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Antithrombin

Pronunciation

(an tee THROM bin)

Index Terms

  • Antithrombin Alfa
  • Antithrombin III
  • AT
  • AT-III
  • hpAT
  • rhAT
  • rhATIII

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, powder for reconstitution [human, preservative free]:

Thrombate III: 500 units, 1000 units [contains heparin; exact potency labeled on each vial]

Injection, powder for reconstitution [recombinant, preservative free]:

ATryn: 525 units, 1750 units [contains goat protein; exact potency labeled on each vial]

Brand Names: U.S.

  • ATryn
  • Thrombate III

Pharmacologic Category

  • Anticoagulant
  • Blood Product Derivative

Pharmacology

Antithrombin is the primary physiologic inhibitor of in vivo coagulation. It is an alpha2-globulin. Its principal actions are the inactivation of thrombin, plasmin, and other active serine proteases of coagulation, including factors IXa, Xa, XIa, and XIIa. The inactivation of proteases is a major step in the normal clotting process. The strong activation of clotting enzymes at the site of every bleeding injury facilitates fibrin formation and maintains normal hemostasis. Thrombosis in the circulation would be caused by active serine proteases if they were not inhibited by antithrombin after the localized clotting process (Schwartz, 1989).

In patients with hereditary antithrombin (AT) deficiency, spontaneous thrombosis may occur due to decreased AT concentrations; therapy with human or recombinant AT restores functional AT activity.

Distribution

Recombinant derived (ATryn): Vd: Pregnant women: 14.3 L; Nonpregnant patients: 7.7 L

Half-Life Elimination

Plasma derived (Thrombate III): Biologic: 2.5 days (immunologic assay); 3.8 days (functional AT assay). Half-life may be decreased following surgery, with hemorrhage, acute thrombosis, and/or during heparin administration.

Recombinant derived (ATryn): 12-18 hours; surgery, childbirth hemorrhage, and/or concomitant heparin may shorten half-life

Use: Labeled Indications

Treatment and prevention of antithrombin deficiency: Thrombate III: Treatment and prevention of thromboembolism and prevention of peri-operative and peri-partum thromboembolism in patients with hereditary antithrombin (AT) deficiency.

Prevention of thromboembolic events: ATryn: Prevention of perioperative and peripartum thromboembolic events in patients with hereditary antithrombin deficiency.

Limitations of use: Not indicated for treatment of thromboembolic events in patients with hereditary antithrombin deficiency.

Contraindications

ATryn: Known hypersensitivity to goat and goat milk proteins

Thrombate III: There are no contraindications listed in manufacturer's labeling.

Dosing: Adult

Antithrombin deficiency: IV:

ATryn: Prophylaxis of thrombosis during perioperative and peripartum procedures:

Dosing is individualized based on pretherapy antithrombin (AT) activity levels. Therapy should begin before delivery or ~24 hours prior to surgery to obtain target AT activity levels. Dosing should be targeted to keep levels between 80% to 120% of normal. Loading dose should be given as a 15-minute infusion, followed by maintenance dose as a continuous infusion. Doses may be calculated based on the following formulas:

Surgical patients (nonpregnant):

Loading dose: [(100 - baseline AT activity level) divided by 2.3] x body weight (kg) = units of antithrombin required

Maintenance infusion: [(100 - baseline AT activity level) divided by 10.2] x body weight (kg) = units of antithrombin required/hour

Pregnant patients: Note: Pregnant women undergoing surgical procedures (other than a Cesarean section) should also be dosed according to the formula below.

Loading dose: [(100 - baseline AT activity level) divided by 1.3] x body weight (kg) = units of antithrombin required

Maintenance infusion: [(100 - baseline AT activity level) divided by 5.4] x body weight (kg) = units of antithrombin required/hour

Dosing adjustments: Adjustments should be made based on AT activity levels to maintain levels between 80% to 120% of normal. Surgery or delivery may rapidly decrease AT levels; check AT level just after surgery or delivery. The first AT level should be obtained 2 hours after initiation and adjusted as follows:

AT activity level <80%: Increase dose by 30%; recheck AT level 2 hours after adjustment. Alternatively, an additional bolus dose (using loading dose formula) may be needed to rapidly restore AT levels. Calculate the additional bolus/loading dose using the last available AT activity result. After additional loading/bolus dose given, resume maintenance infusion at the same rate prior to bolus administration.

AT activity level 80% to 120%: No dosage adjustment needed; recheck AT level in 6 hours

AT activity level >120%: Decrease dose by 30%; recheck AT level 2 hours after adjustment

Thrombate III: Prophylaxis of thrombosis during surgical or obstetrical procedures or treatment of thromboembolism:

Initial loading dose: Dosing is individualized based on pretherapy antithrombin (AT) levels. The initial dose should raise AT levels to 120% and may be calculated based on the following formula:

[(desired AT level % - baseline AT level %) x body weight (kg)] divided by 1.4 = units of antithrombin required

For example, if a 70 kg adult patient had a baseline AT level of 57%, the initial dose would be

[(120% - 57%) x 70] divided by 1.4 = 3150 units

Maintenance dose: In general, subsequent dosing should be targeted to keep levels between 80% to 120% which may be achieved by administering 60% of the initial loading dose every 24 hours. Adjustments may be made by adjusting dose or interval. Maintain level within normal range for 2-8 days depending on type of procedure/situation.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Reconstitution

ATryn: Bring vial to room temperature prior to reconstitution (≤3 hours). Reconstitute with sterile water for injection. Do not shake; swirl to mix. May administer solution following reconstitution or may further dilute in 0.9% NS to a concentration of 100 units/mL and administer.

Thrombate III: Bring drug and diluent to room temperature prior to reconstitution. Reconstitute with sterile water for injection. Do not shake; swirl to mix to avoid foaming. Filter through sterile filter needle provided prior to administration.

Administration

Administer intravenously.

ATryn: Infuse loading dose over 15 minutes, followed immediately by a continuous maintenance infusion. Administer reconstituted solution (without further dilution) or further diluted 100 units/mL solution. Filter during administration using an infusion set with a 0.22 micron in-line filter.

Thrombate III: Infuse over 10 to 20 minutes.

Dietary Considerations

Some products may contain sodium.

Storage

ATryn: Store intact vials at 2°C to 8°C (38°F to 46°F). Do not shake; swirl to mix. Use within 24 hours after reconstitution when stored at 20°C to 25°C (68°F to 77°F) . Discard any unused portion.

Thrombate III: Store intact vials at temperatures not exceeding 25°C (77°F); avoid freezing. Administer within 3 hours after reconstitution. Do not refrigerate reconstituted product.

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Apixaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

Dabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Consider therapy modification

Edoxaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of edoxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Management: Some limited combined use may be indicated during periods of transition from one anticoagulant to another. See the full edoxaban drug monograph for specific recommendations on switching anticoagulant treatment. Avoid combination

Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone. Consider therapy modification

Hemin: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Heparin: Antithrombin may enhance the anticoagulant effect of Heparin. Monitor therapy

Heparin (Low Molecular Weight): Antithrombin may enhance the anticoagulant effect of Heparin (Low Molecular Weight). Monitor therapy

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Consider therapy modification

Ibritumomab: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy

Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Monitor therapy

Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Avoid combination

Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Monitor therapy

Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Salicylates: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Monitor therapy

Tibolone: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Anticoagulants may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse effects may be increased. Monitor therapy

Urokinase: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Avoid combination

Adverse Reactions

1% to 10%:

Cardiovascular: Chest pain (≤2%)

Central nervous system: Dizziness (2%)

Gastrointestinal: Liver enzyme abnormalities (≤2%)

Genitourinary: Hematuria (≤2%)

Hematologic & oncologic: Hemorrhage (≥5%), hematoma (≤2%)

Local: Infusion site reaction (≥5%)

Neuromuscular & skeletal: Hemarthrosis (≤2%)

<1% (Limited to important or life-threatening): Chest tightness, chills, dizziness, dyspnea, fever, film over eye, gastrointestinal fullness, muscle cramps, nausea, unpleasant taste, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity reactions: Hypersensitivity reactions, including severe hypersensitivity reactions (eg, anaphylaxis), may occur; monitor closely during infusions. If hypersensitivity symptoms occur, discontinue immediately and institute supportive emergency care.

• Infections: Thrombate III: Thrombate III is AT collected from pooled human plasma (hpAT). A product of human plasma, it may potentially contain infectious agents which could transmit disease, including the Creutzfeldt-Jakob Disease (CJD) agent; screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces this risk. Infections suspected to be transmitted by this product should be reported to the manufacturer.

Special populations:

• Pregnancy: ATryn: Pharmacokinetics of the recombinant-derived product are influenced by pregnancy; distinct dosing recommendations are provided for pregnant women.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Immunogenic potential: ATryn: ATryn is AT manufactured using recombinant technology (rhAT). Recombinant human AT, also known as antithrombin alfa, is produced by transgenic goats expressing recombinant human AT in their milk, which is then collected and purified. Antibodies against the recombinant antithrombin protein (or goat-milk protein) may theoretically develop and lead to an immunological reaction. A postmarketing patient registry has been created to monitor for antibody development; physicians are encouraged to enroll by contacting the manufacturer at 1-800-610-3776.

• Pharmacokinetic differences: Half-life and clearance differ significantly (~7 to 9 times) between the plasma-derived and the recombinant-derived product.

Monitoring Parameters

ATryn: Monitor antithrombin activity level at baseline, 2 hours after initiation (and each dosage adjustment), and thereafter, at least once or twice daily when predictable levels achieved (between 80% and 120%). Monitor for hypersensitivity reactions.

Thrombate III: Initially, monitor antithrombin (AT) at baseline, 20 minutes postinfusion (peak), 12 hours postinfusion, then preceding next infusion (trough level). Measure peak and trough AT levels with each subsequent dose until predictable levels achieved (between 80% and 120%). Some situations (eg, following surgery, hemorrhage or acute thrombosis, concurrent IV heparin administration), may require more frequent AT monitoring.

Antithrombin (AT) concentrations in neonates of parents with hereditary AT deficiency should be measured immediately after birth.

Pregnancy Risk Factor

B (Thrombate III); C (ATryn)

Pregnancy Considerations

ATryn: Adverse events were observed in some animal reproduction studies. An increased risk of adverse fetal or neonatal effects has not been observed in studies involving a limited number of pregnant women in their 3rd trimester. Pharmacokinetic studies in pregnant women using the recombinant product showed an increase in clearance and volume of distribution compared to nonpregnant patients. Therefore, distinct initial dosing recommendations are provided for pregnant women compared to nonpregnant patients.

Thrombate III: Adverse events were not observed in animal reproduction studies. Dosing recommendations do not differ for obstetric patients compared to nonpregnant patients.

In patients with hereditary antithrombin (AT) deficiency, the risk of thromboembolic events such as VTE is increased; pregnancy and delivery further increase this risk. These products are specifically indicated for use in pregnant women with hereditary AT deficiency to decrease this risk, although use of other agents may be preferred (Bates, 2012).

Thromboembolism has been reported in children of women with hereditary AT deficiency; AT concentrations in neonates of parents with hereditary AT deficiency should be measured immediately after birth. Plasma AT levels are typically lower in neonates and infants than in adults. Low plasma AT concentrations in neonates may not be indicative of deficiency; consultation with a coagulation expert is recommended.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience cramps or change in taste. Have patient report immediately to prescriber angina, severe dizziness, passing out, severe nausea, vomiting, burning or numbness feeling, restlessness, or shortness of breath (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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