Ultomiris

Ravulizumab

• Brand(s): Ultomiris
• Dosage Form/Strength: 300 mg/30 mL, 300 mg/3 mL,1100 mg/11 mL vial
• Effective date: March 1, 2024

Initial requests:

For the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in patients meeting all the following criteria;

1. Age one month or older;
   AND
2. Has a confirmed diagnosis of PNH at initial presentation based on meeting the following;
   a. Patient has documentation (provide a copy of the reports) of both of the following confirmatory results:
   • Flow cytometry/ Fluorescent aerolysin (FLAER) exam with clone count (i.e., granulocyte or monocyte) equal to or greater than 10%
   • Lactate dehydrogenase (LDH) greater than 1.5 upper limit of normal (ULN)
   AND
   b. At least one of the following clinical features:
   • Has experienced a thrombotic or embolic event which required the institution of therapeutic anticoagulant therapy.
   • Has a minimum transfusion requirement of 4 units of red blood cells in the previous 12 months.
   • Has chronic or recurrent anemia where causes other than hemolysis have been excluded and demonstrated by more than one measure of hemoglobin less than or equal to 70 g/L OR more than one measure of hemoglobin less than or equal to 100 g/L with concurrent symptoms of anemia.
   • Has pulmonary insufficiency: Debilitating shortness of breath and/or chest pain resulting in limitation of normal activity (New York Heart Association Class III) and/or established diagnosis of pulmonary arterial hypertension, where causes other than PNH have been excluded.
   • Has renal insufficiency: History of renal insufficiency, demonstrated by an eGFR less than or equal to 60 mL/min/1.73 m², where causes other than PNH have been excluded.
   • Has smooth muscle spasm: Recurrent episodes of severe pain requiring hospitalization and/or narcotic analgesia, where causes other than PNH have been excluded.
3. Ravulizumab is prescribed by or in consultation with a hematologist or a pediatric hematologist.

Notes:

1. Prescribers should submit relevant bloodwork to support the diagnosis including CBC, transfusion records, bone marrow report, flow cytometry/FLAER exam report, LDH levels, and as possible, recent consult notes.
2. Prescribers should comply with the most current National Advisory Committee on Immunization (NACI) recommendations for meningococcal vaccination in patients with complement deficiencies to reduce the risk of serious infection. Appropriate vaccination for meningococcal disease should be administered at least 2 weeks prior to receiving the first dose of ravulizumab and if this is not possible, refer to the product monograph for mitigating instructions.
3. Funding will not be considered if the patient or treating physician fails to comply adequately with treatment or measures, including monitoring requirements, required to evaluate the effectiveness of the therapy with ravulizumab.
4. Patients stabilized on eculizumab who wish to switch to ravulizumab must meet the initiation and renewal criteria (as applicable) of ravulizumab and will be considered on a case-by-case basis.

Renewal criteria:

Renewals will be considered in patients who demonstrate clinical improvement or disease stabilization of PNH compared to baseline clinical results and symptoms.

As part of the renewal of funding, confirmation of clone size (by flow cytometry) should be submitted with the request. Granulocyte and monocyte clone size should be included to compare against the baseline results.

Exclusion criteria (applies to both initial and renewals)

Patients meeting one of more of the following are not approved for funding under the Ontario drug benefit program.

1. Previously experienced treatment failure with eculizumab administered for the treatment of PNH.
2. Previously experienced treatment failure with ravulizumab administered for the treatment of PNH.
3. Ravulizumab will not be funded in combination with eculizumab.
4. Small granulocyte clone size - the treatment of patients with a granulocyte clone size below 10% will not be eligible for treatment.
5. Aplastic anemia with two or more of the following: neutrophil count below 0.5 x 10⁹/L, platelet count below 20 x 10⁹/L, reticulocytes below 25 x 10⁹/L, or severe bone marrow hypocellularity.
6. Patients diagnosed with another life threatening or severe disease where the long-term prognosis is unlikely to be influenced by therapy (for example acute myeloid leukemia or high-risk myelodysplastic syndrome).
7. The presence of another medical condition that might reasonably be expected to compromise a response to therapy.

Approved doses (loading and maintenance):

Weight-based dosing per the Ultomiris product monograph with maintenance doses administered up to every for weeks for patients under 20 kg and every 8 weeks for those above or equal to 20 kg.

Maintenance dosing in those above or equal to 20 kg that is administered more frequent than every 8 weeks require approval by the EAP on a case-by-case.

Approval duration of initials: 6 months

Approved dosing of renewals: 1 year

Atypical hemolytic uremic syndrome (aHUS)

Initiation Criteria:

For the treatment of atypical hemolytic uremic syndrome (aHUS) in patients meeting all the following criteria:

1. Age one month or older;
   AND
2. Has a confirmed diagnosis of aHUS at initial presentation as defined by meeting all of the following;
   a. Presence of an unexplained non- disseminated intravascular coagulation thrombotic microangiopathy (TMA) (i.e., not a secondary TMA);
   AND
   b. Baseline ADAMTS-13 activity greater than or equal to 10% on blood samples taken prior to plasma exchange (PE) or plasma infusion (PI);
   Note: If the sample for ADAMTS-13 was not collected prior to plasma exchange or plasma infusion, platelet counts greater than 30 x 10⁹/L and eGFR less than 50 mL/min/1.73m² at TMA presentation will be accepted as predictive of ADAMTS-13 greater than or equal to 10% in TMA patients. In this case, measurement of ADAMTS-13 can be taken one to two weeks following the last PE. The ADAMTS-13 result must be provided within 30 days of commencement of ravulizumab and at least 1 week after the last PE;
   AND
   c. STEC-negative test in patients with a history of bloody diarrhea in the preceding two weeks;
   AND
   d. Other diagnoses and causes of TMA must be ruled out
3. Patient must have evidence of ongoing active TMA and progressing, defined by laboratory test abnormalities despite plasmapheresis, if appropriate. This is demonstrated by:
   a. Thrombocytopenia (platelet count less than 150 × 10⁹/L) that is not explained by another cause including secondary TMA and hemolysis as indicated by the documentation of two of the following: red blood cell (RBC) fragmentation (schistocytes) on the blood film; low or absent haptoglobin; or lactate dehydrogenase LDH above normal;
   OR
   b. Tissue biopsy confirms TMA in patients who do not have evidence of platelet consumption and hemolysis.
4. Patient must have documented evidence of at least one of the following clinical features of active organ damage or impairment:
   a. Kidney impairment, as demonstrated by one or more of the following:
   • A decline in estimated glomerular filtration rate (eGFR) or a rise in serum creatinine (SCr) of greater than 20% in a patient with pre-existing renal impairment;
   • SCr greater than upper limit of normal (ULN) for age or eGFR less than 60 mL/min and renal function deteriorating in spite of PE/PI in patients who have no history of preexisting renal impairment (i.e., who have no baseline eGFR measurement);
   • SCr greater than the age-appropriate ULN in pediatric patients (as determined by or in consultation with a pediatric nephrologist)
   • Renal biopsy
   b. The onset of neurological impairment related to TMA e.g., visual field defect, hemiparesis, sensory loss, asymmetric limb weakness, confusion, loss of consciousness/coma, new onset seizure).
   c. Other extra-renal TMA-related manifestations, such as TMA-related cardiac impairment, TMA-related gastrointestinal impairment (e.g. bowel ischemia, pancreatitis); TMA-related pulmonary impairment, and retinal vein occlusion.
5. Ravulizumab is prescribed by or in consultation with a pediatric nephrologist, a nephrologist, a pediatric hematologist or a hematologist.

Notes:

1. Transplant patients with a documented history of aHUS (i.e., history of TMA [not a secondary TMA only] with ADAMTS 13 greater than 10%) would be eligible for ravulizumab if they:
   a. Develop TMA immediately (within hours to 1 month) following a kidney transplant; OR
   b. Previously lost a native or transplanted kidney due to the development of TMA; OR
   c. Have a history of proven aHUS and require prophylaxis with ravulizumab at the time of a kidney transplant [if the genotype of the aHUS is tissue related (i.e., not present in the transplant), then ravulizumab the prescriber may consider ravulizumab to be given pre-transplant and for at least 1-month post-transplant with monitoring closely after discontinuation for recurrence.]
2. Re-initiation criteria: A patient previously diagnosed with aHUS and who responded to treatment with ravulizumab and has not failed ravulizumab is eligible to restart ravulizumab if the patient redevelops a TMA related to aHUS and meets the following clinical conditions:
   a. Significant hemolysis as evidenced by presence of schistocytes on the blood film, or low or absent haptoglobin, or LDH above normal;
   AND EITHER
   b. Platelet consumption as measured by either a greater than or equal to 25?cline from patient baseline or thrombocytopenia (platelet count less than 150,000 × 10⁹/L);
   OR
   TMA-related organ impairment (e.g., unexplained rise in serum creatinine with onset of urine dipstick positive for hemoglobin) including on recent biopsy.
3. Assessment of treatment response should be conducted at 6 months, at 12 months, then annually thereafter.
4. Patients stabilized on eculizumab who wish to switch to ravulizumab must meet the initiation and renewal criteria (as applicable) of ravulizumab and will be considered on a case-by-case basis.

Exclusions: Patients meeting the below will not be funded:

1. Patients who have previously experienced ravulizumab treatment failure (i.e., treated with ravulizumab with a previous aHUS recurrence).
2. Ravulizumab will not be funded in combination with eculizumab.

Renewal Criteria:

Treatment with ravulizumab can be renewed as long as the patient exhibits a response to treatment or as per physician discretion (e.g., long-term funding based on factors like limited organ reserve or high-risk genetic mutation such as Factor H deficiency) AND the patient does not experience treatment failure as defined below.

At the first renewal (i.e., the 6-month assessment) treatment response and no treatment failure is required.

At the 12-month and annual assessments, treatment response, no treatment failure, and the patient has limited organ reserve or high-risk genetic mutation are required.

Treatment failure is defined as:
a. Dialysis-dependent at 6 months, and failed to demonstrate resolution or stabilization of neurological or extrarenal complications if these were originally present;
OR
b. On dialysis for 4 or more of the previous 6 months while receiving ravulizumab and failed to demonstrate resolution or stabilization of neurological or extrarenal complications if these were originally present;
OR
c. Worsening of kidney function with a reduction in eGFR or increase in SCr greater than or equal to 25% from baseline.

Assessment of treatment response should be conducted at 6 months, at 12 months, then annually thereafter.

Treatment response is defined as, but not limited to:
a. hematological normalization (e.g., platelet count, LDH)
b. stabilization of end-organ damage (such as acute kidney injury and brain ischemia)
c. transplant graft survival in susceptible individuals
d. dialysis avoidance in patients who are pre-end-stage kidney disease.

Limited organ reserve is defined as:
a. significant cardiomyopathy, neurological, gastrointestinal, or pulmonary impairment related to TMA;
OR
b. Grade 4 or 5 chronic kidney disease (eGFR less than 30mL/min) is required.

Approval duration of initials: 6 months

Approved dosing of renewals: 1 year

Approved doses (loading and maintenance): Weight-based dosing per the Ultomiris product monograph with maintenance doses administered up to every four weeks for patients under 20 kg and every 8 weeks for those above or equal to 20 kg.

Maintenance dosing in those above or equal to 20 kg that is administered more frequent than every 8 weeks require approval by the EAP on a case-by-case.