Tranexamic Acid

B02A - Antifibrinolytics ATC B02AA02 Small molecule approved 1986 Oral Parenteral Natural product

JFDA label: CYKLOKAPRON TABS

Mechanism of Action

Inhibitor of Plasminogen — Plasminogen inhibitor

Target	Action	Gene / class
Plasminogen efficacy	INHIBITOR	PLG

Indications

Approved

Cyclic heavy menstrual bleeding (oral)

Off-label

Bleeding associated with dental procedures in patients on oral anticoagulant therapy (topical mouth rinse)
Bleeding associated with hip fracture surgery (prevention)
Hereditary angioedema (long-term prophylaxis
Perioperative blood loss in total hip arthroplasty
Perioperative blood loss reduction in bilateral total knee arthroplasty
Perioperative blood loss reduction in unilateral total knee arthroplasty
Post-operative bleeding associated with cervical conization
Postpartum hemorrhage
Reduction of blood loss associated with cesarean delivery
Trauma-associated hemorrhage
Traumatic hyphema
acute treatment)

Contraindications

Source: Lexicomp

Injection, oral: Hypersensitivity to tranexamic acid or any component of the formulation Absolute
Injection: Hypersensitivity to tranexamic acid or any component of the formulation Absolute
acquired defective color vision Absolute
active intravascular clotting Absolute
active thromboembolic disease (eg, cerebral thrombosis, DVT, or PE) Absolute
active thromboembolic disease (eg, deep vein thrombosis, pulmonary embolism, cerebral thrombosis) Absolute
concurrent use of combination hormonal contraception Absolute
history of thrombosis or thromboembolism, including retinal vein or retinal artery occlusion Absolute
history or risk of thrombosis (unless concurrent anticoagulation therapy is possible) Absolute
intrinsic risk of thrombosis or thromboembolism (eg, hypercoagulopathy, thrombogenic cardiac rhythm disease, thrombogenic valvular disease) Absolute
subarachnoid hemorrhage Absolute
subarachnoid hemorrhage Oral: Hypersensitivity to tranexamic acid or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (2)

Very Common Headache

Common Fatigue

Blood and lymphatic system disorders (1)

Common Anemia

Gastrointestinal disorders (1)

Very Common Abdominal pain

Musculoskeletal and connective tissue disorders (5)

Very Common Back pain · musculoskeletal pain

Common Arthralgia · muscle cramps · muscle spasm

Respiratory, thoracic and mediastinal disorders (1)

Very Common Nasal signs and symptoms

Dosing

Source: Lexicomp

Cyclic heavy menstrual bleeding: Oral: Lysteda: 1,300 mg 3 times daily (3,900 mg/day) for up to 5 days during monthly menstruation Cyklokapron [Canadian product]: 1,000 to 1,500 mg 3 to 4 times daily Tooth extraction in patients with hemophilia (in combination with appropriate factor replacement therapy): IV: 10 mg/kg immediately before surgery, then 10 mg/kg 3 to 4 times daily; may be used for 2 to 8 days IV: 10 mg /kg as a single dose 2 hours prior to procedure (in conjunction with Factor VIII and IX); following procedure, administer oral tranexamic acid for 6 to 8 days Oral: Cyklokapron [Canadian product]: 25 mg/kg as a single dose 2 hours prior to procedure, then 25 mg/kg 3 to 4 times daily for 6 to 8 days Off-label uses: Elective cesarean section, blood loss reduction (off-label use): IV: 1,000 mg over 5 minutes at least 10 minutes prior to skin incision (Gungorduk 2011) Hereditary angioedema (HAE) (off-label use): Long-term prophylaxis: Oral: 1,000 to 1,500 mg 2 to 3 times daily; reduce to 500 mg/dose once or twice daily when frequency of attacks reduces (Gompels 2005; Levy 2010) or 25 mg/kg/dose administered 2 to 3 times daily (Bowen 2004) Short-term prophylaxis (eg, for dental work): Oral: 75 mg/kg/day divided 2 to 3 times daily for 5 days before and 2 days after the event (Bowen 2004) or 1,000 mg 4 times daily for 48 hours before and after procedure (Gompels 2005) Treatment of acute HAE attack: Oral, IV: 25 mg/kg/dose (maximum single dose: 1,000 mg) every 3 to 4 hours (maximum: 75 mg/kg/day) (Bowen 2004) or 1,000 mg 4 times daily for 48 hours (Gompels 2005) Hip fracture surgery, blood conservation (off-label use): IV: 15 mg/kg administered at the time of skin incision followed by a second dose (15 mg/kg) 3 hours later (Zufferey 2010). Additional data may be necessary to further define the role of tranexamic acid in this setting. Intracranial hemorrhage associated with thrombolytics (plasminogen-activator) (eg, alteplase, reteplase, or tenecteplase) (off-label use): IV: 10 to 15 mg/kg over 20 minutes (as an alternative to cryoprecipitate); check fibrinogen levels after administration, if fibrinogen Orthognathic surgery, blood loss reduction (off-label use): IV: 20 mg/kg over 15 minutes prior to incision (Choi 2009) Perioperative blood loss reduction in bilateral total knee arthroplasty (off-label use): IV: Three-dose regimen: 10 mg/kg administered as a slow IV infusion 30 minutes before tourniquet deflation for the first operation, 30 minutes before tourniquet deflation for the second operation, and 3 hours after commencement of the second dose (Kim 2014). Two-dose regimen: 10 or 15 mg/kg administered over 10 minutes before deflation of the first tourniquet, with the second dose administered 3 hours after the first dose (MacGillivray 2011). Perioperative blood loss reduction in unilateral total knee arthroplasty (off-label use): IV: Intra- and postoperative regimen: 10 mg/kg at least 10 to 30 minutes prior to tourniquet release (deflation

(For additional information see "Tranexamic acid: Pediatric drug information") Cyclic heavy menstrual bleeding: Children ≥12 years (postmenarche) and Adolescents: Oral: Refer to adult dosing. Hereditary angioedema (HAE) (off-label use): Oral: Long-term prophylaxis: 20 to 40 mg/kg/day in 2 to 3 divided doses (maximum dose: 3,000 mg daily) (Farkas 2007) or 50 mg/kg/day (or 1,000 to 2,000 mg daily; depending on age and size of patient); may consider alternate-day regimen or twice-weekly regimen when frequency of attacks reduces; diarrhea may be a dose-limiting side effect (Gompels 2005) Short-term prophylaxis: 20 to 40 mg/kg/day in 2 to 3 divided doses (maximum dose: 3,000 mg daily) (Farkas 2007) or 500 mg 4 times daily (Gompels 2005). Note: For short-term prophylaxis (eg, dental work), initiate 2-5 days before and continue for 2 days after the procedure (Bowen 2004; Gompels 2005). Prevention of perioperative bleeding associated with cardiac surgery (off-label use): IV: 10 mg/kg given over 30 minutes prior to incision, 10 mg/kg while on cardiopulmonary bypass, and 10 mg/kg administered after protamine reversal (Chauhan 2004a; Chauhan 2004b) or Loading dose of 100 mg/kg over 15 minutes prior to incision, followed by 10 mg/kg/hour infusion (continued until ICU transport); add 100 mg/kg to pump reservoir when cardiopulmonary bypass initiated (Reid, 1997) Prevention of perioperative bleeding associated with craniosynostosis surgery (off-label use): IV: Loading dose of 50 mg/kg over 15 minutes prior to incision, followed by 5 mg/kg/hour (Goobie 2011) or 15 mg/kg over 15 minutes prior to incision, followed by 10 mg/kg/hour until skin closure (Dadure 2011) Prevention of perioperative bleeding associated with spinal surgery (eg, spinal fusion) (off-label use): Children and Adolescents: IV: 10 mg/kg given over 15 minutes prior to incision followed by 1 mg/kg/hour for the remainder of the surgery; discontinue at time of wound closure (Neilipovitz 2001; Verma 2010) or 100 mg/kg over 15 minutes prior to incision followed by 10 mg/kg/hour until skin closure (Sethna 2005) or 30 mg/kg over 20 minutes prior to incision followed by 1 mg/kg/hour during surgery and for 5 hours postoperatively (Elwatidy 2008) Tooth extraction in patients with hemophilia (in combination with appropriate factor replacement therapy): Children and Adolescents: IV: Refer to adult dosing. Traumatic hyphema (off-label use): Oral: Refer to adult dosing.

Refer to adult dosing.

IV formulation: Tooth extraction in patients with hemophilia: Serum creatinine 1.36 to 2.83 mg/dL: Maintenance dose of 10 mg/kg/dose twice daily Serum creatinine 2.83 to 5.66 mg/dL: Maintenance dose of 10 mg/kg/dose once daily Serum creatinine >5.66 mg/dL: Maintenance dose of 10 mg/kg/dose every 48 hours or 5 mg/kg/dose once daily Cardiac surgery (the following dose adjustments have been recommended [Nuttall 2008]): Serum creatinine 1.6 to 3.3 mg/dL: Reduce maintenance infusion to 1.5 mg/kg/hour (based on a 25% reduction from 2 mg/kg/hour) Serum creatinine 3.3 to 6.6 mg/dL: Reduce maintenance infusion to 1 mg/kg/hour (based on a 50% reduction from 2 mg/kg/hour) Serum creatinine >6.6 mg/dL: Reduce maintenance infusion to 0.5 mg/kg/hour (based on a 75% reduction from 2 mg/kg/hour) Oral formulation: Lysteda: Serum creatinine >1.4 to 2.8 mg/dL: 1,300 mg twice daily (2,600 mg/day) for up to 5 days Serum creatinine 2.9 to 5.7 mg/dL: 1,300 mg once daily for up to 5 days Serum creatinine >5.7 mg/dL: 650 mg once daily for up to 5 days Cyklokapron [Canadian product]: Serum creatinine 1.4 to 2.8 mg/dL (120 to 250 micromol/L): 15 mg/kg twice daily Serum creatinine 2.8 to 5.7 mg/dL (250 to 500 micromol/L): 15 mg/kg every 24 hours Serum creatinine ≥5.7 mg/dL (≥500 micromol/L): 15 mg/kg every 48 hours

No dosage adjustment is necessary.

Warnings & Precautions

Source: Lexicomp

CNS depression

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

Hypersensitivity reactions

Severe hypersensitivity reactions, including anaphylaxis or anaphylactoid reaction have been reported.

Ocular effects

Visual defects (eg, color vision change, visual loss) and retinal venous and arterial occlusions have been reported; discontinue treatment if ocular changes occur; prompt ophthalmic examination should be performed by an ophthalmologist. Use of the injection is contraindicated in patients with acquired defective color vision. Ligneous conjunctivitis has been reported with the oral formulation, but resolved upon discontinuation of therapy.

Seizure

Seizures have been reported with use; most often with intraoperative use (eg, open chamber cardiac surgery) and in older patients (Murkin 2010). The mechanism by which tranexamic acid use results in seizures may be secondary to neuronal gamma aminobutyric acid (GABA) inhibition.

Thrombotic events

Venous and arterial thrombosis or thromboembolism, including central retinal artery/vein obstruction, has been reported. Use the injection with caution in patients with thromboembolic disease; oral formulation is contraindicated in patients with a history of or active thromboembolic disease or with an intrinsic risk of thromboembolic events (eg, thrombogenic valvular disease, thrombogenic cardiac rhythm disease, hypercoagulopathy). Concomitant use with certain procoagulant agents (eg, anti-inhibitor coagulant complex/factor IX complex concentrates, oral tretinoin, hormonal contraceptives) may further increase the risk of thrombosis; concurrent use with either the oral or injectable formulation may be contraindicated, not recommended, or to be used with caution.

Ureteral obstruction

Use the injection with caution in patients with upper urinary tract bleeding, ureteral obstruction due to clot formation has been reported. Disease-related concerns:

Disseminated intravascular coagulation (DIC)

Use with extreme caution in patients with DIC requiring antifibrinolytic therapy; patients should be under strict supervision of a health care provider experienced in treating this disorder.

Renal impairment

Use with caution in patients with renal impairment; dosage modification necessary.

Subarachnoid hemorrhage

Use oral formulation with caution in patients with subarachnoid hemorrhage; cerebral edema and infarction may occur. Use of the injection is contraindicated.

Vascular disease

Use with caution in patients with uncorrected cardiovascular or cerebrovascular disease due to the complications of thrombosis. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Pregnancy & Lactation

Pregnancy

FDA category B

Adverse events have not been observed in animal reproduction studies. Tranexamic acid crosses the placenta and concentrations within cord blood are similar to maternal concentrations. Tranexamic acid has been evaluated for the treatment of postpartum hemorrhage (Ducloy-Bouthors 2011; Gungorduk 2011; WOMAN Trial Collaborators 2017). A significant reduction in risk of death due to bleeding was observed when treatment was started within 3 hours of vaginal birth or cesarean section (WOMAN Trial Collaborators 2017). Oral tranexamic acid (Lysteda) is not indicated for use in pregnant women.

Lactation

Avoid

Tranexamic acid is present in breast milk. Concentrations are approximately 1/100th of the maximum maternal serum concentration. Breastfeeding is not recommended by the manufacturer.

Monitoring

Clinical pearl	Ophthalmic examination (visual acuity, color vision, eye-ground, and visual fields) at baseline and regular intervals during the course of therapy in patients being treated for longer than several days; signs/symptoms of hypersensitivity reactions, seizures, thrombotic events, and ureteral obstruction

Chemistry & Properties

Formula	C8H15NO2
Molecular weight	157.21 g/mol
IUPAC name	4-(aminomethyl)cyclohexane-1-carboxylic acid
CAS	701-54-2
PubChem CID	5526
InChIKey	`GYDJEQRTZSCIOI-LJGSYFOKSA-N`
logP	0.84 (XLogP -2.0)
Polar surface area	63.32 Å²
H-bond acceptors / donors	2 / 2
Drug-likeness (QED)	0.62
Lipinski violations	0

SMILES

NC[C@H]1CC[C@H](C(=O)O)CC1

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	1.828 h
Volume of distribution	0.394 L/kg
Protein binding	3.1%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2C9	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OCT1 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (34, DDInter)

Interacting drug	Severity	Management
Anti-inhibitor coagulant complex	major
Carfilzomib	major
Conjugated estrogens	major
Conjugated estrogens (topical)	major
Dienestrol (topical)	major
Diethylstilbestrol	major
Drospirenone	major
Esterified estrogens	major
Estradiol	major
Estradiol (topical)	major
Estramustine	major
Estrone	major
Estrone sulfate	major
Estrone sulfate (topical)	major
Ethinylestradiol	major
Etonogestrel	major
Factor IX Complex (Human)	major
Levonorgestrel	major
Medroxyprogesterone acetate	major
Norethisterone	major
Norgestrel	major
Ospemifene	major
Quinestrol	major
Raloxifene	major
Tamoxifen	major
Toremifene	major
Tretinoin	major
Alteplase	moderate
Anistreplase	moderate
Reteplase	moderate
Streptokinase	moderate
Tenecteplase	moderate
Urokinase	moderate
Ticagrelor	minor

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
CYKLOKAPRON TABS	Tablet 500 mg	50 tab	Khoury Drug Store	7.150
Xenamex 500mg/5ml Solution for Injection	Injection 500 mg/5 ml	10 vial	MS PHARMA/JORDAN	—