The serious adverse reaction that has been reported in clinical studies is hemorrhage (intra-abdominal, hemarthrosis and post procedural). The most common adverse events reported in clinical trials at a frequency of ≥ 5% are hemorrhage and infusion site reaction.
Clinical Trial 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 3 by System Organ Class.
Table 3: Adverse Reactions in Hereditary AT Deficient Patients (one event per patient, 2% of total population, n=47)Gastrointestinal Disorders
Intra-abdominal HemorrhageGeneral Disorders and Administration Site Disorders
Application Site Pruritus
Non-cardiac Chest Pain
Hepatic Enzyme AbnormalMusculoskeletal and Connective Tissue Disorders
HemarthrosisRenal and Urinary Disorders
For ATryn, a potential safety issue is the development of an immunological reaction to the recombinant protein or any of the potential contaminating proteins. Assays were developed and used to detect antibodies directed against antithrombin (Recombinant), goat AT, or goat-milk proteins. No confirmed specific immunological reaction was seen in any of the patients tested, nor were there any clinical adverse events that might indicate such a response.
A post-marketing patient registry has been established to collect additional data on the immunogenic potential of ATryn in patients treated with ATryn on more than one occasion. Physicians are encouraged to participate in the registry by collecting pre- and post-treatment serum samples from patients according to instructions provided by rEVO Biologics, Inc. and submitting them to rEVO Biologics, Inc. for analysis for the development of antibodies to antithrombin (Recombinant). Serum samples should be collected within one week before initiation of treatment and on days 1, 7 and 28 days from initiation of treatment. Physicians wanting to participate in this program are encouraged to contact rEVO Biologics, Inc. at 1-800-610-3776. rEVO Biologics, Inc. will provide detailed instructions for the collection, processing and shipping of samples, as well as all tubes and labels that are necessary for the collection and processing of samples.
Mechanism Of Action
Antithrombin (AT) plays a central role in the regulation of hemostasis. AT is the principal inhibitor of thrombin and
Factor Xa5, 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.
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 peripartum period, the risk of development of VTEs as compared to the normal population in these situations is increased by a factor 10 to 506,7.
In hereditary antithrombin deficient patients ATryn restores (normalizes) plasma AT activity levels during peri-operative and peri-partum periods.
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 5.
Table 5: Baseline Corrected Mean Pharmacokinetic Parameters (%CV)
|Parameter||50 IU/kg||100 IU/kg|
|CL (mL/hr/kg)||9.6 (34.4)||7.2 (15.3)|
|Half-life (hrs)||11.6 (84.7)||17.7 (60.9)|
|MRT (hrs)||16.2 (74.9)||20.5 (40.2)|
|Vss (mL/kg)||126.2 (37.4)||156.1 (43.4)|
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 formulae for surgical and pregnant patients should be used (see Recommended 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 Recommended Dose and Schedule) should be performed to properly treat such patients.
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.
The efficacy of ATryn to prevent the occurrence of venous thromboembolic events was assessed by comparing the incidence of the occurrence of such events in 31 ATryn treated hereditary AT deficient patients with the incidence in 35 human plasma-derived AT treated hereditary AT deficient patients. Data on ATryn-treated patients were derived from two prospective, single-arm, open-label studies. Data on plasma AT treated patients were collected from a prospectively designed concurrently conducted retrospective chart review. Patients in both studies had confirmed hereditary AT deficiency (AT activity ≤ 60% of normal) and a personal history of thromboembolic events. Patients had to be treated in the peri-operative and peri-partum period. ATryn was administered as a continuous infusion for at least 3 days, starting one day prior to the surgery or delivery. Plasma AT was administered for at least two days as single bolus infusions. Due to the retrospective nature of the study, dosing was done with the locally available AT concentrate according to the local practice.
The occurrence of a venous thromboembolic event was confirmed if signs and symptoms for such events were confirmed by a specific diagnostic assessment, or when treatment for an event was initiated based on diagnostic imaging, without the presence of signs and symptoms. The efficacy was assessed during treatment with AT and up to 7 days after stopping AT treatment.
In the ATryn-treated group there was one confirmed diagnosis of an acute deep vein thrombosis (DVT). The incidence of any thromboembolic event from the start of treatment to 7 days after last dosing is summarized by treatment group in Table 6 as are the Clopper-Pearson exact 95% CI for the proportion of patients with a thromboembolic event and the exact 95% lower confidence bound for the difference between treatments.
Table 6: Overall Incidence of Any Confirmed Thromboembolic Event
|No. of Pts. Assessed||No. of Pts. with Events||% of Pts. with Events||95% CI*|
|No. of Pts. Assessed||No. of Pts. with Events||% of Pts. with Events||95% CI|
|*The 95% confidence intervals were calculated using Clopper-Pearson methodology. |
AT=Antithrombin; No.=Number; Pts.=Patients; CI=Confidence Interval
The lower 95% confidence bound of difference between treatment groups was -0.167, a value that is greater than the pre-specified lower confidence bound of -0.20. This demonstrates that ATryn was non-inferior to plasma AT in terms of the prevention of peri-operative or peri-partum thromboembolic events.
Supportive data come from a study in the same population with 5 hereditary AT deficient patients treated on 6 occasions in a compassionate use program and provides additional reassurance of the efficacy of ATryn. None of these patients reported a thromboembolic event.2
(2) Konkle BA, Bauer KA, Weinstein R, Greist A, Holmes HE, Bonfiglio J. Use of recombinant human antithrombin in patients with congenital antithrombin deficiency undergoing surgical procedures. Transfusion 2003 March; 43(3):390-4.
(3) Edmunds T, Van Patten SM, Pollock J et al. Transgenically produced human antithrombin: structural and functional comparison to human plasma-derived antithrombin. Blood 1998 June 15;91(12):4561-71.
(5) Maclean PS, Tait RC. Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options. Drugs 2007;67(10):1429-40.
(6) Buchanan GS, Rodgers GM, Ware Branch. The inherited thrombophilias: genetics, epidemiology, and laboratory evaluation. Best Pract Res Clin Obstet Gynaecol 2003 June;17(3):397-411.
(7) Walker ID, Greaves M, Preston FE. Investigation and management of heritable thrombophilia. Br J Haematol 2001;114:512-28.
Dosing & Uses
Dosage Forms & Strengths
- 1750 International Unit/vial
Prophylaxis of thrombosis during surgical or obstetrical procedures
Increase & maintain antithrombin activity between 80-120% (0.8-1.2 International Unit/mL) during treatment
Loading dose should target 100% AT activity level based on weight & pretreatment AT activity level
Load = [(100 - baseline AT activity level in %)/2.3] x kg Body Weight = units of antithrombin required IV; infuse over 15 minutes
Maintenance (International Unit/hr) = [(100 - baseline AT activity level in %)/10.2] x kg BW = units of antithrombin required/hr IV
Load = [(100 - baseline AT activity level in %)/1.3] x kg Body Weight = units of antithrombin required IV infuse over 15 minutes
Maintenance (International Unit/hr) = [(100 - baseline AT activity level in %)/5.4] x kg BW = units of antithrombin required/hr IV
Draw AT activity levels 2 hours after start of loading dose, AFTER start of maintenance dose infusion
IF AT activity level 80%-120% (0.8-1.2 International Unit/mL): NO dose adjustment
If AT activity level <80%: Increase maintenance infusion rate by 30%; recheck AT level 2 hr after adjustment
If AT activity level >120%: Decrease infusion rate by 30%
GTC Biotherapeutics, Inc.
Biosynthetic (recombinant DNA origin) preparation of human antithrombin III produced in milk of transgenic goats.1 3 4 5 9 Involves insertion of DNA coding sequence for human antithrombin III into specific promotor gene that directs expression in goat mammary glands.1 3 4 9 Isolated and purified using a series of filtration and chromatography steps; includes additional viral inactivation procedures.1 3 4 6
Regulates several key serine proteases in the blood coagulation pathway.1 3 4 7 9 11 Principally inhibits thrombin and factor Xa, and to a lesser extent, factors IXa, XIa, XIIa, trypsin, plasmin, tissue plasminogen activator (tPA), urokinase (no longer commercially available in the US), and kallikrein.1 3 4 7 9 11 Activity enhanced by more than 300- to 1000-fold when antithrombin III is bound to heparin.1 3 4 7 9 10 11
Functionally and structurally similar to endogenous antithrombin III.1 3 4 5 9
Also exhibits anti-inflammatory and antiproliferative effects in endothelium.4 11
Warnings and Precautions
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.
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.
Use in specific populations
Pregnancy Category C: 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.
Labor and Delivery
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 formulae for pregnant patients.
ATryn will be 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.
Safety and effectiveness in pediatric patients have not been established.
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.
ATryn for Injection is a nanofiltered, sterile, terminally heat treated, lyophilized dosage form. Antithrombin (Recombinant), active ingredient of ATryn, is a recombinant human antithrombin. It is a 432 amino acid glycoprotein with a molecular weight of approximately 57,215 Daltons. The molecular formula is: C2191H3457N583O656S18. Antithrombin (Recombinant) is produced by recombinant DNA technology using genetically engineered goats into which the DNA coding sequence for human antithrombin has been introduced along with a mammary gland specific DNA sequence, which directs the expression of the antithrombin into the milk. The goats in which antithrombin (Recombinant) is produced are USDA certified scrapie-free, and controlled for specific pathogens.
The amino acid sequence of Antithrombin (Recombinant) is identical to that of human plasma-derived antithrombin. Antithrombin (Recombinant) and plasma-derived antithrombin both contain six cysteine residues forming three disulphide bridges and 3-4 N-linked carbohydrate moieties. The glycosylation profile of Antithrombin (Recombinant) is different from plasma-derived antithrombin, which results in an increased heparin affinity. When assayed in the presence of excess of heparin the potency of the recombinant product is not different from that of plasma-derived product.
Each vial of ATryn is tested for potency stated on the product label using a reference standard calibrated against the World Health Organization international standard for antithrombin concentrate. In addition to Antithrombin (Recombinant), each vial of the product contains 100 mg glycine, 79 mg sodium chloride, and 26 mg sodium citrate. When reconstituted with 10 mL Sterile Water for Injection, the pH is approximately 7.0. Following reconstitution, the solution may be further diluted into 0.9% sodium chloride for injection.
ATryn does not contain any preservatives nor is it formulated with human plasma proteins. Antithrombin (Recombinant) is affinity purified using a heparin immobilized resin and contains no detectable heparin (<0.0002 IU heparin per IU antithrombin) in the final product.
The purification and drug product manufacturing processes have been validated to demonstrate its capacity for removal and/or inactivation of viruses4. Results of removal and/or inactivation for each of the steps are shown in Table 4.
|NA = Not Applicable since log10 reduction was less than 1.0.|
|Process Step||Pseudorabies Virus||Xenotropic Murine Retrovirus||Human Adenovirus||Porcine Parvovirus|
|Tangential Flow Filtration||≥5.1|
|Ion Exchange Chromatography||3.6||1.0||≥7.1||NA|
|Hydrophobic Interaction Chromatography||≥5.6||≥4.4||≥4.8||≥5.7|
In addition, although the goats are from a closed, USDA certified scrapie-free herd, the purification process was challenged to remove prions. The manufacturing steps were shown capable of achieving the following log10 reductions: 2.0 (tangential filtration), 2.2 (affinity column), ≥ 3.3 (ion exchange column), ≥ 3.8 (hydrophobic interaction column).
How Supplied/Storage and Handling
ATryn 525 IU Vial - NDC 42976-121-01
Approximately 525 IU/vial in a sterile white to off-white lyophilized powder for reconstitution. Each carton contains one single dose vial of ATryn.
The actual potency of ATryn is stated on the vial label and carton.
ATryn 1750 IU Vial - NDC 42976-121-02
Approximately 1750 IU/vial in a sterile white to off-white lyophilized powder for reconstitution. Each carton contains one single dose vial of ATryn.
The actual potency of ATryn is stated on the vial label and carton.
Storage and Handling
Store ATryn refrigerated at between 2-8°C (36-46°F).
Do not use product beyond the expiration date printed on the package. Discard unused portions.
For the Consumer
Applies to antithrombin (recombinant): parenteral injection
Side effects include:
Hemorrhage, infusion site reactions.