2.1 Dose

• Each vial of THROMBATE III has the functional activity, in International Units (units), stated on the label of the vial. The potency assignment has been determined with a standard calibrated against a World Health Organization antithrombin reference preparation. When prepared as directed, the approximate final concentration is 50 units per milliliter.
• A guide for dosing THROMBATE III is provided in Table 1.

• Monitor functional plasma levels of AT. [see table above and Warnings and Precautions (5.3)], and adjust subsequent dosing based on the trough level achieved with the preceding dose until predictable peak and trough levels have been achieved, generally between 80% to 120% of normal.(1)
• Maintain plasma AT levels between 80% to 120% by administering maintenance doses of 60% of the loading dose, administered every 24 hours. Adjust the maintenance dose and interval between doses based on actual plasma AT levels achieved.
• Individualize the exact loading and maintenance dose and/or dose intervals for each patient based on the individual clinical conditions, response to therapy, and actual plasma AT levels achieved. Recovery of THROMBATE III may vary by patient. For example,
  • The half-life of AT has been reported to be shortened following surgery,(2) hemorrhage or acute thrombosis, and during intravenous heparin (or low molecular weight heparin) administration.(3-6) In such conditions, monitor plasma AT levels more frequently, and administer THROMBATE III as necessary. [see Warnings and Precautions (5.3), Drug Interactions (7)]
  • When an infusion of THROMBATE III is indicated for a patient with hereditary deficiency to control an acute thrombotic episode or prevent thrombosis during or following surgical or obstetrical procedures, raise the AT 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. Base the concomitant administration of heparin in each of these situations on the medical judgment of the physician. [see Drug Interactions (7)]

2.2 Reconstitution

1. Warm THROMBATE III and Sterile Water for Injection, USP (diluent) vials to room temperature before reconstitution.
2. Remove shrink band from the THROMBATE III vial. If the shrink band is absent or shows signs of tampering, do not use the product and notify Grifols Therapeutics LLC immediately.
3. Remove the plastic flip top from each vial (Fig. A). Cleanse each vial stopper with an alcohol swab and allow surface to dry.
4. 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).
5. Carefully grip the sheath of the other end of the transfer needle and twist to remove it.
6. Invert the diluent vial and insert the attached needle into the THROMBATE III vial at a 45° angle (Fig. C). This will direct the stream of diluent against the wall of the vial and minimize foaming. The vacuum will draw the diluent into the THROMBATE III vial.*
7. When diluent transfer is complete, remove the diluent vial and transfer needle (Fig. D).
8. Immediately after adding the diluent, swirl the THROMBATE III vial continuously until the product is completely dissolved (Fig. E). Some foaming may occur, but attempt to avoid excessive foaming. Visually inspect the vial for particulate matter and discoloration prior to administration.
9. Clean the top of the vial of reconstituted THROMBATE III again with a new alcohol swab and let surface dry.
10. Attach the filter needle (from the package) to the sterile syringe. Withdraw the THROMBATE III solution into the syringe through the filter needle (Fig. F).
11. Remove the filter needle from the syringe and replace with an appropriate injection or butterfly needle for administration.
12. If the same patient is using more than one vial of THROMBATE III, draw the contents of multiple vials into the same syringe through the filter needles provided.

*

If vacuum is lost in the THROMBATE III vial during reconstitution, use a sterile syringe to remove the sterile water from the diluent vial and inject it into the THROMBATE III vial, directing the stream of fluid against the wall of the vial.

2.3 Administration

• Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit.
• Administer THROMBATE III, once reconstituted, alone without mixing with other agents or diluents.
• Administer within 3 hours following reconstitution. Do not refrigerate after reconstitution.
• Adapt the rate of administration to the response of the individual patient, but administration of the entire dose in 10 to 20 minutes is generally well tolerated.

5.1 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, are possible. Early signs of hypersensitivity reactions, which can progress to anaphylaxis, may include angioedema, chest tightness, hypotension, rash, nausea, vomiting, paresthesia, restlessness, wheezing and dyspnea. If hypersensitivity symptoms occur, discontinue use of the product immediately and administer appropriate emergency treatment. 

5.2 Transmission of Infectious Agents

Because THROMBATE III is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. There is also the possibility that unknown infectious agents may be present in the product. The risk that the product will transmit viruses 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 removing certain viruses during manufacture. Despite these measures, this product may still potentially transmit diseases.     

Report all infections suspected by a physician possibly to have been transmitted by this product to Grifols Therapeutics LLC at 1-800-520-2807.

5.3 Monitoring: Laboratory Tests

• The effect of drugs that use antithrombin to exert their anticoagulation may be altered when THROMBATE III is added or withdrawn. Regularly perform coagulation tests suitable for the anticoagulant used (e.g., aPTT and anti-Factor Xa activity) to avoid excessive or insufficient anticoagulation. Additionally, monitor the patients for the occurrence of bleeding or thrombosis. [see Drug Interactions (7)]
• Measure functional levels of AT in plasma by amidolytic assays using chromogenic substrates or by clotting assays. Do not use immunoassays because they do not detect all hereditary AT deficiencies.

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in other clinical trials of another drug and may not reflect the rates observed in clinical practice.

Two clinical trials were conducted in 33 subjects with congenital AT deficiency. The first was a prospective, open-label, dose-escalation, dose-ranging, and pharmacokinetic study in 11 asymptomatic subjects. Eight subjects received a single dose, escalated sequentially, followed by weekly dose ranging from 25 to 125 unit/kg. Five subjects (including 2 from the first part of the study) received weekly THROMBATE III for periods of up to 23 weeks in doses ranging from 125 to 225 unit/kg. The second trial was a phase III, prospective, open-label study conducted in 24 subjects for additional kinetics (n=3), the prevention of thrombosis (n=13) during high risk conditions (pregnancy, surgery), or the treatment of thrombosis (n=10). Loading doses targeted an AT plasma level of 120% and ranged from 33 to 150 unit/kg. Maintenance doses targeted a plasma AT range of 70% to 120%, which were 23 to 75 unit/kg.

Adverse reactions reported during the 2 clinical trials are listed in Table 2. Nine subjects (27%) experienced 29 adverse reactions which occurred during 17 of 389 infusions. There were no serious adverse reactions reported. The severity of adverse reactions was reported as mild or moderate, except for wound secretion and hematoma, which was severe.

During clinical investigation of THROMBATE III, there were no reports of virus transmission. 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.

8.1 Pregnancy

Risk Summary

There are no data with THROMBATE III use in pregnant women to inform a drug-associated risk. However, there are clinical considerations [see Clinical Considerations]. It is not known whether THROMBATE III can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. THROMBATE III should be given to a pregnant woman only if clearly needed. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Reproduction studies have been performed in rats and rabbits at doses up to four times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to THROMBATE III.

Clinical Considerations

Labor or Delivery

Suspend heparin (or low molecular weight heparin) administration and continue THROMBATE III administration during labor and delivery.

8.2 Lactation

Risk Summary

There is no information regarding the presence of THROMBATE III in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for THROMBATE III and any potential adverse effects on the breastfed infant from THROMBATE III or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

8.5 Geriatric Use

The safety and effectiveness in the geriatric population have not been established.

12.1 Mechanism of Action

Antithrombin, an alpha2-glycoprotein of molecular weight 58,000, is normally present in human plasma at a concentration of approximately 12.5 mg/dL and is the major plasma inhibitor of thrombin. Inactivation of thrombin by AT 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. AT 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 proceeds slowly in the absence of heparin, but is greatly accelerated in the presence of heparin. As the therapeutic antithrombotic effect of heparin is mediated by AT, heparin in vivo is ineffective in the absence or near absence of AT.

After administration, THROMBATE III temporarily replaces the missing AT in patients with hereditary antithrombin deficiency.

12.3 Pharmacokinetics

In a clinical trial of THROMBATE III conducted in asymptomatic subjects with hereditary deficiency of AT, 8 subjects were administered a single dose of THROMBATE III at doses ranging from 25 units/kg to 125 units/kg. Pharmacokinetic parameters were determined using immunologic and functional AT assays (Table 3).