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Thrombate Indications, Dosage, Storage, Stability - Antithrombin

Thrombate Indications, Dosage, Storage, Stability - Antithrombin

INDICATIONS

THROMBATE III is indicated for the treatment of patients with hereditary antithrombin III deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism. Subjects with AT-III deficiency should be informed about the risk of thrombosis in connection with pregnancy and surgery and about the inheritance of the disease.

The diagnosis of hereditary antithrombin III (AT-III) deficiency should be based on a clear family history of venous thrombosis as well as decreased plasma AT-III levels, and the exclusion of acquired deficiency.

AT-III in plasma may be measured by amidolytic assays using synthetic chromogenic substrates, by clotting assays, or by immunoassays. The latter does not detect all hereditary AT-III deficiencies.¹⁶

The AT-III level in neonates of parents with hereditary AT-III deficiency should be measured immediately after birth. (Fatal neonatal thrombo-embolism, such as aortic thrombi in children of women with hereditary antithrombin III deficiency, has been reported.)¹⁷

Plasma levels of AT-III are lower in neonates than adults, averaging approximately 60% in normal term infants.^18,19 AT-III levels in premature infants may be much lower.^18,19 Low plasma AT-III levels, especially in a premature infant, therefore, do not necessarily indicate hereditary deficiency. It is recommended that testing and treatment with Antithrombin III (Human), THROMBATE III of neonates be discussed with an expert on coagulation.¹¹

DOSAGE AND ADMINISTRATION

Each 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 antithrombin III (AT-III) level, in order to increase plasma AT-III levels to the level found in normal human plasma (100%). Dosage of THROMBATE III can be calculated from the following formula:

units required (IU) =

[desired - baseline AT-III level*] x weight (kg) 1.4

*expressed as % normal level based on f unctional AT-III assay

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.¹² Thus, if a 70 kg individual has a base-line AT-III level of 57%, in order to increase plasma AT-III to 120%, the initial THROMBATE III dose would be [(120-57) x 70]/1.4 = 3150 IU total.

However, recovery may vary, and initially levels should be drawn at base-line and 20 minutes postinfusion. Subsequent doses can be calculated based on the recovery of 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 AT-III be initially monitored at least every 12 hours and before the next infusion of THROMBATE III to maintain plasma AT-III levels greater than 80%. In some situations, e.g., following surgery,²⁰ hemorrhage or acute thrombosis, and during intravenous heparin administration,^{13, 21-23} the half-life of Antithrombin III (Human) has been reported to be shortened. In such conditions plasma AT-III 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 following surgical or obstetrical procedures, it is desirable to raise the AT-III 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 AT-III levels achieved:

a) An initial loading dose of THROMBATE III calculated to elevate the plasma AT-III level to 120%, assuming an expected rise over the base-line plasma AT-III level of 1.4% (functional activity) per IU per kg of THROMBATE III administered. Thus if an individual has a baseline AT-III level of 57%, the initial THROMBATE III dose would be (120-57)/1.4 = 45 IU/kg.

b) Measure preinfusion and 20 minutes postinfusion (peak) plasma antithrombin III levels following the initial loading dose, plasma antithrombin III level after 12 hours, then preceding the next infusion (trough level). Subsequently measure antithrombin III 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 AT-III levels achieved.

The above recommendations for dosing are provided as a general guide-line 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 AT-III levels achieved. In some situations, e.g., following surgery,²⁰ with hemorrhage or acute thrombosis and during intravenous heparin administration,^{13, 21-23} 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 should be reconstituted with Sterile Water for Injection, USP and brought to room temperature prior to administration. 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

1. Warm the unopened diluent and the concentrate to room temperature (NMT 37°C, 99°F).
2. After removing the plastic flip-top caps, aseptically cleanse the rubber stoppers of both bottles.
3. Remove the protective cover from the plastic transfer needle cartridge with tamper-proof seal and penetrate the stopper of the diluent bottle.
4. Remove the remaining portion of the plastic cartridge, invert the diluent bottle and penetrate the rubber seal on the concentrate bottle with the needle at an angle. Alternate method of transferring sterile water: With a sterile needle and syringe, withdraw the appropriate volume of diluent and transfer to the bottle of lyophilized concentrate.
5. The vacuum will draw the diluent into the concentrate bottle. Hold the diluent bottle at an angle to the concentrate bottle in order to direct the jet of diluent against the wall of the concentrate bottle. Avoid excessive foaming.
6. After removing the diluent bottle and transfer needle, swirl continuously until completely dissolved.
7. After the concentrate powder is completely dissolved, withdraw solution into the syringe through the filter needle which is supplied in the package. Replace the filter needle with an administration set (not provided) and inject intravenously.
8. If the same patient is to receive more than one bottle, the contents of two bottles may be drawn into the same syringe through a separate unused filter needle before attaching the vein needle.

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

Antithrombin III (Human), THROMBATE III is supplied in the following single use vials with the potency in international units stated on the label of each vial. A suitable volume of Sterile Water for Injection, USP, a sterile double-ended transfer needle, and a sterile filter needle are provided.

NDC Number	Approximate Antithrombin III Potency	Diluent
0026-0603-20	500 IU	10 mL
0026-0603-30	1000 IU	20 mL

STORAGE

THROMBATE III should be stored under refrigeration (2-8°C; 36-46°F). Freezing should be avoided as breakage of the diluent bottle might occur.

CAUTION U.S. federal law prohibits dispensing without prescription.

LIMITED WARRANTY

A number of factors beyond our control could reduce the efficacy of this product or even result in an ill effect following its use. These include improper storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration, and biological differences in individual patients. Because of these factors, it is important that this product be stored properly, that the directions be followed carefully during use, and that the risk of transmitting viruses be carefully weighed before the product is prescribed.

No warranty, express or implied, including any warranty of merchantability or fitness is made. Representatives of the Company are not authorized to vary the terms or the contents of the printed labeling, including the package insert for this product, except by printed notice from the Company's headquarters. The prescriber and user of this product must accept the terms hereof.

REFERENCES

1. Cohn EJ, Strong LE, Hughes WL Jr, et al: Preparation and properties of serum and plasma proteins. IV. A system for the separation into fractions of the protein and lipoprotein components of biological tissues and fluids. J Am Chem Soc 68(3):459-75,1946.
2. Rosenberg RD, Bauer KA, Marcum JA: Antithrombin III ''the heparin-antithrombin system.'' Rev Hematol 2:351-416, 1986.
3. Murano G, Williams L, Miller-Andersson M: Some properties of antithrombin-III and its concentration in human plasma. Thromb Res 18(1-2):259-62, 1980.
4. Rosenberg RD: Action and interactions of antithrombin and heparin. N Engl J Med 292(3):146-51, 1975.
5. Winter JH, Fenech A, Ridley W, et al: Familial antithrombin III deficiency. Q J Med 51(204):373-95, 1982.
6. Marciniak E, Farley CH, DeSimone PA: Familial thrombosis due to antithrombin III deficiency. Blood 43(2):219-31, 1974.
7. Thaler E, Lechner K: Antithrombin III deficiency and thromboembolism. Clin Haematol 10(2):369-90, 1981.
8. Blauhut B, Necek S, Kramar H, et al: Activity of antithrombin III and effect of heparin on coagulation in shock. Thromb Res 19(6):775-82, 1980.
9. Samson D, Stirling Y, Woolf L, et al: Management of planned pregnancy in a patient with congenital antithrombin III deficiency. Br J Haematol 56(2):243-9, 1984.
10. Brandt P: Observations during the treatment of antithrombin-III deficient women with heparin and antithrombin concentrate during pregnancy, parturition, and abortion. Thromb Res 22(1-2):15-24, 1981.
11. Hellgren M, Tengborn L, Abildgaard U: Pregnancy in women with congenital antithrombin III deficiency: experience of treatment with heparin and antithrombin. Gynecol Obstet Invest 14(2):127-41, 1982.
12. Schwartz RS, Bauer KA, Rosenberg RD, at al: Clinical experience with antithrombin III concentrate in treatment of congenital and acquired deficiency of antithrombin. Am J Med 87 (Suppl 3B): 53S-60S, 1989.
13. Collen D, Schetz J, de Cock F, et al: Metabolism of antithrombin III (heparin cofactor) in man: effects of venous thrombosis and of heparin administration. Eur J Clin Invest 7(1):27-35, 1977.
14. Knot E.R. de Jong E, ten Cate JW, et al: Purified radiolabeled antithrombin III metabolism in three families with hereditary AT III deficiency: application of a three-compartment model. Blood 67(1):93-8, 1986.
15. Tengborn L, Frohm B, Nilsson LE, et a]: Antithrombin III concentrate: its catabolism in health and in antithrombin III deficiency. Scand J Clin Lab Invest 41(5):469-77, 1981.
16. Sas G, Blasko G, Banhegyi D, et al: Abnormal antithrombin III (antithrombin III ''Budapest'') as a cause of familial thrombophilia. Thromb Diath Haemorrh 32(1):105-15, 1974.
17. Bjarke B, Herin P, Blomback M: Neonatal aortic thrombosis. A possible clinical manifestation of congenital antithrombin III deficiency. Acta Paediatr Scand 63:297-301, 1974.
18. Hathaway WE, Bonnar J: Perinatal coagulation. New York, Grune & Stratton, 1978, p.68.
19. Peters M, Jansen E ten Cate JW, et al: Neonatal antithrombin III. Br J Haematol 58(4):579-87, 1984.
20. Mannucci PM, Boyer C, Wolf M, et al: Treatment of congenital antithrombin III deficiency with concentrates. Br J Haematol 50(3):531-5, 1982.
21. Marciniak E, Gockerman JP: Heparin-induced decrease in circulating antithrombin-III. Lancet 2(8038):581-4, 1977.
22. O'Brien JR, Etherington MD: Effect of heparin and warfarin on antithrombin III. Lancet 2(8050):1232, 1977.
23. Kakkar VV, Bentley PG, Scully MF, et al: Antithrombin III and heparin. Lancet 1(8159):103-4, 1980.

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