4.1. Therapeutic indications

Paroxysmal nocturnal haemoglobinuria (PNH)

Ultomiris is indicated in the treatment of adult and paediatric patients with a body weight of 10 kg or above 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 the past 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 or above with aHUS who are complement inhibitor treatment-naïve or have received eculizumab for at least 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 gMG who 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).

4.2. Posology and method of administration

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

Posology

Adult patients with PNH, aHUS, gMG, or NMOSD

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

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

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

Body weight range (kg)

Loading dose (mg)

Maintenance dose (mg)*

Dosing interval

≥ 40 to < 60

2,400

3,000

Every 8 weeks

≥ 60 to < 100

2,700

3,300

Every 8 weeks

≥ 100

3,000

3,600

Every 8 weeks

* First maintenance dose is administered 2 weeks after loading dose

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

Table 2: Ravulizumab treatment initiation instructions

Population

Weight-based ravulizumab loading dose

Time of first ravulizumab weight-based maintenance dose

Not currently on ravulizumab or eculizumab treatment

At treatment start

2 weeks after ravulizumab loading dose

Currently treated with eculizumab

At time of next scheduled eculizumab dose

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

Table 3: Ravulizumab weight-based dosing regimen for paediatric patients with PNH or aHUS below 40 kg

Body weight range (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. The recommended posology for these patients is based on the posology used for paediatric patients with aHUS, on the basis of the pharmacokinetic/pharmacodynamic (PK/PD) data available in aHUS and PNH patients treated with ravulizumab.

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

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

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

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

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

Plasma exchange (PE), plasmapheresis (PP) and intravenous immunoglobulin (IVIg) have been shown to reduce 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

Body weight range (kg)

Most recent ravulizumab dose (mg)

Supplemental dose (mg) following each PE or PP intervention

Supplemental dose (mg) following completion of an IVIg cycle

≥ 40 to < 60

2,400

1,200

600

3,000

1,500

≥ 60 to < 100

2,700

1,500

600

3,300

1,800

≥ 100

3,000

1,500

600

3,600

1,800

Timing of ravulizumab supplemental dose

Within 4 hours following each PE or PP intervention

Within 4 hours following completion of an IVIg cycle

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

Special populations

Elderly

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

Renal impairment

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

Hepatic impairment

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

Paediatric population

The safety and efficacy of ravulizumab in children with a body weight below 10 kg with PNH or aHUS have not been established. Currently available data are described in section 4.8 but no recommendation 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.

Method of administration

For intravenous infusion only.

This medicinal product must be administered through a 0.2 µm filter and should not be administered as an intravenous push or bolus injection. After administration of Ultomiris, flush the entire line with 0.9% Sodium Chloride Injection, USP.

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

Table 5: Dose administration rate for Ultomiris

Body weight range (kg)a

Loading dose

(mg)

Minimum infusion duration

minutes (hours)

Maintenance dose

(mg)

Minimum infusion duration

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

Body weight range (kg)a

Supplemental doseb (mg)

Minimum infusion duration

minutes (hours)

≥ 40 to < 60

600

15 (0.25)

1,200

25 (0.42)

1,500

30 (0.5)

≥ 60 to < 100

600

12 (0.20)

1,500

22 (0.36)

1,800

25 (0.42)

≥ 100

600

10 (0.17)

1,500

15 (0.25)

1,800

17 (0.28)

a Body weight at time of treatment.

b Refer to Table 4 for selection of ravulizumab supplemental dose

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 (see section 4.8). 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 all available serogroups including A, C, Y, W135 and B, are recommended in preventing the commonly pathogenic meningococcal serogroups. Patients must be vaccinated and revaccinated according to current national guidelines for vaccination use. If the patient is being switched from eculizumab treatment, physicians should verify that meningococcal vaccination is current according to national guidelines for vaccination use.

Vaccination may not be sufficient to prevent meningococcal infection. Consideration should be given to official guidance on the appropriate use of antibacterial agents. Cases of serious or fatal meningococcal infections/sepsis have been reported in patients treated with ravulizumab and 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 guide and a Patient card.

Immunisation

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

Vaccination may further activate complement. As a result, patients with complement-mediated diseases may experience increased signs and symptoms of their underlying disease. 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 Information Leaflet to increase their awareness of potential serious infections and their signs and symptoms. Physicians should advise patients about gonorrhoea prevention.

Infusion-related reactions

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

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

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. 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:

- At least 2 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

- 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, reinitiation of ravulizumab treatment should 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 who discontinue treatment should be monitored for symptoms of the underlying disease. If symptoms of gMG occur after discontinuation, consider restarting treatment with ravulizumab.

Treatment discontinuation for NMOSD

Considering that NMOSD is a chronic disease, patients benefiting from ravulizumab treatment who discontinue 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 with ravulizumab is not recommended.

Sodium content

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

Polysorbate 80 content

This medicinal product contains 1.5 mg of polysorbate 80 in each 3 mL vial and 5.5 mg in each 11 mL vial, which is equivalent to 0.53 mg/kg or less at the maximum dose for adult patients and paediatric patients with body weight more than 10 kg. Polysorbates may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

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

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.

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

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should use effective contraception methods during treatment and for 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 immunoglobulin G (IgG) are known to cross the human placental barrier, and thus ravulizumab may potentially cause terminal complement inhibition in the foetal circulation.

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

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

Breast-feeding

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

A risk to infants cannot be excluded.

Since many medicinal products and immunoglobulins are secreted into human milk, and because of the potential for serious adverse reactions in nursing infants, breast-feeding should be discontinued during treatment with ravulizumab and for 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 reactions with ravulizumab are headache (30.6%), upper respiratory tract infection (21.6%), nasopharyngitis (20.4%), diarrhoea (18.7%), pyrexia (17.7%), nausea (15%), arthralgia (14.4%), back pain (13.6%), fatigue (13.3%), abdominal pain (12.3%), dizziness (10.7%) and urinary tract infection (10.7%). The most serious adverse reactions are meningococcal infection (0.7%) including meningococcal sepsis, meningococcal meningitis, encephalitis meningococcal, meningococcal infection (see section 4.4) and disseminated gonococcal infection (0.2%) including disseminated gonococcal infection and gonococcal infection.

Tabulated list of adverse reactions

Table 7 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 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 7: Adverse Drug reactions from clinical trials and postmarketing experience

MedDRA System Organ Class

Very common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon (≥ 1/1,000 to < 1/100)

Infections and infestations

Urinary tract infectiona

Upper respiratory tract infection, Nasopharyngitis

Meningococcal infectionb, Disseminated Gonococcal infectionc

Immune system disorders

Hypersensitivitye

Anaphylactic reactiond

Nervous system disorders

Dizziness, Headache

Gastrointestinal disorders

Diarrhoea, Nausea, Abdominal pain

Vomiting, Dyspepsia

Skin and subcutaneous tissue disorders

Urticaria, Pruritus, Rash

Musculoskeletal and connective tissue disorders

Arthralgia, Back pain

Myalgia, Muscle spasms

General disorders and administration site conditions

Pyrexia, Fatigue

Influenza like illness, Chills, Asthenia

Injury, poisoning and procedural complications

Infusion-related reaction

a Urinary tract infection is a group term that includes Preferred Terms: Urinary tract infection, Urinary tract infection bacterial, Urinary tract infection enterococcal, and Escherichia urinary tract infection.

bMeningococcal infection includes preferred terms of meningococcal infection, meningococcal sepsis, meningococcal meningitis and encephalitis meningococcal

c Disseminated gonococcal infection includes preferred terms of disseminated gonococcal infection and gonococcal infection

d Estimated from postmarketing experience

e Hypersensitivity is a group term for Preferred Term drug hypersensitivity with related causality and Preferred Term hypersensitivity

Description of selected adverse reactions

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 with ravulizumab; 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 meningococcal infection. In patients treated with ravulizumab, meningococcal infections have presented as meningococcal sepsis and encephalitis meningococcal. Patients should be informed of the signs and symptoms of meningococcal infection and advised to seek medical care immediately.

Infusion-related reactions

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

Immunogenicity

In adult PNH patient studies (N = 475), a paediatric PNH study (N = 13), aHUS studies (N = 89), a gMG 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 and 1 adult patient with aHUS). These anti-drug antibodies were transient in nature with low titre and did not correlate with clinical response or adverse events.

Paediatric population

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) 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 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 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 below:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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