6540-02

DOSAGE FORMS AND STRENGTHS
A long-term open-label extension study of subjects from the two short-term efficacy studies was also conducted 12.2 Pharmacodynamics
in which subjects were treated with 3900 mg/day for up to 5 days during each menstrual period for up to Tranexamic acid, at in vitro concentrations of 25 - 100 M, reduces by 20 - 60% the maximal rate of plasmin lysis (tranexamic acid) tablets
9 menstrual cycles. A total of 288 subjects were enrolled and 196 subjects completed the study through 9 menstrual of fibrin catalyzed by tissue plasminogen activator (tPA). CONTRAINDICATIONS
HIGHLIGHTS OF PRESCRIBING INFORMATION
cycles. A total of 2.1% of the subjects withdrew due to adverse events. The total exposure to 3900 mg/day LYSTEDA Thromboembolic Risk
Elevated concentrations of endometrial, uterine, and menstrual blood tPA are observed in women with heavy in this study was 1,956 cycles. The average duration of LYSTEDA use was 3.5 days per cycle. These highlights do not include all the information needed to use LYSTEDA safely and effectively. See full
Do not prescribe LYSTEDA to women who are known to have the following conditions: menstrual bleeding (HMB) compared to women with normal menstrual blood loss. The effect of tranexamic acid prescribing information for LYSTEDA.
The types and severity of adverse events in these two long-term open-label trials were similar to those observed Active thromboembolic disease (e.g., deep vein thrombosis, pulmonary embolism, or cerebral thrombosis) on lowering endometrial tPA activity and menstrual fluid fibrinolysis is observed in women with HMB receiving LYSTEDA® (tranexamic acid) Tablets
in the double-blind, placebo-controlled studies although the percentage of subjects reporting them was greater A history of thrombosis or thromboembolism, including retinal vein or artery occlusion tranexamic acid total oral doses of 2-3 g/day for 5 days.
Initial U.S. Approval: 1986
in the 27-month study, most likely because of the longer study duration. An intrinsic risk of thrombosis or thromboembolism (e.g., thrombogenic valvular disease, thrombogenic In healthy subjects, tranexamic acid at blood concentrations less than 10 mg/mL has no effect on the platelet ------------------------------------------RECENT MAJOR CHANGES------------------------------------------
A case of severe allergic reaction to LYSTEDA was reported in the extension trial, involving a subject on her fourth cardiac rhythm disease, or hypercoagulopathy) count, the coagulation time or various coagulation factors in whole blood or citrated blood. Tranexamic acid, cycle of treatment who experienced dyspnea, tightening of her throat, and facial flushing that required emergency however, at blood concentrations of 1 and 10 mg/mL prolongs the thrombin time.
Venous and arterial thrombosis or thromboembolism, as well as cases of retinal artery and retinal vein occlusions, ------------------------------------------INDICATIONS AND USAGE------------------------------------------
have been reported with tranexamic acid.
LYSTEDA (tranexamic acid) Tablets is an antifibrinolytic indicated for the treatment of cyclic heavy menstrual Postmarketing Experience
The effect of LYSTEDA on QT interval was evaluated in a randomized, single-dose, 4-way crossover study in 48 Hypersensitivity to Tranexamic Acid
The following adverse reactions have been identified from postmarketing experience with tranexamic acid. Because Do not prescribe LYSTEDA to women with known hypersensitivity to tranexamic acid [see Warnings and Precautions healthy females aged 18 to 49 years. Subjects received (1) LYSTEDA 1300 mg (two 650 mg tablets), (2) LYSTEDA these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably ---------------------------------------DOSAGE AND ADMINISTRATION--------------------------------------
(5.2) and Adverse Reactions (6.1) ].
3900 mg (six 650 mg tablets; three times the recommended single dose), (3) moxifloxacin 400 mg, and (4) placebo.
estimate their frequency or establish a causal relationship to drug exposure.
• 1,300 mg (two 650 mg tablets) three times a day (3,900 mg/day) for a maximum of 5 days during monthly There was no significant increase in the corrected QT interval at any time up to 24 hours after the administration WARNINGS AND PRECAUTIONS
Based on US and worldwide postmarketing reports, the following have been reported in patients receiving of either dose of LYSTEDA. Moxifloxacin, the active control, was associated with a maximum 14.11 msec mean • Renal impairment: Dosage adjustment is needed if serum creatinine concentration (Cr) is higher than Thromboembolic Risk
tranexamic acid for various indications: increase in corrected QT interval (moxifloxacin – placebo) at 3 hours after administration. Concomitant Use of Hormonal Contraceptives 12.3 Pharmacokinetics
• Cr above 1.4 mg/dL and ≤ 2.8 mg/dL: 1,300 mg (two 650 mg tablets) two times a day (2,600 mg/day) for Combination hormonal contraceptives are known to increase the risk of venous thromboembolism, as well as arterial thromboses such as stroke and myocardial infarction. Because LYSTEDA is antifibrinolytic, the risk of venous thromboembolism, as well as arterial thromboses such as stroke, may increase further when hormonal Anaphylactic shock and anaphylactoid reactions • Cr above 2.8 mg/dL and ≤ 5.7 mg/dL: 1,300 mg (two 650 mg tablets) once a day (1,300 mg/day) for a After a single oral administration of two 650 mg tablets of LYSTEDA, the peak plasma concentration (Cmax) occurred contraceptives are administered with LYSTEDA. This is of particular concern in women who are obese or smoke Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal at approximately 3 hours (Tmax). The absolute bioavailability of LYSTEDA in women aged 18-49 is approximately • Cr above 5.7 mg/dL: 650 mg (one 650 mg tablet) once a day (650 mg/day) for a maximum of 5 days during cigarettes, especially smokers over 35 years of age [see Contraindications (4.1) and Drug Interactions (7.1)].
cortical necrosis, and central retinal artery and vein obstruction) 45%. Following multiple oral doses (two 650 mg tablets three times daily) administration of LYSTEDA for 5 days, Women using hormonal contraception were excluded from the clinical trials supporting the safety and efficacy of Impaired color vision and other visual disturbances max increased by approximately 19% and the mean area under the plasma concentration-time curve (AUC) remained unchanged, compared to a single oral dose administration (two 650 mg tablets). Plasma ---------------------------------------DOSAGE FORMS AND STRENGTHS--------------------------------------
LYSTEDA, and there are no clinical trial data on the risk of thrombotic events with the concomitant use of LYSTEDA concentrations reached steady state at the 5th dose of LYSTEDA on Day 2.
with hormonal contraceptives. There have been US postmarketing reports of venous and arterial thrombotic eventsin women who have used LYSTEDA concomitantly with combined hormonal contraceptives. Women using hormonal DRUG INTERACTIONS
--------------------------------------------CONTRAINDICATIONS----------------------------------------------
The mean plasma pharmacokinetic parameters of tranexamic acid determined in 19 healthy women following a contraception, especially those who are obese or smoke, should use LYSTEDA only if there is a strong medical need No drug-drug interaction studies were conducted with LYSTEDA.
single (two 650 mg tablets) and multiple (two 650 mg tablets three times daily for 5 days) oral dose of LYSTEDA • Women with active thromboembolic disease or a history or intrinsic risk of thrombosis or thromboembolism, and the benefit of treatment will outweigh the potential increased risk of a thrombotic event. Do not use LYSTEDA including retinal vein or artery occlusion (4.1) Hormonal Contraceptives
in women who are taking more than the approved dose of a hormonal contraceptive. • Hypersensitivity to tranexamic acid (4.2) Because LYSTEDA is antifibrinolytic, concomitant use of hormonal contraception and LYSTEDA may further Factor IX Complex Concentrates or Anti-Inhibitor Coagulant Concentrates Table 3. Mean (CV%) Pharmacokinetic Parameters Following a Single (two 650 mg tablets) and Multiple
exacerbate the increased thrombotic risk associated with combination hormonal contraceptives. Women using --------------------------------------WARNINGS AND PRECAUTIONS---------------------------------------
Oral Dose (two 650 mg tablets three time daily for 5 days) Administration of LYSTEDA in 19 Healthy Women
LYSTEDA is not recommended for women taking either Factor IX complex concentrates or anti-inhibitor coagulant hormonal contraception should use LYSTEDA only if there is a strong medical need and the benefit of treatment • The risk of thrombotic and thromboembolic events may increase further when hormonal contraceptives are under Fasting Conditions
concentrates because the risk of thrombosis may be increased [see Drug Interactions (7.3) and Clinical will outweigh the potential increased risk of a thrombotic event [see Warnings and Precautions (5.1) and Clinical administered with LYSTEDA, especially in women who are obese or smoke cigarettes. Women using hormonal contraception should use LYSTEDA only if there is a strong medical need and the benefit of treatment will outweigh Arithmetic Mean (CV%)
Parameter
the potential increased risk of a thrombotic event. Do not use LYSTEDA in women who are taking more than the Tissue Plasminogen Activators
Single dose
Multiple dose
approved dose of a hormonal contraceptive. (5.1) Exercise caution when prescribing LYSTEDA to women with acute promyelocytic leukemia taking all trans retinoic Concomitant therapy with tissue plasminogen activators may decrease the efficacy of both LYSTEDA and tissue • Concomitant use of LYSTEDA with Factor IX complex concentrates, anti-inhibitor coagulant concentrates or all-trans acid for remission induction because of possible exacerbation of the procoagulant effect of all-trans retinoic acid plasminogen activators. Therefore, exercise caution if a woman taking LYSTEDA therapy requires tissue retinoic acid (oral tretinoin) may increase the risk of thrombosis. (5.1) [see Drug Interactions (7.4) and Clinical Pharmacology (12.3)].
• Visual or ocular adverse effects may occur with LYSTEDA. Immediately discontinue use if visual or ocular Factor IX Complex Concentrates or Anti-Inhibitor Coagulant Concentrates
Retinal venous and arterial occlusion has been reported in patients using tranexamic acid. Patients should be LYSTEDA is not recommended for women taking either Factor IX complex concentrates or anti-inhibitor coagulant • In case of severe allergic reaction, discontinue LYSTEDA and seek immediate medical attention. (5.2) instructed to report visual and ocular symptoms promptly. In the event of such symptoms, patients should be instructed concentrates because the risk of thrombosis may be increased [see Warnings and Precautions (5.1) and Clinical • Cerebral edema and cerebral infarction may be caused by use of LYSTEDA in women with subarachnoid to discontinue LYSTEDA immediately and should be referred to an ophthalmologist for a complete ophthalmic evaluation, including dilated retinal examination, to exclude the possibility of retinal venous or arterial occlusion.
All-Trans Retinoic Acid (Oral Tretinoin)
• Ligneous conjunctivitis has been reported in patients taking tranexamic acid. (5.4) 5.2 Severe Allergic Reaction
Exercise caution when prescribing LYSTEDA to women with acute promyelocytic leukemia taking all-trans retinoic AUCtldc = area under the drug concentration curve from time 0 to time of last determinable concentration A case of severe allergic reaction to LYSTEDA was reported in the clinical trials, involving a subject who experienced acid for remission induction because of possible exacerbation of the procoagulant effect of all-trans retinoic acid ------------------------------------------ADVERSE REACTIONS---------------------------------------------
AUCinf = area under the drug concentration curve from time 0 to infinity dyspnea, tightening of her throat, and facial flushing that required emergency medical treatment. A case of [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. Most common adverse reactions in clinical trials (≥ 5%, and more frequent in LYSTEDA subjects compared to anaphylactic shock has also been reported in the literature, involving a patient who received an intravenous bolus placebo subjects) are headache, sinus and nasal symptoms, back pain, abdominal pain, musculoskeletal pain, joint USE IN SPECIFIC POPULATIONS
pain, muscle cramps, migraine, anemia and fatigue. (6.1) 0-tau (mcg·h/mL) = area under the drug concentration curve from time 0 to 8 hours Pregnancy (Category B)
5.3 Subarachnoid Hemorrhage
To report SUSPECTED ADVERSE REACTIONS, contact Ferring Pharmaceuticals Inc. at 1-888-FERRING
LYSTEDA is not indicated for use in pregnant women. Reproduction studies have been performed in mice, rats and (1-888-337-7464) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Cerebral edema and cerebral infarction may be caused by use of LYSTEDA in women with subarachnoid hemorrhage.
Effect of food: LYSTEDA may be administered without regard to meals. A single dose administration (two 650 mg rabbits and have revealed no evidence of impaired fertility or harm to the fetus due to tranexamic acid. However, 5.4 Ligneous Conjunctivitis
-------------------------------------------DRUG INTERACTIONS----------------------------------------------
tranexamic acid is known to cross the placenta and appears in cord blood at concentrations approximately tablets) of LYSTEDA with food increased both Cmax and AUC by 7% and 16%, respectively. Ligneous conjunctivitis has been reported in patients taking tranexamic acid. The conjunctivitis resolved following Concomitant therapy with tissue plasminogen activators may decrease the efficacy of both LYSTEDA and tissue equal to the maternal concentration. There are no adequate and well-controlled studies in pregnant women [see Nonclinical Toxicology (13.1) ].
Tranexamic acid is 3% bound to plasma proteins with no apparent binding to albumin. Tranexamic acid is ---------------------------------------USE IN SPECIFIC POPULATIONS----------------------------------------
ADVERSE REACTIONS
An embryo-fetal developmental toxicity study in rats and a perinatal developmental toxicity study in rats were distributed with an initial volume of distribution of 0.18 L/kg and steady-state apparent volume of distribution of • Renal impairment: Dosage adjustment is needed. (2.2, 8.6) Clinical Trial Experience
conducted using tranexamic acid. No adverse effects were observed in either study at doses up to 4 times the • Hepatic impairment: No dosage adjustment is needed. (8.7) Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the recommended human oral dose of 3900 mg/day based on mg/m2 (actual animal dose 1500 mg/kg/day).
Tranexamic acid crosses the placenta. The concentration in cord blood after an intravenous injection of 10 mg/kg clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Nursing Mothers
to pregnant women is about 30 mg/L, as high as in the maternal blood. Revised: 4/2011
reflect the rates observed in clinical practice.
Tranexamic acid is present in the mother’s milk at a concentration of about one hundredth of the corresponding Tranexamic acid concentration in cerebrospinal fluid is about one tenth of the plasma concentration. Short-term Studies
serum concentration. LYSTEDA should be used during lactation only if clearly needed. FULL PRESCRIBING INFORMATION: CONTENTS*
The safety of LYSTEDA in the treatment of heavy menstrual bleeding (HMB) was studied in two randomized, The drug passes into the aqueous humor of the eye achieving a concentration of approximately one tenth of Pediatric Use
INDICATIONS AND USAGE
double-blind, placebo-controlled studies [see Clinical Studies (14) ]. One study compared the effects of two doses LYSTEDA is indicated for women of reproductive age and is not intended for use in premenarcheal girls.
DOSAGE AND ADMINISTRATION
of LYSTEDA (1950 mg and 3900 mg given daily for up to 5 days during each menstrual period) versus placebo over a 3-cycle treatment duration. A total of 304 women were randomized to this study, with 115 receiving at least one LYSTEDA has not been studied in adolescents under age 18 with heavy menstrual bleeding. dose of 3900 mg/day of LYSTEDA. A second study compared the effects of LYSTEDA (3900 mg/day) versus placebo A small fraction of the tranexamic acid is metabolized.
Geriatric Use
DOSAGE FORMS AND STRENGTHS
OVERDOSAGE
over a 6-cycle treatment duration. A total of 196 women were randomized to this study, with 117 receiving at least LYSTEDA is indicated for women of reproductive age and is not intended for use by postmenopausal women.
CONTRAINDICATIONS
DESCRIPTION
one dose of LYSTEDA. In both studies, subjects were generally healthy women who had menstrual blood loss of ≥ 80 mL. Renal Impairment
Tranexamic acid is eliminated by urinary excretion primarily via glomerular filtration with more than 95% of the CLINICAL PHARMACOLOGY
The effect of renal impairment on the pharmacokinetics of LYSTEDA has not been studied. Because tranexamic dose excreted unchanged. Excretion of tranexamic acid is about 90% at 24 hours after intravenous administration In these studies, subjects were 18 to 49 years of age with a mean age of approximately 40 years, had cyclic acid is primarily eliminated via the kidneys by glomerular filtration with more than 95% excreted as unchanged of 10 mg/kg. Most elimination post intravenous administration occurred during the first 10 hours, giving an WARNINGS AND PRECAUTIONS
menses every 21-35 days, and a BMI of approximately 32 kg/m2. On average, subjects had a history of HMB for in urine, dosage adjustment in patient with renal impairment is needed [see Dosage and Administration (2.2) and apparent elimination half-life of approximately 2 hours. The mean terminal half-life of LYSTEDA is approximately approximately 10 years and 40% had fibroids as determined by transvaginal ultrasound. Approximately 70% were 11 hours. Plasma clearance of tranexamic acid is 110-116 mL/min. NONCLINICAL TOXICOLOGY
Caucasian, 25% were Black, and 5% were Asian, Native American, Pacific Islander, or Other. Seven percent (7%)of all subjects were of Hispanic origin. Women using hormonal contraception were excluded from the trials. Hepatic Impairment
13.1 Carcinogenesis, Mutagenesis, Impairment Specific Populations
The effect of hepatic impairment on the pharmacokinetics of LYSTEDA has not been studied. Because only a small The rates of discontinuation due to adverse events during the two clinical trials were comparable between LYSTEDA fraction of the drug is metabolized, dosage adjustment in patients with hepatic impairment is not needed [see ADVERSE REACTIONS
13.2 Animal Toxicology and/or Pharmacology and placebo. In the 3-cycle study, the rate in the 3900 mg LYSTEDA dose group was 0.8% as compared to 1.4% LYSTEDA is not indicated for use in pregnant women. Tranexamic acid is known to cross the placenta and appears CLINICAL STUDIES
in the placebo group. In the 6-cycle study, the rate in the LYSTEDA group was 2.4% as compared to 4.1% in the in cord blood at concentrations approximately equal to maternal concentration. There are no adequate and placebo group. Across the studies, the combined exposure to 3900 mg/day LYSTEDA was 947 cycles and the OVERDOSAGE
well-controlled studies in pregnant women [see Use in Specific Populations (8.1) ].
average duration of use was 3.4 days per cycle. DRUG INTERACTIONS
There are no known cases of intentional overdose with LYSTEDA and no subjects in the clinical program took more A list of adverse events occurring in ≥ 5% of subjects and more frequently in LYSTEDA treated subjects receiving than 2 times the prescribed amount of LYSTEDA in a 24-hour period (>7800 mg/day). However, cases of overdose Tranexamic acid is present in the mother’s milk at a concentration of about one hundredth of the corresponding HOW SUPPLIED/STORAGE AND HANDLING
3900 mg/day compared to placebo is provided in Table 2.
of tranexamic acid have been reported. Based on these reports, symptoms of overdose may include gastrointestinal serum concentrations. LYSTEDA should be used during lactation only if clearly needed [see Use in Specific PATIENT COUNSELING INFORMATION
(nausea, vomiting, diarrhea); hypotensive (e.g., orthostatic symptoms); thromboembolic (arterial, venous, embolic); Table 2: Adverse Events Reported by ≥ 5% of Subjects Treated with LYSTEDA and More Frequently in
visual impairment; mental status changes; myoclonus; or rash. No specific information is available on the treatment LYSTEDA-treated Subjects
*Sections or subsections omitted from the full
of overdose with LYSTEDA. In the event of overdose, employ the usual supportive measures (e.g., clinical monitoring USE IN SPECIFIC POPULATIONS
prescribing information are not listed
and supportive therapy) as dictated by the patient's clinical status.
LYSTEDA is indicated for women of reproductive age and is not intended for use in premenarcheal girls.
3900 mg/day
DESCRIPTION
LYSTEDA has not been studied in adolescents under age 18 with heavy menstrual bleeding. FULL PRESCRIBING INFORMATION
LYSTEDA is an antifibrinolytic drug. The chemical name is trans-4-aminomethyl-cyclohexanecarboxylic acid. The INDICATIONS AND USAGE
LYSTEDA is indicated for women of reproductive age and is not intended for use by postmenopausal women.
LYSTEDA® (tranexamic acid) Tablets is indicated for the treatment of cyclic heavy menstrual bleeding [see Clinical Number of Subjects with at Least One Adverse Event Prior to prescribing LYSTEDA, exclude endometrial pathology that can be associated with heavy menstrual bleeding. The effect of renal impairment on the disposition of LYSTEDA has not been evaluated. Urinary excretion following a single intravenous injection of tranexamic acid declines as renal function decreases. Following a single 10 mg/kg DOSAGE AND ADMINISTRATION
intravenous injection of tranexamic acid in 28 patients, the 24-hour urinary fractions of tranexamic acid with Recommended Dosage
The recommended dose of LYSTEDA for women with normal renal function is two 650 mg tablets taken three serum creatinine concentrations 1.4 – 2.8, 2.8 – 5.7, and greater than 5.7 mg/dL were 51, 39, and 19%, times daily (3900 mg/day) for a maximum of 5 days during monthly menstruation. LYSTEDA may be administered respectively. The 24-hour tranexamic acid plasma concentrations for these patients demonstrated a direct without regard to meals. Tablets should be swallowed whole and not chewed or broken apart. relationship to the degree of renal impairment. Therefore, dose adjustment is needed in patients with renalimpairment [see Dosage and Administration (2.2) ].
Renal Impairment
Tranexamic acid is a white crystalline powder. It is freely soluble in water and in glacial acetic acid and is very In patients with renal impairment, the plasma concentration of tranexamic acid increased as serum creatinine slightly soluble in ethanol and practically insoluble in ether. The molecular formula is C concentration increased [see Clinical Pharmacology (12.3) ]. Dosage adjustment is needed in patients with serum The effect of hepatic impairment on the disposition of LYSTEDA has not been evaluated. One percent and creatinine concentration higher than 1.4 mg/dL (Table 1).
Tranexamic acid tablets are provided as white oval-shaped tablets and are not scored. Each tablet is debossed with 0.5 percent of an oral dose are excreted as a dicarboxylic acid and acetylated metabolite, respectively. Because only Table 1. Dosage of LYSTEDA in Patients with Renal Impairment
the marking “XP650.” The active ingredient in each tablet is 650 mg tranexamic acid. The inactive ingredients a small fraction of the drug is metabolized, no dose adjustment is needed in patients with hepatic impairment.
contained in each tablet are: microcrystalline cellulose, colloidal silicon dioxide, pregelatinized corn starch, Drug Interactions
povidone, hypromellose, stearic acid, and magnesium stearate.
Serum Creatinine
No drug-drug interaction studies were conducted with LYSTEDA.
Adjusted Dose
Total Daily Dose
Nasal and sinus symptoms include nasal, respiratory tract and sinus congestion, sinusitis, acute sinusitis, sinus headache, allergic sinusitis and CLINICAL PHARMACOLOGY
sinus pain, and multiple allergies and seasonal allergies 12.1 Mechanism of Action
Abdominal pain includes abdominal tenderness and discomfort Because LYSTEDA is antifibrinolytic, concomitant use of hormonal contraception and LYSTEDA may further Tranexamic acid is a synthetic lysine amino acid derivative, which diminishes the dissolution of hemostatic fibrin Musculoskeletal pain includes musculoskeletal discomfort and myalgia exacerbate the increased thrombotic risk associated with combination hormonal contraceptives. Women using e Arthralgia includes joint stiffness and swelling by plasmin. In the presence of tranexamic acid, the lysine receptor binding sites of plasmin for fibrin are occupied, hormonal contraception should use LYSTEDA only if there is a strong medical need and the benefit of treatment preventing binding to fibrin monomers, thus preserving and stabilizing fibrin’s matrix structure.
Long-term Studies
will outweigh the potential increased risk of a thrombotic event [see Warnings and Precautions (5.1) and Drug Long-term safety of LYSTEDA was studied in two open-label studies. In one study, subjects with physician-diagnosed The antifibrinolytic effects of tranexamic acid are mediated by reversible interactions at multiple binding sites heavy menstrual bleeding (not using the alkaline hematin methodology) were treated with 3900 mg/day for up to within plasminogen. Native human plasminogen contains 4 to 5 lysine binding sites with low affinity for tranexamic 5 days during each menstrual period for up to 27 menstrual cycles. A total of 781 subjects were enrolled and 239 Factor IX Complex Concentrates or Anti-inhibitor Coagulant Concentrates d = 750 µmol/L) and 1 with high affinity (Kd = 1.1 µmol/L). The high affinity lysine site of plasminogen is completed the study through 27 menstrual cycles. A total of 12.4% of the subjects withdrew due to adverse events.
involved in its binding to fibrin. Saturation of the high affinity binding site with tranexamic acid displaces LYSTEDA is not recommended in patients taking either Factor IX complex concentrates or anti-inhibitor coagulant Women using hormonal contraception were excluded from the study. The total exposure in this study to plasminogen from the surface of fibrin. Although plasmin may be formed by conformational changes in concentrates because the risk of thrombosis may be increased [see Warnings and Precautions (5.1) and Drug 3900 mg/day LYSTEDA was 10,213 cycles. The average duration of LYSTEDA use was 2.9 days per cycle. plasminogen, binding to and dissolution of the fibrin matrix is inhibited.
14.2 Six-Cycle Treatment Study
PATIENT INFORMATION
What are the possible side effects of LYSTEDA?
Concomitant therapy with tissue plasminogen activators may decrease the efficacy of both LYSTEDA and tissue This study compared the effects of LYSTEDA 3900 mg/day given daily for up to 5 days during each menstrual period LYSTEDA (pronounced lye-sted-a ) tranexamic acid tablets
plasminogen activators. Therefore, exercise caution if a patient taking LYSTEDA therapy requires tissue versus placebo on MBL over a 6-cycle treatment duration. Of the 187 evaluable subjects, 115 LYSTEDA subjects LYSTEDA can cause serious side effects, including:
plasminogen activators [see Drug Interactions (7.2) ].
and 72 placebo subjects took at least one dose of study drug and had post-treatment data available. Read the Patient Information that comes with LYSTEDA before you start using Blood clots. The risk of serious blood clots may be increased when All-Trans Retinoic Acid (Oral Tretinoin) Results are shown in Table 6. MBL was statistically significantly reduced in patients treated with 3900 mg/day the drug and each time you get a refill. There may be new information. This In a study involving 28 patients with acute promyelocytic leukemia who were given either orally administered LYSTEDA compared to placebo. Study success also required achieving a reduction in MBL that was determined leaflet does not take the place of talking with your healthcare provider about hormonal contraceptives, especially if you are taking higher than your all-trans retinoic acid plus intravenously administered tranexamic acid, all-trans retinoic acid plus chemotherapy, to be clinically meaningful to the subjects.
or all-trans retinoic acid plus tranexamic acid plus chemotherapy, all 4 patients who were given all-trans retinoic Table 6. Mean Reduction from Baseline in MBL
your medical condition or your treatment.
normal dose of birth control, are overweight, or if you smoke cigarettes acid plus tranexamic acid died, with 3 of the 4 deaths due to thrombotic complications. It appears that theprocoagulant effect of all-trans retinoic acid may be exacerbated by concomitant use of tranexamic acid. Therefore, Treatment Arm
Baseline Mean
Least Squares Mean
Percent Reduction
What is LYSTEDA?
exercise caution when prescribing LYSTEDA to patients with acute promyelocytic leukemia taking all-trans retinoic Reduction in MBL (mL)
LYSTEDA is a prescription medicine used to treat your heavy monthly period acid [see Warnings and Precautions (5.1) and Drug Interactions (7.4) ]. (menstruation) when your bleeding gets in the way of social, leisure and NONCLINICAL TOXICOLOGY
Eye changes. Stop taking LYSTEDA and promptly report any eye problems physical activities. LYSTEDA does not contain any hormones. On average, 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
you have while taking LYSTEDA. Your doctor will refer you to an eye doctor LYSTEDA has been shown to lower the amount of blood lost during your Carcinogenicity studies with tranexamic acid in male mice at doses as high as 6 times the recommended human Limitations on social, leisure, and physical activities were also statistically significantly reduced in the LYSTEDA monthly period by about one-third, but it is not meant to stop your period. dose of 3900 mg/day showed an increased incidence of leukemia which may have been related to treatment.
group compared to placebo (see Table 7). No statistically significant treatment difference was observed in response Allergic reaction. If you have severe shortness of breath and your throat Female mice were not included in this experiment. rates on the number of large stains.
LYSTEDA is taken only during your period and is not meant to treat feels tight, stop taking LYSTEDA and get medical care right away.
The dose multiple referenced above is based on body surface area (mg/m2). Actual daily dose in mice was up to Table 7. Secondary Outcomes in 6-Cycle Study
pre-menstrual symptoms (symptoms that occur before your bleeding starts).
The most common side effects of LYSTEDA include: Baseline
Least Squares Mean
LYSTEDA does not affect your fertility and cannot be used as birth control.
Hyperplasia of the biliary tract and cholangioma and adenocarcinoma of the intrahepatic biliary system have been Outcome Measure
Reduction b
reported in one strain of rats after dietary administration of doses exceeding the maximum tolerated dose for LYSTEDA does not protect you against diseases that you may get if you have 22 months. Hyperplastic, but not neoplastic, lesions were reported at lower doses. Subsequent long-term dietary Social and Leisure Activities
administration studies in a different strain of rat, each with an exposure level equal to the maximum level employed in the earlier experiment, have failed to show such hyperplastic/neoplastic changes in the liver. Physical Activities
LYSTEDA has not been studied in adolescents younger than 18 years Tranexamic acid was neither mutagenic nor clastogenic in the in vitro Bacterial Reverse Mutation Assay (Ames test), in vitro chromosome aberration test in Chinese hamster cells, and in in vivo chromosome aberration tests in Responders d
Who should not take LYSTEDA?
Reduction in Large Stains
Reproductive studies performed in mice, rats and rabbits have not revealed any evidence of impaired fertility or adverse effects on the fetus due to tranexamic acid. a Response categories: 1=not at all limited; 2=slightly limited; 3=moderately limited; 4=quite a bit limited; 5=extremely limited Tell your healthcare provider if you have any side effect that bothers you or b Positive means reflect an improvement from baseline In a rat embryo-fetal developmental toxicity study, tranexamic acid had no adverse effects on embryo-fetal development when administered during the period of organogenesis (from gestation days 6 through 17) at doses d Responders are defined as subjects who experienced a reduction from baseline in frequency of large stains Have been told that you are at risk of having a blood clot 1, 2 and 4 times the recommended human oral dose of 3900 mg/day. In a perinatal-postnatal study in rats, Non-significant difference versus placebo Are allergic to LYSTEDA or tranexamic acid These are not all of the possible side effects of LYSTEDA. For more tranexamic acid had no adverse effects on pup viability, growth or development when administered from gestation 14.3 MBL Results over Time
information, ask your healthcare provider or pharmacist. day 6 through postnatal day 20 at doses 1, 2 and 4 times the recommended human oral dose of 3900 mg/day. The efficacy of LYSTEDA 3900 mg/day over 3 menstrual cycles and over 6 menstrual cycles was demonstrated What should I tell my healthcare provider before taking LYSTEDA?
The dose multiples referenced above are based on body surface area (mg/m2). Actual daily doses in rats were 300, versus placebo in the double-blind, placebo-controlled efficacy studies (see Figure 1). The change in MBL from If you notice a change in your usual bleeding pattern that worries you,
Before taking LYSTEDA, tell your healthcare provider about all of your medical baseline was similar across all post-baseline treatment cycles.
or your heavy bleeding continues, contact your healthcare provider right
13.2 Animal Toxicology and/or Pharmacology
Figure 1: MBL Levels over Duration of Therapy
away. This may be a sign of a more serious condition.
You have ever had a blood clot or been told that you are at risk of
In a 9-month toxicology study, dogs were administered tranexamic acid in food at doses of 0, 200, 600, or having a blood clot
Call your healthcare provider for medical advice about side effects. You may 1200 mg/kg/day. These doses are approximately 2, 5, and 6 times, respectively, the recommended human oral report side effects to the FDA at 1-800-FDA-1088. You may also report side dose of 3900 mg/day based on AUC. At 6 times the human dose, some dogs developed reversible reddening and You are using a form of birth control that contains hormones (like a
gelatinous discharge from the eyes. Ophthalmologic examination revealed reversible changes in the nictitating effects to Ferring Pharmaceuticals Inc. at 1-888-FERRING (1-888-337-7464). birth control pill, patch, vaginal ring or intrauterine device). Also tell your membrane/conjunctiva. In some female dogs, the presence of inflammatory exudate over the bulbar conjunctivalmucosa was observed. Histopathological examinations did not reveal any retinal alteration. No adverse effects were healthcare provider if you are taking higher than your normally-prescribed How should I store LYSTEDA?
dose of birth control. Using hormonal products along with LYSTEDA, Store LYSTEDA at room temperature between 59°F to 86°F (15°C to 30°C).
In other studies, focal areas of retinal degeneration were observed in cats, dogs and rats following oral or especially if you are overweight or smoke, may increase your chance of intravenous tranexamic acid doses at 6-40 times the recommended usual human dose based on mg/m2 (actual Keep LYSTEDA and all medicines out of the reach of children.
animal doses between 250-1600 mg/kg/day). having a serious blood clot, stroke, or heart attack.
CLINICAL STUDIES
You are pregnant or think you may be pregnant General information about LYSTEDA
The efficacy and safety of LYSTEDA in the treatment of heavy menstrual bleeding (HMB) was demonstrated in one Medicines are sometimes prescribed for conditions that are not mentioned in You are breastfeeding or plan to breast-feed. LYSTEDA can pass into your 3-cycle treatment and one 6-cycle treatment, randomized, double-blind, placebo-controlled study [see Adverse Patient Information Leaflets. Do not use LYSTEDA for a condition for which it Reactions (6) ]. In these studies, HMB was defined as an average menstrual blood loss of ≥ 80 mL as assessed by milk. Talk to your healthcare provider about the best way to feed your alkaline hematin analysis of collected sanitary products over two baseline menstrual cycles. Subjects were 18 to was not prescribed. Do not give LYSTEDA to other people, even if they have 49 years of age with a mean age of approximately 40 years, had cyclic menses every 21-35 days, and a BMI of the same symptoms that you have. It may harm them.
approximately 32 kg/m2. On average, subjects had an HMB history of approximately 10 years and 40% had fibroids The time between the start of your periods is less than 21 days or more than as determined by transvaginal ultrasound. Approximately 70% were Caucasian, 25% were Black, and 5% were This patient information leaflet summarizes the most important information Asian, Native American, Pacific Islander, or Other. Seven percent (7%) of all subjects were of Hispanic origin. about LYSTEDA. If you would like more information about LYSTEDA, talk with In these studies, the primary outcome measure was menstrual blood loss (MBL), measured using the alkaline your healthcare provider. You can ask your healthcare provider or pharmacist hematin method. The endpoint was change from baseline in MBL, calculated by subtracting the mean MBL during Tell your healthcare provider about all the medicines you take, including
treatment from the mean pretreatment MBL. HOW SUPPLIED/STORAGE AND HANDLING
for information about LYSTEDA that is written for healthcare professionals. prescription and over-the-counter medicines, vitamins, and herbal supplements.
The key secondary outcome measures were based on specific questions concerning limitations in social or leisure LYSTEDA (tranexamic acid) tablets are provided as white oval-shaped tablets. Each tablet is debossed with the For more information, go to www.lysteda.com or call 1-888-FERRING activities (LSLA) and limitations in physical activities (LPA). Large stains (soiling beyond the undergarment) were LYSTEDA and other medicines can affect each other, causing side effects.
also included as a key secondary outcome measure.
Quantity
Package Type
NDC Number
LYSTEDA can affect the way other medicines work and other medicines can 14.1 Three-Cycle Treatment Study
What are the ingredients of LYSTEDA?
This study compared the effects of two doses of LYSTEDA (1950 mg and 3900 mg given daily for up to 5 days during each menstrual period) versus placebo on MBL over a 3-cycle treatment duration. Of the 294 evaluable Especially tell your healthcare provider if you take:
subjects, 115 LYSTEDA 1950 mg/day subjects, 112 LYSTEDA 3900 mg/day subjects and 67 placebo subjects took Inactive ingredients: microcrystalline cellulose, colloidal silicon dioxide, at least one dose of study drug and had post-treatment data available. Birth control pills or other hormonal birth control pregelatinized corn starch, povidone, hypromellose, stearic acid, and Results are shown in Table 4. MBL was statistically significantly reduced in patients treated with 3900 mg/day LYSTEDA compared to placebo. Study success also required achieving a reduction in MBL that was determined Store at room temperature 25° C (77° F); excursions permitted to 15-30° C (59-86° F). [See USP Controlled Room to be clinically meaningful to the subjects. The 1950 mg/day LYSTEDA dose did not meet the criteria for success. Table 4. Mean Reduction from Baseline in MBL
PATIENT COUNSELING INFORMATION
Treatment Arm
Baseline Mean
Least Squares Mean
Percent Reduction
See FDA-approved patient labeling (Patient Information) Ask your healthcare provider if you are not sure if your medicine is one that Reduction in MBL (mL)
Instruct patients that the usual schedule is to take two tablets with liquids, three times a day during menstruation.
Patients should be instructed not to exceed 3 doses (6 tablets) in a 24-hour period or to take for more than 5 daysin any menstrual cycle. How should I take LYSTEDA?
Inform patients that they should immediately stop LYSTEDA if they notice any eye symptoms or change in their Take LYSTEDA exactly as your healthcare provider tells you. vision. Instruct them to report any such problems promptly to their physician and to follow-up with anophthalmologist for a complete ophthalmic evaluation, including dilated retinal examination of the retina. Do not take LYSTEDA until your period has started.
Inform patients that they should stop LYSTEDA and seek immediate medical attention if they notice symptoms of LYSTEDA also statistically significantly reduced limitations on social, leisure, and physical activities in the Do not take LYSTEDA for more than 5 days in a row.
a severe allergic reaction (e.g., shortness of breath or throat tightening).
3900 mg/day dose group compared to placebo (see Table 5). No statistically significant treatment difference was Do not take LYSTEDA when you do not have your period.
observed in response rates on the number of large stains. Instruct patients that common side effects of LYSTEDA include headache, sinus and nasal symptoms, back pain, abdominal pain, musculoskeletal pain, joint pain, muscle cramps, migraine, anemia and fatigue. Table 5: Secondary Outcomes in 3-Cycle Study
Once your period has started, take 2 tablets of LYSTEDA three times per Advise patients to contact their healthcare provider if their heavy menstrual bleeding symptoms persist or worsen.
Baseline
Least Squares Mean
day (e.g., in the morning, afternoon, and evening).
Outcome Measure
Reduction b
Remind patients to read the Patient Labeling carefully.
LYSTEDA tablets should be swallowed whole and not chewed or broken Social and Leisure Activities
LYSTEDA may be taken with or without food.
Physical Activities
Do not take more than 6 tablets of LYSTEDA in a day. If you take more than 6 tablets, call your healthcare provider.
Responders d
Reduction in Large Stains
If you miss a dose, take it when you remember, and then take your next dose at least six hours later. Do not take more than two tablets at a time a Response categories: 1=not at all limited; 2=slightly limited; 3=moderately limited; 4=quite a bit limited; 5=extremely limitedb Positive means reflect an improvement from baseline.
If LYSTEDA does not help to lessen bleeding with your periods after c p-value <0.05 versus placebod Responders are defined as subjects who experienced a reduction from baseline in frequency of large stains.
2 cycles or seems to stop working, talk to your healthcare provider.
e Non-significant difference versus placebo

Source: http://www.lysteda.com/assets/pi_ferring2011-cc84bfc1677818f9e319c9c77fc494b4.pdf