Antithrombin, Recombinant

Trade Names:ATryn- Injection, lyophilized powder for solution 1,750 units (recombinant)

Trade Names:Thrombate III- Injection, lyophilized powder for solution 500 units (human)

Pharmacology

Regulates hemostasis by neutralizing the activity of thrombin and factor Xa by forming a complex that is removed from the circulation.

Forms a covalent bond with thrombin, resulting in an inactive complex. Thrombate III is also capable of inactivating other components of the coagulation cascade, including factors IXa, Xa, XIa, and XIIa, as well as plasmin.

Pharmacokinetics

Distribution

At doses of 50 and 100 units/kg, the apparent Vd is 126.2 and 156.1 mL/kg, respectively.

Elimination

At doses of 50 and 100 units/kg, the Cl is 9.6 and 7.2 mL/h/kg, respectively. At doses of 50 and 100 units/kg, the half-lives are 11.6 and 17.7 h, respectively.

The biologic half-life was 2.5 days based on immunologic assays and 3.8 days based on functional assays of antithrombin III (AT-III).

Indications and Usage

Prevention of perioperative and peripartum thromboembolic events in hereditary AT-deficient patients.

For the treatment of patients with hereditary AT-III deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism.

Contraindications

Hypersensitivity to goat and goat milk proteins.

None known.

Dosage and Administration

IV

Individualize the dose based on the patient's pretreatment functional AT (expressed in percent of normal) and body weight (expressed in kg), and using therapeutic monitoring. The goal of treatment is to restore and maintain functional AT activity levels in the range of 80% to 120% of normal. Loading dose (units) = ([100 − baseline AT activity level] ÷ 1.3) × body weight (kg) Maintenance dose (units/h) = ([100 − baseline AT activity level] ÷ 5.4) × body weight (kg)

Determine the dose on an individual basis according to the pretreatment plasma AT-III level, in order to increase plasma AT-III levels to the level found in healthy human plasma. Dosage of Thrombate III can be calculated from the following formula: Units required = ([desired − baseline AT-III level expressed as percent of normal level based on functional AT-III assay] × weight in kg) ÷ 1.4

Administer 60% of initial loading dose every 24 h to maintain plasma levels between 80% and 120%.

IV

The dose is individualized based on the patient's pretreatment functional AT (expressed in percent of normal) and body weight (expressed in kg) and using therapeutic monitoring. The goal of treatment is to restore and maintain functional AT activity levels in the range of 80% to 120% of normal. Loading dose (units) = ([100 − baseline AT activity level] ÷ 2.3) × body weight (kg) Maintenance dose (units/h) = ([100 − baseline AT activity level] ÷ 10.2) × body weight (kg)

Determine the dose on an individual basis based on the pretreatment plasma AT-III level, in order to increase plasma AT-III levels to the level found in normal human plasma. Dosage of Thrombate III can be calculated from the following formula: Units required = ([desired − baseline AT-III level expressed as percent of normal level based on functional AT-III assay] × weight in kg) ÷ 1.4

Administer 60% of initial loading dose every 24 h to maintain plasma levels between 80% and 120%.

IV

2 h after the initiation of treatment, if the AT level is less than 80% of normal, increase the dose by 30% and recheck the AT level 2 h after each dose adjustment. 2 h after the initiation of treatment, if the AT level is 80% to 120% of normal, no dosage adjustment is needed, and recheck the AT level 6 h after initiation of treatment or dose adjustment. 2 h after initiation of treatment, if the AT level is more than 120% of normal, decrease the dose by 30% and recheck the AT level 2 h after each dose adjustment.

Measure preinfusion and 20 min postinfusion (peak) plasma AT-III levels following the initial loading dose, plasma AT-III level after 12 h, then preceding the next infusion (trough level). Subsequently measure levels preceding and 20 min after each infusion until predictable peak and trough levels have been achieved, generally between 80% and 120%.

General Advice

• ATryn
• Administer loading dose as a 15-min IV infusion, immediately followed by a continuous infusion of the maintenance dose.
• Bring vials to room temperature no more than 3 h prior to reconstitution.
• Reconstitute with 10 mL of sterile water for injection immediately prior to use.
• Do not shake.
• Do not use solution containing visible particulates or if solution is discolored or cloudy.
• Administer using an infusion set with a 0.22 micron pore-size, in-line filter.
• Treatment should be initiated prior to delivery or approximately 24 h prior to surgery to ensure that the plasma AT level is in the target range at that time.
• Continue treatment until adequate follow-on anticoagulation is established.

• Thrombate III
• Do not refrigerate after reconstitution.
• After reconstitution, administer alone without mixing with other agents or diluting solutions.
• When administration is indicated for a patient with hereditary deficiency to control an acute thrombotic episode or prevent thrombosis following surgery 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, type and extent of surgery, patient's medical condition, past history, and health care provider's judgment.
• The exact loading and maintenance dosages and dosing interval should be individualized for each patient, based on the clinical condition, response to therapy, and actual plasma AT-III levels achieved.
• Reconstitute with sterile water for injection and bring to room temperature before administration.
• Filter through the sterile filter needle supplied in the package prior to administration and administer within 3 h of reconstitution.
• Infuse over 10 to 20 min.

Storage/Stability

Store refrigerated at 36° to 46°F. Administer contents of infusion syringes or diluted solution within 8 to 12 h of preparation when stored at 68° to 77°F.

Store at temperatures not exceeding 77°F. Avoid freezing. Administer within 3 h after reconstitution.

Drug Interactions

Effects are enhanced by AT. The half-life of AT may be altered by concurrent treatment with these anticoagulants because of an altered AT turnover.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hematoma (2%).

CNS

Dizziness, light-headedness.

Dermatologic

Hives.

EENT

Film over eye.

GI

Bowel fullness, foul taste in mouth, nausea.

Genitourinary

Hematuria (2%).

Hematologic-Lymphatic

Hemorrhage including intra-abdominal, hemarthrosis, and postprocedural (at least 5%).

Hepatic

Abnormal hepatic enzymes (2%).

Local

Infusion-site reaction (at least 5%); application-site pruritus (2%).

Respiratory

Shortness of breath.

Miscellaneous

Feeling hot, noncardiac chest pain (2%).

Chest pain, chest tightness, chills, cramps, fever, oozing and hematoma formation.

Precautions

Pregnancy

Category C .

Category B .

Lactation

Excreted in breast milk.

Undetermined.

Children

Safety and efficacy not established.

Elderly

Use with caution, usually starting at the low end of the dosage range, because of the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapy.

Hypersensitivity

Allergic-type hypersensitivity reactions may occur. If hives, generalized urticaria, chest tightness, wheezing, hypotension, or anaphylaxis occur during administration, immediately discontinue treatment and administer emergency treatment.

Infections

Because Thrombate III is prepared from human plasma, there is a risk of transmitting infectious agents (eg, viruses), including Creutzfeldt-Jakob disease.

Overdosage

Symptoms

No information.

Patient Information

• ATryn
• Instruct patients to inform health care provider about past or present known hypersensitivity to goat or goat milk proteins prior to treatment.
• Advise patients to notify health care provider immediately if they develop signs of hypersensitivity reactions, including anaphylaxis, chest tightness, generalized urticaria, hives, hypotension, and wheezing.
• Advise patients to notify health care provider if they develop any bleeding events while being treated with antithrombin.

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