Sunday, June 19, 2016

When the FDA Met #FOAMed

For a while now, there has been a lot of discussion among folks in the free open access medical education (FOAMed) community related to the acknowledgement and recognition in the academic realm. Recently, one major academic institution that has now set the stage for the recognition of FOAMed as scholarly activity for the purposes of promotion and tenure: The Mayo Clinic. This unprecedented move should surely serve as a stepping stone for other academic institutions to follow suit.

Nonetheless, I think it is important to go back to the very beginning and ask ourselves, at least those of us involved in free open access medical education, one essential question. Why do we do what we do?

In no way, shape, or form did I ever anticipate that my engagement in the world of FOAMed, at least in producing content, could ever lead to much. To be quite frank, I have been of the opinion that if FOAMed is recognized by the academy, all the better; but if not, then no love is lost on that end. The opportunities that are built out of FOAMed, whether it be speaking gigs, research and educational collaborations with colleagues, and leadership roles within professional organizations, may come to fruition unexpectedly, but are of much value. As discussed in a multitude of other forums, these are traditional platforms that are indeed recognized by promotion and tenure committees.

From my own perspective, when I set out to engage in this endeavor as a side activity of sorts, I did it for my own sake; really, to educate myself on a disease state or treatment based on experiences during my clinical shifts in the emergency department. It has been therapeutic in some ways as well, as not only does writing help me retain facts and controversies related to clinical topics more readily, but it also helps facilitate reflection on my own experiences. If anything that I have written is of benefit to anyone in a challenging situation during a difficult clinical shift that can be applied at the bedside, then all the power goes to the reader. I am certainly appreciative of the feedback that I do receive from international colleagues related to my posts, especially that which pertains to being of much benefit to clinicians in the emergency department in a tight situation.

But I digress...

For the most part, with every post that I write for this blog (and anything else I do in the world of social media), I try as much as possible to include solid references - not only to cover myself, but also to spark the reader to look into the referenced information for themselves. I firmly believe that any educational blog post, podcast, or other tool that falls under the umbrella of "FOAMed" ought to follow this standard. Most do; but it is essential to emphasize to our audience that they themselves need to critically read and analyze literature and decide whether the information in the medium may be something that is not only worth practical application at the bedside, but is also solid and accurate from this standpoint - especially since you may never know who may be tuning in to your podcast or reading your blog post.

So imagine my surprise a couple of weeks ago when I came across this traffic source via the administrative functions for the blog:

I thought at first it was a mistake and that my eyes were playing tricks on me. I mean, after all, this occurred during the first few days of Ramadan, and my energy levels do tend to wane throughout the day.

So I did what any sane person would do: I clicked the link.

The link indeed led to the actual US Food and Drug Administration (FDA) website. It was a detailed drug safety communication related to cardiotoxicity secondary to loperamide abuse, an occurrence that has become increasingly recognized and reported in the literature here in the States.

I had written about this topic nearly a year ago on the blog after having to manage a patient in the emergency department who presented with Torsdes de Pointes secondary to this very phenomenon. Prior to this experience, I knew nothing about it, so again, writing the post was simply a means of educating myself...and anyone else who stumbled upon the post.

I kept reading through the safety communication...and then I got to the references section. My heart dropped when I saw that the third reference listed was the very same blog post that I authored, fully cited in true form.

Needless to say, I am still in the "mind blown" state.

I am not quite sure how the FDA happened to find the post, nor am I fully aware of the exact reason as to why the individuals who pieced together the safety communication decided to include my post in their list of references. Perhaps because it is what it is - FOAMed - and any individual of the general public who accessed the communication can easily find more information covered in the post.

We now arrive at the state of things. For all intents and purposes, it is safe to say that FOAMed has officially gone mainstream. Can this keep up? I think (and hope) so, as quality content continues to be produced by us creators.

This may be a bold statement, but given the circumstances, I think it ought to be said. If FOAMed is good enough to be recognized by the FDA, then it certainly ought to be good enough to be recognized by any other entity - yes, that includes academic institutions.

Mic drop.

"Nice to meet you, where have you been?
I could show you incredible things..."

Monday, June 13, 2016

Replacement for Unused Alteplase (tPA)

A 78-year-old female with acute onset of right-sided weakness, facial droop, and slurred speech presents via ambulance to your emergency department (ED). After CT and labs are completed, the neurology team decides to administer alteplase (tPA) for acute ischemic stroke and the pharmacist begins reconstituting the medication. However, the family arrives and states they do not want the patient to receive tPA. What should you do with the reconstituted product that is now not to be administered to the patient?

Although posted on Genetech’s website, many pharmacists may be unaware that Activase® can be returned for replacement if it is mixed and not administered under certain situations. According to the Activase Spoilage Replacement Program, when the medication is “… prescribed for a labeled indication and unable to be administered, the product might be eligible for replacement.” As tPA is FDA-approved for the treatment of acute submassive PE, STEMI, and acute ischemic stroke, tPA that is reconstituted for any of these indications is potentially eligible for replacement. A Spoilage Replacement Form is required to be completed and faxed to the manufacturer for review and approval of replacement. More detailed information regarding how to obtain and submit the Spoilage Replacement Form can be found here.

Potential reasons for replacement include:
  • Delivery system failure 
  • Patient/family refused 
  • Patient missed time window/time elapsed 
  • Patient expired/coded prior to administration 
  • Patient transferred to a medical floor 
Based on the reasons above, there is a wide range of possible situations in which a replacement may be eligible. The eligibility criteria have been updated in the past year and unfortunately are now more stringent as several reasons for replacements were removed such as “Contraindicated/Misdiagnosed,” “Physician Preference,” “Duplicate Reconstitution,” and “Admixture Error.”

Here are some tips for maximizing the chances of replacement of unused alteplase:
  • Return all product to the vial 
    • This includes the bolus and waste and as much volume as possible from the IV tubing if you have primed it 
    • Given the potential for replacement, never dispose of the waste until the product is actually infusing into the patient in case the situation changes at the last second 
  • Keep everything 
    • If possible, return the drug vial, diluent vial, and box to Genetech 
    • Returning everything increases the chances of a replacement as some representatives may require everything (including the box) be returned for eligibility
  • Write an explanation as soon as possible 
    • The Spoilage Replacement Form requires a “detailed explanation of how the spoilage occurred” 
    • The sooner you write your explanation the better as you may forget or leave out pertinent information if completed at a later date 
  • Although not listed formally in the “Potential reasons for replacement” section, there is a checkbox for “other” as a reason for spoilage 
    • If you have a compelling situation in which the medication was prepared but ultimately withheld and does not meet the criteria, try to explain in attempts to ensure that replacement can occur 
As the EM pharmacist is intimately involved with the care of these patients, you have a great opportunity to help the pharmacy department’s budget by identifying situations to request a replacement for unused product. Acquisition costs for tPA are approximately $10,000/dose and any replacement product you can obtain will be a substantial win for your department’s bottom line. Work with your pharmacy manager or buyer to develop a system for requesting replacements and assigning the various required tasks.

If the product is not eligible for a replacement based on the reasons above, consider saving the medication for use on another patient as per the package insert, tPA can be used within 8 hours of reconstitution. If you work in a busy stroke center you’ll likely see additional stroke patients within those 8 hours and can potentially utilize the previous vial instead of mixing a new one.

As a last resort for unused tPA, instead of disposing it, consider using it as an educational tool for pharmacists and pharmacy technicians at your institution. Pharmacy personnel who may not be as experienced reconstituting tPA can benefit from the hands-on practice with real vials and transfer devices.

*** UPDATE ***
As of November 15, 2016 Genentech’s new Spoilage Replacement Request Form has gone into effect with several updates compared to the previous form including a revised list of spoilage reasons. Thankfully, this list has expanded and now aligns with the package insert list of contraindications and also includes patients whose symptoms have significantly improved.

Eleven new potential reasons for replacement include:
  • Active internal bleeding
  • Bleeding diathesis (February 2016 update of package insert does not state specific laboratory cutoffs)
  • Current intracranial hemorrhage
  • Current severe uncontrolled hypertension (February 2016 update of package insert does not state specific cutoffs)
  • History of recent stroke (for PE/AMI patients only)
  • Intracranial conditions that may increase risk of bleeding
  • Recent (within 3 months) intracranial or intraspinal surgery or serious head trauma
  • Subarachnoid hemorrhage
  • History of cerebrovascular accident
  • Intracranial neoplasm, arteriovenous malformation, or aneurysm
  • Patient symptoms returned to a nondisabling deficit
Four reasons have remained unchanged:
  • Patient/family refused product
  • Patient missed time window/time elapsed
  • Patient expired/coded prior to administration
  • Other medical reason, not listed above
Two reasons for replacement have been removed:
  • Delivery system failure
  • Patient transferred to a medical floor
Additional updates to the Spoilage Replacement process include:
  • The replacement instructions now specifically state: “Please retain all original product packaging for returns processing”
    • As mentioned previously, returning everything possible (including the box) will increase your chances of replacement
  • Inclusion of product’s serial number on the Spoilage Replacement Form (in addition to NDC and Lot numbers)
  • Requirement that a Physician or Director of Pharmacy sign the attestation section
    • This new requirement may necessitate changes in your institution's current process for tPA replacement to decide who will be responsible for signing off forms to be submitted
  • Changes to the timeframe requirements for replacement
    • The Spoilage Replacement Form must be faxed within 30 days from the date of spoilage occurrence
    • The unused product must be returned to Genentech within 60 days from the date of Genentech approval of the spoilage request (or a valid Certificate of Destruction)

Overall, the new expanded list of reasons for replacement is a big win. This new list will now encompass a larger percentage of stroke patients and hopefully increase the number of successful product returns and decrease the costly waste associated with unused tPA.

Scott Dietrich, PharmD (@PCC_PharmD)
EM Clinical Pharmacist
University of Colorado Health - North
Fort Collins, Colorado

Peer reviewed by Craig Cocchio, PharmD, BCPS (@iEMPharmD) and Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)

Sunday, June 5, 2016

Diltiazem IV to PO Explained

One of the oldest posts on EMPharmD has finally received an update. One of the most prominent lessons I've learned since graduating residency years ago is that the more I learn, the more I realize I do not know, and seeking out help is not a sign of weakness, but a strength.  
Artist rendering of diltiazem formula investigation

As such, when I encountered a wall in trying to trace the origin of the diltiazem IV to PO estimations, I re-published the post on, hoping someone smarter than me would help explain. That strategy paid off and Dr. Varela from Nova Southeastern University College of Pharmacy was gracious enough to give permission to publish his reply to me on this blog:

There is no one recommended conversion to an oral dosage regimen when using an intravenous drip of diltiazem. You elegantly stated one estimate of total daily oral dose from the standard diltiazem drip rates:

   5 mg/hr                            180 mg/day
   7.5 mg/hr                         255 mg/day  (the 260 mg is rounded, [7.5 mg/hr x 30] + 30 = 255 mg/day)
   10 mg/hr                          330 mg/day
   15 mg/hr                          480 mg/day

The formula: Oral dose = {IV drip rate (mg/hr) x 3 + 3} x 10 can be algebraically expanded to obtain
TDD = 30 (rate) + 30 

Note how it looks like the linear form y= mx + b.

Just use linear regression software, making “x” the IV rate and the corresponding “y” the total oral daily dose; the slope (m) will be 30 and the y-intercept (b) will also be 30.  Letting y = TDD (Total Daily Dose) in the oral regimen, slope = 30, x = drip rate in mg/hr, and the y-intercept = 30 the “linear” representation (of the small table) is obtained. There are no references for this formula since it just a linear regression transformation that anyone can perform using any scientific calculator. There is no mystery, nor clinical studies, just linear regression.

I do have to caution that diltiazem has nonlinear pharmacokinetics and linear regression would not be appropriate; however there is no harm in just "plotting" the above 4 sets of points and obtaining an easy "mnemonic formula". It is not clinical just math.

Excellent description on how to tapper the iv drip and "bridging' to the oral diltiazem regimen. 

To be complete using pharmacokinetic principles  and a bioavailability factor of 40% for immediate-release diltiazem another formula: MD/day = 60 R: R = infusion rate in mg/hr, MD = oral maintenance dose. This gives a much higher oral dosing regimen.

Thank you

Jorge Varela, PharmD
Department of Pharmaceutical Sciences
NSU College of Pharmacy

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