical Protocols effective immediately. Please see the attached protocol pages.[2]

 

Unfortunately, the obvious substitutes are also in short supply – fentanyl (Sublimaze), hydromorphone (Dilaudid), and other opioids.[3]

One interesting part of the Maryland protocols is the addition of abdominal pain to their standing orders for morphine or fentanyl administration. The Maryland protocols have leapfrogged past Pennsylvania’s protocols with a couple of big changes.
 


Image credit.

Even a surgical journal has research showing that treating undifferentiated abdominal pain with opioids does not make diagnosis more difficult.
 

CONCLUSION:
The literature addressing early pain relief for abdominal pain is characterized by weaknesses, but there is a common theme suggesting that analgesia is safe. Pending further research, which should address some of the shortcomings of extant studies, a practice of judicious provision of analgesia appears safe, reasonable and in the best interests of patients in pain.
[4]

 

A much more recent Cochrane Review comes to the same conclusion.

MAIN RESULTS:
Eight studies fulfilled the inclusion criteria. Differences with use of opioid analgesia were verified in variables: Change in the intensity of the pain, change in the patients comfort level.

AUTHORS’ CONCLUSIONS:
The use of opioid analgesics in the therapeutic diagnosis of patients with AAP does not increase the risk of diagnosis error or the risk of error in making decisions regarding treatment.
[5]

 

If we were to ask the patients what they prefer, I expect that a lot would choose to decrease their pain, even if there is the minimal possibility of alteration in physical assessment. That alteration may be for the better – if the patient is not in severe pain at the slightest touch, the patient may be able to localize the pain, which is a big part of the physical assessment of undifferentiated abdominal pain.

Footnotes:

[1] Drug Shortages Affect Those Still in the Dark Ages – Furosemide
Rogue Medic
Thu, 26 Aug 2010
Article

[2] NEW (June 2012) – Emergency Medication Addition Due to Medication Shortage: FENTANYL
Maryland Institute for Emergency Medical Services Systems
June 12, 2012
MIEMSS page with links to this and other updates and to current protocols

There is also information at that page about the following two changes because of the drug shortage –

NEW (April 2012) – Emergency Medication Addition Due to Medication Shortage: KETAMINE

NEW (May 2012) – Emergency Medication Addition Due to Medication Shortage: DIAZEPAM

[3] Current Drug Shortages Index
FDA
Current Drug Shortages Index

[4] Effect on diagnostic efficiency of analgesia for undifferentiated abdominal pain.
Thomas SH, Silen W.
Br J Surg. 2003 Jan;90(1):5-9. Review.
PMID: 12520567 [PubMed – indexed for MEDLINE]

[5] Analgesia in patients with acute abdominal pain.
Manterola C, Vial M, Moraga J, Astudillo P.
Cochrane Database Syst Rev. 2011 Jan 19;(1):CD005660. Review.
PMID: 21249672 [PubMed – indexed for MEDLINE]

.

Drug Causing Meningitis is NOT the Same as What EMS Uses

 

There has been some news coverage of cases of meningitis caused by a fungal contaminant in a drug with a name very similar to a drug regularly used by EMS and regularly used in EDs (Emergency Departments).

Methylprednisolone is the drug, but it is more complicated than just that part of the drug name.

The emergency medicine is methylprednisolone sodium succinate (Solu-Medrol) – this is used to treat asthma and is very effective at improving outcomes. This is NOT the affected drug.

As of 04:00 today, I could not find any information available on the FDA (Food and Drug Administration) web site. Usually, there are several pages of information available on any recall.

There is a CDC conference call about this, but some of the information is not accurate. Methylprednisolone sodium succinate is injectible for asthma, but this is not the drug involved. Considering the number of people in the room, that nobody realized this.

The EMS drug is safe and efficacious. More evidence is needed, but methylprednisolone sodium succinate (Solu-Medrol) appears to improve outcomes in acute asthma.
 

Only 12.9% (4) of the patients receiving prehospital solumedrol were admitted versus 33.3% (11) of those receiving the medication in the emergency department (p=0.025). Patients were 3.375 times more likely to be admitted if they received methylprednisolone in the emergency department versus in the prehospital setting.

CONCLUSION:
Patients with moderate to severe asthma who receive intravenous methylprednisolone in the prehospital setting have significantly fewer hospital admissions.
[1]

 

RESULTS:
Of the group who received prehospital steroids, none resulted in hospital admission. Due to the small sample size in the steroid-receiving group, the differences in these admission rates are not yet significant. No differences were detected in the ED length of stay between the two patient groups (157 vs. 160 minutes in year 2, p = 0.9).

CONCLUSION:
The differences in admission rates suggested by this study suggest a simple yet potentially powerful tool for improving patient outcome in the treatment of asthma.
[2]

 

Results indicate that the evidence base is frequently limited to small, single-center studies. Findings suggest that therapy with systemic corticosteroids accelerates the resolution of acute asthma and reduces the risk of relapse.[3]

The problem is with methylprednisolone acetate (Depo-Medrol). The contaminant is fungal, fungus was observed in at least one container at the manufacturer, and aspergillus (a fungus) was isolated from at least one patient.

The treatment is for spinal cord (intrathecal, in the subarachnoid space – deeper than epidural) injections. This is why it presents as meningitis, which is an inflammation of the linings of the central nervous system. The spinal cord is part of the central nervous system. The dura, arachnoid, and pia mater are the meninges.

New England Compounding Center is the only manufacturer involved.

The following is the complete less-than-helpful message displayed on their web site –
 

This website is temporarily unavailable.[4]

 

According to CNN, these are the affected lots –

Food and Drug Administration officials identified the manufacturer as New England Compounding Center (NECC), which conducted a voluntary recall of three lots of methylprednisolone acetate 80mg/mlinjection produced at NECC. The lot numbers are #05212012@68, #06292012@26 and #08102012@51.[5]

 

Persons with meningitis linked to epidural steroid injections: Indiana (1), Maryland (2), Virginia (4), Tennessee (25), North Carolina (1), Florida (2).[6]

At-A-Glance

  • Infection:Fungal Meningitis
  • Facility Type: Outpatient Setting
  • Case Count: 35
  • States: 6
  • Deaths: 5[6]

The following is from cached web pages of their site (stored images of the pages from before the site went down).

Contact Us

(New England Compounding Center)
697 Waverly Street
Framingham, MA 01702

                  Phone: 508-820-0606
                  Toll Free: 800-994-6322
                  Fax: 888-820-0583

                  Contact Us[7]

I have not tried their phones or emails. I am not that much of an optimist.

As part of this process, NECC has initiated a series of recalls encompassing all methylprednisolone acetate products – as well as other injectable medications – distributed from our facility in Framingham, Massachusetts.[8]

 

For this type of meningitis, symptoms include worsening to severe headache, nausea, dizziness and fever, Dreyzehner said. Other symptoms can include slurred speech, unsteady gait, urinary retention, weakness and sensory deficit.[5]

 

The contaminated drug came from New England Compounding Center, a company based in Framingham, Mass., that abruptly suspended operations this week, took its main website offline and stopped answering phone calls.[9]

To repeat –

The methylprednisolone sodium succinate (Solu-Medrol) used to treat asthma is safe and unrelated to the contaminated drug.

Updated 02:40 on 10/06/2012 – the FDA has added an information page on the meningitis outbreak with links to further information. FDA Statement on Fungal Meningitis Outbreak.

Footnotes:

[1] The prehospital administration of intravenous methylprednisolone lowers hospital admission rates for moderate to severe asthma.
Knapp B, Wood C.
Prehosp Emerg Care. 2003 Oct-Dec;7(4):423-6.
PMID: 14582090 [PubMed – indexed for MEDLINE]

[2] Evaluation of a new EMS asthma protocol in New York City: a preliminary report.
Stead L, Whiteside T.
Prehosp Emerg Care. 1999 Oct-Dec;3(4):338-42.
PMID: 10534036 [PubMed – indexed for MEDLINE]

[3] An umbrella review: corticosteroid therapy for adults with acute asthma.
Krishnan JA, Davis SQ, Naureckas ET, Gibson P, Rowe BH.
Am J Med. 2009 Nov;122(11):977-91. Review.
PMID: 19854321 [PubMed – indexed for MEDLINE]

Free Full Text from PubMed Central.

[4] New England Compounding Center
Web page at 04:00 10/05/2012.

[5] Meningitis outbreak spreads to 5 states; 4 dead
By Ann J. Curley,
CNN
updated 7:43 PM EDT, Wed October 3, 2012
Article

[6] Multi-State Meningitis Outbreak
This information will be updated daily at 2pm EST
CDC
Web page.

CDC conference call.

The first 14:30 of the conference call is jazz, so to advance the player to for the beginning of the talking, or just listen to the jazz.

[7] New England Compounding Center
Google cache of this page from 08:36:54 on 9/25/2012 – the image is at the end of the footnotes.
Web page at 04:00 10/05/2012.

[8] Statement from New England Compounding Center
Yahoo finance
New England Compounding Center
10/04/2012
Press release

[9] Rare Fungal Meningitis Outbreak Spreads To Six States
by Richard Knox
NPR
07:51 pm October 4, 2012
Article

.

Voluntary Recall of HYDROmorphone (Dilaudid) – What does it mean?

Today the FDA (Food and Drug Administration) and Hospira announced a voluntary recall of generic Dilaudid (HYDROmorphone HCL – the capitalization is to avoid confusion[1]).

If the intent is safer drug administration, the focus is misdirected.

Issue: Hospira and FDA notified healthcare professional of a nationwide voluntraty recall of one lot of Hydromorphone Injection, USP, 2 mg/mL, (C-II), 1 mL fill in 2.5 mL Carpuject, NDC 0409-1312-30, due to a reported complaint of a single Carpuject containing more than the 1 mL labeled fill volume.[2]

How much was in that single syringe?

The FDA and Hospira have not yet released that information.

Is it 1.1 mL (2.2 mg, rather than 2.0 mg) in the 2.5 mL syringe, rather than 1 mL?

In that case, the extra medication is not a big difference. The difference in response among patients will have so more of an effect on the dose, that this would not be significant.

Is it 2.5 mL (5.0 mg, rather than 2.0 mg) in the 2.5 mL syringe, rather than 1 mL?

In that case, the extra medication might make a big difference. The difference in response among patients will still have more of an effect on the dose, but this would be worth knowing.

This is what the packaging should look like –


Images credit.[3]

This is what to look for to specifically identify the affected medication.

HYDROmorphone HCL

2 mg/mL

1 mL fill in 2.5 mL Carpuject

NDC 0409-1312-30

The expiration date is December 1, 2013. The expiration date is useful in this case, but not visible here. 😉

The way we should be giving this medication is to break the seal by holding the syringe by the glass with the cap end up, push down on the cap, then insert it in the Carpuject. Screw the plunger on to the stopper and expel all of the air, so that only the medication remains.
 


 

The volume of medication is supposed to be 1 mL, but the recall states that there is a report of one case of a syringe containing more than 1 mL of hydromorphone. While it is possible that this is due to dilution, it is much more likely that the concentration is unchanged and that there is more of the same concentration of hydromorphone in the syringe.

Opioid pain medications such as Hydromorphone have life-threatening consequences if overdosed. Those consequences can include respiratory depression (slowed breathing or suspension of breathing), low blood pressure and reduced heart rate including circulatory collapse.[2]

That is not true. This is a corrected version of what the FDA wrote.

Opioid pain medications such as Hydromorphone MAY have life-threatening consequences if overdosed.

Perhaps they mean to suggest that there is no overdose, unless there are life-threatening consequences.

That does not appear to be a reasonable definition of overdose. An unintentionally large dose that causes permanent disability, but never threatens the life of the patient, should also be considered to be an overdose.

What about an unintentionally large dose that does not cause any harm? Is that not an overdose?

No harm, no foul?

I wouldn’t count on the QA/QI/CYA department taking that approach.

overdose (OD),
n an excessive use of a drug, resulting in adverse reactions ranging from mania or hysteria to coma or death.
Mosby’s Dental Dictionary, 2nd edition. © 2008 Elsevier, Inc. All rights reserved.
[4]

Does this require a recall, or does this require competence on the part of people administering the medications?

Is it appropriate for any medical professional to ever give a medication and not know the dose of the medication being given?[5]

This is the basis of naturopathy – the dose doesn’t really matter – it is more important that the treatment is all-natural. This is an over-simplification of naturopathy, but it is also the essence of naturopathy. Naturopathy depends on the ignorance of trusting in the naturalistic fallacy.[6]

The dose does matter.

A competent person administering the dose is important.

According to Paracelsus, the dose is more important than anything else.

All things are poison and nothing is without poison, only the dose permits something not to be poisonous. – Paracelsus.

Everything, no matter how natural, is poisonous.

Is hydromorphone dangerous?

No.

But it has a black box warning!

WARNING: RISK OF RESPIRATORY DEPRESSION AND ABUSE
Hydromorphone Hydrochloride Injection, USP, is an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. Schedule II opioid agonists, including morphine, oxymorphone, hydromorphone, oxycodone, fentanyl and methadone, have the highest potential for abuse and risk of producing fatal overdose due to respiratory depression. Ethanol, other opioids, and other central nervous system depressants (e.g., sedative-hypnotics, skeletal muscle relaxants) can potentiate the respiratory-depressant effects of hydromorphone and increase the risk of adverse outcomes, including death. (5.1)
Hydromorphone can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing Hydromorphone in situations where the healthcare professional is concerned about increased risk of misuse or abuse. (5.2)
[3]

None of that means that hydromorphone is dangerous in the hands of a competent person.

Here is some much more useful information than that black box warning. This is from the same label,[3] but it receives far less attention than that which must not be named the black box warning. Droperidol is almost never used, because it has a black box warning.

 

Opioid Analgesic Equivalents with Approximately Equianalgesic Potency*
Drug Substance IM or SC** Dose Oral Dose
Morphine Sulfate 10 mg 40 – 60 mg
Hydromorphone HCl 1.3 – 2 mg 6.5 – 7.5 mg
Oxymorphone HCl 1 – 1.1 mg 6.6 mg
Levorphanol tartrate 2 – 2.3 mg 4 mg
Meperidine HCl (pethidine HCl) 75 – 100 mg 300 – 400 mg
Methadone HCl 10 mg 10 – 20 mg
Nalbuphine HCl 12 mg
Butorphanol tartrate 1.5 – 2.5 mg

 

What else is good to know, when we are concerned about the strength, or dose, of what we are giving?

Conditions that affect the strength of the medication –

16.3 Storage
PROTECT FROM LIGHT
Keep covered in carton until time of use. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].
[3]

Recommendations: Anyone with an existing inventory should stop use and distribution, quarantine the product immediately, and call Stericycle at 1-866-873-0312 to arrange for the return of the product.[2]

 

Wouldn’t it be better to have a number to arrange for the return of personnel who do not know how to safely administer medication?
 

Footnotes:

[1] HYDROmorphone has the beginning capitalized to decrease the possibility of confusing hydromorphone with other medications that have similar names, such as these – OXYmorphone, hydroCODONE, DIhydroCODEINE, DIhydroMORPHINE, and DIACETYLDIhydroMORPHINE – the capitalization is of the differences. Morphine and morphone only differ in one letter, but morphine is a natural opium alkaloid and morphone appears to indicate only synthetic opium alkaloids.

[2] Hospira Hydromorphone Hydrochloride Injection 2 MG/ML, 1 mL fill in 2.5 mL Carpuject: Recall- May Contain More Than The Intended Fill Volume
Food and Drug Administration
[Posted 08/16/2012]
Safety Information
Voluntary Recall

[3] HYDROMORPHONE HYDROCHLORIDE injection, solution
[Hospira, Inc.]

FDA label
DailyMed
Label

[4] overdose (OD)
The Free Medical Dictionary by Farlex
Definition

[5] What should be the rules for safe drug administration – Part II
Rogue Medic
Mon, 02 Apr 2012
Article

[6] Appeal to nature
Wikipedia
Article

[7] FDA Drug Safety Communication: Prescription Acetaminophen Products to be Limited to 325 mg Per Dosage Unit; Boxed Warning Will Highlight Potential for Severe Liver Failure
FDA Safety Announcement
1-13-2011
FDA Safety Announcement

.

Ondansetron (Zofran) Warning for QT Prolongation – is Amiodarone next? – Part II

Continuing from Part I on the problems with QT segment prolongation and torsades de pointes, which is a form of polymorphic VT (Ventricular Tachycardia).
 

Polymorphic (irregular) VT requires immediate defibrillation with the same strategy used for VF.[1]

 

Is it possible, or common, for patients to maqintain pulses, or to remain stable, with polymorphic VT (torsades or otherwise)?

How long the patient remains stable should be the more important question.
 

If the patient becomes unstable at any time, proceed with synchronized cardioversion or unsynchronized defibrillation should the arrhythmia deteriorate to VF or be due to a polymorphic VT.[1]

 

A slightly different way of stating to immediately shock polymorphic VT. (VF is Ventricular Fibrillation.)
 

Let’s see some torsades.
 


Click on images to make them larger.[2]
 

How do we know that it is torsades?

Because of the long QT segment in the beats preceding the VT.

We are supposed to immediately shock torsades, because it is as bad as VF (Ventricular Fibrillation)?

How does that make sense, if the torsades goes away on its own?

 


 

Torsades is not VF.

The AHA should not be encouraging panic, but their suggestion is almost to skip assessment, skip sedation (if the patient is conscious), and just shock the rhythm. We should not be encouraging this approach to arrhythmias.

Arrhythmias with a polymorphic QRS appearance (such as torsades de pointes) will usually not permit synchronization. Thus, if a patient has polymorphic VT, treat the rhythm as VF and deliver high-energy unsynchronized shocks (ie, defibrillation doses). If there is any doubt whether monomorphic or polymorphic VT is present in the unstable patient, do not delay shock delivery to perform detailed rhythm analysis: provide high-energy unsynchronized shocks (ie, defibrillation doses). Use the ACLS Cardiac Arrest Algorithm (see Part 8.2: “Management of Cardiac Arrest”).[1]

 

Should we defibrillate without first assessing the patient?

No. That is not what the AHA is stating.

Should we shock patients who are conscious without first sedating the patient?

No. That is not what the AHA is stating.

Do we have to defibrillate, rather than cardiovert, when shocking torsades?

No. That is not what the AHA is stating.

If you doubt me, just get a rhythm generator, put torsades on the monitor (on the HeartSim pressing the faster button twice should do it), then press the SYNC button for synchronized cardioversion.

It works, doesn’t it?

Make it harder to synchronize by turning the gain down. It still works.

Turn the gain down again. It still works.

Look at each strip of torsades. There is no reason a monitor should fail to synchronize on these rhythms. The AHA seems to use a definition of usually that does not match what is in the dictionary.

The problem is not that the monitor will not synchronize. The problem is that torsades is an unfamiliar rhythm that scares a lot of people – especially those unfamiliar with cardioversion.

If you are not familiar with the use of the cardioverter(s) you work with, you should have your employer arrange for a practice day somewhere that has a rhythm generator and a mannequin that is connected to the rhythm generator, so that you can practice synchronized cardioversion and practice responding to rhythm changes.

When cardioverting, it is essential to make sure that the monitor is synchronizing appropriately and to press and hold the shock buttons until the shock is delivered. With synchronized shocks, we should expect a delay between when we press the buttons and the shock is delivered.[3]

How bad is torsades (polymorphic VT) compared to ordinary, standard, run of the mill, typical, monomorphic VT?

 

 

No shock was necessary for torsades, but a shock was necessary for ordinary VT.

According to AHA – torsades is very very bad.

According to these researchers torsades is not common, but torsades is manageable.

Oh, look. Torsades. OK (takes a sip of coffee), let’s see what happens. We will stop the drugs that are likely to be causing this. Then we can pace, or give isoproterenol, or try something else, but we can handle this by remaining calm.

To be continued in Part III. Not yet posted.

Footnotes:

[1] 2010 ACLS
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Part 8: Adult Advanced Cardiovascular Life Support
Free Full Text from Circulation

[2] Etiology, warning signs and therapy of torsade de pointes. A study of 10 patients.
Keren A, Tzivoni D, Gavish D, Levi J, Gottlieb S, Benhorin J, Stern S.
Circulation. 1981 Dec;64(6):1167-74.
PMID: 7296791 [PubMed – indexed for MEDLINE]

Abstract with link to Free Full Text Download in PDF format from Circulation

[3] Cardioversion – I’m not doing that, you do it!
Rogue Medic
Mon, 24 Mar 2008
Article

.

Ondansetron (Zofran) Warning for QT Prolongation – is Amiodarone next? – Part I


 

Friday the FDA (Food and Drug Administration) sent out a warning about high doses of ondansetron (Zofran). The doses are not the kind of doses used in EMS, but have been used to treat nausea and vomiting from chemotherapy.
 

GlaxoSmithKline (GSK) has announced changes to the Zofran drug label to remove the 32 mg single intravenous dose. The updated label will state that ondansetron can continue to be used in adults and children with chemotherapy-induced nausea and vomiting at the lower intravenous dose recommended in the drug label, a dose of 0.15 mg/kg administered every 4 hours for three doses; however, no single intravenous dose should exceed 16 mg. Information from the new clinical study will be included in the updated drug label.[1]

 

The usual EMS/ED dose is 4 mg, so this does not directly affect the way we use ondansetron. However, we may see patients treated with much larger doses, so we should be aware of the potential complications.

Here is the not yet changed adult chemotherapy dosing information from the label –
 

2.1 Prevention of Nausea and Vomiting Associated with Initial and Repeat Courses of Emetogenic Chemotherapy

ZOFRAN Injection should be diluted in 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection before administration.

Adults

The recommended adult intravenous dosage of ZOFRAN is a single 32-mg dose or three 0.15-mg/kg doses. A single 32-mg dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. Efficacy of the 32-mg single dose beyond 24 hours has not been established. The recommended infusion rate should not be exceeded [see Overdosage(10)]. With the three-dose (0.15-mg/kg) regimen, the first dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. Subsequent doses (0.15 mg/kg) are administered 4 and 8 hours after the first dose of ZOFRAN.[2]

 

What does QT segment prolongation look like?

 


Image credit.
 

There is a problem with the image. The ventricles contract during the QRS complex, not during the T wave.
 

  • The use of a single 32 mg intravenous dose of ondansetron should be avoided. New information indicates that QT prolongation occurs in a dose-dependent manner, and specifically at a single intravenous dose of 32 mg.
  • Patients who may be at particular risk for QT prolongation with ondansentron are those with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or patients taking concomitant medications that prolong the QT interval
  • Electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia) should be corrected prior to the infusion of ondansetron.
  • The lower dose intravenous regimen of 0.15 mg/kg every 4 hours for three doses may be used in adults with chemotherapy-induced nausea and vomiting. However, no single intravenous dose of ondansetron should exceed 16 mg due to the risk of QT prolongation.
  • The new information does not change any of the recommended oral dosing regimens for ondansetron, including the single oral dose of 24 mg for chemotherapy induced nausea and vomiting.[1]

 

There are many drugs that prolong the QT segment. There are three lists of these drugs broken down by potential to cause torsades, from qtdrugs.org.[4]

Some of these drugs are given for VT (Ventricular Tachycardia) because of a lack of awareness of the QT segment prolonging effects of antiarrhythmics. When will amiodarone receive some sort of warning for the same problem, especially since amiodarone is given like candy to patients with cardiac conduction disorders?

I will look at the problems with amiodarone and the ACLS recommendation that amiodarone be given to patients with polymorphic VT (Ventricular Tachycardia) in Part II.

The study referenced by the FDA does not appear to be available, yet. It is listed as completed –

ClinicalTrials.gov Identifier:     NCT01449188

Footnotes:

[1] Ondansetron (Zofran) IV: Drug Safety Communication – QT prolongation
FDA
FDA Safety Information and Adverse Event Reporting Program Safety Information
[Posted 06/29/2012]
Safety Alert

[2] ZOFRAN (ondansetron hydrochloride) injection
[GlaxoSmithKline LLC]

FDA label
Label

[3] QT Drug Lists by Risk Groups
qtdrugs.org
Home page

To view QT-prolonging drugs grouped by either 1) risk of torsades, 2) possible risk of torsades or 3) conditional risk of torsades, Click Here

.

Drug Shortage Update Affecting a Lot of the Ex-Code Drugs

Today’s drug shortage update from the FDA (Food and Drug Administration) includes a lot of drugs that used to be routine drugs for cardiac arrest.

Once upon a time, I was a code drug.

Atropine is the most recent drug to be dumped by the AHA (American Heart Association). In the past week, two manufacturers have stated that they have atropine available. FDA Update.

It was nice to see the AHA admit that there is not a good reason to keep treating every PEA (Pulseless Electrical Activity) or asystole patient with a drug that has never had good evidence that it improves survival. The next revision of the ACLS (Advanced Cardiac Life Support) guidelines will provide more opportunity to get rid of some drugs that are routinely used for cardiac arrest, even though there is no evidence that they improve survival – lidocaine (farther down on this list), amiodarone, and the everybody’s favorite drug to not improve survival – epinephrine (also farther down on the list).

Calcium Chloride has increased availability from one manufacturer, but decreased availability from another. Calcium is still the best drug for hyperkalemia, but it was once used routinely in cardiac arrest, as if there has been a lot of sudden onset hypocalcemia. FDA Update.

Epinephrine 1:10,000 has not yet been dumped by the FDA, but the recent evidence suggests that we are decreasing survival by using epinephrine – and those who do survive the epinephrine are more likely to have significant brain damage. FDA Update

Tomorrow, I will be talking about the evidence for and against epinephrine at the EMS Web Summit.

Lidocaine has new manufacturing delays. Lidocaine is still just barely in the ACLS guidelines –

Amiodarone may be considered when VF/VT is unresponsive to CPR, defibrillation, and vasopressor therapy (Class IIb, LOE A). If amiodarone is unavailable, lidocaine may be considered, but in clinical studies lidocaine has not been demonstrated to improve rates of ROSC and hospital admission compared with amiodarone (Class IIb, LOE B).[1]

Maybe lidocaine is there to make amiodarone look good, because nothing else makes amiodarone look good.

For victims of witnessed VF arrest, early CPR and rapid defibrillation can significantly increase the chance for survival to hospital discharge.128,–,133 In comparison, other ACLS therapies such as some medications and advanced airways, although associated with an increased rate of ROSC, have not been shown to increase the rate of survival to hospital discharge.31,33,134,–,138 [2]

In other words, these drugs are probably only as effective as atropine, and maybe less harmful than atropine, but the AHA has not given up on them, yet. FDA Update.

Magnesium Sulfate is another once-promising code drug, now used for the ever-impressive torsades and for the less impressive hypomagnesemia. FDA Update

Sodium Bicarbonate used to be given almost as much as epinephrine.

Now, Sodium Bicarbonate is only given when it is specifically indicated – the way that real medicine should be used. 😯

Sodium Bicarbonate is second line for hyperkalemia and probably is just the hypertonic saline (5.8% saline) that is working, rather than treatment of acidosis, but acidotic patients may benefit from that, too – if they are well ventilated. Sodium Bicarbonate is CO2 in a syringe.

FDA Update.

Vasopressin is now available, again. Not useful in cardiac arrest, but we feel we need to inject something, so this permits some variety. FDA Update.

Important non-code EMS drugs on the FDA Current Drug Shortages list are:

Alfentanyl – Possibly substituting for fentanyl, but not having enough to make up for the lack of fentanyl. Probably also due to increased realization that the side effects of opioids are easily managed by competent medical personnel.

Atracurium (Tracrium).

Diazepam (Valium).

Digoxin.

Diltiazem (Cardizem).

Diphenhydramine (Benadryl).

Etomidate (Amidate).

Fentanyl (Sublimaze).

Hydromorphone (Dilaudid).

Ketorolac (Toradol).

Lorazepam (Ativan).

Mannitol.

Metoclopramide (Reglan).

Midazolam (Versed).

Morphine.

Multi-vitamin injection (banana bags?).

Naloxone (Narcan).

Naltrexone.

Ondansetron (Zofran).

Oxytocin (Pitocin).

Pancuronium (Pavulon).

Phentolamine (Regitine).

Procainamide (Pronestyl) – the only ventricular antiarrhythmic that works (of those commonly available in the US – [sotalol also works]).

Prochlorperazine (Compazine).

Promethazine (Phenergan)

Propofol (Diprivan).

Sufentanyl (Sufenta).

Tromethamine (Tham).

Vecuronium (Norcuron).

and something new –

Sodium Chloride 0.9% (5.8mL and 20mL) (Initial Posting Date) – 5/4/2012. FDA Update.

Footnotes:

[1] Drug Therapy in VF/Pulseless VT
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science
Part 8: Advanced Life Support
Part 8.2: Management of Cardiac Arrest
Free Full Text from Circulation

[2] Overview
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science
Part 8: Advanced Life Support
Part 8.2: Management of Cardiac Arrest
Free Full Text from Circulation

.

How Bad are the Drug Shortages

I rant a bit about the misuse of many of these drugs, but there are a lot of drugs used in EMS on the current drug shortage list.

There is a lot written about the drug shortages, but what drugs are affected right now? I copied a list of what drugs are currently experiencing shortages as of today from the FDA (Food and Drug Administration).[1], [2]

What about EMS drugs?

Alfentanil Injection (Alfenta, Rapifen) – An opioid that may be used in some EMS systems as a substitute for fentanyl. Or another reason for EMS to use ketamine.[7]

Atracurium besylate (Tracrium) – A paralytic used in RSI (Rapid Sequence Induction/Intubation).

Atropine Sulfate Injection – Amphastar lists no delays, but other manufacturers list manufacturing delays and an increase in product demand. One manufacturer temporarily suspended production in April 2011.

The FDA search shows that there were drug shortages updates for atropine on 12/11/2008, 4/07/2009, and 9/30/2011 (the current shortage?), but all of the cached pages are the most recent, so the original information is not there.[3]

Following concerns about possible terrorist attacks using poisons that may be treated with atropine, the long term stability of atropine, and the continuing lack of evidence of benefit of atropine in treating cardiac arrest.[4]

How much did each of those contribute to another magic treatment biting the dust?

Caffeine, anhydrous (125 mg/mL) and Sodium benzoate (125 mg/mL) (Starbucks, Dunkin’ Donuts) – OK, that is not the kind of caffeine they are referring to. There might be true rebellion among EMS and hospital personnel if caffeine were not available.

What does that tell us about sleep deprivation, medicine, and the need for naps on the job?

Calcium Chloride Injection – If we are treating emergency hyperkalemia (which I recently saw written as hyperpotassiumemia :oops:) with anything other than calcium chloride as the first line drug, we are not providing good patient care.[5]

But calcium is dangerous!!

The danger of calcium is just another EMS myth.

What is dangerous is using much less effective treatments, such as sodium bicarbonate.

What is even more dangerous is using harmful, but ineffective treatments, such as sodium polystyrene sulfonate (Kayexalate)

Calcium Gluconate – A less concentrated form of calcium, that is safer in IV (IntraVenous) lines of questionable patency, not that this is the biggest concern in treating peri-arrest patients. IO (IntraOsseous) works for calcium chloride.[6]

Desmopressin Injection (DDAVP, Stimate, Minirin) – Similar to vasopressin.

Dexamethasone Injection (Decadron) – Methylprednisolone (Medrol, Solu-Medrol) is a good alternative that is not listed as a current drug shortage.

Diazepam Injection (Valium, Diastat) – The common alternative benzodiazepine sedatives (lorazepam [Ativan] and midazolam [Versed]) are also listed as current drug shortages.

Maybe this is a good reason to start carrying ketamine.[7]

Digoxin Injection – An inotrope alternative to catecholamines. The only inotrope not supposed to raise heart rate or myocardial oxygen demand at therapeutic levels. On the other hand, there is debate about whether digoxin improves outcomes.[8], [9]

Diltiazem Injection (Cardizem) – Verapamil (Calan, Isoptin, and Verelan) is the common alternative calcium channel blocker that should be used in the place of diltiazem for A Fib (Atrial Fibrillation) or SVT (SupraVentricular Tachycardia).

Diphenhydramine Hydrochloride Injection (Benadryl) – A medication to treat dystonic reactions. For dystonia, it can be replaced by benztropine (Cogentin). The more common use of diphenhydramine is as an antihistamine, such as after IM (IntraMuscular) epinephrine for anaphylaxis. It may sedate and decrease itching, but do not expect diphenhydramine to reverse anaphylaxis.


An example of dystonia. Image credit.

Etomidate Injection (New!!) (Amidate) – Etomidate is commonly used for pseudo-RSI or DFI (Drug Facilitated Intubation). In Pennsylvania, we have a dose of 0.3 mg/kg, that is often restricted even more by some medical command doctors out of an apparent fear of giving a dose that might be effective. Should they want to give orders for more, the maximum dose listed in the protocol is 30 mg. The medical command doctor can order more, but few seem to realize that this is not a restriction on what they can order. Etomidate is only supposed to be used with a paralytic for RSI, but is expected to be both sedative and paralytic, when EMS uses it in Pennsylvania. 😳

Why use a not-very-effective drug at a dose that is not expected to be effective?

Fentanyl Citrate Injection (Sublimaze) – The shortage of both benzodiazepines and opioids are just more reasons for EMS to use ketamine.[7]

Furosemide Injection (Lasix) – A drug that EMS should not use. Furosemide is so far down on the list of treatments for CHF (Congestive Heart Failure), that it suggests we have been digging a grave for the patient, if we stay on scene long enough to give furosemide. A worthless EMS treatment.[10], [11] Pennsylvania is ahead of most states in moving furosemide to medical command order only, but the better move is to remove it from EMS use completely.

Ketorolac Injection (Toradol) – A pain medicine related to aspirin, so not a good idea for trauma, but some people are less worried about interfering with the ability of trauma patients to stop bleeding than they are about the possibility that the 10/10 severe pain patient might stop screaming and, without anyone noticing, stop breathing. 😳

One possible superiority is for calculi (kidney stones and gall stones). Of course, this is just another reason for EMS to use ketamine.[7]

Labetalol Hydrochloride Injection (Normodyne, Trandate) – A beta blocker. Beta blockers have been de-emphasized since the CRUSADE trial, but there are still EMS indications in heart attack. Patients with signs of dramatic catcholamine release (they look as if someone gave them epinephrine) except for patients with tachycardia (greater than 110 beats per minute).

Lorazepam Injection (Ativan) – Not the best, or even the second best, EMS sedative, but one that is preferred by a lot of people. A much better idea is midazolam, because aggressive doses can be given and they should be wearing off at about the time the patient is being transferred to the ED (Emergency Department), so that one-on-one observation of a heavily sedated patient is not required and flumazenil (Romazicon) is not given. Another reason for EMS to use ketamine.[7]

Magnesium Sulfate Injection – A safer antiarrhythmic than amiodarone and a treatment for some of the arrhythmias caused by amiodarone, such as torsades des pointes.-

Mannitol Injection – An osmotic diuretic used in some EMS systems.

Methylphenidate HCl (Ritalin) – Possibly the second most common EMS drug – after caffeine.

Metoclopramide injection (Reglan) – Anti-nausea medication.

Midazolam Injection (Versed) – This used to be my favorite EMS sedative, but this is one more reason for EMS to use ketamine.[7]

Morphine Sulfate Injection – For pain management and another reason for EMS to use ketamine.[7]

Nalbuphine Injection (Nubain) – A poor substitute for morphine and a pathetic excuse for risk management. Just another reason for EMS to use ketamine.[7]

Naltrexone Oral Tablets (New!!) (Depade, ReVia) – With the use of nebulized naloxone, who knows what might be next? As long as we are treating something other than respiratory depression (patients unlikely to be able to use a nebulizer), maybe oral tablets will be next and the longer acting opioid antagonist may appeal to those terrified of any potential for respiratory depression.

NeoProfen (ibuprofen lysine) Injection – For treatment of PDA (Patent Ductus Arteriosus) in premature babies. Some EMS may use this, but it is more likely to be found in the ED or neonatal ICU.

Ondansetron Injection 2 mg/mL (Zofran) – One effective antiemetic.

Ondansetron Injection 32 mg/50 mL premixed bags (Zofran) – Same thing, different preparation.

Oxytocin Injection, USP (synthetic) (Pitocin) – For post-partum hemorrhage that is not otherwise controlled. Massage the fundus and consider direct pressure. Direct pressure is not in EMS protocols, but when the alternative is the death of the patient, do we want to stop the bleeding, or do we want to follow protocols?

Pancuronium Bromide Injection (Pavulon) – A paralytic used in RSI.

Phentolamine Mesylate for Injection (Regitine) – For treatment of extravasation of catecholamines (epinephrine, dopamine, dobutamine). Not usually carried by EMS (after all, it only happens in other EMS systems), but used in the ED (even to treat the extravasation of catecholamines from EMS IVs – but only from those other EMS systems). 😎

Procainamide HCL Injection (Pronestyl) – An antiarrhythmic that is very effective, but it has a lot of side effects – just like the much less effective drugs that are used in its place.

Prochlorperazine Injection (Compazine) – Another anti-nause medication. This is also one of the drugs that may cause dystonic reactions.

Promethazine Injection (Phenergan) – Still another anti-nause medication. Another drug that may cause dystonic reactions.

Vasopressin Injection (Pitressin) – An alternative to epinephrine as a pressor to treat cardiac arrest, even though there is no evidence of improved survival. Also goes by the name “pit,” so that it can be easily confused with Pitocin (“pit”) used in OB/GYN.

Vecuronium Injection (Norcuron) – A paralytic used in RSI.

That is it for the drugs that are used in some EMS systems. Fortunately, a lot can be replaced by ketamine, or their use can be reduced by the use of ketamine. Pain management, sedation, RSI, excited delirium, DSI (Delayed Sequence Intubation), et cetera. One long list of reasons for EMS to use ketamine.[7]

Also see Stressful Drug Shortage Update.

Footnotes:

[1] Current Drug Shortages
Drug Shortages
FDA
02/15/2012
Drug shortage Update

[2] List of medications from FDA drug shortages update on 02/15/2012

Acetylcysteine Inhalation Solution

Alcohol Dehydrated (Ethanol > 98%)

Alfentanil Injection

Amikacin Injection

Amino Acid Products (New!!)

Aminocaproic Acid

Ammonium Chloride Injection

Ammonium Molybdate Injection

Ammonul (sodium phenylacetate and sodium benzoate) Injection 10%/10%

Amphetamine Mixed Salts, ER Capsules

Amphetamine Mixed Salts Immediate-Release Tablets

Anadrol-50 tablets (Oxymetholone Tablets)

Aquasol A

Atracurium besylate

Atropine Sulfate Injection

Avalide (irbesartan and hydrochlorothiazide)Tablets

Bleomycin Injection

Bupivacaine Hydrochloride Injection

Buprenorphine Injection

Butorphanol Injection

Caffeine, anhydrous (125 mg/mL) and Sodium benzoate (125 mg/mL)

Calcitriol 1 mcg/mL Injection

Calcium Chloride Injection

Calcium Gluconate

Cerezyme (imiglucerase for injection)

Chromic Chloride Injection

Cisplatin injection 1 mg/mL solution

Corticorelin Ovine Triflutate (New!!)

Cosyntropin Injection

Cyanocobalamin injection

Daunorubicin hydrochloride solution for injection

Desmopressin Injection

Dexamethasone Injection

Dexrazoxane Injection

Dextroamphetamine Tablets

Diazepam Injection

Digoxin Injection

Diltiazem Injection

Diphenhydramine Hydrochloride Injection

Doxorubicin (adriamycin) lyophilized powder

Doxorubicin Liposomal (Doxil) Injection

Doxorubicin Solution for Injection

Ethiodol (ETHIODIZED OIL) ampules

Etomidate Injection (New!!)

Etoposide solution for injection

Fabrazyme (agalsidase beta)

Fentanyl Citrate Injection

Fluorouracil Injection

Foscarnet Sodium Injection

Fosphenytoin Sodium Injection

Furosemide Injection

Haloperidol Decanoate Injection

Indigo Carmine Injection

Insulin glulisine [rDNA origin] injection) solution for injection (Apidra SoloStar)

Intravenous Fat Emulsion

Isoniazid Tablets

Ketorolac Injection

Labetalol Hydrochloride Injection

L-cysteine hydrochloride

Leucovorin Calcium Lyophilized Powder for Injection

Leuprolide Injection

Levaquin Injection

Levofloxacin Injection

Levoleucovorin (Fusilev) 50 mg single use vials

Lorazepam Injection

Magnesium Sulfate Injection

Mannitol Injection

Mesna 100 mg/mL Injection

Methotrexate Injection

Methylphenidate HCl

Methyldopate Injection

Metoclopramide injection

Mexiletine Capsules (150mg, 200mg, and 250mg)

Midazolam Injection

Mitomycin Powder for Injection

Morphine Sulfate Injection

Multi-Vitamin Infusion (Adult and pediatric)

Mustargen (mechlorethamine HCl) injection

Nalbuphine Injection

Naltrexone Oral Tablets (New!!)

NeoProfen (ibuprofen lysine) Injection

Neupro (rotigotine transdermal system)

Ondansetron Injection 2 mg/mL

Ondansetron Injection 32 mg/50 mL premixed bags

Ontak injection

Opana ER (oxymorphone hydrochloride) Extended-Release Tablets CII (New!!)

Orphenadrine Citrate Injection

Oxsoralen (methoxsalen) 1% topical lotion

Oxytocin Injection, USP (synthetic)

Paclitaxel Injection

Pancuronium Bromide Injection

Phentolamine Mesylate for Injection

Phytonadione Injectable Emulsion (Vitamin K)

Potassium Phosphate

Primaquine Phosphate Tablets

Procainamide HCL Injection

Prochlorperazine Injection

Promethazine Injection

Selenium injection

Sodium Acetate Injection

Sodium Chloride 23.4%

Sodium Phosphate Injection

Sulfamethoxazole 80mg/trimethoprim 16mg/ml injection (SMX/TMP)

Telavancin (Vibativ) Injection

Tetracycline Capsules

Thiotepa for Injection

Thyrogen (thyrotropin alfa) injection 1.1mg/vial

Thyrolar Tablets

Ticlopidine Tablets

Tobramycin Solution for Injection

Vasopressin Injection

Vecuronium Injection

Vinblastine Sulfate Injection

Voltaren gel 1% (Diclofenac Sodium Topical Gel) (New!!)

[3] Atropine Sulfate Injection
FDA
FDA Search

[4] What Will We Do With All of That Atropine
Rogue Medic
Fri, 22 Oct 2010
Article

[5] Management of severe hyperkalemia.
Weisberg LS.
Crit Care Med. 2008 Dec;36(12):3246-51. Review.
PMID: 18936701 [PubMed – indexed for MEDLINE]

Free Full Text PDF

[6] Comparison study of intraosseous, central intravenous, and peripheral intravenous infusions of emergency drugs.
Orlowski JP, Porembka DT, Gallagher JM, Lockrem JD, VanLente F.
Am J Dis Child. 1990 Jan;144(1):112-7.
PMID: 1688484 [PubMed – indexed for MEDLINE]

[7] Is Ketamine an EMS Wonder Drug
Rogue Medic
Sun, 01 Jan 2012
Article

[8] Update on digoxin therapy in congestive heart failure.
Haji SA, Movahed A.
Am Fam Physician. 2000 Jul 15;62(2):409-16. Review.
PMID: 10929703 [PubMed – indexed for MEDLINE]

Free Full Text from Am Fam Physician.

For many more years, digitalis continued to be an important part of heart failure management. The detrimental aspects of digoxin therapy were not considered important until excess mortality was reported in survivors of myocardial infarction who received digitalis.13,14 Uncontrolled observations that the withdrawal of digoxin produced no ill effects also raised concerns about the efficacy of the drug.15,16

[9] The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group.
[No authors listed]
N Engl J Med. 1997 Feb 20;336(8):525-33.
PMID: 9036306 [PubMed – indexed for MEDLINE]

Free Full Text from N Engl J Med.

In conclusion, digoxin had no effect on overall mortality in patients receiving diuretics and angiotensin-converting–enzyme inhibitors, but it did reduce the overall number of hospitalizations and the combined outcome of death or hospitalization attributable to worsening heart failure. In clinical practice, digoxin therapy is likely to affect the frequency of hospitalization, but not survival.

On the other hand, that is not a study of digoxin for emergency use.

[10] Prehospital therapy for acute congestive heart failure: state of the art.
Mosesso VN Jr, Dunford J, Blackwell T, Griswell JK.
Prehosp Emerg Care. 2003 Jan-Mar;7(1):13-23. Review.
PMID: 12540139 [PubMed – indexed for MEDLINE]

Free Full Text PDF

[11] Modern management of cardiogenic pulmonary edema.
Mattu A, Martinez JP, Kelly BS.
Emerg Med Clin North Am. 2005 Nov;23(4):1105-25. Review.
PMID: 16199340 [PubMed – indexed for MEDLINE]

Free Full Text PDF

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Where are the Black Box Warnings on These Drugs – II

Continuing with the answer to Where are the Black Box Warnings on These Drugs – I.

There is a black box warning on droperidol for prolonging the QT segment, but there is no black box warning for this commonly used EMS drug (Drug X) that also prolongs the QT segment. Are we supposed to think that Drug X is safer than droperidol?

What is Drug X?

Proarrhythmia
Like all antiarrhythmic agents, amiodarone I.V. may cause a worsening of existing arrhythmias or precipitate a new arrhythmia. Proarrhythmia, primarily torsades de pointes (TdP), has been associated with prolongation by amiodarone I.V. of the QTc interval to 500 ms or greater. Although QTc prolongation occurred frequently in patients receiving amiodarone I.V., torsades de pointes or new-onset VF occurred infrequently (less than 2%). Patients should be monitored for QTc prolongation during infusion with amiodarone I.V. Combination of amiodarone with other antiarrhythmic therapy that prolongs the QTc should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent.
[1]

Have you ever been warned about the possibility of inducing torsades de pointes or new-onset VF with amiodarone?

What is the incidence of torsades de pointes or new-onset VF with droperidol?

Much much less than 2%.

Although QTc prolongation occurred frequently in patients receiving amiodarone I.V., torsades de pointes or new-onset VF occurred infrequently (less than 2%). Patients should be monitored for QTc prolongation during infusion with amiodarone I.V.

Where is the black box warning for amiodarone for more frequent torsades and VF?


VT source. Torsades source.

Maybe you have not seen torsades even with semi-frequent administration of amiodarone.

How many people have seen torsades even with more frequent administration of droperidol?

Electrolyte Disturbances
Patients with hypokalemia or hypomagnesemia should have the condition corrected whenever possible before being treated with amiodarone I.V., as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics.
[1]

Have you ever been warned to avoid giving amiodarone to hypokalemic or hypomagnesemic patients?

In EMS, other than guessing based on the patient’s history, how would we know that the patient has hypokalemia or hypomagnesemia?

In the ED (Emergency Department), are magnesium or potassium levels checked before giving amiodarone?

 

Why does droperidol have a black box warning?

 

Amiodarone is associated with more frequent torsades and VF than droperidol.

We give out amiodarone more often than banks give political donations.

 

Why doesn’t amiodarone have a black box warning?

 

Footnotes:

[1] AMIODARONE HYDROCHLORIDE injection, solution
[Bedford Laboratories]

FDA label
Label

.