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Indication & Important Safety Information for Soliris® (eculizumab)

INDICATION

Paroxysmal Nocturnal Hemoglobinuria (PNH)
Soliris is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis.

IMPORTANT SAFETY INFORMATION

WARNING: SERIOUS MENINGOCOCCAL INFECTIONS

Life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris.
Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early.

  • Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies.
  • Immunize patients with meningococcal vaccines at least 2 weeks prior to administering the first dose of Soliris, unless the risks of delaying Soliris therapy outweigh the risk of developing a meningococcal infection. (See Serious Meningococcal Infections for additional guidance on the management of the risk of meningococcal infection)
  • Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected.

Soliris is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the Soliris REMS, prescribers must enroll in the program. Enrollment in the Soliris REMS program and additional information are available by telephone: 1-888-SOLIRIS (1-888-765-4747) or at www.solirisrems.com.

Contraindications

Soliris is contraindicated in:

  • Patients with unresolved serious Neisseria meningitidis infection
  • Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying Soliris treatment outweigh the risks of developing a meningococcal infection

Warnings and Precautions

Serious Meningococcal Infections

Risk and Prevention

See Boxed WARNING for additional information on serious meningococcal infections.

Life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris. The use of Soliris increases a patient’s susceptibility to serious meningococcal infections (septicemia and/or meningitis).

Vaccinate for meningococcal disease according to the most current ACIP recommendations for patients with complement deficiencies. Revaccinate patients in accordance with ACIP recommendations, considering the duration of Soliris therapy.

Immunize patients without a history of meningococcal vaccination at least 2 weeks prior to receiving the first dose of Soliris. If urgent Soliris therapy is indicated in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible and provide patients with two weeks of antibacterial drug prophylaxis.

The benefits and risks of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving Soliris have not been established.
Vaccination reduces, but does not eliminate, the risk of meningococcal infections.

Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if an infection is suspected. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Discontinue Soliris in patients who are undergoing treatment for serious meningococcal infections.

REMS
Because of the risk of meningococcal infections, Soliris is available only through a restricted program under a REMS. Under the Soliris REMS, prescribers must enroll in the program.

Prescribers must counsel patients about the risk of meningococcal infection, provide the patients with the REMS educational materials, and ensure patients are vaccinated with meningococcal vaccine(s).

Other Infections
Serious infections with Neisseria species (other than N. meningitidis), including disseminated gonococcal infections, have been reported.

Soliris blocks terminal complement activation; therefore patients may have increased susceptibility to infections, especially with encapsulated bacteria. Additionally, Aspergillus infections have occurred in immunocompromised and neutropenic patients. Children treated with Soliris may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP guidelines. Use caution when administering Soliris to patients with any systemic infection.

Monitoring Disease Manifestations After Soliris Discontinuation

Treatment Discontinuation for PNH
Monitor patients after discontinuing Soliris for at least 8 weeks to detect hemolysis.

Thrombosis Prevention and Management
The effect of withdrawal of anticoagulant therapy during Soliris treatment has not been established. Therefore, treatment with Soliris should not alter anticoagulant management.

Infusion Reactions
Administration of Soliris may result in infusion reactions, including anaphylaxis or other hypersensitivity reactions. In clinical trials, no patients experienced an infusion reaction which required discontinuation of Soliris. Interrupt Soliris infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur.

Adverse Reactions
The most frequently reported adverse reactions in the PNH randomized trial (≥10% overall and greater than placebo) are: headache, nasopharyngitis, back pain, and nausea.

Please see full Prescribing Information for Soliris, including boxed WARNING regarding serious meningococcal infections.

Who do I test for PNH?

PNH: A progressive and life-threatening disease that causes thrombosis, end-organ damage, and impaired quality of life1

The life-threatening and destructive consequences of chronic hemolysis (as measured by LDH) warrant early identification in high-risk patient populations1,2

Chronic complement-mediated hemolysis is the underlying cause of progressive morbidities in PNH2,3; therefore, reducing chronic hemolysis is the primary goal of PNH treatment.2,4 Early identification of PNH in high-risk patient populations is optimal for long-term disease management.5

Early diagnosis is essential for improved patient management and prognosis5

  • Consistently evaluate high-risk patient populations for PNH5

The International Clinical Cytometry Society (ICCS) recommends testing for PNH in the following patient populations

Evidence of Hemolysis with any of the following5:

  • Hemoglobinuria or elevated plasma hemoglobin

  • Iron-deficiency

  • Abdominal pain or esophageal spasm

  • Thrombosis with unusual features

  • Granulocytopenia and/or thrombocytopenia


Thrombosis with unusual features5,6

  • Atypical sites

    • Hepatic vein (Budd-Chiari syndrome)

    • Other intra-abdominal veins (portal, splenic, splanchnic)

    • Cerebral sinuses

    • Dermal veins

  • Typical sites, including one or more of the following:

    • Prior thromboembolism in typical sites

    • Evidence of hemolysis

    • Accompanying bone marrow disorder

    • While receiving anticoagulant therapy

    • Unexplained cytopenia


Evidence of bone marrow failure5

  • Suspected or proven aplastic or hypoplastic anemia

  • Refractory cytopenia with unilineage dysplasia

  • Other cytopenias of unknown etiology after adequate workup

  • Identification of PNH cells has important prognostic and therapeutic implications5

  • ICCS guidelines and the International PNH Interest Group (IPIG) recommend continued monitoring of patients at high risk for PNH4,5

Hemolysis

Chronic complement-mediated hemolysis is the underlying cause of progressive morbidities in PNH3

  • Even in the absence of symptoms, hemolysis is ongoing and destructive7

  • The consequences of hemolysis can be unpredictable, sudden, and potentially painful8

  • Hemolysis-induced nitric oxide depletion results in thrombosis, abdominal pain, pulmonary hypertension, dysphagia, and erectile dysfunction2

Hemolysis and clinical symptoms are associated with increased risk of TE16
Study description: A retrospective analysis of 301 medical charts of patients with PNH in a South Korean registry to describe the burden of disease, the clinical characteristics of TE, and the risk factors associated with TE in PNH. Data presented as odds ratios between PNH patients with and without listed symptoms compared with LDH <1.5x ULN and no symptoms.

  • Patients with LDH≥1.5x ULN and 1 or more clinical symptoms such as abdominal pain and dyspnea had an increased risk of TE16

ICCS guidelines recommend that any patient with unexplained hemoglobinuria should be tested for PNH5

  • Hemoglobinuria is a sign of intravascular hemolysis5

According to ICCS Guidelines, routine PNH screening may be appropriate for all patients with Coombs-negative hemolytic anemia, particularly when

  • Characteristic cellular abnormalities including, spherocytes, sickled cells, or schistocytes are not present5

  • Patients present with concomitant iron deficiency, as chronic intravascular hemolysis in PNH leads to urinary iron loss5

Thrombosis with unusual features

Thrombosis is the leading cause of death in PNH6

Thromboembolism (TE) in PNH is complex and multifactorial and may occur at any site, including intra-abdominal and cerebral veins6

Venous thromboembolism (VTE) is 62x more likely in patients with PNH vs the general population10

Relative risk of VTE in PNH vs other risk factors for venous thrombosis10-14a

Relative risk graph developed based on data from different studies.
b VTE event rate (no. per 100 patient-years) is based on 105 VTE events in 1683.4 patient-years and a VTE rate in the general population of 0.001 per year.

ICCS and IPIG recommend testing for PNH in patients with unusual presentation of thrombosis and additional risk factors4,5

  • TE involving unusual sites: Budd-Chiari syndrome, other intra-abdominal sites, cerebral or dermal veins

  • Patients with unexplained thrombosis with evidence of intravascular hemolysis

  • Patients with unexplained thrombosis with coexisting cytopenias

Evidence of bone marrow failure

PNH consensus guidelines recommend testing for PNH in all patients with aplastic anemia (AA) at diagnosis and routinely4

The number of PNH cells in patients with AA may increase rapidly and unpredictably over time15

  • In a study of 27 patients with AA, 48% experienced an increase in PNH clone size16

    • 78% received immunosuppressive therapy (IST)

  • In another study, of 83 patients with AA with a detectable PNH clone and treated with IST alone, 30% showed an increase in clone size17

    • 8% showed evidence of hemolysis and thrombosis

Select myelodysplastic syndrome (MDS) subgroups are more likely to present with a PNH granulocyte clone18

  • Approximately 10% of patients with MDS have PNH granulocyte clones, as identified by high-sensitivity flow cytometry19,a

  • Patients with MDS found to have a PNH clone are more likely to present with the following characteristics20:

    • Hypocellular marrow

    • Normal cytogenetics

    • Human leukocyte antigen (HLA)-DR15 positivity

    • High likelihood of response to IST

    • Moderate to severe thrombocytopenia

IPIG recommends that patients with RA-MDS be tested for PNH at diagnosis and annually4

PNH Consensus guidelines recommend testing patients with cytopenias and hemolysis or thrombosis, or patients with cytopenias that remain unexplained after a thorough workup5

  • Approximately 9% of patients with unexplained cytopenia have PNH19

  • Terminal complement C5 activity leads to platelet activation and consumption, with subsequent thrombocytopenia and an increased risk of TE in patients with PNH21

aDetects PNH cells down to a 0.01% clone size.

Important Safety Information

Indication & Important Safety Information for Soliris® (eculizumab)

INDICATION

Paroxysmal Nocturnal Hemoglobinuria (PNH)
Soliris is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis.

IMPORTANT SAFETY INFORMATION

WARNING: SERIOUS MENINGOCOCCAL INFECTIONS

Life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris.
Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early.

  • Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies.
  • Immunize patients with meningococcal vaccines at least 2 weeks prior to administering the first dose of Soliris, unless the risks of delaying Soliris therapy outweigh the risk of developing a meningococcal infection. (See Serious Meningococcal Infections for additional guidance on the management of the risk of meningococcal infection)
  • Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected.

Soliris is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the Soliris REMS, prescribers must enroll in the program. Enrollment in the Soliris REMS program and additional information are available by telephone: 1-888-SOLIRIS (1-888-765-4747) or at www.solirisrems.com.

Contraindications

Soliris is contraindicated in:

  • Patients with unresolved serious Neisseria meningitidis infection
  • Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying Soliris treatment outweigh the risks of developing a meningococcal infection

Warnings and Precautions

Serious Meningococcal Infections

Risk and Prevention

See Boxed WARNING for additional information on serious meningococcal infections.

Life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris. The use of Soliris increases a patient’s susceptibility to serious meningococcal infections (septicemia and/or meningitis).

Vaccinate for meningococcal disease according to the most current ACIP recommendations for patients with complement deficiencies. Revaccinate patients in accordance with ACIP recommendations, considering the duration of Soliris therapy.

Immunize patients without a history of meningococcal vaccination at least 2 weeks prior to receiving the first dose of Soliris. If urgent Soliris therapy is indicated in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible and provide patients with two weeks of antibacterial drug prophylaxis.

The benefits and risks of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving Soliris have not been established.
Vaccination reduces, but does not eliminate, the risk of meningococcal infections.

Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if an infection is suspected. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Discontinue Soliris in patients who are undergoing treatment for serious meningococcal infections.

REMS
Because of the risk of meningococcal infections, Soliris is available only through a restricted program under a REMS. Under the Soliris REMS, prescribers must enroll in the program.

Prescribers must counsel patients about the risk of meningococcal infection, provide the patients with the REMS educational materials, and ensure patients are vaccinated with meningococcal vaccine(s).

Other Infections
Serious infections with Neisseria species (other than N. meningitidis), including disseminated gonococcal infections, have been reported.

Soliris blocks terminal complement activation; therefore patients may have increased susceptibility to infections, especially with encapsulated bacteria. Additionally, Aspergillus infections have occurred in immunocompromised and neutropenic patients. Children treated with Soliris may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP guidelines. Use caution when administering Soliris to patients with any systemic infection.

Monitoring Disease Manifestations After Soliris Discontinuation

Treatment Discontinuation for PNH
Monitor patients after discontinuing Soliris for at least 8 weeks to detect hemolysis.

Thrombosis Prevention and Management
The effect of withdrawal of anticoagulant therapy during Soliris treatment has not been established. Therefore, treatment with Soliris should not alter anticoagulant management.

Infusion Reactions
Administration of Soliris may result in infusion reactions, including anaphylaxis or other hypersensitivity reactions. In clinical trials, no patients experienced an infusion reaction which required discontinuation of Soliris. Interrupt Soliris infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur.

Adverse Reactions
The most frequently reported adverse reactions in the PNH randomized trial (≥10% overall and greater than placebo) are: headache, nasopharyngitis, back pain, and nausea.

Please see full Prescribing Information for Soliris, including boxed WARNING regarding serious meningococcal infections.

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