This information is intended for use by health professionals

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Ultomiris 300 mg concentrate for solution for infusion

2. Qualitative and quantitative composition

One vial of 30 mL contains 300 mg of ravulizumab, produced in Chinese hamster ovary (CHO) cell culture by recombinant DNA technology.

After dilution, the final concentration of the solution to be infused is 5 mg/mL.

Excipient(s) with known effect:

Sodium (5 mmol per vial)

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Concentrate for solution for infusion (sterile concentrate).

Clear to translucent, slight whitish colour, pH 7.0 solution.

4. Clinical particulars
4.1 Therapeutic indications

Ultomiris is indicated in the treatment of adult patients with paroxysmal nocturnal haemoglobinuria (PNH):

- in patients with haemolysis with clinical symptom(s) indicative of high disease activity

- in patients who are clinically stable after having been treated with eculizumab for at least the past 6 months (see section 5.1).

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 disorders.

Posology

Adult patients with PNH

The recommended dosing regimen for adult patients (≥ 18 years of age) with PNH 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. 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 infusion, and then 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

Body weight range (kg)

Loading dose (mg)

Maintenance dose (mg)

≥ 40 to < 60

2,400

3,000

≥ 60 to < 100

2,700

3,300

≥ 100

3,000

3,600

Ravulizumab has not been studied in patients with PNH who weigh less than 40 kg.

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).

Special populations

Elderly population (> 65 years old)

No dose adjustment is required for patients with PNH 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 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

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

Method of administration

For intravenous infusion only.

Ultomiris must be diluted to a final concentration of 5 mg/mL.

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 must be diluted prior to administration by intravenous infusion over a minimal period of 1.7 to 2.4 hours depending of body weight, see Table 2 below.

Table 2: Dose administration rate

Body weight range (kg)a

Loading dose (mg)

Minimum infusion duration

minutes (hours)

Maintenance dose (mg)

Minimum infusion duration

minutes (hours)

≥ 40 to < 60

2,400

114 (1.9)

3,000

140 (2.4)

≥ 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.

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

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Patients with unresolved Neisseria meningitidis infection at treatment initiation (see section 4.4).

- Patients who are not currently vaccinated against Neisseria meningitidis unless they receive prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination (see section 4.4).

4.4 Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Serious meningococcal infection

Due to its mechanism of action, the use of ravulizumab increases the patient's susceptibility to meningococcal infection/sepsis (Neisseria meningitidis). Meningococcal disease due to any serogroup may occur. To reduce this risk of infection, all patients must be vaccinated against meningococcal infections at least two weeks prior to initiating ravulizumab unless the risk of delaying ravulizumab therapy outweighs the risk of developing a meningococcal infection. Patients who initiate ravulizumab treatment less than 2 weeks after receiving a meningococcal vaccine, must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. Vaccines against serogroups A, C, Y, W135 and B where available, are recommended in preventing the commonly pathogenic meningococcal serogroups. Patients must be vaccinated or revaccinated according to current national guidelines for vaccination use. If the patient is being switched from eculizumab treatment, physicians should verify that meningococcal vaccination is current according to national guidelines for vaccination use.

Vaccination may not be sufficient to prevent meningococcal infection. Consideration should be given to official guidance on the appropriate use of antibacterial agents. Cases of serious meningococcal infections/sepsis have been reported in patients treated with ravulizumab. Cases of serious or fatal meningococcal infections/sepsis have been reported in patients treated with other terminal complement inhibitors. All patients should be monitored for early signs of meningococcal infection and sepsis, evaluated immediately if infection is suspected, and treated with appropriate antibiotics. Patients should be informed of these signs and symptoms and steps should be taken to seek medical care immediately. Physicians should provide patients with a patient information brochure and a patient safety card.

Immunization

Vaccination may further activate complement. As a result, patients with complement-mediated diseases, including PNH, may experience increased signs and symptoms of their underlying disease, such as haemolysis. Therefore, patients should be closely monitored for disease symptoms after recommended vaccination.

Other systemic infections

Ravulizumab therapy should be administered with caution to patients with active systemic infections. Ravulizumab blocks terminal complement activation; therefore patients may have increased susceptibility to infections caused by Neisseria species and encapsulated bacteria. Serious infections with Neisseria species (other than Neisseria meningitidis), including disseminated gonococcal infections, have been reported in patients treated with other terminal complement inhibitors.

Patients should be provided with information from the Package Leaflet to increase their awareness of potential serious infections and their signs and symptoms. Physicians should advise patients about gonorrhoea prevention.

Infusion reactions

Administration of ravulizumab may result in infusion reactions. In clinical trials, some patients with PNH experienced infusion reactions which were mild in severity and transient (e.g., lower back pain and drop in blood pressure). In case of infusion reaction, infusion of ravulizumab should be interrupted and appropriate supportive measures should be instituted if signs of cardiovascular instability or respiratory compromise occur.

Treatment discontinuation

If patients with PNH discontinue treatment with ravulizumab, they should be closely monitored for signs and symptoms of serious intravascular haemolysis, identified by elevated LDH (lactate dehydrogenase) levels along with sudden decrease in PNH clone size or haemoglobin, or re-appearance of symptoms such as fatigue, haemoglobinuria, abdominal pain, shortness of breath (dyspnoea), major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction. Any patient who discontinues ravulizumab should be monitored for at least 16 weeks to detect haemolysis and other reactions. If signs and symptoms of haemolysis occur after discontinuation, including elevated LDH, consider restarting treatment with ravulizumab.

Sodium content

This medicinal product when diluted with sodium chloride 9 mg/mL (0.9 %) solution for injection contains 2.65 g sodium per 720 mL at the maximal dose, equivalent to 133 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Chronic intravenous human immunoglobulin (IVIg) treatment may interfere with the endosomal neonatal Fc receptor (FcRn) recycling mechanism of monoclonal antibodies such as ravulizumab and thereby decrease serum ravulizumab concentrations.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should use effective contraception methods during treatment and up to 8 months after treatment.

Pregnancy

There are no clinical data from the use of ravulizumab in pregnant women.

Nonclinical reproductive toxicology studies were not conducted with ravulizumab (see section 5.3).

Reproductive toxicology studies were conducted in mice using the murine surrogate molecule BB5.1, which assessed effect of C5 blockade on the reproductive system. No specific test-article related reproductive toxicities were identified in these studies. Human IgG are known to cross the human placental barrier, and thus ravulizumab may potentially cause terminal complement inhibition in the foetal circulation.

Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

In pregnant women the use of ravulizumab may be considered following an assessment of the risks and benefits.

Breast-feeding

It is unknown whether ravulizumab is excreted into human milk. Nonclinical reproductive toxicology studies conducted in mice with the murine surrogate molecule BB5.1 identified no adverse effect to pups resulting from consuming milk from treated dams.

A risk to infants cannot be excluded.

Since many medicinal products and immunoglobulins are secreted into human milk, and because of the potential for serious adverse reactions in nursing infants, breast-feeding should be discontinued during treatment with ravulizumab and up to 8 months after treatment.

Fertility

No specific non-clinical study on fertility has been conducted with ravulizumab.

Nonclinical reproductive toxicology studies conducted in mice with a murine surrogate molecule (BB5.1) identified no adverse effect on fertility of the treated females or males.

4.7 Effects on ability to drive and use machines

Ultomiris has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The most common adverse drug reactions are upper respiratory tract infection (very common), nasopharyngitis (very common) and headache (very common). The most serious adverse reactions in patients in clinical trials are meningococcal infection and meningococcal sepsis (see section 4.4).

Tabulated list of adverse reactions

Table 3 gives the adverse reactions observed from clinical trials.

Adverse reactions are listed by MedDRA system organ class (SOC) and frequency, using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (cannot be estimated from available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3: Adverse reactions

MedDRA System Organ Class

Very common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Infections and infestations

Upper respiratory tract infection, Nasopharyngitis

Meningococcal infection*

Nervous system disorders

Headache

Dizziness

Gastrointestinal disorders

Vomiting, Nausea, Diarrhoea, Abdominal pain, Dyspepsia

Skin and subcutaneous tissue disorders

Rash, Pruritus

Musculoskeletal and connective tissue disorders

Back pain, Arthralgia, Myalgia, Muscle spasms

General disorders and administration site conditions

Pyrexia, Influenza like illness, Fatigue, Chills, Asthenia

*Meningococcal infection includes preferred terms of meningococcal infection and meningococcal sepsis

Description of selected adverse reactions

Meningococcal infection/sepsis

Vaccination reduces, but does not eliminate, the risk of meningococcal infections. In clinical trials, 3 out of 261 PNH patients developed serious meningococcal infections/sepsis while receiving treatment with ravulizumab; all 3 had been vaccinated. All 3 recovered while continuing treatment with ravulizumab. Please refer to section 4.4 for information on prevention and treatment of suspected meningococcal infection. Meningococcal infections in patients treated with ravulizumab presented as meningococcal sepsis. Patients should be informed of the signs and symptoms of meningococcal septicaemia and advised to seek medical care immediately.

Immunogenicity

Treatment with any therapeutic protein may induce an immune response. In PNH patient studies (N = 261), only 1 (0.38 %) case with development of treatment-emergent anti-drug antibody has been reported with ravulizumab. This anti-drug antibody was transient in nature with low titre and did not correlate with clinical response or adverse events.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system detailed below;

United Kingdom: Yellow card system, via https://yellowcard.mhra.gov.uk/

Ireland: HPRA Pharmacovigilance, Website: www.hpra.ie; E-mail: [email protected]

Adverse events should also be reported to Alexion Pharma UK Ltd on [email protected], Freephone (UK): 0800 321 3902, Freephone (Ireland): 1 800 936 544.

4.9 Overdose

No case of overdose has been reported to date.

Patients who experience overdose should have immediate interruption of their infusion and be closely monitored.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code: L04AA43

Mechanism of action

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

Pharmacodynamic effects

Following ravulizumab treatment in both complement-inhibitor naïve patients and eculizumab-experienced patients with PNH in Phase 3 studies, immediate and complete inhibition of serum free C5 (concentration of < 0.5 µg/mL) was observed by the end of the first infusion and sustained throughout the entire 26-week treatment period in all patients.

Free C5 levels less than 0.5 µg/mL were correlated with maximal intravascular haemolysis control and complete terminal complement inhibition.

Clinical efficacy and safety

The safety and efficacy of ravulizumab in patients with PNH were assessed in two open-label, randomised, active-controlled Phase 3 trials:

- a complement-inhibitor naïve study in adult patients with PNH who were naïve to complement inhibitor treatment,

- an eculizumab -experienced study in patients with PNH who were clinically stable after having been treated with eculizumab for at least the previous 6 months.

Ravulizumab was dosed in accordance with the recommended dosing described in section 4.2 (4 infusions of ravulizumab over 26 weeks) while eculizumab was administered according to the approved dosing regimen of eculizumab of 600 mg every week for the first 4 weeks and 900 mg every 2 weeks (15 infusions over 26 weeks).

Patients were vaccinated against meningococcal infection prior to or at the time of initiating treatment with ravulizumab or eculizumab, or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination.

There were no noteworthy differences in the demographic or baseline characteristics between the ravulizumab and eculizumab treatment groups in either of the Phase 3 studies. The 12-month transfusion history was similar between ravulizumab and eculizumab treatment groups within each of the Phase 3 studies.

Study in complement-inhibitor naïve patients with PNH

The complement-inhibitor naïve study was a 26-week, multicentre, open-label, randomised, active-controlled, Phase 3 study conducted in 246 patients who were naïve to complement inhibitor treatment prior to study entry. Eligible patients to enter this trial had to demonstrate high disease activity, defined as LDH level ≥ 1.5 × upper limit of normal (ULN) at screening along with the presence of 1 or more of the following PNH-related signs or symptoms within 3 months of screening: fatigue, haemoglobinuria, abdominal pain, shortness of breath (dyspnoea), anaemia (haemoglobin < 10 g/dL), history of a major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction; or history of packed red blood cell (pRBC) transfusion due to PNH.

More than 80 % of patients in both treatment groups had a history of transfusion within 12 months of study entry. The majority of the complement-inhibitor naïve study population was highly haemolytic at baseline; 86.2 % of enrolled patients presented with elevated LDH ≥ 3 × ULN, which is a direct measurement of intravascular haemolysis, in the setting of PNH.

Table 4 presents the baseline characteristics of the PNH patients enrolled in the complement-inhibitor naïve study, with no apparent clinically meaningful differences observed between the treatment arms.

Table 4: Baseline characteristics in the complement-inhibitor naïve study

Parameter

Statistics

Ravulizumab

(N = 125)

Eculizumab

(N = 121)

Age (years) at PNH diagnosis

Mean (SD)

Median

Min, max

37.9 (14.90)

34.0

15, 81

39.6 (16.65)

36.5

13, 82

Age (years) at first infusion in study

Mean (SD)

Median

Min, max

44.8 (15.16)

43.0

18, 83

46.2 (16.24)

45.0

18, 86

Sex (n, %)

Male

Female

65 (52.0)

60 (48.0)

69 (57.0)

52 (43.0)

Pre-treatment LDH levels

Mean (SD)

Median

1633.5 (778.75)

1513.5

1578.3 (727.06)

1445.0

Number of patients with packed red blood cell (pRBC) transfusions within 12 months prior to first dose

n (%)

103 (82.4)

100 (82.6)

Units of pRBC transfused within 12 months prior to first dose

Total

Mean (SD)

Median

925

9.0 (7.74)

6.0

861

8.6 (7.90)

6.0

Total PNH RBC clone size

Median

33.6

34.2

Total PNH granulocyte clone size

Median

93.8

92.4

Patients with any PNH conditionsa prior to informed consent

n (%)

121 (96.8)

120 (99.2)

Anaemia

103 (82.4)

105 (86.8)

Haematuria or haemoglobinuria

81 (64.8)

75 (62.0)

Aplastic anaemia

41 (32.8)

38 (31.4)

Renal failure

19 (15.2)

11 (9.1)

Myelodysplastic syndrome

7 (5.6)

6 (5.0)

Pregnancy complication

3 (2.4)

4 (3.3)

Otherb

27 (21.6)

13 (10.7)

a Based on medical history.

b “Other” as specified on case report form included thrombocytopenia, chronic kidney disease, and pancytopenia, as well as a number of other conditions.

The coprimary endpoints were transfusion avoidance, and haemolysis as directly measured by normalisation of LDH levels (LDH levels ≤ 1 × ULN; the ULN for LDH is 246 U/L). Key secondary endpoints included the percent change from baseline in LDH levels, change in quality of life (FACIT-Fatigue), the proportion of patients with breakthrough haemolysis and proportion of patients with stabilized haemoglobin.

Ravulizumab was non-inferior compared to eculizumab for both coprimary endpoints, avoidance of pRBC transfusion per protocol-specified guidelines and LDH normalisation from day 29 to day 183, and for all 4 key secondary endpoints (Figure 1).

Figure 1: Analysis of coprimary and secondary endpoints – Full analysis set (complement-inhibitor naïve study)

Note: The black triangle indicates the non-inferiority margins, and grey dots indicates point estimates

Note: LDH = lactate dehydrogenase, CI = Confidence Interval.

Study in PNH patients previously treated with eculizumab

The eculizumab-experienced study was a 26-week, multicentre, open-label, randomised, active-controlled Phase 3 study conducted in 195 patients with PNH who were clinically stable (LDH ≤ 1.5 x ULN) after having been treated with eculizumab for at least the past 6 months.

PNH medical history was similar between ravulizumab and eculizumab treatment groups. The 12-month transfusion history was similar between ravulizumab and eculizumab treatment groups and more than 87 % of patients in both treatment groups had not received a transfusion within 12 months of study entry. The mean total PNH RBC clone size was 60.05 %, mean total PNH granulocyte clone size was 83.30 %, and the mean total PNH monocyte clone size was 85.86 %.

Table 5 presents the baseline characteristics of the PNH patients enrolled in the eculizumab-experienced study, with no apparent clinically meaningful differences observed between the treatment arms.

Table 5: Baseline characteristics in the eculizumab-experienced study

Parameter

Statistics

Ravulizumab

(N = 97)

Eculizumab

(N = 98)

Age (years) at PNH diagnosis

Mean (SD)

Median

Min, max

34.1 (14.41)

32.0

6, 73

36.8 (14.14)

35.0

11, 74

Age (years) at first infusion in study

Mean (SD)

Median

Min, max

46.6 (14.41)

45.0

18, 79

48.8 (13.97)

49.0

23, 77

Sex (n, %)

Male

Female

50 (51.5)

47 (48.5)

48 (49.0)

50 (51.0)

Pre-treatment LDH levels

Mean (SD)

Median

228.0 (48.71)

224.0

235.2 (49.71)

234.0

Number of patients with pRBC/whole blood transfusions within 12 months prior to first dose

n (%)

13 (13.4)

12 (12.2)

Units of pRBC/whole blood transfused within 12 months prior to first dose

Total

Mean (SD)

Median

103

7.9 (8.78)

4.0

50

4.2 (3.83)

2.5

Patients with any PNH conditionsa prior to informed consent

n (%)

90 (92.8)

96 (98.0)

Anaemia

64 (66.0)

67 (68.4)

Haematuria or haemoglobinuria

47 (48.5)

48 (49.0)

Aplastic anaemia

34 (35.1)

39 (39.8)

Renal failure

11 (11.3)

7 (7.1)

Myelodysplastic syndrome

3 (3.1)

6 (6.1)

Pregnancy complication

4 (4.1)

9 (9.2)

Othera

14 (14.4)

14 (14.3)

a Based on medical history.

b “Other” category included neutropenia, renal dysfunction, and thrombopenia, as well as a number of other conditions.

The primary endpoint was haemolysis as measured by LDH percent change from baseline. Secondary endpoints included the proportion of patients with breakthrough haemolysis, quality-of-life (FACIT-Fatigue), transfusion avoidance (TA), and proportion of patients with stabilised haemoglobin.

Ravulizumab was non-inferior compared to eculizumab for the primary endpoint, percent change in LDH from baseline to day 183, and for all 4 key secondary endpoints (Figure 2).

Figure 2: Analysis of primary and secondary endpoints – full analysis set (eculizumab-experienced study)

Note: The black triangle indicates the non-inferiority margins, and grey dot indicates point estimates.

Note: LDH = lactate dehydrogenase; CI = Confidence Interval.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Ultomiris in one or more subsets of the paediatric population in paroxysmal nocturnal haemoglobinuria (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Because the route of ravulizumab administration is an intravenous infusion and the dosage form is a solution, 100 % of the administered dose is considered bioavailable. The time to maximum observed concentration (tmax) is expected at the end of infusion (EOI) or soon after EOI. Therapeutic steady-state drug concentrations are reached after the first dose.

Distribution

The mean (standard deviation [SD]) volume of distribution at steady state for patients with PNH on the studied weight-based dose regimen was 5.34 (0.92) L.

Biotransformation and elimination

As an immunoglobulin gamma (IgG) monoclonal antibody, ravulizumab is expected to be metabolized in the same manner as any endogenous IgG (degraded into small peptides and amino acids via catabolic pathways), and is subject to similar elimination. Ravulizumab contains only natural occurring amino acids and has no known active metabolites. The mean (SD) values for terminal elimination half-life and clearance of ravulizumab in patients with PNH are 49.7 (8.9) days and 0.003 (0.001) L/h, respectively.

Linearity/non-linearity

Over the studied dose and regimen range, ravulizumab exhibited dose proportional and time linear pharmacokinetics (PK).

Special populations

Weight

When given the same dose, heavier patients with PNH had lower median serum ravulizumab concentrations compared with lighter patients. Weight-based dosing is proposed in section 4.2, Table 1.

No formal trial of the effect of sex, race, age (geriatric), hepatic or renal impairment on the pharmacokinetics of ravulizumab was conducted. However, based on population-PK assessment no impact of sex, age, race and hepatic or renal function on ravulizumab PK was identified in the studied healthy volunteers subjects and patients with PNH, and as a result, no dosing adjustment is considered necessary.

5.3 Preclinical safety data

Animal reproductive toxicology studies have not been conducted with ravulizumab, but were conducted in mice with a murine surrogate complement inhibitory antibody, BB5.1. No clear treatment-related effects or adverse effects were observed in the murine surrogate reproductive toxicology studies in mice. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose (approximately 4 times the maximum recommended human ravulizumab dose, based on a body weight comparison); however, the exposure did not increase foetal loss or neonatal death.

No animal studies have been conducted to evaluate the genotoxic and carcinogenic potential of ravulizumab.

Non-clinical data reveal no special hazard for humans based on nonclinical studies using a murine surrogate molecule, BB5.1, in mice.

6. Pharmaceutical particulars
6.1 List of excipients

Sodium dihydrogen phosphate dihydrate

Disodium phosphate dihydrate

Sodium chloride

Polysorbate 80

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Dilution should only use sodium chloride 9 mg/mL (0.9 %) solution for injection as diluent.

6.3 Shelf life

2 years.

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

6.4 Special precautions for storage

Store in a refrigerator (2°C–8°C)

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

30 mL of sterile concentrate in a vial (Type I glass) with a stopper and a seal.

Pack size of one vial.

6.6 Special precautions for disposal and other handling

Each vial is intended for single use only.

Ultomiris requires dilution to a final concentration of 5 mg/mL.

Aseptic technique must be used.

Prepare Ultomiris as follows:

1. The number of vials to be diluted is determined based on the individual patient's weight and the prescribed dose, see section 4.2.

2. Prior to dilution, the solution in the vials should be visually inspected; the solution should be free of any particulate matter or precipitation. Do not use if there is evidence of particulate matter or precipitation.

3. The calculated volume of medicinal product is withdrawn from the appropriate number of vials and diluted in an infusion bag using sodium chloride 9 mg/mL (0.9 %) solution for injection as diluent. Refer to the administration reference tables below. The product should be mixed gently. It should not be shaken.

4. After dilution, the final concentration of the solution to be infused is 5 mg/mL.

5. The prepared solution should be administered immediately following preparation unless it is stored at 2-8°C. If stored at 2-8°C, allow the diluted solution to warm to room temperature prior to administration. Do not administer as an intravenous push or bolus injection. Refer to the administration reference tables below for minimum infusion duration. Infusion must be administered through a 0.2 µm filter.

6. If the medicinal product is not used immediately after dilution, storage times must not exceed 24 hours at 2°C - 8°C or 6 hours at room temperature taking into account the expected infusion time.

Table 6: Loading dose administration reference table

Body weight range (kg)a

Loading dose (mg)

Ultomiris volume (mL)

Volume of NaCl diluentb (mL)

Total volume (mL)

≥ 40 to < 60

2,400

240

240

480

≥ 60 to < 100

2,700

270

270

540

≥ 100

3,000

300

300

600

a Body weight at time of treatment.

b Ultomiris should only be diluted using sodium chloride 9 mg/mL (0.9 %) solution for injection.

Table 7: Maintenance dose administration reference table

Body weight range (kg)a

Maintenance dose (mg)

Ultomiris volume (mL)

Volume of NaCl diluentb (mL)

Total volume (mL)

≥ 40 to < 60

3,000

300

300

600

≥ 60 to < 100

3,300

330

330

660

≥ 100

3,600

360

360

720

a Body weight at time of treatment.

b Ultomiris should only be diluted using sodium chloride 9 mg/mL (0.9 %) solution for injection.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Alexion Europe SAS

103-105 rue Anatole France

92300 Levallois-Perret

FRANCE

8. Marketing authorisation number(s)

EU/1/19/1371/001

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 02 July 2019

10. Date of revision of the text

02 July 2019

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.