Lysteda: Indications, Dosage, Precautions, Adverse Effects
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Lysteda - Product Information

Manufacture: Ferring Pharmaceuticals
Country: United States
Condition: Menorrhagia, Menstrual Disorders
Class: Miscellaneous coagulation modifiers
Form: Tablets
Ingredients: tranexamic acid, microcrystalline cellulose, colloidal silicon dioxide, pregelatinized corn starch, povidone, hypromellose, stearic acid, magnesium stearate

Indications and Usage

LYSTEDA (tranexamic acid, USP) Tablets is indicated for the treatment of cyclic heavy menstrual bleeding [see Clinical Studies].

Prior to prescribing LYSTEDA, exclude endometrial pathology that can be associated with heavy menstrual bleeding.

Dosage and Administration

Recommended Dosage

The recommended dose of LYSTEDA for women with normal renal function is two 650 mg tablets taken three times daily (3900 mg/day) for a maximum of 5 days during monthly menstruation. LYSTEDA may be administered without regard to meals. Tablets should be swallowed whole and not chewed or broken apart.

Renal Impairment

In patients with renal impairment, the plasma concentration of tranexamic acid increased as serum creatinine concentration increased [see Clinical Pharmacology]. Dosage adjustment is needed in patients with serum creatinine concentration higher than 1.4 mg/dL (Table 1).

Table 1. Dosage of LYSTEDA in Patients with Renal Impairment
Serum Creatinine (mg/dL)Adjusted DoseTotal Daily Dose
Cr above 1.4 and ≤ 2.81300 mg (two 650 mg tablets) two times a day for a maximum of 5 days during menstruation2600 mg
Cr above 2.8 and ≤ 5.71300 mg (two 650 mg tablets) once a day for a maximum of 5 days during menstruation1300 mg
Cr above 5.7650 mg (one 650 mg tablet) once a day for a maximum of 5 days during menstruation650 mg

Dosage Forms and Strengths

650 mg tablets

Contraindications

Thromboembolic Risk

Do not prescribe LYSTEDA to women who are

  • using combination hormonal contraception
  • known to have any of the following conditions:
    • Active thromboembolic disease (e.g., deep vein thrombosis, pulmonary embolism, or cerebral thrombosis)
    • A history of thrombosis or thromboembolism, including retinal vein or artery occlusion
    • An intrinsic risk of thrombosis or thromboembolism (e.g., thrombogenic valvular disease, thrombogenic cardiac rhythm disease, or hypercoagulopathy)

Venous and arterial thrombosis or thromboembolism, as well as cases of retinal artery and retinal vein occlusions, have been reported with tranexamic acid.

Hypersensitivity to Tranexamic Acid

Do not prescribe LYSTEDA to women with known hypersensitivity to tranexamic acid [see Warnings and Precautions and Adverse Reactions].

Warnings and Precautions

Thromboembolic Risk

Concomitant Use of Hormonal Contraceptives

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 contraceptives are administered with LYSTEDA. This is of particular concern in women who are obese or smoke cigarettes, especially smokers over 35 years of age.

Women using hormonal contraception were excluded from the clinical trials supporting the safety and efficacy of LYSTEDA, and there are no clinical trial data on the risk of thrombotic events with the concomitant use of LYSTEDA with hormonal contraceptives. However, there have been US postmarketing reports of venous and arterial thrombotic events in women who have used LYSTEDA concomitantly with combination hormonal contraceptives. For this reason, concomitant use of LYSTEDA with combination hormonal contraceptives is contraindicated. [see Contraindications and Drug Interactions].

Factor IX Complex Concentrates or Anti-Inhibitor Coagulant Concentrates

LYSTEDA is not recommended for women taking either Factor IX complex concentrates or anti-inhibitor coagulant concentrates because the risk of thrombosis may be increased [see Drug Interactions and Clinical Pharmacology].

All-Trans Retinoic Acid (Oral Tretinoin)

Exercise caution when prescribing LYSTEDA to women with acute promyelocytic leukemia taking all-trans retinoic acid for remission induction because of possible exacerbation of the procoagulant effect of all-trans retinoic acid [see Drug Interactions (7.4) and Clinical Pharmacology (12.3)].

Ocular Effects

Retinal venous and arterial occlusion has been reported in patients using tranexamic acid. Patients should be instructed to report visual and ocular symptoms promptly. In the event of such symptoms, patients should be instructed 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.

Severe Allergic Reaction

A case of severe allergic reaction to LYSTEDA was reported in the clinical trials, involving a subject who experienced dyspnea, tightening of her throat, and facial flushing that required emergency medical treatment. A case of anaphylactic shock has also been reported in the literature, involving a patient who received an intravenous bolus of tranexamic acid.

Subarachnoid Hemorrhage

Cerebral edema and cerebral infarction may be caused by use of LYSTEDA in women with subarachnoid hemorrhage.

Ligneous Conjunctivitis

Ligneous conjunctivitis has been reported in patients taking tranexamic acid. The conjunctivitis resolved following cessation of the drug.

Adverse Reactions

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Short-term Studies

The safety of LYSTEDA in the treatment of heavy menstrual bleeding (HMB) was studied in two randomized, double-blind, placebo-controlled studies [see Clinical Studies]. One 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 over a 3-cycle treatment duration. A total of 304 women were randomized to this study, with 115 receiving at least one dose of 3900 mg/day of LYSTEDA. A second study compared the effects of LYSTEDA (3900 mg/day) versus placebo over a 6-cycle treatment duration. A total of 196 women were randomized to this study, with 117 receiving at least one dose of LYSTEDA. In both studies, subjects were generally healthy women who had menstrual blood loss of ≥ 80 mL.

In these studies, subjects were 18 to 49 years of age with a mean age of approximately 40 years, had cyclic menses every 21-35 days, and a BMI of approximately 32 kg/m2. On average, subjects had a history of HMB for approximately 10 years and 40% had fibroids as determined by transvaginal ultrasound. Approximately 70% were 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.

The rates of discontinuation due to adverse events during the two clinical trials were comparable between LYSTEDA and placebo. In the 3-cycle study, the rate in the 3900 mg LYSTEDA dose group was 0.8% as compared to 1.4% 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 placebo group. Across the studies, the combined exposure to 3900 mg/day LYSTEDA was 947 cycles and the average duration of use was 3.4 days per cycle.

A list of adverse events occurring in ≥ 5% of subjects and more frequently in LYSTEDA treated subjects receiving 3900 mg/day compared to placebo is provided in Table 2.

Dosage Forms and Strengths

650 mg tablets

Contraindications

Thromboembolic Risk

Do not prescribe LYSTEDA to women who are

  • using combination hormonal contraception
  • known to have any of the following conditions:
    • Active thromboembolic disease (e.g., deep vein thrombosis, pulmonary embolism, or cerebral thrombosis)
    • A history of thrombosis or thromboembolism, including retinal vein or artery occlusion
    • An intrinsic risk of thrombosis or thromboembolism (e.g., thrombogenic valvular disease, thrombogenic cardiac rhythm disease, or hypercoagulopathy)

Venous and arterial thrombosis or thromboembolism, as well as cases of retinal artery and retinal vein occlusions, have been reported with tranexamic acid.

Hypersensitivity to Tranexamic Acid

Do not prescribe LYSTEDA to women with known hypersensitivity to tranexamic acid [see Warnings and Precautions and Adverse Reactions].

Warnings and Precautions

Thromboembolic Risk

Concomitant Use of Hormonal Contraceptives

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 contraceptives are administered with LYSTEDA. This is of particular concern in women who are obese or smoke cigarettes, especially smokers over 35 years of age.

Women using hormonal contraception were excluded from the clinical trials supporting the safety and efficacy of LYSTEDA, and there are no clinical trial data on the risk of thrombotic events with the concomitant use of LYSTEDA with hormonal contraceptives. However, there have been US postmarketing reports of venous and arterial thrombotic events in women who have used LYSTEDA concomitantly with combination hormonal contraceptives. For this reason, concomitant use of LYSTEDA with combination hormonal contraceptives is contraindicated. [see Contraindications and Drug Interactions].

Factor IX Complex Concentrates or Anti-Inhibitor Coagulant Concentrates

LYSTEDA is not recommended for women taking either Factor IX complex concentrates or anti-inhibitor coagulant concentrates because the risk of thrombosis may be increased [see Drug Interactions and Clinical Pharmacology].

All-Trans Retinoic Acid (Oral Tretinoin)

Exercise caution when prescribing LYSTEDA to women with acute promyelocytic leukemia taking all-trans retinoic acid for remission induction because of possible exacerbation of the procoagulant effect of all-trans retinoic acid [see Drug Interactions and Clinical Pharmacology].

Ocular Effects

Retinal venous and arterial occlusion has been reported in patients using tranexamic acid. Patients should be instructed to report visual and ocular symptoms promptly. In the event of such symptoms, patients should be instructed 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.

Severe Allergic Reaction

A case of severe allergic reaction to LYSTEDA was reported in the clinical trials, involving a subject who experienced dyspnea, tightening of her throat, and facial flushing that required emergency medical treatment. A case of anaphylactic shock has also been reported in the literature, involving a patient who received an intravenous bolus of tranexamic acid.

Subarachnoid Hemorrhage

Cerebral edema and cerebral infarction may be caused by use of LYSTEDA in women with subarachnoid hemorrhage.

Ligneous Conjunctivitis

Ligneous conjunctivitis has been reported in patients taking tranexamic acid. The conjunctivitis resolved following cessation of the drug.

Adverse Reactions

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Short-term Studies

The safety of LYSTEDA in the treatment of heavy menstrual bleeding (HMB) was studied in two randomized, double-blind, placebo-controlled studies [see Clinical Studies]. One 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 over a 3-cycle treatment duration. A total of 304 women were randomized to this study, with 115 receiving at least one dose of 3900 mg/day of LYSTEDA. A second study compared the effects of LYSTEDA (3900 mg/day) versus placebo over a 6-cycle treatment duration. A total of 196 women were randomized to this study, with 117 receiving at least one dose of LYSTEDA. In both studies, subjects were generally healthy women who had menstrual blood loss of ≥ 80 mL.

In these studies, subjects were 18 to 49 years of age with a mean age of approximately 40 years, had cyclic menses every 21-35 days, and a BMI of approximately 32 kg/m2. On average, subjects had a history of HMB for approximately 10 years and 40% had fibroids as determined by transvaginal ultrasound. Approximately 70% were 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.

The rates of discontinuation due to adverse events during the two clinical trials were comparable between LYSTEDA and placebo. In the 3-cycle study, the rate in the 3900 mg LYSTEDA dose group was 0.8% as compared to 1.4% 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 placebo group. Across the studies, the combined exposure to 3900 mg/day LYSTEDA was 947 cycles and the average duration of use was 3.4 days per cycle.

A list of adverse events occurring in ≥ 5% of subjects and more frequently in LYSTEDA treated subjects receiving 3900 mg/day compared to placebo is provided in Table 2.

Table 2. Adverse Events Reported by ≥ 5% of Subjects Treated with LYSTEDA and More Frequently in LYSTEDA-treated Subjects
LYSTEDA
3900 mg/day
n (%)
(N=232)
Placebo
n (%)
(N=139)
Total Number of Adverse Events1500923
Number of Subjects with at Least One Adverse Event208 (89.7%)122 (87.8%)
HEADACHEa117 (50.4%)65 (46.8%)
NASAL and SINUS SYMPTOMSb59 (25.4%)24 (17.3%)
BACK PAIN48 (20.7%)21 (15.1%)
ABDOMINAL PAINc46 (19.8%)25 (18.0%)
MUSCULOSKELETAL PAINd26 (11.2%)4 (2.9%)
ARTHRALGIAe16 (6.9%)7 (5.0%)
MUSCLE CRAMPS and SPASMS15 (6.5%)8 (5.8%)
MIGRAINE14 (6.0%)8 (5.8%)
ANEMIA13 (5.6%)5 (3.6%)
FATIGUE12 (5.2%)6 (4.3%)

aIncludes headache and tension headache
b Nasal and sinus symptoms include nasal, respiratory tract and sinus congestion, sinusitis, acute sinusitis, sinus headache, allergic sinusitis and sinus pain, and multiple allergies and seasonal allergies
c Abdominal pain includes abdominal tenderness and discomfort
d Musculoskeletal pain includes musculoskeletal discomfort and myalgia
e Arthralgia includes joint stiffness and swelling

Long-term Studies

Long-term safety of LYSTEDA was studied in two open- label studies. In one study, subjects with physician- diagnosed heavy menstrual bleeding (not using the alkaline hematin methodology) were treated with 3900 mg/day for up to 5 days during each menstrual period for up to 27 menstrual cycles. A total of 781 subjects were enrolled and 239 completed the study through 27 menstrual cycles. A total of 12.4% of the subjects withdrew due to adverse events. Women using hormonal contraception were excluded from the study. The total exposure in this study to 3900 mg/day LYSTEDA was 10,213 cycles. The average duration of LYSTEDA use was 2.9 days per cycle.

A long-term open-label extension study of subjects from the two short-term efficacy studies was also conducted in which subjects were treated with 3900 mg/day for up to 5 days during each menstrual period for up to 9 menstrual cycles. A total of 288 subjects were enrolled and 196 subjects completed the study through 9 menstrual cycles. A total of 2.1% of the subjects withdrew due to adverse events. The total exposure to 3900 mg/day LYSTEDA in this study was 1,956 cycles. The average duration of LYSTEDA use was 3.5 days per cycle.

The types and severity of adverse events in these two long-term open-label trials were similar to those observed in the double- blind, placebo-controlled studies although the percentage of subjects reporting them was greater in the 27-month study, most likely because of the longer study duration.

A case of severe allergic reaction to LYSTEDA was reported in the extension trial, involving a subject on her fourth cycle of treatment, who experienced dyspnea, tightening of her throat, and facial flushing that required emergency medical treatment.

Postmarketing Experience

The following adverse reactions have been identified from postmarketing experience with tranexamic acid. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Based on US and worldwide postmarketing reports, the following have been reported in patients receiving tranexamic acid for various indications:

Nausea, vomiting, and diarrhea Allergic skin reactions

Anaphylactic shock and anaphylactoid reactions

Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein obstruction); cases have been associated with concomitant use of combination hormonal contraceptives

Impaired color vision and other visual disturbances Dizziness

Drug Interactions

No drug-drug interaction studies were conducted with LYSTEDA.

Hormonal Contraceptives

Because LYSTEDA is antifibrinolytic, concomitant use of hormonal contraception and LYSTEDA may further exacerbate the increased thrombotic risk associated with combination hormonal contraceptives. For this reason, concomitant use of LYSTEDA with combination hormonal contraceptives is contraindicated [see Contraindications and Warnings and Precautions].

Tissue Plasminogen Activators

Concomitant therapy with tissue plasminogen activators may decrease the efficacy of both LYSTEDA and tissue plasminogen activators. Therefore, exercise caution if a woman taking LYSTEDA therapy requires tissue plasminogen activators.

Factor IX Complex Concentrates or Anti-Inhibitor Coagulant Concentrates

LYSTEDA is not recommended for women taking either Factor IX complex concentrates or anti-inhibitor coagulant concentrates because the risk of thrombosis may be increased [see Warnings and Precautions and Clinical Pharmacology].

All-Trans Retinoic Acid (Oral Tretinoin)

Exercise caution when prescribing LYSTEDA to women with acute promyelocytic leukemia taking all-trans retinoic acid for remission induction because of possible exacerbation of the procoagulant effect of all-trans retinoic acid [see Warnings and Precautions and Clinical Pharmacology].

Use in Specific Populations

Pregnancy (Category B)

LYSTEDA is not indicated for use in pregnant women. Reproduction studies have been performed in mice, rats and rabbits and have revealed no evidence of impaired fertility or harm to the fetus due to tranexamic acid. However, tranexamic acid is known to cross the placenta and appears in cord blood at concentrations approximately equal to the maternal concentration. There are no adequate and well-controlled studies in pregnant women [see Nonclinical Toxicology ].

An embryo-fetal developmental toxicity study in rats and a perinatal developmental toxicity study in rats were conducted using tranexamic acid. No adverse effects were observed in either study at doses up to 4 times the recommended human oral dose of 3900 mg/day based on mg/m2 (actual animal dose 1500 mg/kg/day).

Nursing Mothers

Tranexamic acid is present in the mother’s milk at a concentration of about one hundredth of the corresponding serum concentration. LYSTEDA should be used during lactation only if clearly needed.

Pediatric Use

LYSTEDA is indicated for women of reproductive age and is not intended for use in premenarcheal girls. Based on a pharmacokinetic study in 20 adolescent females, 12 to 16 years of age, no dose adjustment is needed in the adolescent population [see Clinical Pharmacology].

Geriatric Use

LYSTEDA is indicated for women of reproductive age and is not intended for use by postmenopausal women.

Renal Impairment

The effect of renal impairment on the pharmacokinetics of LYSTEDA has not been studied. Because tranexamic acid is primarily eliminated via the kidneys by glomerular filtration with more than 95% excreted as unchanged in urine, dosage adjustment in patient with renal impairment is needed [see Dosage and Administration and Clinical Pharmacology].

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of LYSTEDA has not been studied. Because only a small fraction of the drug is metabolized, dosage adjustment in patients with hepatic impairment is not needed [see Clinical Pharmacology].

Overdosage

There are no known cases of intentional overdose with LYSTEDA and no subjects in the clinical program took more than 2 times the prescribed amount of LYSTEDA in a 24-hour period (>7800 mg/day). However, cases of overdose of tranexamic acid have been reported. Based on these reports, symptoms of overdose may include gastrointestinal (nausea, vomiting, diarrhea); hypotensive (e.g., orthostatic symptoms); thromboembolic (arterial, venous, embolic); visual impairment; mental status changes; myoclonus; or rash. No specific information is available on the treatment of overdose with LYSTEDA. In the event of overdose, employ the usual supportive measures (e.g., clinical monitoring and supportive therapy) as dictated by the patient's clinical status.

How Supplied/Storage and Handling

LYSTEDA (tranexamic acid, USP) tablets are provided as white oval-shaped tablets. Each tablet is debossed with the marking “FP650” and are supplied as:

QuantityPackage TypeNDC Number
30 tablets HDPE bottle 55566-2110-2
100 tablets HDPE bottle 55566-2110-1

Storage

Store at room temperature 25 °C (77 F); excursions permitted to 15-30 °C (59-86 °F). [See USP Controlled Room Temperature].

Patient Counseling Information

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 days in any menstrual cycle.

Inform patients that they should immediately stop LYSTEDA if they notice any eye symptoms or change in their vision. Instruct them to report any such problems promptly to their physician and to follow-up with an ophthalmologist for a complete ophthalmic evaluation, including dilated retinal examination of the retina.

Inform patients that they should stop LYSTEDA and seek immediate medical attention if they notice symptoms of a severe allergic reaction (e.g., shortness of breath or throat tightening).

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.

Advise patients to contact their healthcare provider if their heavy menstrual bleeding symptoms persist or worsen.

Remind patients to read the Patient Labeling carefully.