Saturday, September 29, 2012

TEDMED Talk - Publication Bias

"Evidence Based" Medicine - Ben Goldacre

It's amazing how fast ideas spread. I recently watched this TEDMED talk with the pharmacy students on my rotation as well as my pharmacy resident.  I've linked the Life In The Fast Lane post about it, since I've followed this site for a while and hope to see how the discussion grows.
It's something we should all consider whenever interpreting data about new or old drugs... Are we getting the whole story?

Thursday, September 27, 2012

The best drug you aren’t using: Fosphenytoin

Fosphenytoin (fosPHT) is not a new drug. It was designed to improve the water solubility of phenytoin (PHT) thereby reducing the risk of cardiac arrhythmias and hypotension during administration (from lack of propylene glycol, although PHT is still a 1b antiarrhythmic). Improved water solubility also eliminates the risk of tissue necrosis if extravasation occurs. This allows for much more rapid infusion of fosPHT (150mg/min) as well as ability to administer IM.  Unfortunately, the drug failed to take-off as a PHT replacement because of its considerably higher acquisition cost.

That was 20 years ago. Today, the two drugs cost virtually the same amount of money. Even when cost is taken out of the equation, hesitance to leave PHT on the shelf still exists.

The main concern that has been expressed to me regarding replacing fosPHT with PHT is the time that it takes to convert fosPHT to active drug will negate its ability to be infused faster.  While this thought is completely logical, pharmacokinetic studies tell us otherwise.

When fosPHT is administered at appropriate infusion rates (150mg/min) and because fosPHT displaces PHT from plasma protein binding sites, the delay in conversion from prodrug to PHT will be compensated.

Let me explain.

In order for fosPHT to be activated, it must be cleaved by phosphatases in the blood and tissues and then spontaneously hydrolyses to PHT. The half-life of this process ranges from 7-15 minutes and conversion occurs faster with higher doses and faster infusions.  This evidence taken alone would certainly lead one to agree with the above concern.

The game-changing characteristic of fosPHT is that it competitively displaces PHT from plasma protein binding sites (albumin).  So after rapid IV administration, the fosPHT that has yet to be activated is increasing the amount of free PHT in the blood due to displacement.  Since only free (unbound) PHT can enter the CNS and exert its antiepileptic activity, free PHT levels are a better measure of pharmacologic activity. As a result, free PHT therapeutic concentrations are reached faster with fosPHT compared to PHT.

What advantage could PHT have now? I say none.

Fischer JH, Patel TV, Fischer PA. Fosphenytoin: Clinical Pharmacokinetics and Comparative Advantages in the Acute Treatment of Seizures. Clin Pharmacokinet 2003; 42(1):33-58
Browne TR, Kugler AR, Eldon MA. Pharmacology and pharmacokinetics of fosphenytoin. Neurology. 1996 Jun;46(6 Suppl 1):S3-7

Tuesday, September 25, 2012

Hypercalcemia: Pamidronate vs Zoledronic acid

We use IV bisphosphonates in acute hypercalcemia with theunderstanding that they’ll help achieve a normal calcium level in about 72hours.  Aside from the importantcomponents of this treatment that will have more of an immediate effect (fluid,diuretics, steroids, calcitonin); which bisphosphonate is best?

Since oral bisphosphonates have extremely low bioavailablity(1-2%), IV agents like pamidronate and zoledronic acid become the two leadingcandidates.

Even though these drugs do reach their peak effect for days,we do want to administer them as soon as possible (often in the ED).  Zoledronic acid can be given over 15minutes; faster than pamidronate, which must be infused over 2 - 4 hours. 

There is only one study comparing the two agents head tohead (pamidronate 90mg, zoledronic acid 4mg, and zoledronic 8mg).  The study showed that zoledronic acid issuperior compared to pamidronate at achieving a “complete response” which wasdefined as a corrected serum calcium level less than 10.8 mg/dL by day 10 (88.4%vs 69.7%, respectively).  Although thisdifference reached statistical significance, its clinical significance as wellas the clinical significance of the mean nadir corrected calcium concentrations(zoledronic acid 9.8mg/dL; pamidronate 10.5mg/dL) is disputed. [Major P, et al. J Clin Oncol 19:558-567]

Regarding safety, both agents have similar incidences ofnephrotoxicity, flu-like symptoms after infusion (often, acetaminophen beforeinfusion can prevent this). Zoledronic does require dose adjustment for renalimpairment, and both should generally be avoided if GFR is less than 30 mL/min.

Cost… Zoledronic acid 4mg - $1100 per dose. Pamidronate90mg - $100 per dose.  I don’t usuallyget hung up on cost differences between drugs, but in this case with this evidence, andsafety profile, it’s hard to justify utilizing a drug that is 10x moreexpensive than it’s alternative. 

My recommendation (after adequate fluid, calciuresis,calcitonin, steroids):

First line:
Pamidronate 90mg IV in 1000mL NS, infuse over 4 hours

Second line:
Zoledronic acid 4mg IV in 100mL NS, infuse over 15 min
GFR 50-59 mL/min: 3.5 mg
GFR 40-49 mL/min: 3.3 mg
GFR 30-39 mL/min: 3.0 mg

Tuesday, September 18, 2012

Equiosmolar loads from sodium chloride vs sodium bicarbonate

It's an interesting dilemma when considering how exactly to safely integrate hyperosmolar sodium chloride products into the emergency department.  Stocking vials of 23.4% sodium chloride in the ED, whether in a Pyxis/Omnicell or a locked cabinet, creates an unnecessary risk for significant medication errors. Though no specific threshold exists for what is considered a 'concentrated sodium chloride' product by the joint commission, the decision must be made by the hospital P&T committee. Lower concentrations (3% and 5% saline) will most likely still exceed the threshold.

However, these products can be stocked on the patient unit if 1) they are in their most ready to administer form and 2) if their absence places patients at risk for delays in therapy.

Or, 8.4% sodium bicarbonate could be considered. In most EDs it's already readily accessible from Pyxis/Omnicells.  It's been theorized that administering an equiosmolar load of hyperosmolar treatment to TBI patients should achieve the same ICP reduction. And there is some evidence to suggest this may in fact be the case. (Bourdeaux CP, Brown JM. Randomized controlled trial comparing the effect of 8.4% sodium bicarbonate and 5% sodium chloride on raised intracranial pressure after traumatic brain injury. Neurocrit Care. 2011 Aug;15(1):42-5)

Not to suggest that one should replace the other, but in an emergent situation, if the pharmacy is not able to deliver the hypertonic sodium chloride in a timely fashion, an equiosmolar dose of sodium bicarbonate could be considered.

Friday, September 14, 2012


I was recently asked what I thought about FEIBA as a reversal agent for warfarin or dabigatran related bleeds.  At first, I was as excited about FEIBA as the individuals who asked me my opinion of the drug for this use. A prothombin complex concentrate that had active factor VII? In effect, a four factor PCC product available in the US? A small study suggesting it effectively lowers supratherapeutic INRs?[1] Sign me up!

But then I started to wonder why save for a small study published back in 20091, everything that I’ve either read or hear of focuses on either rFVIIa or 3 factor PCC for warfarin or dabigatran reversal…  Has FEIBA been blown over?

Short answer: no it hasn’t.

Long answer: Thrombosis risk.

FEIBA is an acronym for factor eight inhibitor bypassing activity. FEIBA belongs to a class of PCCs referred to as four factor active prothrombin complex concentrate. It’s considered active since it contains activated factor VII and a mix of active and inactive (mostly) factors II, IX and X.[2] Interestingly, its hemostatic effects are associated with its factor X and prothrombin content, not factor VIIa.[3] Three factor PCCs on the other hand (in the US, most of us are familiar with BebulinVH or ProfilnineSD), are inactive PCCs.  They’re composed of factor II, IX and X, all inactive.[4]

At this point, I thought that of course FEIBA is going to work better than 3 factor PCC! Why would I want to give an inactivate PCC to a patient that has warfarin or dabigatran on board that will continue to prevent their activation?

The safety experience with FEIBA sheds light on part of the problem. True, between 4 and 9 thrombotic events occur per every 100,000 FEIBA infusions in the hemophilia population.[5] Using FEIBA for its labeled use is relatively safe. However, using it as a warfarin or dabigatran reversal agent is not its intended purpose. It wasn’t created for this indication, nor appropriately assessed for appropriate dosing, efficacy and safety. Not to say there isn’t a role for drugs like FEIBA or other PCCs off-label; but we must understand as best as possible the risks and benefits.

Thrombotic complications like VTE, DIC, MI, PE, etc., are of concern when administering PCCs.[6] Patients at risk of excessive thrombin generation and thrombosis from PCCs are those who are of 1) advanced age, and 2) have athleroscloerotic disease.[7] Equally, there are inherent risks involved with the product itself: prothrombin content is the major determinant of excessive thrombin generation in PCCs.[8] FEIBA, has a high content of prothrombin as well as thrombin. In addition, the balance between procoagulant and anticoagulant activity plays a large role in thrombosis related to FEIBA and PCCs.  Going back to the comparison between 3 factor PCC and FEIBA once again, other 3 factor and 4 factor PCCs contain either heparin or a combination of Protein C, Protein S and Protein Z to balance procoagulation and anticoagulation.[6,9] FEIBA does not contain an anticoagulant.

Lets put it all together.

In a patient with a supratherapeutic INR from warfarin and ICH, their ability to activate factors II, VII, IX and X are severely impaired.  Importantly, warfarin reduces Protein C, S and Z concentrations as well as these active coagulation factors.  Ultimately, administering FEIBA will certainly replace the inactive factors, but place the patient at high risk of thrombosis because, as mentioned above, it contains no anticoagulant and its prothrombin content.  Off label use is likely to increase incidence of thrombotic events, similar to what has been observed with rFVIIa.[10,11,12] Not forgetting the reason the patient required anticoagulation in the first place for some previous thrombotic event, and the patient is likely elderly and has athlerosclerotic disease (all increasing risk of thrombosis).  In the case of a similar patient with ICH on dabigatran, FEIBA will replace some active factor II, but the same risks of thrombosis as with any other patient on warfarin still exist.  Certainly three factor PCCs could pose a similar risk, albeit presumably lower (we need data). But the risk/benefit seems to favor three factor vs FEIBA to me.

So what do I think of FEIBA? Since that was the whole question.

I think when matched up with the other 3 factor PCCs, FEIBA seems to pose a higher risk of thrombosis.  FEIBA will stop bleeding but at the cost of giving the patient an MI, VTE or causing DIC.  Of all the products, Bebulin should have the best efficacy/safety balance since it contains inactive factor II and heparin.  Remember though, these products are being used not for their intended purposes; square pegs and round holes.

1. Wojcik C, Schymik ML, Cure EG. Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarin-induced coagulopathy. Int J Emerg Med (2009) 2:217–225
2. Gallistl S, Cvirn G, Leschnik B, Muntean W. Respective roles of factors II, VII, IX, and X in the procoagulant activity of FEIBA. Blood Coagulation and Fibrinolysis 2002, 13:653–655
3. Turecek PL, Váradi K, Gritsch H, Schwarz HP. FEIBA: mode of action. Haemophilia 2004;10(Suppl 2):3–9
4. Patanwala AE, Acquisto NM, Erstad BL Prothrombin Complex Concentrate for Critical Bleeding. Ann Pharmacother 2011;45:990-9
5.Aledort LM. Factor VIII inhibitor bypassing activity (FEIBA) – addressing safety issues. Haemophilia (2008), 14, 39–43
6.Sørensen et al. Clinical review: Prothrombin complex concentrates - evaluation of safety and thrombogenicity. Critical Care 2011, 15:201-10
7. Cromwell C, Aledort LM. FEIBA: A Prohemostatic Agent. Semin Thromb Hemost 2012;38:265–267
8. S. Gallistl et al. Roles of FII, FVII, FIX and FX in activity of FEIBA. Blood Coagulation and Fibrinolysis 2002;13(7):653-55
9. Key NS, Negrier C. Coagulation factor concentrates: past, present, and future. Lancet 2007; 370: 439–48
10. O’Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006; 295: 293–8
11. Yank V, Tuohy V, Logan AC, et al. Effectiveness of off-label use of recombinant factor VIIa. Ann Intern Med. 2011;154:529-540
12. Levi M, Levy JH, Andersen HF, Truloff D. Safety of Recombinant Activated Factor VII in Randomized Clinical Trials. N Engl J Med 2010;363:1791-800

I.          Zareh M, Davis A, Henderson S. Reversal of Warfarin-Induced Hemorrhage in the Emergency Department. West J Emerg Med. 2011;12(4):386–392
II.         van Ryn et al. Effect of dabigatran on coagulation assays and reversal strategies. Thromb Haemost 2010; 103: 1116–1127
III.       Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011 Oct 4;124(14):1573-9. Epub 2011 Sep 6.
IV.        Hellstern P. Production and composition of prothrombin complex concentrates: correlation between composition and therapeutic efficiency. Thromb Res. 1999;95(4 suppl 1):S7-S12.
V.         Lusher JM. Thrombogenicity associated with factor IX complex concentrates. Semin Hematol. 1991;28(3 suppl 6):3-5.
VI.        Kohler M. Thrombogenicity of prothrombin complex concentrates. Thromb Res. 1999;95(4 suppl 1):S13-S17.

Thursday, September 6, 2012


Welcome to the ED PharmD blog!

My name is Craig Cocchio and I am an emergency medicine pharmacist.  I've created this blog to accomplish a few goals.
1- To describe the activities of pharmacists practicing in the emergency department
2- Share the experiences and knowledge of an established emergency medicine pharmacy team
3- Create an open forum for discussion of all things emergency medicine, of course, focusing on medications
4- Complement the various (and excellent) emergency medicine and toxicology blogs out there

I'll reflect these goals by filling the pages and posts of this blog with everything from pharmacy pearls, new and old drug reviews to medication safety musings.

Craig Cocchio, Pharm.D., BCPS
Clinical Assistant Professor of Pharmacy Practice, Emergency Medicine
Residency Program Director - Emergency Medicine Pharmacy PGY-2
Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey
Robert Wood Johnson University Hospital

Featured Post

Giapreza - A Closer Look at the Pharmacology of Ang2

Angiotensin-II (Ang2) is now an FDA approved vasopressor. With this new addition to the available options, experts are combing over the ...