Ultomiris

  • Name:

    Ultomiris

  • Company:
    info
  • Active Ingredients:

    Ravulizumab

  • Legal Category:

    Product subject to restricted prescription (C)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 24/09/20

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Summary of Product Characteristics last updated on medicines.ie: 23/9/2020
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

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Alexion Pharma UK Ltd

Alexion Pharma UK Ltd

Company Products

Medicine NameActive Ingredients
Medicine Name Kanuma Active Ingredients Sebelipase alfa
Medicine Name Soliris Active Ingredients Eculizumab
Medicine Name Strensiq 100mg/ml Active Ingredients Asfotase alfa
Medicine Name Strensiq 40mg/ml Active Ingredients Asfotase alfa
Medicine Name Ultomiris Active Ingredients Ravulizumab
1 - 0 of 5 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 24 September 2020 PIL

Reasons for updating

  • Change to Section 1 - what the product is
  • Change to section 2 - use in children and adolescents
  • Change to section 3 - use in children/adolescents
  • Change to section 3 - duration of treatment
  • Change to section 4 - possible side effects
  • Change to section 4 - how to report a side effect
  • Change to section 6 - date of revision
  • Changes to therapeutic indications

Free text change information supplied by the pharmaceutical company

Addition of aHUS indication 

Updated on 23 September 2020 SmPC

Reasons for updating

  • Change to section 6.3 - Shelf life
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

Extension of shelf life to 30 months

Updated on 27 August 2020 Ed-Both

Reasons for updating

  • Add New Doc

Updated on 27 August 2020 Ed-HCP

Reasons for updating

  • Replace document

Updated on 27 August 2020 Ed-Both

Reasons for updating

  • Replace document

Updated on 27 August 2020 Ed-Both

Reasons for updating

  • Replace document

Updated on 30 June 2020 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

Addition of a new therapeutic indication - treatment of atypical haemolytic uremic syndrome (aHUS) in adults and children - resulted in the following SmPC updates (changes highlighted in red):

4.1     Therapeutic indications

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

  • in patients with haemolysis with clinical symptom(s) indicative of high disease activity.
  • in patients who are clinically stable after having been treated with eculizumab for at least the past 6 months (see section 5.1).

Ultomiris is indicated in the treatment of patients with a body weight of 10 kg or above with atypical haemolytic uremic syndrome (aHUS) who are complement inhibitor treatment-naïve or have received eculizumab for at least 3 months and have evidence of response to eculizumab (see section 5.1).

4.2     Posology and method of administration

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

Posology

Adult patients with PNH and aHUS

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

(...)

Table 1 have been updated to include dosing interval

Table 1:                Ravulizumab weight-based dosing regimen

Body weight range (kg)

Loading dose (mg)

Maintenance dose (mg)*

Dosing interval

≥ 40 to < 60

2,400

3,000

Every 8 weeks

≥ 60 to < 100

2,700

3,300

Every 8 weeks

≥ 100

3,000

3,600

Every 8 weeks

*Maintenance dose is administered 2 weeks after loading dose

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

There is no experience of concomitant PE/PI (plasmapheresis or plasma exchange, or fresh frozen plasma infusion) use with ravulizumab. Administration of PE/PI may reduce ravulizumab serum levels.

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

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

Special populations

(...)

Renal impairment

In aHUS clinical trials, patients with renal impairment including on dialysis were included. No dose adjustment is required in this population, see section 5.2.

(...)

Paediatric population

Paediatric patients with aHUS with body weight ≥ 40 kg are treated in accordance with the adult dosing recommendations. The weight-based doses and dosing intervals for paediatric patients ≥ 10 kg to < 40 kg is shown in Table 2.

Table 2:     Ravulizumab weight-based dosing regimen for paediatric patient below 40 kg

Body weight range (kg)

Loading dose (mg)

Maintenance dose (mg)*

Dosing interval

≥ 10 to < 20

600

600

Every 4 weeks

≥ 20 to < 30

900

2,100

Every 8 weeks

≥ 30 to < 40

1200

2,700

Every 8 weeks

*Maintenance dose is administered 2 weeks after loading dose

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

(...)

Method of administration

Table 3 has been update to include paediatric patients with body weight less than 40kg

Table 3:    Dose administration rate

Body weight range (kg)a

Loading dose (mg)

Minimum infusion duration

minutes (hours)

Maintenance dose (mg)

Minimum infusion duration

minutes (hours)

≥ 10 to < 20

600

113 (1.9)

600

113 (1.9)

≥ 20 to < 30

900

86 (1.5)

2,100

194 (3.3)

≥ 30 to < 40

1,200

77 (1.3)

2,700

167 (2.8)

 40 to < 60

2,400

114 (1.9)

3,000

140 (2.4)

 60 to < 100

2,700

102 (1.7)

3,300

120 (2.0)

 100

3,000

108 (1.8)

3,600

132 (2.2)

a Body weight at time of treatment.

(...)

4.4     Special warnings and precautions for use

(...)

Immunization

Prior to initiating ravulizumab therapy, it is recommended that PNH and aHUS patients initiate immunizations according to current immunization guidelines.

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

Patients below the age of 18 years old must be vaccinated against Haemophilus influenzae and pneumococcal infections, and strictly need to adhere to the national vaccination recommendations for each age group.

(...)

Infusion reactions

Administration of ravulizumab may result in infusion reactions. In clinical trials with PNH and aHUS, [(4 out of 296 in patients with PNH) and (4 of 89 patients with aHUS)] patients experienced infusion reactions which were mild in severity and transient [e.g., lower back pain, drop in blood pressure, elevation in blood pressure, limb discomfort,  drug hypersensitivity (allergic reaction), and dysgeusia (bad taste)]. In case of infusion reaction, infusion of ravulizumab should be interrupted and appropriate supportive measures should be instituted if signs of cardiovascular instability or respiratory compromise occur.

(...)

Treatment discontinuation for aHUS

There are no specific data on ravulizumab discontinuation. In a long-term prospective observational study, discontinuation of complement C5 inhibitor treatment (eculizumab) resulted in a 13.5-fold higher rate of TMA recurrence and showed a trend toward reduced renal function compared to patients who continued treatment.

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

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

(i)      At least two of the following laboratory results observed concurrently: a decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ravulizumab treatment; an increase in serum creatinine of 25% or more as compared to baseline or to nadir during ravulizumab treatment; or, an increase in serum LDH of 25% or more as compared to baseline or to nadir during ravulizumab treatment (results should be confirmed by a second measurement )

Or

(ii)     any one of the following symptoms of TMA: a change in mental status or seizures or other extra‑renal TMA manifestations including cardiovascular abnormalities, pericarditis, gastrointestinal symptoms/diarrhoea; or thrombosis.

If TMA complications occur after ravulizumab discontinuation, consider reinitiation of ravulizumab treatment beginning with the loading dose and maintenance dose described in section 4.2.

(...)

4.8     Undesirable effects

Summary of the safety profile

The most common adverse drug reactions (very common frequency) are diarrhoea, nausea, vomiting, nasopharyngitis and headache. The most serious adverse reactions in patients in clinical trials are meningococcal infection and meningococcal sepsis (see section 4.4).

Tabulated list of adverse reactions

Table 4 gives the adverse reactions observed from PNH and aHUS clinical trials.

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

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

Table 4:        Adverse reactions

MedDRA System Organ Class

Very common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon (≥ 1/1,000 to < 1/100)

Infections and infestations

Upper respiratory tract infection, Nasopharyngitis

 

Meningococcal infection*

Nervous system disorders

Headache

Dizziness

 

Gastrointestinal disorders

Diarrhoea, Nausea,

Abdominal pain, Vomiting, Dyspepsia

 

Skin and subcutaneous tissue disorders

 

Rash, Pruritus

 

Musculoskeletal and connective tissue disorders

 

Arthralgia, Back pain, Myalgia, Muscle spasms

 

General disorders and administration site conditions

Pyrexia, Fatigue

Influenza like illness, Asthenia

Chills

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

Description of selected adverse reactions

Meningococcal infection/sepsis

Vaccination reduces, but does not eliminate, the risk of meningococcal infections. In clinical trials, 3 out of 261 PNH patients developed serious meningococcal infections/sepsis while receiving treatment with ravulizumab; all 3 had been vaccinated. All 3 recovered while continuing treatment with ravulizumab. In aHUS studies, no meningococcal infections occurred among 89 patients receiving treatment with ravulizumab. Please refer to section 4.4 for information on prevention and treatment of suspected meningococcal infection. Meningococcal infections in patients treated with ravulizumab presented as meningococcal sepsis. Patients should be informed of the signs and symptoms of meningococcal septicaemia and advised to seek medical care immediately.

Immunogenicity

Treatment with any therapeutic protein may induce an immune response. In PNH patient studies (N = 261) and aHUS studies (N=89), only 2 (0.57 %) cases of development of treatment-emergent anti-drug antibody have been reported with ravulizumab. These anti-drug antibodies were transient in nature with low titre and did not correlate with clinical response or adverse events.

Paediatric population

In paediatric patients with evidence of aHUS (aged 10 months to less than 18 years) included in ALXN1210‑aHUS‑312 study, the safety profile of ravulizumab appeared similar to that observed in adult patients with evidence of aHUS. The safety profiles in the different paediatric subsets of age appear similar. The safety data for patient below 2 years of age is limited to four patients. The most common adverse reaction reported in paediatric patients was pyrexia. 

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

 

Reporting of suspected adverse reactions

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

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

Adverse events should also be reported to Alexion Pharma UK Ltd on uk.adverseevents@alexion.com, Freephone (Ireland): 1 800 936 544.

(...)

5.1     Pharmacodynamic properties

(...)

Pharmacodynamic effects

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

The extent and duration of the pharmacodynamic response in patients with PNH and aHUS were exposure dependent for ravulizumab. Free C5 levels less than 0.5 µg/mL were correlated with maximal intravascular haemolysis control and complete terminal complement inhibition.

(...)

Atypical Haemolytic Uremic Syndrome (aHUS)

Study in adult patients with aHUS

The adult study was a multicentre, single arm, Phase 3 study conducted in patients with documented aHUS who were naïve to complement inhibitor treatment prior to study entry and had evidence of thrombotic microangiopathy (TMA). The study consisted of a 26-week Initial Evaluation Period and patients were allowed to enter an extension period for up to 4.5 years.

A total of 58 patients with documented aHUS were enrolled. Enrolment criteria excluded patients presenting with TMA due to thrombotic thrombocytopenic purpura (TTP) or Shiga toxin Escherichia coli related haemolytic uremic syndrome (STEC HUS). Two patients were excluded from the Full Analysis Set due to a confirmed diagnosis of STEC HUS. Ninety-three percent of patients had extra renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline.

Table 7 presents the demographics and baseline characteristics of the 56 adult patients enrolled in Study ALXN1210‑aHUS‑311 that constituted the Full Analysis Set.

Table 7:     Baseline characteristics in the adult study

Parameter

Statistics

Ravulizumab
(N = 56)

Age at time of first infusion (years)

Mean (SD)

Min, max

42.2 (14.98)

19.5, 76.6

Sex

  Male

 

n (%)

 

19 (33.9)

Race a

  Asian

  White

  Other

n (%)

 

15 (26.8)

29 (51.8)

12 (21.4)

History of transplant

n (%)

8 (14.3)

Platelets (109/L) blood

 

n

Median (min,max)

56

95.25 (18, 473)

Haemoglobin (g/L) blood

 

n

Median (min,max)

56

85.00 (60.5, 140)

LDH (U/L) serum

 

n

Median (min,max)

56

508.00 (229.5, 3249)

eGFR (mL/min/1.73 m2)

 

n (%)

Median (min,max)

55

10.00 (4, 80)

Patients on dialysis

N (%)

29 (51.8)

Patients post-partum

N (%)

8 (14.3)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Note: Percentages are based on the total number of patients.

Abbreviations: aHUS = atypical haemolytic uremic syndrome; eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; max = maximum; min = minimum.

The primary endpoint was Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalisation of haematological parameters (platelet count ≥ 150 x 109/L and LDH ≤ 246U/L) and ≥ 25% improvement in serum creatinine from baseline. Patients had to meet each Complete TMA Response criteria at 2 separate assessments obtained at least 4 weeks (28 days) apart, and any measurement in between.

Complete TMA Response was observed in 30 of the 56 patients (53.6%) during the 26-week Initial Evaluation Period as shown in Table 8.

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

 

       Total

                        Responder

     n                 Proportion (95% CI)a

Complete TMA Response

56

30

0.536 (0.396, 0.675)

Components of Complete TMA Response

 

 

 

Platelet count normalisation

56

47

0.839 (0.734, 0.944)

LDH normalisation

56

43

0.768 (0.648, 0.887)

≥25% improvement in serum creatinine from baseline

56

33

0.589 (0.452, 0.727)

Haematologic normalisation

56

41

0.732 (0.607, 0.857)

 

a 95% CIs for the proportion were based on the asymptotic Gaussian approximation method with a continuity correction.

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

Four additional patients had a Complete TMA Response that was confirmed after the 26-week Initial Evaluation Period (with a Complete TMA Response occurring at Days 169, 302, 401 and 407). resulting in an overall Complete TMA Response in 34 of 56 patients (60.7%; 95% CI: 47.0%, 74.4%). Individual component response increased to 48 (85.7%; 95% CI: 75.7%, 95.8%) patients for platelet count normalization, 47 (83.9%; 95% CI: 73.4%, 94.4%) patients for LDH normalization, and 35 (62.5%; 95% CI: 48.9%, 76.1%) patients for renal function improvement.

Complete TMA Response was achieved at a median time of 86 days (7 to 169 days). An increase in mean platelet count was observed rapidly after commencement of ravulizumab, increasing from 118.52 × 109/L at baseline to 240.34 × 109/L at Day 8 and remaining above 227 × 109/L at all subsequent visits in the Initial Evaluation Period (26 weeks). Similarly, mean LDH value decreased from baseline over the first 2 months of treatment and was sustained over the duration of the Initial Evaluation Period (26 weeks).

Of the patients who presented at CKD Stage 5, 67.6% (23/34) showed an improvement of 1 or more CKD Stages. Chronic kidney disease stage continued to improve for many patients (19/30) after achieving Complete TMA Response during the 26-week Initial Evaluation Period. Seventeen of the 29 patients who required dialysis at study entry were able to discontinue dialysis by the end of the available follow-up while 6 of 27 patients who were off dialysis at baseline were on dialysis at last available follow-up. Table 9 summarises the secondary efficacy outcomes for Study ALXN1210‑aHUS-311.

Table 9:     Secondary Efficacy Outcome for Study ALXN1210‑aHUS‑311

Parameters

Study ALXN1210‑aHUS‑311

(N = 56)

Haematologic TMA parameters, Day 183

Platelets (109/L) blood

Mean (SD)

Median

LDH (U/L) serum

Mean (SD)

Median

Observed value (n=48)

 

237.96 (73.528)

232.00

 

194.46 (58.099)

176.50

Change from baseline (n=48)

 

114.79 (105.568)

125.00

 

-519.83 (572.467)

-310.75

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

m/n

proportion (95% CI)**

 

 

 

40/56

0.714 (0.587, 0.842)

CKD stage shift from baseline, Day 183

Improveda

m/n

Proportion (95% CI)*

Worsenedb

m/n

Proportion (95% CI)*

 

 

32/47

0.681 (0.529, 0.809)

 

2/13

0.154 (0.019, 0.454)

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

Mean (SD)

Median

Observed value (n=48)

51.83 (39.162)

40.00

Change from baseline (n=47)

34.80 (35.454)

29.00

Note: n: number of patients with available data for specific assessment at Day 183 visit. m: number of patients meeting specific criterion. Chronic kidney disease (CKD) stage is classified based on the National Kidney Foundation Chronic Kidney Disease Stage. Stage 5 is considered the worst category, while Stage 1 is considered the best category. Baseline is derived based on the last available eGFR before starting treatment. Improved/Worsened: compared to CKD stage at baseline. *95% confidence intervals (95% CIs) are based on exact confidence limits using the Clopper‑Pearson method  aExcludes those with CKD Stage 1 at baseline as they cannot improve .bExcludes patients with Stage 5 at baseline as they cannot worsen.

Abbreviations: eGFR = estimated glomerular filtration rate; Therapy; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy.

 

Paediatric population

Paroxysmal Nocturnal Haemoglobinuria

Ultomiris has not been evaluated in paediatric patients with PNH.

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

 

Atypical Haemolytic Uremic Syndrome (aHUS)

Use of Ultomiris in paediatric patients for treatment of aHUS is supported by evidence from one paediatric clinical study (a total of 31 patients with documented aHUS were enrolled. 28 patients aged 10 months to 17 years were included in the Full Analysis set).

Study in Paediatric Patients with aHUS

The Paediatric Study is a 26-week ongoing, multicenter, single arm, Phase 3 study conducted in paediatric patients.

A total of 21 eculizumab-naïve patients with documented diagnosis of aHUS and evidence of TMA were enrolled, of which 18 were included in the Full Analysis set. Enrolment criteria excluded patients presenting with TMA due to TTP and STEC-HUS. Two patients were given a single dose, and one patient received 2 doses, but then discontinued and were excluded from the Full Analysis Set because aHUS was not confirmed. The overall mean weight at baseline was 22.2 kg;majority of the patients were in the baseline weight category ≥ 10 to < 20 kg. The majority of patients (72.2%) had pretreatment extra renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline. At baseline, 33.3% (n = 6) of patients had CKD Stage 5.

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

Table 10 presents the baseline characteristics of the paediatric patients enrolled in Study ALXN1210-aHUS-312.

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

Parameter

Statistics

Ravulizumab
(Naïve, N = 18)

Ravulizumab
(Switch, N = 10)

Age at time of first infusion (years) category

Birth to < 2 years

2 to < 6 years

6 to < 12 years

12 to < 18 years

n (%)

 

2 (11.1)

9 (50.0)

5 (27.8)

2 (11.1)

 

1 (10.0)

1 (10.0)

1 (10.0)

7 (70.0)

Sex

Male

n (%)

 

8 (44.4)

 

9 (90.0)

Racea

American Indian or Alaskan Native

Asian

Black or African American

White

Unknown

n (%)

 

1 (5.6)

5 (27.8)

3 (16.7)

9 (50.0)

1 (5.6)

 

0 (0.0)

4 (40.0)

1 (10.0)

5 (50.0)

0 (0.0)

History of transplant

n (%)

1 (5.6)

1 (10.0)

Platelets (109/L) blood

Median (min, max)

51.25 (14, 125)

281.75 (207, 415.5)

Haemoglobin (g/L)

Median (min, max)

74.25 (32, 106)

132.0 (114.5, 148)

LDH (U/L)

Median (min, max)

1963.0 (772, 4985)

206.5 (138.5, 356)

eGFR (mL/min/1.73 m2)

Median (min, max)

22.0 (10, 84)

99.75 (54, 136.5)

Required dialysis at baseline

n (%)

6 (33.3)

0 (0.0)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Note: Percentages are based on the total number of patients.

a Patients can have multiple races selected.

Abbreviations: aHUS = atypical haemolytic uremic syndrome; eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; max = maximum; min = minimum.

The primary endpoint was Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalisation of haematological parameters (platelet ≥ 150 x 109/L and LDH ≤246 U/L) and ≥ 25% improvement in serum creatinine from baseline. Patients had to meet all Complete TMA Response criteria at 2 separate assessments obtained at least 4 weeks (28 days) apart, and any measurement in between.

Complete TMA Response was observed in 14 of the 18 naïve patients (77.8%) during the 26-week Initial Evaluation Period as shown in Table 11.

Table 11:   Complete TMA Response and Complete TMA Response Components Analysis During the 26-Week Initial Evaluation Period (ALXN1210-aHUS-312)

 

Total

Responder

n           Proportion (95% CI)a

Complete TMA Response

18

14

0.778 (0.524, 0.936)

Components of Complete TMA Response

 

 

 

  Platelet count normalisation

18

17

0.944 (0.727, 0.999)

  LDH normalisation

18

16

0.889 (0.653, 0.986)

  ≥25% improvement in serum creatinine from baseline

18

15

0.833 (0.586, 0.964)

Haematologic normalisation

18

16

0.889 (0.653, 0.986)

Note: 1 patient withdrew from study after receiving 2 doses of ravulizumab.

a 95% CIs for the proportion were based on the asymptotic Gaussian approximation method with a continuity correction.

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

Complete TMA Response during the Initial Evaluation Period was achieved at a median time of 30 days (15 to 97 days). All patients with Complete TMA Response maintained it through the Initial Evaluation Period with continuous improvements seen in renal function. An increase in mean platelet count was observed rapidly after commencement of ravulizumab, increasing from 60.50 × 109/L at baseline to 296.67 × 109/L at Day 8 and remained above 296 × 109/L at all subsequent visits in the Initial Evaluation Period (26 weeks).

Three additional patients had a Complete TMA Response that was confirmed after the 26-week Initial Evaluation Period (with a Complete TMA Response occurring at Days 291, 297 and 353); thus, 17 of 18 (94.4%) paediatric patients (95% CI: 72.7%, 99.9%) had a Complete TMA Response .  Individual component response increased to 17 of 18 (94.4%; 95% CI: 72.7%, 99.9%) patients for platelet count normalization, 17 of 18 (94.4%; 95% CI: 72.7%, 99.9%) patients for LDH normalization, and 17 of 18 (94.4%; 95% CI: 72.7%, 99.9%) patients for renal function improvement.

All 6 of the patients who required dialysis at study entry were able to discontinue dialysis; 5 of which had already done so by Day 43. No patient started dialysis during the study. The majority of the patient population (15/17), improved by 1 or more CKD stages by Day 183; 14 patients improved by 2 or more stages. Table 12 summarises the secondary efficacy results for Study ALXN1210‑aHUS‑312.

Table 12:   Secondary Efficacy Outcome for Study ALXN1210‑aHUS‑312

Parameters

Study ALXN1210‑aHUS‑312

(N=18)

Haematologic TMA parameters, Day 183

Platelets (109/L) blood

Mean (SD)

Median

LDH (U/L) serum

Mean (SD)

Median

Observed value (n=17)

 

304.94 (75.711)

318.00

 

262.41 (59.995)

247.00

Change from baseline (n=17)

 

245.59 (91.827)

247.00

 

-2044.13 (1328.059)

-1851.50

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

m/N

proportion (95% CI)*

 

 

 

16/18

0.889 (0.653, 0.986)

CKD stage shift from baseline, Day 183

Improveda

m/n

Proportion (95% CI)*

Worsenedb

m/n

Proportion (95% CI)*

 

 

15/17

0.882 (0.636, 0.985)

 

0/11

0.000 (0.000, 0.285)

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

Mean (SD)

Median

Observed value (n=17)

108.5 (56.87)

108.0

Change from baseline

(n=17)

85.4 (54.33)

80.0

Note: n: number of patients with available data for specific assessment at Day 183 visit. m: number of patients meeting specific criterion. Chronic kidney disease (CKD) stage is classified based on the National Kidney Foundation Chronic Kidney Disease Stage. . Stage 1 is considered the best category ,while Stage 5 is considered the worst category. Baseline is derived based on the last available eGFR before starting treatment. Improved/Worsened: Compared to CKD stage at baseline.

*95% confidence intervals (95% CIs) are based on exact confidence limits using the Clopper Pearson method.

a Improved excludes patients with Stage 1 at baseline, as they cannot improve; bworsened excludes patients with Stage 5 at baseline as they cannot worsen.

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

In eculizumab-experienced patients, switching to ravulizumab maintained disease control as evidenced by stable hematologic and renal parameters, with no apparent impact on safety.

The efficacy of ravulizumab for the treatment of aHUS appears similar in paediatric and adult patients.

5.2    Pharmacokinetic properties

(...)

Distribution

The mean (standard deviation [SD]) volume of distribution at steady state for patients with PNH and aHUS on the studied weight-based dose regimen was 5.35 (0.92) L and 5.22 (1.85) L respectively.

Biotransformation and elimination

As an immunoglobulin gamma (IgG) monoclonal antibody, ravulizumab is expected to be metabolized in the same manner as any endogenous IgG (degraded into small peptides and amino acids via catabolic pathways), and is subject to similar elimination. Ravulizumab contains only natural occurring amino acids and has no known active metabolites. The mean (SD) values for terminal elimination half-life and clearance of ravulizumab in patients with PNH and aHUS are 49.7 (8.9) days and 0.08 (0.022) L/day and 51.8 (16.2) days and 0.08 (0.04) L/day, respectively.

(...)

Weight

Body weight is a significant covariate in patients with PNH and aHUS, resulting in lower exposures in heavier patients. Weight-based dosing is proposed in section 4.2, Table 1.

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

The pharmacokinetics of ravulizumab have been studied in aHUS patients with a range of renal impairment including patients receiving dialysis. There have been no observed differences in pharmacokinetic parameters noted in these subpopulations of patients including patients with proteinuria.

(...)

6.6     Special precautions for disposal and other handling

(...)

Table 13:   Loading dose administration reference table

Body weight range (kg)a

Loading dose (mg)

Ultomiris volume (mL)

Volume of NaCl diluentb (mL)

Total volume (mL)

≥ 10 to < 20

600

60

60

120

≥ 20 to < 30

900

90

90

180

≥ 30 to < 40

1200

120

120

240

 40 to < 60

2,400

240

240

480

 60 to < 100

2,700

270

270

540

 100

3,000

300

300

600

a   Body weight at time of treatment.

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

 

Table 14:   Maintenance dose administration reference table

Body weight range (kg)a

Maintenance dose (mg)

Ultomiris volume (mL)

Volume of NaCl diluentb (mL)

Total volume (mL)

≥ 10 to < 20

600

60

60

120

≥ 20 to < 30

2100

210

210

420

≥ 30 to < 40

2700

270

270

540

 40 to < 60

3,000

300

300

600

 60 to < 100

3,300

330

330

660

 100

3,600

360

360

720

a  Body weight at time of treatment.

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

(...)

10.    DATE OF REVISION OF THE TEXT

25 June 2020

 

Updated on 30 June 2020 PIL

Reasons for updating

  • Change to section 1 - what the product is used for
  • Change to section 2 - use in children and adolescents
  • Change to section 3 - use in children/adolescents
  • Change to section 3 - how to take/use
  • Change to section 3 - duration of treatment
  • Change to section 4 - possible side effects
  • Change to section 4 - how to report a side effect
  • Change to section 6 - date of revision
  • Change to information for healthcare professionals

Free text change information supplied by the pharmaceutical company

    What Ultomiris is and what it is used for

(...)

What is Ultomiris used for

Ultomiris is used to treat adult patients with a disease called Paroxysmal Nocturnal Haemoglobinuria (PNH). In patients with PNH, the complement system is overactive and attacks their red blood cells, which can lead to low blood counts (anaemia), tiredness, difficulty in functioning, pain, abdominal pain, dark urine, shortness of breath, difficulty swallowing, erectile dysfunction and blood clots. By attaching to and blocking the C5 protein, this medicine can stop complement proteins from attacking red blood cells and so control symptoms of the disease.

Ultomiris is also used to treat both adult and children patients with a disease affecting the blood system and kidney called atypical Haemolytic Uremic Syndrome  (aHUS). In patients with aHUS, their kidneys and blood vessels, including platelets, can be inflamed which can lead to low blood counts (thrombocytopenia and anaemia), reduced or lost kidney function, blood clots, tiredness and difficulty in functioning. Ultomiris can block the body’s inflammatory response, and its ability to attack and destroy its own vulnerable blood vessels and so control symptoms of the disease including injury to the kidneys.

(...)

2.       What you need to know before you use Ultomiris

(...)

Children and adolescents

Patients less than 18 years of age must be vaccinated against Haemophilus influenzae and pneumococcal infections.

(...)

3.       How to use Ultomiris

At least 2 weeks before you start treatment with Ultomiris, your doctor will give you a vaccine against meningococcal infections if you have not previously had one or if your vaccination is outdated. If you cannot be vaccinated at least 2 weeks before you start treatment with Ultomiris, your doctor will prescribe antibiotics to reduce the risk of infection until 2 weeks after you have been vaccinated.

If your child is less than 18 years, your doctor will administer a vaccine (if not yet done) against Haemophilus influenzae and pneumococcal infections according to the national vaccination recommendations for each age group.

Instructions for proper use

Ultomiris is given by infusion (drip) into a vein. The infusion will take approximately 2 hours.

Your dose will be worked out by your doctor, based on your body weight, as shown in Table 1. Your first dose is called the loading dose. Two weeks after receiving your loading dose, you will be given a maintenance dose of Ultomiris, and this will then be repeated once every 8 weeks for patient above 20 kg and every 4 weeks for patient less than 20 kg.

If you were previously receiving another medicine for PNH and aHUS called Soliris, the loading dose should be given 2 weeks after the last Soliris infusion.

Table 1:  Ultomiris weight-based dosing regimen

Body weight range (kg)

Loading dose (mg)

Maintenance dose (mg)

10 to less than 20

600

600

20 to less than 30

900

2,100

30 to less than 40

1,200

2,700

40 to less than 60

2,400

3,000

60 to less than 100

2,700

3,300

above 100

3,000

3,600

(...)

If you stop using Ultomiris for aHUS

Interrupting or ending treatment with Ultomiris may cause your aHUS symptoms to come back. Your doctor will discuss the possible side effects with you and explain the risks. Your doctor will want to monitor you closely.

The risks of stopping Ultomiris include an increase in small blood vessel damage, which may cause:

-        A significant fall in your platelets (thrombocytopenia),

-        A significant rise in destruction of your red blood cells,

-        Decreased urination (problems with your kidneys),

-        An increase in your serum creatinine level (problems with your kidneys),

-        Confusion or change in how alert you are,

-        Change in your vision

-        Chest pain, or angina,

-        Shortness of breath, or

-        Thrombosis (blood clotting).  

If you have any of these symptoms, contact your doctor.

(...)

4.      Possible side effects

(...)

Very common (may affect more than 1 in 10 people):

  • Headache
  • Nausea, diarrhoea, upper respiratory tract infection
  • Common cold (nasopharyngitis)
  • Fever (pyrexia), feeling tired (fatigue)

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

  • dizziness
  • abdominal pain, vomiting, stomach discomfort after meals (dyspepsia)
  • rash, itchy skin (pruritus) 
  • back pain, joint pain (arthralgia), muscle pain (myalgia) and muscle spasms
  • Influenza like illness, feeling tired (asthenia)

Uncommon (may affect up to 1 in 100 people):

  • meningococcal infection
  • chills

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system detailed below:

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

(...)

6.       Contents of the pack and other information

(...)

This leaflet was last revised in June 2020.

(...)

Instructions for Use for Healthcare Professionals Handling Ultomiris (tables updated to include patients with weight less than 40kg)

(...)

Table 1: Loading dose administration reference table

Body weight range (kg)a

Loading dose (mg)

Ultomiris volume (mL)

Volume of NaCl diluentb (mL)

Total volume (mL)

Minimum infusion duration

minutes (hours)

≥ 10 to < 20

600

60

60

120

113 (1.9)

≥ 20 to < 30

900

90

90

180

86 (1.5)

≥ 30 to < 40

1,200

120

120

240

77 (1.3)

≥ 40 to < 60

2,400

240

240

480

114 (1.9)

≥ 60 to < 100

2,700

270

270

540

102 (1.7)

≥ 100

3,000

300

300

600

108 (1.8)

a Body weight at time of treatment

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

Table 2: Maintenance dose administration reference table

Body weight range (kg)a

Maintenance dose (mg)

Ultomiris volume (mL)

Volume of NaCl diluentb (mL)

Total volume (mL)

Minimum infusion duration

minutes (hours)

≥ 10 to < 20

600

60

60

120

113 (1.9)

≥ 20 to < 30

2,100

210

210

420

194 (3.3)

≥ 30 to < 40

2,700

270

270

540

167 (2.8)

≥ 40 to < 60

3,000

300

300

600

140 (2.4)

≥ 60 to < 100

3,300

330

330

660

120 (2.0)

≥ 100

3,600

360

360

720

132 (2.2)

a Body weight at time of treatment

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

(...)

 

Updated on 24 February 2020 Ed-HCP

Reasons for updating

  • Add New Doc

Updated on 24 February 2020 Ed-Both

Reasons for updating

  • Add New Doc

Updated on 24 February 2020 Ed-Both

Reasons for updating

  • Add New Doc

Updated on 12 July 2019 PIL

Reasons for updating

  • New PIL for new product

Updated on 12 July 2019 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

New medcinal product Ultomiris:   ravulizumab 300mg concentrate for solution for infusion.