Introduction

Biosynthetic (recombinant DNA origin) preparation of human antithrombin III, a naturally occurring anticoagulant.

Uses for Antithrombin alfa

Congenital Antithrombin III Deficiency

Prevention of perioperative and peripartum thromboembolism in patients with congenital antithrombin III deficiency; designated an orphan drug by FDA for use in these conditions.

Short-term thromboprophylaxis with an appropriate anticoagulant recommended in patients with congenital antithrombin III deficiency during high-risk situations (e.g., surgery, pregnancy, postpartum period); antithrombin III concentrates may be used when anticoagulant therapy is neither feasible (e.g., due to a bleeding risk) nor sufficient.

Not indicated for treatment of thromboembolic events.

Heparin Resistance

Has been used for management of heparin resistance during cardiopulmonary bypass (CPB)^{† [off-label]}.

May reduce requirements for fresh frozen plasma and additional heparin during CPB.

Antithrombin alfa Dosage and Administration

Administration

IV Administration

Administer by IV infusion using 0.22-µm inline filter.

Reconstitution

Allow vials of antithrombin alfa (antithrombin [recombinant]) powder for injection to reach room temperature (20–25°C) ≤3 hours prior to reconstitution.

Reconstitute vial containing approximately 1750 units of drug with 10 mL sterile water for injection immediately before use; do not shake. May be further diluted (e.g., to obtain a concentration of 100 units/mL) for IV administration. Withdraw reconstituted contents of 1 or more vials (depending on calculated dose) into a sterile disposable syringe or add to an infusion bag containing 0.9% sodium chloride injection.

Administer as soon as possible or within 8–12 hours of preparation. May be stored at room temperature until administration. Discard any unused portions.

Rate of Administration

Administer initial IV loading dose over 15 minutes followed by a continuous IV maintenance infusion.

Dosage

Potency expressed in international units (IU, units) as tested against activity of the WHO reference standard. Each vial contains approximately 1750 units.

Use different dosing formulas for treatment of pregnant versus nonpregnant patients. (See Distribution: Special Populations, under Pharmacokinetics and see Elimination: Special Populations, under Pharmacokinetics.)

Adults

Congenital Antithrombin III Deficiency

Pregnant Women

Pregnant women undergoing a surgical procedure should be treated according to the dosing formula for pregnant patients. Initiate treatment prior to delivery or approximately 24 hours before surgery; continue until adequate follow-on anticoagulation is established.

Loading dose (units) = [ (100 − baseline antithrombin III activity level) / 1.3] × body weight in kg

Maintenance dose (units/hr) = [ (100 − baseline antithrombin III activity level) / 5.4] × body weight in kg

Adjust dosage based on serial monitoring of serum antithrombin III activity levels (expressed as a percentage of normal). Monitor serum antithrombin III activity levels prior to initiation of therapy and at regular intervals (i.e., once or twice daily) during therapy to achieve therapeutic antithrombin III activity levels in the range of 80–120% of normal.

Nonpregnant Surgical Patients

Initiate treatment approximately 24 hours before surgery; continue until adequate follow-on anticoagulation is established.

Loading dose (units) = [ (100 − baseline antithrombin III activity level) / 2.3] × body weight in kg

Maintenance dose (units/hr) = [ (100 − baseline antithrombin III activity level) / 10.2] × body weight in kg

Adjust dosage based on serial monitoring of serum antithrombin III activity levels (expressed as a percentage of normal). Monitor serum antithrombin III activity levels prior to initiation of therapy and at regular intervals (i.e., once or twice daily) during therapy to achieve therapeutic antithrombin III activity levels in the range of 80–120% of normal.

Dosage Adjustments

Adjust dosage based on serum antithrombin III activity levels. Obtain measurement of antithrombin III activity 2 hours following initiation of therapy. If measured activity level is <80%, increase infusion rate by 30%; if measured activity level is >120%, decrease infusion rate by 30%. Recheck serum antithrombin III activity level 2 hours after each dosage adjustment.

If initial measurement of antithrombin III activity after starting therapy is within target range of 80–120%, maintain same dosage and recheck activity level in 6 hours. Perform subsequent antithrombin III activity level measurements 2 hours after each dosage adjustment or 6 hours after each measurement that falls within the target range of 80–120%.

Obtain serum antithrombin III activity level immediately following surgery or delivery. If measured level <80%, may administer an additional loading dose using same formula for initial loading dose (substituting last available serum antithrombin III activity level for baseline value); resume maintenance infusion at previously administered rate.

Contraindications

• Known hypersensitivity to goat and goat milk proteins.

Warnings/Precautions

Warnings

Concomitant Anticoagulant Therapy

Potential for enhanced anticoagulant effects if used concomitantly with unfractionated heparin, low molecular weight heparin, or other drugs that use antithrombin III to exert their anticoagulant effects. (See Interactions.)

Perform coagulation tests (e.g., aPTT, anti-factor Xa activity) at regular and frequent intervals in patients receiving concomitant anticoagulant therapy, especially in the first few hours following initiation or withdrawal of antithrombin alfa (antithrombin [recombinant]) therapy. Closely monitor for bleeding or thrombosis.

Sensitivity Reactions

Hypersensitivity Reactions

Potential for allergic-type hypersensitivity reactions, including anaphylaxis. Closely monitor for manifestations of hypersensitivity (e.g., hives, generalized urticaria, chest tightness, wheezing, hypotension, anaphylaxis). Immediately discontinue drug and administer appropriate emergency treatment if hypersensitivity occurs.

Immunogenicity

Potential for antibody development to antithrombin alfa, goat antithrombin, or goat-milk proteins. Confirmed immunologic reactions not reported to date.

A patient registry has been established to further evaluate immunogenic potential of antithrombin alfa. Clinicians encouraged to participate by calling Lundbeck Inc. at 800-455-1141.

Specific Populations

Pregnancy

Category C.

Does not appear to be associated with an increased risk of fetal abnormalities when administered during the third trimester. However, use during pregnancy only if clearly indicated.

Lactation

Distributed into milk in low concentrations. Use with caution and only if clearly indicated.

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger patients. Select dosage with caution, initiating at low end of dosage range, because of age-related decreases in hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.

Common Adverse Effects

Hemorrhage, infusion site reactions.

Administration

IV Administration

Administer by IV infusion using 0.22-µm inline filter.

Reconstitution

Allow vials of antithrombin alfa (antithrombin [recombinant]) powder for injection to reach room temperature (20–25°C) ≤3 hours prior to reconstitution.

Reconstitute vial containing approximately 1750 units of drug with 10 mL sterile water for injection immediately before use; do not shake. May be further diluted (e.g., to obtain a concentration of 100 units/mL) for IV administration. Withdraw reconstituted contents of 1 or more vials (depending on calculated dose) into a sterile disposable syringe or add to an infusion bag containing 0.9% sodium chloride injection.

Administer as soon as possible or within 8–12 hours of preparation. May be stored at room temperature until administration. Discard any unused portions.

Rate of Administration

Administer initial IV loading dose over 15 minutes followed by a continuous IV maintenance infusion.

Dosage

Potency expressed in international units (IU, units) as tested against activity of the WHO reference standard. Each vial contains approximately 1750 units.

Use different dosing formulas for treatment of pregnant versus nonpregnant patients. (See Distribution: Special Populations, under Pharmacokinetics and see Elimination: Special Populations, under Pharmacokinetics.)

Adults

Congenital Antithrombin III Deficiency

Pregnant Women

Pregnant women undergoing a surgical procedure should be treated according to the dosing formula for pregnant patients. Initiate treatment prior to delivery or approximately 24 hours before surgery; continue until adequate follow-on anticoagulation is established.

Loading dose (units) = [ (100 − baseline antithrombin III activity level) / 1.3] × body weight in kg

Maintenance dose (units/hr) = [ (100 − baseline antithrombin III activity level) / 5.4] × body weight in kg

Adjust dosage based on serial monitoring of serum antithrombin III activity levels (expressed as a percentage of normal). Monitor serum antithrombin III activity levels prior to initiation of therapy and at regular intervals (i.e., once or twice daily) during therapy to achieve therapeutic antithrombin III activity levels in the range of 80–120% of normal.

Nonpregnant Surgical Patients

Initiate treatment approximately 24 hours before surgery; continue until adequate follow-on anticoagulation is established.

Loading dose (units) = [ (100 − baseline antithrombin III activity level) / 2.3] × body weight in kg

Maintenance dose (units/hr) = [ (100 − baseline antithrombin III activity level) / 10.2] × body weight in kg

Adjust dosage based on serial monitoring of serum antithrombin III activity levels (expressed as a percentage of normal). Monitor serum antithrombin III activity levels prior to initiation of therapy and at regular intervals (i.e., once or twice daily) during therapy to achieve therapeutic antithrombin III activity levels in the range of 80–120% of normal.

Dosage Adjustments

Adjust dosage based on serum antithrombin III activity levels. Obtain measurement of antithrombin III activity 2 hours following initiation of therapy. If measured activity level is <80%, increase infusion rate by 30%; if measured activity level is >120%, decrease infusion rate by 30%. Recheck serum antithrombin III activity level 2 hours after each dosage adjustment.

If initial measurement of antithrombin III activity after starting therapy is within target range of 80–120%, maintain same dosage and recheck activity level in 6 hours. Perform subsequent antithrombin III activity level measurements 2 hours after each dosage adjustment or 6 hours after each measurement that falls within the target range of 80–120%.

Obtain serum antithrombin III activity level immediately following surgery or delivery. If measured level <80%, may administer an additional loading dose using same formula for initial loading dose (substituting last available serum antithrombin III activity level for baseline value); resume maintenance infusion at previously administered rate.

Specific Drugs