Krystexxa

• Anaphylaxis and infusion reactions have been reported to occur during and after administration of KRYSTEXXA. (

  5.1 Anaphylaxis

  In a 52-week controlled trial, which evaluated KRYSTEXXA co-administered with methotrexate compared to KRYSTEXXA alone, subjects were pre-treated with standardized infusion reaction prophylaxis and were discontinued from treatment with KRYSTEXXA if serum uric acid levels increased to above 6 mg/dL at 2 consecutive visits after the initiation of KRYSTEXXA therapy to reduce the risk of anaphylaxis. One subject randomized to the group treated with KRYSTEXXA co-administered with methotrexate (1%) experienced anaphylaxis during the first infusion and no subjects experienced anaphylaxis in the group treated with KRYSTEXXA alone

  [see Adverse Reactions (6.1), Clinical Studies (14)]

  .

  During pre-marketing clinical trials with KRYSTEXXA alone, KRYSTEXXA was not discontinued following 2 consecutive serum uric acid levels above 6 mg/dL. Anaphylaxis was reported with a frequency of 6.5% (8/123) of subjects treated with KRYSTEXXA every 2 weeks and 4.8% (6/126) for the every 4-week dosing regimen. There were no cases of anaphylaxis in subjects receiving placebo. Anaphylaxis generally occurred within 2 hours after treatment.

  Diagnostic criteria of anaphylaxis were skin or mucosal tissue involvement, and, either airway compromise, and/or reduced blood pressure with or without associated symptoms, and a temporal relationship to KRYSTEXXA or placebo injection with no other identifiable cause. Manifestations included wheezing, peri-oral or lingual edema, or hemodynamic instability, with or without rash or urticaria, nausea or vomiting. Cases occurred in patients being pre-treated with one or more doses of an oral antihistamine, an intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of anaphylaxis and therefore the reported frequency may be an underestimate.

  KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage anaphylaxis. Patients should be pre-treated with antihistamines and corticosteroids. Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion. However, delayed type hypersensitivity reactions have also been reported. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Patients should be informed of the symptoms and signs of anaphylaxis and instructed to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting.

  The risk of anaphylaxis is higher in patients whose uric acid level increases to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. Monitor serum uric acid levels prior to infusions and discontinue treatment if levels increase to above 6 mg/dL. Because of the possibility that concomitant use of oral urate-lowering therapy and KRYSTEXXA may potentially blunt the rise of serum uric acid levels, it is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.

  ,

  5.2 Infusion Reactions

  In a 52-week, controlled trial which evaluated KRYSTEXXA co-administered with methotrexate compared to KRYSTEXXA alone

  [see Adverse Reactions (6.1), Clinical Studies (14)]

  , subjects were pre-treated with standardized infusion reaction prophylaxis and were discontinued from treatment with KRYSTEXXA if serum uric acid levels increased to above 6 mg/dL at 2 consecutive visits after the initiation of KRYSTEXXA therapy to reduce the risk of infusion reactions

  .

  Infusion reactions were reported in 4% of subjects in the KRYSTEXXA co-administered with methotrexate group compared to 31% of subjects treated with KRYSTEXXA alone experienced infusion reactions

  [see Adverse Reactions (6.1), Clinical Studies (14)]

  . In both treatment groups, the majority of infusion reactions occurred at the first or second KRYSTEXXA infusion and during the time of infusion. Manifestations of these infusion reactions were similar to that observed in the pre-marketing trials.

  During pre-marketing 24-week controlled clinical trials with KRYSTEXXA alone, KRYSTEXXA was not discontinued following 2 consecutive serum uric acid levels above 6 mg/dL. Infusion reactions were reported in 26% of subjects treated with KRYSTEXXA 8 mg every 2 weeks, and 41% of subjects treated with KRYSTEXXA 8 mg every 4 weeks, compared to 5% of subjects treated with placebo. These infusion reactions occurred in subjects being pre-treated with an oral antihistamine, intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of infusion reactions and therefore the reported frequency may be an underestimate.

  Manifestations of these reactions included urticaria (frequency of 10.6%), dyspnea (frequency of 7.1%), chest discomfort (frequency of 9.5%), chest pain (frequency of 9.5%), erythema (frequency of 9.5%), and pruritus (frequency of 9.5%). These manifestations overlap with the symptoms of anaphylaxis, but in a given patient did not occur together to satisfy the clinical criteria for diagnosing anaphylaxis. Infusion reactions are thought to result from release of various mediators, such as cytokines. Infusion reactions occurred at any time during a course of treatment with approximately 3% occurring with the first infusion, and approximately 91% occurred during the time of infusion.

  KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage infusion reactions. Patients should be pre-treated with antihistamines and corticosteroids. KRYSTEXXA should be infused slowly over no less than 120 minutes. In the event of an infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate.

  The risk of infusion reaction is higher in patients whose uric acid level increases to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. Monitor serum uric acid levels prior to infusions and discontinue treatment if levels increase to above 6 mg/dL. Because of the possibility that concomitant use of oral urate-lowering therapy and KRYSTEXXA may potentially blunt the rise of serum uric acid levels, it is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.

  )
• Anaphylaxis may occur with any infusion, and generally manifests within 2 hours of the infusion. However, delayed hypersensitivity reactions have also been reported. (

  5.1 Anaphylaxis

  In a 52-week controlled trial, which evaluated KRYSTEXXA co-administered with methotrexate compared to KRYSTEXXA alone, subjects were pre-treated with standardized infusion reaction prophylaxis and were discontinued from treatment with KRYSTEXXA if serum uric acid levels increased to above 6 mg/dL at 2 consecutive visits after the initiation of KRYSTEXXA therapy to reduce the risk of anaphylaxis. One subject randomized to the group treated with KRYSTEXXA co-administered with methotrexate (1%) experienced anaphylaxis during the first infusion and no subjects experienced anaphylaxis in the group treated with KRYSTEXXA alone

  [see Adverse Reactions (6.1), Clinical Studies (14)]

  .

  During pre-marketing clinical trials with KRYSTEXXA alone, KRYSTEXXA was not discontinued following 2 consecutive serum uric acid levels above 6 mg/dL. Anaphylaxis was reported with a frequency of 6.5% (8/123) of subjects treated with KRYSTEXXA every 2 weeks and 4.8% (6/126) for the every 4-week dosing regimen. There were no cases of anaphylaxis in subjects receiving placebo. Anaphylaxis generally occurred within 2 hours after treatment.

  Diagnostic criteria of anaphylaxis were skin or mucosal tissue involvement, and, either airway compromise, and/or reduced blood pressure with or without associated symptoms, and a temporal relationship to KRYSTEXXA or placebo injection with no other identifiable cause. Manifestations included wheezing, peri-oral or lingual edema, or hemodynamic instability, with or without rash or urticaria, nausea or vomiting. Cases occurred in patients being pre-treated with one or more doses of an oral antihistamine, an intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of anaphylaxis and therefore the reported frequency may be an underestimate.

  KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage anaphylaxis. Patients should be pre-treated with antihistamines and corticosteroids. Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion. However, delayed type hypersensitivity reactions have also been reported. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Patients should be informed of the symptoms and signs of anaphylaxis and instructed to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting.

  The risk of anaphylaxis is higher in patients whose uric acid level increases to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. Monitor serum uric acid levels prior to infusions and discontinue treatment if levels increase to above 6 mg/dL. Because of the possibility that concomitant use of oral urate-lowering therapy and KRYSTEXXA may potentially blunt the rise of serum uric acid levels, it is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.

  )
• KRYSTEXXA should be administered in healthcare settings and by healthcare providers prepared to manage anaphylaxis and infusion reactions. (

  5.1 Anaphylaxis

  In a 52-week controlled trial, which evaluated KRYSTEXXA co-administered with methotrexate compared to KRYSTEXXA alone, subjects were pre-treated with standardized infusion reaction prophylaxis and were discontinued from treatment with KRYSTEXXA if serum uric acid levels increased to above 6 mg/dL at 2 consecutive visits after the initiation of KRYSTEXXA therapy to reduce the risk of anaphylaxis. One subject randomized to the group treated with KRYSTEXXA co-administered with methotrexate (1%) experienced anaphylaxis during the first infusion and no subjects experienced anaphylaxis in the group treated with KRYSTEXXA alone

  [see Adverse Reactions (6.1), Clinical Studies (14)]

  .

  During pre-marketing clinical trials with KRYSTEXXA alone, KRYSTEXXA was not discontinued following 2 consecutive serum uric acid levels above 6 mg/dL. Anaphylaxis was reported with a frequency of 6.5% (8/123) of subjects treated with KRYSTEXXA every 2 weeks and 4.8% (6/126) for the every 4-week dosing regimen. There were no cases of anaphylaxis in subjects receiving placebo. Anaphylaxis generally occurred within 2 hours after treatment.

  Diagnostic criteria of anaphylaxis were skin or mucosal tissue involvement, and, either airway compromise, and/or reduced blood pressure with or without associated symptoms, and a temporal relationship to KRYSTEXXA or placebo injection with no other identifiable cause. Manifestations included wheezing, peri-oral or lingual edema, or hemodynamic instability, with or without rash or urticaria, nausea or vomiting. Cases occurred in patients being pre-treated with one or more doses of an oral antihistamine, an intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of anaphylaxis and therefore the reported frequency may be an underestimate.

  KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage anaphylaxis. Patients should be pre-treated with antihistamines and corticosteroids. Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion. However, delayed type hypersensitivity reactions have also been reported. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Patients should be informed of the symptoms and signs of anaphylaxis and instructed to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting.

  The risk of anaphylaxis is higher in patients whose uric acid level increases to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. Monitor serum uric acid levels prior to infusions and discontinue treatment if levels increase to above 6 mg/dL. Because of the possibility that concomitant use of oral urate-lowering therapy and KRYSTEXXA may potentially blunt the rise of serum uric acid levels, it is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.

  ,

  5.2 Infusion Reactions

  In a 52-week, controlled trial which evaluated KRYSTEXXA co-administered with methotrexate compared to KRYSTEXXA alone

  [see Adverse Reactions (6.1), Clinical Studies (14)]

  , subjects were pre-treated with standardized infusion reaction prophylaxis and were discontinued from treatment with KRYSTEXXA if serum uric acid levels increased to above 6 mg/dL at 2 consecutive visits after the initiation of KRYSTEXXA therapy to reduce the risk of infusion reactions

  .

  Infusion reactions were reported in 4% of subjects in the KRYSTEXXA co-administered with methotrexate group compared to 31% of subjects treated with KRYSTEXXA alone experienced infusion reactions

  [see Adverse Reactions (6.1), Clinical Studies (14)]

  . In both treatment groups, the majority of infusion reactions occurred at the first or second KRYSTEXXA infusion and during the time of infusion. Manifestations of these infusion reactions were similar to that observed in the pre-marketing trials.

  During pre-marketing 24-week controlled clinical trials with KRYSTEXXA alone, KRYSTEXXA was not discontinued following 2 consecutive serum uric acid levels above 6 mg/dL. Infusion reactions were reported in 26% of subjects treated with KRYSTEXXA 8 mg every 2 weeks, and 41% of subjects treated with KRYSTEXXA 8 mg every 4 weeks, compared to 5% of subjects treated with placebo. These infusion reactions occurred in subjects being pre-treated with an oral antihistamine, intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of infusion reactions and therefore the reported frequency may be an underestimate.

  Manifestations of these reactions included urticaria (frequency of 10.6%), dyspnea (frequency of 7.1%), chest discomfort (frequency of 9.5%), chest pain (frequency of 9.5%), erythema (frequency of 9.5%), and pruritus (frequency of 9.5%). These manifestations overlap with the symptoms of anaphylaxis, but in a given patient did not occur together to satisfy the clinical criteria for diagnosing anaphylaxis. Infusion reactions are thought to result from release of various mediators, such as cytokines. Infusion reactions occurred at any time during a course of treatment with approximately 3% occurring with the first infusion, and approximately 91% occurred during the time of infusion.

  KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage infusion reactions. Patients should be pre-treated with antihistamines and corticosteroids. KRYSTEXXA should be infused slowly over no less than 120 minutes. In the event of an infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate.

  The risk of infusion reaction is higher in patients whose uric acid level increases to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. Monitor serum uric acid levels prior to infusions and discontinue treatment if levels increase to above 6 mg/dL. Because of the possibility that concomitant use of oral urate-lowering therapy and KRYSTEXXA may potentially blunt the rise of serum uric acid levels, it is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.

  )
• Premedicate with antihistamines and corticosteroids and closely monitor for anaphylaxis for an appropriate period of time after administration of KRYSTEXXA. (

  5.1 Anaphylaxis

  In a 52-week controlled trial, which evaluated KRYSTEXXA co-administered with methotrexate compared to KRYSTEXXA alone, subjects were pre-treated with standardized infusion reaction prophylaxis and were discontinued from treatment with KRYSTEXXA if serum uric acid levels increased to above 6 mg/dL at 2 consecutive visits after the initiation of KRYSTEXXA therapy to reduce the risk of anaphylaxis. One subject randomized to the group treated with KRYSTEXXA co-administered with methotrexate (1%) experienced anaphylaxis during the first infusion and no subjects experienced anaphylaxis in the group treated with KRYSTEXXA alone

  [see Adverse Reactions (6.1), Clinical Studies (14)]

  .

  During pre-marketing clinical trials with KRYSTEXXA alone, KRYSTEXXA was not discontinued following 2 consecutive serum uric acid levels above 6 mg/dL. Anaphylaxis was reported with a frequency of 6.5% (8/123) of subjects treated with KRYSTEXXA every 2 weeks and 4.8% (6/126) for the every 4-week dosing regimen. There were no cases of anaphylaxis in subjects receiving placebo. Anaphylaxis generally occurred within 2 hours after treatment.

  Diagnostic criteria of anaphylaxis were skin or mucosal tissue involvement, and, either airway compromise, and/or reduced blood pressure with or without associated symptoms, and a temporal relationship to KRYSTEXXA or placebo injection with no other identifiable cause. Manifestations included wheezing, peri-oral or lingual edema, or hemodynamic instability, with or without rash or urticaria, nausea or vomiting. Cases occurred in patients being pre-treated with one or more doses of an oral antihistamine, an intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of anaphylaxis and therefore the reported frequency may be an underestimate.

  KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage anaphylaxis. Patients should be pre-treated with antihistamines and corticosteroids. Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion. However, delayed type hypersensitivity reactions have also been reported. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Patients should be informed of the symptoms and signs of anaphylaxis and instructed to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting.

  The risk of anaphylaxis is higher in patients whose uric acid level increases to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. Monitor serum uric acid levels prior to infusions and discontinue treatment if levels increase to above 6 mg/dL. Because of the possibility that concomitant use of oral urate-lowering therapy and KRYSTEXXA may potentially blunt the rise of serum uric acid levels, it is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.

  ,

  5.2 Infusion Reactions

  In a 52-week, controlled trial which evaluated KRYSTEXXA co-administered with methotrexate compared to KRYSTEXXA alone

  [see Adverse Reactions (6.1), Clinical Studies (14)]

  , subjects were pre-treated with standardized infusion reaction prophylaxis and were discontinued from treatment with KRYSTEXXA if serum uric acid levels increased to above 6 mg/dL at 2 consecutive visits after the initiation of KRYSTEXXA therapy to reduce the risk of infusion reactions

  .

  Infusion reactions were reported in 4% of subjects in the KRYSTEXXA co-administered with methotrexate group compared to 31% of subjects treated with KRYSTEXXA alone experienced infusion reactions

  [see Adverse Reactions (6.1), Clinical Studies (14)]

  . In both treatment groups, the majority of infusion reactions occurred at the first or second KRYSTEXXA infusion and during the time of infusion. Manifestations of these infusion reactions were similar to that observed in the pre-marketing trials.

  During pre-marketing 24-week controlled clinical trials with KRYSTEXXA alone, KRYSTEXXA was not discontinued following 2 consecutive serum uric acid levels above 6 mg/dL. Infusion reactions were reported in 26% of subjects treated with KRYSTEXXA 8 mg every 2 weeks, and 41% of subjects treated with KRYSTEXXA 8 mg every 4 weeks, compared to 5% of subjects treated with placebo. These infusion reactions occurred in subjects being pre-treated with an oral antihistamine, intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of infusion reactions and therefore the reported frequency may be an underestimate.

  Manifestations of these reactions included urticaria (frequency of 10.6%), dyspnea (frequency of 7.1%), chest discomfort (frequency of 9.5%), chest pain (frequency of 9.5%), erythema (frequency of 9.5%), and pruritus (frequency of 9.5%). These manifestations overlap with the symptoms of anaphylaxis, but in a given patient did not occur together to satisfy the clinical criteria for diagnosing anaphylaxis. Infusion reactions are thought to result from release of various mediators, such as cytokines. Infusion reactions occurred at any time during a course of treatment with approximately 3% occurring with the first infusion, and approximately 91% occurred during the time of infusion.

  KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage infusion reactions. Patients should be pre-treated with antihistamines and corticosteroids. KRYSTEXXA should be infused slowly over no less than 120 minutes. In the event of an infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate.

  The risk of infusion reaction is higher in patients whose uric acid level increases to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. Monitor serum uric acid levels prior to infusions and discontinue treatment if levels increase to above 6 mg/dL. Because of the possibility that concomitant use of oral urate-lowering therapy and KRYSTEXXA may potentially blunt the rise of serum uric acid levels, it is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.

  )
• Monitor serum uric acid levels prior to each infusion and discontinue treatment if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. (

  5.2 Infusion Reactions

  In a 52-week, controlled trial which evaluated KRYSTEXXA co-administered with methotrexate compared to KRYSTEXXA alone

  [see Adverse Reactions (6.1), Clinical Studies (14)]

  , subjects were pre-treated with standardized infusion reaction prophylaxis and were discontinued from treatment with KRYSTEXXA if serum uric acid levels increased to above 6 mg/dL at 2 consecutive visits after the initiation of KRYSTEXXA therapy to reduce the risk of infusion reactions

  .

  Infusion reactions were reported in 4% of subjects in the KRYSTEXXA co-administered with methotrexate group compared to 31% of subjects treated with KRYSTEXXA alone experienced infusion reactions

  [see Adverse Reactions (6.1), Clinical Studies (14)]

  . In both treatment groups, the majority of infusion reactions occurred at the first or second KRYSTEXXA infusion and during the time of infusion. Manifestations of these infusion reactions were similar to that observed in the pre-marketing trials.

  During pre-marketing 24-week controlled clinical trials with KRYSTEXXA alone, KRYSTEXXA was not discontinued following 2 consecutive serum uric acid levels above 6 mg/dL. Infusion reactions were reported in 26% of subjects treated with KRYSTEXXA 8 mg every 2 weeks, and 41% of subjects treated with KRYSTEXXA 8 mg every 4 weeks, compared to 5% of subjects treated with placebo. These infusion reactions occurred in subjects being pre-treated with an oral antihistamine, intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of infusion reactions and therefore the reported frequency may be an underestimate.

  Manifestations of these reactions included urticaria (frequency of 10.6%), dyspnea (frequency of 7.1%), chest discomfort (frequency of 9.5%), chest pain (frequency of 9.5%), erythema (frequency of 9.5%), and pruritus (frequency of 9.5%). These manifestations overlap with the symptoms of anaphylaxis, but in a given patient did not occur together to satisfy the clinical criteria for diagnosing anaphylaxis. Infusion reactions are thought to result from release of various mediators, such as cytokines. Infusion reactions occurred at any time during a course of treatment with approximately 3% occurring with the first infusion, and approximately 91% occurred during the time of infusion.

  KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage infusion reactions. Patients should be pre-treated with antihistamines and corticosteroids. KRYSTEXXA should be infused slowly over no less than 120 minutes. In the event of an infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate.

  The risk of infusion reaction is higher in patients whose uric acid level increases to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. Monitor serum uric acid levels prior to infusions and discontinue treatment if levels increase to above 6 mg/dL. Because of the possibility that concomitant use of oral urate-lowering therapy and KRYSTEXXA may potentially blunt the rise of serum uric acid levels, it is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.

  )
• Screen patients at risk for G6PD deficiency prior to starting KRYSTEXXA. Hemolysis and methemoglobinemia have been reported with KRYSTEXXA in patients with G6PD deficiency. KRYSTEXXA is contraindicated in patients with G6PD deficiency. (

  4 CONTRAINDICATIONS

  KRYSTEXXA is contraindicated in:

  • Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency
    [see Warnings and Precautions (5.3)].
  • Patients with history of serious hypersensitivity reactions, including anaphylaxis, to KRYSTEXXA or any of its components.

  • Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
  • Patients with history of serious hypersensitivity reactions, including anaphylaxis, to KRYSTEXXA or any of its components.

  ,

  5.3 G6PD Deficiency Associated Hemolysis and Methemoglobinemia

  Life threatening hemolytic reactions and methemoglobinemia have been reported with KRYSTEXXA in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Because of the risk of hemolysis and methemoglobinemia, do not administer KRYSTEXXA to patients with G6PD deficiency

  [see Contraindications (4)]

  . Screen patients at risk for G6PD deficiency prior to starting KRYSTEXXA. For example, patients of African, Mediterranean (including Southern European and Middle Eastern), and Southern Asian ancestry are at increased risk for G6PD deficiency.

  )

KRYSTEXXA^® (pegloticase) is indicated, for the treatment of chronic gout in adult patients refractory to conventional therapy.

Gout refractory to conventional therapy occurs in patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these drugs are contraindicated.

• The recommended dosage is KRYSTEXXA 8 mg every two weeks given as an intravenous infusion, co-administered with weekly methotrexate 15 mg orally. KRYSTEXXA alone may be used in patients for whom methotrexate is contraindicated or not clinically appropriate. (
  2.2 Recommended Dosage and Administration

  The recommended dosage is KRYSTEXXA 8 mg given as an intravenous infusion every two weeks, co-administered with weekly oral methotrexate 15 mg and folic acid or folinic acid supplementation. KRYSTEXXA alone may be used in patients for whom methotrexate is contraindicated or not clinically appropriate.

  If co-administering with methotrexate, start weekly methotrexate and folic acid or folinic acid supplementation at least 4 weeks prior to initiating, and throughout treatment with KRYSTEXXA

  [see Clinical Studies (14)]

  . Refer to the Full Prescribing Information for methotrexate.

  The optimal treatment duration with KRYSTEXXA has not been established.
  )
• Methotrexate with folic acid or folinic acid supplementation should be initiated at least 4 weeks prior to initiating, and throughout treatment with KRYSTEXXA. (
  2.2 Recommended Dosage and Administration

  The recommended dosage is KRYSTEXXA 8 mg given as an intravenous infusion every two weeks, co-administered with weekly oral methotrexate 15 mg and folic acid or folinic acid supplementation. KRYSTEXXA alone may be used in patients for whom methotrexate is contraindicated or not clinically appropriate.

  If co-administering with methotrexate, start weekly methotrexate and folic acid or folinic acid supplementation at least 4 weeks prior to initiating, and throughout treatment with KRYSTEXXA

  [see Clinical Studies (14)]

  . Refer to the Full Prescribing Information for methotrexate.

  The optimal treatment duration with KRYSTEXXA has not been established.
  )
• Discontinue oral urate-lowering agents before starting KRYSTEXXA. (
  2.1 Important Administration Instructions

  Precautions Prior to Treatment

  It is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while patients are on KRYSTEXXA therapy.

  Monitoring Therapy: The risk of infusion reactions, including anaphylaxis, is higher in patients who have lost therapeutic response. Monitor serum uric acid levels prior to each infusion and discontinue treatment if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed

  [see Warnings and Precautions (5.1, 5.2)].

  Infusion Reaction Precautions

  KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage infusion reactions, including anaphylaxis. Observe patients for an appropriate period of time after administration

  [see Warnings and Precautions (5.1, 5.2)].

  Patients should receive pre-infusion medications (e.g., antihistamines, corticosteroids), to minimize the risk of infusion reactions, including anaphylaxis.

  If an infusion reaction occurs during the administration of KRYSTEXXA, the infusion may be slowed, or stopped and restarted at a slower rate, at the discretion of the physician. Since infusion reactions can occur after completion of infusion, observation of patients for approximately an hour post-infusion should be considered

  [see Warnings and Precautions (5.2), Adverse Reactions (6.1)].

  Administration Precautions

  Do not administer KRYSTEXXA as an intravenous push or bolus.

  KRYSTEXXA should only be administered by intravenous infusion. An infusion pump may be used for the Ready-to-Use vial. Gravity feed, syringe-type pump, or infusion pump may be used for the To-Be-Diluted vial

  [see Dosage and Administration (2.3)]

  .
  )
• Monitor serum uric acid levels before each infusion. (
  2.1 Important Administration Instructions

  Precautions Prior to Treatment

  It is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while patients are on KRYSTEXXA therapy.

  Monitoring Therapy: The risk of infusion reactions, including anaphylaxis, is higher in patients who have lost therapeutic response. Monitor serum uric acid levels prior to each infusion and discontinue treatment if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed

  [see Warnings and Precautions (5.1, 5.2)].

  Infusion Reaction Precautions

  KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage infusion reactions, including anaphylaxis. Observe patients for an appropriate period of time after administration

  [see Warnings and Precautions (5.1, 5.2)].

  Patients should receive pre-infusion medications (e.g., antihistamines, corticosteroids), to minimize the risk of infusion reactions, including anaphylaxis.

  If an infusion reaction occurs during the administration of KRYSTEXXA, the infusion may be slowed, or stopped and restarted at a slower rate, at the discretion of the physician. Since infusion reactions can occur after completion of infusion, observation of patients for approximately an hour post-infusion should be considered

  [see Warnings and Precautions (5.2), Adverse Reactions (6.1)].

  Administration Precautions

  Do not administer KRYSTEXXA as an intravenous push or bolus.

  KRYSTEXXA should only be administered by intravenous infusion. An infusion pump may be used for the Ready-to-Use vial. Gravity feed, syringe-type pump, or infusion pump may be used for the To-Be-Diluted vial

  [see Dosage and Administration (2.3)]

  .
  )
• Pre-medicate patients with antihistamines and corticosteroids. (
  2.1 Important Administration Instructions

  Precautions Prior to Treatment

  It is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while patients are on KRYSTEXXA therapy.

  Monitoring Therapy: The risk of infusion reactions, including anaphylaxis, is higher in patients who have lost therapeutic response. Monitor serum uric acid levels prior to each infusion and discontinue treatment if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed

  [see Warnings and Precautions (5.1, 5.2)].

  Infusion Reaction Precautions

  KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage infusion reactions, including anaphylaxis. Observe patients for an appropriate period of time after administration

  [see Warnings and Precautions (5.1, 5.2)].

  Patients should receive pre-infusion medications (e.g., antihistamines, corticosteroids), to minimize the risk of infusion reactions, including anaphylaxis.

  If an infusion reaction occurs during the administration of KRYSTEXXA, the infusion may be slowed, or stopped and restarted at a slower rate, at the discretion of the physician. Since infusion reactions can occur after completion of infusion, observation of patients for approximately an hour post-infusion should be considered

  [see Warnings and Precautions (5.2), Adverse Reactions (6.1)].

  Administration Precautions

  Do not administer KRYSTEXXA as an intravenous push or bolus.

  KRYSTEXXA should only be administered by intravenous infusion. An infusion pump may be used for the Ready-to-Use vial. Gravity feed, syringe-type pump, or infusion pump may be used for the To-Be-Diluted vial

  [see Dosage and Administration (2.3)]

  .
  ,
  5.1 Anaphylaxis

  In a 52-week controlled trial, which evaluated KRYSTEXXA co-administered with methotrexate compared to KRYSTEXXA alone, subjects were pre-treated with standardized infusion reaction prophylaxis and were discontinued from treatment with KRYSTEXXA if serum uric acid levels increased to above 6 mg/dL at 2 consecutive visits after the initiation of KRYSTEXXA therapy to reduce the risk of anaphylaxis. One subject randomized to the group treated with KRYSTEXXA co-administered with methotrexate (1%) experienced anaphylaxis during the first infusion and no subjects experienced anaphylaxis in the group treated with KRYSTEXXA alone

  [see Adverse Reactions (6.1), Clinical Studies (14)]

  .

  During pre-marketing clinical trials with KRYSTEXXA alone, KRYSTEXXA was not discontinued following 2 consecutive serum uric acid levels above 6 mg/dL. Anaphylaxis was reported with a frequency of 6.5% (8/123) of subjects treated with KRYSTEXXA every 2 weeks and 4.8% (6/126) for the every 4-week dosing regimen. There were no cases of anaphylaxis in subjects receiving placebo. Anaphylaxis generally occurred within 2 hours after treatment.

  Diagnostic criteria of anaphylaxis were skin or mucosal tissue involvement, and, either airway compromise, and/or reduced blood pressure with or without associated symptoms, and a temporal relationship to KRYSTEXXA or placebo injection with no other identifiable cause. Manifestations included wheezing, peri-oral or lingual edema, or hemodynamic instability, with or without rash or urticaria, nausea or vomiting. Cases occurred in patients being pre-treated with one or more doses of an oral antihistamine, an intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of anaphylaxis and therefore the reported frequency may be an underestimate.

  KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage anaphylaxis. Patients should be pre-treated with antihistamines and corticosteroids. Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion. However, delayed type hypersensitivity reactions have also been reported. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Patients should be informed of the symptoms and signs of anaphylaxis and instructed to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting.

  The risk of anaphylaxis is higher in patients whose uric acid level increases to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. Monitor serum uric acid levels prior to infusions and discontinue treatment if levels increase to above 6 mg/dL. Because of the possibility that concomitant use of oral urate-lowering therapy and KRYSTEXXA may potentially blunt the rise of serum uric acid levels, it is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.
  ,
  5.2 Infusion Reactions

  In a 52-week, controlled trial which evaluated KRYSTEXXA co-administered with methotrexate compared to KRYSTEXXA alone

  [see Adverse Reactions (6.1), Clinical Studies (14)]

  , subjects were pre-treated with standardized infusion reaction prophylaxis and were discontinued from treatment with KRYSTEXXA if serum uric acid levels increased to above 6 mg/dL at 2 consecutive visits after the initiation of KRYSTEXXA therapy to reduce the risk of infusion reactions

  .

  Infusion reactions were reported in 4% of subjects in the KRYSTEXXA co-administered with methotrexate group compared to 31% of subjects treated with KRYSTEXXA alone experienced infusion reactions

  [see Adverse Reactions (6.1), Clinical Studies (14)]

  . In both treatment groups, the majority of infusion reactions occurred at the first or second KRYSTEXXA infusion and during the time of infusion. Manifestations of these infusion reactions were similar to that observed in the pre-marketing trials.

  During pre-marketing 24-week controlled clinical trials with KRYSTEXXA alone, KRYSTEXXA was not discontinued following 2 consecutive serum uric acid levels above 6 mg/dL. Infusion reactions were reported in 26% of subjects treated with KRYSTEXXA 8 mg every 2 weeks, and 41% of subjects treated with KRYSTEXXA 8 mg every 4 weeks, compared to 5% of subjects treated with placebo. These infusion reactions occurred in subjects being pre-treated with an oral antihistamine, intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of infusion reactions and therefore the reported frequency may be an underestimate.

  Manifestations of these reactions included urticaria (frequency of 10.6%), dyspnea (frequency of 7.1%), chest discomfort (frequency of 9.5%), chest pain (frequency of 9.5%), erythema (frequency of 9.5%), and pruritus (frequency of 9.5%). These manifestations overlap with the symptoms of anaphylaxis, but in a given patient did not occur together to satisfy the clinical criteria for diagnosing anaphylaxis. Infusion reactions are thought to result from release of various mediators, such as cytokines. Infusion reactions occurred at any time during a course of treatment with approximately 3% occurring with the first infusion, and approximately 91% occurred during the time of infusion.

  KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage infusion reactions. Patients should be pre-treated with antihistamines and corticosteroids. KRYSTEXXA should be infused slowly over no less than 120 minutes. In the event of an infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate.

  The risk of infusion reaction is higher in patients whose uric acid level increases to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. Monitor serum uric acid levels prior to infusions and discontinue treatment if levels increase to above 6 mg/dL. Because of the possibility that concomitant use of oral urate-lowering therapy and KRYSTEXXA may potentially blunt the rise of serum uric acid levels, it is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.
  )

Preparation and Administration

• Do not administer as an intravenous push or bolus. (
  2.1 Important Administration Instructions

  Precautions Prior to Treatment

  It is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while patients are on KRYSTEXXA therapy.

  Monitoring Therapy: The risk of infusion reactions, including anaphylaxis, is higher in patients who have lost therapeutic response. Monitor serum uric acid levels prior to each infusion and discontinue treatment if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed

  [see Warnings and Precautions (5.1, 5.2)].

  Infusion Reaction Precautions

  KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage infusion reactions, including anaphylaxis. Observe patients for an appropriate period of time after administration

  [see Warnings and Precautions (5.1, 5.2)].

  Patients should receive pre-infusion medications (e.g., antihistamines, corticosteroids), to minimize the risk of infusion reactions, including anaphylaxis.

  If an infusion reaction occurs during the administration of KRYSTEXXA, the infusion may be slowed, or stopped and restarted at a slower rate, at the discretion of the physician. Since infusion reactions can occur after completion of infusion, observation of patients for approximately an hour post-infusion should be considered

  [see Warnings and Precautions (5.2), Adverse Reactions (6.1)].

  Administration Precautions

  Do not administer KRYSTEXXA as an intravenous push or bolus.

  KRYSTEXXA should only be administered by intravenous infusion. An infusion pump may be used for the Ready-to-Use vial. Gravity feed, syringe-type pump, or infusion pump may be used for the To-Be-Diluted vial

  [see Dosage and Administration (2.3)]

  .
  )
• KRYSTEXXA injection is supplied as a Ready-to-Use (with hanger label) single-dose vial or a To-be-Diluted single-dose vial. (
  2.3 Preparation and Administration Instructions

  KRYSTEXXA injection is supplied as either a Ready-to-Use

  single-dose vial

  (with hanger label) or a To-be-Diluted single-dose vial.

  Ready-to-Use KRYSTEXXA 8 mg/50 mL (0.16 mg/mL) single-dose vial (with hanger label)

  Step 1: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use vial if either is present.

  Step 2: Allow the Ready-to-Use vial to reach room temperature at 20°C to 25°C (68°F to 77°F). KRYSTEXXA in a vial should never be subjected to artificial heating (e.g., hot water, microwave). Unopened vial may be stored for up to 4 hours at room temperature.

  Step 3: Use appropriate aseptic technique. Insert a vented intravenous set through the septum of the vial. Once the stopper is punctured, use immediately.

  Step 4: To administer, invert and hang the vial utilizing the built-in hanger label affixed to the bottom of the vial.

  Step 5: Administer as an intravenous infusion over a period of no less than 120 minutes using an infusion pump. After the entire contents of the vial have been administered, flush the injection line with Sodium Chloride Injection to ensure delivery of the required dose.

  To-be-Diluted KRYSTEXXA 8 mg/mL single-dose vial

  Step 1: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use vial if either is present.

  Step 2: Use appropriate aseptic technique. Withdraw 1 mL of KRYSTEXXA (To-be-Diluted) from the vial into a sterile syringe. Discard any unused portion of product remaining in the vial. Inject into a single 250 mL bag of 0.9% Sodium Chloride Injection, USP or 0.45% Sodium Chloride Injection, USP for intravenous infusion. Do not mix or dilute with other drugs.

  Step 3: Gently invert the infusion bag containing the dilute KRYSTEXXA solution a number of times to ensure thorough mixing. Do not shake.

  Step 4: Before administration, allow the diluted solution of KRYSTEXXA to reach room temperature. KRYSTEXXA in a vial or in an intravenous infusion fluid should never be subjected to artificial heating (e.g., hot water, microwave).

  KRYSTEXXA diluted in infusion bags is stable for 4 hours at 2°C to 8°C (36°F to 46°F) and at room temperature at 20°C to 25°C (68°F to 77°F). However, it is recommended that diluted solutions be stored under refrigeration, not frozen, protected from light, and used within 4 hours of dilution

  [see How Supplied/Storage and Handling (16)].

  Step 5: Administer as an intravenous infusion over 120 minutes using gravity feed, syringe-type pump, or infusion pump.
  )
• See full prescribing information for information on preparation and administration for each vial presentation. (
  2.1 Important Administration Instructions

  Precautions Prior to Treatment

  It is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while patients are on KRYSTEXXA therapy.

  Monitoring Therapy: The risk of infusion reactions, including anaphylaxis, is higher in patients who have lost therapeutic response. Monitor serum uric acid levels prior to each infusion and discontinue treatment if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed

  [see Warnings and Precautions (5.1, 5.2)].

  Infusion Reaction Precautions

  KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage infusion reactions, including anaphylaxis. Observe patients for an appropriate period of time after administration

  [see Warnings and Precautions (5.1, 5.2)].

  Patients should receive pre-infusion medications (e.g., antihistamines, corticosteroids), to minimize the risk of infusion reactions, including anaphylaxis.

  If an infusion reaction occurs during the administration of KRYSTEXXA, the infusion may be slowed, or stopped and restarted at a slower rate, at the discretion of the physician. Since infusion reactions can occur after completion of infusion, observation of patients for approximately an hour post-infusion should be considered

  [see Warnings and Precautions (5.2), Adverse Reactions (6.1)].

  Administration Precautions

  Do not administer KRYSTEXXA as an intravenous push or bolus.

  KRYSTEXXA should only be administered by intravenous infusion. An infusion pump may be used for the Ready-to-Use vial. Gravity feed, syringe-type pump, or infusion pump may be used for the To-Be-Diluted vial

  [see Dosage and Administration (2.3)]

  .
  ,
  2.2 Recommended Dosage and Administration

  The recommended dosage is KRYSTEXXA 8 mg given as an intravenous infusion every two weeks, co-administered with weekly oral methotrexate 15 mg and folic acid or folinic acid supplementation. KRYSTEXXA alone may be used in patients for whom methotrexate is contraindicated or not clinically appropriate.

  If co-administering with methotrexate, start weekly methotrexate and folic acid or folinic acid supplementation at least 4 weeks prior to initiating, and throughout treatment with KRYSTEXXA

  [see Clinical Studies (14)]

  . Refer to the Full Prescribing Information for methotrexate.

  The optimal treatment duration with KRYSTEXXA has not been established.
  ,
  2.3 Preparation and Administration Instructions

  KRYSTEXXA injection is supplied as either a Ready-to-Use

  single-dose vial

  (with hanger label) or a To-be-Diluted single-dose vial.

  Ready-to-Use KRYSTEXXA 8 mg/50 mL (0.16 mg/mL) single-dose vial (with hanger label)

  Step 1: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use vial if either is present.

  Step 2: Allow the Ready-to-Use vial to reach room temperature at 20°C to 25°C (68°F to 77°F). KRYSTEXXA in a vial should never be subjected to artificial heating (e.g., hot water, microwave). Unopened vial may be stored for up to 4 hours at room temperature.

  Step 3: Use appropriate aseptic technique. Insert a vented intravenous set through the septum of the vial. Once the stopper is punctured, use immediately.

  Step 4: To administer, invert and hang the vial utilizing the built-in hanger label affixed to the bottom of the vial.

  Step 5: Administer as an intravenous infusion over a period of no less than 120 minutes using an infusion pump. After the entire contents of the vial have been administered, flush the injection line with Sodium Chloride Injection to ensure delivery of the required dose.

  To-be-Diluted KRYSTEXXA 8 mg/mL single-dose vial

  Step 1: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use vial if either is present.

  Step 2: Use appropriate aseptic technique. Withdraw 1 mL of KRYSTEXXA (To-be-Diluted) from the vial into a sterile syringe. Discard any unused portion of product remaining in the vial. Inject into a single 250 mL bag of 0.9% Sodium Chloride Injection, USP or 0.45% Sodium Chloride Injection, USP for intravenous infusion. Do not mix or dilute with other drugs.

  Step 3: Gently invert the infusion bag containing the dilute KRYSTEXXA solution a number of times to ensure thorough mixing. Do not shake.

  Step 4: Before administration, allow the diluted solution of KRYSTEXXA to reach room temperature. KRYSTEXXA in a vial or in an intravenous infusion fluid should never be subjected to artificial heating (e.g., hot water, microwave).

  KRYSTEXXA diluted in infusion bags is stable for 4 hours at 2°C to 8°C (36°F to 46°F) and at room temperature at 20°C to 25°C (68°F to 77°F). However, it is recommended that diluted solutions be stored under refrigeration, not frozen, protected from light, and used within 4 hours of dilution

  [see How Supplied/Storage and Handling (16)].

  Step 5: Administer as an intravenous infusion over 120 minutes using gravity feed, syringe-type pump, or infusion pump.
  )

KRYSTEXXA is a clear and colorless solution, containing 8 mg of pegloticase expressed as concentrations of uricase protein available as:

• Injection: Ready-to-Use 8 mg/50 mL (0.16 mg/mL) in a single-dose vial (with hanger label)
  [see

  2.3 Preparation and Administration Instructions

  KRYSTEXXA injection is supplied as either a Ready-to-Use

  single-dose vial

  (with hanger label) or a To-be-Diluted single-dose vial.

  Ready-to-Use KRYSTEXXA 8 mg/50 mL (0.16 mg/mL) single-dose vial (with hanger label)

  Step 1: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use vial if either is present.

  Step 2: Allow the Ready-to-Use vial to reach room temperature at 20°C to 25°C (68°F to 77°F). KRYSTEXXA in a vial should never be subjected to artificial heating (e.g., hot water, microwave). Unopened vial may be stored for up to 4 hours at room temperature.

  Step 3: Use appropriate aseptic technique. Insert a vented intravenous set through the septum of the vial. Once the stopper is punctured, use immediately.

  Step 4: To administer, invert and hang the vial utilizing the built-in hanger label affixed to the bottom of the vial.

  Step 5: Administer as an intravenous infusion over a period of no less than 120 minutes using an infusion pump. After the entire contents of the vial have been administered, flush the injection line with Sodium Chloride Injection to ensure delivery of the required dose.

  To-be-Diluted KRYSTEXXA 8 mg/mL single-dose vial

  Step 1: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use vial if either is present.

  Step 2: Use appropriate aseptic technique. Withdraw 1 mL of KRYSTEXXA (To-be-Diluted) from the vial into a sterile syringe. Discard any unused portion of product remaining in the vial. Inject into a single 250 mL bag of 0.9% Sodium Chloride Injection, USP or 0.45% Sodium Chloride Injection, USP for intravenous infusion. Do not mix or dilute with other drugs.

  Step 3: Gently invert the infusion bag containing the dilute KRYSTEXXA solution a number of times to ensure thorough mixing. Do not shake.

  Step 4: Before administration, allow the diluted solution of KRYSTEXXA to reach room temperature. KRYSTEXXA in a vial or in an intravenous infusion fluid should never be subjected to artificial heating (e.g., hot water, microwave).

  KRYSTEXXA diluted in infusion bags is stable for 4 hours at 2°C to 8°C (36°F to 46°F) and at room temperature at 20°C to 25°C (68°F to 77°F). However, it is recommended that diluted solutions be stored under refrigeration, not frozen, protected from light, and used within 4 hours of dilution

  [see How Supplied/Storage and Handling (16)].

  Step 5: Administer as an intravenous infusion over 120 minutes using gravity feed, syringe-type pump, or infusion pump.

  ]
  .
• Injection: To-be-Diluted 8 mg/mL in a single-dose vial
  [see

  2.3 Preparation and Administration Instructions

  KRYSTEXXA injection is supplied as either a Ready-to-Use

  single-dose vial

  (with hanger label) or a To-be-Diluted single-dose vial.

  Ready-to-Use KRYSTEXXA 8 mg/50 mL (0.16 mg/mL) single-dose vial (with hanger label)

  Step 1: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use vial if either is present.

  Step 2: Allow the Ready-to-Use vial to reach room temperature at 20°C to 25°C (68°F to 77°F). KRYSTEXXA in a vial should never be subjected to artificial heating (e.g., hot water, microwave). Unopened vial may be stored for up to 4 hours at room temperature.

  Step 3: Use appropriate aseptic technique. Insert a vented intravenous set through the septum of the vial. Once the stopper is punctured, use immediately.

  Step 4: To administer, invert and hang the vial utilizing the built-in hanger label affixed to the bottom of the vial.

  Step 5: Administer as an intravenous infusion over a period of no less than 120 minutes using an infusion pump. After the entire contents of the vial have been administered, flush the injection line with Sodium Chloride Injection to ensure delivery of the required dose.

  To-be-Diluted KRYSTEXXA 8 mg/mL single-dose vial

  Step 1: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use vial if either is present.

  Step 2: Use appropriate aseptic technique. Withdraw 1 mL of KRYSTEXXA (To-be-Diluted) from the vial into a sterile syringe. Discard any unused portion of product remaining in the vial. Inject into a single 250 mL bag of 0.9% Sodium Chloride Injection, USP or 0.45% Sodium Chloride Injection, USP for intravenous infusion. Do not mix or dilute with other drugs.

  Step 3: Gently invert the infusion bag containing the dilute KRYSTEXXA solution a number of times to ensure thorough mixing. Do not shake.

  Step 4: Before administration, allow the diluted solution of KRYSTEXXA to reach room temperature. KRYSTEXXA in a vial or in an intravenous infusion fluid should never be subjected to artificial heating (e.g., hot water, microwave).

  KRYSTEXXA diluted in infusion bags is stable for 4 hours at 2°C to 8°C (36°F to 46°F) and at room temperature at 20°C to 25°C (68°F to 77°F). However, it is recommended that diluted solutions be stored under refrigeration, not frozen, protected from light, and used within 4 hours of dilution

  [see How Supplied/Storage and Handling (16)].

  Step 5: Administer as an intravenous infusion over 120 minutes using gravity feed, syringe-type pump, or infusion pump.

  ]
  .

There are no adequate and well-controlled studies of KRYSTEXXA in pregnant women.

Based on animal reproduction studies, no structural abnormalities were observed when pegloticase was administered by subcutaneous injection to pregnant rats and rabbits during the period of organogenesis at doses up to 50 and 75 times, respectively, the maximum recommended human dose (MRHD). Decreases in mean fetal and pup body weights were observed at approximately 50 and 75 times the MRHD, respectively

All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinical recognized pregnancies is 2% to 4% and 15% to 20%, respectively.