2.1 Dose and Schedule

• ATryn dosage is to be individualized based on the patient’s pre-treatment functional AT activity level (expressed in percent of normal) and body weight (expressed in kilograms) and using therapeutic drug monitoring (Table 1).
  
• Treatment goal is to restore and maintain functional antithrombin (AT) activity levels between 80% - 120% of normal (0.8 - 1.2 IU/mL).
  
• Treatment should be initiated prior to delivery or approximately 24 hours prior to surgery to ensure that the plasma antithrombin level is in the target range at that time.
  
• A different dosing formula is used for the treatment of surgical and pregnant patients. Pregnant women who need a surgical procedure other than Cesarean section should be treated according to the dosing formula for pregnant patients.
  
• A loading dose should be administered as a 15-minute intravenous infusion, immediately followed by a continuous infusion of the maintenance dose.
  
• AT activity monitoring and dose adjustments should be made according to Table 2.
  
• Treatment should be continued until adequate follow-on anticoagulation is established.

AT Activity Monitoring and Dose Adjustment

AT activity monitoring is required for proper treatment. Check AT activity once or twice per day with dose adjustments made according to Table 2.

As surgery or delivery may rapidly decrease the AT activity levels, check the AT level just after surgery or delivery. If AT activity level is below 80%, an additional bolus dose may be administered to rapidly restore decreased AT activity level. In such instances, the loading dose formula in Table 1 should be used, utilizing in the calculation the last available AT activity result. Thereafter, restart the maintenance dose at the same rate of infusion as before the bolus.

2.2 Preparation

• Bring vials to room temperature no more than 3 hours prior to reconstitution.
  
• For the 525 IU vial, reconstitute with 3.2 mL Sterile Water for Injection [(WFI) not supplied with ATryn] immediately prior to use. Do not shake.
  
• For the 1750 IU vial, reconstitute with 10 mL Sterile Water for Injection [(WFI) not supplied with ATryn] immediately prior to use. Do not shake.
  
• Do not use solution containing visible particulates or if it is discolored or cloudy.
  
• Draw solution from one or more vials into a sterile disposable syringe for intravenous administration or add solution to an infusion bag containing 0.9% sterile sodium chloride for injection (e.g., dilute solution to obtain a concentration of 100 IU/mL).

2.3 Administration

• Administer using an infusion set with a 0.22 micron pore-size, in-line filter.
  
• Administer contents of infusion syringes or diluted solution within 24 hours of preparation when stored at room temperature (68-77°F (20-25°C)).
  
• Discard unused product in accordance with local requirements.
  
• Administer ATryn alone without mixing with other agents, with the exception of the medications in Table 3, which demonstrated compatibility with ATryn in an in vitro mixing study2 when co-infused at selected doses and infusion rates in the same IV tubing with 100 IU/mL of ATryn.
  
• Do not co-infuse ATryn in the same IV line with vecuronium or labetalol, since these medications demonstrated IV incompatibility (i.e., precipitation and/or reduction in ATryn activity).

5.1 Hypersensitivity Reactions

Allergic-type hypersensitivity reactions are possible. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If these symptoms occur during administration, treatment must be discontinued immediately and emergency treatment should be administered.

5.2 Coagulation Monitoring Tests

The anticoagulant effect of drugs that use antithrombin to exert their anticoagulation may be altered when ATryn is added or withdrawn. To avoid excessive or insufficient anticoagulation, coagulation tests suitable for the anticoagulant used (e.g., aPTT and anti-Factor Xa activity) are to be performed regularly, at close intervals, and in particular in the first hours following the start or withdrawal of ATryn. Additionally, monitor the patients for the occurrence of bleeding or thrombosis in such situation.

6.1 Clinical Trials Experience

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

Adverse reactions that occurred in clinical trials with hereditary AT deficient patients are shown in Table 4 by System Organ Class.

Table 4: Adverse Reactions in Hereditary AT Deficient Patients
(one per patient, 2% of total population, n=47)

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to antithrombin (Recombinant) in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In clinical trials, serum samples were collected from individuals before treatment and at various time points (1, 7, 21-30, 60 and 90 days) after one or more treatments with ATryn. Samples were screened by enzyme-linked immunosorbent assays (ELISA) for IgM and IgG antibodies to antithrombin (Recombinant). Serum samples that were screen-positive were tested by a confirmatory assay: either a radio-immunoprecipitation assay or by an inhibition of binding dose response ELISA. Samples that were confirmed positive in the confirmatory assay were to be tested using a thrombin inhibitory activity assay to assess the endogenous antithrombin level.

Serum samples were also collected from individuals before treatment and at various time points after one or more treatments with ATryn to assess the potential for an immune response to residual goat milk proteins in ATryn. Pre- and post-treatment serum samples were analyzed by an immunodot blot assay.

No confirmed specific immunological reaction was seen in any of the patients tested, nor were there any clinical adverse reactions that might indicate such a response.

In post-marketing patient registry studies, seven patients (four pregnant, three surgical) were enrolled in the studies after a single exposure to ATryn. Patient serum samples were collected within one week from initiation of treatment and on days 1, 7 and 28 days from initiation of treatment and were tested to detect antibodies against antithrombin (Recombinant), goat and goat milk proteins. No antibodies were detected.

8.1 Pregnancy

Risk Summary

ATryn is indicated for the treatment of pregnant women during the peri-partum period. Pregnant patients who need a surgical procedure other than Cesarean section are to be treated according to the dosing formula for pregnant patients.

In rats, a dose of 210 mg/kg/day ATryn (5-6 times the human dose for pregnant women) administered during most of the pregnancy and entire lactation showed a slight but statistically significant increase in pup mortality in day one through day four when compared to concurrent control (90% compared to 94% viability index for 210 mg/kg/day versus control). This slight statistical difference does not reflect a true treatment-related effect. This same dose was shown to be safe in a second rat study when administered around parturition and during lactation where the no adverse effect level for dam and pups was 210 mg/kg/day.

There are no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Studies in pregnant women have not shown that ATryn increases the risk of fetal abnormalities if administered during the third trimester of pregnancy. In clinical trials in hereditary AT deficient patients, 22 pregnant women have been treated with ATryn around parturition.

No adverse reactions were reported in 22 neonates born from pregnant women treated with ATryn during clinical trials.

8.2 Lactation

Risk Summary

ATryn is present in breast milk at levels estimated to be 1/50 to 1/100 of its concentration in the blood. This level is the same as that estimated to be present in breast milk of normal lactating women which is not known to be harmful to breastfed neonates. However, caution should be exercised when ATryn is administered to a nursing woman. Use only if clearly needed.

In 2 reproductive toxicology studies performed in rats, antithrombin (Recombinant) was administered to pregnant dams at doses up to 210 mg/kg/day, resulting in supraphysiologic plasma levels of antithrombin. Pups were allowed to breastfeed and were monitored for changes in prothrombin (PT) or aPTT, as well as pup viability, body weight at birth, growth, and development. In these studies, there were no adverse effects in offspring who consumed milk from dams treated with ATryn.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of ATryn did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

12.1 Mechanism of Action

Antithrombin (AT) plays a central role in the regulation of hemostasis. AT is the principal inhibitor of thrombin and Factor Xa4, the serine proteases that play pivotal roles in blood coagulation. AT neutralizes the activity of thrombin and Factor Xa by forming a complex which is rapidly removed from the circulation. The ability of antithrombin to inhibit thrombin and Factor Xa can be enhanced by greater than 300 to 1000 fold when AT is bound to heparin.

12.2 Pharmacodynamics

Hereditary AT deficiency causes an increased risk of venous thromboembolism (VTE). During high-risk situations such as surgery or trauma or for pregnant women, during the peri-partum period, the risk of development of VTEs as compared to the normal population in these situations is increased by a factor 10 to 504,5,6.

In hereditary antithrombin deficient patients ATryn restores (normalizes) plasma AT activity levels during peri-operative and peri-partum periods.

12.3 Pharmacokinetics

In an open-label, single dose pharmacokinetic study, male and female patients (≥ 18 years of age) with hereditary AT deficiency, received either 50 (n = 9, all females) or 100 (n = 6, 2 males and 4 females) IU/kg ATryn intravenously. These patients were not in high-risk situations. The baseline corrected pharmacokinetic parameters for antithrombin (Recombinant) are summarized in Table 6.

Incremental recovery [mean (%CV)] was 2.24 (20.2) and 1.94 (14.8) %/IU/kg body weight for 50 and 100 IU/kg, respectively.

Population pharmacokinetic analysis of hereditary deficient patients in a high risk situation revealed that the clearance and volume of distribution in pregnant patients were (1.38 L/h and 14.3 L respectively) which are higher than non-pregnant patients (0.67 L/h and 7.7 L respectively). Therefore, distinct dosing formula for surgical and pregnant patients should be used (see 2.1, Dose and Schedule).

As compared to plasma derived antithrombin, ATryn has a shorter half-life and more rapid clearance (approximately nine and seven times, respectively).

Pharmacokinetics may be influenced by concomitant heparin administration, as well as surgical procedures, delivery, or bleeding. AT activity monitoring (see 2.1 Dose and Schedule) should be performed to properly treat such patients.

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis: No carcinogenicity data for ATryn are available in animals or humans.

Mutagenesis and Genotoxicity: ATryn was not mutagenic when tested in the Ames bacterial test and in in vitro cytogenetic assays nor was it shown to be genotoxic when tested in an in vivo test to assess chromosomal aberration.

Impairment of Fertility: No studies have been conducted to evaluate the effects of ATryn on fertility in humans.

13.2 Animal Toxicology and/or Pharmacology

Pharmacokinetic and toxicokinetic (1 single, 2 repeated dose) studies of antithrombin (Recombinant) were performed in mice, rats, dogs and monkeys. In toxicokinetic studies in monkeys the area under the curve was 3-4 times greater than in the rat at all doses used.

The toxicological profile of antithrombin (Recombinant) administered by the intravenous route as bolus injections and infusions has been evaluated in both single- and repeat-dose studies performed in rats, dogs, and monkeys across a range of doses from 2.1 to 360 mg/kg. The highest doses in the single dose toxicity studies in rats and dogs were 360 mg/kg and 210 mg/kg, respectively. Toxicities observed were limited to transient injection site swelling observed in rats and dogs at the highest doses tested, and increased AST at highest dose in the dog study, both resolved during recovery period.

The highest dose in the 28-day repeated-dose toxicity study in rats was 360 mg/kg/day. The toxicity at this dose was limited to transient limb swelling and local injection site bruising and swelling. The highest dose in the 14-day repeated-dose toxicity study in monkeys was 300 mg/kg/day or approximately 7-8 times human dose. Toxicities observed in female monkeys at this dose included internal bleeding, hematological changes and liver toxicity, with one out of three female animals showing multifocal hepatic necrosis. Both sexes showed increased AST and ALK on day 15, with both parameters returning to normal by day 22. There was no adverse effect in monkeys dosed with 120 mg/kg/day.