Ultomiris

Brand name: Ultomiris

Common name: ravulizumab-cwvz

Dosage form: injection

Chinese name: Eculizumab injection solution

Company: Alexion Pharmaceuticals, Inc

Treatment: Paroxysmal Nocturnal Hemoglobinuria

Drug Introduction

On September 5, 2021, the European Commission (EC) has approved the long-acting C5 inhibitor Ultomiris (ravulizumab) to expand the use of the population, For the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in children (weight ≥10 kg) and adolescent patients. Specifically: children and adolescents with PNH who experience bleeding and have clinical symptoms indicating high disease activity, and children and adolescents with PNH who are clinically stable after at least 6 months of treatment with Soliris (eculizumab).

King’s College Hospital Austin, London, UK Dr. Kulasekaraj said: "PNH is a devastating disease that can have a significant impact on children's quality of life. The approval of Ultomiris will bring treatment advancements to pediatric patients with PNH in the EU. Compared with Soliris, Ultomiris requires fewer infusions per year and has good efficacy and safety. The drug will reduce the number of these pediatric patients." The need for patients to miss school for treatment. ”

Mechanism of action

Ravulizumab is a monoclonal antibody IgG2/4K that specifically binds to the complement protein C5, thereby inhibiting its cleavage into C5a (pro-inflammatory anaphylatoxin) and C5b (initiating subunit of the terminal complement complex [C5b-9]) and preventing the production of C5b-9. Ravulizumab preserves early components of complement activation that are critical for microbial opsonization and clearance of immune complexes.

Indications

Ultomiris is indicated for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH):

- Hemolytic patients with clinical symptoms indicating high disease activity.

- Patients who have been clinically stable after receiving eculizumab for at least the past 6 months.

Ultomiris is indicated for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) weighing 10 kg or more who have never received complement inhibitor therapy or have been treated with eculizumab for at least 3 months and have evidence of response to eculizumab.

Dosage and Dosage

Dosage

Adult patients with PNH and aHUS

The recommended dosage regimen includes a loading dose and a maintenance dose, administered by intravenous infusion. Dosage is based on patient weight, as shown in Table 1. For adult patients (≥ 18 years), maintenance doses should be administered at 8-week intervals, beginning 2 weeks after the loading dose.

Dosing schedules are allowed to occasionally change within ±7 days of the scheduled infusion day (except for the first maintenance dose of ravulizumab, but subsequent doses should be administered according to the original schedule).

For patients switching from eculizumab to ravulizumab, a loading dose of ravulizumab should be given 2 weeks after the last eculizumab infusion, followed by maintenance doses every 8 weeks, starting 2 weeks after the loading dose, as shown in Table 1.

Ravulizumab weight-based dosing schedule

Weight range (kg) Loading dose (mg) Maintenance dose (mg) Dosing interval

≥40 to <60 2400 3000 Every 8 weeks

≥60 to<100 2700 3300 Every 8 weeks

≥100 3000 3600 Every 8 weeks

Maintenance dose administered 2 weeks after loading dose

Ravulizumab has not been studied in PNH patients weighing less than 40 kg.

There is no experience with concomitant PE/PI (plasma exchange or plasmapheresis, or fresh frozen plasma infusion) with ravulizumab. Administration of PE/PI may decrease ravulizumab serum levels.

PNH is a chronic disease and it is recommended that treatment with ravulizumab be continued throughout the patient's lifetime unless there is a clinical indication to discontinue ravulizumab.

In aHUS, treatment with ravulizumab to resolve manifestations of thrombotic microangiopathy (TMA) should be continued for at least 6 months, beyond which the duration of treatment needs to be considered individually for each patient. Patients who are at higher risk for TMA recurrence as determined by the treating healthcare provider (or as clinically indicated) may require long-term treatment.

Special Populations

Geriatric

No dose adjustment is required for PNH and aHUS patients 65 years and older. There is no evidence that treating the elderly population requires any special precautions—although experience with ravulizumab in older patients is limited.

Renal Impairment

No dosage adjustment is required in patients with renal insufficiency.

Hepatic Impairment

The safety and efficacy of ravulizumab have not been studied in patients with hepatic impairment; however, pharmacokinetic data suggest that no dose adjustment is required in patients with hepatic impairment.

Pediatric population

Atypical hemolytic uremic syndrome (aHUS)

Pediatric patients with aHUS weighing ≥40kg should be treated according to adult dosing recommendations. Weight-based dosage and dosing intervals for pediatric patients ≥10 kg to <40 kg are shown in Table 2.

Weight-based dosing regimen for Ravulizumab in pediatric patients under 40 kg

Weight range (kg) Loading dose (mg) Maintenance dose (mg) Dosing interval

≥10 to <20 600 600 Every 4 weeks

≥20 to <30 900 2100 Every 8 weeks

≥30 to <40 1200 2700 Every 8 weeks

The maintenance dose is administered 2 weeks after the loading dose

There are limited data supporting the safety and efficacy of ravulizumab in patients weighing less than 10 kg. Currently available data are described but no dosing recommendations can be made for patients weighing less than 10 kg.

Paroxysmal nocturnal hemoglobinuria (PNH)

The safety and efficacy of ravulizumab in children 0 to <18 years of age with PNH have not been established. No data available.

Administration

For intravenous infusion only.

This medicine must be administered through a 0.2 µm filter and should not be administered as an intravenous push or bolus injection.

In the absence of compatibility studies, Ultomiris 300mg/30mL Concentrate for Infusion Solutions should not be mixed with Ultomiris 300mg/3mL or 1,100mg/11mL Concentrate for Infusion Solutions.

Ultomiris at a concentration of 10 mg/mL (30 ml vial) must be diluted to a final concentration of 5 mg/mL.

Ultomiris concentrate for infusion as a 30 mL vial (10 mg/mL) must be diluted by intravenous infusion using a syringe-type pump or an infusion pump over a minimum of 1.3 to 3.3 hours (77 to 194 minutes) prior to administration) depending on body weight (see Table 3 below).

Dose administration rate for Ultomiris 300mg/30mL concentrate for infusion solution

Weight range Loading dose Minimum infusion duration Maintenance dose Minimum infusion time

(kga) (mg) (mg) Minutes (hours) (mg) Minutes (hours)

≥10 to <20 600 113(1.9) 600 113(1.9)

≥20 to <30 900 86(1.5) 2100 194(3.3)

≥30 to <40 1200 77(1.3) 2700 167(2.8)

≥40 to <60 2400 114(1.9) 3000 140(2.4)

≥60 to <100 2700 102(1.7) 3300 120(2.0)

≥ 100 3000 108(1.8) 3600 132(2.2)

a Weight at treatment.

Instructions for diluting the medication before administration.

Contraindications

- Hypersensitivity to the active substance or any of the listed excipients.

- Patients with unresolved Neisseria meningitidis infection at the start of treatment.

- Patients who are not currently vaccinated against Neisseria meningitidis unless they receive prophylactic treatment with appropriate antibiotics within 2 weeks of vaccination.

Shelf life

30 months.

Diluted medicines should be used immediately. However, the chemical and physical stability of the diluted product has been demonstrated for up to 24 hours at 2°C-8°C and up to 6 hours at room temperature.

Special Storage Precautions

Store in refrigerator (2 °C–8 °C)

Do not freeze.

Place vials in outer carton to protect from light.

Regarding the storage conditions of diluted drugs.

Nature and contents of the dissolver

Pack size of the bottle.

30mL sterile concentrate in stoppered and sealed vial (Type I glass).