ULTOMIRIS 1100mg / 11ml perfusive solution concentrate medication leaflet

Ultomiris 300 mg/3 mL concentrate for solution for infusion

Ultomiris 1 100 mg/11 mL concentrate for solution for infusion

Ultomiris 300 mg/30 mL concentrate for solution for infusion

Ultomiris is a formulation of ravulizumab produced in Chinese hamster ovary (CHO) cell culture byrecombinant DNA technology.

Ultomiris 300 mg/3 mL concentrate for solution for infusion

Each vial of 3 mL contains 300 mg of ravulizumab (100 mg/mL).

After dilution, the final concentration of the solution to be infused is 50 mg/mL.

Sodium (4.6 mg per 3 mL vial)

Ultomiris 1 100 mg/11 mL concentrate for solution for infusion

Each vial of 11 mL contains 1 100 mg of ravulizumab (100 mg/mL).

After dilution, the final concentration of the solution to be infused is 50 mg/mL.

Sodium (16.8 mg per 11 mL vial)

Ultomiris 300 mg/30 mL concentrate for solution for infusion

Each vial of 30 mL contains 300 mg of ravulizumab (10 mg/mL).

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

Sodium (115 mg per 30 mL vial)

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate)

Ultomiris 300 mg/3 mL and 1 100 mg/11 mL concentrates for solution for infusion

Translucent, clear to yellowish colour, pH 7.4 solution.

Ultomiris 300 mg/30 mL concentrate for solution for infusion

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

Paroxysmal nocturnal haemoglobinuria (PNH)

Ultomiris is indicated in the treatment of adult and paediatric patients with a body weight of 10 kg orabove with 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 thepast 6 months.

Atypical haemolytic uremic syndrome (aHUS)

Ultomiris is indicated in the treatment of adult and paediatric patients with a body weight of 10 kg orabove with aHUS who are complement inhibitor treatment-naïve or have received eculizumab for atleast 3 months and have evidence of response to eculizumab.

Generalised myasthenia gravis (gMG)

Ultomiris is indicated as an add-on to standard therapy for the treatment of adult patients with gMGwho are anti-acetylcholine receptor (AChR) antibody-positive.

Neuromyelitis optica spectrum disorder (NMOSD)

Ultomiris is indicated in the treatment of adult patients with NMOSD who are anti-aquaporin 4(AQP4) antibody-positive (see section 5.1).

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

Adult patients with PNH, aHUS, gMG, or NMOSD

The recommended dosing regimen consists of a loading dose followed by maintenance dosing,administered by intravenous infusion. The doses to be administered are based on the patient’s bodyweight, as shown in Table 1. For adult patients (≥ 18 years of age), maintenance doses should beadministered 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 forthe first maintenance dose of ravulizumab), but the subsequent dose should be administered accordingto the original schedule.

Table 1: Ravulizumab weight-based dosing regimen for adult patients with body weightgreater than or equal to 40 kg

Body weight range (kg) Loading dose (mg) Maintenance dose (mg)* Dosing interval≥ 40 to < 60 2,400 3,000 Every 8 weeks≥ 60 to < 100 2,700 3,300 Every 8 weeks≥ 100 3,000 3,600 Every 8 weeks

* First maintenance dose is administered 2 weeks after loading dose

Treatment initiation instructions in patients who are complement-inhibitor treatment-naïve orswitching treatment from eculizumab are shown in Table 2.

Table 2: Ravulizumab treatment initiation instructions

Population Weight-based ravulizumab Time of first ravulizumab weight-loading dose based maintenance dose

Not currently on ravulizumab or At treatment start 2 weeks after ravulizumab loading doseeculizumab treatment

Currently treated with At time of next scheduled 2 weeks after ravulizumab loading doseeculizumab eculizumab dose

Paediatric patients with PNH or aHUS

Paediatric patients with body weight ≥ 40 kg

These patients should be treated in accordance with the adult dosing recommendations (See Table 1).

Paediatric patients with body weight ≥ 10 kg to < 40 kg

The weight-based doses and dosing intervals for paediatric patients ≥ 10 kg to < 40 kg are shown in

Table 3.

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

Table 3: Ravulizumab weight-based dosing regimen for paediatric patients with PNH oraHUS 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 1,200 2,700 Every 8 weeks

* First maintenance dose is administered 2 weeks after loading dose

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

PNH patients treated with ravulizumab.

PNH is a chronic disease and treatment with ravulizumab is recommended to continue for the patient’slifetime, unless the discontinuation of ravulizumab is clinically indicated (see section 4.4).

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

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

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

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

Plasma exchange (PE), plasmapheresis (PP) and intravenous immunoglobulin (IVIg) have been shownto reduce ravulizumab serum levels. A supplemental dose of ravulizumab is required in the setting of

PE, PP or IVIg (Table 4).

Table 4: Supplemental dose of ravulizumab after PP, PE, or IVIg

Most recent Supplemental dose (mg) Supplemental dose (mg)

Body weightravulizumab dose following each PE or PP following completion of anrange (kg)(mg) intervention IVIg cycle2,400 1,200≥ 40 to < 60 6003,000 1,5002,700 1,500≥ 60 to < 100 6003,300 1,8003,000 1,500≥ 1 00 6003,600 1,800

Timing of ravulizumab supplemental Within 4 hours following Within 4 hours followingdose each PE or PP intervention completion of an IVIg cycle

Abbreviations: IVIg = intravenous immunoglobulin, kg = kilogram, PE = plasma exchange, PP = plasmapheresis

No dose adjustment is required for patients with PNH, aHUS, gMG, or NMOSD aged 65 years andover. There is no evidence indicating any special precautions are required for treating a geriatricpopulation - although experience with ravulizumab in elderly patients with PNH, aHUS, or NMOSDin clinical studies is limited.

No dose adjustment is required for patients with renal impairment (see section 5.2).

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 hepaticimpairment.

The safety and efficacy of ravulizumab in children with a body weight below 10 kg with PNH oraHUS have not been established. Currently available data are described in section 4.8 but norecommendation on a posology can be made.

The safety and efficacy of ravulizumab in children with gMG or NMOSD have not been established.

No data are available.

For intravenous infusion only.

This medicinal product must be administered through a 0.2 µm filter and should not be administeredas an intravenous push or bolus injection.

Ultomiris 300 mg/30 mL concentrate for solution for infusion must not be mixed with Ultomiris300 mg/3 mL or 1 100 mg/11 mL concentrates for solution for infusion.

Ultomiris 300 mg/3 mL and 1 100 mg/11 mL concentrates for solution for infusion

Ultomiris concentrate for solution for infusion is presented as 3 mL and 11 mL vials (100 mg/mL) andmust be diluted to a final concentration of 50 mg/mL. Following dilution, Ultomiris is to beadministered by intravenous infusion using a syringe-type pump or an infusion pump over a minimalperiod of 0.17 to 1.3 hours (10 to 75 minutes) depending on body weight (see Table 5 and Table 6below).

Table 5: Dose administration rate for Ultomiris 300 mg/3 mL and 1 100 mg/11 mLconcentrates for solution for infusion

Body weight Loading dose Minimum infusion Maintenance dose Minimum infusionrange (kg)a (mg) duration (mg) durationminutes (hours) minutes (hours)≥ 10 to < 20b 600 45 (0.8) 600 45 (0.8)≥ 20 to < 30b 900 35 (0.6) 2,100 75 (1.3)≥ 30 to < 40b 1,200 31 (0.5) 2,700 65 (1.1)≥ 40 to < 60 2,400 45 (0.8) 3,000 55 (0.9)≥ 60 to < 100 2,700 35 (0.6) 3,300 40 (0.7)≥ 100 3,000 25 (0.4) 3,600 30 (0.5)a Body weight at time of treatment.b For PNH and aHUS indications only.

Table 6: Dose administration rate for supplemental doses of Ultomiris 300 mg/3 mL and1 100 mg/11 mL concentrates for solution for infusion

Body weight range (kg)a Supplemental doseb (mg) Minimum infusion durationminutes (hours)≥ 40 to < 60 600 15 (0.25)1,200 25 (0.42)1,500 30 (0.5)≥ 60 to < 100 600 12 (0.20)1,500 22 (0.36)1,800 25 (0.42)≥ 100 600 10 (0.17)1,500 15 (0.25)1,800 17 (0.28)a Body weight at time of treatment.b Refer to Table 4 for selection of ravulizumab supplemental dose

Ultomiris 300 mg/30 mL concentrate for solution for infusion

Ultomiris concentrate for solution for infusion is presented as 30 mL vial (10 mg/mL) and must bediluted to a final concentration of 5 mg/mL. Following dilution, Ultomiris is to be administered byintravenous infusion using a syringe-type pump or an infusion pump over a minimal period of 0.4 to3.3 hours (22 to 194 minutes) depending on body weight (see Table 7 and Table 8 below).

Table 7: Dose administration rate for Ultomiris 300 mg/30 mL concentrate for solution forinfusion

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

Table 8: Dose administration rate for supplemental doses of Ultomiris 300 mg/30 mLconcentrate for solution for infusion

Body weight range (kg)a Supplemental dose b (mg) Minimum infusion durationminutes (hours)≥ 40 to < 60 600 30 (0.5)1,200 60 (1.0)1,500 72 (1.2)≥ 60 to < 100 600 23 (0.4)1,500 60 (1.0)1,800 65 (1.1)≥ 100 600 22 (0.4)1,500 60 (1.0)1,800 65 (1.1)a Body weight at time of treatment.b Refer to Table 4 for selection of ravulizumab supplemental dose

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

* 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 (seesection 4.4).

* Patients who are not currently vaccinated against Neisseria meningitidis unless they receiveprophylactic treatment with appropriate antibiotics until 2 weeks after vaccination (seesection 4.4).

In order to improve the traceability of biological medicinal products, the name and the batch numberof 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 tomeningococcal infection/sepsis (Neisseria meningitidis). Meningococcal disease due to any serogroupmay occur (see section 4.8). To reduce this risk of infection, all patients must be vaccinated againstmeningococcal infections at least two weeks prior to initiating ravulizumab unless the risk of delayingravulizumab therapy outweighs the risk of developing a meningococcal infection. Patients who initiateravulizumab treatment less than 2 weeks after receiving a meningococcal vaccine, must receivetreatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. Vaccines againstall available serogroups including A, C, Y, W135 and B, are recommended in preventing thecommonly pathogenic meningococcal serogroups. Patients must be vaccinated and revaccinatedaccording to current national guidelines for vaccination use. If the patient is being switched fromeculizumab treatment, physicians should verify that meningococcal vaccination is current according tonational guidelines for vaccination use.

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

Patient guide and a Patient card.

Prior to initiating ravulizumab therapy, it is recommended that patients initiate immunisationsaccording to current immunisation guidelines.

Vaccination may further activate complement. As a result, patients with complement-mediateddiseases may experience increased signs and symptoms of their underlying disease. Therefore, patientsshould be closely monitored for disease symptoms after recommended vaccination.

Patients below the age of 18 years old must be vaccinated against Haemophilus influenzae andpneumococcal infections, and strictly need to adhere to the national vaccination recommendations foreach 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 increasedsusceptibility to infections caused by Neisseria species and encapsulated bacteria. Serious infectionswith Neisseria species (other than Neisseria meningitidis), including disseminated gonococcalinfections, have been reported.

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

Administration of ravulizumab may result in systemic infusion-related reactions and allergic orhypersensitivity reactions, including anaphylaxis (see section 4.8).

In case of systemic infusion-related reaction, if signs of cardiovascular instability or respiratorycompromise occur, administration of ravulizumab should be interrupted and appropriate supportivemeasures should be instituted.

Treatment discontinuation for PNH

If patients with PNH discontinue treatment with ravulizumab, they should be closely monitored forsigns and symptoms of serious intravascular haemolysis, identified by elevated LDH (lactatedehydrogenase) levels along with sudden decrease in PNH clone size or haemoglobin, orre-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 detecthaemolysis 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 observationalstudy, discontinuation of complement C5 inhibitor treatment (eculizumab) resulted in a 13.5-foldhigher rate of TMA recurrence and showed a trend toward reduced renal function compared to patientswho continued treatment.

If patients must discontinue treatment with ravulizumab, they should be monitored closely for signsand symptoms of TMA on an on-going basis. However, monitoring may be insufficient to predict orprevent severe TMA complications.

TMA complications post-discontinuation can be identified if any of the following is observed:

- At least 2 of the following laboratory results observed concurrently: a decrease in plateletcount of 25% or more as compared to either baseline or to peak platelet count duringravulizumab treatment; an increase in serum creatinine of 25% or more as compared tobaseline or to nadir during ravulizumab treatment; or, an increase in serum LDH of 25% ormore as compared to baseline or to nadir during ravulizumab treatment (results should beconfirmed by a second measurement)

Or

- any one of the following symptoms of TMA: a change in mental status or seizures or otherextra-renal TMA manifestations including cardiovascular abnormalities, pericarditis,gastrointestinal symptoms/diarrhoea; or thrombosis.

If TMA complications occur after ravulizumab discontinuation, reinitiation of ravulizumab treatmentshould be considered, beginning with the loading dose and maintenance dose (see section 4.2).

Treatment discontinuation for gMG

Considering that gMG is a chronic disease, patients benefiting from ravulizumab treatment whodiscontinue treatment should be monitored for symptoms of the underlying disease. If symptoms ofgMG occur after discontinuation, consider restarting treatment with ravulizumab.

Considering that NMOSD is a chronic disease, patients benefiting from ravulizumab treatment whodiscontinue treatment should be monitored for symptoms of NMOSD relapse. If symptoms of

NMOSD relapse occur after discontinuation, consider restarting treatment with ravulizumab.

Switch from eculizumab to ravulizumab

In gMG patients who are not responding to eculizumab approved dosing regimen, treatment withravulizumab is not recommended.

Ultomiris 300 mg/3 mL and 1 100 mg/11 mL concentrates for solution for infusion

Once diluted with sodium chloride 9 mg/mL (0.9%) solution for injection, this medicinal productcontains 0.18 g sodium per 72 mL at the maximal dose, equivalent to 9.1% of the WHO recommendedmaximum daily intake of 2 g sodium for an adult.

Ultomiris 300 mg/30 mL concentrate for solution for infusion

Once diluted with sodium chloride 9 mg/mL (0.9%) solution for injection, this medicinal productcontains 2.65 g sodium per 720 mL at the maximal dose, equivalent to 133% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

No interaction studies have been performed. Based on the potential inhibitory effect of ravulizumab oncomplement-dependent cytotoxicity of rituximab, ravulizumab may reduce the expectedpharmacodynamic effects of rituximab.

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

See section 4.2 for guidance in case of concomitant PE, PP, or IVIg treatment.

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

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 relatedreproductive toxicities were identified in these studies. Human immunoglobulin G (IgG) are known tocross the human placental barrier, and thus ravulizumab may potentially cause terminal complementinhibition 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 risksand benefits.

It is unknown whether ravulizumab is excreted into human milk. Nonclinical reproductive toxicologystudies conducted in mice with the murine surrogate molecule BB5.1 identified no adverse effect topups 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 ofthe potential for serious adverse reactions in nursing infants, breast-feeding should be discontinuedduring treatment with ravulizumab and up to 8 months after treatment.

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.

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

The most common adverse reactions with ravulizumab are headache (30%), upper respiratory tractinfection (21.1%), nasopharyngitis (20.1%), diarrhoea (18.1%), pyrexia (17.6%), nausea (14.6%),arthralgia (14.1%), back pain (13.5%), fatigue (13.1%), abdominal pain (12.3%), dizziness (10.5%) andurinary tract infection (10.2%). The most serious adverse reactions are meningococcal infection (0.7%)including meningococcal sepsis, encephalitis meningococcal, meningococcal infection (see section 4.4)and disseminated gonococcal infection (0.2%).

Table 9 gives the adverse reactions observed from clinical trials and from post-marketing experience.

Adverse reactions are listed by MedDRA System Organ Class (SOC) and frequency, using thefollowing convention: very common (≥ 1/ 10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (cannot beestimated from available data).

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

Table 9: Adverse Drug reactions from clinical trials and postmarketing experience

MedDRA System Organ Very common Common Uncommon (≥ 1/1,000

Class (≥ 1/10) (≥ 1/100 to to < 1/100)< 1/10)

Infections and Urinary tract infectiona Meningococcalinfestations Upper respiratory tract infectionb,infection, Nasopharyngitis Disseminated

Gonococcal infectionc

Immune system Hypersensitivitye Anaphylactic reactionddisorders

Nervous system Dizziness, Headachedisorders

Gastrointestinal Diarrhoea, Vomiting,disorders Nausea, Dyspepsia

Abdominal pain

Skin and subcutaneous Urticaria,tissue disorders Pruritus,

Musculoskeletal and Arthralgia, Myalgia,connective tissue Back pain Muscle spasmsdisorders

General disorders and Pyrexia, Influenza likeadministration site Fatigue illness, Chills,conditions Asthenia

Injury, poisoning and Infusion-relatedprocedural reactioncomplicationsa Urinary tract infection is a group term that includes Preferred Terms: Urinary tract infection, Urinary tractinfection bacterial, Urinary tract infection enterococcal, and Escherichia urinary tract infection.

bMeningococcal infection includes preferred terms of meningococcal infection, meningococcal sepsis, andencephalitis meningococcalc Disseminated gonococcal infection includes preferred terms of disseminated gonococcal infection andgonococcal infectiond Estimated from postmarketing experiencee Hypersensitivity is a group term for Preferred Term drug hypersensitivity with related causality and Preferred

Term hypersensitivity

Meningococcal infection/sepsis/encephalitis

Vaccination reduces, but does not eliminate, the risk of meningococcal infections. In clinical trials,< 1% of patients developed serious meningococcal infections while receiving treatment withravulizumab; all were adult patients with PNH or NMOSD who had been vaccinated.

Please refer to section 4.4 for information on prevention and treatment of suspected meningococcalinfection. In patients treated with ravulizumab, meningococcal infections have presented asmeningococcal sepsis and encephalitis meningococcal. Patients should be informed of the signs andsymptoms of meningococcal infection and advised to seek medical care immediately.

In clinical trials, infusion-related reactions were common (≥1%). These events, which were mild tomoderate in severity and transient, included back pain, abdominal pain, muscle spasms, drop in bloodpressure, elevation in blood pressure, rigors, limb discomfort, hypersensitivity (allergic reaction),dysgeusia (bad taste), and drowsiness. These reactions did not require discontinuation of ravulizumab.

In adult PNH patient studies (N = 475), a paediatric PNH study (N = 13), aHUS studies (N = 89), agMG study (N = 86), and an NMOSD study (N = 58), 2 (0.3%) cases of development of treatment-emergent anti-drug antibody have been reported with ravulizumab (1 adult patient with PNH and1 adult patient with aHUS). These anti-drug antibodies were transient in nature with low titre and didnot correlate with clinical response or adverse events.

Paroxysmal nocturnal haemoglobinuria (PNH)

In paediatric PNH patients (N= 13, aged 9 to 17 years old) enrolled in the paediatric PNH Study(ALXN1210-PNH-304), the safety profile appeared similar to that observed in adult PNH patients.

The most common adverse reactions reported in paediatric PNH patients were abdominal pain, nausea,nasopharyngitis and headache which occurred in 3 patients (23.1%).

Atypical haemolytic uremic syndrome (aHUS)

In paediatric patients with evidence of aHUS (N= 34, aged 10 months to less than 18 years) includedin ALXN1210-aHUS-312 study, the safety profile of ravulizumab appeared similar to that observed inadult patients with evidence of aHUS. The safety profiles in the different paediatric subsets of ageappear similar. The safety data for patient below 2 years of age is limited to four patients. The mostcommon adverse reactions (> 20%) reported in paediatric patients were pyrexia, vomiting, diarrhoea,headache, nasopharyngitis, upper respiratory tract infection and abdominal pain.

Generalised Myasthenia Gravis (gMG)

Ravulizumab has not been studied in paediatric patients with gMG.

Neuromyelitis Optica Spectrum Disorder (NMOSD)

Ravulizumab has not been studied in paediatric patients with NMOSD.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Patients who experience overdose should have immediate interruption of their infusion and be closelymonitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment beinstituted.

Pharmacotherapeutic group: Immunosuppressants, complement inhibitors, ATC code: L04A J02

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 initiatingsubunit of the membrane attack complex [MAC or C5b-9]) and preventing the generation of the

C5b-9. Ravulizumab preserves the early components of complement activation that are essential foropsonisation of microorganisms and clearance of immune complexes.

Following ravulizumab treatment in both adult and paediatric complement inhibitor-naïve patients andeculizumab-experienced patients with PNH in Phase 3 studies, immediate, complete and sustainedinhibition of serum free C5 (concentration of < 0.5 µg/mL) was observed by the end of the firstinfusion and sustained throughout the entire 26-week treatment period in all patients. Immediate andcomplete inhibition of serum free C5 was also observed in adult and paediatric patients with aHUS, inadult patients with gMG, and in adult patients with NMOSD by the end of the first infusion andthroughout the primary treatment period.

The extent and duration of the pharmacodynamic response in patients with PNH, aHUS, gMG, or

NMOSD were exposure dependent for ravulizumab. Free C5 levels less than 0.5 µg/mL werecorrelated with maximal intravascular haemolysis control and complete terminal complementinhibition. In gMG, terminal complement activation leads to MAC deposition at the neuromuscularjunction and impairment of neuromuscular transmission. In NMOSD, terminal complement activationleads to MAC formation and C5a-dependent inflammation, astrocyte necrosis, and damage tosurrounding glial cells and neurons.

Paroxysmal nocturnal haemoglobinuria (PNH)

The safety and efficacy of ravulizumab in adult 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 complementinhibitor treatment,

* an eculizumab-experienced study in adult patients with PNH who were clinically stable afterhaving 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 theapproved dosing regimen of eculizumab of 600 mg every week for the first 4 weeks and 900 mg every2 weeks (15 infusions over 26 weeks).

Patients were vaccinated against meningococcal infection prior to or at the time of initiating treatmentwith ravulizumab or eculizumab or received prophylactic treatment with appropriate antibiotics until2 weeks after vaccination.

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

Study in complement inhibitor-naïve adult patients with PNH (ALXN1210-PNH-301)

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 inhibitortreatment prior to study entry and was followed by a long-term extension period where all patientsreceived ravulizumab. 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 ormore 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 ofstudy entry. The majority of the complement inhibitor-naïve study population was highly haemolyticat baseline; 86.2 % of enrolled patients presented with elevated LDH ≥ 3 × ULN, which is a directmeasurement of intravascular haemolysis, in the setting of PNH.

Table 10 presents the baseline characteristics of the PNH patients enrolled in the complementinhibitor-naïve study, with no apparent clinically meaningful differences observed between thetreatment arms.

Table 10: Baseline characteristics in the complement inhibitor-naïve study

Parameter Statistics Ravulizumab Eculizumab(N = 125) (N = 121)

Age (years) at PNH diagnosis Mean (SD) 37.9 (14.90) 39.6 (16.65)

Median 34.0 36.5

Min, max 15, 81 13, 82

Age (years) at first infusion in study Mean (SD) 44.8 (15.16) 46.2 (16.24)

Median 43.0 45.0

Min, max 18, 83 18, 86

Sex (n, %) Male 65 (52.0) 69 (57.0)

Female 60 (48.0) 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 n (%) 103 (82.4) 100 (82.6)blood cell (pRBC) transfusions within12 months prior to first dose

Units of pRBC transfused within Total 925 86112 months prior to first dose 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 n (%) 121 (96.8) 120 (99.2)prior to informed consent

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 bynormalisation of LDH levels (LDH levels ≤ 1 × ULN; the ULN for LDH is 246 U/L). Key secondaryendpoints 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 patientswith stabilised haemoglobin.

Ravulizumab was non-inferior compared to eculizumab for both coprimary endpoints, avoidance ofpRBC 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 (complementinhibitor-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.

The final efficacy analysis for the study included all patients ever treated with ravulizumab (n=244)and had a median treatment duration of 1423 days. The final analysis confirmed that ravulizumabtreatment responses observed during the Primary Evaluation Period were maintained throughout theduration of the study.

Study in adult PNH patients previously treated with eculizumab (ALXN1210-PNH-302)

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 and wasfollowed by a long-term extension period where all patients received ravulizumab.

PNH medical history was similar between ravulizumab and eculizumab treatment groups. The12-month transfusion history was similar between ravulizumab and eculizumab treatment groups andmore than 87 % of patients in both treatment groups had not received a transfusion within 12 monthsof study entry. The mean total PNH RBC clone size was 60.05 %, mean total PNH granulocyte clonesize was 83.30 %, and the mean total PNH monocyte clone size was 85.86 %.

Table 11 presents the baseline characteristics of the PNH patients enrolled in the eculizumab-experienced study, with no apparent clinically meaningful differences observed between the treatmentarms.

Table 11: Baseline characteristics in the eculizumab-experienced study

Parameter Statistics Ravulizumab Eculizumab(N = 97) (N = 98)

Age (years) at PNH diagnosis Mean (SD) 34.1 (14.41) 36.8 (14.14)

Median 32.0 35.0

Min, max 6, 73 11, 74

Age (years) at first infusion in study Mean (SD) 46.6 (14.41) 48.8 (13.97)

Median 45.0 49.0

Min, max 18, 79 23, 77

Sex (n, %) Male 50 (51.5) 48 (49.0)

Female 47 (48.5) 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 n (%) 13 (13.4) 12 (12.2)transfusions within 12 months prior to first dose

Units of pRBC/whole blood transfused within Total 103 5012 months prior to first dose Mean (SD) 7.9 (8.78) 4.2 (3.83)

Median 4.0 2.5

Patients with any PNH conditionsa prior to n (%) 90 (92.8) 96 (98.0)informed consent

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)

Otherb 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 otherconditions.

The primary endpoint was haemolysis as measured by LDH percent change from baseline. Secondaryendpoints 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.

The final efficacy analysis for the study included all patients ever treated with ravulizumab (n=192)and had a median treatment duration of 968 days. The final analysis confirmed that ravulizumabtreatment responses observed during the primary evaluation period were maintained throughout theduration of the study.

Atypical haemolytic uremic syndrome (aHUS)

Study in adult patients with aHUS (ALXN1210-aHUS-311)

The adult study was a multicentre, single arm, Phase 3 study conducted in patients with documentedaHUS who were naïve to complement inhibitor treatment prior to study entry and had evidence ofthrombotic microangiopathy (TMA). The study consisted of a 26-week initial evaluation period andpatients 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 patientspresenting with TMA, due to a disintegrin and metalloproteinase with a thrombospondin type 1 motif,member 13 (ADAMTS13) deficiency, Shiga toxin Escherichia coli related haemolytic uremicsyndrome (STEC-HUS) and genetic defect in cobalamin C metabolism. Two patients were excludedfrom the full analysis set due to a confirmed diagnosis of STEC-HUS. Ninety-three percent of patientshad extra renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin,skeletal muscle) or symptoms of aHUS at baseline.

Table 12 presents the demographics and baseline characteristics of the 56 adult patients enrolled in

Study ALXN1210-aHUS-311 that constituted the full analysis set.

Table 12: Baseline characteristics in the adult study

Ravulizumab

Parameter Statistics (N = 56)

Age at time of first infusion (years) Mean (SD) 42.2 (14.98)

Min, max 19.5, 76.6

Sex

Male n (%) 19 (33.9)

Race n (%)

Asian 15 (26.8)

White 29 (51.8)

Unknown/other 12 (21.4)

History of transplant n (%) 8 (14.3)

Platelets (109/L) blood n 56

Median (min,max) 95.25 (18, 473)

Haemoglobin (g/L) blood n 56

Median (min,max) 85.00 (60.5, 140)

LDH (U/L) serum n 56

Median (min,max) 508.00 (229.5, 3249)eGFR (mL/min/1.73 m2) n (%) 55

Median (min,max) 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: 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, asevidenced by normalisation of haematological parameters (platelet count ≥ 150 x 109/L and LDH≤ 246 U/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 initialevaluation period as shown in Table 13.

Table 13: Complete TMA response and complete TMA response components analysis forthe 26-week initial evaluation period (ALXN1210-aHUS-311)

Total Respondern 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 56 33 0.589 (0.452, 0.727)creatinine from baseline

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 continuitycorrection.

Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy.

Complete TMA Response was observed in six additional patients during the extension period at

Days 169, 302, 401,407, 1247 and 1359 resulting in an overall Complete TMA Response in 36 of 56patients (64.3%; 95% CI: 50.8%, 77.7%) through end of study. Individual component responseincreased to 48 (85.7%; 95% CI: 75.7%, 95.8%) patients for platelet count normalisation, 49 (87.5%;95% CI: 77.9%, 97.1%) patients for LDH normalisation, and 37 (66.1%; 95% CI: 52.8%, 79.4%)patients for renal function improvement.

The median time to Complete TMA Response was 86 days (7 to 1359 days). A rapid increase in meanplatelet count was observed after commencement of ravulizumab, increasing from 118.52 × 109/L atbaseline to 243.54 × 109/L at Day 8 and remaining above 227 × 109/L at all subsequent visits in theinitial evaluation period (26 weeks). Similarly, mean LDH value decreased from baseline over the first2 months of treatment and was sustained over the duration of the initial evaluation period (26 weeks).

Over two thirds of the patient population who were mostly CKD Stage 4 or 5 at baseline improved by1 or more CKD stages by Day 743 of study. Improvement in renal function as measured by eGFRcontinued to be stable through end of study. Chronic kidney disease stage continued to improve formany patients (19/30) after achieving Complete TMA Response during the 26-week initial evaluationperiod.

Of the 27 patients who did not require dialysis at study entry, 19 patients remained off dialysis duringthe entire study period and 8 patients initiated dialysis during the study, with 2 of these patientsdiscontinuing dialysis during the study. One of the patients that discontinued dialysis during theextension study period, then reinitiated dialysis and continued through study completion.

Table 14: Secondary efficacy outcome for the 26-Week Initial Evaluation Period ofstudy ALXN1210-aHUS-311

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

Haematologic TMA parameters, Day 183 Observed value (n=48) Change from baseline (n=48)

Platelets (109/L) blood

Mean (SD) 237.96 (73.528) 114.79 (105.568)

Median 232.00 125.00

LDH (U/L) serum

Mean (SD) 194.46 (58.099) -519.83 (572.467)

Median 176.50 -310.75

Increase in haemoglobin of ≥ 20 g/L frombaseline with a confirmatory resultthrough Initial Evaluation Periodn/m 40/56proportion (95% CI)* 0.714 (0.587, 0.842)

CKD stage shift from baseline, Day 183

Improvedan/m 32/47

Proportion (95% CI)* 0.681 (0.529, 0.809)

Worsenedbn/m 2/13

Proportion (95% CI)* 0.154 (0.019, 0.454)eGFR (mL/min/1.73 m2), Day 183 Observed value (n=48) Change from baseline (n=47)

Mean (SD) 51.83 (39.162) 34.80 (35.454)

Median 40.00 29.00

Note: n: number of patients with available data for specific assessment at Day 183 visit. m: number of patientsmeeting 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 consideredthe 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 onexact confidence limits using the Clopper-Pearson method. aExcludes those with CKD Stage 1 at baseline asthey cannot improve. bExcludes patients with Stage 5 at baseline as they cannot worsen.

Abbreviations: eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; TMA = thromboticmicroangiopathy.

The final efficacy analysis for the study on all patients treated with ravulizumab over a mediantreatment duration of 130.36 weeks confirmed that ravulizumab treatment responses observed duringthe Primary Evaluation Period were maintained throughout the duration of the study.

Generalised Myasthenia Gravis (gMG)

Study in adult patients with gMG

The efficacy and safety of ravulizumab in adult patients with gMG was assessed in a Phase 3,randomised, double-blind, placebo-controlled, multicentre study (ALXN1210-MG-306). Patientsparticipating in this study were subsequently allowed to enter an Open-Label Extension Period duringwhich all patients received ravulizumab.

Patients with gMG (diagnosed for at least 6 months) with a positive serologic test for anti-acetylcholine receptor (AChR) antibodies, MGFA (Myasthenia Gravis Foundation of America)clinical classification Class II to IV and remaining symptomatology as evidenced by a Myasthenia

Gravis Activities of Daily Living (MG-ADL) total score ≥ 6 were randomised to receive eitherravulizumab (N = 86) or placebo (N = 89). Patients on immunosuppressant therapies (corticosteroids,azathioprine, cyclophosphamide, cyclosporine, methotrexate, mycophenolate mofetil, or tacrolimus)were permitted to continue on therapy throughout the course of the study. In addition, rescue therapy(including high dose corticosteroid, PE/PP, or IVIg) was allowed if a patient experienced clinicaldeterioration, as defined by the study protocol.

A total of 162 (92.6%) patients completed the 26-week Randomised-Controlled Period of Study

ALXN1210-MG-306. The baseline characteristics of patients are presented in Table 15. The majority(97%) of patients included in the study had been treated with at least one immunomodulatory therapyincluding immunosuppressant therapies, PE/PP, or IVIg in the last two years prior to enrolment.

Table 15: Baseline disease characteristics in study ALXN1210-MG-306

Parameter Statistics Placebo Ravulizumab(N = 89) (N = 86)

Sex n (%)

Male 44 (49.4) 42 (48.8)

Female 45 (50.6) 44 (51.2)

Age at first dose of study drug (years) Mean (SD) 53.3 (16.05) 58.0 (13.82)(min, max) (20, 82) (19, 79)

Elderly (≥ 65 years of age) at study entry n (%) 24 (27.0) 30 (34.9)

Duration of MG since diagnosis (years) Mean (SD) 10.0 (8.90) 9.8 (9.68)(min, max) (0.5, 36.1) (0.5, 39.5)

Median 7.6 5.7

Baseline MG-ADL Score Mean (SD) 8.9 (2.30) 9.1 (2.62)(min, max) (6.0, 15.0) (6.0, 24.0)

Median 9.0 9.0

Baseline QMG Score Mean (SD) 14.5 (5.26) 14.8 (5.21)(min, max) (2.0, 27.0) (6.0, 39.0)

Median 14.0 15.0

Baseline MGFA classification n (%)

Class II (mild weakness) 39 (44) 39 (45)

Class III (moderate weakness) 45 (51) 41 (48)

Class IV (severe weakness) 5 (6) 6 (7)

Any prior intubation since diagnosis n (%) 9 (10.1) 8 (9.3)(MGFA Class V)

Number of patients with prior MG crisis n (%) 17 (19.1) 21 (24.4)since diagnosisa

Number of stable immunosuppressant n (%)therapiesb at study entry0 8 (9.0) 10 (11.6)1 34 (38.2) 40 (46.5)≥ 2 47 (52.8) 36 (41.9)a Prior MG crisis information was collected as part of medical history and not evaluated as per the clinicalprotocol definition.

b Immunosuppressant therapies include corticosteroids, azathioprine, cyclophosphamide, cyclosporine,methotrexate, mycophenolate mofetil, or tacrolimus.

Abbreviations: Max = maximum; min = minimum; MG = myasthenia gravis; MG-ADL = Myasthenia Gravis

Activities of Daily Living; MGFA = Myasthenia Gravis Foundation of America; QMG = Quantitative

Myasthenia Gravis; SD = standard deviation

The primary endpoint was the change from Baseline to Week 26 in the MG-ADL total score.

The secondary endpoints, also assessing changes from Baseline to Week 26, included the change inthe Quantitative Myasthenia Gravis (QMG) total score, the proportion of patients with improvementsof at least 5 and 3 points in the QMG and MG-ADL total scores, respectively, as well as changes inquality-of-life assessments.

Ravulizumab demonstrated a statistically significant change in the MG-ADL total score as comparedto placebo. Primary and secondary endpoint results are presented in Table 16.

Table 16: Analysis of primary and secondary efficacy endpoints

Efficacy Placebo Ravulizumab Statistic for Treatment p-value

Endpoints at (N = 89) (N = 86) Comparison Effect (Using Mixed

Week 26 LS Mean LS Mean (95% CI) Effect(SEM) (SEM) Repeated

Measures)

MG-ADL -1.4 (0.37) -3.1 (0.38) Difference in -1.6 (-2.6, -0.7) 0.0009change frombaseline

QMG -0.8 (0.45) -2.8 (0.46) Difference in -2.0 (-3.2, -0.8) 0.0009change frombaseline

MG-QoL15r -1.6 (0.70) -3.3 (0.71) Difference in -1.7 (-3.4, 0.1) 0.0636change frombaseline

Neuro-QoL-fatigue -4.8 (1.87) -7.0 (1.92) Difference in -2.2 (-6.9, 2.6) 0.3734achange frombaselinea The endpoint was not formally tested for statistical significance; a nominal p-value was reported.

Abbreviations: CI = confidence interval; LS = least squares; MG-ADL = Myasthenia Gravis Activities of Daily

Living; MG-QoL15r = Revised Myasthenia Gravis Quality of Life 15-item scale; Neuro-QoL-fatigue = Neurological Quality of Life Fatigue; QMG = Quantitative Myasthenia Gravis; SEM = standard errorof mean.

In Study ALXN1210-MG-306, a clinical responder in the MG-ADL total score was defined as havingat least a 3-point improvement. The proportion of clinical responders at Week 26 was 56.7% onravulizumab compared with 34.1% on placebo (nominal p=0.0049). A clinical responder in the QMGtotal score was defined as having at least a 5-point improvement. The proportion of clinical respondersat Week 26 was 30.0% on ravulizumab compared with 11.3% on placebo (p=0.0052).

Table 17 presents an overview of the patients with clinical deterioration and patients requiring rescuetherapy over the 26-week Randomised-Controlled Period.

Table 17: Clinical deterioration and rescue therapy

Variable Statistic Placebo Ravulizumab(N = 89) (N = 86)

Total number of patients with clinical deterioration n (%) 15 (16.9) 8 (9.3)

Total number of patients requiring rescue therapya n (%) 14 (15.7) 8 (9.3)a Rescue therapy included high-dose corticosteroid, plasma exchange/plasmapheresis, or intravenousimmunoglobulin.

In patients who initially received ULTOMIRIS during the Randomised-Controlled Period andcontinued to receive ULTOMIRIS up to 164-weeks of the Open-Label Extension Period, the treatmenteffect continued to be sustained (Figure 3). In patients who initially received placebo during the 26-week Randomised-Controlled Period and initiated treatment with ULTOMIRIS during the Open-Label

Extension Period, a rapid and sustained treatment response on all endpoints including MG-ADL and

QMG (Figure 3), was observed over a median treatment duration of approximately 2 years.

Figure 3: Change from randomised-controlled period baseline in MG-ADL total score (A)and QMG total score (B) up to week 164 (mean and 95% CI)

Note: Randomized Controlled Period figures are based on data from 175 patients. Open Label Extension Periodfigures are based on data from 161 patients.

Abbreviations: CI = confidence interval; MG-ADL = Myasthenia Gravis Activities of Daily Living;

QMG = Quantitative Myasthenia Gravis

In the Open-Label Extension Period of the study, clinicians had the option to adjustimmunosuppressant therapies. At the end of the Open-Label Extension Period (median duration of

ULTOMIRIS treatment both during Randomised-Control Period and Open-Label Extension was 759days), 30.1% of patients decreased their daily dose of corticosteroid therapy and 12.4% of patientsstopped corticosteroid therapy. The most common reason for change in corticosteroid therapies wasimprovement in MG symptoms while on ravulizumab treatment.

Neuromyelitis Optica Spectrum Disorder (NMOSD)

Study in adult patients with NMOSD

The efficacy of ravulizumab in adult patients with anti-AQP4 antibody-positive NMOSD was assessedin a global, open-label clinical study (ALXN1210-NMO-307).

Study ALXN1210-NMO-307 enrolled 58 adult patients with NMOSD who had a positive serologictest for anti-AQP4 antibodies, at least 1 relapse in the last 12 months prior to the Screening Period, andan Expanded Disability Status Scale (EDSS) score of ≤ 7. Prior treatment with immunosuppressanttherapies (ISTs) was not required for enrolment and 51.7% of patients were on ravulizumabmonotherapy. Patients on selected ISTs (i.e., corticosteroids, azathioprine, mycophenolate mofetil,tacrolimus) were permitted to continue on therapy in combination with ravulizumab, with arequirement for stable dosing until they reached Week 106 in the study. In addition, acute therapy forrelapse treatment (including high-dose corticosteroids, PE/PP, and IVIg) was allowed if a patientexperienced a relapse during the study.

Patients included in the study had a mean age of 47.4 years (ranging from 18 to 74 years) and most ofthem were female (90%). Median age at NMOSD initial clinical presentation was of 42.5 years,ranging from 16 to 73 years. Baseline disease characteristics are shown in Table 18.

Table 18: Patient disease history and baseline characteristics in study

ALXN1210-NMO-307

Statistic ALXN1210-NMO-307

Variable Ravulizumab(N = 58)

Time from NMOSD initial clinical presentation to Mean (SD) 5.2 (6.38)first dose of study drug (years) Median 2.0

Min, max 0.19, 24.49

Historical ARR within 24 months prior to screening Mean (SD) 1.87 (1.59)

Median 1.44

Min, max 0.5, 6.9

Baseline HAI score Mean (SD) 1.2 (1.42)

Median 1.0

Min, max 0, 7

Baseline EDSS score Mean (SD) 3.30 (1.58)

Median 3.25

Min, max 0.0, 7.0

Any historical rituximab use n (%) 21 (36.2)

Number of patients receiving stable corticosteroids n (%) 12 (20.7)only at study entry

Number of patients not receiving any IST at study n (%) 30 (51.7)entry

Abbreviations: ARR = annualised relapse rate; EDSS = Expanded Disability Status Scale; HAI = Hauser

Ambulation Index; IST = immunosuppressant therapy; Max = maximum; Min = minimum; NMOSD =neuromyelitis optica spectrum disorder; SD = standard deviation.

The primary endpoint of Study ALXN1210-NMO-307 was the time to first adjudicated on-trialrelapse as determined by an independent adjudication committee. No adjudicated on-trial relapse wasobserved in ravulizumab-treated patients during the primary treatment period. All ravulizumab-treatedpatients remained relapse free over the median follow-up of 90.93 weeks. Ravulizumab-treatedpatients experienced consistent relapse-free primary endpoint result with or without concomitant ISTtreatment.

Ravulizumab has not been studied for the acute treatment of relapses in NMOSD patients.

Paroxysmal nocturnal haemoglobinuria (PNH)

Study in paediatric patients with PNH (ALXN1210-PNH-304)

The paediatric study (ALXN1210-PNH-304) is a multicentre, open-label, Phase 3 study conducted ineculizumab-experienced and complement inhibitor-naïve paediatric patients with PNH.

From interim results, a total of 13 PNH paediatric patients completed ravulizumab treatment duringthe primary evaluation period (26 weeks) of Study ALXN1210-PNH-304. Five of the 13 patients hadnever been treated with a complement inhibitor and 8 patients received treatment with eculizumabprior to study entry.

Most of the patients were between 12 years and 17 years of age at first infusion (mean: 14.4 years),with 2 patients under 12 years old (11 years and 9 years old). Eight of the 13 patients were female.

Mean weight at baseline was 56 kg, ranging from 37 to 72 kg. Table 19 presents the baseline diseasehistory and characteristics of the paediatric patients enrolled in Study ALXN1210-PNH-304.

Table 19: Disease history and characteristics at baseline (full analysis set)

Variable Complement inhibitor- Eculizumab-naïve patients experienced patients(N = 5) (N = 8)

Total PNH RBC clone size (%) (N = 4) (N = 6)

Median (min, max) 40.05 (6.9, 68.1) 71.15 (21.2, 85.4)

Total PNH granulocyte clone size (%)

Median (Min, max) 78.30 (36.8, 99.0) 91.60 (20.3, 97.6)

Number of patients with pRBC/whole blood 2 (40.0) 2 (25.0)transfusions within 12 months prior to first dose, n (%)

Number of pRBC/whole blood transfusions within12 months prior to first dose

Total 10 2

Median (min, max) 5.0 (4, 6) 1.0 (1, 1)

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

Total 14 2

Median (min, max) 7.0 (3, 11) 2.0 (2, 2)

Patients with any PNH-associated conditions prior to 5 (100) 8 (100)informed consent, n (%)

Anaemia 2 (40.0) 5 (62.5)

Haematuria or haemoglobinuria 2 (40.0) 5 (62.5)

Aplastic anaemia 3 (60.0) 1 (12.5)

Renal failure 2 (40.0) 2 (25.0)

Othera 0 1 (12.5)

Pre-treatment LDH levels (U/L)

Median (min, max) 588.50 (444, 2269.7) 251.50 (140.5, 487)a Other PNH-associated conditions were reported as “renal and splenic infarcts” and “multiple lesionsconcerning for embolic process”.

Note: Percentages were based on the total number of patients in each cohort.

Abbreviations: LDH = lactate dehydrogenase; max = maximum; min = minimum; PNH = paroxysmal nocturnalhaemoglobinuria; pRBC = packed red blood cell; RBC = red blood cell.

Based on body weight, patients received a loading dose of ravulizumab on Day 1, followed bymaintenance treatment on Day 15 and once every 8 weeks (q8w) thereafter for patients weighing≥ 20 kg, or once every 4 weeks (q4w) for patients weighing < 20 kg. For patients who entered thestudy on eculizumab therapy, Day 1 of study treatment was planned to occur 2 weeks from thepatient’s last dose of eculizumab.

The weight-based dose regimen of ravulizumab provided immediate, complete, and sustainedinhibition of terminal complement throughout the 26-week primary evaluation period regardless ofprior experience with eculizumab. Following initiation of ravulizumab treatment, steady-statetherapeutic serum concentrations of ravulizumab were achieved immediately after the first dose andmaintained throughout the 26-week primary evaluation period in both cohorts. There were nobreakthrough haemolysis events in the study and no patients had post-baseline free C5 levels above0.5 µg/mL.

Mean percent change from baseline in LDH was -47.91% on Day 183 in the complement inhibitor-naïve cohort and remained stable in the eculizumab-experienced cohort during the 26-week primaryevaluation period. Sixty percent (3/5) of complement inhibitor-naïve patients and 75% (6/8) ofeculizumab-experienced patients achieved haemoglobin stabilisation by Week 26 respectively.

Transfusion-avoidance was reached by 84.6% (11/13) of patients during the 26-week primaryevaluation period.

These interim efficacy results are presented in Table 20 below.

Table 20: Efficacy outcomes from the paediatric study in PNH patients (ALXN1210-PNH-304) - 26-week primary evaluation period

End Point Ravulizumab Ravulizumab(Naïve, N = 5) (Switch, N = 8)

LDH- Percent change from Baseline

Mean (SD) -47.91 (52.716) 4.65 (44.702)

Transfusion Avoidance

Percentage (95% CI) 60.0 (14.66, 94.73) 100.0 (63.06, 100.00)

Haemoglobin Stabilisation

Percentage (95% CI) 60.0 (14.66, 94.73) 75 (34.91, 96.81)

Breakthrough Haemolysis (%) 0 0

Abbreviations: LDH = lactate dehydrogenase

Long term efficacy results through end of study over a median treatment duration of 915 days resultedin a sustained treatment response in paediatric patients with PNH.

Based on data from these interim results, the efficacy of ravulizumab in paediatric PNH patientsappears to be similar to that observed in adult PNH patients.

Atypical haemolytic uremic syndrome (aHUS)

Use of Ultomiris in paediatric patients for treatment of aHUS is supported by evidence from onepaediatric clinical study (a total of 31 patients with documented aHUS were enrolled; 28 patients aged10 months to 17 years were included in the full analysis set).

Study in paediatric patients with aHUS (ALXN1210 aHUS 312)

The paediatric study was a 26-week, multicentre, single arm, Phase 3 study conducted in paediatricpatients and patients were allowed to enter an extension period for up to 4.5 years.

A total of 24 eculizumab-naïve patients with documented diagnosis of aHUS and evidence of TMAwere enrolled, of which 20 were included in the Full Analysis set. Enrolment criteria excluded patientspresenting with TMA due to a disintegrin and metalloproteinase with a thrombospondin type 1 motif,member 13 (ADAMTS13) deficiency, STEC-HUS and genetic defect in cobalamin C metabolism.

Four patients were given 1 or 2 doses, but then discontinued and were excluded from the full analysisset because aHUS eligibility was not confirmed. The overall mean weight at baseline was 21.2 kg;majority of the patients were in the baseline weight category ≥ 10 to < 20 kg. The majority of patients(70.0%) had pretreatment extra renal signs (cardiovascular, pulmonary, central nervous system,gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline. At baseline, 35.0% (n = 7) ofpatients had CKD Stage 5.

A total of 10 patients, who switched from eculizumab to ravulizumab, had documented diagnosis ofaHUS and evidence of TMA were enrolled. Patients had to have clinical response to eculizumab priorto enrolment (i.e. LDH < 1.5 X ULN and platelet count ≥ 150,000/μL, and eGFR> 30 mL/min/1.73 m2). Consequently, there is no information on the use of ravulizumab in patientrefractory to eculizumab.

Table 21 presents the baseline characteristics of the paediatric patients enrolled in Study

ALXN1210-aHUS-312.

Table 21: Demographics and baseline characteristics in study ALXN1210-aHUS-312

Ravulizumab Ravulizumab

Parameter Statistics (Naïve, N = 20) (Switch, N = 10)

Age at time of first infusion (years) category n (%)

Birth to < 2 years 4 (20.0) 1 (10.0)2 to < 6 years 9 (45.0) 1 (10.0)6 to < 12 years 5 (25.0) 1 (10.0)12 to < 18 years 2 (10.0) 7 (70.0)

Sex n (%)

Male 8 (40.0) 9 (90.0)

Racea n (%)

American Indian or Alaskan Native 1 (5.0) 0 (0.0)

Asian 5 (25.0) 4 (40.0)

Black or African American 3 (15.0) 1 (10.0)

White 11 (55.0) 5 (50.0)

Unknown 1 (5.0) 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 (%) 7 (35.0) 0 (0.0)

Note: Percentages are based on the total number of patients.a Patients can have multiple races selected.

Abbreviations: 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, asevidenced by normalisation of haematological parameters (platelet ≥ 150 x 109/L and LDH ≤ 246 U/L)and ≥ 25% improvement in serum creatinine from baseline in eculizumab-naïve patients. Patients hadto 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 15 of the 20 naïve patients (75.0%) during the 26-weekinitial evaluation period as shown in Table 22.

Table 22: Complete TMA response and complete TMA response components analysisduring the 26-week initial evaluation period (ALXN1210-aHUS-312)

Total Respondern Proportion (95% CI)a

Complete TMA Response 20 15 0.750 (0.509, 0.913)

Components of Complete TMA Response

Platelet count normalisation 20 19 0.950 (0.751, 0.999)

LDH normalisation 20 18 0.900 (0.683, 0.988)≥ 25% improvement in serum creatinine from baseline 20 16 0.800 (0.563, 0.943)

Haematologic normalisation 20 18 0.900 (0.683, 0.988)a 95% CIs for the proportion were based on the asymptotic Gaussian approximation method with a continuitycorrection.

Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy.

Complete TMA Response during the initial evaluation period was achieved at a median time of30 days (15 to 99 days). All patients with Complete TMA Response maintained it through the initialevaluation period with continuous improvements seen in renal function. An increase in mean plateletcount was observed rapidly after commencement of ravulizumab, increasing from 71.70 × 109/L atbaseline to 302.41 × 109/L at Day 8 and remained above 304 × 109/L at all subsequent visits after Day22 in the initial evaluation period (26 weeks).

Complete TMA Response was observed in three additional patients during the Extension Period at

Days 295 for 2 patients and Day 351 for 1 patient) resulting in the achievement of Complete TMAresponse in 18 of 20 paediatric patients (90%; 95% CI: 68.3%, 98.8%) through end of study.

Individual component response increased to 19 of 20 (95.0%; 95% CI: 75.1%, 99.9%) patients forplatelet count normalisation, 19 of 20 (95.0%; 95% CI: 75.1%, 99.9%) patients for LDHnormalisation, and in 18 of 20 (90.0%; 95% CI: 68.3%, 98.8%) patients for renal functionimprovement.

All 7 of the patients who required dialysis at study entry were able to discontinue dialysis; 6 of whichhad already done so by Day 36. No patient started or re-initiated dialysis during the study. For the 16patients with available baseline and Week 52 (Day 351) data, 16 patients had improvement in chronickidney disease (CKD) stage compared with baseline. Patients with available data through the end ofthe study continued to have improvements or no changes in CKD stage. Improvement in renal functionas measured by eGFR continued to be stable through end of study. Table 23 summarises the secondaryefficacy results for Study ALXN1210-aHUS-312.

Table 23: Secondary efficacy outcome for the 26-Week Initial Evaluation Period forstudy ALXN1210-aHUS-312

Parameters Study ALXN1210-aHUS-312(N = 20)

Haematologic TMA parameters, Day 183 Observed value (n = 17) Change from baseline (n = 17)

Platelets (109/L) blood

Mean (SD) 304.94 (75.711) 245.59 (91.827)

Median 318.00 247.00

LDH (U/L) serum

Mean (SD) 262.41 (59.995) -2044.13 (1328.059)

Median 247.00 -1851.50

Increase in haemoglobin of ≥ 20 g/L frombaseline with a confirmatory resultthrough Initial Evaluation Periodn/m 17/20proportion (95% CI)* 0.850 (0.621, 0.968)

CKD stage shift from baseline, Day 183

Improvedan/m 15/17

Proportion (95% CI)* 0.882 (0.636, 0.985)

Worsenedbn/m 0/11

Proportion (95% CI)* 0.000 (0.000, 0.285)eGFR (mL/min/1.73 m2), Day 183 Observed value (n = 17) Change from baseline (n = 17)

Mean (SD) 108.5 (56.87) 85.4 (54.33)

Median 108.0 80.0

Note: n: number of patients with available data for specific assessment at Day 183 visit. m: number of patientsmeeting 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 consideredthe 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 = thromboticmicroangiopathy.

In eculizumab-experienced patients, switching to ravulizumab maintained disease control as evidencedby 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.

The final efficacy analysis for the study on all paediatric patients treated with ravulizumab over amedian treatment duration of 130.60 weeks confirmed that ravulizumab treatment responses observedduring the Primary Evaluation Period were maintained throughout the duration of the study.

Generalised myasthenia gravis (gMG)

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 the treatment of myasthenia gravis.

See 4.2 for information on paediatric use.

Neuromyelitis optica spectrum disorder (NMOSD)

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 the treatment of NMOSD. See 4.2 forinformation on paediatric use.

Because the route of administration is an intravenous infusion and the pharmaceutical form is asolution, 100 % of the administered dose of ravulizumab is considered bioavailable. The time tomaximum 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.

The mean (standard deviation [SD]) central volume and volume of distribution at steady state for adultand paediatric patients with PNH or aHUS and adult patients with gMG or NMOSD are presented in

Table 24.

As an immunoglobulin gamma (IgG) monoclonal antibody, ravulizumab is expected to be metabolisedin the same manner as any endogenous IgG (degraded into small peptides and amino acids viacatabolic pathways) and is subject to similar elimination. Ravulizumab contains only natural occurringamino acids and has no known active metabolites. The mean (SD) values for terminal elimination half-life and clearance of ravulizumab in adult and paediatric patients with PNH, adult and paediatricpatients with aHUS, and adult patients with gMG or NMOSD are presented in Table 24.

Table 24: Estimated central volume, distribution, biotransformation and eliminationparameters following ravulizumab administration

Adult and Adult and Adult patients Adult patientspaediatric paediatric patients with gMG with NMOSDpatients with with aHUS

PNH

Estimated central volume Adults: 3.44 (0.66) Adults: 3.25 (0.61) 3.42 (0.756) 2.91 (0.571)(litres) Mean (SD) Paediatrics: 2.87 Paediatrics: 1.14(0.60) (0.51)

Volume of distribution at 5.30 (0.9) 5.22 (1.85) 5.74 (1.16) 4.77 (0.819)steady state (litres)

Mean (SD)

Terminal elimination half- 49.6 (9.1) 51.8 (16.2) 56.6 (8.36) 64.3 (11.0)life (days)

Mean (SD)

Adult and Adult and Adult patients Adult patientspaediatric paediatric patients with gMG with NMOSDpatients with with aHUS

PNH

Estimated central volume Adults: 3.44 (0.66) Adults: 3.25 (0.61) 3.42 (0.756) 2.91 (0.571)(litres) Mean (SD) Paediatrics: 2.87 Paediatrics: 1.14(0.60) (0.51)

Clearance (litres/day) 0.08 (0.022) 0.08 (0.04) 0.08 (0.02) 0.05 (0.016)

Mean (SD)

Abbreviations: aHUS = atypical haemolytic uremic syndrome; gMG = generalised myasthenia gravis; NMOSD= neuromyelitis optica spectrum disorder; PNH = paroxysmal nocturnal haemoglobinuria; SD = standarddeviation.

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

Weight

Body weight is a significant covariate in patients with PNH, aHUS, gMG, or NMOSD resulting inlower exposures in heavier patients. Weight-based dosing is proposed in section 4.2, Table 1, Table 3and Table 4.

No formal trial of the effect of sex, race, age (geriatric), hepatic or renal impairment on thepharmacokinetics of ravulizumab was conducted. However, based on population-PK assessment noimpact of sex, age, race and hepatic or renal function on ravulizumab PK was identified in the studiedhealthy volunteers, subjects and patients with PNH, aHUS, gMG, or NMOSD, and as a result, nodosing adjustment is considered necessary.

The pharmacokinetics of ravulizumab have been studied in aHUS patients with a range of renalimpairment including patients receiving dialysis. There have been no observed differences inpharmacokinetic parameters noted in these subpopulations of patients including patients withproteinuria.

Animal reproductive toxicology studies have not been conducted with ravulizumab but wereconducted in mice with a murine surrogate complement inhibitory antibody, BB5.1. No cleartreatment-related effects or adverse effects were observed in the murine surrogate reproductivetoxicology 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 offspringborn to mothers exposed to the higher antibody dose (approximately 4 times the maximumrecommended human ravulizumab dose, based on a body weight comparison); however, the exposuredid not increase foetal loss or neonatal death.

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

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

Ultomiris 300 mg/3 mL and 1 100 mg/11 mL concentrates for solution for infusion

Sodium phosphate dibasic heptahydrate

Sodium phosphate monobasic monohydrate

Polysorbate 80

Arginine

Sucrose

Water for injections

Ultomiris 300 mg/30 mL concentrate for solution for infusion

Sodium phosphate dibasic heptahydrate

Sodium phosphate monobasic monohydrate

Sodium chloride

Polysorbate 80

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

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

Ultomiris 300 mg/3 mL and 1 100 mg/11 mL concentrates for solution for infusion18 months.

After dilution, the medicinal product should be used immediately. However, chemical and physicalstability of the diluted product have been demonstrated for up to 24 hours at 2 °C-8 °C and up to4 hours at room temperature.

Ultomiris 300 mg/30 mL concentrate for solution for infusion30 months.

After dilution, the medicinal product should be used immediately. However, chemical and physicalstability of the diluted product have been demonstrated for up to 24 hours at 2 °C-8 °C and up to6 hours at room temperature.

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.

Pack size of one vial.

Ultomiris 300 mg/3 mL concentrate for solution for infusion3 mL of sterile concentrate in a vial (Type I glass) with a stopper and a seal.

Ultomiris 1 100 mg/11 mL concentrate for solution for infusion11 mL of sterile concentrate in a vial (Type I glass) with a stopper and a seal.

Ultomiris 300 mg/30 mL concentrate for solution for infusion30 mL of sterile concentrate in a vial (Type I glass) with a stopper and a seal.

Each vial is intended for single use only.

Ultomiris 300 mg/3 mL and 1 100 mg/11 mL concentrates for solution for infusion

This medicinal product requires dilution to a final concentration of 50 mg/mL.

Aseptic technique must be used.

Prepare Ultomiris concentrate for solution for infusion as follows:1. The number of vials to be diluted is determined based on the individual patient’s weight and theprescribed dose, see section 4.2.2. Prior to dilution, the solution in the vials should be visually inspected; the solution should befree of any particulate matter or precipitation. Do not use if there is evidence of particulatematter or precipitation.

3. The calculated volume of medicinal product is withdrawn from the appropriate number of vialsand diluted in an infusion bag using sodium chloride 9 mg/mL (0.9 %) solution for injection asdiluent. 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 50 mg/mL.5. The prepared solution should be administered immediately following preparation unless it isstored at 2 °C-8 °C. If stored at 2 °C-8 °C, allow the diluted solution to warm to roomtemperature prior to administration. Do not administer as an intravenous push or bolus injection.

Refer to the Table 5 and Table 6 for minimum infusion duration. Infusion must be administeredthrough a 0.2 µm filter.

6. If the medicinal product is not used immediately after dilution, storage times must not exceed24 hours at 2 °C - 8 °C or 4 hours at room temperature taking into account the expectedinfusion time.

Table 25: Loading dose administration reference table for Ultomiris 300 mg/3 mL and1 100 mg/11 mL concentrates for solution for infusion

Body weight Loading dose Ultomiris volume Volume of NaCl Total volumerange (kg)a (mg) (mL) diluentb (mL) (mL)≥ 10 to < 20 600 6 6 12≥ 20 to < 30 900 9 9 18≥ 30 to < 40 1,200 12 12 24≥ 40 to < 60 2,400 24 24 48≥ 60 to < 100 2,700 27 27 54≥ 100 3,000 30 30 60a Body weight at time of treatment.b Ultomiris should only be diluted using sodium chloride 9 mg/mL (0.9 %) solution for injection.

Table 26: Maintenance dose administration reference table for Ultomiris 300 mg/3 mL and1 100 mg/11 mL concentrates for solution for infusion

Body weight Maintenance Ultomiris volume Volume of NaCl Total volumerange (kg)a dose (mg) (mL) diluentb (mL) (mL)≥ 10 to < 20 600 6 6 12≥ 20 to < 30 2,100 21 21 42≥ 30 to < 40 2,700 27 27 54≥ 40 to < 60 3,000 30 30 60≥ 60 to < 100 3,300 33 33 66≥ 100 3,600 36 36 72a Body weight at time of treatment.b Ultomiris should only be diluted using sodium chloride 9 mg/mL (0.9 %) solution for injection.

Table 27: Supplemental dose administration reference table for Ultomiris 300 mg/3 mLand 1 100 mg/11 mL concentrates for solution for infusion

Body weight Supplemental ULTOMIRIS Volume of NaCl Total volumerange (kg)a dose (mg) volume (mL) diluentb (mL) (mL)≥ 40 to < 60 600 6 6 121,200 12 12 241,500 15 15 30≥ 60 to < 100 600 6 6 121,500 15 15 301,800 18 18 36≥ 100 600 6 6 121,500 15 15 301,800 18 18 36a Body weight at time of treatmentb Ultomiris should be only 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 localrequirements.

Ultomiris 300 mg/30 mL concentrate for solution for infusion

This medicinal product requires dilution to a final concentration of 5 mg/mL.

Aseptic technique must be used.

Prepare Ultomiris concentrate for solution for infusion as follows:1. The number of vials to be diluted is determined based on the individual patient’s weight and theprescribed dose, see section 4.2.2. Prior to dilution, the solution in the vials should be visually inspected; the solution should befree of any particulate matter or precipitation. Do not use if there is evidence of particulatematter or precipitation.

3. The calculated volume of medicinal product is withdrawn from the appropriate number of vialsand diluted in an infusion bag using sodium chloride 9 mg/mL (0.9 %) solution for injection asdiluent. 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 isstored at 2 °C-8 °C. If stored at 2 °C-8 °C, allow the diluted solution to warm to roomtemperature prior to administration. Do not administer as an intravenous push or bolus injection.

Refer to the Table 7 and Table 8 for minimum infusion duration. Infusion must be administeredthrough a 0.2 µm filter.

6. If the medicinal product is not used immediately after dilution, storage times must not exceed24 hours at 2 °C - 8 °C or 6 hours at room temperature taking into account the expectedinfusion time.

Table 28: Loading dose administration reference table for Ultomiris 300 mg/30 mLconcentrate for solution for infusion

Body weight Loading dose Ultomiris volume Volume of NaCl Total volumerange (kg)a (mg) (mL) diluentb (mL) (mL)≥ 10 to < 20 600 60 60 120≥ 20 to < 30 900 90 90 180≥ 30 to < 40 1,200 120 120 240≥ 40 to < 60 2,400 240 240 480≥ 60 to < 100 2,700 270 270 540≥ 100 3,000 300 300 600a Body weight at time of treatment.b Ultomiris should only be diluted using sodium chloride 9 mg/mL (0.9 %) solution for injection.

Table 29: Maintenance dose administration reference table for Ultomiris 300 mg/30 mLconcentrate for solution for infusion

Body weight Maintenance Ultomiris volume Volume of NaCl Total volumerange (kg)a dose (mg) (mL) diluentb (mL) (mL)≥ 10 to < 20 600 60 60 120≥ 20 to < 30 2,100 210 210 420≥ 30 to < 40 2,700 270 270 540≥ 40 to < 60 3,000 300 300 600≥ 60 to < 100 3,300 330 330 660≥ 100 3,600 360 360 720a Body weight at time of treatment.b Ultomiris should only be diluted using sodium chloride 9 mg/mL (0.9 %) solution for injection.

Table 30: Supplemental dose administration reference table for Ultomiris 300 mg/30mLconcentrate for solution for infusion

Body weight Supplemental ULTOMIRIS Volume of NaClrange (kg)a dose (mg) volume (mL) diluentb (mL) Total volume (mL)≥ 40 to < 60 600 60 60 1201,200 120 120 2401,500 150 150 300≥ 60 to < 100 600 60 60 1201,500 150 150 3001,800 180 180 360≥ 100 600 60 60 1201,500 150 150 3001,800 180 180 360a Body weight at time of treatmentb 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 localrequirements.

Alexion Europe SAS103-105 rue Anatole France92300 Levallois-Perret

FRANCE

EU/1/19/1371/001

EU/1/19/1371/002

EU/1/19/1371/003

Date of first authorisation: 02 July 2019

Date of latest renewal: 19 April 2024

Detailed information on this medicinal product is available on the website of the European Medicines

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