Dilution Tranexamic Acid

Tranexamic acid (CYKLOKAPRON®)

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Usual Diluents

NS, D5W, others (see below)

Standard Dilutions [Amount of drug] [Infusion volume] [Infusion rate]

[Beta] monograph - future revisions possible.
-----------------------------
Update: Oct 14,2014.
[Usual dose: 1-2 grams] [ 50 - 250 mL] [ Max 100 mg/min]
[1000 mg] [50-100mL] [10 to 30 minutes or as directed]
[2000 mg] [50-250 mL] [20 minutes or longer]
Note: Repeated doses must be adjusted for renal function.
Protocols also exist for continuous infusions after a loading dose
e.g. 1 to 4.5 mg/kg/hr

Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; October 14, 2014.
-----------------------------

Previous monograph:
Usual concentration: 10-20 mg/ml^1,2
[1 gram] [100 ml] [max 50 mg/min - as directed]
[2 grams] [100 ml] [max 50 mg/min - as directed]
(Some sources indicate a maximum infusion rate of 100mg/min)³
"To prevent drug-induced hypotension, intravenous application should be slow, not exceeding 100mg/min."

Note: Many of the Indications listed below are considered 'unlabeled' uses in the U.S.
Direct quotes from 'Pfizer Canada', and 'Pfizer New Zealand' are included below:

"Cyklokapron solution for injection is intended for intravenous administration (intravenous injection and infusion). The recommended rate of administration is 50 mg/min. Undiluted Cyklokapron solution for injection (100 mg/mL) may be administered at 0.5 ml/min by intravenous infusion or intravenous injection. Solutions diluted to 1% tranexamic acid (i.e., 1 g in 100 mL or 10 mg/mL), may be administered at 5 mL/min or solutions diluted to 2% tranexamic acid, may be administered at 2.5 mL/min by intravenous infusion."²

"For adult cardiac surgery, a loading dose is administered prior to surgery followed by a prolonged infusion during surgery. The recommended rate of prolonged infusion is 4.5 mg/kg patient body weight per hour. For a patient who weighs 100 kg, undiluted Cyklokapron solution for injection (100 mg/mL) may be administered at 4.5 mL/hour. Solutions diluted to 1% tranexamic acid may be administered at 45 mL/hour and solutions diluted to 2% tranexamic acid may be administered at 22.5 mL/hour."²

Stability / Miscellaneous

Mechanism of Action¹
Tranexamic acid is a competitive inhibitor of plasminogen activation and at much higher concentrations a noncompetitive inhibitor of plasmin, thus implying that tranexamic acid interferes with the fibrinolytic process in the same way as aminocaproic acid. Tranexamic acid is about 10 times more potent in vitro than aminocaproic acid.

Tranexamic acid binds considerably more strongly than aminocaproic acid to both the strong and weak sites of the plasminogen molecule in a ratio corresponding to the difference in potency between the compounds.

Tranexamic acid in a concentration of 1 mg/mL does not aggregate platelets in vitro. Tranexamic acid in concentrations up to 10 mg/mL blood has no influence on the platelet count, the coagulation time or various coagulation factors in whole blood or citrated blood in normal subjects. On the other hand tranexamic acid in concentrations of 10 mg/mL and 1 mg/mL blood prolongs the thrombin time.

DOSAGE AND ADMINISTRATION²
Intravenous administration is necessary only if it is difficult to give adequate doses by mouth. The recommended standard dose is 2-3 tablets of 0.5g, or 5-10mL by slow intravenous injection at a rate of 1mL/minute, two to three times daily. For the indications listed below the following doses are recommended.

Prostatectomy
5-10mL by slow intravenous injection every eight hours (the first injection being given during the operation) for the first three days after surgery; thereafter 1-1.5g orally three to four times daily until macroscopic hematuria is no longer present.

Dental Surgery in Patients with Coagulopathies
Immediately before surgery, 10mg per kg body-weight should be given intravenously. After surgery, 25mg per kg body-weight are given orally three to four times daily for six to eight days. It may be necessary to administer coagulation factor concentrate. This decision should be made after consulting a specialist on coagulation.

General Fibrinolysis
1 gram (10mL) by slow intravenous injection three to four times daily. With fibrinolysis in conjunction with diagnosed, increased intravascular coagulation, i.e., defibrillation syndrome, an anticoagulant such as heparin may be given with caution.

Intravenous Administration-----------------
Adult Cardiac Surgery
After induction of anesthesia and prior to skin incision, administer a pre-surgical loading dose of 15 mg/kg tranexamic acid, followed by infusion of 4.5 mg/kg/hour for the duration of surgery. 0.6 mg/kg of this infusion dose may be added in the priming volume of the heart-lung machine.²

Alternatively:^4,5
30 mg/kg IV over 30 minutes initially prior to incision, then 16 mg/kg/hr IV until closure. Add an additional 2 mg/kg to bypass priming solution.

10 - 15 mg/kg IV over 10 - 15 minutes, then 1 - 2 mg/kg/hr. May add 2 - 2.5 mg/kg to bypass priming solution.

Adult Total Knee Arthroplasty
Administration of 15 mg/kg tranexamic acid prior to release of the tourniquet followed by repeat bolus injection of 15 mg/kg at 8 hourly intervals after the initial dose. The last bolus dose is to be administered 16 hours after the initial dose.²

Alternatively:^4,5
10 mg/kg IV over 30 minutes before tourniquet deflation, followed by 10 mg/kg IV given 3 hours after the first dose.

10 mg/kg IV given 30 minutes before tourniquet release, then 1 mg/kg/hr IV beginning at the end of surgery and continuing for 6 hours afterward.

Adult Total Hip Arthroplasty
Administration of 15mg/kg tranexamic acid immediately prior to skin incision, followed by a repeat bolus of 15 mg/kg at 8 hourly intervals after the initial dose. The last bolus dose is to be administered 16 hours after the initial dose.²

Immediately before tooth extraction in patients with hemophilia⁶, administer 10 mg per kg body weight of CYKLOKAPRON intravenously together with replacement therapy (see PRECAUTIONS). Following tooth extraction, intravenous therapy, at a dose of 10 mg per kg body weight three to four times daily, may be used for 2 to 8 days.

Note: For patients with moderate to severe impaired renal function, the following dosages are recommended:

Serum Creatinine (µmol/L)	Tranexamic Acid I.V. Dosage
120 to 250 (1.36 to 2.83 mg/dL)	10 mg/kg BID
250 to 500 (2.83 to 5.66 mg/dL)	10 mg/kg daily
>500 (>5.66 mg/dL)	10 mg/kg every 48 hours or 5 mg/kg every 24 hours

Use in Special Populations
Elderly patients
No reduction in dosage is necessary, unless there is evidence of renal failure.

Use in Renal Impairment²
Adult Cardiac Surgery - Dosage adjustment for Cyklokapron solution for injection

eGFR (mL/min/1.73m2)	Loading	Prime	Infusion
60-89	15 mg/kg	0.6 mg/kg	3.75 mg/kg/h
30- 59	15 mg/kg	0.6 mg/kg	2.5 mg/kg/h
< 29	15 mg/kg	0.6 mg/kg	1.25 mg/kg/h

Adult Total Knee Arthroplasty eGFR (mL/min/1.73m2)	Dosage adjustment for Cyklokapron solution for injection
60-89	Administration of 15 mg/kg tranexamic acid immediately prior to tourniquet release followed by a repeat bolus of 11.25 mg/kg at 8 hourly intervals after the initial dose. The last bolus dose is to be administered 16 hours after the initial dose.
30-59	Administration of 15 mg/kg tranexamic acid immediately prior to tourniquet release followed by a repeat bolus of 8.4 mg/kg at 8 hourly intervals after the initial dose. The last bolus dose is to be administered 16 hours after the initial dose.
<29	Administration of 15 mg/kg tranexamic acid immediately prior to tourniquet release followed by a repeat bolus of 6.3 mg/kg at 8 hourly intervals after the initial dose. The last bolus dose is to be administered 16 hours after the initial dose.

Adult Total Hip Arthroplasty eGFR (mL/min/1.73m2)	Dosage adjustment for Cyklokapron solution for injection
60-89	Administration of 15 mg/kg tranexamic acid immediately prior to skin incision followed by a repeat bolus of 11.25 mg/kg at 8 hourly intervals after the initial dose. The last bolus dose is to be administered 16 hours after the initial dose.
30-59	Administration of 15 mg/kg tranexamic acid immediately prior to skin incision followed by a repeat bolus of 8.4 mg/kg at 8 hourly intervals after the initial dose. The last bolus dose is to be administered 16 hours after the initial dose.
< 29	Administration of 15 mg/kg tranexamic acid immediately prior to skin incision followed by a repeat bolus of 6.3 mg/kg at 8 hourly intervals after the initial dose. The last bolus dose is to be administered 16 hours after the initial dose.

Incompatibilities²
CYKLOKAPRON solution for injection should NOT be mixed with blood for transfusion or infusion solutions containing penicillin.

Compatibilities & Stability:
Cyklokapron solution for injection can be mixed with the following solutions:

0.9% NaCl solution
D5W
Dextran 40
Dextran 70
Ringer’s solution

The required volume of Cyklokapron solution for injection may be added to the chosen infusion solution to achieve final concentrations of 1 or 2 g in 100 mL (10 or 20 mg/mL, 1% or 2%). The mixture should be used immediately after preparation. If storage is necessary, the mixture should be stored at 2 - 8^oC for a maximum of 24 hours. Mixture not used within 24 hours of preparation, should be discarded.

Storage
Solution for injection: Store below 25°C. Do not freeze. Protect from light. This product does not contain antimicrobial agents. It is for single use in one patient only. Any unused product should be discarded.

SUPPLIED:
CYKLOKAPRON 1000 mg/10 mL solution for injection is supplied as packs of 1 x 10 mL ampule and 10 x 10 mL ampules.

References:
1] PRODUCT MONOGRAPH - CYKLOKAPRON. Pfizer Canada Inc.17300 Trans-Canada Highway, Kirkland, Quebec, H9J 2M5. Date of Preparation: December 2, 2010. Accessed April 2013.

2] PRODUCT MONOGRAPH -CYKLOKAPRON® Tranexamic acid. 500 mg tablets, 500 mg/5 mL & 1000 mg/10 mL solution for injection. Pfizer New Zealand Ltd. P O Box 3998. Auckland, New Zealand, 1140. DATE OF PREPARATION: 25 February 2013. Accessed April 2013.

3] Seeber P, Shander A. Basics of Blood Management. 2nd ed. Chichester, UK: Wiley-Blackwell; 2013.

4] Lacy CF, Armstrong LL, Goldman MP, Lance LL, eds. Lexi-Comp Online. 14th ed. Hudson, OH: Lexi-Comp; 2013.

5] ASHP: Current Shortages - Bulletin. Accessed April 2013.

6] PRODUCT MONOGRAPH: CYKLOKAPRON Injection 100 mg/mL. Pfizer Injectables: Distributed by Pharmacia and Upjohn Company - Division of Pfizer Inc. New York, NY 10017. Revised Jan 2011. Accessed April 2013.

Additional reading:
Coffey A, Pittmam J, Halbrook H, Fehrenbacher J, Beckman D, Hormuth D. The use of tranexamic acid to reduce postoperative bleeding following cardiac surgery: a double-blind randomized trial. Am Surg. 1995 Jul;61(7):566-8. [" The treatment group received tranexamic acid, given intravenously as 10 mg/kg over 30 minutes, at the time of skin incision, followed by a 1 mg/kg/hr infusion for 12 hours. "]