T-Syl

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T-Syl uses


RECENT MAJOR CHANGES

Contraindications (4.1) 10/2013

Warnings and Precautions (5.1) 10/2013

1 INDICATIONS AND USAGE

T-Syl tablets are indicated for the treatment of cyclic heavy menstrual bleeding [see Clinical Studies ( 14 )].

Prior to prescribing T-Syl tablets, exclude endometrial pathology that can be associated with heavy menstrual bleeding.

T-Syl tablets are an antifibrinolytic indicated for the treatment of cyclic heavy menstrual bleeding. (1)

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dose of T-Syl tablets 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. T-Syl tablets may be administered without regard to meals. Tablets should be swallowed whole and not chewed or broken apart.

2.2 Renal Impairment

In patients with renal impairment, the plasma concentration of T-Syl increased as serum creatinine concentration increased [see Clinical Pharmacology ( 12.3 )]. Dosage adjustment is needed in patients with serum creatinine concentration higher than 1.4 mg/dL (Table 1).

T-Syl Tablets
Serum Creatinine

(mg/dL)

Adjusted Dose Total Daily Dose
Cr above 1.4 and

≤ 2.8

1300 mg (two 650 mg tablets) two times a day for a maximum of 5 days during menstruation 2600 mg
Cr above 2.8 and

≤ 5.7

1300 mg (two 650 mg tablets) once a day for a maximum of 5 days during menstruation 1300 mg
Cr above 5.7 650 mg (one 650 mg tablet) once a day for a maximum of 5 days during menstruation 650 mg
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3 DOSAGE FORMS AND STRENGTHS

650 mg tablets

Tablets: 650 mg (3)

4 CONTRAINDICATIONS

4.1 Thromboembolic Risk

Do not prescribe T-Syl tablets to women who are


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

4.2 Hypersensitivity to T-Syl

Do not prescribe T-Syl tablets to women with known hypersensitivity to T-Syl [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )].

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5 WARNINGS AND PRECAUTIONS

5.1 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 T-Syl tablets are antifibrinolytic, the risk of venous thromboembolism, as well as arterial thromboses such as stroke, may increase further when hormonal contraceptives are administered with T-Syl tablets. 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 T-Syl tablets, and there are no clinical trial data on the risk of thrombotic events with the concomitant use of T-Syl tablets with hormonal contraceptives. However, there have been US postmarketing reports of venous and arterial thrombotic events in women who have used T-Syl tablets concomitantly with combination hormonal contraceptives. For this reason, concomitant use of T-Syl tablets with combination hormonal contraceptives is contraindicated. [see Contraindications (4.1) and Drug Interactions (7.1) ].

Factor IX Complex Concentrates or Anti-Inhibitor Coagulant Concentrates

T-Syl tablets 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 (7.3) and Clinical Pharmacology (12.3) ].

All-Trans Retinoic Acid (Oral Tretinoin)

Exercise caution when prescribing T-Syl tablets 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 T-Syl. Patients should be instructed to report visual and ocular symptoms promptly. In the event of such symptoms, patients should be instructed to discontinue T-Syl tablets 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.

5.2 Severe Allergic Reaction

A case of severe allergic reaction to T-Syl tablets 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 T-Syl.

5.3 Subarachnoid Hemorrhage

Cerebral edema and cerebral infarction may be caused by use of T-Syl tablets in women with subarachnoid hemorrhage.

5.4 Ligneous Conjunctivitis

Ligneous conjunctivitis has been reported in patients taking T-Syl. The conjunctivitis resolved following cessation of the drug.

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6 ADVERSE REACTIONS

Most common adverse reactions in clinical trials are headache, sinus and nasal symptoms, back pain, abdominal pain, musculoskeletal pain, joint pain, muscle cramps, migraine, anemia and fatigue. (6.1)



To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.



6.1 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 T-Syl tablets in the treatment of heavy menstrual bleeding (HMB) was studied in two randomized, double-blind, placebo-controlled studies [see Clinical Studies ( 14 )]. One study compared the effects of two doses of T-Syl tablets (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 T-Syl tablets. A second study compared the effects of T-Syl tablets (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 T-Syl tablets. 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 to 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 T-Syl tablets and placebo. In the 3-cycle study, the rate in the 3900 mg T-Syl tablets dose group was 0.8% as compared to 1.4% in the placebo group. In the 6-cycle study, the rate in the T-Syl tablets group was 2.4% as compared to 4.1% in the placebo group. Across the studies, the combined exposure to 3900 mg/day T-Syl tablets 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 T-Syl tablets treated subjects receiving 3900 mg/day compared to placebo is provided in Table 2.

T-Syl

Tablets

3900 mg/day n (%)

(N=232)

Placebo

n (%)

(N=139)

Total Number of Adverse Events 1500 923
Number of Subjects with at Least One Adverse Event 208 (89.7%) 122 (87.8%)
HEADACHE a 117 (50.4%) 65 (46.8%)
NASAL & SINUS SYMPTOMS b 59 (25.4%) 24 (17.3%)
BACK PAIN 48 (20.7%) 21 (15.1%)
ABDOMINAL PAIN c 46 (19.8%) 25 (18.0%)
MUSCULOSKELETAL PAIN d 26 (11.2%) 4 (2.9%)
ARTHRALGIA e 16 (6.9%) 7 (5.0%)
MUSCLE CRAMPS & SPASMS 15 (6.5%) 8 (5.8%)
MIGRAINE 14 (6.0%) 8 (5.8%)
ANEMIA 13 (5.6%) 5 (3.6%)
FATIGUE 12 (5.2%) 6 (4.3%)

a Includes 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 T-Syl tablets 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 T-Syl tablets was 10,213 cycles. The average duration of T-Syl tablets 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 T-Syl tablets in this study was 1,956 cycles. The average duration of T-Syl tablets 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 T-Syl tablets 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified from postmarketing experience with T-Syl. 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 T-Syl for various

Indications:

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7 DRUG INTERACTIONS

No drug-drug interaction studies were conducted with T-Syl tablets.

Concomitant therapy with tissue plasminogen activators may decrease the efficacy of both T-Syl tablets and tissue plasminogen activators.

7.1 Hormonal Contraceptives

Because T-Syl tablets are antifibrinolytic, concomitant use of hormonal contraception and T-Syl tablets may further exacerbate the increased thrombotic risk associated with combination hormonal contraceptives. For this reason, concomitant use of T-Syl tablets with combination hormonal contraceptives is contraindicated [see Contraindications (4) and Warnings and Precautions ( 5.1 )].

7.2 Tissue Plasminogen Activators

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

7.3 Factor IX Complex Concentrates or Anti-Inhibitor Coagulant Concentrates

T-Syl tablets are 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 (12.3) ].

7.4 All-Trans Retinoic Acid (Oral Tretinoin)

Exercise caution when prescribing T-Syl tablets 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 ( 5.1 ) and Clinical Pharmacology ( 12.3 )].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy(CategoryB)

T-Syl tablets are 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 T-Syl. However, T-Syl 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 ( 13.1 )].

An embryo-fetal developmental toxicity study in rats and a perinatal developmental toxicity study in rats were conducted using T-Syl. 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).

8.3 Nursing Mothers

T-Syl is present in the mother’s milk at a concentration of about one hundredth of the corresponding serum concentration. T-Syl tablets should be used during lactation only if clearly needed.

8.4 Pediatric Use

T-Syl tablets are indicated for women of reproductive age and are 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 ].

8.5 Geriatric Use

T-Syl tablets are indicated for women of reproductive age and are not intended for use by postmenopausal women.

8.6 Renal Impairment

The effect of renal impairment on the pharmacokinetics of T-Syl tablets has not been studied. Because T-Syl 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 ( 12.3 )].

8.7 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of T-Syl tablets 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 ( 12.3 )].

10 OVERDOSAGE

There are no known cases of intentional overdose with T-Syl tablets and no subjects in the clinical program took more than 2 times the prescribed amount of T-Syl tablets in a 24-hour period (>7800 mg/day). However, cases of overdose of T-Syl 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 T-Syl tablets. 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.

11 DESCRIPTION

T-Syl tablets are an antifibrinolytic drug. The chemical name is trans-4-aminomethyl-cyclohexanecarboxylic acid. The structural formula is:

T-Syl is a white crystalline powder. It is freely soluble in water and in glacial acetic acid and is very slightly soluble in ethanol and practically insoluble in ether. The molecular formula is C8H15N02 and the molecular weight is 157.2.

T-Syl tablets are provided as white to off-white, oval-shaped, film coated tablets, debossed with “WPI 3720” on one side of the tablet. The active ingredient in each tablet is 650 mg T-Syl. The inactive ingredients contained in each tablet are: colloidal silicon dioxide, copovidone, crospovidone, eudragit, glyceryl behenate, lactose monohydrate, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and triethyl citrate.

Structural Formula for T-Syl

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

T-Syl is a synthetic lysine amino acid derivative, which diminishes the dissolution of hemostatic fibrin by plasmin. In the presence of T-Syl, 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 T-Syl 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 T-Syl 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 T-Syl 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.

12.2 Pharmacodynamics

T-Syl, at in vitro concentrations of 25 to 100 M, reduces by 20 to 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 T-Syl on lowering endometrial tPA activity and menstrual fluid fibrinolysis is observed in women with HMB receiving T-Syl total oral doses of 2 to 3 g/day for 5 days.

In healthy subjects, T-Syl 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. T-Syl, however, at blood concentrations of 1 and 10 mg/mL prolongs the thrombin time.

Cardiac Electrophysiology

The effect of T-Syl tablets 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) T-Syl tablets 1300 mg (two 650 mg tablets), (2) T-Syl tablets 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 T-Syl tablets. 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.

12.3 Pharmacokinetics

Absorption

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

The mean plasma pharmacokinetic parameters of T-Syl 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 T-Syl tablets are shown in Table 3.

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) 77.67 a (29.39)
AUCinf (mcg-h/mL) 80.19 (30.43) -
Tmax (h)b 2.5 (1 to 5) 2.5 (2 to 3.5)
t1/2 (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

t1/2 = terminal elimination half-life

a AUC0-tau (mcg-h/mL) = area under the drug concentration curve from time 0 to 8 hours

b Data presented as median (range)

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

Distribution

T-Syl is 3% bound to plasma proteins with no apparent binding to albumin. T-Syl 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.

T-Syl 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.

T-Syl 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 T-Syl is metabolized.

Excretion

T-Syl is eliminated by urinary excretion primarily via glomerular filtration with more than 95% of the dose excreted unchanged. Excretion of T-Syl 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 T-Syl tablets is approximately 11 hours. Plasma clearance of T-Syl is 110 to 116 mL/min.

Specific Populations

Pregnancy (Category B)

T-Syl tablets are not indicated for use in pregnant women. T-Syl 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 ( 8.1 )].

Nursing Mothers

T-Syl is present in the mother’s milk at a concentration of about one hundredth of the corresponding serum concentrations. T-Syl tablets should be used during lactation only if clearly needed [see Use in Specific Populations ( 8.3 )].

Pediatric Use

T-Syl tablets are indicated for women of reproductive age and are 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 T-Syl 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 to 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 to 25% less than those in the adult females given the same dose in a separate study. [See Use in Specific Populations (8.4)]

Geriatric Use

T-Syl tablets are indicated for women of reproductive age and are not intended for use by postmenopausal women.

Renal Impairment

The effect of renal impairment on the disposition of T-Syl tablets has not been evaluated. Urinary excretion following a single intravenous injection of T-Syl declines as renal function decreases. Following a single 10 mg/kg intravenous injection of T-Syl in 28 patients, the 24-hour urinary fractions of T-Syl with serum creatinine concentrations 1.4 to 2.8, 2.8 to 5.7, and greater than 5.7 mg/dL were 51, 39, and 19%, respectively. The 24-hour T-Syl 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 (2.2)].

Hepatic Impairment

The effect of hepatic impairment on the disposition of T-Syl tablets 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 T-Syl tablets.

Hormonal Contraceptives

Because T-Syl tablets are antifibrinolytic, concomitant use of hormonal contraception and T-Syl tablets may further exacerbate the increased thrombotic risk associated with combination hormonal contraceptives. For this reason, concomitant use of T-Syl tablets with combination hormonal contraceptives is contraindicated [see Contraindications (4) , Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 )].

Factor IX Complex Concentrates or Anti-inhibitor Coagulant Concentrates

T-Syl tablets are 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 ( 5.1 ) and Drug Interactions ( 7.3 ) ].

Tissue Plasminogen Activators

Concomitant therapy with tissue plasminogen activators may decrease the efficacy of both T-Syl tablets and tissue plasminogen activators. Therefore, exercise caution if a patient taking T-Syl tablets therapy requires tissue plasminogen activators [see Drug Interactions ( 7.2 ) ].

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 T-Syl, all-trans retinoic acid plus chemotherapy, or all-trans retinoic acid plus T-Syl plus chemotherapy, all 4 patients who were given all-trans retinoic acid plus T-Syl 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 T-Syl. Therefore, exercise caution when prescribing T-Syl tablets to patients with acute promyelocytic leukemia taking all-trans retinoic acid [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.4 )].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies with T-Syl in male mice at doses as high as 6 times the recommended human dose of 3900 mg/day showed an increased incidence of leukemia which may have been related to treatment. Female mice were not included in this experiment.

The dose multiple referenced above is based on body surface area. Actual daily dose in mice was up to 5000 mg/kg/day in food.

Hyperplasia of the biliary tract and cholangioma and adenocarcinoma of the intrahepatic biliary system have been reported in one strain of rats after dietary administration of doses exceeding the maximum tolerated dose for 22 months. Hyperplastic, but not neoplastic, lesions were reported at lower doses. Subsequent long-term dietary 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.

Mutagenesis

T-Syl 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 mice and rats.

Impairment of Fertility

Reproductive studies performed in mice, rats and rabbits have not revealed any evidence of impaired fertility or adverse effects on the fetus due to T-Syl.

In a rat embryo-fetal developmental toxicity study, T-Syl had no adverse effects on embryo-fetal development when administered during the period of organogenesis (from gestation days 6 through 17) at doses 1, 2 and 4 times the recommended human oral dose of 3900 mg/day. In a perinatal-postnatal study in rats, T-Syl had no adverse effects on pup viability, growth or development when administered from gestation day 6 through postnatal day 20 at doses 1, 2 and 4 times the recommended human oral dose of 3900 mg/day.

The dose multiples referenced above are based on body surface area (mg/m2). Actual daily doses in rats were 300, 750 or 1500 mg/kg/day.

13.2 Animal Toxicology and/or Pharmacology

Ocular Effects

In a 9-month toxicology study, dogs were administered T-Syl 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 T-Syl doses at 6 to 40 times the recommended usual human dose based on mg/m2 (actual animal doses between 250 to 1600 mg/kg/day).

14 CLINICAL STUDIES

The efficacy and safety of T-Syl tablets in the treatment of heavy menstrual bleeding was demonstrated in one 3-cycle treatment and one 6-cycle treatment, randomized, double-blind, placebo-controlled study [see Adverse Reactions ( 6 .1 )]. 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 to 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.

14.1 Three-Cycle Treatment Study

This study compared the effects of two doses of T-Syl tablets (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 T-Syl tablets 1950 mg/day subjects, 112 T-Syl tablets 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 T-Syl tablets 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 T-Syl tablets dose did not meet the criteria for success.

Treatment Arm N Baseline Mean

MBL (mL)

Least

Squares Mean

Reduction

in MBL (mL)

Percent

Reduction

in MBL

T-Syl

tablets 3900

mg/day

112 169 65* 39%
T-Syl

tablets 1950

mg/day

115 178 44 25%
Placebo 67 154 7 5%

* p<0.001 versus placebo

T-Syl tablets 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.

Outcome Measure N Baseline

Mean a

Least

Squares Mean

Reduction b

Social and Leisure Activities
3900 mg/day

T-Syl tablets

112 3.00 0.98c
Placebo 66 2.85 0.39
Physical Activities
3900 mg/day

T-Syl tablets

112 3.07 0.94c
Placebo 66 2.96 0.34
N Responders d
Reduction in Large Stains
3900 mg/day

T-Syl tablets

111 64%e
Placebo 67 52%

a Response categories: 1=not at all limited; 2=slightly limited; 3=moderately limited; 4=quite a bit limited; 5=extremely limited

b Positive means reflect an improvement from baseline.

c p-value <0.05 versus placebo

d Responders are defined as subjects who experienced a reduction from baseline in frequency of large stains.

e Non-significant difference versus placebo

14.2 Six-Cycle Treatment Study

This study compared the effects of T-Syl tablets 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 T-Syl tablets 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 T-Syl tablets compared to placebo. Study success also required achieving a reduction in MBL that was determined to be clinically meaningful to the subjects.

Treatment Arm N Baseline Mean

MBL

Least

Squares Mean

Reduction

in MBL (mL)

Percent

Reduction in

MBL

T-Syl tablets

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 T-Syl tablets group compared to placebo (see Table 7). No statistically significant treatment difference was observed in response rates on the number of large stains.

Outcome Measure N Baseline

Mean a

Least

Squares Mean

Reduction b

Social and Leisure Activities
3900 mg/day

T-Syl tablets

115 2.92 0.85c
Placebo 72 2.74 0.44
Physical Activities
3900 mg/day

T-Syl tablets

115 3.05 0.87c
Placebo 72 2.90 0.40
N Responders d
Reduction in Large Stains
3900 mg/day

T-Syl tablets

115 57%e
Placebo 72 51%

a Response categories: 1=not at all limited; 2=slightly limited; 3=moderately limited; 4=quite a bit limited; 5=extremely limited

b Positive means reflect an improvement from baseline

c p-value <0.05 versus placebo

d Responders are defined as subjects who experienced a reduction from baseline in frequency of large stains

e Non-significant difference versus placebo

14.3 MBL Results over Time

The efficacy of T-Syl tablets 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

Figure 1 - The efficacy of T-Syl tablets 3900 mg/day over 3 menstrual cycles and over 6 menstrual cycles was demonstrated versus placebo in the double-blind, placebo-controlled efficacy studies.

16 HOW SUPPLIED/STORAGE AND HANDLING

T-Syl tablets are provided as white to off-white, oval-shaped, film coated tablets. Each tablet is debossed with “WPI 3720” on one side of the tablet and are supplied as:


Quantity


Package Type


NDC Number


30 tablets


HDPE Bottle


0591-3720-30


1000 tablets


HDPE Bottle


0591-3720-10


Storage

Store at 20º to 25º C (68º to 77º F)..

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient 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 T-Syl tablets 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 T-Syl tablets 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 T-Syl tablets 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.

PATIENT INFORMATION

Tranexamic (tran-eks-am-ik) acid tablets

Read the Patient Information that comes with T-Syl tablets before you start using the drug and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What are T-Syl tablets ?

T-Syl tablets are a prescription medicine used to treat your heavy monthly period (menstruation) when your bleeding gets in the way of social, leisure and physical activities. T-Syl tablets do not contain any hormones. On average, T-Syl tablets have been shown to lower the amount of blood lost during your monthly period by about one-third, but it is not meant to stop your period.

T-Syl tablets are taken only during your period and are not meant to treat pre-menstrual symptoms (symptoms that occur before your bleeding starts). T-Syl tablets do not affect your fertility and cannot be used as birth control. T-Syl tablets do not protect you against diseases that you may get if you have unprotected sex.

T-Syl tablets have not been studied in adolescents younger than 18 years of age.

T-Syl tablets are not for women who have already gone through menopause (post-menopausal).

Who should not take t ranexamic acid tablets ?

Do not take T-Syl tablets if you:


What should I tell my healthcare provider before taking t ranexamic acid tablets ?

Before taking T-Syl tablets, tell your healthcare provider about all of your medical conditions, including whether:


Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. T-Syl tablets and other medicines can affect each other, causing side effects. T-Syl tablets can affect the way other medicines work and other medicines can affect how T-Syl tablets work.

Especially tell your healthcare provider if you take:


Ask your healthcare provider if you are not sure if your medicine is one that is described above.

How should I take t ranexamic acid tablets ?


What are the possible side effects of t ranexamic acid tablets ?

T-Syl tablets can cause serious side effects, including:


The most common side effects of T-Syl tablets include:


Tell your healthcare provider if you have any side effect that bothers you or does not go away.

These are not all of the possible side effects of T-Syl tablets. For more information, ask your healthcare provider or pharmacist.

If you notice a change in your usual bleeding pattern that worries you, or your heavy bleeding continues, contact your healthcare provider right away. This may be a sign of a more serious condition .

Call your healthcare provider for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects to Actavis at 1-800-272-5525.

How should I store t ranexamic acid tablets ?

Store T-Syl tablets at room temperature between 20º to 25º C (68º to 77º F).

Keep t ranexamic acid tablets and all medicines out of the reach of children.

General information about t ranexamic acid tablets

Medicines are sometimes prescribed for conditions that are not mentioned in Patient Information Leaflets. Do not use T-Syl tablets for a condition for which it was not prescribed. Do not give T-Syl tablets to other people, even if they have the same symptoms that you have. It may harm them.

This patient information leaflet summarizes the most important information about T-Syl tablets. If you would like more information about T-Syl tablets, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about T-Syl tablets that is written for healthcare professionals. For more information, go to www.actavis.com or call 1-800-272-5525.

What are the ingredients of T-Syl tablets ?

Active ingredient: T-Syl

Inactive ingredients: colloidal silicon dioxide, copovidone, crospovidone, eudragit, glyceryl behenate, lactose monohydrate, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and triethyl citrate.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Actavis Laboratories FL, Inc.

Fort Lauderdale, FL 33314 USA

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Revised: November 2014 197511-2

NDC 0591-3720-30


T-Syl Tablets 650 mg

PHARMACIST: PLEASE DISPENSE IN THIS CHILD-RESISTANT

CONTAINER WITH PATIENT INFORMATION LEAFLET PROVIDED.

Watson 30 Tablets Rx only

NDC 0591-3720-30 T-Syl Tablets 650 mg PHARMACIST: PLEASE DISPENSE IN THIS CHILD-RESISTANT CONTAINER WITH PATIENT INFORMATION LEAFLET PROVIDED. Watson 30 Tablets Rx only

T-Syl pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


T-Syl available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


T-Syl destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


T-Syl Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


T-Syl pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."TRANEXAMIC ACID TABLET, FILM COATED [ACTAVIS PHARMA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."TRANEXAMIC ACID: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "tranexamic acid". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming T-Syl?

Depending on the reaction of the T-Syl after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider T-Syl not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is T-Syl addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on T-Syl, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of T-Syl consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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