Posology : מינונים

4.2   Posology and method of administration

Ravulizumab must be administered by a healthcare professional and under the supervision of a physician experienced in the management of patients with haematological, renal, neuromuscular, or neuroinflammatory disorders.

Posology

Adult patients with PNH, aHUS, gMG or NMOSD
The recommended dosing regimen consists of a loading dose followed by maintenance dosing, administered by intravenous infusion. The doses to be administered are based on the patient’s body weight, as shown in Table 1. For adult patients (≥ 18 years of age), maintenance doses should be administered at a once every 8-week interval, starting 2 weeks after loading dose administration.

Dosing schedule is allowed to occasionally vary by ± 7 days of the scheduled infusion day (except for the first maintenance dose of ravulizumab), but the subsequent dose should be administered according to the original schedule.

For patients switching from eculizumab to ravulizumab, the loading dose of ravulizumab should be administered 2 weeks after the last eculizumab maintenance infusion (or 1 week after the last eculizumab induction infusion), and then ravulizumab maintenance doses are administered once every 8 weeks, starting 2 weeks after loading dose administration, as shown in Table 1.


Table 1:        Ravulizumab weight-based dosing regimen for adult patients with body weight greater than or equal to 40 kg
Body weight range (kg) Loading dose (mg) Maintenance dose (mg)* Dosing interval ≥ 40 to < 60              2,400              3,000                       Every 8 weeks ≥ 60 to < 100             2,700              3,300                       Every 8 weeks ≥ 100                     3,000              3,600                       Every 8 weeks *First maintenance dose is administered 2 weeks after loading dose

Supplemental dosing following treatment with plasma exchange (PE), plasmapheresis (PP), or intravenous immunoglobulin (IVIg)

Plasma exchange (PE), plasmapheresis (PP) and intravenous immunoglobulin (IVIg) have been shown to reduce ULTOMIRIS serum levels. A supplemental dose of ULTOMIRIS is required in the setting of PE, PP or IVIg (Table 2).

Table 2:          Supplemental Dose of ULTOMIRIS after PE, PP, or IVIg Most Recent              Supplemental Dose (mg)         Supplemental Dose (mg) Body Weight
ULTOMIRIS Dose           following each PE or PP        following Completion of Range (kg)
(mg)                     Intervention                   an IVIg Cycle 2,400                    1,200
≥ 40 to < 60                                                                600 3,000                    1,500
2,700                    1,500
≥ 60 to < 100                                                               600 3,300                    1,800
3,000                    1,500
≥ 100                                                                       600 3,600                    1,800
Within 4 hours following
Timing of ULTOMIRIS                          Within 4 hours following completion of an IVIg
Supplemental Dose                            each PE or PP intervention cycle
Abbreviations: IVIg = intravenous immunoglobulin; kg = kilogram; PE = plasma exchange; PP = plasmapheresis 
PNH is a chronic disease and treatment with ravulizumab is recommended to continue for the patient’s lifetime, unless the discontinuation of ravulizumab is clinically indicated (see section 4.4).

In aHUS, ravulizumab treatment to resolve thrombotic microangiopathy (TMA) manifestations should be for a minimum duration of 6 months, beyond which length of treatment needs to be considered for each patient individually. Patients who are at higher risk for TMA recurrence, as determined by the treating healthcare provider (or clinically indicated), may require chronic therapy (see section 4.4).

In patients with gMG or NMOSD, treatment with ravulizumab has only been studied in the setting of chronic administration (see section 4.4).

Ravulizumab has not been studied in gMG patients with an MGFA Class V.

Special populations
Elderly
No dose adjustment is required for patients with PNH, aHUS, gMG or NMOSD aged 65 years and over. There is no evidence indicating any special precautions are required for treating a geriatric population – although experience with ravulizumab in elderly patients with PNH, aHUS or NMOSD in clinical studies is limited.

Renal impairment
No dose adjustment is required for patients with renal impairment, see section 5.2.

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.

Paediatric population
Paediatric patients with PNH and aHUS with body weight ≥ 40 kg are treated in accordance with the adult dosing recommendations (Table 1). The weight-based doses and dosing intervals for paediatric patients ≥ 10 kg to < 40 kg are shown in Table 3.

For patients switching from eculizumab to ravulizumab, the loading dose of ravulizumab should be administered 2 weeks after the last eculizumab infusion, and then maintenance doses should be administered per weight-based dosing regimen shown in Table 3, starting 2 weeks after loading dose administration.

Table 3:    Ravulizumab weight-based dosing regimen for paediatric patients with PNH or aHUS below 40 kg
Body weight range       Loading dose        Maintenance dose        Dosing (kg)                    (mg)                (mg)*                   interval ≥ 10 to < 20            600                 600                     Every 4 weeks ≥ 20 to < 30            900                 2,100                   Every 8 weeks ≥ 30 to < 40            1200                2,700                   Every 8 weeks *First maintenance dose is administered 2 weeks after loading dose

Data to support safety and efficacy of ravulizumab for patients with body weight below 10 kg are limited. Currently available data are described in section 4.8 but no recommendation on a posology can be made for patients below 10 kg body weight.

Ravulizumab has not been studied in paediatric patients with PNH who weigh less than 30 kg.
The posology of ravulizumab for paediatric patients less than 30 kg is based on the posology used for paediatric patients with aHUS, on the basis of the pharmacokinetic/pharmacodynamic (PK/PD) data available in aHUS and PNH patients treated with ravulizumab.

Ravulizumab has not been studied in paediatric patients with gMG or NMOSD.

Method of administration
For intravenous infusion only.
This medicinal product must be administered through a 0.2 µm filter and should not be administered as an intravenous push or bolus injection.

Ultomiris 300 mg/30 mL concentrate for solution for infusion must not be mixed with Ultomiris 300 mg/3 mL or 1,100 mg/11 mL concentrates for solution for infusion.

Ultomiris 300 mg/3 mL and 1,100 mg/11 mL concentrates for solution for infusion 
Ultomiris concentrate for solution for infusion is presented as 3 mL and 11 mL vials (100 mg/mL) and must be diluted to a final concentration of 50 mg/mL. Following dilution, Ultomiris is to be administered by intravenous infusion using a syringe-type pump or an infusion pump over a minimal period of 0.17 to 1.3 hours (10 to 75 minutes) depending on body weight (see Table 4 and Table 5 below).


Table 4:   Dose administration rate for Ultomiris 300 mg/3 mL and 1,100 mg/11 mL concentrates for solution for infusion
Body weight       Loading dose      Minimum            Maintenance      Minimum infusion range (kg)a       (mg)              infusion duration dose (mg)         duration minutes (hours)                     minutes (hours) b
≥ 10 to < 20      600               45 (0.8)           600              45 (0.8) ≥ 20 to < 30b     900               35 (0.6)           2,100            75 (1.3) b
≥ 30 to < 40      1,200             31 (0.5)           2,700            65 (1.1) ≥ 40 to < 60      2,400             45 (0.8)           3,000            55 (0.9) ≥ 60 to < 100     2,700             35 (0.6)           3,300            40 (0.7) ≥ 100             3,000             25 (0.4)           3,600            30 (0.5) a
Body weight at time of treatment.
b
For PNH and aHUS indications only.

Table 5:     Dose administration rate for supplemental doses of Ultomiris 300 mg/3 mL and 1,100 mg/11 mL concentrates for solution for infusion
Minimum infusion duration
Body weight range (kg)a         Supplemental dose b (mg) minutes (hours)
≥ 40 to < 60                    600                             15 (0.25) 1,200                           25 (0.42)
1,500                           30 (0.5)
≥ 60 to < 100                   600                             12 (0.20) 1,500                           22 (0.36)
1,800                           25 (0.42)
≥ 100                           600                             10 (0.17) 1,500                           15 (0.25)
1,800                           17 (0.28) a
Body weight at time of treatment.
b
Refer to Table 2 for selection of ravulizumab supplemental dose

Ultomiris 300 mg/30 mL concentrate for solution for infusion

Ultomiris concentrate for solution for infusion is presented as 30 mL vial (10 mg/mL) and must be diluted to a final concentration of 5 mg/mL. Following dilution, Ultomiris is to be administered by intravenous infusion using a syringe-type pump or an infusion pump over a minimal period of 0.4 to 3.3 hours (22 to 194 minutes) depending on body weight (see Table 6 and Table 7 below).

Table 6: Dose administration rate for Ultomiris 300 mg/30 mL concentrate for solution for infusion
Body weight       Loading dose   Minimum            Maintenance      Minimum infusion range (kg)a       (mg)           infusion duration dose (mg)         duration minutes (hours)                     minutes (hours)
≥ 10 to < 20b     600            113 (1.9)          600              113 (1.9) b
≥ 20 to < 30      900            86 (1.5)           2,100            194 (3.3) ≥ 30 to < 40b     1,200          77 (1.3)           2,700            167 (2.8) ≥ 40 to < 60      2,400          114 (1.9)          3,000            140 (2.3) ≥ 60 to < 100     2,700          102 (1.7)          3,300            120 (2.0) ≥ 100             3,000          108 (1.8)          3,600            132 (2.2) a
Body weight at time of treatment.
b
For PNH and aHUS indications only

Table 7:     Dose administration rate for supplemental doses of Ultomiris 300 mg/30 mL concentrate for solution for infusion
Minimum infusion duration
Body weight range (kg)a          Supplemental dose b (mg) minutes (hours)
≥ 40 to < 60                     600                               30 (0.5) 1,200                             60 (1.0)
1,500                             72 (1.2)
≥ 60 to < 100                    600                               23 (0.4) 1,500                             60 (1.0)
1,800                             65 (1.1)
≥ 100                            600                               22 (0.4) 1,500                             60 (1.0)
1,800                             65 (1.1) a
Body weight at time of treatment.
b
Refer to Table 2 for selection of ravulizumab supplemental dose

For instructions on dilution of the medicinal product before administration, see section 6.6.