THROMBATE III is a human antithrombin (AT) indicated in patients with hereditary antithrombin deficiency for:

{ "type": "p", "children": [], "text": "THROMBATE III is a human antithrombin (AT) indicated in patients with hereditary antithrombin deficiency for:" }

{ "type": "ul", "children": [ "Treatment and prevention of thromboembolism", "Prevention of peri-operative and peri-partum thromboembolism" ], "text": "" }

<div class="scrollingtable"><table border="1" cellpadding="4" cellspacing="0" class="Botrule"> <caption> <span>Table 1: Dosing Guidelines</span> </caption> <colgroup> <col/> <col/> <col/> <col/> </colgroup> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>The dose calculation is based on an expected incremental <span class="Italics">in vivo</span> recovery of 1.4% per unit per kilogram above baseline or trough levels.</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Expressed as % normal level based on functional AT assay.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">Regimen <br/> (timing)</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">Target AT <br/>Level</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">Dose (Units)</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">Monitor AT Level </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule">Loading Dose<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td><td align="center" class="Botrule Lrule Rrule Toprule">120% of normal<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Underline">120 % - baseline %  x  body weight (kg)</span> <br/> 1.4%</td><td class="Botrule Lrule Rrule Toprule"> <ul> <li>baseline</li> <li>20 minutes (peak) post-injection</li> <li>12 hours post-injection</li> <li>pre-injection (trough)</li> </ul> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule">Dose Adjustment<a class="Sup" href="#footnote-1">*</a> <br/>(adjust as needed)</td><td align="center" class="Botrule Lrule Rrule Toprule">80% to 120% of normal<a class="Sup" href="#footnote-2">†</a></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Underline">Target % - trough %  x  body weight (kg)</span> <br/> 1.4%</td><td class="Botrule Lrule Rrule Toprule"> <ul> <li>20 minutes (peak) post-injection</li> <li>at least every 12 hours post-injection</li> <li>pre-injection (trough)</li> </ul> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule">Maintenance <br/>Dose<br/>(approximately <br/>every 24 hours, <br/>adjust as needed)</td><td align="center" class="Botrule Lrule Rrule Toprule">80% to 120% of normal<a class="Sup" href="#footnote-2">†</a></td><td align="center" class="Botrule Lrule Rrule Toprule">Loading Dose x 0.6</td><td class="Botrule Lrule Rrule Toprule"> <ul> <li>approximately every 24 hours, as needed</li> </ul> </td> </tr> </tbody> </table></div>

THROMBATE III is a sterile lyophilized powder for reconstitution in single use vials.  Each vial of THROMBATE III contains the labeled amount of antithrombin in units per vial, typically 500 units. When reconstituted with 10 mL of Sterile Water for Injection, USP, the final concentration is approximately 50 units per mL.

{ "type": "p", "children": [], "text": "THROMBATE III is a sterile lyophilized powder for reconstitution in single use vials.  Each vial of THROMBATE III contains the labeled amount of antithrombin in units per vial, typically 500 units. When reconstituted with 10 mL of Sterile Water for Injection, USP, the final concentration is approximately 50 units per mL. " }

The potency is determined with a standard calibrated in International Units against a World Health Organization (WHO) antithrombin reference preparation.

{ "type": "p", "children": [], "text": "The potency is determined with a standard calibrated in International Units against a World Health Organization (WHO) antithrombin reference preparation." }

None.

{ "type": "p", "children": [], "text": "None." }

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. 

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.

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.

<div class="scrollingtable"><table border="1" cellpadding="4" cellspacing="0" class="Botrule" width="60%"> <caption> <span>Table 2: Adverse Reactions Occurring during Hereditary Deficiency Trials</span> </caption> <colgroup> <col/> <col/> <col/> </colgroup> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>MedDRA Preferred Term; an adverse reaction is defined as any adverse event where either a) the event was related, or possibly related to the drug, b) the occurrence was during infusion or shortly after treatment,   or c) the event recurred after withdrawal and re-administration (challenge/dechallenge).</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>N = 33 subjects</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">‡</a> </dt> <dd>N = 389 infusions</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule"> Adverse Reaction<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a>   </td><td align="center" class="Botrule Lrule Rrule Toprule"> Number of Subjects with<br/> Adverse Reaction (%)<a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a>  </td><td align="center" class="Botrule Lrule Rrule Toprule"> Number of Adverse Reactions<br/>(% of All Infusions)<a class="Sup" href="#footnote-5" name="footnote-reference-5">‡</a></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="bottom"> Any adverse reaction </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 9 (27) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 29 (7.5) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="bottom"> Dizziness </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 4 (12) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 8 (2.1) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="bottom"> Chest discomfort </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 3 (9) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 3 (0.8) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="bottom"> Nausea </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 3 (9) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 3 (0.8) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="bottom"> Dysgeusia </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 2 (6) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 3 (0.8) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="bottom"> Pain (cramps) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 2 (6) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 2 (0.5) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="bottom"> Chills </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 1 (3) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 2 (0.5) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="bottom"> Wound secretion and hematoma </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 1 (3) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 2 (0.5) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="bottom"> Vision blurred </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 1 (3) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 1 (0.3) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="bottom"> Chest pain </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 1 (3) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 1 (0.3) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="bottom"> Dyspnea </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 1 (3) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 1 (0.3) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="bottom"> Intestinal dilatation </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 1 (3) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 1 (0.3) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="bottom"> Pyrexia </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 1 (3) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 1 (0.3) </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="bottom"> Urticaria </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 1 (3) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 1 (0.3) </td> </tr> </tbody> </table></div>

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.

The anticoagulant effect of heparin is enhanced by concurrent treatment with THROMBATE III in patients with hereditary AT deficiency. Thus, in order to avoid bleeding, the dosage of heparin (or low molecular weight heparin) may need to be reduced during treatment with THROMBATE III.

{ "type": "p", "children": [], "text": "The anticoagulant effect of heparin is enhanced by concurrent treatment with THROMBATE III in patients with hereditary AT deficiency. Thus, in order to avoid bleeding, the dosage of heparin (or low molecular weight heparin) may need to be reduced during treatment with THROMBATE III. " }

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) and at close intervals to avoid excessive or insufficient anticoagulation. Adjust dosage of anticoagulant as necessary. Additionally, monitor the patients for the occurrence of bleeding or thrombosis.

{ "type": "p", "children": [], "text": "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) and at close intervals to avoid excessive or insufficient anticoagulation. Adjust dosage of anticoagulant as necessary. Additionally, monitor the patients for the occurrence of bleeding or thrombosis." }

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.

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.

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

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

THROMBATE III, Antithrombin III (Human), is a sterile, non-pyrogenic concentrate of human antithrombin (AT) in lyophilized powder form for reconstitution for intravenous injection. When reconstituted with Sterile Water for Injection, USP, THROMBATE III has a pH of 6.0 to 7.5 and contains 110 mEq/L to 210 mEq/L sodium, 110 mEq/L to 210 mEq/L chloride, 0.075 M to 0.125 M alanine, and not more than 0.1 unit of heparin per 1 unit of AT. THROMBATE III contains no preservative.

{ "type": "p", "children": [], "text": "THROMBATE III, Antithrombin III (Human), is a sterile, non-pyrogenic concentrate of human antithrombin (AT) in lyophilized powder form for reconstitution for intravenous injection. When reconstituted with Sterile Water for Injection, USP, THROMBATE III has a pH of 6.0 to 7.5 and contains 110 mEq/L to 210 mEq/L sodium, 110 mEq/L to 210 mEq/L chloride, 0.075 M to 0.125 M alanine, and not more than 0.1 unit of heparin per 1 unit of AT. THROMBATE III contains no preservative. " }

THROMBATE III is prepared from pooled units of human plasma from normal donors. The capacity of the THROMBATE III manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model using a wide range of viruses with diverse physicochemical properties. There are two dedicated virus inactivation/removal steps included in the THROMBATE III manufacturing process: a heat treatment step at 60°C ± 0.5°C for not less than 10 hours for virus inactivation and a nanofiltration step for effective removal of viruses as small as 18 nm.

{ "type": "p", "children": [], "text": "THROMBATE III is prepared from pooled units of human plasma from normal donors. The capacity of the THROMBATE III manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model using a wide range of viruses with diverse physicochemical properties. There are two dedicated virus inactivation/removal steps included in the THROMBATE III manufacturing process: a heat treatment step at 60°C ± 0.5°C for not less than 10 hours for virus inactivation and a nanofiltration step for effective removal of viruses as small as 18 nm." }

The THROMBATE III manufacturing process was also investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the variant Creutzfeldt-Jakob disease (vCJD) and Creutzfeldt-Jakob disease (CJD) agents. An individual production step in the THROMBATE III manufacturing process has been shown to decrease TSE infectivity of that experimental model agent. The TSE reduction step is the Effluent I to Effluent II + III fractionation step (6.0 log10). These studies provide reasonable assurance that low levels of vCJD/CJD agent infectivity, if present in the starting material, would be removed.

{ "type": "p", "children": [], "text": "The THROMBATE III manufacturing process was also investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the variant Creutzfeldt-Jakob disease (vCJD) and Creutzfeldt-Jakob disease (CJD) agents. An individual production step in the THROMBATE III manufacturing process has been shown to decrease TSE infectivity of that experimental model agent. The TSE reduction step is the Effluent I to Effluent II + III fractionation step (6.0 log10). These studies provide reasonable assurance that low levels of vCJD/CJD agent infectivity, if present in the starting material, would be removed." }

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.

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).

<div class="scrollingtable"><table border="1" cellpadding="4" cellspacing="0" class="Botrule" width="60%"> <caption> <span>Table 3: Pharmacokinetic Analyses of THROMBATE III in Asymptomatic Subjects with Congenital AT Deficiency</span> </caption> <thead> <tr class="First Last"> <td class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold"> </span></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> Immunological Assay</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> Functional Assay </td> </tr> </thead> <tfoot> <tr> <td align="left" colspan="0"> <dl class="Footnote"> <dt> <a href="#footnote-reference-6" name="footnote-6">*</a> </dt> <dd>Mean ± SEM</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> AT recovery, % / unit / kg </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1.6 ± 0.1<a class="Sup" href="#footnote-6" name="footnote-reference-6">*</a></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1.4 ± 0.1 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> 50% disappearance time, hr </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 17.4 ± 3.9 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 22.3 ± 8.6 </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> t<span class="Sub">½</span>, day </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2.5 ± 1.5 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3.8 ± 1.8 </td> </tr> </tbody> </table></div>

In a prospective, open-label clinical trial, 21 subjects were administered THROMBATE III for 16 prophylaxis events (n=13 subjects) and 10 for treatment of thrombosis (n=10 subjects) with 2 subjects receiving THROMBATE III for both prophylaxis and treatment of thrombosis. None of the 13 subjects with hereditary AT deficiency and histories of thromboembolism treated prophylactically on 16 separate occasions with THROMBATE III for high thrombotic risk situations (11 surgical procedures, 5 pregnancies and/or deliveries) developed a thrombotic complication. Heparin was administered in 3 of the 11 surgical procedures. Two of the pregnant subjects received LMW heparin prophylactically during the first trimester, but which was unable to maintain anti-coagulation with increasing dosages. [see Drug Interactions (7)] They experienced a thrombosis, which subsequently resolved with the addition of THROMBATE III, and were therefore administered THROMBATE III and LMW heparin prophylaxis weekly during the second and third trimesters, and during labor and delivery. These two subjects did not experience a new thrombosis.

{ "type": "p", "children": [], "text": "In a prospective, open-label clinical trial, 21 subjects were administered THROMBATE III for 16 prophylaxis events (n=13 subjects) and 10 for treatment of thrombosis (n=10 subjects) with 2 subjects receiving THROMBATE III for both prophylaxis and treatment of thrombosis. None of the 13 subjects with hereditary AT deficiency and histories of thromboembolism treated prophylactically on 16 separate occasions with THROMBATE III for high thrombotic risk situations (11 surgical procedures, 5 pregnancies and/or deliveries) developed a thrombotic complication. Heparin was administered in 3 of the 11 surgical procedures. Two of the pregnant subjects received LMW heparin prophylactically during the first trimester, but which was unable to maintain anti-coagulation with increasing dosages. [see Drug Interactions (7)] They experienced a thrombosis, which subsequently resolved with the addition of THROMBATE III, and were therefore administered THROMBATE III and LMW heparin prophylaxis weekly during the second and third trimesters, and during labor and delivery. These two subjects did not experience a new thrombosis." }

Ten subjects with hereditary AT deficiency were treated with THROMBATE III as well as heparin (n=9) for major thrombotic or thromboembolic complications, including 4 subjects with thrombosis during the first trimester of pregnancy.  Nine subjects recovered with no additional thromboses or extension of existing thrombosis. The tenth subject died due to complications from the original pulmonary embolism with infarction which preceded treatment with THROMBATE III.

{ "type": "p", "children": [], "text": "Ten subjects with hereditary AT deficiency were treated with THROMBATE III as well as heparin (n=9) for major thrombotic or thromboembolic complications, including 4 subjects with thrombosis during the first trimester of pregnancy.  Nine subjects recovered with no additional thromboses or extension of existing thrombosis. The tenth subject died due to complications from the original pulmonary embolism with infarction which preceded treatment with THROMBATE III." }

{ "type": "", "children": [], "text": "" }

THROMBATE III is supplied in a kit containing one single use vial of THROMBATE III lyophilized powder for reconstitution, one vial of Sterile Water for Injection, USP, one sterile double-ended transfer needle, and one sterile filter needle. The total activity of AT in International Units is stated on the label of the THROMBATE III vial.

{ "type": "p", "children": [], "text": "THROMBATE III is supplied in a kit containing one single use vial of THROMBATE III lyophilized powder for reconstitution, one vial of Sterile Water for Injection, USP, one sterile double-ended transfer needle, and one sterile filter needle. The total activity of AT in International Units is stated on the label of the THROMBATE III vial. " }

 Components of the packaging do not contain natural rubber latex.

{ "type": "p", "children": [], "text": " Components of the packaging do not contain natural rubber latex." }

<div class="scrollingtable"><table cellpadding="4" width="50%"> <tbody class="Headless"> <tr class="First"> <td align="center" valign="bottom"> NDC Number<br/> <span class="Underline">Carton (Kit)</span></td><td align="center" valign="bottom"> Approximate<br/> <span class="Underline">Antithrombin Potency</span></td><td align="center" valign="bottom"><span class="Underline">Diluent</span></td> </tr> <tr class="Last" valign="bottom"> <td align="center" valign="top"> 13533-603-20, <br/>13533-602-50 <br/>or <br/>13533-606-12 </td><td align="center"> 500 units </td><td align="center"> 10 mL </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table cellpadding=\"4\" width=\"50%\">\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" valign=\"bottom\"> NDC Number<br/>\n<span class=\"Underline\">Carton (Kit)</span></td><td align=\"center\" valign=\"bottom\"> Approximate<br/>\n<span class=\"Underline\">Antithrombin Potency</span></td><td align=\"center\" valign=\"bottom\"><span class=\"Underline\">Diluent</span></td>\n</tr>\n<tr class=\"Last\" valign=\"bottom\">\n<td align=\"center\" valign=\"top\"> 13533-603-20, <br/>13533-602-50 <br/>or <br/>13533-606-12 </td><td align=\"center\"> 500 units </td><td align=\"center\"> 10 mL </td>\n</tr>\n</tbody>\n</table></div>" }

{ "type": "ul", "children": [ "Store THROMBATE III at temperatures not to exceed 25°C (77°F).", "Avoid freezing as breakage of the diluent vial might occur." ], "text": "" }

Hypersensitivity Reactions

{ "type": "p", "children": [], "text": "\nHypersensitivity Reactions\n" }

Inform patients that allergic-type hypersensitivity reactions are possible and instruct them to inform their physicians about any past or present known hypersensitivity to human plasma proteins prior to treatment with THROMBATE III. Inform patients of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis and to notify their health care provider immediately if these events develop. [see Warnings and Precautions (5.1)]

{ "type": "p", "children": [], "text": "Inform patients that allergic-type hypersensitivity reactions are possible and instruct them to inform their physicians about any past or present known hypersensitivity to human plasma proteins prior to treatment with THROMBATE III. Inform patients of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis and to notify their health care provider immediately if these events develop. [see Warnings and Precautions (5.1)]\n" }

Transmission of Infectious Disease

{ "type": "p", "children": [], "text": "\nTransmission of Infectious Disease\n" }

Inform patients that THROMBATE III is made from human plasma and may carry a risk of transmitting infectious agents that can cause disease (e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent). Inform patients that this risk has been reduced by screening plasma donors for prior exposure to certain infectious agents, by testing the donated plasma for markers of certain current infections, and by inactivating and/or removing pathogens during manufacturing. [see Warnings and Precautions (5.2)]

{ "type": "p", "children": [], "text": "Inform patients that THROMBATE III is made from human plasma and may carry a risk of transmitting infectious agents that can cause disease (e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent). Inform patients that this risk has been reduced by screening plasma donors for prior exposure to certain infectious agents, by testing the donated plasma for markers of certain current infections, and by inactivating and/or removing pathogens during manufacturing. [see Warnings and Precautions (5.2)]\n" }

Manufactured by: GRIFOLS Grifols Therapeutics LLC Research Triangle Park, NC 27709 USAU.S. License No. 1871 3056479

{ "type": "p", "children": [], "text": "\nManufactured by:\nGRIFOLS\n\nGrifols Therapeutics LLC\nResearch Triangle Park, NC 27709 USAU.S. License No. 1871\n3056479\n\n" }

NDC 13533-605-21 500 IU / 10 mL Antithrombin III (Human) Thrombate III® Lyophilized Powder Rx only For Intravenous Administration Only Heat-Treated              Nanofiltered The patient and physician should discuss the risks and benefits of this product. No Preservative Sterile — Nonpyrogenic Reconstitute with 10 mL Sterile Water for Injection, USP. Store at temperatures not to exceed 25°C (77°F). Do not freeze. Dosage and Administration: Read package insert. Grifols Therapeutics LLC Research Triangle Park, NC 27709 USA U.S. License No. 1871 3060449 Lot Exp. IU

{ "type": "p", "children": [], "text": "NDC 13533-605-21\n\n500 IU / 10 mL\n\nAntithrombin III (Human)\n\nThrombate III®\n Lyophilized Powder\n\nRx only\n\n\nFor Intravenous Administration Only\n\n\nHeat-Treated              Nanofiltered\nThe patient and physician should discuss the risks and benefits of this product.\nNo Preservative Sterile — Nonpyrogenic\nReconstitute with 10 mL Sterile Water for Injection, USP. \nStore at temperatures not to exceed 25°C (77°F). Do not freeze. Dosage and Administration: Read package insert.\n\nGrifols Therapeutics LLC \nResearch Triangle Park, NC 27709 USA U.S. License No. 1871\n3060449\nLot \nExp. \nIU\n" }

NDC 13533-602-50                                                  500 IU / 10 mL Antithrombin III (Human) Thrombate III® Lyophilized Powder Rx only For Intravenous Administration Only GRIFOLS Heat-Treated              Nanofiltered Contents:One vial of THROMBATE III10 mL Sterile Water for Injection,USPOne sterile filter needleOne sterile double-ended transferneedle No Preservative Sterile — Nonpyrogenic GRIFOLS The patient and physician should discuss the risks and benefits of this product.This product when reconstituted with 10 mL Sterile Water forInjection, USP, contains 110-210 mEq/L sodium, 110-210 mEq/L chloride, 0.075-0.125 M alanine, and not more than0.1 IU heparin/IU ATIII.Administer within 3 hours after reconstitution. Dosage and Administration: Read enclosed package insert. Store at temperatures not to exceed 25°C (77°F). Do not freeze.  If the shrink band is absent or shows any sign of tampering, do notuse the product and notify Grifols Therapeutics LLC immediately. Not Returnable for Credit or Exchange GRIFOLS This product is prepared from large pools of human plasma which may contain infectious agents. See package insert Warnings. Grifols Therapeutics LLC Research Triangle Park, NC 27709 USA U.S. License No. 1871 GRIFOLS Open other end Carton: 3060457 GTIN XXXXXXXXXXXXXXLOT XXXXXXXXXXEXP DDMMMYYYYSN 4001XXXXXXXXXXIU XXX NDC 13533-602-50            500 IU / 10 mL Antithrombin III (Human) Thrombate III®

{ "type": "p", "children": [], "text": "NDC 13533-602-50                                                  500 IU / 10 mL\n\nAntithrombin III (Human) \nThrombate III®\n\nLyophilized Powder\nRx only \n\nFor Intravenous Administration Only\n\nGRIFOLS\n\n\nHeat-Treated              Nanofiltered\n\nContents:One vial of THROMBATE III10 mL Sterile Water for Injection,USPOne sterile filter needleOne sterile double-ended transferneedle\n\nNo Preservative Sterile — Nonpyrogenic\n\nGRIFOLS\n\nThe patient and physician should discuss the risks and benefits of this product.This product when reconstituted with 10 mL Sterile Water forInjection, USP, contains 110-210 mEq/L sodium, 110-210 mEq/L chloride, 0.075-0.125 M alanine, and not more than0.1 IU heparin/IU ATIII.Administer within 3 hours after reconstitution.\nDosage and Administration: Read enclosed package insert.\nStore at temperatures not to exceed 25°C (77°F). Do not freeze. \n\nIf the shrink band is absent or shows any sign of tampering, do notuse the product and notify Grifols Therapeutics LLC immediately.\nNot Returnable for Credit or Exchange\nGRIFOLS\n\nThis product is prepared from large pools of human plasma which may contain infectious agents.\nSee package insert Warnings.\n\n\nGrifols Therapeutics LLC \nResearch Triangle Park, \n\nNC 27709 USA\n\nU.S. License No. 1871\n\n\nGRIFOLS\n\n\nOpen other end\n\nCarton: 3060457\nGTIN XXXXXXXXXXXXXXLOT XXXXXXXXXXEXP DDMMMYYYYSN 4001XXXXXXXXXXIU XXX \nNDC 13533-602-50            500 IU / 10 mL Antithrombin III (Human) \nThrombate III®\n\n" }

NDC 13533-200-10 Sterile Water for Injection, USP 10 mL Rx Only For reconstitution of accompanying product Single-Dose Container, NonpyrogenicDo not use unless clear. No antimicrobial agent or other substance has been added. Do not use for intravascular injection without making approximately isotonic by addition of suitable solute. Discard unused portion. Mfd by: Laboratorios Grifols, S. A., Parets del Vallès, Barcelona, 08150 SpainMfd for: Grifols Therapeutics LLC, Research Triangle Park, NC, 27709 USA 3051810 Lot / Exp.

{ "type": "p", "children": [], "text": "NDC 13533-200-10\n\nSterile Water for Injection, USP\n\n\n10 mL\n\n\nRx Only\n\n\nFor reconstitution of accompanying product \n\nSingle-Dose Container, NonpyrogenicDo not use unless clear. No antimicrobial agent or other substance has been added. Do not use for intravascular injection without making approximately isotonic by addition of suitable solute. Discard unused portion.\nMfd by: Laboratorios Grifols, S. A., Parets del Vallès, Barcelona, 08150 SpainMfd for: Grifols Therapeutics LLC, Research Triangle Park, NC, 27709 USA\n3051810\nLot / Exp." }

NDC 76297-002-12 Sterile Water for Injection, USP 10 mL Rx Only For reconstitution of accompanying product Single-Dose Container, NonpyrogenicDo not use unless clear. No antimicrobial agent or other substance has been added. Do not use for intravascular injection without making approximately isotonic by addition of suitable solute. Discard unused portion. Mfd by: Laboratorios Grifols, S. A. Parets del Vallès, Barcelona 08150 Spain 3057423 Lot EXP

{ "type": "p", "children": [], "text": "NDC 76297-002-12\n\nSterile Water for Injection, USP\n\n\n10 mL\n\n\nRx Only\n\n\nFor reconstitution of accompanying product \n\nSingle-Dose Container, NonpyrogenicDo not use unless clear. No antimicrobial agent or other substance has been added. Do not use for intravascular injection without making approximately isotonic by addition of suitable solute. Discard unused portion.\nMfd by: Laboratorios Grifols, S. A. Parets del Vallès, Barcelona 08150 Spain\n3057423\nLot\nEXP" }