Soliris® (eculizumab) and PNH

Soliris®  is the first and only therapy approved for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis.1 Soliris ® is approved for the treatment of patients with PNH in nearly 50 countries worldwide, including the United States (U.S.), European Union (EU), and Japan.

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Diagnosed with PNH at 24 years old

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About PNH

PNH is an ultra-rare, life-threatening  blood disorder in which uncontrolled activation of complement, a component of the normal immune system, results in chronic hemolysis (destruction of the patient’s red blood cells).2,3  Chronic hemolysis is the main cause of serious health problems in people with PNH and can lead to blood clots and end organ damage.4-6  In healthy individuals, normal red blood cells (RBCs) are protected from complement attack by a shield of terminal complement inhibitors. These protective proteins inhibit uncontrolled complement activation and chronic hemolysis. In patients with 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 impaired health-quality of life.4-6

®PNH develops without warning and can occur in men and women of all races, backgrounds and ages.7 The average age of onset is in the early 30s.8 Historically, up to 35% of patients with PNH treated with available supportive care did not survive beyond five years from diagnosis due to serious clinical outcomes such as thromboembolism (blockage of a blood vessel by a blood clot) and chronic kidney disease (CKD).2

Treating Patients Who Have PNH with Soliris® 

Today, patients with PNH have the benefit of an approved therapy for the treatment of their condition. The safety and efficacy of Soliris®  in patients with PNH with hemolysis were assessed in the randomized, double-blind, multi-center placebo-controlled 26-week TRIUMPH Study, which comprised 87 transfusion-dependent patients with PNH receiving Soliris®  (n=43) or placebo (n=44).9 Patients were also treated in a single-arm multi-center study comprising 97 patients with PNH treated with Soliris®  over 52 weeks (SHEPHERD Study).10 A long-term extension study included 187 patients with PNH initially enrolled in one of 3 parent trials (N=195) who continued to receive Soliris®  for a range of 10 to 54 months.1,11

Data from the trials demonstrated that patients treated with Soliris®  experienced significantly reduced hemolysis, as measured by lactate dehydrogenase (LDH) levels, leading to an improvement in symptoms and a reduction of thrombotic events, a major health problem associated with the disease. Approximately half the patients received concomitant anticoagulant therapy. The effect of anticoagulant withdrawal during Soliris®  treatment has not been studied.1,12 Please see PNH Clinical Trials Results page for more information.

The most frequently reported adverse reactions in the PNH randomized trial (≥10% overall and greater than placebo) are: headache, nasopharyngitis, back pain, and nausea.1

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INDICATIONS & IMPORTANT SAFETY INFORMATION FOR
SOLIRIS® (eculizumab)

INDICATIONS

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).

Generalized Myasthenia Gravis (gMG)
Soliris is indicated for the treatment of adult patients with generalized Myasthenia Gravis (gMG) who are anti-acetylcholine receptor (AchR) antibody positive.

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. meningitides), 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 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
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.

The most frequently reported adverse reaction in the gMG placebo-controlled clinical trial (≥10%) is: musculoskeletal pain.

Please see full prescribing information for Soliris® , including boxed WARNING regarding serious meningococcal infections.

References:

  1. Soliris®  [package insert]. New Haven, CT: Alexion Pharmaceuticals Inc; 2018.
  2. Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995 Nov 9;333(19):1253-8.
  3. Kelly R, Richards, S, Hillmen, P, Hill, A. The pathophysiology of paroxysmal nocturnal hemoglobinuria and treatment with eculizumab. Therapeutics and Clinical Risk Management. 2009 Oct 14;5: 911-921
  4. Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Hematology: Basic Principles and Practice. 4 ed. Churchill Livingstone, Inc.; 2005: 419-427.
  5. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005 Apr 6;293(13):1653-62.
  6. Hillmen P, Elebute M, Kelly R, Urbano-Ispizua A, Rother R, Khursigara G, Fu C, Omine M, Browne P, Rosee W. Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria. Am J Hematol. 2010 May 2;85: 553-559.
  7. Socie G, Mary JY, de Gramont A., et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet. 1996 Aug 31;348(9027):573-7.
  8. Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005 Dec 1;106(12):3699-709.
  9. Hillmen P, Young N, Schubert J, et al. The Complement Inhibitor Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. N Eng J Med. 2006 Sept 21;355(12): 1233-1243.
  10. Brodsky R. Advances in the diagnosis and therapy of paroxysmal nocturnal hemoglobinuria. Blood. 2008 22:65-74.
  11. Hillmen P, Muus P, Röth A, Elebute MO, Risitano AM, Schrezenmeier H. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2013;162:62–73.
  12. Hillmen P, Muus P, Duhrsen U, Risitano AM, Schubert J, Luzzatto L, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 2007 Dec 1;110(12):4123-8.