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Pharmacology
 Antithrombin III (AT-III), an alpha 2-glycoprotein of molecular weight 58000, is normally present in human plasma at a concentration of approximately 12.5mg/dL and is the major plasma inhibitor of thrombin. 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. AT-III is also capable of inactivating other components of the coagulation cascade including factors IXa, Xa, XIa, and XIIa, as well as plasmin.

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. As the therapeutic antithrombotic effect in vivo of heparin is mediated by AT-IIII, heparin is ineffective in the absence or near absence of AT-III.

The prevalence of the hereditary deficiency of AT-III is estimated to be 1 per 2000 to 5000 in the general population. 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 to 60% of normal. 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 antithrombinIII (AT-III) deficiency during pregnancy has been reported to be 70% and several studies of the beneficial use of antithrombinIII (human) concentrates during pregnancy in women with hereditary deficiency have been reported. In many cases, however, no precipitating factor can be identified for venous thrombosis or pulmonary embolism. Greater than 85% of individuals with hereditary AT-III deficiency have had at least 1thrombotic episode by the age of 50years. In about 60% of patients thrombosis is recurrent. Clinical signs of pulmonary embolism occur in 40% of affected individuals. In some individuals, treatment with oral anticoagulants leads to an increase in the endogenous levels of AT-III, and treatment with oral anticoagulants may be effective in the prevention of thrombosis in such individuals.

In clinical studies of ThrombateIII conducted in 10 asymptomatic subjects with hereditary deficiency at 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. The mean 50% disappearance time (the time to fall to 50% of the peak plasma level following an initial administration) was approximately 22hours and the biologic half-life was 2.5days based on immunologic assays and 3.8 days based on functional assays of AT-III. These values are similar to the half-life for radiolabeled antithrombinIII (human) reported in the literature of 2.8 to 4.8days.

In clinical studies of ThrombateIII, none of 13patients with hereditary AT-III deficiency and histories of thromboembolism treated prophylactically on 16separate occasions with ThrombateIII for high thrombotic risk situations (11surgical procedures, 5deliveries) developed a thrombotic complication. Heparin was also administered in 3 of the 11surgical procedures and all 5deliveries. Eight patients with hereditary AT-III deficiency were treated with ThrombateIII as well as heparin for major thrombotic or thromboembolic complications, with 7patients recovering. Treatment with ThrombateIII reversed heparin resistance in 2patients with hereditary AT-III deficiency being treated for thrombosis or thromboembolism.

During clinical investigation of ThrombateIII, none of 12subjects monitored for a median of 8months (range 2 to 19months) after receiving ThrombateIII, became antibody positive to human immunodeficiency virus (HIV-1). None of 14subjects monitored for ³3months demonstrated any evidence of hepatitis B, or hepatitisC.

Indications
 Antithrombin III (AT-III), An Alpha 2-glycoprotein Of Molecular Weight 58000, Is Normally Present In Human Plasma At A Concentration Of Approximately 12.5mg/dL And Is The Major Plasma Inhibitor Of Thrombin. 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. AT-III Is Also Capable Of Inactivating Other Components Of The Coagulation Cascade Including Factors IXa, Xa, XIa, And XIIa, As Well As Plasmin.

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. As The Therapeutic Antithrombotic Effect In Vivo Of Heparin Is Mediated By AT-IIII, Heparin Is Ineffective In The Absence Or Near Absence Of AT-III.

The Prevalence Of The Hereditary Deficiency Of AT-III Is Estimated To Be 1 Per 2000 To 5000 In The General Population. 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 To 60% Of Normal. 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 AntithrombinIII (AT-III) Deficiency During Pregnancy Has Been Reported To Be 70% And Several Studies Of The Beneficial Use Of AntithrombinIII (human) Concentrates During Pregnancy In Women With Hereditary Deficiency Have Been Reported. In Many Cases, However, No Precipitating Factor Can Be Identified For Venous Thrombosis Or Pulmonary Embolism. Greater Than 85% Of Individuals With Hereditary AT-III Deficiency Have Had At Least 1thrombotic Episode By The Age Of 50years. In About 60% Of Patients Thrombosis Is Recurrent. Clinical Signs Of Pulmonary Embolism Occur In 40% Of Affected Individuals. In Some Individuals, Treatment With Oral Anticoagulants Leads To An Increase In The Endogenous Levels Of AT-III, And Treatment With Oral Anticoagulants May Be Effective In The Prevention Of Thrombosis In Such Individuals.

In Clinical Studies Of ThrombateIII Conducted In 10 Asymptomatic Subjects With Hereditary Deficiency At 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. The Mean 50% Disappearance Time (the Time To Fall To 50% Of The Peak Plasma Level Following An Initial Administration) Was Approximately 22hours And The Biologic Half-life Was 2.5days Based On Immunologic Assays And 3.8 Days Based On Functional Assays Of AT-III. These Values Are Similar To The Half-life For Radiolabeled AntithrombinIII (human) Reported In The Literature Of 2.8 To 4.8days.

In Clinical Studies Of ThrombateIII, None Of 13patients With Hereditary AT-III Deficiency And Histories Of Thromboembolism Treated Prophylactically On 16separate Occasions With ThrombateIII For High Thrombotic Risk Situations (11surgical Procedures, 5deliveries) Developed A Thrombotic Complication. Heparin Was Also Administered In 3 Of The 11surgical Procedures And All 5deliveries. Eight Patients With Hereditary AT-III Deficiency Were Treated With ThrombateIII As Well As Heparin For Major Thrombotic Or Thromboembolic Complications, With 7patients Recovering. Treatment With ThrombateIII Reversed Heparin Resistance In 2patients With Hereditary AT-III Deficiency Being Treated For Thrombosis Or Thromboembolism.

During Clinical Investigation Of ThrombateIII, None Of 12subjects Monitored For A Median Of 8months (range 2 To 19months) After Receiving ThrombateIII, Became Antibody Positive To Human Immunodeficiency Virus (HIV-1). None Of 14subjects Monitored For ³3months Demonstrated Any Evidence Of Hepatitis B, Or HepatitisC.

Contraindications
 None known.

Safety Information / Warning
ThrombateIII is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly hepatitisC. All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Bayer Inc. at 1-800-622-2937 ext. 5425.

The physician should discuss the risks and benefits of this product with the patient, before prescribing or administering to the patient.

 The anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III (human) in patients with hereditary AT-III deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with antithrombin III (human).

Precautions
 General: 1. Administer within 3hours after reconstitution. Do not refrigerate after reconstitution. 2.Administer only by the i.v. route. 3.AntithrombinIII (human) should be given alone, without mixing with other agents or diluting solutions. 4.Product administration and handling of the needles must be done with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious virus including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs.

Diagnosis: 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.

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

Plasma levels of AT-III are lower in neonates than adults, averaging approximately 60% in normal term infants. AT-III levels in premature infants may be much lower. 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), of neonates be discussed with an expert on coagulation.

It is recommended that AT-III plasma levels be monitored during the treatment period.

Drug Interactions : The anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombinIII (human) in patients with hereditary AT-III deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with antithrombin III(human).

Pregnancy:  Reproduction studies have been performed in rats and rabbits at doses up to 4times the human dose and have revealed no evidence of harm to the fetus due to antithrombinIII (human). It is not known whether antithrombinIII (human) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Children: Only a few neonates and children have so far been treated with antithrombin III(human). Safety and effectiveness in children have not been established.

Side Effects / Adverse Effects
 In clinical studies involving antithrombin III (human) adverse reactions have been reported in association with 17 of 340 infusions (5%). Reported adverse reactions include: dizziness 7, nausea 3, foul taste 3, chest tightness 3, abdominal cramps 2, chills 2, fever 1, hives 1, chest pain 1, shortness of breath 1, bowel fullness 1, oozing and hematoma formation 1, film over eye 1 and lightheadedness 1.

If adverse reactions are experienced, the infusion rate should be decreased, or if indicated, the infusion should be interrupted until symptoms abate.

Overdose
Information not available

Recommended Dosage
Each bottle 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 antithrombin III (human) can be calculated from the following formula:
    
The above formula is based on an expected incremental in vivo recovery above baseline levels for antithrombinIII (human) of 1.4% per IU per kg administered. Thus, if a 70kg individual has a baseline AT-III level of 57%, in order to increase plasma AT-III to 120%, the initial antithrombin III(human) dose would be [(120-57)´70]/1.4=3150IU total.

However, recovery may vary, and initially levels should be drawn at baseline and 20minutes 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 antithrombin III (human), plasma levels of AT-III be initially monitored at least every 12hours and before the next infusion of antithrombin III (human) to maintain plasma AT-III levels greater than 80%. In some situations, e.g., following surgery, hemorrhage or acute thrombosis, and during i.v. heparin administration, the half-life of antithrombin III (human) has been reported to be shortened, and in such conditions, plasma AT-III levels should be monitored more frequently, administering antithrombin III (human) as necessary.

When an infusion of antithrombin III (human) 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 8days, 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 antithrombin III (human) 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 antithrombin III (human) administered. Thus, if an individual has a baseline AT-III level of 57%, the initial dose would be (120-57)/1.4=45IU/kg.

b) Measure pre- and 20minutes postinfusion (peak) plasma antithrombinIII levels following the initial loading dose, plasma antithrombinIII level after 12hours, then preceding the next infusion (trough level). Subsequently measure antithrombinIII levels preceding and 20minutes after each infusion until predictable peak and trough levels have been achieved, generally between 80 to 120%. Plasma levels between 80 to 120% may be maintained by administration of maintenance doses of 60% of the initial loading dose, administered every 24hours. 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, with hemorrhage or acute thrombosis and during i.v. heparin administration, in vivo survival of infused antithrombin III (human) has been reported to be shortened, resulting in the need to administer antithrombin III (human) more frequently.

Antithrombin III (human) should be reconstituted with sterile water for injection, USP and brought to room temperature prior to administration. It should be filtered through a sterile filter needle as supplied in the package prior to use, and should be administered within 3hours following reconstitution. It may be infused over 10 to 20minutes.

Antithrombin III(human) must be administered i.v.

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). 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 the administration set provided and inject i.v. 8.If the same patient is to receive more than one bottle, the contents of 2bottles 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 20minutes is generally well tolerated.

Supplied / Packaging
Each vial of sterile, stable, nonpyrogenic, lyophilized preparation contains: antithrombin III (human) 500IU or 1000IU. A suitable volume of sterile water for injection, USP, a sterile double ended transfer needle and a sterile filter needle are provided. Each vial contains the labeled amount of antithrombin III in international units (IU) per vial. The potency assignment has been determined with a standard calibrated against a World Health Organization (WHO) antithrombin III reference preparation. It is prepared from pooled units of human plasma from normal donors by modifications and refinements of the cold ethanol method of Cohn. In addition, antithrombinIII (human) has been heat-treated in solution at 60.0±0.5°C for not less than 10hours. When reconstituted, the final product has a pH of 6.0 to 7.5, a sodium content of 110 to 210mEq/L, a chloride content of 110 to 210mEq/L, an alanine content of 0.075 to 0.125M and a heparin content of NMT 0.004unit/IU AT-III. Must be administered by the i.v. route. Preservative-free. Store under refrigeration (2 to 8°C). Freezing should be avoided as breakage of the diluent bottle might occur.