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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.

Complications of PNH

Chronic hemolysis: The underlying cause of progressive morbidities in PNH.1

The consequences of hemolysis can be unpredictable, sudden, and potentially fatal.2

Hemolysis

Chronic complement-mediated hemolysis is the underlying cause of progressive morbidities in paroxysmal nocturnal hemoglobinuria (PNH)1

Consequences of Hemolysis in PNH
  • Even in the absence of symptoms, hemolysis (LDH ≥1.5 ULN) is ongoing and destructive3,4

  • The consequences of hemolysis can be unpredictable, sudden, and potentially fatal2

  • Hemolysis-induced nitric oxide depletion results in thrombosis, abdominal pain, pulmonary hypertension, dysphagia, and erectile dysfunction5

  • Thrombosis is markedly elevated in patients with smaller clones, as low as 10%, when compared to the normal population6

Thrombosis

Thrombosis: The leading cause of death in PNH7

Venous thromboembolism (VTE) is 62x more likely in patients with PNH as compared to the general population8

Risk of developing VTE in PNH versus other risk factors for venous thrombosis8-12,a
a 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.

Because of its destructive nature, continue to monitor high-risk patients with unexplained thrombosis for PNH6

Sites of thromboembolism in patients with PNH13

Study description:The number of TE events and the incidence rates were determined in patients from 3 independent parent clinical studies and the common phase 3 extension study. TE events included all events in all patients prior to enrollment in each of the studies (and during placebo treatment in one study).

a Includes 18.5% lower extremity and 14.5% other (inferior vena cava, bilateral lower extremity, pelvic, ureter, axillary, subclavian, and brachiocephalic veins).

Thromboembolism with ANY of the following risk factors should raise the suspicion for PNH6:

  • Atypical sites

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

    • Prior thromboembolism in typical sites

    • Evidence of hemolysis

    • Accompanying bone marrow failure disorder

    • While receiving anticoagulant therapy

    • Anemia, thrombocytopenia, and/or granulocytopenia

Patients with PNH are at risk for thromboembolism events (TE)6

  • While risk of thrombosis increases with clone size, even patients with smaller clone sizes can experience thrombosis6

  • Abdominal pain is a predictor of TE6

  • 60% of patients with PNH have evidence of undiagnosed thrombosis14

  • D-dimers are a marker of elevated inflammatory response that may indicate increased risk for thrombosis15

  • First thrombotic event can be fatal3


Patients with PNH showing signs and symptoms of hemolysis are at an increased risk for TEs and premature mortality16

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

Chronic Kidney Disease

64% of patients with PNH have chronic kidney disease (CKD)17

  • End-stage renal disease (ESRD) accounts for approximately 8 to 18% of patient deaths in PNH18

  • Renal insufficiency prevalence in PNH is 6.6x higher than reported in the general population17

  • Chronic exposure to toxic cell-free hemoglobin leads to CKD and other serious sequelae17

  • 21% of patients with PNH have Stage 3-5 CKD, which is associated with premature mortality17

In PNH, free hemoglobin and hemosiderin deposits contribute to CKD17
Prevalence of CKD at Screening17,a
Study description:A clinical study of 195 patients with PNH showing evidence of renal dysfunction or damage as evidenced by spot urinalysis with proteinuria or by abnormal imaging findings.

aNational Kidney Foundation criteria applied at initial screening visit. CKD stages as defined by the Kidney Disease Outcomes Quality Initiative: Stage 1 (GFR >90 mL/min/1.73 m2); Stage 2 (GFR 60-90 mL/min/1.73 m2); Stage 3 (GFR 30-60 mL/min/1.73 m2); Stage 4 (GFR 15-30 mL/min/1.73 m2); Stage 5 (GFR <15 mL/min/1.73 m2).

Microinfarcts and interstitial fibrosis also contribute to a decline in kidney function in patients with PNH19

Renal microscopy19

Normal Tissue

Edge of a renal cortical
infarct with interstitial scarring

This image was originally published in Blood. Clark DA, Butler SA, Braren V, Hartmann RC, Jenkins DE Jr. The kidneys in paroxysmal nocturnal hemoglobinuria. Blood. 1981;57;83-89. © The American Society of Hematology

Dyspnea / PHT

Nearly 50% of patients with PNH have evidence of PHT20

Dyspnea may be an indicator of PHT and TE20

The majority of patients with PNH reported dyspnea21
Study Description: A multi-national validation study including 29 patients with PNH (19 men, 10 women, mean age 41.2 13.2 years) from the United Kingdom, United States, France and Spain. Validation instruments included: Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and the European Organization for Research and Treatment of Cancer Quality of Life Core 30 (EORTC QLQ-C30).

  • 72% of those patients qualified shortness of breath as moderate to severe21

  • 88% of those patients reported distress due to dyspnea21

Dyspnea is a significant predictor of pulmonary embolism22

Hemolysis-induced nitric oxide scavenging results in impaired smooth muscle tone, leading to5:

  • Vascular constriction

  • Pulmonary hypertension

  • Dyspnea

PHT is an end result of hemolysis-induced nitric oxide (NO) depletion5

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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  2. Brodsky RA. Blood. 2008;111(4):1840-1847.

  3. Sahin F, et al. Am J Blood Res. 2015;5(1):30-33.

  4. Sahin F. Am J Blood Res. 2016;6(2):19–27.

  5. Rother RP, et al. JAMA. 2005;293(13):1653-1662.

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  9. Cushman M. Semin Hematol. 2007;44(2):62-69.

  10. Wahl DG, et al. Lupus. 1998;7(1):15-22.

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  12. Cheng YJ, et al. PLoS Med. 2013;10(9):e1001515.

  13. Hillmen P, et al. Blood. 2007;110(12):4123-4128.

  14. Hill A, et al. Blood. 2006;108:1-2.

  15. Weitz IC. Semin Thromb Hemost. 2011;37(3):315-321.

  16. Lee JW, et al. Int J Hematol. 2013;97(6):749-757.

  17. Hillmen P, et al. Am J Hematol. 2010;85(8):553-559.

  18. Nishimura J, et al. Medicine (Baltimore). 2004;83(3):193-207.

  19. Clark DA, et al. Blood 1981;57(1):83-89.

  20. Hill A, et al. Br J Haematol. 2010;149(3):414-425.

  21. Meyers G, et al. Blood. 2007;110: Abstract 3683.

  22. Bĕlohlávek J, et al. Exp Clin Cardiol. 2013;18(2):129-138.