Data from FDA - Curated by EPG Health - Last updated 14 August 2018

Indication(s)

1 INDICATIONS AND USAGE 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.

ATryn is a recombinant antithrombin indicated for the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients.

(1) It is not indicated for treatment of thromboembolic events in hereditary antithrombin deficient patients.

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Advisory information

contraindications
4 CONTRAINDICATIONS ATryn is contraindicated in patients with known hypersensitivity to goat and goat milk proteins. Known hypersensitivity to goat and goat milk proteins. (4)
Adverse reactions

6 ADVERSE REACTIONS 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.

Most common adverse reactions reported in clinical trials at a frequency of?

5 % were hemorrhage and infusion site reaction.

(6) To report SUSPECTED ADVERSE REACTIONS, contact rEVO Biologics, Inc. at 1-800-610-3776 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug can not 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, 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.

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION For Intravenous Use Only after Reconstitution • For intravenous use only after reconstitution • The dosage of ATryn is individualized for each patient.

Treatment goal is to restore and maintain functional antithrombin (AT) activity levels between 80 % - 120 % (0.8 - 1.2 IU/mL) of normal.

• Administer loading dose as a 15-minute intravenous infusion immediately followed by continuous infusion of the maintenance dose.

(2.2) Loading Dose (IU) Maintenance Dose (IU/hour) Surgical Patients (100?baseline AT activity) 2.3 x Body Wt (kg) (100?baseline AT activity) 10.2 x Body Wt (kg) Pregnant Women (100?baseline AT activity) 1.3 x Body Wt (kg) (100?baseline AT activity) 5.4 x Body Wt (kg) AT activity monitoring is required for proper treatment.

Check AT activity once or twice per day with dose adjustments made according to table below.

(2.2) 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 80 % to 120 % None 6 hours after initiation of treatment or dose adjustment > 120 % Decrease 30 % 2 hours after each dose adjustment Continue administration of ATryn until adequate follow-on anticoagulation has been established.

• Store at 2-8°C (36-46°F).

Discard any unused portion.

(2.1, 16) 2.1 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] 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).

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.

2.2 Recommended Dose and Schedule The dosage of ATryn 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).

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 80 % to 120 % None 6 hours after initiation of treatment or dose adjustment > 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.

Use in special populations

8 USE IN SPECIFIC POPULATIONS Administration of ATryn during the third trimester of pregnancy has not shown an increased risk of fetal abnormalities.

No data is available for use of ATryn in earlier stages of pregnancy.

(8.1) Labor and Delivery: ATryn is used in the treatment of peri-partum women with hereditary antithrombin deficiency.

(8.2) Nursing Mothers: ATryn administered by infusion will be present in breast milk at estimated concentrations 1/50 to 1/100 that of concentration in blood.

Use only if clearly needed.

(8.3) 8.1 Pregnancy 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.

8.2 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.

8.3 Nursing Mothers 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.

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.

Pregnancy and lactation

8.3 Nursing Mothers 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.

Interactions

7 DRUG INTERACTIONS 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.

ATryn enhances anticoagulant effect of heparin and low molecular weight heparin.

(7) The half-life of ATryn may be altered by concomitant treatment with anticoagulants that use antithrombin to exert their anticoagulant effect.

(7)

More information

Category Value
Authorisation number BLA125284
Agency product number AWV6I5L6H2
Orphan designation No
Product NDC 42976-125
Date Last Revised 01-12-2013
Type HUMAN PRESCRIPTION DRUG
RXCUI 1661563
Marketing authorisation holder rEVO Bioloigics, Inc.