Cyklokapron

1 INDICATIONS AND USAGE CYKLOKAPRON ® is indicated in patients with hemophilia for short-term use (2 to 8 days) to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction. CYKLOKAPRON is an antifibrinolytic indicated in patients with hemophilia for short-term use (2 to 8 days) to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction. ( 1 )

2 DOSAGE AND ADMINISTRATION • Before Extraction: Administer 10 mg/kg actual body weight of CYKLOKAPRON intravenously with replacement therapy as a single‑dose. ( 2.1 ) • After Extraction: Administer 10 mg/kg actual body weight of CYKLOKAPRON intravenously 3 to 4 times daily for 2 to 8 days. ( 2.1 ) • Infuse undiluted solution no more than 1 mL/minute to avoid hypotension. ( 2.3 ) • Reduce the dosage for patients with renal impairment. ( 2.2 , 8.6 ) 2.1 Recommended Dosage The recommended dose of CYKLOKAPRON is 10 mg/kg actual body weight administered as a single intravenous dose immediately before tooth extractions . Following tooth extraction, CYKLOKAPRON may be administered at a dose of 10 mg/kg actual body weight intravenously 3 to 4 times daily for 2 to 8 days . 2.2 Recommended Dosage for Patients With Varying Degrees of Renal Impairment For patients with moderate to severe impaired renal function, the following dosages are recommended: Table 1. Recommended Dosage in Patients With Varying Degrees of Renal Impairment Dose reduction is recommended for all doses, both before and after tooth extraction. Serum Creatinine (mg/dL) CYKLOKAPRON Dosage 1.36 mg/dL to 2.83 mg/dL 10 mg/kg intravenously twice daily 2.83 mg/dL to 5.66 mg/dL 10 mg/kg intravenously daily >5.66 mg/dL 10 mg/kg intravenously every 48 hours or 5 mg/kg intravenously every 24 hours 2.3 Preparation and Administration CYKLOKAPRON is for intravenous administration only. CYKLOKAPRON can be administered undiluted or as a diluted solution. • Use aseptic technique to prepare CYKLOKAPRON. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. CYKLOKAPRON is a clear and colorless solution. Discard the vial if particulate matter is observed. • Calculate the dose (mg) based on the patient’s actual body weight and the total volume (mL) of CYKLOKAPRON solution required. If diluting CYKLOKAPRON , follow the instructions below: • From the diluent infusion bag, withdraw a volume equal to the volume of the CYKLOKAPRON solution required for the patient’s dose. • Withdraw the required volume of CYKLOKAPRON solution from the vial and dilute with a compatible diluent (see below) to make a final concentration of 10 mg/mL or 20 mg/mL. Discard any unused portion left in the vial. o For intravenous infusion, CYKLOKAPRON Injection may be mixed with most solutions for infusion such as electrolyte solutions, carbohydrate solutions, amino acid solutions, and Dextran solutions. o Heparin may be added to CYKLOKAPRON Injection. o CYKLOKAPRON Injection should NOT be mixed with blood. o The drug is a synthetic amino acid and should NOT be mixed with solutions containing penicillin. • Gently invert the infusion bag to mix the diluted solution. DO NOT SHAKE. • If not used immediately, store the diluted CYKLOKAPRON infusion solution at room temperature 20ºC to 25°C (68ºF to 77°F) for up to 4 hours. Administration Infuse undiluted solution no more than 1 mL/minute to avoid hypotension [see Adverse Reactions (6.2) ]. Administer the undiluted and diluted solutions intravenously according to Table 2. Table 2. Administration Rates for Undiluted and Diluted Solutions Undiluted solution Diluted solution Final concentration 100 mg/mL 10 mg/mL 20 mg/mL Administration rate 0.5 mL/minute (no more than 1 mL/minute) 5 mL/minute 2.5 mL/minute

4 CONTRAINDICATIONS CYKLOKAPRON Injection is contraindicated: • As a neuraxial (i.e., intrathecal, epidural) injection [see Warnings and Precautions (5.1) ] . • In patients with subarachnoid hemorrhage. Anecdotal experience indicates that cerebral edema and cerebral infarction may be caused by CYKLOKAPRON in such patients. • In patients with active intravascular clotting [see Warnings and Precautions (5.2) ] . • In patients with hypersensitivity to tranexamic acid or any of the ingredients [see Warnings and Precautions (5.4) ] . • As a neuraxial (i.e., intrathecal, epidural) injection. ( 4 ) • In patients with subarachnoid hemorrhage, due to risk of cerebral edema and cerebral infarction. ( 4 ) • In patients with active intravascular clotting. ( 4 ) • In patients with severe hypersensitivity reactions to tranexamic acid or any of the ingredients. ( 4 )

5 WARNINGS AND PRECAUTIONS • Risk of Thrombosis with Concomitant Use of Factor IX: Avoid concomitant use. ( 5.2 ) • Seizures: Inadvertent injection into neuraxial system may result in seizures. ( 5.3 ) • Hypersensitivity Reactions: In case of severe reaction, discontinue use and seek immediate medical attention. ( 5.4 ) • Visual Disturbances: Visual or ocular adverse effects may occur. Discontinue use if visual or ocular symptoms occur. ( 5.5 ) • Dizziness: Advise patients not to drive if dizziness occurs. ( 5.6 ) 5.1 Risk of Medication Errors Due to Incorrect Route of Administration CYKLOKAPRON is for intravenous use only. Serious , including fatal , adverse reactions including seizures and cardiac arrythmias have occurred when CYKLOKAPRON was inadvertently administered via the neuraxial route . Confirm the correct route of administration for CYKLOKAPRON and avoid confusion with other injectable solutions that might be administered at the same time as CYKLOKAPRON. Clearly label syringes containing CYKLOKAPRON with the intravenous route of administration. 5.2 Thromboembolic Risk CYKLOKAPRON is contraindicated in patients with active intravascular clotting. Tranexamic acid is an antifibrinolytic and may increase the risk of thromboembolic events. Venous and arterial thrombosis or thromboembolism has been reported in patients treated with CYKLOKAPRON. Avoid concomitant use of CYKLOKAPRON and medical products that are pro-thrombotic, as the risk of thrombosis may be increased. These medications include but are not limited to, Factor IX Complex concentrates, Anti-inhibitor Coagulant concentrates, and hormonal contraceptives [see Drug Interactions (7.1) , Use in Specific Populations (8.3) ] . 5.3 Seizures CYKLOKAPRON may cause seizures, including focal and generalized seizures. The most common setting for tranexamic acid-induced seizures has been during cardiovascular surgery (a setting in which CYKLOKAPRON is not FDA‑approved and which uses doses of up to 10‑fold higher than the recommended human dose and in patients inadvertently given tranexamic acid via the neuraxial route ). CYKLOKAPRON is contraindicated for neuraxial administration (i.e., epidural, intrathecal) . Consider dose reduction during surgery and dose adjustments for patients with clinical conditions such as renal dysfunction. Closely monitor the patient during surgery. Consider electroencephalogram (EEG) monitoring for patients with history of seizures or who experience myoclonic movements, twitching, or show evidence of focal seizures. Discontinue CYKLOKAPRON if seizures occur. 5.4 Hypersensitivity Reactions Cases of hypersensitivity reactions, including anaphylactic reactions, have occurred with use of intravenous tranexamic acid. Discontinue treatment with CYKLOKAPRON if serious reaction occurs, provide appropriate medical management, and do not restart treatment. CYKLOKAPRON is contraindicated in patients with a history of hypersensitivity to tranexamic acid. 5.5 Visual Disturbances Although not seen in humans, focal areas of retinal degeneration have been observed in cats and dogs following oral or intravenous tranexamic acid at doses between 250 to 1600 mg/kg/day (1.6 to 22 times the recommended usual human dose based on body surface area) from 6 days to 1 year. No retinal changes have been observed in eye examinations of patients treated with tranexamic acid for up to 8 years. Patients expected to be treated for greater than 3 months may consider ophthalmic monitoring including visual acuity and optical coherence tomography at regular intervals. Discontinue CYKLOKAPRON if changes in ophthalmological examination occurs. 5.6 Dizziness CYKLOKAPRON may cause dizziness. Concomitant use of other drugs that may also cause dizziness may worsen this effect. Advise patients to avoid driving or using machines until they know how CYKLOKAPRON affects them.

7 DRUG INTERACTIONS Prothrombotic Medical Products: Avoid concomitant use, can further increase the risk of thromboembolic adverse reactions associated with tranexamic acid. ( 5.2 , 7.1 , 8.3 ) 7.1 Prothrombotic Medical Products Avoid concomitant use of CYKLOKAPRON with medical products that are prothrombotic because concomitant use can further increase the risk of thromboembolic adverse reactions associated with tranexamic acid [see Warnings and Precautions (5.2) , Use in Specific Populations (8.3) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Risk of Medication Errors Due to Incorrect Route of Administration [see Warnings and Precautions (5.1) ] • Thromboembolic Risk [see Warnings and Precautions (5.2) ] • Seizures [see Warnings and Precautions (5.3) ] • Hypersensitivity Reactions [see Warnings and Precautions (5.4) ] • Visual Disturbances [see Warnings and Precautions (5.5) ] • Dizziness [see Warnings and Precautions (5.6) ] Most common adverse reactions are nausea, vomiting, diarrhea, allergic dermatitis, giddiness, hypotension, and thromboembolic events. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of 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. Gastrointestinal disturbances (nausea, vomiting, diarrhea) may occur and may resolve with dose-reduction. Allergic dermatitis and giddiness have been reported. Hypotension has been reported when intravenous injection is too rapid. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery, vein obstruction and cases associated with concomitant use of combination hormonal contraceptives) have been rarely reported in patients receiving tranexamic acid for indications other than hemorrhage prevention in patients with hemophilia. Convulsion, chromatopsia, and visual impairment have also been reported. Anaphylaxis or anaphylactoid reactions have been reported that are suggestive of a causal relationship.

8.1 Pregnancy Risk Summary Available data from published studies, case series and case reports with tranexamic acid use in pregnant women in the second and third trimester and at the time of delivery have not clarified whether there is a drug-associated risk of miscarriage or adverse maternal or fetal outcomes. There are 2 (0.02%) infant cases with structural abnormalities that resulted in death when tranexamic acid was used during conception or the first trimester of pregnancy; however, due to other confounding factors the risk of major birth defects with use of tranexamic acid during pregnancy is not clear. Tranexamic acid is known to pass the placenta and appears in cord blood at concentrations approximately equal to maternal concentration (see Data ) . Reproduction studies performed in mice, rats, and rabbits have not revealed any adverse effects on the fetus due to tranexamic acid administered during organogenesis. Doses examined were multiples of up to 3 times (mouse), 6 times (rat), and 3 times (rabbit) the maximum human dose based on body surface area in the mouse, rat, and rabbit, respectively (see Data ) . The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2–4% and 15–20%, respectively. It is not known whether tranexamic acid use in pregnant women may cause a drug-associated risk of miscarriage or adverse maternal or fetal outcomes. For decisions regarding the use of CYKLOKAPRON during pregnancy, the potential risk of CYKLOKAPRON administration on the fetus should always be considered along with the mother's clinical need for CYKLOKAPRON; an accurate risk-benefit evaluation should drive the treating physician's decision. Data Human Data Tranexamic acid passes through 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. There were 13 clinical studies that described fetal and/or neonatal functional issues such as low Apgar score, neonatal sepsis, cephalohematoma and 9 clinical studies that discussed alterations to growth including low birth weight and preterm birth at 22–36 weeks of gestation in fetuses and infants exposed to tranexamic acid in-utero. Animal Data In embryo-fetal development studies, tranexamic acid was administered to pregnant mice from Gestation Day (GD) 6 through GD 12 and rats from GD 9 through GD 14 at daily doses of 0.3 or 1.5 g/kg. There was no evidence of adverse developmental outcomes in mice and rats at multiple of 3 and 6 times the maximum recommended human dose based on body surface area in the mouse and rat, respectively. In rabbits, tranexamic acid was administered intravenously at doses of 50, 100, or 200 mg/kg/day or orally at doses of 100, 200, or 400 mg/kg/day from GD 6 through GD 18. There was no evidence of adverse developmental outcomes at dose multiples of 2 or 3 times, respectively, the maximum recommended human dose based on body surface area. Intravenous doses of 200 mg/kg/day showed slightly retarded weight gain in pregnant rabbits.