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Lysteda

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Lysteda

Lysteda

CLINICAL PHARMACOLOGY

Mechanism of Action

Tranexamic acid is a synthetic lysine amino acid derivative, which diminishes the dissolution of hemostatic fibrin by plasmin. In the presence of tranexamic acid, the lysine receptor binding sites of plasmin for fibrin are occupied, preventing binding to fibrin monomers, thus preserving and stabilizing fibrin's matrix structure.

The antifibrinolytic effects of tranexamic acid are mediated by reversible interactions at multiple binding sites within plasminogen. Native human plasminogen contains 4 to 5 lysine binding sites with low affinity for tranexamic acid (K d = 750 μmol/L) and 1 with high affinity (Kd = 1.1 μmol/L). The high affinity lysine site of plasminogen is involved in its binding to fibrin. Saturation of the high affinity binding site with tranexamic acid displaces plasminogen from the surface of fibrin. Although plasmin may be formed by conformational changes in plasminogen, binding to and dissolution of the fibrin matrix is inhibited.

Pharmacodynamics

Tranexamic acid, at in vitro concentrations of 25 - 100 M, reduces by 20 - 60% the maximal rate of plasmin lysis of fibrin catalyzed by tissue plasminogen activator (tPA).

Elevated concentrations of endometrial, uterine, and menstrual blood tPA are observed in women with heavy menstrual bleeding (HMB) compared to women with normal menstrual blood loss. The effect of tranexamic acid on lowering endometrial tPA activity and menstrual fluid fibrinolysis is observed in women with HMB receiving tranexamic acid total oral doses of 2-3 g/day for 5 days.

In healthy subjects, tranexamic acid at blood concentrations less than 10 mg/mL has no effect on the platelet count, the coagulation time or various coagulation factors in whole blood or citrated blood. Tranexamic acid, however, at blood concentrations of 1 and 10 mg/mL prolongs the thrombin time.

Cardiac Electrophysiology

The effect of LYSTEDA on QT interval was evaluated in a randomized, single-dose, 4-way crossover study in 48 healthy females aged 18 to 49 years. Subjects received (1) LYSTEDA 1300 mg (two 650 mg tablets), (2) LYSTEDA 3900 mg (six 650 mg tablets; three times the recommended single dose), (3) moxifloxacin 400 mg, and (4) placebo. There was no significant increase in the corrected QT interval at any time up to 24 hours after the administration of either dose of LYSTEDA. Moxifloxacin, the active control, was associated with a maximum 14.11 msec mean increase in corrected QT interval (moxifloxacin – placebo) at 3 hours after administration.

Pharmacokinetics

Absorption

After a single oral administration of two 650 mg tablets of LYSTEDA, the peak plasma concentration (Cmax ) occurred at approximately 3 hours (Tmax ). The absolute bioavailability of LYSTEDA in women aged 18-49 is approximately 45%. Following multiple oral doses (two 650 mg tablets three times daily) administration of LYSTEDA for 5 days, the mean C 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 concentrations reached steady state at the 5th dose of LYSTEDA on Day 2.

The mean plasma pharmacokinetic parameters of tranexamic acid determined in 19 healthy women following a single (two 650 mg tablets) and multiple (two 650 mg tablets three times daily for 5 days) oral dose of LYSTEDA are shown in Table 3.

Table 3: Mean (CV%) Pharmacokinetic Parameters Following a Single (two 650 mg tablets) and Multiple Oral Dose (two 650 mg tablets three time daily for 5 days) Administration of LYSTEDA in 19 Healthy Women under Fasting Conditions

Parameter Arithmetic Mean (CV%)
Single dose Multiple dose
Cmax (mcg/mL) 13.83 (32.14) 16.41 (26.19)
AUCtldc (mcg•h/mL) 77.96 (31.14) 77.67a (29.39)
AUCinf (mcg•h/mL) 80.19 (30.43) -
Tmax (h)b 2.5 (1 – 5) 2.5 (2 – 3.5)
t½ (h) 11.08 (16.94) -
Cmax = maximum concentration
AUCtldc = area under the drug concentration curve from time 0 to time of last determinable concentration
AUCinf = area under the drug concentration curve from time 0 to infinity
Tmax = time to maximum concentration
t½ = terminal elimination half-life
aAUC0-tau (mcg·h/mL) = area under the drug concentration curve from time 0 to 8 hours
bData presented as median (range)

Effect of food: LYSTEDA may be administered without regard to meals. A single dose administration (two 650 mg tablets) of LYSTEDA with food increased both Cmax and AUC by 7% and 16%, respectively.

Distribution

Tranexamic acid is 3% bound to plasma proteins with no apparent binding to albumin. Tranexamic acid is distributed with an initial volume of distribution of 0.18 L/kg and steady-state apparent volume of distribution of 0.39 L/kg.

Tranexamic acid crosses the placenta. The concentration in cord blood after an intravenous injection of 10 mg/kg to pregnant women is about 30 mg/L, as high as in the maternal blood.

Tranexamic acid concentration in cerebrospinal fluid is about one tenth of the plasma concentration.

The drug passes into the aqueous humor of the eye achieving a concentration of approximately one tenth of plasma concentrations.

Metabolism

A small fraction of the tranexamic acid is metabolized.

Excretion

Tranexamic acid is eliminated by urinary excretion primarily via glomerular filtration with more than 95% of the dose excreted unchanged. Excretion of tranexamic acid is about 90% at 24 hours after intravenous administration of 10 mg/kg. Most elimination post intravenous administration occurred during the first 10 hours, giving an apparent elimination half-life of approximately 2 hours. The mean terminal half-life of LYSTEDA is approximately 11 hours. Plasma clearance of tranexamic acid is 110-116 mL/min.

Specific Populations

Pregnancy (Category B)

LYSTEDA is not indicated for use in pregnant women. Tranexamic acid is known to cross the placenta and appears in cord blood at concentrations approximately equal to maternal concentration. There are no adequate and well-controlled studies in pregnant women [see Use In Specific Populations].

Nursing Mothers

Tranexamic acid is present in the mother's milk at a concentration of about one hundredth of the corresponding serum concentrations. LYSTEDA should be used during lactation only if clearly needed [see Use in Specific Populations].

Pediatric Use

LYSTEDA is indicated for women of reproductive age and is not intended for use in premenarcheal girls. In a randomized, single dose, two-way crossover study of two dose levels (650 mg and 1,300 mg [two 650 mg tablets]), pharmacokinetics of tranexamic acid was evaluated in 20 female adolescents (12 to 16 years of age) with heavy menstrual bleeding. The Cmax and AUC values after a single oral dose of 650 mg in the adolescent females were 32 – 36% less than those after a single oral dose of 1,300 mg in the adolescent females. The Cmax and AUC values after a single oral dose of 1300 mg in the adolescent females were 20 – 25% less than those in the adult females given the same dose in a separate study. [See Use In Specific Populations]

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 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 intravenous injection of tranexamic acid in 28 patients, the 24-hour urinary fractions of tranexamic acid with serum creatinine concentrations 1.4 – 2.8, 2.8 – 5.7, and greater than 5.7 mg/dL were 51, 39, and 19%, respectively. The 24-hour tranexamic acid plasma concentrations for these patients demonstrated a direct relationship to the degree of renal impairment. Therefore, dose adjustment is needed in patients with renal impairment [see DOSAGE AND ADMINISTRATION].

Hepatic Impairment

The effect of hepatic impairment on the disposition of LYSTEDA has not been evaluated. One percent and 0.5 percent of an oral dose are excreted as a dicarboxylic acid and acetylated metabolite, respectively. Because only a small fraction of the drug is metabolized, no dose adjustment is needed in patients with hepatic impairment.

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, WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

Factor IX Complex Concentrates or Anti-inhibitor Coagulant Concentrates

LYSTEDA is not recommended in patients taking either Factor IX complex concentrates or anti-inhibitor coagulant concentrates because the risk of thrombosis may be increased [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

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 patient taking LYSTEDA therapy requires tissue plasminogen activators [see DRUG INTERACTIONS].

All-Trans Retinoic Acid (Oral Tretinoin)

In a study involving 28 patients with acute promyelocytic leukemia who were given either orally administered all-trans retinoic acid plus intravenously administered tranexamic acid, all-trans retinoic acid plus chemotherapy, or all-trans retinoic acid plus tranexamic acid plus chemotherapy, all 4 patients who were given all-trans retinoic acid plus tranexamic acid died, with 3 of the 4 deaths due to thrombotic complications. It appears that the procoagulant effect of all-trans retinoic acid may be exacerbated by concomitant use of tranexamic acid. Therefore, exercise caution when prescribing LYSTEDA to patients with acute promyelocytic leukemia taking all-trans retinoic acid [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

Animal Toxicology and/or Pharmacology

Ocular Effects

In a 9-month toxicology study, dogs were administered tranexamic acid in food at doses of 0, 200, 600, or 1200 mg/kg/day. These doses are approximately 2, 5, and 6 times, respectively, the recommended human oral dose of 3900 mg/day based on AUC. At 6 times the human dose, some dogs developed reversible reddening and gelatinous discharge from the eyes. Ophthalmologic examination revealed reversible changes in the nictitating membrane/conjunctiva. In some female dogs, the presence of inflammatory exudate over the bulbar conjunctival mucosa was observed. Histopathological examinations did not reveal any retinal alteration. No adverse effects were observed at 5 times the human dose.

In other studies, focal areas of retinal degeneration were observed in cats, dogs and rats following oral or intravenous tranexamic acid doses at 6-40 times the recommended usual human dose based on mg/m² (actual animal doses between 250-1600 mg/kg/day).

Clinical Studies

The efficacy and safety of LYSTEDA in the treatment of heavy menstrual bleeding (HMB) was demonstrated in one 3-cycle treatment and one 6-cycle treatment, randomized, double-blind, placebo-controlled study [see ADVERSE REACTIONS]. In these studies, HMB was defined as an average menstrual blood loss of ≥ 80 mL as assessed by alkaline hematin analysis of collected sanitary products over two baseline menstrual cycles. 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 an HMB history of 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.

In these studies, the primary outcome measure was menstrual blood loss (MBL), measured using the alkaline hematin method. The endpoint was change from baseline in MBL, calculated by subtracting the mean MBL during treatment from the mean pretreatment MBL.

The key secondary outcome measures were based on specific questions concerning limitations in social or leisure activities (LSLA) and limitations in physical activities (LPA). Large stains (soiling beyond the undergarment) were also included as a key secondary outcome measure.

Three-Cycle Treatment Study

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 subjects, 115 LYSTEDA 1950 mg/day subjects, 112 LYSTEDA 3900 mg/day subjects and 67 placebo subjects took at least one dose of study drug and had post-treatment data available.

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 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

Treatment Arm N Baseline Mean MBL (mL) Least Squares Mean Reduction in MBL (mL) Percent Reduction in MBL
LYSTEDA 3900 mg/day 112 169 65* 39%
LYSTEDA 1950 mg/day 115 178 44 25%
Placebo 67 154 7 5%
*p < 0.001 versus placebo

LYSTEDA also statistically significantly reduced limitations on social, leisure, and physical activities in the 3900 mg/day dose group compared to placebo (see Table 5). No statistically significant treatment difference was observed in response rates on the number of large stains.

Table 5: Secondary Outcomes in 3-Cycle Study

Outcome Measure N Baseline Mean a Least Squares Mean Reduction b
Social and Leisure Activities
  3900 mg/day LYSTEDA 112 3.00 0.98c
  Placebo 66 2.85 0.39
Physical Activities
  3900 mg/day LYSTEDA 112 3.07 0.94c
  Placebo 66 2.96 0.34
  N   Responders d
Reduction in Large Stains
  3900 mg/day LYSTEDA 111   64%e
  Placebo 67   52%
aResponse categories: 1=not at all limited; 2=slightly limited; 3=moderately limited; 4=quite a bit limited; 5=extremely limited
bPositive means reflect an improvement from baseline.
cp-value < 0.05 versus placebo
cResponders are defined as subjects who experienced a reduction from baseline in frequency of large stains.
eNon-significant difference versus placebo

Six-Cycle Treatment Study

This study compared the effects of LYSTEDA 3900 mg/day given daily for up to 5 days during each menstrual period versus placebo on MBL over a 6-cycle treatment duration. Of the 187 evaluable subjects, 115 LYSTEDA subjects and 72 placebo subjects took at least one dose of study drug and had post-treatment data available.

Results are shown in Table 6. 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 to be clinically meaningful to the subjects.

Table 6: Mean Reduction from Baseline in MBL

Treatment Arm N Baseline Mean MBL (mL) Least Squares Mean Reduction in MBL (mL) Percent Reduction in MBL
LYSTEDA 3900 mg/day 115 172 66* 38%
Placebo 72 153 18 12%
* p < 0.001 versus placebo

Limitations on social, leisure, and physical activities were also statistically significantly reduced in the LYSTEDA group compared to placebo (see Table 7). No statistically significant treatment difference was observed in response rates on the number of large stains.

Table 7: Secondary Outcomes in 6-Cycle Study

Outcome Measure N Baseline Mean a Least Squares Mean Reduction b
Social and Leisure Activities
  3900 mg/day LYSTEDA 115 2.92 0.85c
  Placebo 72 2.74 0.44
Physical Activities
  3900 mg/day LYSTEDA 115 3.05 0.87c
  Placebo 72 2.90 0.40
  N   Responders d
Reduction in Large Stains
  3900 mg/day LYSTEDA 115   57%e
  Placebo 72   51%
aResponse categories: 1=not at all limited; 2=slightly limited; 3=moderately limited; 4=quite a bit limited; 5=extremely limited
bPositive means reflect an improvement from baseline
cp-value < 0.05 versus placebo
dResponders are defined as subjects who experienced a reduction from baseline in frequency of large stains
eNon-significant difference versus placebo

MBL Results over Time

The efficacy of LYSTEDA 3900 mg/day over 3 menstrual cycles and over 6 menstrual cycles was demonstrated versus placebo in the double-blind, placebo-controlled efficacy studies (see Figure 1). The change in MBL from baseline was similar across all post-baseline treatment cycles.

Figure 1: MBL Levels over Duration of Therapy

MBL Levels over Duration of Therapy - Illustration

Last reviewed on RxList: 10/25/2013
This monograph has been modified to include the generic and brand name in many instances.

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