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.

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

Even in the absence of symptoms, hemolysis (LDH ≥1.5 ULN) is ongoing and destructive7,11

Consequences of Hemolysis in PNH
blood-cells
PNH RBC3,4,5

PNH RBCs lack a terminal complement inhibitor.

Complement Attack3,4,5

PNH RBCs are susceptible to complement attack.

PNH RBC Lysis3,4,5 (hemolysis)

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

Chronic Kidney Disease6,7
  • Renal insufficiency
  • Dialysis
  • Hemosiderosis
Pulmonary Hypertension (PHT)3
  • Dyspnea
  • Cardiac Dysfunction
Anemia7,8
  • Transfusions
Fatigue/Impaired QoL7,8
  • Abdominal pain
  • Dysphagia
  • Poor physical functioning
  • Erectile dysfunction
End Organ Damage9,10
  • Brain
  • GI
  • Liver
  • Lung
Thrombosis2,9,10
  • Venous
  • PE/DVT
  • Cerebral
  • Dermal
  • Hepatic/Portal
  • Abdominal ischemia
  • Arterial
  • Stroke/TIA
  • MI
  • Even in the absence of symptoms, hemolysis (LDH ≥1.5 ULN) is ongoing and destructive4,11

  • 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 population12

Thrombosis

Thrombosis: The leading cause of death in PNH13,14

Venous thromboembolism (VTE) is 62x more likely in patients with PNH as compared to the general population15,16

Relative risk of VTE in PNH vs inherited hypercoagulable states *15,16,17
Relative risk of VTE compared
to general population
70x
64
10
10
10
1
5
60x
50x
40x
30x
20x
10x
0
PNH AT deficiency PS deficiency PC deficiency PT mutation Factor V Leiden
Proportion of general
population (%)
0.0015 0.02 0.03 0.20 2.00 4.80
Expected patients
with VTE per year
280 1020 630 4200 6600 14,400
*Based on US population.

Because of its destructive nature, continue to monitor high-risk patients with unexplained thrombosis for PNH18

Sites of thromboembolism in patients with PNH9,18,19
Venous and arterial thrombotic events

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).

* 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 PNH:18,19

  • 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)20

  • While risk of thrombosis increases with clone size, even patients with smaller clone sizes can experience thrombosis21

  • Abdominal pain is a predictor of TE and mortality21

  • 60% of patients with PNH have evidence of undiagnosed thrombosis22

  • D-dimers are a marker of elevated inflammatory response that may indicate increased risk for thrombosis23

  • First thrombotic event can be fatal13,14,24


Common PNH symptoms are associated with morbidities in PNH patients21

Hemolysis and clinical symptoms are associated with increased risk of TE21
LDH ≥1.5 x ULN
7.0

P=0.013

Abdominal pain
2.8

P=0.006

LDH ≥1.5 x ULN + abdominal pain
17.8

P=0.006

Chest pain
2.7

P=0.022

LDH ≥1.5 x ULN + chest pain
19.0

P<0.001

Dyspnea
2.9

P=0.003

LDH ≥1.5 x ULN + dyspnea
10.3

P=0.002

Hemoglobinuria
1.3

P=0.493

LDH ≥1.5 x ULN + hemoglobinuria
10.3

P=0.025

0 5 10 15 20 25
Odds ratio of TE
Study description: Multivariate, retrospective analysis of the medical charts of 301 PNH patients in a national registry. Data presented as odds ratios between PNH patients with and without listed symptoms.
  • The combination of LDH ≥1.5 x ULN with any one of these clinical symptoms is associated with a greater increased risk of TE than elevated hemolysis or clinical symptoms alone21

  • In addition to being associated with TE, dyspnea and chest pain may also be symptoms of pulmonary hypertension (PHT)3,25


Patients are at risk for TE regardless of clone size21

Prevalence of TE in different PNH granulocyte clone size categories21
TE (%) 25
16
19
20
20
15
10
5
0
<20
(n=43)
20-50
(n=59)
>50
(n=93)
PNH granulocyte clone size (%)
Study description: A retrospective analysis of the medical charts of 301 PNH patients in a national registry, showing % TE in different PNH clone sizes.
  • LDH, which indicates hemolysis, has been found to be elevated in all clone sizes (P=0.01)26

Soliris is indicated for the treatment of PNH to reduce hemolysis. The effect of withdrawal of anticoagulant therapy during Soliris treatment has not been established. Therefore, treatment with Soliris should not alter anticoagulant management.

Chronic Kidney Disease

64% of patients with PNH have chronic kidney disease (CKD)6

Renal failure is a leading cause of death in PNH4

  • End-stage renal disease (ESRD) accounts for approximately 8 to 18% of patient deaths in PNH24

  • Renal insufficiency prevalence in PNH is 6.6x higher than reported in the general population6,27

  • Chronic exposure to toxic cell-free hemoglobin leads to CKD and other serious sequelae6

  • 21% of patients with PNH have Stage 3-5 CKD, which is associated with premature mortality6

In PNH, free hemoglobin and hemosiderin deposits contribute to CKD5,6,7,28,29
In PNH, free hemoglobin and hemosiderin deposits contribute to CKD
Prevalence of CKD renal characteristics at screening*6
Patients (%) 50
21
43
36
40
30
20
10
0
Stage 3-5 CKD
(n=40)
Stage 1-2 CKD
(n=84)
No CKD
(n=69)
Kidney Function
* National Kidney Foundation criteria applied at initial screening visit. CKD stages: 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).
† †With evidence of kidney damage (spot urinalysis with proteinuria or by imaging techniques).

Microinfarcts and interstitial fibrosis also contribute to a decline in kidney function in patients with PNH30

Renal microscopy30
renal microscopy

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 PHT31

Dyspnea may be an indicator of PHT and TE8,20

The majority of patients with PNH reported dyspnea32
The majority of patients with PNH reported dyspnea
  • 72% of those patients qualified shortness of breath as moderate to severe32

  • 88% of those patients reported distress due to dyspnea32

Dyspnea is a significant predictor of TE (P=0.015)20

  • Degree of dyspnea may be independent of hemoglobin level31

Hemolysis-induced nitric oxide scavenging results in impaired smooth muscle tone, leading to5,8,33:

  • Vascular constriction

  • Pulmonary hypertension

  • Dyspnea

PHT is an end result of hemolysis-induced nitric oxide (NO) depletion5,8
PHT is an end result of hemolysis-induced nitric oxide (NO) depletion

In a national registry of PNH patients, dyspnea had a statistically significant correlation to TE (P=0.015)20

During the full clinical assessment, it is important to question patients about whether they have experienced dyspnea.

blood

PNH Diagnostic Laboratory Services

A list of labs that perform high-sensitivity flow cytometry tests for PNH

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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.