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What is atypical‑HUS?

Atypical hemolytic uremic syndrome (atypical‑HUS) is a rare, life-threatening disease caused by dysregulation of the alternative pathway of the complement system, leading to excessive complement activation and thrombotic microangiopathy (TMA).1-3

For treatment of atypical-HUS in adult and pediatric patients 1 month of age and older. Not indicated in STEC‑HUS.4

Complement system dysfunction in atypical‑HUS5-8

In atypical‑HUS, the complement part of the innate immune system is overactivated. This chronic activation leads to microvascular damage, thrombosis, and multi-organ ischemic damage.5

TMA triggersThrombotic microangiopathy (TMA)
can be associated with various triggers3

Atypical‑HUS may be triggered by conditions that activate complement.3 Persistence of TMA despite treatment of associated conditions may suggest atypical‑HUS.9

Triggers that may accelerate activation
of the complement system3

Postpartum

Hypertensive emergency

Transplantation

Transplantation

Autoimmune disease

Medications

Infections

Medications

Infections

Glomerulonephritis

Malignancy

Surgery or trauma

Surgery or trauma

Differential diagnosis Diagnosing atypical‑HUS requires excluding
other conditions3,9

Many of the signs and symptoms of atypical‑HUS are shared by other causes of TMA.3 Because of its high morbidity and mortality when untreated, identifying atypical‑HUS quickly is important.3,9

Differential diagnosis of TMA, including atypical-HUS1,3,7,9

Thrombocytopenia

Platelet count <150x 109/L
or <25% decrease from baseline

AND

Microangiopathic hemolysis

Schistocytes and/or elevated LDH and/or
decrease haptoglobin
and/or
decreased hemoglobin

Plus 1 or more of the following

Common Symptoms

Neurological symptoms

Confusion and/or seizures
and/or stroke
and/or other cerebral
abnormalities

Renal impairment

Elevated creatinine level
and/or decreased eGFR
and/or elevated
blood
pressure
and/or abnormal

urinary results

GI symptoms

Diarrhea ± blood and/or
nausea/
vomiting
and/or

abdominal pain and/or

gastroenteritis/pancreatitis

Other Symptoms

CV symptoms

MI and/or hypertension and/
or
arterial stenosis and/or

peripheral gangrene

Pulmonary symptoms

Dyspnea and/or pulmonary

hemorrhage

and/or pulmonary
edema

Visual symptoms

Pain and blurred vision
and/or
retinal vessel
occlusion
and/or
ocular
hemorrhage

Evaluate ADAMTS13 activity and Shiga toxin/EHEC testb

While ADAMTS13 results are
awaited, a platelet count
<30 x 109/L and /or sCr <1.7 to

2.3 mg/dL almost eliminates a
diagnosis of severe ADAMTS13
deficiency (TTP)

≤5%c ADAMTS13 activity

TTP

>5% ADAMTS13 activity

Atypical-HUS

Shiga toxin/EHEC positive

STEC-HUSb

bShiga toxin/EHEC test is warranted with history/presence of gastrointestinal symptoms.

cRange found in published data is 5%-10%.

ADAMTS13=a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13; CV=cardiovascular; EHEC=enterohemorrhagic Escherichia coli; eGFR=estimated glomerular filtration rate; GI=gastrointestinal; HUS=hemolytic uremic syndrome; LDH=lactate dehydrogenase; MI=myocardial infarction; sCr=serum creatinine; STEC=Shiga toxin-producing Escherichia coli; TTP=thrombotic thrombocytopenic purpura.

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References:
  1. Asif A, et al. J Nephrol. 2017;30:347-362.
  2. Jamme M, et al. PLoS One. 2017;12:e0177894.
  3. Laurence J. Clin Adv Hematol Oncol. 2016;14:2-15.
  4. ULTOMIRIS. Prescribing information. Alexion Pharmaceuticals, Inc.
  5. Raina R, et al. Ther Apher Dial. 2019;23:4-21.
  6. Legendre CM, et al. N Engl J Med. 2013;368:2169-2181.
  7. Goodship THJ, et al. Kidney Int. 2017;91:539-551.
  8. Nester CM, et al. Hematology Am Soc Hematol Educ Program. 2012;2012:617-625.
  9. Azoulay E, et al. Chest. 2017;152:424-434.

INDICATION & IMPORTANT SAFETY INFORMATION

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WARNING: SERIOUS MENINGOCOCCAL INFECTIONS

ULTOMIRIS, a complement inhibitor, increases the risk of serious infections caused by Neisseria meningitidis [see Warnings and Precautions (5.1)] Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early.

  • Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS therapy outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against meningococcal bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by meningococcal bacteria.
  • Patients receiving ULTOMIRIS are at increased risk for invasive disease caused by Neisseria meningitidis, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious meningococcal infections and evaluate immediately if infection is suspected.

Because of the risk of serious meningococcal infections, ULTOMIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called ULTOMIRIS REMS [see Warnings and Precautions (5.2)].

CONTRAINDICATIONS

  • Initiation in patients with unresolved serious Neisseria meningitidis infection.

WARNINGS AND PRECAUTIONS
Serious Meningococcal Infections

ULTOMIRIS, a complement inhibitor, increases a patient’s susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria (septicemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors.

Revaccinate patients in accordance with ACIP recommendations considering the duration of ULTOMIRIS therapy. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent ULTOMIRIS therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide antibacterial drug prophylaxis and administer meningococcal vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including ULTOMIRIS. The benefits and risks of treatment with ULTOMIRIS, as well as those associated with antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by Neisseria meningitidis.

Vaccination does not eliminate the risk of serious meningococcal infections, despite development of antibodies following vaccination.

Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if they occur. Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of ULTOMIRIS in patients who are undergoing treatment for serious meningococcal infection depending on the risks of interrupting treatment in the disease being treated.

ULTOMIRIS REMS
Due to the risk of serious meningococcal infections, ULTOMIRIS is available only through a restricted program called ULTOMIRIS REMS.

Under the REMS, prescribers must enroll in the REMS, counsel patients about the risk of meningococcal infection, provide patients with the REMS educational materials, assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y, and B) and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of ULTOMIRIS.  Antibacterial drug prophylaxis must be prescribed if treatment must be started urgently and the patient is not up to date with both meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of ULTOMIRIS.  Patients must receive counseling about the need to receive meningococcal vaccines and to take antibiotics as directed, signs and symptoms of meningococcal infection, and be instructed to carry the Patient Safety Card at all times during and for 8 months following ULTOMIRIS treatment.

Further information is available at www.ultomirisrems.com or 1-888-765-4747.

Other Infections
Serious infections with Neisseria species (other than Neisseria meningitidis), including disseminated gonococcal infections, have been reported.

ULTOMIRIS blocks terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections caused by Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Children treated with ULTOMIRIS 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 recommendations. Patients receiving ULTOMIRIS are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination.

Monitoring Disease Manifestations after ULTOMIRIS Discontinuation
ULTOMIRIS treatment of aHUS should be a minimum duration of 6 months. Due to heterogeneous nature of aHUS events and patient-specific risk factors, treatment duration beyond the initial 6 months should be individualized. There are no specific data on ULTOMIRIS discontinuation. After discontinuing treatment with ULTOMIRIS, patients should be monitored for clinical symptoms and laboratory signs of TMA complications for at least 12 months. TMA complications post-discontinuation can be identified if any of the following is observed: Clinical symptoms of TMA include changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure. In addition, at least two of the following laboratory signs observed concurrently and results should be confirmed by a second measurement 28 days apart with no interruption: a decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ULTOMIRIS treatment; an increase in serum creatinine of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment; or, an increase in serum LDH of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment. If TMA complications occur after discontinuation, consider reinitiation of ULTOMIRIS treatment or appropriate organ-specific supportive measures.

Thromboembolic Event Management
The effect of withdrawal of anticoagulant therapy during treatment with ULTOMIRIS has not been established. Treatment should not alter anticoagulant management.

Infusion-Related Reactions
Intravenous administration of ULTOMIRIS may result in systemic infusion-related reactions, including anaphylaxis and hypersensitivity reactions. In clinical trials, infusion-related reactions occurred in approximately 1% of patients treated with ULTOMIRIS.  These events included lower back pain, drop in blood pressure, limb discomfort, drug hypersensitivity (allergic reaction), dysgeusia (bad taste), and drowsiness. These reactions did not require discontinuation of ULTOMIRIS. If signs of cardiovascular instability or respiratory compromise occur, interrupt ULTOMIRIS infusion and institute appropriate supportive measures.

ADVERSE REACTIONS
Most common adverse reactions in patients with aHUS (incidence ≥20%) were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension and pyrexia. Serious adverse reactions were reported in 42 (57%) patients with aHUS receiving ULTOMIRIS. The most frequent serious adverse reactions reported in more than 2 patients (2.7%) treated with ULTOMIRIS were hypertension, pneumonia and abdominal pain.

Adverse reactions reported in 20% of pediatric patients treated with ULTOMIRIS were diarrhea, constipation, vomiting, pyrexia, upper respiratory tract infection, decreased vitamin D, headache, cough, rash, and hypertension.

DRUG INTERACTIONS
Plasma Exchange, Plasmapheresis, and Intravenous Immunoglobulins
Concomitant use of ULTOMIRIS with plasma exchange (PE), plasmapheresis (PP), or intravenous immunoglobulin (IVIg) treatment can reduce serum ravulizumab concentrations and requires a supplemental dose of ULTOMIRIS.

Neonatal Fc Receptor Blockers
Concomitant use of ULTOMIRIS with neonatal Fc receptor (FcRn) blockers (e.g., efgartigimod) may lower systemic exposures and reduce effectiveness of ULTOMIRIS. Closely monitor for reduced effectiveness of ULTOMIRIS. 

INDICATION
ULTOMIRIS is indicated for the treatment of adult and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).

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

To report SUSPECTED ADVERSE REACTIONS, contact Alexion Pharmaceuticals, Inc. at 1-844-259-6783 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see accompanying full Prescribing Information for ULTOMIRIS, including Boxed WARNING regarding serious and life-threatening or fatal meningococcal infections.

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Healthcare Professionals:
Answers to your questions are
a phone call away! Connect
with a live representative.
833-551-2539

Alexion Connect