ADVATE® [Antihemophilic Factor (Recombinant)] Important Information

INDICATIONS

ADVATE is a recombinant antihemophilic factor indicated for use in children and adults with hemophilia A (congenital factor VIII deficiency) for:

  • Control and prevention of bleeding episodes.
  • Perioperative management.
  • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

ADVATE is not indicated for the treatment of von Willebrand disease.

DETAILED IMPORTANT RISK INFORMATION

CONTRAINDICATIONS

Patients who have life-threatening hypersensitivity reactions, including anaphylaxis, to mouse or hamster protein or other constituents of the product.

WARNINGS & PRECAUTIONS

Hypersensitivity Reactions

Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. Symptoms include dizziness, paresthesia, rash, flushing, facial swelling, urticaria, dyspnea, pruritus, and vomiting. Discontinue ADVATE if hypersensitivity symptoms occur and administer appropriate emergency treatment.

Neutralizing Antibodies

Neutralizing antibodies (inhibitors) have been reported following administration of ADVATE predominantly in previously untreated patients (PUPs) and previously minimally treated patients (MTPs). Monitor all patients for the development of factor VIII inhibitors by appropriate clinical observation and laboratory testing. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures factor VIII inhibitor concentration.

ADVERSE REACTIONS

  • Serious adverse reactions seen with ADVATE are hypersensitivity reactions, including anaphylaxis, and the development of high-titer inhibitors necessitating alternative treatments to factor VIII.
  • The most common adverse reactions observed in clinical trials (>5% of subjects) were pyrexia, headache, cough, nasopharyngitis, arthralgia, vomiting, upper respiratory tract infection, limb injury, nasal congestion, and diarrhea.

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ADYNOVATE® [Antihemophilic Factor (Recombinant), PEGylated] Important Information

Indications and Limitation of Use

ADYNOVATE is a human antihemophilic factor indicated in children and adults with hemophilia A (congenital factor VIII deficiency) for:

  • On-demand treatment and control of bleeding episodes
  • Perioperative management
  • Routine prophylaxis to reduce the frequency of bleeding episodes

ADYNOVATE is not indicated for the treatment of von Willebrand disease.

DETAILED IMPORTANT RISK INFORMATION

CONTRAINDICATIONS

Prior anaphylactic reaction to ADYNOVATE, to the parent molecule (ADVATE [Antihemophilic Factor (Recombinant)]), mouse or hamster protein, or excipients of ADYNOVATE (e.g. Tris, mannitol, trehalose, glutathione, and/or polysorbate 80).

WARNINGS & PRECAUTIONS

Hypersensitivity Reactions

Hypersensitivity reactions are possible with ADYNOVATE. Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with other recombinant antihemophilic factor VIII products, including the parent molecule, ADVATE. Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, and pruritus. Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur.

Neutralizing Antibodies

Formation of neutralizing antibodies (inhibitors) to factor VIII can occur following administration of ADYNOVATE. Monitor patients regularly for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. Perform an assay that measures factor VIII inhibitor concentration if the plasma factor VIII level fails to increase as expected, or if bleeding is not controlled with expected dose.

ADVERSE REACTIONS

The most common adverse reactions (≥1% of subjects) reported in the clinical studies were headache and nausea.

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FEIBA® [Anti-Inhibitor Coagulant Complex] Indications and Detailed Important Risk Information

Indications

FEIBA is an Anti-Inhibitor Coagulant Complex indicated for use in hemophilia A and B patients with inhibitors for:

  • Control and prevention of bleeding episodes.
  • Perioperative management.
  • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

FEIBA is not indicated for the treatment of bleeding episodes resulting from coagulation factor deficiencies in the absence of inhibitors to coagulation factor VIII or coagulation factor IX.

DETAILED IMPORTANT RISK INFORMATION

WARNING: EMBOLIC AND THROMBOEMBOLIC EVENTS

  • Thromboembolic events have been reported during post-marketing surveillance following infusion of FEIBA, particularly following the administration of high doses (above 200 units per kg per day) and/or in patients with thrombotic risk factors.
  • Monitor patients receiving FEIBA for signs and symptoms of thromboembolic events.

CONTRAINDICATIONS

FEIBA is contraindicated in patients with:

  • History of anaphylactic or severe hypersensitivity reactions to FEIBA or any of its components, including factors of the kinin generating system
  • Disseminated intravascular coagulation (DIC)
  • Acute thrombosis or embolism (including myocardial infarction)

WARNINGS AND PRECAUTIONS

Thromboembolic events (including venous thrombosis, pulmonary embolism, myocardial infarction, and stroke) can occur, particularly following the administration of high doses (>200 units/kg/day) and/or in patients with thrombotic risk factors.

Patients with DIC, advanced atherosclerotic disease, crush injury, septicemia, or concomitant treatment with recombinant factor VII have an increased risk of developing thrombotic events due to circulating tissue factor or predisposing coagulopathy. Potential benefit of treatment should be weighed against the potential risk of these thromboembolic events.

Infusion should not exceed a single dose of 100 units/kg and daily doses of 200 units/kg. Maximum injection or infusion rate must not exceed 2 units/kg/minute. Monitor patients receiving >100 units/kg for the development of DIC, acute coronary ischemia and signs and symptoms of other thromboembolic events. If clinical signs or symptoms occur, such as chest pain or pressure, shortness of breath, altered consciousness, vision, or speech, limb or abdomen swelling and/or pain, discontinue FEIBA and initiate appropriate diagnostic and therapeutic measures.

Safety and efficacy of FEIBA for breakthrough bleeding in patients receiving emicizumab has not been established. Cases of thrombotic microangiopathy (TMA) were reported in a clinical trial where subjects received FEIBA as part of a treatment regimen for breakthrough bleeding following emicizumab treatment. Consider the benefits and risks with FEIBA if considered required for patients receiving emicizumab prophylaxis. If treatment with FEIBA is required for patients receiving emicizumab, the hemophilia treating physician should closely monitor for signs and symptoms of TMA. In FEIBA clinical studies TMA has not been reported.

Hypersensitivity and allergic reactions, including severe anaphylactoid reactions, can occur. Symptoms include urticaria, angioedema, gastrointestinal manifestations, bronchospasm, and hypotension. Reactions can be severe and systemic (e.g., anaphylaxis with urticaria and angioedema, bronchospasm, and circulatory shock). Other infusion reactions, such as chills, pyrexia, and hypertension have also been reported. If signs and symptoms of severe allergic reactions occur, immediately discontinue FEIBA and provide appropriate supportive care.

Because FEIBA is made from human plasma 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.

FEIBA contains blood group isohemagglutinins (anti-A and anti-B). Passive transmission of antibodies to erythrocyte antigens, e.g., A, B, D, may interfere with some serological tests for red cell antibodies, such as antiglobulin test (Coombs test).

ADVERSE REACTIONS

Most frequently reported adverse reactions observed in >5% of subjects in the prophylaxis trial were anemia, diarrhea, hemarthrosis, hepatitis B surface antibody positive, nausea, and vomiting.

Serious adverse reactions seen are hypersensitivity reactions and thromboembolic events, including stroke, pulmonary embolism and deep vein thrombosis.

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HEMOFIL M [Antihemophilic Factor (Human), Method M, Monoclonal Purified] Important Information

Indications

HEMOFIL M is indicated in hemophilia A (classical hemophilia) for the prevention and control of hemorrhagic episodes.

HEMOFIL M is not indicated in von Willebrand's disease.

DETAILED IMPORTANT RISK INFORMATION

CONTRAINDICATIONS

Patients with a known hypersensitivity to the active substance, to excipients, or to mouse proteins.

WARNINGS & PRECAUTIONS

Anaphylaxis and Severe Hypersensitivity Reactions

Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with HEMOFIL M with symptoms of bronchospasm, dyspnea, hypotension, chest pain, facial edema, urticaria, rash, flushing, pruritus, and nausea. If symptoms occur, immediately discontinue HEMOFIL M and initiate emergency treatment.

Identification of the clotting defect as a Factor VIII deficiency is essential before the administration of HEMOFIL M is initiated.

Neutralizing Antibodies

Formation of neutralizing antibodies (inhibitors) to factor VIII can occur following administration of HEMOFIL M. Monitor patients regularly for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. Perform an assay that measures factor VIII inhibitor concentration if the plasma factor VIII level fails to increase as expected, or if bleeding is not controlled with expected dose.

Transmission of Infection

Because HEMOFIL M is made from human blood, it may carry a risk of transmitting infectious agents, such as viruses. These agents may include the parvovirus B19, hepatitis A, Creutzfeldt-Jakob disease agent or a variant of it, and other unknown or emerging viruses or disease causing agents. Discuss the risks and benefits of this product with the patient.

All infections thought by a physician possibly to have been transmitted by this product should be reported to Shire, at 1-800-999-1785 (Baxalta related products in the U.S.).

Increase in Pulse Rate

Determine the pulse rate before and during administration of HEMOFIL M. Should a significant increase occur, reduce the rate of administration or temporarily halt the injection to allow the symptoms to disappear promptly.

ADVERSE REACTIONS

The adverse reactions (1 or more subjects) reported in the clinical studies were Factor VIII inhibition, infusion site inflammation, dizziness, headache, dysgeusia, and pyrexia.

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OBIZUR® [Antihemophilic Factor (Recombinant), Porcine Sequence] Important Information

Indications

OBIZUR, Antihemophilic Factor (Recombinant), Porcine Sequence, is a recombinant DNA derived, antihemophilic factor indicated for the on-demand treatment and control of bleeding episodes in adults with acquired hemophilia A.

Limitations of Use:

  • Safety and efficacy of OBIZUR has not been established in patients with baseline anti-porcine factor VIII inhibitor titer greater than 20 BU
  • OBIZUR is not indicated for the treatment of congenital hemophilia A or von Willebrand disease

DETAILED IMPORTANT RISK INFORMATION

CONTRAINDICATIONS

OBIZUR is contraindicated in patients who have had life-threatening hypersensitivity reactions to OBIZUR or its components (including traces of hamster proteins).

WARNINGS & PRECAUTIONS

Hypersensitivity Reactions

Hypersensitivity reactions can occur with OBIZUR. OBIZUR contains trace amounts of hamster proteins. Early signs of allergic reactions, which can progress to anaphylaxis, include angioedema, chest-tightness, dyspnea, hypotension, wheezing, urticaria, and pruritus. Immediately discontinue administration and initiate appropriate treatment if allergic or anaphylactic-type reactions occur.

Inhibitory Antibodies

Inhibitory antibodies to OBIZUR, including anamnestic reactions with rise in human FVIII inhibitors and/or porcine FVIII inhibitors, have occurred. Monitor patients for the development of antibodies to OBIZUR by appropriate assays. If the plasma factor VIII level fails to increase as expected, or if bleeding is not controlled after OBIZUR administration, suspect the presence of an anti-porcine factor VIII antibody.

If such inhibitory antibodies are suspected and there is a lack of clinical response, consider other therapeutic options such as discontinuing OBIZUR and initiating other therapeutics such as a factor VIII bypassing agent.

Monitoring Laboratory Tests

  • Perform one-stage clotting assay to confirm that adequate factor VIII levels have been achieved and maintained - Monitor factor VIII activity 30 minutes and 3 hours after initial dose
    - Monitor factor VIII activity 30 minutes after subsequent doses
  • Monitor the development of inhibitory antibodies to OBIZUR. Perform a Nijmegen Bethesda inhibitor assay if expected plasma factor VIII activity levels are not attained or if bleeding is not controlled with the expected dose of OBIZUR. Use Bethesda Units (BU) to report inhibitor levels

ADVERSE REACTIONS

Common adverse reactions observed in greater than 5% of subjects in the clinical trial were development of inhibitors to porcine factor VIII.

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RECOMBINATE [Antihemophilic Factor (Recombinant)] Important Information

Indications

RECOMBINATE is indicated in hemophilia A (classical hemophilia) for:

  • Prevention and control of hemorrhagic episodes
  • Perioperative management

RECOMBINATE is not indicated for von Willebrand's disease

DETAILED IMPORTANT RISK INFORMATION

CONTRAINDICATIONS

Patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including bovine, mouse or hamster proteins.

WARNINGS & PRECAUTIONS

Anaphylaxis and Severe Hypersensitivity Reactions

Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with RECOMBINATE with symptoms of dizziness, pruritus, rash, urticaria, flushing, angioedema/face swelling, laryngeal edema, dyspnea, pallor, pyrexia, nausea, paresthesia, hypotension, and loss of consciousness. If symptoms occur, immediately discontinue RECOMBINATE and initiate emergency treatment.

Identification of the clotting defect as a Factor VIII deficiency is essential before the administration of RECOMBINATE [Antihemophilic Factor (Recombinant)] is initiated.

Neutralizing Antibodies

Inhibitors have been reported following administration of RECOMBINATE predominantly in previously untreated and minimally treated patients. Patients treated with antihemophilic factor (AHF) products should be carefully monitored for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. Perform an assay that measures factor VIII inhibitor concentration if the plasma factor VIII level fails to increase as expected, or if bleeding is not controlled with expected dose.

ADVERSE REACTIONS

The most common adverse reactions reported in clinical studies were chills, flushing, rash, and epistaxis.

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RIXUBIS® [Coagulation Factor IX (Recombinant)] Important Information

Indications

RIXUBIS [Coagulation Factor IX (Recombinant)] is an antihemophilic factor indicated in adults and children with hemophilia B for:

  • On-demand treatment and control of bleeding episodes
  • Perioperative management of bleeding
  • Routine prophylaxis to reduce the frequency of bleeding episodes

RIXUBIS is not indicated for induction of immune tolerance in patients with hemophilia B.

DETAILED IMPORTANT RISK INFORMATION

CONTRAINDICATIONS

RIXUBIS is contraindicated in patients who have:

  • Known hypersensitivity to RIXUBIS or its excipients including hamster protein
  • Disseminated Intravascular Coagulation (DIC)
  • Signs of fibrinolysis

WARNINGS & PRECAUTIONS

Hypersensitivity Reactions

Hypersensitivity reactions have been reported with RIXUBIS. Anaphylaxis and other hypersensitivity reactions are possible. The risk is highest during the early phases of initial exposure in previously untreated patients (PUPs), in particular in patients with high-risk gene mutations. Early signs of allergic reactions, which can progress to anaphylaxis, include angioedema, chest tightness, hypotension, lethargy, nausea, vomiting, paresthesia, restlessness, wheezing, and dyspnea. Should symptoms occur, immediately discontinue RIXUBIS and administer appropriate treatment.

Inhibitors

Development of neutralizing antibodies (inhibitors) to RIXUBIS may occur. Regularly evaluate patients for the development of factor IX inhibitors by appropriate clinical observations and laboratory tests. If expected factor IX plasma activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures factor IX inhibitor concentration. Contact a specialized hemophilia treatment center if a patient develops an inhibitor.

Patients with factor IX inhibitors are at an increased risk of severe hypersensitivity reactions or anaphylaxis if re-exposed to RIXUBIS.

Nephrotic Syndrome

Nephrotic syndrome has been reported following attempted immune tolerance induction with factor IX products in hemophilia B patients that have factor IX inhibitors. The safety and efficacy of using RIXUBIS for immune tolerance induction have not been established.

Thromboembolic Complications

The use of factor IX containing products has been associated with the development of thromboembolic complications. Monitor patients for early signs of thromboembolic and consumptive coagulopathy, when administering RIXUBIS to patients with liver disease, with signs of fibrinolysis, peri- and post-operatively, or at risk for thromboembolic events or DIC. The benefit of treatment with RIXUBIS should be weighed against the risk of these complications in patients with DIC or those at risk for DIC or thromboembolic events.

ADVERSE REACTIONS

Common adverse reactions observed in >1% of subjects in clinical studies were: dysgeusia, pain in extremity, and positive test for furin antibody.

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VONVENDI® [von Willebrand factor (recombinant)] Important Information

Indications

VONVENDI [von Willebrand factor (recombinant)] is a recombinant von Willebrand factor (rVWF) indicated for use in adults (age 18 and older) diagnosed with von Willebrand disease (VWD) for:

  • On-demand treatment and control of bleeding episodes
  • Perioperative management of bleeding

DETAILED IMPORTANT RISK INFORMATION

CONTRAINDICATIONS

Do not use in patients who have had life-threatening hypersensitivity reactions to VONVENDI or its components (tri-sodium citrate-dihydrate, glycine, mannitol, trehalose-dihydrate, polysorbate 80, and hamster or mouse proteins).

WARNINGS & PRECAUTIONS

Embolism and Thrombosis

Thromboembolic reactions, including disseminated intravascular coagulation, venous thrombosis, pulmonary embolism, myocardial infarction, and stroke, can occur, particularly in patients with known risk factors for thrombosis, including low ADAMTS13 levels. Monitor for early signs and symptoms of thrombosis such as pain, swelling, discoloration, dyspnea, cough, hemoptysis, and syncope, and institute prophylaxis measures against thromboembolism based on current recommendations.

In patients requiring frequent doses of VONVENDI in combination with recombinant factor VIII, monitor plasma levels for FVIII:C activity because sustained excessive factor VIII plasma levels can increase the risk of thromboembolic events.

One out of 80 subjects treated with VONVENDI in clinical trials developed proximal deep vein thrombosis in perioperative period after total hip replacement surgery.

Hypersensitivity Reactions

Hypersensitivity reactions have occurred with VONVENDI. These reactions can include anaphylactic shock, generalized urticaria, angioedema, chest tightness, hypotension, shock, lethargy, nausea, vomiting, paresthesia, pruritus, restlessness, blurred vision, wheezing and/or acute respiratory distress. Discontinue VONVENDI if hypersensitivity symptoms occur and administer appropriate emergency treatment.

Neutralizing Antibodies (Inhibitors)

Inhibitors to VWF and/or factor VIII can occur. If the expected plasma levels of VWF activity (VWF:RCo) are not attained, perform an appropriate assay to determine if anti-VWF or anti-factor VIII inhibitors are present. Consider other therapeutic options and direct the patient to a physician with experience in the care of either VWD or hemophilia A.

In patients with high levels of inhibitors to VWF or factor VIII, VONVENDI therapy may not be effective and infusion of this protein may lead to severe hypersensitivity reactions. Since inhibitor antibodies can occur concomitantly with anaphylactic reactions, evaluate patients experiencing an anaphylactic reaction for the presence of inhibitors.

ADVERSE REACTIONS

In clinical trials, the most common adverse reactions observed in ≥2% of subjects (n=80) were generalized pruritus, vomiting, nausea, dizziness, and vertigo.

One subject treated with VONVENDI in perioperative setting developed deep vein thrombosis after total hip replacement surgery.

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