In this episode I’ll:
1. Discuss an article about the anticoagulant reversal agent ciraparantag / PER977.
2. Answer the drug information question “How can serum sodium be re-lowered if hyponatremia is corrected too fast?”
3. Share a resource about intranasal medication delivery.
Article
Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban
Lead author: J. E. Ansell
Published in Thrombosis and Haemostasis January 2017
Background
Ciraparantag or PER977 is a broad spectrum anticoagulant reversal agent under fast track review at the FDA.
As I discussed in episode 75, ciraparantag is reported to antagonize the effects of all anticoagulants except warfarin and agratroban – even enoxaparin and fondaparinux. It binds anticoagulants through noncovalent hydrogen bonding and charge–charge interactions.
The authors of this study sought to assess the safety, tolerability and impact on anticoagulation reversal of ciraparantag (PER977) alone and following a 60 mg dose of the oral factor Xa inhibitor edoxaban.
Methods
The study was a double-blind, placebo-controlled trial. 80 healthy patients were given escalating, single IV doses of ciraparantag alone and following a 60 mg oral dose of edoxaban.
Results
Following 60 mg edoxaban, a single IV dose of ciraparantag (100 to 300 mg) demonstrated full reversal of anticoagulation within 10 minutes. This effect was sustained for 24 hours. Fibrin diameter within clots was measured, and this returned to normal within 30 minutes of ciraparantag. Periorbital / facial flushing and a cool sensation occurred in some patients following IV injection of ciraparantag. The primary route of excretion for the metabolite of ciraparatag was renal.
The authors looked for evidence of procoagulant activity from ciraparantag by examining D-dimer, prothrombin fragments, and tissue factor pathway inhibitor levels. No procoagulant effect of ciraparantag was detected.
Conclusion
The authors concluded:
…ciraparantag in healthy subjects is safe and well tolerated with minor, non-dose limiting adverse events. Baseline haemostasis was restored from the anticoagulated state with doses of 100 to 300 mg ciraparantag within 10–30 minutes of administration and sustained for at least 24 hours.
Discussion
The idea of being able to completely reverse medications with ciraparantag that have until now been unreversible is very exciting. There is certainly an unmet clinical need in this area. The potential procoagulant effects of andexanet alfa for reversal of oral factor Xa inhibitors is disturbing. If the lack of procoagulant effect holds up in further trials with ciraparantag it will be the ideal agent for reversing non-warfarin anticoagulants. The only thing I don’t look forward to is learning how much it costs.
I cannot locate any additional trials or information that give any hint on when the FDA will approve ciraparantag. The only clinical trials seem to be phase 1/2 trials in healthy patients. It would seem that at least 1 trial in patients requiring anticoagulant reversal would be needed before FDA approval would be granted.
Drug information question
Q: How can serum sodium be re-lowered if hyponatremia is corrected too fast?
A: With dextrose and desmopressin.
As I discussed in episode 32, serum sodium should not be corrected faster than 9 mEq in the first 24 hours of hyponatremia treatment. The risk of correcting the serum sodium concentration too quickly is osmotic demyelination of the nervous system. This syndrome results in irreversible or partially reversible neurologic damage.
The risk is serious enough that if a patient with hyponatremia has a serum sodium rise greater than 9 mEq in 24 hours (or 18 mEq in 48 hrs), re-lowering of the serum sodium should be considered. This is supported by animal data which show it is effective in preventing osmotic demyelination syndrome.
The regimen to use is 6mL/kg of 5% dextrose in water IV, repeated until the serum sodium rise is back below 9 mEq in 24 hours (or 18 mEq in 48 hours). Desmopressin also is given at a dose of 2 mcg every 6 hours IV or subcutaneously.
Resource
Shoutout to “Pharmacy Cole” for mentioning the resource for this episode in the Pharmacy Nation slack group: intranasal.net. Intranasal.net is a website that aggregates information on the intranasal delivery of medications. Concepts, clinical uses, educational material, a bibliography, and protocols for the intranasal use of medications are found on this website.
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If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.
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