Antithrombin III dosage and administration

Antithrombin III
THROMBATE III® FDA Package Insert
Indications and Usage
Dosage and Administration
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Description
Clinical Pharmacology
How Supplied/Storage and Handling

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2]

Dosage and Administration

Eavv ch bottle of THROMBATE III has the functional activity, in international units (IU), stated on the label of the bottle. The potency assignment has been determined with a standard calibrated against a World Health Organization antithrombin III reference preparation.

Dosage should be determined on an individual basis based on the pre-therapy plasma ATIII level, in order to increase plasma ATIII levels to the level found in normal human plasma (80-120%). Dosage of THROMBATE III can be calculated from the following formula:

The above formula is based on an expected incremental in vivo recovery above baseline levels for Antithrombin III (Human), THROMBATE III® of 1.4% per IU per kg administered.(14) Thus, if a 70 kg individual has a baseline ATIII level of 57%, in order to increase plasma ATIII to 120%, the initial THROMBATE III dose would be [(120–57) × 70]/1.4 = 3150 IU total.

However, recovery may vary, and initially levels should be drawn at baseline and 20 minutes post infusion. Subsequent doses can be calculated based on the level achieved with the first dose. These recommendations are intended only as a guide for therapy. The exact loading dose and maintenance intervals should be individualized for each patient.

It is recommended that following an initial dose of THROMBATE III, plasma levels of ATIII be initially monitored at least every 12 hours and before the next infusion of THROMBATE III to maintain plasma ATIII levels greater than 80%. In some situations, e.g., following surgery,(26) hemorrhage or acute thrombosis, and during intravenous heparin administration,(19,27–29) the half-life of Antithrombin III (Human) has been reported to be shortened. In such conditions, plasma ATIII levels should be monitored more frequently, and THROMBATE III administered as necessary.

When an infusion of THROMBATE III is indicated for a patient with hereditary deficiency to control an acute thrombotic episode or prevent thrombosis during or following surgical or obstetrical procedures, it is desirable to raise the ATIII level to normal and maintain this level for 2 to 8 days, depending on the indication for treatment, type and extent of surgery, patient’s medical condition, past history and physician’s judgment. Concomitant administration of heparin in each of these situations should be based on the medical judgment of the physician.

As a general recommendation, the following therapeutic program may be utilized as a starting program for treatment, modifying the program based on the actual plasma ATIII levels achieved:

a) An initial loading dose of THROMBATE III calculated to elevate the plasma ATIII level to 120%, assuming an expected rise over the baseline plasma ATIII level of 1.4% (functional activity) per IU per kg of THROMBATE III administered. Thus, for an individual with a body weight of 70 kg and a baseline ATIII level of 57%, the initial THROMBATE III dose would be 3150 IU:

b) Measure preinfusion and 20 minutes postinfusion (peak) plasma ATIII levels following the initial loading dose, plasma ATIII level after 12 hours, then preceding the next infusion (trough level). Subsequently measure ATIII levels preceding and 20 minutes after each infusion until predictable peak and trough levels have been achieved, generally between 80%–120%. Plasma levels between 80%–120% may be maintained by administration of maintenance doses of 60% of the initial loading dose, administered every 24 hours. Adjustments in the maintenance dose and/or interval between doses should be made based on actual plasma ATIII levels achieved.

The above recommendations for dosing are provided as a general guideline for therapy only. The exact loading and maintenance dosages and dosing intervals should be individualized for each subject, based on the individual clinical conditions, response to therapy, and actual plasma ATIII levels achieved. In some situations, e.g., following surgery,(26) with hemorrhage or acute thrombosis and during intravenous heparin administration,(19,27–29) in vivo survival of infused THROMBATE III has been reported to be shortened, resulting in the need to administer THROMBATE III more frequently.

Antithrombin III (Human), THROMBATE III is reconstituted with Sterile Water for Injection, USP at room temperature. THROMBATE III should be filtered through a sterile filter needle as supplied in the package prior to use, and should be administered within 3 hours following reconstitution. THROMBATE III may be infused over 10–20 minutes. THROMBATE III must be administered intravenously.

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

Reconstitution

Vacuum Transfer Note: Aseptic technique should be carefully followed. All needles and vial tops that will come into contact with the product to be administered via the intravenous route should not come in contact with any nonsterile surface. Any contaminated needles should be discarded by placing in a puncture-proof container and new equipment should be used.

1. THROMBATE III and diluent should be at room temperature before reconstitution.
2. Remove shrink band from product vial. If the shrink band is absent or shows signs of tampering, do not use the product and notify Grifols Therapeutics Inc. immediately.
3. Remove the plastic flip tops from each vial (Fig. A). Cleanse vial tops (grey stoppers) with alcohol swab and allow surface to dry. After cleaning, do not allow anything to touch the stopper.
4. Carefully remove the plastic sheath from the short end of the transfer needle. Insert the exposed needle into the diluent vial to the hub (Fig. B).
5. Carefully grip the sheath of the other end of the transfer needle and twist to remove it.
6. Invert the diluent vial and insert the attached needle into the THROMBATE III vial at a 45° angle (Fig. C). This will direct the stream of diluent against the wall of the vial and minimize foaming. The vacuum will draw the diluent into the THROMBATE III vial.*
7. When diluent transfer is complete, remove the diluent vial and transfer needle (Fig. D).
8. Immediately after adding the diluent, swirl continuously until completely dissolved (Fig. E). Some foaming may occur, but attempt to avoid excessive foaming. The vial should then be visually inspected for particulate matter and discoloration prior to administration.
9. Clean the top of the vial of reconstituted THROMBATE III again with alcohol swab and let surface dry.
10. Attach the filter needle (from the package) to sterile syringe. Withdraw the THROMBATE III solution into the syringe through the filter needle (Fig. F).
11. Remove the filter needle from the syringe and replace with an appropriate injection or butterfly needle for administration. Discard filter needle into a puncture-proof container.
12. If the same patient is using more than one vial of THROMBATE III, the contents of multiple vials may be drawn into the same syringe through the filter needles provided.

• If vacuum is lost in the THROMBATE III vial during reconstitution, use a sterile syringe to remove the sterile water from the diluent vial and inject it into the THROMBATE III vial, directing the stream of fluid against the wall of the vial.

Rate of Administration

The rate of administration should be adapted to the response of the individual patient, but administration of the entire dose in 10 to 20 minutes is generally well tolerated.

How Supplied

THROMBATE III is supplied in a kit containing one single use vial of THROMBATE III lyophilized powder, one vial of Sterile Water for Injection, USP, one sterile double-ended transfer needle, and one sterile filter needle. The total activity of ATIII in International Units is stated on the label of the THROMBATE III vial.

Storage

THROMBATE III should be stored at temperatures not to exceed 25°C (77°F). Freezing should be avoided as breakage of the diluent bottle might occur.

References

Adapted from the FDA Package Insert.