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.
    • 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 solirisrems.com.

What is PNH?

PNH: A progressive, destructive, and life-threatening disease that causes thrombosis, end organ damage, and impaired quality of life1,2,3

blood cells
PNH RBCs

PNH RBCs lack a terminal complement inhibitor.

Complement Attack

PNH RBCs are susceptible to complement attack.

PNH RBC Lysis (hemolysis)

PNH RBCs are lysed, and contents are released into the surrounding plasma.

Survival of patients with PNH compared to patients receiving historical supportive care4
Survival of patients with PNH compared to controls

Study description: Researchers followed 80 consecutive patients with PNH referred to Hammersmith Hospital. They were treated with supportive measures, such as oral anticoagulant therapy after established thromboses and transfusions.

  • Thrombosis and renal failure are leading causes of death4,5

  • PNH may be diagnosed at any age; median age is in the early 30s5

  • Diagnosis is typically delayed from 1 to more than 10 years6

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.2,7,8

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.7,8

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.9

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).2,7,8

Free Hemoglobin/Nitric Oxide Depletion

Hemolysis leads to free hemoglobin and nitric oxide (NO) depletion2

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.10 Reduced NO can also lead to processes considered to be precursors to thrombotic events such as:2,10,11

  • 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.2 These dystonias include:

  • Vascular constriction, leading to pulmonary and systemic hypertension and erectile dysfunction12

  • Gastrointestinal contractions that can cause abdominal pain and dysphagia2

Complement

Complement is a complex array of more than 20 proteins present in the blood and plays a fundamental role in the body’s innate immune response against infection.13,14

  • Insufficient regulation of the complement cascade can have highly destructive effects15

  • In PNH, the deficiency of complement inhibitors leads to chronic, uncontrolled complement activation, resulting in chronic hemolysis and granulocyte and platelet activation2,16,17,18

Consequences of chronic, uncontrolled complement activation8,18,19,20
Soliris consequence of action

The complement cascade is a sequential process13,14

  • 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 pathway14

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

  • All 3 pathways aid in the generation of C3 convertase complexes; these complexes facilitate the cleavage of C3, yielding C3a and C3b

  • These cleaved fragments are important to the proximal complement pathway, as individuals with C3 deficiencies are susceptible to polysaccharide-coated bacterial infections14

The terminal complement pathway14

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

  • Individuals harboring C3 deficiencies have reduced abilities to opsonize infectious pathogens and mount an inflammatory response

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

  • C5b interacts with C6-C9, allowing for the formation of the terminal complement complex (TCC)

  • Deposition of TCC on erythrocytes, as in PNH, results in hemolysis14

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Important Safety Information

CLOSE

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.
  • 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 solirisrems.com.

Indications and Usage

Paroxysmal Nocturnal Hemoglobinuria (PNH)

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

Atypical Hemolytic Uremic Syndrome (aHUS)

Soliris is indicated for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy.

Limitation of Use

Soliris is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).

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

Other Infections

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 influenza type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenza 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.

Treatment Discontinuation for aHUS

After discontinuing Soliris, monitor patients with aHUS for signs and symptoms of thrombotic microangiopathy (TMA) complications for at least 12 weeks. In aHUS clinical trials, 18 patients (5 in the prospective studies) discontinued Soliris treatment. TMA complications occurred following a missed dose in 5 patients, and Soliris was reinitiated in 4 of these 5 patients.

Clinical signs and symptoms of TMA include changes in mental status, seizures, angina, dyspnea, or thrombosis. In addition, the following changes in laboratory parameters may identify a TMA complication: occurrence of two, or repeated measurement of any one of the following: a decrease in platelet count by 25% or more compared to baseline or the peak platelet count during Soliris treatment; an increase in serum creatinine by 25% or more compared to baseline or nadir during Soliris treatment; or, an increase in serum LDH by 25% or more over baseline or nadir during Soliris treatment.

If TMA complications occur after Soliris discontinuation, consider reinstitution of Soliris treatment, plasma therapy [plasmapheresis, plasma exchange, or fresh frozen plasma infusion (PE/PI)], or appropriate organ-specific supportive measures.

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

As with all protein products, 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.

The most frequently reported adverse reactions in aHUS single arm prospective trials (≥20%) are: headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary tract infections, pyrexia.

Please see full Prescribing Information for Soliris, including Boxed WARNING regarding serious meningococcal infection.

 
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