Drug: Atryn

ATryn (recombinant lyophilized powder) 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 (recombinant lyophilized powder) 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 (recombinant lyophilized powder) 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. Table 4: Viral Clearance Results (log10 reductions)
Process Step Pseudorabies
Virus Xenotropic
Murine
Retrovirus Human
Adenovirus Porcine
Parvovirus Tangential Flow Filtration ≥ 5.1       Affinity Chromatography 1.6 1.2 NA 1.4 Nanofiltration   ≥ 3.8 ≥ 6.3 ≥ 3.7 Ion Exchange Chromatography 3.6 1.0 ≥ 7.1 NA Hydrophobic Interaction Chromatography ≥ 5.6 ≥ 4.4 ≥ 4.8 ≥ 5.7 Heat Treatment 2.8 ≥ 5.0 ≥ 1.8 2.4 Total Reduction ≥ 18.7 ≥ 15.4 ≥ 20.0 ≥ 13.2 NA = Not Applicable since log10 reduction was less than 1.0. 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). REFERENCES (4) Echelard Y, Meade H, Ziomek C. The first biopharmaceutical from transgenic animals: ATryn (recombinant lyophilized powder) . Modern Biopharmaceuticals 2005;995-1016. Last reviewed on RxList: 3/10/2009
This monograph has been modified to include the generic and brand name in many instances.

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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 Hemorrhage General Disorders and Administration Site Disorders Application Site Pruritus Feeling Hot Non-cardiac Chest Pain Investigations Hepatic Enzyme Abnormal Musculoskeletal and Connective Tissue Disorders Hemarthrosis Renal and Urinary Disorders Hematuria Vascular Disorders Hematoma Immunogenicity For ATryn (recombinant lyophilized powder) , 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 (recombinant lyophilized powder) in patients treated with ATryn (recombinant lyophilized powder) 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 Ovation Pharmaceuticals, Inc. and submitting them to Ovation 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 Ovation Pharmaceuticals, Inc. at 1-800-455-1141. Ovation 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. Read the Atryn (recombinant lyophilized powder) Side Effects Center for a complete guide to possible side effectsLearn More »

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For Intravenous Use Only after Reconstitution Preparation for Administration
  • Bring vials to room temperature no more than 3 hours prior to reconstitution.
  • Reconstitute with 10 mL Sterile Water for Injection [(WFI) not supplied with ATryn (recombinant lyophilized powder) ] 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).
  • Administer using an infusion set with a 0.22 micron pore-size, in-line filter.
  • Administer contents of infusion syringes or diluted solution within 8 to 12 hours of preparation when stored at room temperature (68-77°F (20-25°C)).
  • Discard unused product in accordance with local requirements.
Recommended Dose and Schedule
  • The dosage of ATryn (recombinant lyophilized powder) is to be individualized based on the patient's pretreatment functional AT activity level (expressed in percent of normal) and body weight (expressed in kilograms) and using therapeutic drug monitoring (Table 1).
  • The goal of treatment 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.
  • Different dosing formulae are 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 formulae for pregnant patients.
  • Administer loading dose 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.
  • Continue treatment until adequate follow-on anticoagulation is established.
Table 1: Dosing Formula for Surgical Patients and Pregnant Women
  Loading Dose (IU) Maintenance Dose (IU/hour) Surgical Patients (100 - baseline AT activity level)/2.3 x Body Weight (kg) (100 - baseline AT activity level)/10.2 x Body Weight (kg) Pregnant Women (100 - baseline AT activity level)/1.3 x Body Weight (kg) (100 - baseline AT activity level)/5.4 x Body Weight (kg) 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. Table 2: AT Activity Monitoring and Dose Adjustment
Initial Monitor Time AT Level Dose Adjustment Recheck AT Level 2 hours after initiation of treatment < 80% Increase 30% 2 hours after each dose adjustment 6 hours after initiation of treatment or dose adjustment 80% to 120% None > 120% Decrease 30% 2 hours after each dose adjustment 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 formulae 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.

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The anticoagulant effect of heparin and low molecular weight heparin (LMWH) is enhanced by antithrombin. The half-life of antithrombin may be altered by concomitant treatment with these anticoagulants due to an altered antithrombin turnover. Thus, concurrent administration of antithrombin with heparin, low molecular weight heparin, or other anticoagulants that use antithrombin to exert their anticoagulant effect must be monitored clinically and biologically. To avoid excessive anticoagulation, regular coagulation tests (aPTT, and where appropriate, anti-Factor Xa activity) are to be performed at close intervals, with adjustment in dosage of the anticoagulant as necessary. Read the Atryn Drug Interactions Center for a complete guide to possible interactions Learn More »

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ATryn® is a recombinant antithrombin indicated for the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients1. It is not indicated for treatment of thromboembolic events in hereditary antithrombin deficient patients.

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ATryn (recombinant lyophilized powder) is contraindicated in patients with known hypersensitivity to goat and goat milk proteins. Last reviewed on RxList: 3/10/2009
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

No information provided.

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Dosage Forms And Strengths ATryn (recombinant lyophilized powder) is a sterile lyophilized formulation. Each vial of ATryn (recombinant lyophilized powder) contains the potency stated on the label, which is approximately 1750 IU. Dosage Form NDC 67386-521-51 Approximately 1750 IU/vial in a sterile white to off-white lyophilized powder for reconstitution.Each carton contains one single dose vial of ATryn (recombinant lyophilized powder) . The actual potency of ATryn (recombinant lyophilized powder) is stated on the vial label and carton. Storage and Handling Store ATryn (recombinant lyophilized powder) refrigerated at between 2-8°C (36-46°F). Do not use product beyond the expiration date printed on the package. Discard unused portions. Manufacturer: GTC Biotherapeutics, Inc. Framingham, MA 01702, U.S.A.,. Marketed by: Ovation Pharmaceuticals, Inc. Deerfield, IL 60015, U.S.A., Issued: February 2009. REFERENCES (1) Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia 2008;14:1229-39. (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. Last reviewed on RxList: 3/10/2009
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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. Coagulation Monitoring Tests The anticoagulant effect of drugs that use antithrombin to exert their anticoagulation may be altered when ATryn (recombinant lyophilized powder) 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 (recombinant lyophilized powder) . Additionally, monitor the patients for the occurrence of bleeding or thrombosis in such situation. Nonclinical Toxicology Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis No carcinogenicity data for ATryn (recombinant lyophilized powder) are available in animals or humans. Mutagenesis and Genotoxicity ATryn (recombinant lyophilized powder) 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 (recombinant lyophilized powder) on fertility in humans. Use In Specific Populations Pregnancy Pregnancy Category C: In rats, a dose of 210 mg/kg/day ATryn (recombinant lyophilized powder) (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 (recombinant lyophilized powder) 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 (recombinant lyophilized powder) around parturition. No adverse reactions were reported in 22 neonates born from pregnant women treated with ATryn (recombinant lyophilized powder) during clinical trials. Labor and Delivery ATryn (recombinant lyophilized powder) 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. Nursing Mothers ATryn (recombinant lyophilized powder) 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 (recombinant lyophilized powder) 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 (recombinant lyophilized powder) . Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of ATryn (recombinant lyophilized powder) 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. Last reviewed on RxList: 3/10/2009
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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