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TRANEXAMIC ACID

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Tranexamic acid is a synthetic amino acid analogue that interferes with the activation of plasminogen to plasmin. This produces an antifibrinolytic effect preventing clot breakdown reducing the risk of bleeding.

Specific Substances

    1) trans-4-(Aminomethyl)cyclohexanecarboxylic acid
    2) Cyclohexanecarboxylic acid, 4-aminomethyl)-, trans-
    3) AMCA
    4) trans-AMCHA
    5) CL-65336
    6) Molecular Formula: C8-H15-N-O2
    7) CAS 1197-18-8
    1.2.1) MOLECULAR FORMULA
    1) C8-H15-NO2 (Prod Info LYSTEDA(TM) oral tablets, 2009; Prod Info CYKLOKAPRON(R) injection, 2008)

Available Forms Sources

    A) FORMS
    1) Tranexamic acid is available as 500 mg tablets and 100 mg/mL intravenous injection (Prod Info CYKLOKAPRON(R) oral tablets, injection, 2005).
    B) USES
    1) Tranexamic acid is indicated for the short-term use (2 to 8 days) to reduce or prevent hemorrhage and to reduce the need for replacement therapy during and following tooth extraction in hemophiliac patients (Prod Info CYKLOKAPRON(R) oral tablets, injection, 2005). Tranexamic acid has also been studied extensively in non-hemophiliacs in an effort to prevent bleeding in patients undergoing cardiac surgery and spinal surgery, and in women with menorrhagia.
    2) In the United Kingdom, the Defence Medical Services analyzed the use of tranexamic acid to minimize deaths from exsanguination following trauma by British troops. In this setting the drug could be safely administered via the intramuscular route. Tranexamic acid may have a role in minimizing deaths due to bleeding in both the military and civilian setting. (Wright, 2014).
    3) As an antifibrinolytic agent, tranexamic has been studied as a potential agent to be used for both the prevention and treatment of postpartum hemorrhage in women following cesarean or vaginal delivery. At present, clinical evidence is lacking as to its efficacy and the benefit:harm ratio has not been determined. The World Health Organization (WHO) only recommends its use in cases in which other measures have failed and suggests that further clinical studies are needed (Sentilhes et al, 2015).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Tranexamic acid is indicated for the short-term use (2 to 8 days) to reduce or prevent hemorrhage and to reduce the need for replacement therapy during and following tooth extraction in hemophiliac patients.
    B) PHARMACOLOGY: Tranexamic acid is a synthetic amino acid analogue that interferes with the activation of plasminogen to plasmin. This produces an antifibrinolytic effect preventing clot breakdown reducing the risk of bleeding.
    C) EPIDEMIOLOGY: Overdoses are rare. Several cases of unintentional administration of tranexamic acid have been reported.
    D) WITH THERAPEUTIC USE
    1) COMMON: Nausea, vomiting, and diarrhea are common occurrences with tranexamic acid therapy. INFREQUENT: Adverse effects that may occur less frequently following therapeutic administration of tranexamic acid include thromboembolism, myocardial infarction, renal cortical necrosis, visual disturbances, headaches and giddiness.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Tranexamic overdose data are limited. Nausea, vomiting, orthostatic hypotension may occur in the event of an overdose.
    2) SEVERE TOXICITY: The major adverse events due to tranexamic acid are the potential thromboembolic events, such as myocardial infarctions, deep vein thrombosis, and pulmonary embolism. Severe pain, seizures, myoclonic twitching of facial muscles, ventricular fibrillation, coma, and death have been reported in patients following unintentional intrathecal administration of tranexamic acid.
    0.2.20) REPRODUCTIVE
    A) Tranexamic acid is classified as FDA pregnancy category B. Tranexamic acid can cross the placenta and has also been shown to be excreted in breast milk.

Laboratory Monitoring

    A) While there are no specific lab tests that will be altered after therapeutic or overdose of tranexamic acid, including coagulation studies, the following would be appropriate to monitor: CBC with differential, platelets, renal function after significant overdose.
    B) Vital signs should be closely observed, as hypotension may occur with therapeutic infusion and overdose.
    C) Look for clinical evidence of thromboembolic complications (e.g. chest pain, shortness of breath, flank pain, extremity pain). Obtain specific studies (e.g. CT, angiography) to evaluate for thromboembolic complications as needed. Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    D) Monitor fluid and electrolyte status in patients with severe vomiting or diarrhea.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Treat patients with hypotension (IV 0.9% NS, dopamine, norepinephrine).
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive; closely monitor neurologic function. Treat severe hypotension (IV 0.9% NS, dopamine, norepinephrine). Treat seizures with benzodiazepines and barbiturates, or with propofol if seizures persist or recur. Look for clinical evidence of thromboembolic complications (eg; chest pain, shortness of breath, flank pain, extremity pain) and use specific studies (eg; CT, angiography) to evaluate for thromboembolic complications.
    a) INTRATHECAL OVERDOSE: Highly neurotoxic. Intrathecal injection has been rapidly lethal. Information is derived from limited case reports and experience with antineoplastic agents. Keep the patient upright and begin aggressive attempts to remove as much drug as possible. Immediately drain at least 20 ml CSF; drainage of up to 70 ml has been tolerated in adults. Follow with CSF exchange (remove serial 20 ml aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline or LR through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 18 to 24 hours). Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis. Aggressive seizure control (benzodiazepines, barbiturates, propofol) may be necessary. Support blood pressure with fluids and pressors as needed. Endotracheal intubation and mechanical ventilation are likely to be needed. Monitor for ventricular dysrhythmias and treat per ACLS guidelines.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal following oral exposure if patient is alert or airway is protected.
    2) HOSPITAL: Consider activated charcoal following oral exposure if patient is alert or airway is protected; decontamination is not indicated following parenteral exposure.
    D) AIRWAY MANAGEMENT
    1) Assess airway; intubation and ventilation may be necessary in a patient unable to protect their airway due to significant CNS depression.
    E) ANTIDOTE
    1) None
    F) SEIZURES
    1) Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients with a minor inadvertent ingestion may be monitored at home.
    2) OBSERVATION CRITERIA: All symptomatic patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve.
    3) ADMISSION CRITERIA: Patients with a deliberate ingestions demonstrating cardiotoxicity, seizure activity, or other persistent neurotoxicity should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Call a Poison Center for assistance in managing patients with severe toxicity, any patient with intrathecal injection, or in whom the diagnosis is unclear.
    H) PITFALLS
    1) When managing a suspected tranexamic acid overdose, the treating physician should be cognizant of the possibility of multi-drug involvement.
    I) PHARMACOKINETICS
    1) Approximately 30% to 50% of an ingested dose of tranexamic acid is absorbed. Tranexamic acid is only minimally bound (approximately 3%) to plasma proteins, primarily plasminogen, at therapeutic concentrations (5 to 10 mcg/mg). The initial volume of distribution for tranexamic acid is approximately 9 to 12 liters. Metabolism is minimal. Following IV administration, about 95% of a dose is excreted unchanged in the urine. The overall renal clearance matches the overall plasma clearance at 110 to 116 mL/min. The elimination half-life of tranexamic acid is about 2 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Thromboembolic events: Includes other agents (e.g. oral contraceptives) or disorders such as a history of deep vein thrombosis, superficial thrombophlebitis, trauma, soft tissue injury, immobility, or cellulitis. Seizures: Head trauma, drug withdrawal, bupropion. Hypotension: Hypovolemia (other causes), antihypertensive agents.
    0.4.6) PARENTERAL EXPOSURE
    A) INTRATHECAL OVERDOSE: Highly neurotoxic. Intrathecal injection has been rapidly lethal. Information is derived from limited case reports and experience with antineoplastic agents. Keep the patient upright and begin aggressive attempts to remove as much drug as possible. Immediately drain at least 20 ml CSF; drainage of up to 70 ml has been tolerated in adults. Follow with CSF exchange (remove serial 20 ml aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline or LR through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 18 to 24 hours). Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis. Aggressive seizure control (benzodiazepines, barbiturates, propofol) may be necessary. Support blood pressure with fluids and pressors as needed. Endotracheal intubation and mechanical ventilation are likely to be needed. Monitor for ventricular dysrhythmias and treat per ACLS guidelines.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Unintentional intrathecal administration of 500 mg tranexamic acid resulted in the development of seizures, refractory ventricular fibrillation, and death in an adult patient.
    B) THERAPEUTIC DOSE: ADULTS AND CHILDREN: ORAL: For hemorrhage prophylaxis in hemophiliacs, 25 mg/kg 3 to 4 times daily for 2 to 8 days following dental extraction surgery OR 25 mg/kg 3 to 4 times daily beginning 1 day prior to surgery. IV: For hemorrhage prophylaxis in hemophiliacs, 10 mg/kg immediately prior to tooth extraction, combined with factor VIII or IX concentrate OR, for those patients unable to take oral medication, 10 mg/kg IV may be administered 3 to 4 times daily postoperatively. NOTE: For patients with moderate to severely impaired renal function, a decreased dose is recommended.

Clinical Effects

Summary Of Exposure

    A) USES: Tranexamic acid is indicated for the short-term use (2 to 8 days) to reduce or prevent hemorrhage and to reduce the need for replacement therapy during and following tooth extraction in hemophiliac patients.
    B) PHARMACOLOGY: Tranexamic acid is a synthetic amino acid analogue that interferes with the activation of plasminogen to plasmin. This produces an antifibrinolytic effect preventing clot breakdown reducing the risk of bleeding.
    C) EPIDEMIOLOGY: Overdoses are rare. Several cases of unintentional administration of tranexamic acid have been reported.
    D) WITH THERAPEUTIC USE
    1) COMMON: Nausea, vomiting, and diarrhea are common occurrences with tranexamic acid therapy. INFREQUENT: Adverse effects that may occur less frequently following therapeutic administration of tranexamic acid include thromboembolism, myocardial infarction, renal cortical necrosis, visual disturbances, headaches and giddiness.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Tranexamic overdose data are limited. Nausea, vomiting, orthostatic hypotension may occur in the event of an overdose.
    2) SEVERE TOXICITY: The major adverse events due to tranexamic acid are the potential thromboembolic events, such as myocardial infarctions, deep vein thrombosis, and pulmonary embolism. Severe pain, seizures, myoclonic twitching of facial muscles, ventricular fibrillation, coma, and death have been reported in patients following unintentional intrathecal administration of tranexamic acid.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) RETINOPATHY: Two cases of central venous stasis retinopathy were reported in women receiving tranexamic acid for severe menorrhagia. Both cases occurred within 1 week of beginning use of tranexamic acid 2 grams/day, and both resolved within 8 to 10 weeks following discontinuation of the therapy and administration of prednisone 60 mg/day and dipyridamole 225 mg/day. No further ophthalmological problems occurred during follow-up (minimum 2 years) (Snir et al, 1990).
    2) CONJUNCTIVITIS: A 25-year-old woman, with Epstein's syndrome, presented with a nine-month history of conjunctivitis, as well as gingival and peritoneal lesions. Her current systemic drug therapy included pindolol, enalapril, indoramin, sotalol, alfacalcidol, erythropoietin, and tranexamic acid. A histological exam of the conjunctival membrane revealed fibrin masses with inflammatory cells. Despite topical ocular therapies that included antibiotics, corticosteroids, cromoglycate, and hyaluronidase, the conjunctivitis persisted. In addition, she also developed bilateral corneal ulcers that only healed after prolonged occlusion. Approximately 5 weeks after discontinuation of all systemic drug therapy, the patient's conjunctivitis completely resolved. Three months later, a rechallenge with tranexamic acid resulted in the recurrence of lesions. Resolution of lesions occurred following cessation of tranexamic acid therapy (Diamond et al, 1991).
    B) WITH POISONING/EXPOSURE
    1) VISUAL IMPAIRMENT: A 56-year-old man, undergoing chronic hemodialysis, developed blindness after receiving tranexamic acid, 2000 mg/day for 27 days, as a hemostat following emergency surgery for a bleeding ulcer of the stomach and duodenum. Approximately 10 days after cessation of tranexamic acid therapy, his vision returned to normal. Four months later, rechallenge with tranexamic acid resulted in a similar impairment of his vision. Since tranexamic acid is primarily renally excreted, it is believed that the patient accumulated an elevated concentration of tranexamic acid, which resulted in his visual impairment (Kitamura et al, 2003).
    C) ANIMAL STUDIES
    1) RETINAL DEGENERATION: Areas of retinal degeneration have occurred in dogs, cats, and rats following oral or intravenous administration of tranexamic acid at doses of 250 to 1600 mg/kg/day (6 to 40 times the recommended human dose), administered over a period of 6 days to 1 year. The incidence of the degeneration varied from 25% to 100% of the animals treated and it appeared to be dose-related (Prod Info CYKLOKAPRON(R) oral tablets, injection, 2005). Some of the lesions appeared to be reversible at lower doses.
    2) RETINAL CHANGES occurred in cats and rabbits with tranexamic acid doses as low as 126 mg/kg/day (approximately 3 times the recommended human dose) following administration over a period of weeks to months (Prod Info CYKLOKAPRON(R) oral tablets, injection, 2005).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) GINGIVAL HYPERPLASIA: A 25-year-old woman, with Epstein's syndrome, presented with generalized gingival hyperplasia with ulcers at the gingival margins. Her current systemic drug therapy included pindolol, enalapril, indoramin, sotalol, alfacalcidol, erythropoietin, and tranexamic acid. A gingival biopsy showed hyperkeratosis, ulceration, and fibrin leakage, edema, and fibrosis. Five weeks after discontinuation of all systemic drug therapy, the patient's gingival lesions completely disappeared. Three months later, rechallenge with tranexamic acid resulted in the recurrence of the lesions; however, the lesions again disappeared after cessation of tranexamic acid therapy (Diamond et al, 1991).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension has been reported occasionally with the use of tranexamic acid, primarily when intravenous injection of the drug is too rapid, (ie, administered at a rate greater than 1 mL/min). With oral administration of tranexamic acid, hypotension has not been reported (Prod Info CYKLOKAPRON(R) oral tablets, injection, 2005).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 55-year-old woman developed severe burning pain bilaterally in her lower extremities immediately after intrathecal administration of 3 mL of 10% tranexamic acid instead of 0.5% bupivacaine. Ten minutes later, the patient developed myoclonic twitching of her facial muscles and, 25 minutes post-administration, she became hypotensive and comatose. Ten hours following intrathecal administration, she died due to ventricular fibrillation (Garcha et al, 2007).
    B) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 77-year-old woman developed chest pain and dyspnea approximately 1 week after beginning tranexamic acid, 500 mg twice daily, for treatment of intermittent hemoptysis. Approximately 2 days prior to presentation of symptoms, her tranexamic acid dose was doubled because of recurrent minor hemoptysis. On admission, her troponin I level was elevated at 5 mcg/mL and an echocardiography showed an akinetic motion at the apex of the left ventricle with an ejection fraction of 45%. A coronary angiogram revealed 30% stenosis of the left anterior descending artery; however, no percutaneous coronary intervention was performed and the patient recovered with supportive care (Mekontso-Dessap et al, 2002).
    C) VENTRICULAR FIBRILLATION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 55-year-old woman developed severe burning pain bilaterally in her lower extremities immediately after intrathecal administration of 3 mL of 10% tranexamic acid instead of 0.5% bupivacaine. Ten minutes later, the patient developed myoclonic twitching of her facial muscles and, 25 minutes post-administration, she became hypotensive and comatose. Ten hours following intrathecal administration, she died due to ventricular fibrillation (Garcha et al, 2007).
    b) CASE REPORT: A 49-year-old woman developed severe pain in her back and gluteal region and became hypertensive (200/130 mmHg) immediately following inadvertent administration of 500 mg tranexamic acid intrathecally. Two minutes later, she developed generalized seizures that resolved following intravenous diazepam administration; however, the patient developed ventricular fibrillation. Despite aggressive resuscitative measures, the ventricular fibrillation persisted and the patient died within 2 hours post-administration (Yeh et al, 2003).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PULMONARY EMBOLISM
    1) WITH THERAPEUTIC USE
    a) Several patients reportedly developed pulmonary emboli while receiving tranexamic acid therapy (Taparia et al, 2002; Woo et al, 1989; Fodstad et al, 1981).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ISCHEMIC STROKE
    1) WITH THERAPEUTIC USE
    a) Tranexamic acid has been demonstrated to cause or aggravate cerebral ischemic complications when administered for the prevention of rebleeding in patients with subarachnoid hemorrhage (Fodstad et al, 1981; Vermeulen et al, 1984). Several case reports of cerebral thrombosis and infarction have been published (Agnelli et al, 1982; Rydin & Lundberg, 1976; Gelmers, 1980; Verstraete, 1985b). A statistically higher incidence of cerebral infarction was reported in tranexamic acid-treated patients as compared to placebo-treated patients undergoing therapy for subarachnoid hemorrhage (Vermeulen et al, 1984).
    b) An increased incidence of severe vasospasm, fatal delayed cerebral ischemia, pulmonary embolism and myocardial infarction was reported in tranexamic acid-treated patients, as compared to control patients, in a randomized controlled study (Fodstad et al, 1981). These data also support the contention that tranexamic acid may produce cerebral ischemic complications.
    c) Fatal cerebral arterial thrombosis was described in a 26-year-old woman who received tranexamic acid 1.5 g daily for persistent uterine bleeding following insertion of an intrauterine device (IUD) (Agnelli et al, 1982).
    d) Intracranial arterial thrombosis was described in two women who received tranexamic acid for the treatment of menorrhagia. Both patients received the drug in doses of 0.5 to 4.5 g daily for approximately one year, during periods of menstrual blood loss. One patient was discharged after one month with no residual symptoms, whereas the other patient retained some left-sided weakness, dysesthesia and hemianopia after a period of three months (Rydin & Lundberg, 1976).
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT/COMORBIDITY: A 45-year-old woman, with chronic kidney disease (CKD) and a recent history of severe anemia secondary to menorrhagia, received 3 units of packed red blood cells and was started on tranexamic acid (1 g IV every 8 hours). Approximately 2 hours after receiving her sixth dose, she developed a generalized tonic-clonic seizure. Symptoms were treated with lorazepam (2 mg) and discontinuation of tranexamic acid. She underwent several diagnostic studies (ie, EEG, MRI of the brain) and all were normal. No further seizure activity was reported up to 2 months later (Bhat et al, 2014). The authors suggested that due to the patient's CKD her dose of tranexamic acid should have been adjusted based on her reduced glomerular filtration rate.
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 49-year-old woman developed severe pain in her back and gluteal region and became hypertensive (200/130 mmHg) immediately following inadvertent administration of 500 mg tranexamic acid intrathecally. Two minutes later, she developed generalized seizures that resolved following intravenous diazepam administration; however, the patient developed ventricular fibrillation. Despite aggressive resuscitative measures, the ventricular fibrillation persisted and the patient died within 2 hours post-administration (Yeh et al, 2003).
    b) In a trial comparing the safety of tranexamic acid to aprotinin in pediatric cardiac surgery, tranexamic acid had a higher incidence of seizures (Breuer et al, 2009).
    C) HYDROCEPHALUS
    1) WITH THERAPEUTIC USE
    a) Since tranexamic acid inhibits fibrinolysis, retained clots around the arachnoid villi may induce scarring and decrease cerebrospinal fluid absorption, predisposing to the development of hydrocephalus (Adams, 1982).
    b) The occurrence of hydrocephalus, requiring drainage of cerebrospinal fluid, was reported in more patients receiving tranexamic acid than placebo; however, this difference did not reach a level of statistical significance (Vermeulen et al, 1984). Other investigators have reported the occurrence of hydrocephalus during prophylaxis of rebleeding in subarachnoid hemorrhage (Maurice-Williams, 1978).
    D) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has rarely occurred during tranexamic acid therapy (Biggs et al, 1976; Castelli & Vogt, 1977).
    E) GIDDINESS
    1) WITH THERAPEUTIC USE
    a) Giddiness has been reported to occur occasionally with the use of tranexamic acid (Prod Info CYKLOKAPRON(R) oral tablets, injection, 2005).
    F) MYOCLONUS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 61-year-old man, with polycystic kidney disease and on chronic peritoneal dialysis, developed myoclonus and altered mental status approximately 6 days after beginning oral tranexamic acid therapy, 500 mg 4 times daily. An EEG showed intermittent spike waves. Four days after cessation of tranexamic acid therapy, the patient's mental status returned to normal and his myoclonus disappeared. A repeat EEG showed normal activity without further epileptiform discharges (Hui et al, 2003). Since tranexamic acid is primarily renally excreted, it is believed that the patient accumulated an elevated concentration of medication which resulted in his myoclonus and altered mental state.
    b) CASE REPORT: A 55-year-old woman developed severe burning pain bilaterally in her lower extremities immediately after intrathecal administration of 3 mL of 10% tranexamic acid instead of 0.5% bupivacaine. Ten minutes later, the patient developed myoclonic twitching of her facial muscles and, 25 minutes post-administration, she became hypotensive and comatose. Ten hours following intrathecal administration, she died due to ventricular fibrillation (Garcha et al, 2007).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal disturbances (nausea, vomiting, and diarrhea) are the primary side effects of tranexamic acid therapy; these symptoms will abate if the tranexamic acid dosage is reduced (Prod Info CYKLOKAPRON(R) oral tablets, injection, 2005; Verstraete, 1985b; Munch & Weeke, 1985; Vermeulen et al, 1984; Adams, 1982; Fodstad et al, 1981). Nausea and diarrhea appear to be more common with oral as opposed to intravenous therapy. Abdominal pain has also been reported with oral therapy (Munch & Weeke, 1985).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL CORTICAL NECROSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 37-year-old man developed acute renal cortical necrosis with glomerular thrombosis after receiving tranexamic acid therapy for hemoptysis. He had a history of pulmonary tuberculosis and recently developed hemoptysis for which treatment included tranexamic acid 3 grams daily for 5 days. After 6 days, he suddenly developed anuria and azotemia with a normal coagulation profile. Light microscopy revealed an infarction with fibrin thrombi in the intraglomerular capillaries and arterioles. He received hemodialysis for 2 weeks with slow improvement of his renal function (Koo et al, 1999).
    b) CASE REPORT: Acute bilateral renal cortical necrosis occurred in a 21-year-old man with hemophilia A who was treated with a 4-day course of tranexamic acid 3 grams/day for epistaxis. Three days later, the patient developed oligoanuria and azotemia. Urinary analysis showed no proteinuria or hematuria. On day 6 of hospitalization, serum creatinine increased to 8.1 mg/dL. He was treated with hemodialysis for 3 weeks. During follow-up, urine output decreased below 20 mL/day, and did not increase again. Renal angiography was performed and a diagnosis of renal cortical necrosis was made (Odabas et al, 2001).
    B) URINARY SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) URETERAL OBSTRUCTION: Ureteral obstruction due to clot formation has occurred in patients who were given tranexamic acid for treatment of upper urinary tract bleeding (Prod Info CYKLOKAPRON(R) oral tablets, injection, 2005).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOEMBOLIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Systemic thromboembolic complications have been reported with tranexamic acid, including thromboembolism, myocardial infarction, and pulmonary embolism (Prod Info CYKLOKAPRON(R) oral tablets, injection, 2005; Woo et al, 1989; Fodstad et al, 1981; Davies & Howell, 1977; Verstraete, 1985b; Maurice-Williams, 1978). However, these complications do not appear to be frequent. Preoperative deep vein thrombosis occurred in 2 of 30 patients receiving tranexamic acid; both patients also had pulmonary embolism and two additional cases of pulmonary embolism were described in tranexamic acid-treated patients (Fodstad et al, 1981). Deep vein thrombosis has been associated with tranexamic acid for the treatment of idiopathic thrombocytopenia purpura (Endo et al, 1988).
    b) Administration of tranexamic acid to decrease blood loss in patients undergoing transurethral prostatectomy has been associated with intravesical blood clotting (Ward & Richards, 1979). In this study, three of six patients who received 1 g by mouth preoperatively and 1 g three times per day postoperatively until macroscopic bleeding subsided, developed indissoluble blood clots adherent to the bladder wall. Irrigation had no effect and surgery was required. The drug is not recommended for routine use after prostatectomy.
    c) In a nested case-control study of women (aged 15 to 49 years) with menorrhagia, tranexamic acid was associated with an increased risk of developing venous thromboembolism, but the risk estimate did not reach statistical significance (Sundstrom et al, 2009).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FIXED DRUG ERUPTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 33-year-old woman, receiving tranexamic acid for persistent microscopic hematuria following pyeloplasty of her right kidney, developed a patchy, itchy rash. The woman had tolerated tranexamic acid 1 gram three times daily for 8 years. Her other medications included furosemide and ibuprofen. The rash started on her hands and progressed to her trunk and limbs. There was no response to terfenadine, miconazole cream, or oral doxycycline. Prednisolone provided some relief. With the discontinuation of tranexamic acid, the rash resolved within days. After rechallenge, the rash recurred within 2 to 3 hours. After 4 months without drug therapy, desensitization with tranexamic acid 25 micrograms was attempted, however, the rash recurred after 5 days (Kavanagh et al, 1993).
    b) CASE REPORT: A 36-year-old woman developed a pruritic bullous eruption a few hours after receiving tranexamic acid 500 mg intravenously. A skin biopsy revealed intraepidermic blisters and necrotic keratinocytes. The eruption resolved within 3 days after cessation of tranexamic acid therapy and administration of antihistamines (Carrion-Carrion et al, 1994).
    B) PAIN
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 55-year-old woman developed severe burning pain bilaterally in her lower extremities immediately after intrathecal administration of 3 mL of 10% tranexamic acid instead of 0.5% bupivacaine. Ten minutes later, the patient developed myoclonic twitching of her facial muscles and, 25 minutes post-administration, she became hypotensive and comatose. Ten hours following intrathecal administration, she died due to ventricular fibrillation (Garcha et al, 2007).
    b) CASE REPORT: A 49-year-old woman developed severe pain in her back and gluteal region and became hypertensive (200/130 mmHg) immediately following inadvertent administration of 500 mg tranexamic acid intrathecally. Two minutes later, she developed generalized seizures that resolved following intravenous diazepam administration; however, the patient was pulseless and cyanotic and ventricular fibrillation was noted on her ECG. Despite aggressive resuscitative measures, the ventricular fibrillation persisted and the patient died within 2 hours post-administration (Yeh et al, 2003).

Reproductive

    3.20.1) SUMMARY
    A) Tranexamic acid is classified as FDA pregnancy category B. Tranexamic acid can cross the placenta and has also been shown to be excreted in breast milk.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT: Reproduction studies, involving mice, rats, and rabbits, have shown no evidence of adverse effects on the fetus following tranexamic acid administration (Prod Info CYKLOKAPRON(R) injection, 2008). No adverse effects were noted in either of 2 studies in which rats were exposed to tranexamic acid at doses up to 1500 mg/kg/day (4 times the recommended human oral dose of 3900 mg/day based on mg/m(2)) (Prod Info LYSTEDA(TM) oral tablets, 2009).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Tranexamic acid is classified by the manufacturer as FDA pregnancy category B (Prod Info LYSTEDA(TM) oral tablets, 2009; Prod Info CYKLOKAPRON(R) injection, 2008).
    B) PLACENTAL BARRIER
    1) Tranexamic acid can cross the placenta. After a tranexamic acid 10-mg/kg IV injection, the concentration in cord blood is approximately 30 mg/L which is about equal to the maternal concentration (Prod Info LYSTEDA(TM) oral tablets, 2009; Prod Info CYKLOKAPRON(R) injection, 2008).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) There are limited data on nursing an infant while on tranexamic acid. Data have shown that only minimal amounts of the drug are excreted in breast milk. Breast milk concentrations were reported to be approximately 1% of peak serum concentrations 1 hour following the last dose of a 2-day treatment regimen (Prod Info LYSTEDA(TM) oral tablets, 2009; Verstraete, 1985a).
    2) In a prospective, controlled observational study conducted from 2010 to 2013, mothers (n=21) using tranexamic acid while breastfeeding were compared to a matched control group of breastfeeding mothers (n=42) using amoxicillin (known to be safe during breastfeeding), no increase risk in adverse outcomes was observed in infants exposed to tranexamic acid. Mothers were contacted 1 to 3 years after the initial interview using a structured questionnaire to assess for possible adverse effects in the mother and infant. Dose (range, 1500 to 4000 mg/day) and duration of tranexamic acid varied depending on the indication. Neonatal outcomes included normal growth for both groups, one possible adverse event (ie, gastroesophageal reflux disease, restlessness) in the tranexamic acid group compared to 2 in the control group and no abnormal neurologic development in the tranexamic acid group compared to 2 children in the control group (Gilad et al, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) In animal reproductive studies, there was no evidence of impaired fertility when mice, rats and rabbits were exposed to tranexamic acid (Prod Info LYSTEDA(TM) oral tablets, 2009).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS1197-18-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.4) ANIMAL STUDIES
    A) LEUKEMIA
    1) MICE - An increased incidence of leukemia occurred in male mice receiving approximately 5 grams per kg of body weight per day of tranexamic acid (added to food in a concentration of 4.8%) (Prod Info CYKLOKAPRON(R) oral tablets, injection, 2005).
    B) NEOPLASM
    1) RATS - Tranexamic acid produced cholangiomas, adenocarcinomas, and hyperplasia of the biliary tract when administered orally to one strain of rats in doses exceeding the maximum tolerated dose for a period of 22 months. Lower doses produced hyperplastic, but not neoplastic, changes. No hyperplastic or neoplastic changes were observed in subsequent long-term studies in which equivalent doses were administered to a different strain of rats (Prod Info CYKLOKAPRON(R) oral tablets, injection, 2005).

Genotoxicity

    A) There was no mutagenicity detected in several in vivo and in vitro tests (Prod Info CYKLOKAPRON(R) oral tablets, injection, 2005).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) While there are no specific lab tests that will be altered after therapeutic or overdose of tranexamic acid, including coagulation studies, the following would be appropriate to monitor: CBC with differential, platelets, renal function after significant overdose.
    B) Vital signs should be closely observed, as hypotension may occur with therapeutic infusion and overdose.
    C) Look for clinical evidence of thromboembolic complications (e.g. chest pain, shortness of breath, flank pain, extremity pain). Obtain specific studies (e.g. CT, angiography) to evaluate for thromboembolic complications as needed. Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    D) Monitor fluid and electrolyte status in patients with severe vomiting or diarrhea.

Methods

    A) CHROMATOGRAPHY
    1) High performance liquid chromatography with tandem mass spectrometry has been used for the determination of tranexamic acid in human plasma. With this method, the lower limit of quantification was 0.02 mcg/mL and the lower limit of detection was 0.01 mcg/mL (Chang et al, 2004).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with a deliberate ingestions demonstrating cardiotoxicity, seizure activity, or other persistent neurotoxicity should be admitted.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) Asymptomatic patients with a minor inadvertent ingestion may be monitored at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Call a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) All symptomatic patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve.

Monitoring

    A) While there are no specific lab tests that will be altered after therapeutic or overdose of tranexamic acid, including coagulation studies, the following would be appropriate to monitor: CBC with differential, platelets, renal function after significant overdose.
    B) Vital signs should be closely observed, as hypotension may occur with therapeutic infusion and overdose.
    C) Look for clinical evidence of thromboembolic complications (e.g. chest pain, shortness of breath, flank pain, extremity pain). Obtain specific studies (e.g. CT, angiography) to evaluate for thromboembolic complications as needed. Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    D) Monitor fluid and electrolyte status in patients with severe vomiting or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Consider activated charcoal following oral exposure; decontamination is not indicated following parenteral exposure.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. There is no known antidote.
    B) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    7) RECURRING SEIZURES
    a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:
    1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
    2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
    3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
    4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)
    b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
    c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).
    D) FLUID BALANCE REGULATION
    1) Vomiting and diarrhea may develop in overdose. Monitor serum electrolytes in patients with severe gastrointestinal losses. Administer IV fluids and replace electrolytes as necessary.
    E) MONITORING OF PATIENT
    1) While there are no specific lab tests that will be altered after therapeutic or overdose of tranexamic acid, including coagulation studies, the following would be appropriate to monitor: CBC with differential, platelets, renal function after significant overdose.
    2) Vital signs should be closely observed, as hypotension may occur with therapeutic infusion and overdose.
    3) Look for clinical evidence of thromboembolic complications (eg; chest pain, shortness of breath, flank pain, extremity pain). Specific studies (eg; CT, angiography) may be needed to evaluate for thromboembolic complications. Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
    4) Monitor fluid and electrolyte status in patients with severe vomiting or diarrhea.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Unintentional intrathecal administration of 500 mg tranexamic acid resulted in the development of seizures, refractory ventricular fibrillation, and death in an adult patient.
    B) THERAPEUTIC DOSE: ADULTS AND CHILDREN: ORAL: For hemorrhage prophylaxis in hemophiliacs, 25 mg/kg 3 to 4 times daily for 2 to 8 days following dental extraction surgery OR 25 mg/kg 3 to 4 times daily beginning 1 day prior to surgery. IV: For hemorrhage prophylaxis in hemophiliacs, 10 mg/kg immediately prior to tooth extraction, combined with factor VIII or IX concentrate OR, for those patients unable to take oral medication, 10 mg/kg IV may be administered 3 to 4 times daily postoperatively. NOTE: For patients with moderate to severely impaired renal function, a decreased dose is recommended.

Therapeutic Dose

    7.2.1) ADULT
    A) HEAVY CYCLIC MENSTRUAL BLEEDING
    1) ORAL: Two 650 mg tablets administered orally 3 times daily, for a total dose of 3900 mg/day for up to 5 days during monthly menstruation (Prod Info LYSTEDA(TM) oral tablets, 2013)
    2) Tablets should NOT be chewed or split apart (Prod Info LYSTEDA(TM) oral tablets, 2013).
    B) HEMORRHAGE PROPHYLAXIS FOR HEMOPHILIA
    1) IV: The recommended dose is 10 mg/kg IV administered with replacement therapy immediately before tooth extraction. Postoperatively, 10 mg/kg IV may be administered 3 to 4 times daily for 2 to 8 days (Prod Info CYKLOKAPRON(R) intravenous injection, 2013).
    7.2.2) PEDIATRIC
    A) HEAVY CYCLIC MENSTRUAL BLEEDING
    1) ORAL: Limited data suggests that adult dosing may be used for pediatric patients, although oral tranexamic acid is not intended for use in premenarcheal girls (Prod Info LYSTEDA(TM) oral tablets, 2013).
    2) Tablets should NOT be chewed or split apart (Prod Info LYSTEDA(TM) oral tablets, 2013).
    B) HEMORRHAGE PROPHYLAXIS FOR HEMOPHILIA
    1) SUMMARY: Limited data suggests that adult dosing may be used for pediatric patients (Prod Info CYKLOKAPRON(R) intravenous injection, 2013).
    2) IV: The recommended dose is 10 mg/kg IV administered with replacement therapy immediately before tooth extraction. Postoperatively, 10 mg/kg IV may be administered 3 to 4 times daily for 2 to 8 days (Prod Info CYKLOKAPRON(R) intravenous injection, 2013).

Minimum Lethal Exposure

    A) CASE REPORT: A 49-year-old woman developed generalized seizures and refractory ventricular fibrillation and subsequently died after inadvertent intrathecal administration of 500 mg tranexamic acid (Yeh et al, 2003).
    B) CASE REPORT: A 55-year-old woman developed severe burning pain bilaterally in her lower extremities immediately after intrathecal administration of 3 mL of 10% tranexamic acid instead of 0.5% bupivacaine. Ten minutes later, the patient developed myoclonic twitching of her facial muscles and, 25 minutes post-administration, she became hypotensive and comatose. Ten hours following intrathecal administration, she died due to ventricular fibrillation (Garcha et al, 2007).

Maximum Tolerated Exposure

    A) CASE REPORT: A 61-year-old man, with polycystic kidney disease and on chronic peritoneal dialysis, developed myoclonus and altered mental status approximately 6 days after beginning oral tranexamic acid therapy, 500 mg four times daily. An EEG showed intermittent spike waves. Four days after cessation of tranexamic acid therapy, the patient's mental status returned to normal and his myoclonus disappeared. A repeat EEG showed normal activity without further epileptiform discharges (Hui et al, 2003). Since tranexamic acid is primarily renally excreted, it is believed that the patient received an overdose of medication which resulted in his myoclonus and altered mental state.

Workplace Standards

    A) ACGIH TLV Values for CAS1197-18-8 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS1197-18-8 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS1197-18-8 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS1197-18-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 4200 mg/kg (RTECS, 2006)
    B) LD50- (ORAL)MOUSE:
    1) >10 g/kg (RTECS, 2006)
    C) LD50- (SUBCUTANEOUS)MOUSE:
    1) 5310 mg/kg (RTECS, 2006)
    D) LD50- (SUBCUTANEOUS)RAT:
    1) 4620 mg/kg (RTECS, 2006)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Tranexamic acid competitively inhibits activation of plasminogen (Prod Info CYKLOKAPRON(R) oral tablets, injection, 2005; Krogh, 1993; Krogh, 1987), thereby reducing conversion of plasminogen to plasmin (fibrinolysin), an enzyme that degrades fibrin clots, fibrinogen, and other plasma proteins, including the procoagulant factors V and VIII (Anon, 1994). Tranexamic acid also directly inhibits plasmin activity, but higher doses are required than are needed to reduce plasmin formation (Prod Info CYKLOKAPRON(R) oral tablets, injection, 2005; Krogh, 1987). In vitro, the antifibrinolytic potency of tranexamic acid is approximately 5 to 10 times that of aminocaproic acid (Prod Info CYKLOKAPRON(R) oral tablets, injection, 2005; Anon, 1994; Krogh, 1993).
    B) In patients with hereditary angioedema, inhibition of the formation and activity of plasmin by tranexamic acid may prevent attacks of angioedema by decreasing plasmin-induced activation of the first complement protein (C1) (Wyngaarden & Smith, 1988).

Physicochemical

Physical Characteristics

    A) Tranexamic acid is a white crystalline powder that is freely soluble in water and glacial acetic acid, very slightly soluble in ethanol, and practically insoluble in ether (Prod Info LYSTEDA(TM) oral tablets, 2009).

Ph

    A) 6.5 to 8 (Prod Info CYKLOKAPRON(R) injection, 2008)

Molecular Weight

    A) 157.2 (Prod Info LYSTEDA(TM) oral tablets, 2009; Prod Info CYKLOKAPRON(R) injection, 2008)

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
    4) 62 FR 58840: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 1997.
    5) 65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
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