Prescription Drug Information: Cyklokapron

CYKLOKAPRON- tranexamic acid injection, solution
Pfizer Laboratories Div Pfizer Inc

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.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dose of CYKLOKAPRON is 10 mg/kg actual body weight intravenously administered as a single dose, immediately before tooth extractions Infuse no more than 1 mL/minute to avoid hypotension [see Warnings and Precautions (5.1)]. Following tooth extraction, CYKLOKAPRON may be administered for 2 to 8 days at a dose of 10 mg/kg actual body weight 3 to 4 times daily, intravenously.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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. Heparin may be added to CYKLOKAPRON Injection. CYKLOKAPRON Injection should NOT be mixed with blood. The drug is a synthetic amino acid and should NOT be mixed with solutions containing penicillin.

Discard any unused portion.

The diluted mixture may be stored for up to 4 hours at room temperature prior to patient administration.

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
Serum Creatinine (mg/dL) CYKLOKAPRON Intravenous Dosage
* Dose reduction is recommended for all doses, both before and after tooth extraction.
1.36 to 2.83(120 to 250 micromol/L) 10 mg/kg twice daily
2.83 to 5.66 (250 to 500 micromol/L) 10 mg/kg daily
>5.66 (>500 micromol/L) 10 mg/kg every 48 hoursor5 mg/kg every 24 hours

3 DOSAGE FORMS AND STRENGTHS

Injection: 1,000 mg tranexamic acid (100 mg/mL) clear and colorless solution in 10 mL single-dose ampules

Injection: 1,000 mg tranexamic acid (100 mg/mL) clear and colorless solution in 10 mL single-dose vials

4 CONTRAINDICATIONS

CYKLOKAPRON Injection is contraindicated:

  • 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 (5.1)].
  • In patients with hypersensitivity to tranexamic acid or any of the ingredients [ see Warnings and Precautions (5.4)].

5 WARNINGS AND PRECAUTIONS

5.1 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)].

5.2 Risk of Medication Errors Due to Incorrect Route of Administration

CYKLOKAPRON is for intravenous use only. Serious adverse reactions including seizures and cardiac arrythmias have occurred when CYKLOKAPRON was inadvertently administered intrathecally instead of intravenously.

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. Syringes containing CYKLOKAPRON should be clearly labeled with the intravenous route of administration.

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 into the neuraxial system). CYKLOKAPRON is not approved and not recommended for neuraxial administration. 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.

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

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, cromatopsia, and visual impairment have also been reported.

Anaphylaxis or anaphylactoid reactions have been reported that are suggestive of a causal relationship.

7 DRUG INTERACTIONS

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 (5.1), Use in Specific Populations (8.3)].

8 USE IN SPECIFIC POPULATIONS

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.

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