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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.

What is PNH?

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

PNH RBCs2
PNH RBCs lack a terminal complement inhibitor.

Complement Attack2
PNH RBCs are susceptible to complement attack.

PNH RBC Lysis (hemolysis)2
PNH RBCs are lysed, and contents are released into the surrounding plasma.

Hemolysis-induced complications increase the risk of premature mortality in patients with PNH3-6
aPatients in the de Latour 2008 study were followed up to 40 years.
bPatients in the Hillmen 1995 study were followed up to 25 years.

  • Thrombosis and renal failure are leading causes of death2

  • PNH may be diagnosed at any age; median age is in the early 30s7,8

  • Diagnosis is typically delayed from 1 to more than 10 years9

 

Pathophysiology

What causes PNH?

PNH is an acquired hematopoietic stem cell disorder in which blood cells lack a key, naturally occurring terminal complement inhibitor on the cell surface.2

In PNH there is an expansion of hematopoietic stem cells that possess a mutation of the phosphatidylinositol glycan class A (PIG-A) gene. PIG-A is one of several genes involved in the protein synthesis of an enzyme responsible for assembly of a fatty acid tail, known as a glycosyl- phosphatidylinositol (GPI) anchor. GPI anchor synthesis is a necessary step in surface attachment of some proteins.8

In PNH, the lack of these protective proteins renders RBCs vulnerable to lysis by complement. Without this protective complement inhibitor shield, PNH RBCs are destroyed (hemolysis), which can result in thrombosis, end organ damage, and increased mortality.2

Normal red blood cells (RBCs) are protected from complement attack by a shield of terminal complement inhibitors created by 2 crucial proteins, CD59 and CD55. These protective proteins inhibit uncontrolled complement activation and the formation of the terminal complement complex (TCC), also known as C5b-9 or the membrane attack complex (MAC).8

Free Hemoglobin/Nitric Oxide Depletion

Hemolysis leads to free hemoglobin and nitric oxide (NO) depletion10

During chronic hemolysis, excess free hemoglobin depletes plasma nitric oxide (NO), which may play an important role in normal platelet function.10

NO may down regulate platelet aggregation, adhesion, and regulating molecules in the coagulation cascade. Therefore, NO depletion may lead to platelet activation and aggregation.7 Reduced NO can also lead to processes considered to be precursors to thrombotic events such as10:

  • Platelet activation and aggregation

  • Platelet hyperreactivity

  • Hypercoagulability

  • Impaired fibrinolysis

In addition, reduced NO can have an array of consequences for PNH patients, including smooth muscle dystonias.10 These dystonias include:

  • Vascular constriction, leading to pulmonary and systemic hypertension and erectile dysfunction2

  • Gastrointestinal contractions that can cause abdominal pain and dysphagia2

Complement

Complement is a complex array of more than 30 proteins present in the blood and plays a fundamental role in the body’s innate immune response against infection.11

Insufficient regulation of the complement cascade can have highly destructive effects11

In PNH, the deficiency of complement inhibitors leads to chronic, uncontrolled complement activation, resulting in chronic hemolysis and granulocyte and platelet activation11

Consequences of chronic, uncontrolled complement activation12-14

The complement cascade is a sequential process11

  • Triggered by infectious agents, foreign molecules, and immune complexes

  • Proceeds through an enzymatic cascade capable of lysing susceptible cells

  • Compartmentalized into proximal and terminal complement pathways

The proximal complement pathway

  • Initially triggered via 3 different pathways: lectin, classical, and alternative11

  • All 3 pathways aid in the generation of C3 convertase complexes; these complexes facilitate the cleavage of C3, yielding C3a and C3b11

  • These cleaved fragments are important to the proximal complement pathway, as individuals with C3 deficiencies are susceptible to polysaccharide-coated bacterial infections15

The terminal complement pathway

  • C3 components are also required for the downstream engagement of the terminal complement pathway11

  • Initiated when C5b complexes with other factors, forming C5 convertases, which then cleave C5, yielding C5a and C5b11

  • C5b interacts with C6-C9, allowing for the formation of the membrane attack complex (MAC)11

  • Deposition of MAC on erythrocytes, as in PNH, results in hemolysis2,11

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.

1. Sahin F, et al. Am J Blood Res. 2016;6(2):19-27.
2. Sahin F, et al. Am J Blood Res. 2015;5(1):1-9.
3. Hillmen P, et al. N Engl J Med. 1995;333:1253-1259.
4. Kelly RJ, et al.  Blood. 2011;117:6786-6792.
5.
de Latour R, et al. Blood. 2008;112:3099-3106.
6.
Loschi M, et al. Am J Hematol. 2016;91:366-370.
7.
Socie G, et al. Lancet. 1996;348(9027):573-577.
8. Brodsky RA. Blood. 2009;113(26):6522-6527.
9. Dacie JV, Lewis SM. Ser Haematol. 1972;5(3):3-23.
10. Rother RP, et al. JAMA. 2005;293(13):1653-1662.
11. Sharma JV, Ward PA. Cell Tissue Res. 2011;343(1):227-235.
12.  Walport MJ. N Engl J Med. 2001;344(14):1058-1066.
13. Murphy K. Innate immunity: the first lines of defense. In: Scobie J, et al, eds. Janeway’s Immunobiology. 8th ed. New York, NY: Garland Science; 2012:37-73.
14. Kelly R, et al. Ther Clin Risk Manag. 2009;5:911-921.
15. Nilsson B, Ekdahl KN. Clin Dev Immunol. 2012;2012:962702.