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Tranexamic Acid

Pronunciation

Pronunciation

(tran eks AM ik AS id)

Index Terms

  • Cyklokapron

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Cyklokapron: 100 mg/mL (10 mL)

Generic: 100 mg/mL (10 mL)

Solution, Intravenous [preservative free]:

Generic: 100 mg/mL (10 mL)

Tablet, Oral:

Lysteda: 650 mg

Generic: 650 mg

Brand Names: U.S.

  • Cyklokapron
  • Lysteda

Pharmacologic Category

  • Antifibrinolytic Agent
  • Antihemophilic Agent
  • Hemostatic Agent
  • Lysine Analog

Pharmacology

Forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; it also inhibits the proteolytic activity of plasmin

With reduction in plasmin activity, tranexamic acid also reduces activation of complement and consumption of C1 esterase inhibitor (C1-INH), thereby decreasing inflammation associated with hereditary angioedema.

Distribution

Vd: 9-27 L

Excretion

Urine (>95% as unchanged drug)

Time to Peak

Oral: ~3 hours

Half-Life Elimination

~2-11 hours

Protein Binding

~3%, primarily to plasminogen

Special Populations: Renal Function Impairment

Following administration of a single IV injection, the 24-hour urinary fractions of tranexamic acid with serum creatinine concentrations 1.4 to 2.8, 2.8 to 5.7, and more than 5.7 mg/dL were 51%, 39%, and 19%, respectively. The 24-hour plasma concentrations demonstrated a direct relationship to degree of renal impairment.

Special Populations: Children

The Cmax and AUC values after a single oral dose of 1300 mg in adolescent females were 20% to 25% less than those in adult females given the same dose.

Use: Labeled Indications

Tooth extraction in patients with hemophilia (injection): Short-term use (2 to 8 days) in hemophilia patients to reduce or prevent hemorrhage and reduce need for replacement therapy during and following tooth extraction

Cyclic heavy menstrual bleeding (oral): Treatment of cyclic heavy menstrual bleeding

Use: Unlabeled

Trauma-associated hemorrhage; Traumatic hyphema; Bleeding associated with dental procedures in patients on oral anticoagulant therapy (topical mouth rinse); prevention of bleeding associated with cardiac surgery, craniosynostosis surgery, extracorporeal membrane oxygenation (ECMO), orthognathic surgery, spinal surgery (eg, spinal fusion), hip fracture surgery, total hip replacement surgery, total knee replacement surgery, or transurethral prostatectomy; reduction of blood loss associated with cesarean delivery; hereditary angioedema (long-term prophylaxis)

Contraindications

Injection: Hypersensitivity to tranexamic acid or any component of the formulation; acquired defective color vision; active intravascular clotting; subarachnoid hemorrhage

Oral: Hypersensitivity to tranexamic acid or any component of the formulation; active thromboembolic disease (eg, cerebral thrombosis, DVT, or PE); history of thrombosis or thromboembolism, including retinal vein or retinal artery occlusion; intrinsic risk of thrombosis or thromboembolism (eg, hypercoagulopathy, thrombogenic cardiac rhythm disease, thrombogenic valvular disease); concurrent use of combination hormonal contraception

Dosage

Oral:

Children ≥12 years, Adolescents, and Adults: Menorrhagia: 1300 mg 3 times daily (3900 mg daily) for up to 5 days during monthly menstruation

Children:

Hereditary angioedema (HAE) (off-label use):

Long-term prophylaxis: 20-40 mg/kg/day in 2-3 divided doses (maximum dose: 3000 mg daily) (Farkas 2007) or 50 mg/kg/day (or 1000-2000 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: 20-40 mg/kg/day in 2-3 divided doses (maximum dose: 3000 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).

Children and Adults: Traumatic hyphema (off-label use): 25 mg/kg administered 3 times daily for 5-7 days (Rahmani, 1999; Vangsted, 1983; Varnek, 1980). Note: This same regimen may also be used for secondary hemorrhage after an initial traumatic hyphema event.

Adults:

Hereditary angioedema (HAE) (off-label use):

Long-term prophylaxis: 1000-1500 mg 2-3 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 2-3 times daily (Bowen 2004)

Short-term prophylaxis (eg, for dental work): 75 mg/kg/day divided 2-3 times daily for 5 days before and 2 days after the event (Bowen 2004) or 1000 mg 4 times daily for 48 hours before and after procedure (Gompels 2005)

Treatment of acute HAE attack: 25 mg/kg/dose (maximum single dose: 1000 mg) every 3-4 hours (maximum: 75 mg/kg/day) (Bowen 2004) or 1000 mg 4 times daily for 48 hours (Gompels 2005)

Prevention of dental procedure bleeding in patients on oral anticoagulant therapy (off-label use): Oral rinse: 4.8% solution: Hold 10 mL in mouth and rinse for 2 minutes then spit out. Repeat 4 times daily for 2 days after procedure. Note: Patient should not eat or drink for 1 hour after using oral rinse (Carter 2003).

Transurethral prostatectomy, blood loss reduction (off-label use): 2000 mg 3 times daily on the operative and first postoperative day (Rannikko 2004)

IV:

Children:

Prevention of perioperative bleeding associated with cardiac surgery (off-label use): 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): 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)

Children and Adolescents:

Prevention of perioperative bleeding associated with spinal surgery (eg, spinal fusion) (off-label use): 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)

Children and Adults: Tooth extraction in patients with hemophilia (in combination with appropriate factor replacement therapy): 10 mg/kg immediately before surgery, then 10 mg/kg/dose 3-4 times daily; may be used for 2-8 days

Adults:

Elective cesarean section, blood loss reduction (off-label use): 1000 mg over 5 minutes at least 10 minutes prior to skin incision (Gungorduk 2011)

Hereditary angioedema (HAE), treatment of acute attack (off-label use): 25 mg/kg/dose (maximum single dose: 1000 mg) every 3-4 hours (maximum: 75 mg/kg/day) (Bowen 2004) or 1000 mg 4 times daily for 48 hours (Gompels 2005)

Hip fracture surgery, blood conservation (off-label use): 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.

Orthognathic surgery, blood loss reduction (off-label use): 20 mg/kg over 15 minutes prior to incision (Choi 2009)

Perioperative blood loss reduction in bilateral total knee arthroplasty (off-label use):

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):

Intra- and postoperative regimen: 10 mg/kg at least 10 to 30 minutes prior to tourniquet release (deflation) and 10 mg/kg at 3 hours after the first dose (Alvarez 2008; Camarasa 2006; Maniar 2012). Instead of the second dose, a postoperative infusion may be administered at 1 mg/kg/hour for 6 hours (Alvarez 2008).

Pre- and intraoperative regimen: 10 mg/kg at least 20 minutes or immediately before tourniquet inflation and repeated at least 15 minutes prior to deflation or immediately after release of tourniquet (Lozano 2008; Maniar 2012).

Pre-, intra-, and postoperative regimen: 10 mg/kg at least 20 minutes before tourniquet inflation, repeated at least 15 minutes prior to deflation and postoperatively at 3 hours after the second dose (Maniar 2012).

Prevention of perioperative bleeding associated with cardiac surgery (off-label use): Loading dose of 30 mg/kg over 30 minutes (total loading dose includes a test dose administered over the first 10 minutes followed by the remainder of dose) prior to incision, followed by 16 mg/kg/hour until sternal closure; add an additional 2 mg/kg to cardiopulmonary bypass circuit (Fergusson 2008)

or

Loading dose of 10 mg/kg over 20 minutes prior to incision followed by 2 mg/kg/hour continued for 2 hours after transfer to ICU; add a prime dose of 50 mg for a 2.5 L cardiopulmonary bypass circuit; maintenance infusion adjusted for renal insufficiency (Nuttall 2008)

or

Loading dose of 10-15 mg/kg over 10-15 minutes, followed by 1-1.5 mg/kg/hour. The authors suggest adding 2–2.5 mg/kg to cardiopulmonary bypass circuit; however, amounts have varied widely in clinical trials (Gravlee 2008).

Prevention of perioperative bleeding associated with spinal surgery (eg, spinal fusion) (off-label use): 2000 mg over 20 minutes prior to incision followed by 100 mg/hour during surgery and for 5 hours postoperatively (Elwatidy 2008) or 10 mg/kg prior to incision followed by 1 mg/kg/hour for the remainder of the surgery; discontinue at time of wound closure (Wong 2008)

Total hip replacement surgery, blood conservation (off-label use): 10 to 15 mg/kg (or 1000 mg) administered over 5 to 10 minutes immediately before the operation or 15 minutes before skin incision; the preoperative dose may be followed by 10 mg/kg administered 3 to 12 hours after the operation. Postoperative doses ranged from a 10 mg/kg IV bolus (or 1000 mg) to a 1 mg/kg/hour infusion over 10 hours (Gandhi 2013; Oremus 2014).

Note: Multiple regimens have been evaluated in varying degrees of evidence quality. The regimen listed here reflects the more commonly used dosing based on a number of prospective randomized controlled trials (Johansson 2005; McConnell 2011; Niskanen 2005; Oremus 2014). Metaanalyses have also been conducted demonstrating significant reduction in blood loss perioperatively without an increased risk of thromboembolic events (Gandhi 2013; Sukeik 2011; Zhou 2013). The use of intra-articular tranexamic acid (ie, 1000 mg/50 mL of NaCl 0.9% sprayed into the wound at the end of the procedure) has also been evaluated demonstrating effectiveness (Alshryda 2014a; Alshryda 2014b).

Trauma-associated hemorrhage (off-label use): Loading dose: 1000 mg over 10 minutes, followed by 1000 mg over the next 8 hours. Note: Clinical trial included patients with significant hemorrhage (SBP <90 mm Hg, heart rate >110 bpm, or both) or those at risk of significant hemorrhage. Treatment began within 8 hours of injury (CRASH-2 Trial Collaborators 2010).

Dosage adjustment/interval in renal impairment:

IV formulation:

Tooth extraction in patients with hemophilia:

Serum creatinine 1.36-2.83 mg/dL: Maintenance dose of 10 mg/kg/dose twice daily

Serum creatinine 2.83-5.66 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 1.6-3.3 mg/dL: Reduce maintenance infusion to 1.5 mg/kg/hour (based on a 25% reduction from 2 mg/kg/hour)

Serum creatinine 3.3-6.6 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: Cyclic heavy menstrual bleeding:

Serum creatinine >1.4-2.8 mg/dL: 1300 mg twice daily (2600 mg daily) for up to 5 days

Serum creatinine 2.9-5.7 mg/dL: 1300 mg once daily for up to 5 days

Serum creatinine >5.7 mg/dL: 650 mg once daily for up to 5 days

Dosage adjustment in hepatic impairment: No dosage adjustment necessary.

Reconstitution

Tranexamic acid doses may be diluted in 50 to 250 mL of NS or D5W (Trissels 2015). According to the manufacturer, tranexamic acid may be mixed with most solutions for infusion such as electrolyte solutions, carbohydrate solutions, amino acid solutions, and dextran solutions.

Extemporaneously Prepared

A 5% (50 mg/mL) oral solution may be prepared by diluting 5 mL of 10% (100 mg/mL) tranexamic acid injection with 5 mL sterile water. Label “refrigerate”. Stable for 5 days refrigerated.

A 25 mg/mL oral suspension may be prepared with tablets. Place one 500 mg tablet (strength not available in U.S.) into 20 mL water and let stand ~2-5 minutes. Begin stirring and continue until the tablet is completely disintegrated, forming a fine particulate suspension (dispersion time for each 500 mg tablet is ~2-5 minutes). Administer immediately after preparation.

Lam MS, "Extemporaneous Compounding of Oral Liquid Dosage Formulations and Alternative Drug Delivery Methods for Anticancer Drugs," Pharmacotherapy 2011, 31(2):164-92.21275495

Administration

Injection: May be administered by direct IV injection at a maximum rate of 100 mg/minute; use plastic syringe only for IV push

In general, tranexamic acid loading doses are diluted in 50 to 250 mL of D5W or NS and are administered over 5 to 30 minutes.

Oral: Administer without regard to meals. Swallow tablet whole; do not break, chew, or crush.

Compatibility

Compatible with dextrose, saline, electrolyte, amino acid, or dextran solutions, heparin; incompatible with solutions containing penicillin.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Injection: According to the manufacturer, the diluted mixture may be stored for up to 4 hours at room temperature. However, solutions prepared in NS are chemically stable for up to 180 days at room temperature (McCluskey 2014 ). Solutions prepared in D5W should be used within the same day of preparation (Trissels 2015). In another study, tranexamic acid (undiluted) was shown to be chemically stable for up to 12 weeks when stored at -20°C, 4°C, 22°C, and 50°C; freezing tranexamic acid in original ampuls is unacceptable due to cracking of the ampuls (de Guzman 2013). Freezing tranexamic acid in original vials has not been evaluated.

Drug Interactions

Anti-inhibitor Coagulant Complex (Human): Antifibrinolytic Agents may enhance the thrombogenic effect of Anti-inhibitor Coagulant Complex (Human). Avoid combination

Contraceptives (Estrogens): May enhance the thrombogenic effect of Tranexamic Acid. Avoid combination

Contraceptives (Progestins): May enhance the thrombogenic effect of Tranexamic Acid. Avoid combination

Fibrinogen Concentrate (Human): Antifibrinolytic Agents may enhance the adverse/toxic effect of Fibrinogen Concentrate (Human). Specifically, the risk for thrombosis may be increased. Fibrinogen Concentrate (Human) may enhance the adverse/toxic effect of Antifibrinolytic Agents. Specifically, the risk for thrombosis may be increased. Monitor therapy

Tretinoin (Systemic): May enhance the thrombogenic effect of Antifibrinolytic Agents. Monitor therapy

Adverse Reactions

Injection: Frequency not defined:

Cardiovascular: Hypotension (with rapid IV injection)

Central nervous system: Giddiness

Dermatologic: Allergic dermatitis

Endocrine & metabolic: Unusual menstrual discomfort

Gastrointestinal: Diarrhea, nausea, vomiting

Ocular: Blurred vision

Oral:

>10%:

Central nervous system: Headache (50%)

Gastrointestinal: Abdominal pain (20%)

Neuromuscular & skeletal: Back pain (21%), muscle pain (11%)

Respiratory: Nasal/sinus symptoms (25%)

1% to 10%:

Central nervous system: Fatigue (5%)

Hematologic: Anemia (6%)

Neuromuscular & skeletal: Arthralgia (7%), muscle cramps/spasms (7%)

All formulations: <1% (Limited to important or life-threatening): Allergic skin reaction, anaphylactic shock, anaphylactoid reactions, cerebral thrombosis, deep vein thrombosis (DVT), diarrhea, dizziness, nausea, pulmonary embolism, renal cortical necrosis, retinal artery/vein obstruction, seizure, ureteral obstruction, visual disturbances (including impaired color vision and loss), vomiting

Warnings/Precautions

Concerns related to adverse effects:

• 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 have rarely been reported. A case of anaphylactic shock has also been reported in a patient who received an IV bolus of tranexamic acid.

• 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 since this would prohibit monitoring one endpoint as a measure of ophthalmic toxicity. 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 these patients. 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 physician experienced in treating this disorder.

• Renal impairment: Use with caution in patients with renal impairment; dosage modification may be necessary.

• Subarachnoid hemorrhage: Use oral formulation with caution in patients with subarachnoid hemorrhage; cerebral edema and infarction may occur.

• 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.

Monitoring Parameters

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

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were not 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). Lysteda is not indicated for use in pregnant women.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dyspepsia, back pain, myalgia, arthralgia, rhinitis, muscle cramps, nausea, or diarrhea. Have patient report immediately to prescriber dyspnea, hemoptysis, strength differences from one side to another, difficulty speaking or thinking, change in balance, blurred vision, considerable headache, ecchymosis, hemorrhaging, vision changes, ophthalmalgia, significant eye irritation, edema of extremities, extremity discoloration, painful extremities, angina, intolerable asthenia, severe dizziness, or syncope (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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