Ultomiris

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 
 
 
 
 
 
 
 
 
 



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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). 
 
Ultomiris is indicated in the treatment of patients with a body weight of 10 kg or above with atypical 
haemolytic uremic syndrome (aHUS) who are complement inhibitor treatment-naïve or have received 
eculizumab for at least 3 months and have evidence of response to eculizumab (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 or renal disorders. 
 
Posology 
 
Adult patients with PNH and aHUS 
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). 
 



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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)* 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 

*Maintenance dose is administered 2 weeks after loading dose 
Ravulizumab has not been studied in patients with PNH who weigh less than 40 kg. 
 
There is no experience of concomitant PE/PI (plasmapheresis or plasma exchange, or fresh frozen 
plasma infusion) use with ravulizumab. Administration of PE/PI may reduce ravulizumab serum 
levels.  
 
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 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). 
 
Special populations 
 
Elderly population (> 65 years old) 
No dose adjustment is required for patients with PNH and aHUS 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 
In aHUS clinical trials, patients with renal impairment including on dialysis were included. No dose 
adjustment is required in this population, 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 aHUS with body weight ≥ 40 kg are treated in accordance with the adult 
dosing recommendations. The weight-based doses and dosing intervals for paediatric patients ≥ 10 kg 
to < 40 kg is shown in Table 2.  
 
Table 2:  Ravulizumab weight-based dosing regimen for paediatric patient below 40 kg 

Body weight range (kg) Loading dose (mg) Maintenance dose (mg)* Dosing 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 

*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.  
 



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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 3 below.  
 
Table 3: Dose administration rate 

Body weight 
range (kg)a 

Loading dose 
(mg) 

Minimum 
infusion duration 
minutes (hours) 

Maintenance 
dose (mg) 

Minimum infusion 
duration 

minutes (hours) 
≥ 10 to < 20 600 113 (1.9) 600 113 (1.9) 
≥ 20 to < 30 900 86 (1.5) 2,100 194 (3.3) 
≥ 30 to < 40 1,200 77 (1.3) 2,700 167 (2.8) 
≥ 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 



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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 
 
Prior to initiating ravulizumab therapy, it is recommended that PNH and aHUS patients initiate 
immunizations according to current immunization guidelines.  
 
Vaccination may further activate complement. As a result, patients with complement-mediated 
diseases, including PNH and aHUS, 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.  
 
Patients below the age of 18 years old must be vaccinated against Haemophilus influenzae and 
pneumococcal infections, and strictly need to adhere to the national vaccination recommendations for 
each age group.  
 
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. 
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 with PNH and aHUS, 
[(4 out of 296 in patients with PNH) and (4 of 89 patients with aHUS)] patients experienced infusion 
reactions which were mild in severity and transient [e.g., lower back pain, drop in blood pressure, 
elevation in blood pressure, limb discomfort,  drug hypersensitivity (allergic reaction), and dysgeusia 
(bad taste)]. 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 for PNH 
 
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. 



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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.  
 
Treatment discontinuation for aHUS 
 
There are no specific data on ravulizumab discontinuation. In a long-term prospective observational 
study, discontinuation of complement C5 inhibitor treatment (eculizumab) resulted in a 13.5-fold 
higher rate of TMA recurrence and showed a trend toward reduced renal function compared to patients 
who continued treatment.  
If patients must discontinue treatment with ravulizumab, they should be monitored closely for signs 
and symptoms of TMA on an on-going basis. However, monitoring may be insufficient to predict or 
prevent severe TMA complications.   
TMA complications post-discontinuation can be identified if any of the following is observed: 
(i) At least two of the following laboratory results observed concurrently: a decrease in platelet 
count of 25% or more as compared to either baseline or to peak platelet count during ravulizumab 
treatment; an increase in serum creatinine of 25% or more as compared to baseline or to nadir during 
ravulizumab treatment; or, an increase in serum LDH of 25% or more as compared to baseline or to 
nadir during ravulizumab treatment (results should be confirmed by a second measurement ) 
Or 
(ii) any one of the following symptoms of TMA: a change in mental status or seizures or other 
extra-renal TMA manifestations including cardiovascular abnormalities, pericarditis, gastrointestinal 
symptoms/diarrhoea; or thrombosis. 
If TMA complications occur after ravulizumab discontinuation, consider reinitiation of ravulizumab 
treatment beginning with the loading dose and maintenance dose described in section 4.2. 
  
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). 



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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 (very common frequency) are diarrhoea, nausea, vomiting, 
nasopharyngitis and headache. 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 4 gives the adverse reactions observed from PNH and aHUS 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 4:  Adverse reactions  

MedDRA System 
Organ Class 

Very common 
(≥ 1/10) 

Common 
(≥ 1/100 to < 1/10) 

Uncommon (≥ 
1/1,000 to < 1/100) 

Infections and 
infestations 

Upper respiratory tract 
infection, Nasopharyngitis 

 Meningococcal 
infection* 

Nervous system 
disorders 

Headache Dizziness  

Gastrointestinal 
disorders 

Diarrhoea, Nausea,  Abdominal pain, 
Vomiting, Dyspepsia 

 

Skin and 
subcutaneous tissue 

disorders 

 Rash, Pruritus  



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Musculoskeletal and 
connective tissue 

disorders 

 Arthralgia, Back pain, 
Myalgia, Muscle 

spasms 

 

General disorders and 
administration site 

conditions 

Pyrexia, Fatigue Influenza like illness, 
Asthenia 

Chills 

* 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. In aHUS studies, no meningococcal infections occurred among 89 patients 
receiving 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) and aHUS studies (N=89), only 2 (0.57 %) cases of development of treatment-emergent 
anti-drug antibody have been reported with ravulizumab. These anti-drug antibodies were transient in 
nature with low titre and did not correlate with clinical response or adverse events. 
 
Paediatric population 
In paediatric patients with evidence of aHUS (aged 10 months to less than 18 years) included in 
ALXN1210-aHUS-312 study, the safety profile of ravulizumab appeared similar to that observed in 
adult patients with evidence of aHUS. The safety profiles in the different paediatric subsets of age 
appear similar. The safety data for patient below 2 years of age is limited to four patients. The most 
common adverse reaction reported in paediatric patients was pyrexia.   
 
The safety of ravulizumab in children with PNH aged 0 to < 18 years have not been established. No 
data are available.  
 
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 
listed in Appendix V.  
 
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 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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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. Immediate and complete 
inhibition of serum free C5 was also observed in adult and paediatric patients with aHUS by the end of 
the first infusion and throughout the 26-week treatment period. 
The extent and duration of the pharmacodynamic response in patients with PNH and aHUS were 
exposure dependent for ravulizumab. 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 
Paroxysmal Nocturnal Haemoglobinuria 
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.  



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Table 5 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 5:  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) 1633.5 (778.75) 1578.3 (727.06) 
Median 1513.5 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 925 861 
Mean (SD) 9.0 (7.74) 8.6 (7.90) 
Median 6.0 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).  
 



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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; FACIT = Functional Assessment of Chronic 
Illness Therapy. 
 
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 6 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. 
 



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Table 6:  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) 228.0 (48.71) 235.2 (49.71) 
Median 224.0 234.0 

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 103 50 
Mean (SD) 7.9 (8.78) 4.2 (3.83) 
Median 4.0 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. 



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Note: LDH = lactate dehydrogenase; CI = confidence interval. 
 
Atypical Haemolytic Uremic Syndrome (aHUS) 
 
Study in adult patients with aHUS 
 
The adult study was a multicentre, single arm, Phase 3 study conducted in patients with documented 
aHUS who were naïve to complement inhibitor treatment prior to study entry and had evidence of 
thrombotic microangiopathy (TMA). The study consisted of a 26-week Initial Evaluation Period and 
patients were allowed to enter an extension period for up to 4.5 years.  
A total of 58 patients with documented aHUS were enrolled. Enrolment criteria excluded patients 
presenting with TMA due to thrombotic thrombocytopenic purpura (TTP) or Shiga toxin Escherichia 
coli related haemolytic uremic syndrome (STEC HUS). Two patients were excluded from the Full 
Analysis Set due to a confirmed diagnosis of STEC HUS. Ninety-three percent of patients had extra 
renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) 
or symptoms of aHUS at baseline.  
 
Table 7 presents the demographics and baseline characteristics of the 56 adult patients enrolled in 
Study ALXN1210-aHUS-311 that constituted the Full Analysis Set.  
 
Table 7:  Baseline characteristics in the adult study 

Parameter Statistics 
Ravulizumab 

(N = 56) 
Age at time of first infusion (years) 
 

Mean (SD) 
Min, max 

42.2 (14.98) 
19.5, 76.6 

Sex  
  Male 

 
n (%) 

 
19 (33.9) 

Race a 
  Asian 
  White 
  Other 

n (%)  
15 (26.8) 
29 (51.8) 
12 (21.4) 

History of transplant n (%) 8 (14.3) 
Platelets (109/L) blood  
  

n 
Median (min,max) 

56 
95.25 (18, 473) 

Haemoglobin (g/L) blood  
  

n 
Median (min,max) 

56 
85.00 (60.5, 140) 

LDH (U/L) serum  
  

n 
Median (min,max) 

56 
508.00 (229.5, 3249) 

eGFR (mL/min/1.73 m2)  
  

n (%) 
Median (min,max) 

55 
10.00 (4, 80) 

Patients on dialysis N (%) 29 (51.8) 
Patients post-partum  N (%) 8 (14.3) 

Note: Percentages are based on the total number of patients. 
Abbreviations: aHUS = atypical haemolytic uremic syndrome; eGFR = estimated glomerular filtration rate; 
LDH = lactate dehydrogenase; max = maximum; min = minimum. 
 
The primary endpoint was Complete TMA Response during the 26-week Initial Evaluation Period, as 
evidenced by normalisation of haematological parameters (platelet count ≥ 150 x 109/L and LDH 
≤ 246U/L) and ≥ 25% improvement in serum creatinine from baseline. Patients had to meet each 
Complete TMA Response criteria at 2 separate assessments obtained at least 4 weeks (28 days) apart, 
and any measurement in between.  
 
Complete TMA Response was observed in 30 of the 56 patients (53.6%) during the 26-week Initial 
Evaluation Period as shown in Table 8. 
 



14 

Table 8:  Complete TMA Response and Complete TMA Response Components Analysis 
During the 26-Week Initial Evaluation Period (ALXN1210-aHUS-311) 

 Total Responder 
n Proportion (95% CI)a 

Complete TMA Response  56 30 0.536 (0.396, 0.675) 
Components of Complete TMA 
Response 

   

Platelet count normalisation 56 47 0.839 (0.734, 0.944) 
LDH normalisation 56 43 0.768 (0.648, 0.887) 
≥25% improvement in serum 
creatinine from baseline 

56 33 0.589 (0.452, 0.727) 

Haematologic normalisation 56 41 0.732 (0.607, 0.857) 
a 95% CIs for the proportion were based on the asymptotic Gaussian approximation method with a continuity 
correction. 
Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy. 
 
Four additional patients had a Complete TMA Response that was confirmed after the 26-week Initial 
Evaluation Period (with a Complete TMA Response occurring at Days 169, 302, 401 and 407). 
resulting in an overall Complete TMA Response in 34 of 56 patients (60.7%; 95% CI: 47.0%, 74.4%). 
Individual component response increased to 48 (85.7%; 95% CI: 75.7%, 95.8%) patients for platelet 
count normalization, 47 (83.9%; 95% CI: 73.4%, 94.4%) patients for LDH normalization, and 35 
(62.5%; 95% CI: 48.9%, 76.1%) patients for renal function improvement.  
 
Complete TMA Response was achieved at a median time of 86 days (7 to 169 days). An increase in 
mean platelet count was observed rapidly after commencement of ravulizumab, increasing from 
118.52 × 109/L at baseline to 240.34 × 109/L at Day 8 and remaining above 227 × 109/L at all 
subsequent visits in the Initial Evaluation Period (26 weeks). Similarly, mean LDH value decreased 
from baseline over the first 2 months of treatment and was sustained over the duration of the Initial 
Evaluation Period (26 weeks).  
 
Of the patients who presented at CKD Stage 5, 67.6% (23/34) showed an improvement of 1 or more 
CKD Stages. Chronic kidney disease stage continued to improve for many patients (19/30) after 
achieving Complete TMA Response during the 26-week Initial Evaluation Period. Seventeen of the 
29 patients who required dialysis at study entry were able to discontinue dialysis by the end of the 
available follow-up while 6 of 27 patients who were off dialysis at baseline were on dialysis at last 
available follow-up. Table 9 summarises the secondary efficacy outcomes for 
Study ALXN1210-aHUS-311.  
 
Table 9:  Secondary Efficacy Outcome for Study ALXN1210-aHUS-311 

Parameters Study ALXN1210-aHUS-311 
(N = 56) 

Haematologic TMA parameters, Day 183 
Platelets (109/L) blood 

Mean (SD) 
Median 

LDH (U/L) serum 
Mean (SD) 
Median 

Observed value (n=48) 
 

237.96 (73.528) 
232.00 

 
194.46 (58.099) 

176.50 

Change from baseline (n=48) 
 

114.79 (105.568) 
125.00 

 
-519.83 (572.467) 

-310.75 
Increase in haemoglobin of ≥ 20 g/L from 
baseline with a confirmatory result 
through Initial Evaluation Period 

m/n  
proportion (95% CI)** 

 
 
 

40/56 
0.714 (0.587, 0.842) 



15 

CKD stage shift from baseline, Day 183 
Improveda 

m/n 
Proportion (95% CI)* 

Worsenedb 
m/n 
Proportion (95% CI)* 

 
 

32/47 
0.681 (0.529, 0.809) 

 
2/13 

0.154 (0.019, 0.454) 
eGFR (mL/min/1.73 m2), Day 183  

Mean (SD) 
Median 

Observed value (n=48) 
51.83 (39.162) 

40.00 

Change from baseline (n=47) 
34.80 (35.454) 

29.00 
Note: n: number of patients with available data for specific assessment at Day 183 visit. m: number of patients 
meeting specific criterion. Chronic kidney disease (CKD) stage is classified based on the National Kidney 
Foundation Chronic Kidney Disease Stage. Stage 5 is considered the worst category, while Stage 1 is considered 
the best category. Baseline is derived based on the last available eGFR before starting treatment. 
Improved/Worsened: compared to CKD stage at baseline. *95% confidence intervals (95% CIs) are based on 
exact confidence limits using the Clopper-Pearson method  aExcludes those with CKD Stage 1 at baseline as 
they cannot improve .bExcludes patients with Stage 5 at baseline as they cannot worsen. 
Abbreviations: eGFR = estimated glomerular filtration rate; Therapy; LDH = lactate dehydrogenase; 
TMA = thrombotic microangiopathy.  
 
 
Paediatric population 
 
Paroxysmal Nocturnal Haemoglobinuria 
 
Ultomiris has not been evaluated in paediatric patients with PNH.  
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).  
 
Atypical Haemolytic Uremic Syndrome (aHUS) 
 
Use of Ultomiris in paediatric patients for treatment of aHUS is supported by evidence from one 
paediatric clinical study (a total of 31 patients with documented aHUS were enrolled. 28 patients aged 
10 months to 17 years were included in the Full Analysis set).  
 
Study in Paediatric Patients with aHUS 
 
The Paediatric Study is a 26-week ongoing, multicenter, single arm, Phase 3 study conducted in 
paediatric patients. 
A total of 21 eculizumab-naïve patients with documented diagnosis of aHUS and evidence of TMA 
were enrolled, of which 18 were included in the Full Analysis set. Enrolment criteria excluded patients 
presenting with TMA due to TTP and STEC-HUS. Two patients were given a single dose, and one 
patient received 2 doses, but then discontinued and were excluded from the Full Analysis Set because 
aHUS was not confirmed. The overall mean weight at baseline was 22.2 kg;majority of the patients were 
in the baseline weight category ≥ 10 to < 20 kg. The majority of patients (72.2%) had pretreatment extra 
renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) 
or symptoms of aHUS at baseline. At baseline, 33.3% (n = 6) of patients had CKD Stage 5.  
 
A total of 10 patients, who switched from eculizumab to ravulizumab, had documented diagnosis of 
aHUS and evidence of TMA were enrolled. Patients had to have clinical response to eculizumab prior 
to enrolment (i.e LDH <1.5 X ULN and platelet count ≥ 150,000/μL, and eGFR > 30 mL/min/1.73m2). 
Consequently, there is no information on the use of ravulizumab in patient refractory to eculizumab.  
 
Table 10 presents the baseline characteristics of the paediatric patients enrolled in Study ALXN1210-
aHUS-312.  
 



16 

Table 10:  Demographics and Baseline Characteristics in Study ALXN1210-aHUS-312 

Parameter Statistics 
Ravulizumab 

(Naïve, N = 18) 
Ravulizumab 

(Switch, N = 10) 
Age at time of first infusion (years) category 

Birth to < 2 years 
2 to < 6 years 
6 to < 12 years 
12 to < 18 years 

n (%)  
2 (11.1) 
9 (50.0) 
5 (27.8) 
2 (11.1) 

 
1 (10.0) 
1 (10.0) 
1 (10.0) 
7 (70.0) 

 
Sex  

Male 
n (%)  

8 (44.4) 
 

9 (90.0) 
Racea 

American Indian or Alaskan Native 
Asian 
Black or African American 
White 
Unknown 

n (%)  
1 (5.6) 

5 (27.8) 
3 (16.7) 
9 (50.0) 
1 (5.6) 

 
0 (0.0) 

4 (40.0) 
1 (10.0) 
5 (50.0) 
0 (0.0) 

History of transplant n (%) 1 (5.6) 1 (10.0) 
Platelets (109/L) blood Median (min, 

max) 
51.25 (14, 125) 281.75 (207, 

415.5) 
Haemoglobin (g/L)  Median (min, 

max) 
74.25 (32, 106) 132.0 (114.5, 148) 

LDH (U/L)  Median (min, 
max) 

1963.0 (772, 4985) 206.5 (138.5, 356) 

eGFR (mL/min/1.73 m2)  Median (min, 
max) 

22.0 (10, 84) 99.75 (54, 136.5) 

Required dialysis at baseline  n (%) 6 (33.3) 0 (0.0) 
Note: Percentages are based on the total number of patients. 
a Patients can have multiple races selected. 
Abbreviations: aHUS = atypical haemolytic uremic syndrome; eGFR = estimated glomerular filtration rate; 
LDH = lactate dehydrogenase; max = maximum; min = minimum. 
 
The primary endpoint was Complete TMA Response during the 26-week Initial Evaluation Period, as 
evidenced by normalisation of haematological parameters (platelet ≥ 150 x 109/L and LDH ≤246 U/L) 
and ≥ 25% improvement in serum creatinine from baseline. Patients had to meet all Complete TMA 
Response criteria at 2 separate assessments obtained at least 4 weeks (28 days) apart, and any 
measurement in between.  
 
Complete TMA Response was observed in 14 of the 18 naïve patients (77.8%) during the 26-week Initial 
Evaluation Period as shown in Table 11.  
 
Table 11:  Complete TMA Response and Complete TMA Response Components Analysis 

During the 26-Week Initial Evaluation Period (ALXN1210-aHUS-312) 
 Total Responder 

n Proportion (95% CI)a 
Complete TMA Response 18 14 0.778 (0.524, 0.936) 
Components of Complete TMA Response    
  Platelet count normalisation 18 17 0.944 (0.727, 0.999) 
  LDH normalisation 18 16 0.889 (0.653, 0.986) 
  ≥25% improvement in serum creatinine from baseline 18 15 0.833 (0.586, 0.964) 
Haematologic normalisation 18 16 0.889 (0.653, 0.986) 

Note: 1 patient withdrew from study after receiving 2 doses of ravulizumab. 
a 95% CIs for the proportion were based on the asymptotic Gaussian approximation method with a continuity 
correction. 
Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy. 
 
Complete TMA Response during the Initial Evaluation Period was achieved at a median time of 
30 days (15 to 97 days). All patients with Complete TMA Response maintained it through the Initial 
Evaluation Period with continuous improvements seen in renal function. An increase in mean platelet 
count was observed rapidly after commencement of ravulizumab, increasing from 60.50 × 109/L at 



17 

baseline to 296.67 × 109/L at Day 8 and remained above 296 × 109/L at all subsequent visits in the 
Initial Evaluation Period (26 weeks). 
 
Three additional patients had a Complete TMA Response that was confirmed after the 26-week Initial 
Evaluation Period (with a Complete TMA Response occurring at Days 291, 297 and 353); thus, 17 of 
18 (94.4%) paediatric patients (95% CI: 72.7%, 99.9%) had a Complete TMA Response .  Individual 
component response increased to 17 of 18 (94.4%; 95% CI: 72.7%, 99.9%) patients for platelet count 
normalization, 17 of 18 (94.4%; 95% CI: 72.7%, 99.9%) patients for LDH normalization, and 17 of 18 
(94.4%; 95% CI: 72.7%, 99.9%) patients for renal function improvement.  
 
All 6 of the patients who required dialysis at study entry were able to discontinue dialysis; 5 of which 
had already done so by Day 43. No patient started dialysis during the study. The majority of the 
patient population (15/17), improved by 1 or more CKD stages by Day 183; 14 patients improved by 2 
or more stages. Table 12 summarises the secondary efficacy results for Study ALXN1210-aHUS-312.  
 
 
Table 12:  Secondary Efficacy Outcome for Study ALXN1210-aHUS-312 

Parameters Study ALXN1210-aHUS-312 
(N=18) 

Haematologic TMA parameters, Day 183 
Platelets (109/L) blood 

Mean (SD) 
Median 

LDH (U/L) serum 
Mean (SD) 
Median 

Observed value (n=17) 
 

304.94 (75.711) 
318.00 

 
262.41 (59.995) 

247.00 

Change from baseline (n=17) 
 

245.59 (91.827) 
247.00 

 
-2044.13 (1328.059) 

-1851.50 
Increase in haemoglobin of ≥ 20 g/L from 
baseline with a confirmatory result 
through Initial Evaluation Period 

m/N  
proportion (95% CI)* 

 
 
 

16/18 
0.889 (0.653, 0.986) 

CKD stage shift from baseline, Day 183 
Improveda 

m/n 
Proportion (95% CI)* 

Worsenedb 
m/n 
Proportion (95% CI)* 

 
 

15/17 
0.882 (0.636, 0.985) 

 
0/11 

0.000 (0.000, 0.285) 
eGFR (mL/min/1.73 m2), Day 183  

Mean (SD) 
Median 

Observed value (n=17) 
108.5 (56.87) 

108.0 

Change from baseline  
(n=17) 

85.4 (54.33) 
80.0 

Note: n: number of patients with available data for specific assessment at Day 183 visit. m: number of patients 
meeting specific criterion. Chronic kidney disease (CKD) stage is classified based on the National Kidney 
Foundation Chronic Kidney Disease Stage. . Stage 1 is considered the best category ,while Stage 5 is considered 
the worst category. Baseline is derived based on the last available eGFR before starting treatment. 
Improved/Worsened: Compared to CKD stage at baseline.  
*95% confidence intervals (95% CIs) are based on exact confidence limits using the Clopper Pearson method.  
a Improved excludes patients with Stage 1 at baseline, as they cannot improve; bworsened excludes patients with 
Stage 5 at baseline as they cannot worsen. 
Abbreviations: eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; TMA = thrombotic 
microangiopathy. 
 
In eculizumab-experienced patients, switching to ravulizumab maintained disease control as evidenced 
by stable hematologic and renal parameters, with no apparent impact on safety. 
 
The efficacy of ravulizumab for the treatment of aHUS appears similar in paediatric and adult patients.  
 



18 

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 and 
aHUS on the studied weight-based dose regimen was 5.35 (0.92) L and 5.22 (1.85) L respectively.  
 
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 and aHUS are 49.7 (8.9) days 
and 0.08 (0.022) L/day and 51.8 (16.2) days and 0.08 (0.04) L/day, respectively.  
 
Linearity/non-linearity 
 
Over the studied dose and regimen range, ravulizumab exhibited dose proportional and time linear 
pharmacokinetics (PK).  
 
Special populations 
 
Weight 
Body weight is a significant covariate in patients with PNH and aHUS, resulting in lower exposures in 
heavier 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 or aHUS, and as a result, no dosing adjustment is 
considered necessary. 
 
The pharmacokinetics of ravulizumab have been studied in aHUS patients with a range of renal 
impairment including patients receiving dialysis. There have been no observed differences in 
pharmacokinetic parameters noted in these subpopulations of patients including patients with 
proteinuria.  
 
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. 
 



19 

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. 



20 

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 table 
13 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 13: Loading dose administration reference table 

Body weight 
range (kg)a 

Loading dose 
(mg) 

Ultomiris 
volume (mL) 

Volume of NaCl 
diluentb (mL) 

Total volume 
(mL) 

≥ 10 to < 20 600 60 60 120 
≥ 20 to < 30 900 90 90 180 
≥ 30 to < 40 1200 120 120 240 
≥ 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 14:  Maintenance dose administration reference table 

Body weight 
range (kg)a 

Maintenance 
dose (mg) 

Ultomiris volume 
(mL) 

Volume of NaCl 
diluentb (mL) 

Total volume 
(mL) 

≥ 10 to < 20 600 60 60 120 
≥ 20 to < 30 2100 210 210 420 
≥ 30 to < 40 2700 270 270 540 
≥ 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 



21 

 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 02 July 2019 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/.  
 
  

http://www.ema.europa.eu/


22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 

 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE  

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 



23 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
 MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

Name and address of the manufacturer(s) of the biological active substance(s)  

 
FUJIFILM Diosynth Biotechnologies U.S.A., Inc. 
6051 George Watts Hill Drive 
Research Triangle Park, North Carolina 27709 
UNITED STATES 

 
Patheon Biologics LLC 
4766 La Guardia Drive 
St. Louis, Missouri 63134 
UNITED STATES 

 
Lonza Biologics Porriño, S.L. 
C/ La Relba, s/n. 
Porriño  
Pontevedra 36400 
SPAIN 
 
 

Name and address of the manufacturer(s) responsible for batch release 

 
Alexion Pharma International Operations Unlimited Company 
Alexion Dublin Manufacturing Facility (ADMF)  
College Business and Technology Park 
Blanchardstown Road North 
Dublin 15 
IRELAND 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION  

• Periodic Safety Update Reports (PSURs) 
 

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 

The marketing authorisation holder shall submit the first periodic safety update report for this product 
within 6 months following authorisation.  
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 



24 

• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 
marketing authorisation and any agreed subsequent updates of the RMP. 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 

• Additional risk minimisation measures  
 

Prior to launch of Ultomiris in each Member State the Marketing Authorisation Holder (MAH) must 
agree about the content and format of the educational and controlled distribution programme, 
including communication media, distribution modalities, and any other aspects of the programme, 
with the National Competent Authority. 

The educational and controlled distribution programme is aimed at education and instruction of 
healthcare professionals/patients about the detection, careful monitoring, and/or proper management of 
selected safety concerns associated with Ultomiris. 

The MAH shall ensure that in each Member State where Ultomiris is marketed, all healthcare 
professionals and patients who are expected to prescribe, dispense and use Ultomiris have access 
to/are provided with the following educational package to be disseminated through professional 
bodies: 

• Physician educational material  

• Patient information pack 

The physician educational material should contain: 

o The Summary of Product Characteristics  

o Guide for healthcare professionals  

• The Guide for healthcare professionals shall contain the following key elements: 

o To address the risks of meningococcal infection, serious haemolysis after drug 
discontinuation in PNH patients, severe TMA complications in aHUS patients after 
ravulizumab discontinuation, immunogenicity, serious infections, malignancies and 
haematological abnormalities in in PNH patients, use in pregnant and breast-feeding 
women.  

o Treatment with ravulizumab increases the risk of N. meningitidis infections. 

o All patients must be monitored for signs of meningitidis. 

o The need for patients to be vaccinated against N. meningitidis two weeks prior to 
receiving ravulizumab and/or to receive antibiotic prophylaxis. 

o The risk of immunogenicity and advice on post-infusion monitoring. 

o The risk of developing antibodies to ravulizumab. 

o No clinical data on exposed pregnancies is available. Ravulizumab should be given to a 
pregnant woman only if clearly needed. The need for effective contraception in women of 
childbearing potential during and up to eight months after treatment. Breast-feeding 



25 

should be discontinued during and up to eight months after treatment. 

o Risk of serious haemolysis following ravulizumab discontinuation and postponement of 
administration, its criteria, the required post-treatment monitoring and its proposed 
management (PNH only). 

o Risk of severe TMA complications following ravulizumab discontinuation and 
postponement of administration, its signs, symptoms, monitoring and management (aHUS 
only). 

o The need to explain to and ensure understanding of by patients: 

o the risk of treatment with ravulizumab (including potential risks of serious infections) 

o the signs and symptoms of meningococcal infection and what action to take 

o the patient’s/parent’s guides and their contents 

o the need to carry the patient safety card and to tell any healthcare practitioner that 
he/she is receiving treatment with ravulizumab 

o the requirement for pre-treatment vaccinations/antibiotic prophylaxis 

o the enrolment in the PNH registry and aHUS registry  

o Details of the PNH registry, aHUS registry and how to enter patients 

 

The patient/parent’s information pack should contain: 

o Package leaflet 

o A patient guide 

o A parent guide (aHUS only) 

o A patient safety card 

• The patient guide shall contain the following key messages: 

o To address the risks of meningococcal infection, serious haemolysis after drug 
discontinuation in PNH patients, severe TMA complications in aHUS patients after 
ravulizumab discontinuation, immunogenicity, serious infections, malignancies and 
haematological abnormalities in PNH patients, use in pregnant and breast-feeding women.  

o Treatment with ravulizumab increases the risk of N. meningitidis infections. 

o Signs and symptoms of meningococcal infection and the need to obtain urgent medical 
care. 

o The patient alert card and the need to carry it on their person and tell any treating 
healthcare professional that they are being treated with ravulizumab. 

o The importance of meningococcal vaccination prior to treatment and/or to receive 
antibiotic prophylaxis. 

o The risk of immunogenicity with ravulizumab, including anaphylaxis, and the need for 
clinical monitoring post-infusion. 

o The need for effective contraception in women of childbearing potential during and up to 
eight months after treatment, and that breast-feeding should be discontinued during and up 
to eight months after treatment. 

o Risk of severe haemolysis following discontinuation/postponement of ravulizumab 



26 

administrations, their signs and symptoms and the recommendation to consult the 
prescriber before discontinuing/postponing ravulizumab administrations (PNH only). 

o Risk of severe TMA complications following discontinuation/postponement of 
ravulizumab administration, their signs and symptoms and the recommendation to consult 
the prescriber before discontinuing/postponing ravulizumab administration (aHUS only) 

o Potential risks of severe, non-neisserial infections and malignancies and haematologic 
abnormalities in PNH patients treated with ravulizumab. 

o Enrolment in the PNH registry and aHUS registry. 

o The parent guide (provided together with patient guide) shall contain the following key 
messages: 

o To address the risks of meningococcal infection and serious infections in infants 
and children. 

• The patient safety card shall contain the following key messages: 

o Signs and symptoms of meningococcal infection 

o Warning to seek immediate medical care if above are present 

o Statement that the patient is receiving ravulizumab 

o Contact details where a healthcare professional can receive further information 

o Patient safety card should be retained for 8 months after last dose of ravulizumab 

The MAH shall send annually to prescribers or pharmacists who prescribe/dispense ravulizumab, a 
reminder in order that prescriber/pharmacist checks if a (re)-vaccination against Neisseria meningitidis 
is needed for his/her patients on ravulizumab. 

The MAH shall ensure that in each Member State where Ultomiris is marketed, a system aimed to 
control distribution of Ultomiris beyond the level of routine risk minimisation measures is in place. 
The following requirements need to be fulfilled before the product is dispensed: 

• Submission of written confirmation of the patient`s vaccination against all available 
meningococcal infection serotypes N. meningitidis and/or prophylactic antibiotic treatment 
according to national vaccination guideline. 

  



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



29 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Carton Label 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ultomiris 300 mg concentrate for solution for infusion 

ravulizumab  

 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One vial of 30 mL contains 300 mg of ravulizumab. 
 
After dilution with sodium chloride 9 mg/mL (0.9 %) solution for injection, the final concentration of 
the solution is 5 mg/mL.  
 
3. LIST OF EXCIPIENTS 
 
Sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, polysorbate 
80, and water for injections. 
See the leaflet for further information.  
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
1 vial 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For intravenous use, after dilution.  
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children.  
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 

Do not freeze.  
Store in the original package in order to protect from light.  
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 



30 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Alexion Europe SAS 
103-105, rue Anatole France  
92300 Levallois-Perret 
France 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/19/1371/001  
 
13. BATCH NUMBER 
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
15. INSTRUCTIONS ON USE 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including braille accepted.  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included.  
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
  



31 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Single use Type I glass vial  
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Ultomiris 300 mg concentrate for solution for infusion. 
ravulizumab 
For intravenous use after dilution.  
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use.  
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
Lot 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
30 mL 
5 mg/mL after dilution  
 
6. OTHER 
 
  



32 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



33 

Package leaflet: Information for the user 
 

Ultomiris 300 mg concentrate for solution for infusion 
ravulizumab 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects.  
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Ultomiris is and what it is used for  
2. What you need to know before you use Ultomiris 
3. How to use Ultomiris 
4. Possible side effects  
5. How to store Ultomiris 
6. Contents of the pack and other information 
 
1. What Ultomiris is and what it is used for 
 
What is Ultomiris 
Ultomiris is a medicine that contains the active substance ravulizumab and it belongs to a class of 
medicines called monoclonal antibodies, that attach to a specific target in the body. Ravulizumab has 
been designed to attach to the C5 complement protein, which is a part of the body’s defence system 
called the ‘complement system’. 
 
What is Ultomiris used for 
Ultomiris is used to treat adult patients with a disease called Paroxysmal Nocturnal Haemoglobinuria 
(PNH). In patients with PNH, the complement system is overactive and attacks their red blood cells, 
which can lead to low blood counts (anaemia), tiredness, difficulty in functioning, pain, abdominal 
pain, dark urine, shortness of breath, difficulty swallowing, erectile dysfunction and blood clots. By 
attaching to and blocking the C5 protein, this medicine can stop complement proteins from attacking 
red blood cells and so control symptoms of the disease.  
 
Ultomiris is also used to treat both adult and children patients with a disease affecting the blood 
system and kidney called atypical Haemolytic Uremic Syndrome  (aHUS). In patients with aHUS, 
their kidneys and blood vessels, including platelets, can be inflamed which can lead to low blood 
counts (thrombocytopenia and anaemia), reduced or lost kidney function, blood clots, tiredness and 
difficulty in functioning. Ultomiris can block the body’s inflammatory response, and its ability to 
attack and destroy its own vulnerable blood vessels and so control symptoms of the disease including 
injury to the kidneys. 
 
 
2. What you need to know before you use Ultomiris 
 
Do not use Ultomiris: 
- If you are allergic to ravulizumab, proteins derived from mouse products, other monoclonal 

antibodies, or any of the other ingredients of this medicine (listed in section 6). 
- If you have not been vaccinated against meningococcal infection. 



34 

- If you have meningococcal infection. 
Warnings and precautions  
Talk to your doctor before using Ultomiris. 
 
Meningococcal and other Neisseria infections symptoms 
Because the medicine blocks the complement system, which is part of the body’s defences against 
infection, the use of Ultomiris increases your risk of meningococcal infection caused by Neisseria 
meningitidis. These are severe infections affecting the linings of the brain and can spread throughout 
the blood and body (sepsis).  
 
Consult your doctor before you start Ultomiris to be sure that you receive vaccination against 
Neisseria meningitidis at least 2 weeks before beginning therapy. If you cannot be vaccinated 2 weeks 
beforehand, your doctor will prescribe antibiotics to reduce the risk of infection until 2 weeks after you 
have been vaccinated. Ensure that your current meningococcal vaccination is up to date. You should 
also be aware that vaccination may not always prevent this type of infection. In accordance with 
national recommendations, your doctor might consider that you need supplementary measures to 
prevent infection.  
 
Meningococcal infection symptoms 
Because of the importance of rapidly identifying and treating meningococcal infection in patients who 
receive Ultomiris, you will be provided a ‘patient safety card’ to carry with you at all times, listing 
relevant signs and symptoms of meningococcal infection/sepsis.  
If you experience any of the following symptoms, you should immediately inform your doctor:    
- headache with nausea or vomiting 
- headache and fever 
- headache with a stiff neck or stiff back 
- fever 
- fever and rash  
- confusion  
- muscle aches with flu-like symptoms 
- eyes sensitive to light 
 
Treatment for meningococcal infection while travelling 
If you are travelling in a region where you are unable to contact your doctor or will be temporarily 
unable to receive medical treatment, your doctor may prescribe an antibiotic against Neisseria 
meningitidis to bring with you. If you experience any of the symptoms described above, you should 
take the course of antibiotics as prescribed. You should bear in mind that you should still see a doctor 
as soon as possible, even if you feel better after having taken the antibiotics. 
 
Infections 
Before starting Ultomiris, inform your doctor if you have any infections.  
 
Infusion reactions 
When Ultomiris is given, you may experience reactions to the infusion (drip) such as headache, lower 
back pain, and infusion-related pain.  
 
Children and adolescents 
Patients less than 18 years of age must be vaccinated against Haemophilus influenzae and 
pneumococcal infections. 
 
Other medicines and Ultomiris 
Tell your doctor or pharmacist if you are using or have recently used or might use any other 
medicines.  
 
Pregnancy, breast-feeding, and fertility 
 
Women of childbearing potential 



35 

The effects of the medicine on an unborn child are not known. Therefore, effective contraception 
during treatment and up to 8 months after treatment should be used in women who are able to get 
pregnant.  
 
Pregnancy/ Breast-feeding 
Ultomiris is not recommended during pregnancy and in women of childbearing potential not using 
contraception. If you are pregnant or breast-feeding, think you may be pregnant, or are planning to 
have a baby, ask your doctor or pharmacist for advice before using this medicine. 
 
Driving and using machines 
This medicine has no or negligible influence on the ability to drive and use machines.  
 
Ultomiris contains sodium 
This medicine when diluted with sodium chloride 9 mg/mL (0.9%) solution for injection for IV 
administration contains 2.65 g sodium (main component of cooking/table salt) in 720 mL at the 
maximal dose. This is equivalent to 133 % of the recommended maximum daily dietary intake of 
sodium for an adult.  
You should take this into consideration if you are on a controlled sodium diet. 
 
 
3. How to use Ultomiris 
 
At least 2 weeks before you start treatment with Ultomiris, your doctor will give you a vaccine against 
meningococcal infections if you have not previously had one or if your vaccination is outdated. If you 
cannot be vaccinated at least 2 weeks before you start treatment with Ultomiris, your doctor will 
prescribe antibiotics to reduce the risk of infection until 2 weeks after you have been vaccinated. 
If your child is less than 18 years, your doctor will administer a vaccine (if not yet done) against 
Haemophilus influenzae and pneumococcal infections according to the national vaccination 
recommendations for each age group. 
 
Instructions for proper use 
Ultomiris is given by infusion (drip) into a vein. The infusion will take approximately 2 hours. 
 
Your dose will be worked out by your doctor, based on your body weight, as shown in Table 1. Your 
first dose is called the loading dose. Two weeks after receiving your loading dose, you will be given a 
maintenance dose of Ultomiris, and this will then be repeated once every 8 weeks for patient above 20 
kg and every 4 weeks for patient less than 20 kg.  
 
If you were previously receiving another medicine for PNH and aHUS called Soliris, the loading dose 
should be given 2 weeks after the last Soliris infusion.  
 
Table 1:  Ultomiris weight-based dosing regimen 

Body weight range (kg) Loading dose (mg) Maintenance dose (mg) 
10 to less than 20 600 600 
20 to less than 30 900 2,100 
30 to less than 40 1,200 2,700 
40 to less than 60 2,400 3,000 
60 to less than 100 2,700 3,300 

above 100 3,000 3,600 
 
If you receive more Ultomiris than you should  
If you suspect that you have been accidentally given a higher dose of Ultomiris than prescribed, please 
contact your doctor for advice.  
 
If you forget an appointment to receive Ultomiris 
If you forget an appointment, please contact your doctor immediately for advice and see section below 
“If you stop using Ultomiris”.  



36 

 
If you stop using Ultomiris for PNH 
Interrupting or ending treatment with Ultomiris may cause your PNH symptoms to return with greater 
severity. Your doctor will discuss the possible side effects with you and explain the risks. Your doctor 
will want to monitor you closely for at least 16 weeks. 
 
The risks of stopping Ultomiris include an increase in the destruction of your red blood cells, which 
may cause: 
- A significant fall in your red blood cell counts (anaemia),  
- Confusion or change in how alert you are, 
- Chest pain, or angina, 
- An increase in your serum creatinine level (problems with your kidneys), or 
- Thrombosis (blood clotting).    
If you have any of these symptoms, contact your doctor.    
 
If you stop using Ultomiris for aHUS  
Interrupting or ending treatment with Ultomiris may cause your aHUS symptoms to come back. Your 
doctor will discuss the possible side effects with you and explain the risks. Your doctor will want to 
monitor you closely. 
 
The risks of stopping Ultomiris include an increase in small blood vessel damage, which may cause: 
- A significant fall in your platelets (thrombocytopenia), 
- A significant rise in destruction of your red blood cells, 
- Decreased urination (problems with your kidneys), 
- An increase in your serum creatinine level (problems with your kidneys),  
- Confusion or change in how alert you are, 
- Change in your vision 
- Chest pain, or angina, 
- Shortness of breath, or 
- Thrombosis (blood clotting).    
 
If you have any of these symptoms, contact your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor. 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Your doctor will discuss the possible side effects with you and explain the risks and benefits of 
Ultomiris with you prior to treatment. 
 
The most serious side effect was meningococcal infection/sepsis. 
If you experience any of the meningococcal infection symptoms (see section 2 Meningococcal 
infection symptoms), you should immediately inform your doctor. 
 
If you are not sure what the side effects below are, ask your doctor to explain them to you.  
 
Very common (may affect more than 1 in 10 people):  
- Headache 
-  Nausea, diarrhoea, upper respiratory tract infection 
- Common cold (nasopharyngitis) 
- Fever (pyrexia), feeling tired (fatigue) 

 
 
Common (may affect up to 1 in 10 people): 
- dizziness  



37 

- abdominal pain, vomiting, stomach discomfort after meals (dyspepsia)  
- rash, itchy skin (pruritus)   
- back pain, joint pain (arthralgia), muscle pain (myalgia) and muscle spasms 
- Influenza like illness, feeling tired (asthenia)  
 
Uncommon (may affect up to 1 in 100 people): 
- meningococcal infection 
- chills 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. 
By reporting side effects, you can help provide more information on the safety of this medicine.  
 
 
5. How to store Ultomiris 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton after “EXP”. The expiry 
date refers to the last day of that month. 
Store in a refrigerator (2°C–8°C).  
Do not freeze. 
 
Store in the original package in order to protect from light. 
After dilution with sodium chloride 9 mg/mL (0.9 %) solution for injection, the medicine should be 
used immediately, or within 24 hours if refrigerated or within 6 hours at room temperature. 
 
Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines 
you no longer use. These measures will help protect the environment.  
 
 
6. Contents of the pack and other information 
 
What Ultomiris contains 
 
- The active substance is ravulizumab (300 mg/30 mL in a vial corresponding to 10 mg/mL). 

 
- The other ingredients are:  

- sodium dihydrogen phosphate dihydrate 
- disodium phosphate dihydrate  
- sodium chloride 
- polysorbate 80 
Solvent: water for injections 
 

This medicine contains sodium (see section 2 “Ultomiris contains sodium”). 
 
What Ultomiris looks like and contents of the pack 
Ultomiris is presented as a concentrate for solution for infusion (30 mL in a vial – pack size of 1).  
Ultomiris is a clear to translucent, slight whitish colour, practically free from particles solution. 
 
Marketing Authorisation Holder 
Alexion Europe SAS 
103-105, rue Anatole France  
92300 Levallois-Perret 
France 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


38 

 
Manufacturer 
Alexion Pharma International Operations 
Unlimited Company 
Alexion Dublin Manufacturing Facility 
College Business and Technology Park 
Blanchardstown Rd North 
Dublin 15 R925 
Ireland 
 
 

 

This leaflet was last revised in  
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/. There are also links to other websites about rare diseases and treatments.  
  

http://www.ema.europa.eu/


39 

------------------------------------------------------------------------------------------------------------------------ 
The following information is intended for healthcare professionals only:  
 

Instructions for Use for Healthcare Professionals 
Handling Ultomiris 

 
 

1- How is Ultomiris supplied? 
Each vial of Ultomiris contains 300 mg of active substance in 30 mL of product solution.  
 
2- Before administration 
Dilution should be performed in accordance with good practices rules, particularly for the respect of 
asepsis. 
Ultomiris should be prepared for administration by a qualified healthcare professional using aseptic 
technique.  
- Visually inspect Ultomiris solution for particulate matter and discolouration. 
- Withdraw the required amount of Ultomiris from the vial(s) using a sterile syringe. 
- Transfer the recommended dose to an infusion bag. 
- Dilute Ultomiris to a final concentration of 5 mg/mL (initial concentration divided by 2) by 

adding the appropriate amount of sodium chloride 9 mg/mL (0.9%) solution for injection to the 
infusion as per the instructions provided in table below.  

 
Table 1: Loading dose administration reference table 

Body weight 
range (kg)a 

Loading dose 
(mg) 

Ultomiris 
volume (mL) 

Volume of NaCl 
diluentb (mL) 

Total volume 
(mL) 

Minimum infusion 
duration 

minutes (hours) 
≥ 10 to < 20 600 60 60 120 113 (1.9) 
≥ 20 to < 30 900 90 90 180 86 (1.5) 
≥ 30 to < 40 1,200 120 120 240 77 (1.3) 
≥ 40 to < 60 2,400 240 240 480 114 (1.9) 

≥ 60 to < 100 2,700 270 270 540 102 (1.7) 
≥ 100 3,000 300 300 600 108 (1.8) 

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 2: Maintenance dose administration reference table 

Body weight 
range (kg)a 

Maintenance 
dose (mg) 

Ultomiris 
volume (mL) 

Volume of NaCl 
diluentb (mL) 

Total volume 
(mL) 

Minimum infusion 
duration 

minutes (hours) 
≥ 10 to < 20 600 60 60 120 113 (1.9) 
≥ 20 to < 30 2,100 210 210 420 194 (3.3) 
≥ 30 to < 40 2,700 270 270 540 167 (2.8) 
≥ 40 to < 60 3,000 300 300 600 140 (2.4) 

≥ 60 to < 100 3,300 330 330 660 120 (2.0) 
≥ 100 3,600 360 360 720 132 (2.2) 

a  Body weight at time of treatment 
b Ultomiris should be only diluted using sodium chloride 9 mg/mL (0.9 %) solution for injection 
 
- Gently agitate the infusion bag containing the diluted Ultomiris solution to ensure thorough 

mixing of the medicinal product and diluent. Ultomiris should not be shaken. 
- The diluted solution should be allowed to warm to room temperature (18°C–25°C) prior to 

administration by exposure to ambient air during approximately 30 min.  
- The diluted solution must not be heated in a microwave or with any heat source other than the 

prevailing room temperature. 
- Discard any unused portion left in a vial as the medicinal product contains no preservatives. 
- The prepared solution should be administered immediately following preparation. Infusion must 

be administered through a 0.2 µm filter. 



40 

- 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.

3- Administration
- Do not administer Ultomiris as an intravenous push or bolus injection.
- Ultomiris should only be administered via intravenous infusion.
- The diluted solution of Ultomiris should be administered by intravenous infusion over

approximately 2 hours using a syringe-type pump or an infusion pump. It is not necessary to
protect the diluted solution of Ultomiris from light during administration to the patient.

The patient should be monitored for one hour following infusion. If an adverse event occurs during the 
administration of Ultomiris, the infusion may be slowed or stopped at the discretion of the physician.  

4- Special handling and storage
Store in a refrigerator (2°C–8°C). Do not freeze. Store in the original package in order to protect from
light.
Do not use this medicine after the expiry date which is stated on the carton after ‘EXP’. The expiry
date refers to the last day of that month.

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



ANNEX IV 

CONCLUSIONS ON SIMILARITY AND DEROGATION PRESENTED BY THE 
EUROPEAN MEDICINES AGENCY 

41 



42 

Conclusions presented by the European Medicines Agency on: 

• Similarity

The CHMP is of the opinion that Ultomiris is similar to authorised orphan medicinal product(s) 
within the meaning of Article 3 of Commission Regulation (EC) No. 847/2000 as further explained 
in the European Public Assessment Report.  

• Derogation

The CHMP is of the opinion that pursuant to Article 8 of Regulation (EC) No. 141/2000 the 
following derogation laid down in Article 8.3 of the same Regulation apply(ies) as further 
explained in European Public Assessment Report: 

the holder of the marketing authorisation for Soliris has given his consent to the applicant. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	CONCLUSIONS ON SIMILARITY AND DEROGATION PRESENTED BY THE EUROPEAN MEDICINES AGENCY