Antithrombin iii

antithrombin III is part of the drug class:

• Heparin group

This is not a complete list of antithrombin IIIdrug interactions. Ask your doctor or pharmacist for more information.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Antithrombin III falls into category B:

There are no well-done studies that have been done in humans with Antithrombin III. But in animal studies, pregnant animals were given this medication, and the babies did not show any medical issues related to this medication.

OR

In animal studies, pregnant animals were given Antithrombin III, and some babies had problems. But in human studies, pregnant women were given this medication and their babies did not have any problems related to this medication.

antithrombin III is available in the following forms:

• Injectable Solution

Antithrombin III (AT-III), an alpha 2 -glycoprotein of molecular weight 58,000, is normally present in human plasma at a concentration of approximately 12.5 mg/dL 2,3 and is the major plasma inhibitor of thrombin. 4 Inactivation of thrombin by AT-III occurs by formation of a covalent bond resulting in an inactive 1:1 stoichiometric complex between the two, involving an interaction of the active serine of thrombin and an arginine reactive site on AT-III. 4 AT-III is also capable of inactivating other components of the coagulation cascade including factors IXa, Xa, XIa, and XIIa, as well as plasmin. 4

The neutralization rate of serine proteases by AT-III proceeds slowly in the absence of heparin, but is greatly accelerated in the presence of heparin. 4 As the therapeutic antithrombotic effect in vivo of heparin is mediated by AT-III, heparin is ineffective in the absence or near absence of AT-III. 4 - 8

The prevalence of the hereditary deficiency of AT-III is estimated to be one per 2000 to 5000 in the general population. 4-7 The pattern of inheritance is autosomal dominant. In affected individuals, spontaneous episodes of thrombosis and pulmonary embolism may be associated with AT-III levels of 40%-60% of normal. 7 These episodes usually appear after the age of 20, the risk increasing with age and in association with surgery, pregnancy and delivery. The frequency of thromboembolic events in hereditary antithrombin III (AT-III) deficiency during pregnancy has been reported to be 70%, and several studies of the beneficial use of Antithrombin III (Human) concentrates during pregnancy in women with hereditary deficiency have been reported. 9 - 11 In many cases, however, no precipitating factor can be identified for venous thrombosis or pulmonary embolism. 7 Greater than 85% of individuals with hereditary AT-III deficiency have had at least one thrombotic episode by the age of 50 years. 7 In about 60% of patients thrombosis is recurrent. Clinical signs of pulmonary embolism occur in 40% of affected individuals. 7 In some individuals, treatment with oral anticoagulants leads to an increase of the endogenous levels of AT-III, and treatment with oral anticoagulants may be effective in the prevention of thrombosis in such individuals. 6,7

In clinical studies of Antithrombin III (Human), THROMBATE III conducted in 10 asymptomatic subjects with hereditary deficiency of AT-III, the mean in vivo recovery of AT-III was 1.6% per unit per kg administered based on immunologic AT-III assays, and 1.4% per unit per kg administered based on functional AT-III assays. 12 The mean 50% disappearance time (the time to fall to 50% of the peak plasma level following an initial administration) was approximately 22 hours and the biologic half-life was 2.5 days based on immunologic assays and 3.8 days based on functional assays of AT-III. 12 These values are similar to the half-life for radiolabeled Antithrombin III (Human) reported in the literature of 2.8-4.8 days. 13 - 15

In clinical studies of THROMBATE III, none of the 13 patients with hereditary AT-III deficiency and histories of thromboembolism treated prophylactically on 16 separate occasions with THROMBATE III for high thrombotic risk situations (11 surgical procedures, 5 deliveries) developed a thrombotic complication. Heparin was also administered in 3 of the 11 surgical procedures and all 5 deliveries. Eight patients with hereditary AT-III deficiency were treated therapeutically with THROMBATE III as well as heparin for major thrombotic or thromboembolic complications, with seven patients recovering. Treatment with THROMBATE III reversed heparin resistance in two patients with hereditary AT-III deficiency being treated for thrombosis or thromboembolism.

During clinical investigation of THROMBATE III, none of 12 subjects monitored for a median of 8 months (range 2-19 months) after receiving THROMBATE III, became antibody positive to human immunodeficiency virus (HIV-1). None of 14 subjects monitored for >/= 3 months demonstrated any evidence of hepatitis, either non-A, non-B hepatitis or hepatitis B.

None known.

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:

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 baseline AT-III level of 57%, in order to increase plasma AT-III 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 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:

1. An initial loading dose of THROMBATE III calculated to elevate the plasma AT-III level to 120%, assuming an expected rise over the baseline 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.
2. 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 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 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

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. After removing all items from the box, warm the sterile water (diluent) to room temperature (25°C, 77°F).
2. 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.
3. 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).
4. Carefully grip the sheath of the other end of the transfer needle and twist to remove it.
5. Invert the diluent vial and insert the attached needle into the concentrate vial at a 45°angle (Fig. C). This will direct the stream of diluent against the wall of the concentrate vial and minimize foaming. The vacuum will draw the diluent into the concentrate vial. *
6. When diluent transfer is complete, remove the diluent vial and transfer needle (Fig. D).
7. 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.
8. Clean the top of the vial of reconstituted THROMBATE III again with alcohol swab and let surface dry.
9. Attach the filter needle (from the package) to sterile syringe. Withdraw the THROMBATE III solution into the syringe through the filter needle (Fig. F).
10. 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.
11. 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.

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 is stored properly, that the directions are followed carefully during use, and that the risk of transmitting viruses is carefully weighed before the product is prescribed.

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.

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, et 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 EAR, 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 al: 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.

14-7603-007 (Rev. Aug. 2001)

Manufactured by:

Bayer Corporation

Pharmaceutical Division

Elkhart, IN 46515 USA

U.S. License No. 8

Distributed in Canada by:

Bayer Inc.

Healthcare Division

Toronto, ON M9W 1G6

THROMBATE III, Bayer Corporation; Bayer and

Bayer Cross, Bayer AG: under license Bayer Inc.