солирис

Overdose

No case of overdose has been reported.

Contraindications

Солирис therapy must not be initiated in patients :

- with unresolved Neisseria meningitidis infection

- who are not currently vaccinated against Neisseria meningitidis unless they receive prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination.

Pharmaceutical form

Undesirable effects

Summary of the safety profile

Supportive safety data were obtained from 29 completed and one ongoing clinical studies that included 1,407 patients exposed to eculizumab in ten disease populations, including PNH, aHUS, and refractory gMG. The most common adverse reaction was headache, (occurred mostly in the initial phase), and, of all meningococcal infectionsa the most frequently reported serious adverse reaction was meningococcal sepsis.

Tabulated list of adverse reactions

Table 1 gives the adverse reactions observed from spontaneous reporting and in eculizumab completed clinical trials, including PNH, aHUS and refractory gMG studies. Adverse reactions reported at a very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100) or rare (>1/10,000 to <1/1,000) frequency with eculizumab, are listed by system organ class and preferred term. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse Reactions reported in 1,407 patients included in overall eculizumab clinical trials, including patients with PNH, aHUS, and refractory gMG as well as from postmarketing experience

*See paragraph Description of selected adverse reactions

a=Meningococcal infection includes the following group of PTs: Meningococcal sepsis, Meningococcal meningitis, Neisseria infection; b = Adverse reactions identified in postmarketing reports;

Description of selected adverse reactions

In all clinical studies, including PNH and aHUS clinical trials, the most serious adverse reaction was meningococcal septicaemia. No meningococcal infections were reported in completed refractory gMG clinical studies.

Antibodies to Солирис were detected in 2% of patients with PNH using an ELISA assay and 3% of patients with aHUS using the ECL bridging format assay. In refractory gMG placebo-controlled studies, no antidrug antibodies were observed. As with all proteins there is a potential for immunogenicity.

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Paediatric population

In children and adolescent PNH patients (aged 11 years to less than 18 years) included in the paediatric PNH Study M07-005, the safety profile appeared similar to that observed in adult PNH patients. The most common adverse reaction reported in paediatric patients was headache.

In aHUS patients, the safety profile in adolescents (patients aged 12 years to less than 18 years) is consistent with that observed in adults. In paediatric aHUS patients (aged 2 months to less than 18 years) included in the aHUS studies C08-002, C08-003, C09-001r and C10-003, the safety profile appeared similar to that observed in adult aHUS patients. The safety profiles in the different paediatric subsets of age appear similar.

Солирис has not been studied in paediatric patients with refractory gMG.

Elderly population

No overall differences in safety were reported between elderly (> 65 years) and younger refractory gMG patients (< 65 years).

Patients with other diseases

Safety Data from Other Clinical Studies

Supportive safety data were obtained in 13 completed clinical studies that included 856 patients exposed to eculizumab in other disease populations other than PNH, aHUS or refractory gMG. There was an un-vaccinated patient diagnosed with idiopathic membranous glomerulonephropathy who experienced meningococcal meningitis. Adverse reactions reported in patients with disease other than PNH, aHUS, or refractory gMG were similar to those reported in patients with PNH, aHUS, or refractory gMG (see Table 1 above). No specific adverse reactions have emerged from these clinical studies.

Reporting of suspected adverse reactions

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

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

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

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

Preclinical safety data

The specificity of eculizumab for C5 in human serum was evaluated in two in vitro studies.

The tissue cross-reactivity of eculizumab was evaluated by assessing binding to a panel of 38 human tissues. C5 expression in the human tissue panel examined in this study is consistent with published reports of C5 expression, as C5 has been reported in smooth muscle, striated muscle, and renal proximal tubular epithelium. No unexpected tissue cross-reactivity was observed.

Animal reproduction studies have not been conducted with eculizumab due to lack of pharmacologic activity in non-human species.

In a 26 week toxicity study performed in mice with a surrogate antibody directed against murine C5, treatment did not affect any of the toxicity parameters examined. Haemolytic activity during the course of the study was effectively blocked in both female and male mice.

No clear treatment-related effects or adverse effects were observed in reproductive toxicology studies in mice with a surrogate terminal complement inhibitory antibody, which was utilized to assess the reproductive safety of C5 blockade. These studies included assessment of fertility and early embryonic development, developmental toxicity, and pre and post-natal development.

When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose (approximately 4 times the maximum recommended human Солирис dose, based on a body weight comparison); however, the exposure did not increase foetal loss or neonatal death.

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

Therapeutic indications

Солирис is indicated in adults and children for the treatment of:

- Paroxysmal nocturnal haemoglobinuria (PNH).

Evidence of clinical benefit is demonstrated in patients with haemolysis with clinical symptom(s) indicative of high disease activity, regardless of transfusion history.

- Atypical haemolytic uremic syndrome (aHUS).

Солирис is indicated in adults for the treatment of:

- Refractory generalized myasthenia gravis (gMG) in patients who are anti-acetylcholine receptor (AChR) antibody-positive.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Selective immunosuppressants, ATC code: L04AA25

Солирис is a recombinant humanised monoclonal IgG2/4k antibody that binds to the human C5 complement protein and inhibits the activation of terminal complement. The Солирис antibody contains human constant regions and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. Солирис is composed of two 448 amino acid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately 148 kDa.

Солирис is produced in a murine myeloma (NS0 cell line) expression system and purified by affinity and ion exchange chromatography. The bulk drug substance manufacturing process also includes specific viral inactivation and removal steps.

Mechanism of action

Eculizumab, the active ingredient in Солирис, is a terminal complement inhibitor that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. Eculizumab preserves the early components of complement activation that are essential for opsonization of microorganisms and clearance of immune complexes.

In PNH patients, uncontrolled terminal complement activation and the resulting complement-mediated intravascular haemolysis are blocked with Солирис treatment.

In most PNH patients, eculizumab serum concentrations of approximately 35 microgram/mL are sufficient for essentially complete inhibition of terminal complement-mediated intravascular haemolysis.

In PNH, chronic administration of Солирис resulted in a rapid and sustained reduction in complement-mediated haemolytic activity.

In aHUS patients, uncontrolled terminal complement activation and the resulting complement-mediated thrombotic microangiopathy are blocked with Солирис treatment.

All patients treated with Солирис when administered as recommended demonstrated rapid and sustained reduction in terminal complement activity. In all aHUS patients, eculizumab serum concentrations of approximately 50 - 100 microgram/mL are sufficient for essentially complete inhibition of terminal complement activity.

In aHUS, chronic administration of Солирис resulted in a rapid and sustained reduction in complement-mediated thrombotic microangiopathy.

In refractory gMG patients, uncontrolled terminal complement activation causes membrane attack complex (MAC) dependent lysis and C5a-dependent inflammation at the Neuromuscular Junction (NMJ) leading to failure of neuromuscular transmission. Chronic administration of Солирис results in immediate, complete, and sustained inhibition of terminal complement activity.

Clinical efficacy and safety

Paroxysmal Nocturnal Haemoglobinuria

The safety and efficacy of Солирис in PNH patients with haemolysis were assessed in a randomized, double-blind, placebo-controlled 26 week study (C04-001). PNH patients were also treated with Солирис in a single arm 52 week study (C04-002), and in a long term extension study (E05-001). Patients received meningococcal vaccination prior to receipt of Солирис. In all studies, the dose of eculizumab was 600 mg every 7 ± 2 days for 4 weeks, followed by 900 mg 7 ± 2 days later, then 900 mg every 14 ± 2 days for the study duration. Солирис was administered as an intravenous infusion over 25 - 45 minutes. An observational non-interventional Registry in patients with PNH (M07-001) was also initiated to characterize the natural history of PNH in untreated patients and the clinical outcomes during Солирис treatment.

In study C04-001 (TRIUMPH) PNH patients with at least 4 transfusions in the prior 12 months, flow cytometric confirmation of at least 10% PNH cells and platelet counts of at least 100,000/microliter were randomized to either Солирис (n = 43) or placebo (n = 44). Prior to randomization, all patients underwent an initial observation period to confirm the need for RBC transfusion and to identify the haemoglobin concentration (the "set-point") which would define each patient's haemoglobin stabilization and transfusion outcomes. The haemoglobin set-point was less than or equal to 9 g/dL in patients with symptoms and was less than or equal to 7 g/dL in patients without symptoms. Primary efficacy endpoints were haemoglobin stabilization (patients who maintained a haemoglobin concentration above the haemoglobin set-point and avoid any RBC transfusion for the entire 26 week period) and blood transfusion requirement. Fatigue and health-related quality of life were relevant secondary endpoints. Haemolysis was monitored mainly by the measurement of serum LDH levels, and the proportion of PNH RBCs was monitored by flow cytometry. Patients receiving anticoagulants and systemic corticosteroids at baseline continued these medications. Major baseline characteristics were balanced (see Table 2).

In the non-controlled study C04-002 (SHEPHERD), PNH patients with at least one transfusion in the prior 24 months and at least 30,000 platelets/microliter received Солирис over a 52-week period. Concomitant medications included anti-thrombotic agents in 63% of the patients and systemic corticosteroids in 40% of the patients. Baseline characteristics are shown in Table 2.

Table 2: Patient Demographics and Characteristics in C04-001 and C04-002

In TRIUMPH, study patients treated with Солирис had significantly reduced (p< 0.001) haemolysis resulting in improvements in anaemia as indicated by increased haemoglobin stabilization and reduced need for RBC transfusions compared to placebo treated patients (see Table 3). These effects were seen among patients within each of the three pre-study RBC transfusion strata (4 - 14 units; 15 - 25 units; > 25 units). After 3 weeks of Солирис treatment, patients reported less fatigue and improved health-related quality of life. Because of the study sample size and duration, the effects of Солирис on thrombotic events could not be determined. In SHEPHERD study, 96 of the 97 enrolled patients completed the study (one patient died following a thrombotic event). A reduction in intravascular haemolysis as measured by serum LDH levels was sustained for the treatment period and resulted in increased transfusion avoidance, a reduced need for RBC transfusion and less fatigue. See Table 3.

Table 3: Efficacy Outcomes in C04-001 and C04-002

* Results from study C04-002 refer to pre- versus post-treatment comparisons.

From the 195 patients that originated in C04-001, C04-002 and other initial studies, Солирис-treated PNH patients were enrolled in a long term extension study (E05-001). All patients sustained a reduction in intravascular haemolysis over a total Солирис exposure time ranging from 10 to 54 months. There were fewer thrombotic events with Солирис treatment than during the same period of time prior to treatment. However, this finding was shown in non-controlled clinical trials.

The PNH registry (M07-001) was used to evaluate the efficacy of Солирис in PNH patients with no history of RBC transfusion. These patients had high disease activity as defined by elevated haemolysis (LDH >1.5x ULN) and the presence of related clinical symptom(s): fatigue, haemoglobinuria, abdominal pain, shortness of breath (dyspnoea), anaemia (haemoglobin <100 g/L), major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction.

In the PNH Registry, patients treated with Солирис were observed to have a reduction in haemolysis and associated symptoms. At 6 months, patients treated with Солирис with no history of RBC transfusion had significantly (p<0.001) reduced LDH levels (median LDH of 305 U/L; Table 4). Furthermore, 74% of the patients without a history of transfusion and treated with Солирис experienced clinically meaningful improvements in FACIT-Fatigue score (i.e., increase by 4 points or more) and 84% in EORTC fatigue score (i.e., decrease by 10 points or more).

Table 4: Efficacy Outcomes (LDH level and FACIT-Fatigue) in Patients with PNH with No History of Transfusion in M07-001

FACIT-Fatigue is measured on a scale of 0-52, with higher values indicating less fatigue

Atypical Haemolytic Uremic Syndrome

Data from 100 patients in four prospective controlled studies, three in adult and adolescent patients (C08-002A/B C08-003A/B, C10-004) one in paediatric and adolescent patients (C10-003 ) and 30 patients in one retrospective study (C09-001r) were used to evaluate the efficacy of Солирис in the treatment of aHUS.

Study C08-002A/B was a prospective, controlled, open-label study which accrued patients in the early phase of aHUS with evidence of clinical thrombotic microangiopathy manifestations with platelet count ≤ 150 x 109/L despite PE/PI, and LDH and serum creatinine above upper limits of normal.

Study C08-003A/B was a prospective, controlled, open-label study which accrued patients with longer term aHUS without apparent evidence of clinical thrombotic microangiopathy manifestations and receiving chronic PE/PI (>1 PE/PI treatment every two weeks and no more than 3 PE/PI treatments/week for at least 8 weeks before the first dose). Patients in both prospective studies were treated with Солирис for 26 weeks and most patients enrolled into a long-term, open-label extension study. All patients enrolled in both prospective studies had an ADAMTS-13 level above 5%.

Patients received meningococcal vaccination prior to receipt of Солирис or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. In all studies, the dose of Солирис in adult and adolescent aHUS patients was 900 mg every 7 ± 2 days for 4 weeks, followed by 1,200 mg 7 ± 2 days later, then 1,200 mg every 14 ± 2 days for the study duration. Солирис was administered as an intravenous infusion over 35 minutes. The dosing regimen in paediatric patients and adolescents weighing less than 40 kg was defined based on a pharmacokinetic (PK) simulation that identified the recommended dose and schedule based on body weight.

Primary endpoints included platelet count change from baseline in study C08-002A/B and thrombotic microangiopathy (TMA) event-free status in study C08-003A/B. Additional endpoints included TMA intervention rate, haematologic normalization, complete TMA response, changes in LDH, renal function and quality of life. TMA-event free status was defined as the absence for at least 12 weeks of the following: decrease in platelet count of > 25% from baseline, PE/PI, and new dialysis. TMA interventions were defined as PE/PI or new dialysis. Haematologic normalization was defined as normalization of platelet counts and LDH levels sustained for >2 consecutive measurements for >4 weeks. Complete TMA response was defined as haematologic normalization and a >25% reduction in serum creatinine sustained in > 2 consecutive measurements for > 4 weeks.

Baseline characteristics are shown in Table 5.

Table 5: Patient Demographics and Characteristics in C08-002A/B and C08-003A/B

Patients in aHUS Study C08-002 A/B received Солирис for a minimum of 26 weeks. After completion of the initial 26-week treatment period, most patients continued to receive Солирис by enrolling into an extension study. In aHUS Study C08-002A/B, the median duration of Солирис therapy was approximately100 weeks (range: 2 weeks to 145 weeks).

A reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of Солирис. Reduction in terminal complement activity was observed in all patients after commencement of Солирис. Table 6 summarizes the efficacy results for aHUS Study C08-002A/B. All rates of efficacy endpoints improved or were maintained through 2 years of treatment. Complete TMA response was maintained by all responders. When treatment was continued for more than 26 weeks, two additional patients achieved and maintained Complete TMA response due to normalization of LDH (1 patient) and a decrease in serum creatinine (2 patients).

Renal function, as measured by eGFR, was improved and maintained during Солирис therapy. Four of the five patients who required dialysis at study entry were able to discontinue dialysis for the duration of Солирис treatment, and one patient developed a new dialysis requirement. Patients reported improved health-related quality of life (QoL).

In aHUS Study C08-002A/B, responses to Солирис were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins.

Patients in aHUS study C08-003A/B received Солирис for a minimum of 26 weeks. After completion of the initial 26-week treatment period, most patients continued to receive Солирис by enrolling into an extension study. In aHUS Study C08-003A/B, the median duration of Солирис therapy was approximately 114 weeks (range: 26 to 129 weeks). Table 6 summarizes the efficacy results for aHUS Study C08-003A/B.

In aHUS Study C08-003A/B, responses to Солирис were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. Reduction in terminal complement activity was observed in all patients after commencement of Солирис. All rates of efficacy endpoints improved or were maintained through 2 years of treatment. Complete TMA response was maintained by all responders. When treatment was continued for more than 26 weeks, six additional patients achieved and maintained Complete TMA response due to a decrease in serum creatinine. No patient required new dialysis with Солирис. Renal function, as measured by median eGFR, increased during Солирис therapy.

Table 6: Efficacy Outcomes in Prospective aHUS Studies C08-002A/B and C08-003A/B

1 At data cut off (20 April 2012)

2 Study C08-002: 3 patients received ESA which was discontinued after eculizumab initiation

3 Study C08-003: 8 patients received ESA which was discontinued in 3 of them during eculizumab therapy

aHUS Study C10-004 enrolled 41 patients who displayed signs of thrombotic microangiopathy (TMA). In order to qualify for enrolment, patients were required to have a platelet count < lower limit of normal range (LLN), evidence of haemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 35 (range: 18 to 80 years). All patients enrolled in aHUS Study C10-004 had an ADAMTS-13 level above 5%. Fifty-one percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 35 patients received PE/PI prior to eculizumab. Table 7 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in aHUS C10-004.

Table 7: Baseline Characteristics of Patients Enrolled in aHUS Study C10-004

Patients in aHUS Study C10-004 received Солирис for a minimum of 26 weeks. After completion of the initial 26-week treatment period, most patients elected to continue on chronic dosing.

Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of Солирис. Солирис reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In aHUS C10-004, mean (±SD) platelet count increased from 119 ± 66 x109/L at baseline to 200 ± 84 x109/L by one week; this effect was maintained through 26 weeks (mean platelet count (±SD) at week 26: 252 ± 70 x109/L). Renal function, as measured by eGFR, was improved during Солирис therapy. Twenty of the 24 patients who required dialysis at baseline were able to discontinue dialysis during Солирис treatment. Table 8 summarizes the efficacy results for aHUS study C10-004.

Table 8: Efficacy Outcomes in Prospective aHUS Study C10-004

1 Through data cut-off (September 4, 2012), with median duration of Солирис therapy of 50 weeks (range: 13 weeks to 86 weeks).

Longer term treatment with Солирис (median 52 weeks ranging from 15 to 126 weeks) was associated with an increased rate of clinically meaningful improvements in adult patients with aHUS. When Солирис treatment was continued for more than 26 weeks, three additional patients (63% of patients in total) achieved Complete TMA response and four additional patients (98% of patients in total) achiev

Pharmacokinetic properties

Pharmacokinetics and Drug Metabolism

Biotransformation

Human antibodies undergo endocytotic digestion in the cells of the reticuloendothelial system. Eculizumab contains only naturally occurring amino acids and has no known active metabolites. Human antibodies are predominately catabolized by lysosomal enzymes to small peptides and amino acids.

Elimination

No specific studies have been performed to evaluate the hepatic, renal, lung, or gastrointestinal routes of excretion/elimination for Солирис. In normal kidneys, antibodies are not excreted and are excluded from filtration by their size.

Pharmacokinetic Parameters

In 40 patients with PNH, a 1-compartmental model was used to estimate pharmacokinetic parameters after multiple doses. Mean clearance was 0.31 ± 0.12 mL/hr/kg, mean volume of distribution was 110.3 ± 17.9 mL/kg, and mean elimination half-life was 11.3 ± 3.4 days. Based on these data, the onset of steady state is predicted to be approximately 49 - 56 days.

In PNH patients, pharmacodynamic activity correlates directly with eculizumab serum concentrations and maintenance of trough levels above > 35 microgram/mL results in essentially complete blockade of haemolytic activity in the majority of PNH patients.

A second population PK analysis with a standard 1 compartmental model was conducted on the multiple dose PK data from 37 aHUS patients receiving the recommended Солирис regimen in studies C08-002A/B and C08-003A/B. In this model, the clearance of Солирис for a typical aHUS patient weighing 70 kg was 0.0139 L/hr and the volume of distribution was 5.6 L. The elimination half-life was 297 h (approximately 12.4 days).

The second population PK model was applied to the multiple dose PK data from 22 paediatric aHUS patients receiving the recommended Солирис regimen in aHUS C10-003. The clearance and volume of distribution of Солирис are weight dependent, which forms the basis for a weight categorical based dose regimen in paediatric patients . Clearance values of Солирис in paediatric aHUS patients were 10.4, 5.3, and 2.2 mL/hr with body weight of 70, 30, and 10 kg, respectively; and the corresponding volume of distribution values were 5.23, 2.76, and 1.21 L, respectively. The corresponding elimination half-life remained almost unchanged within a range of 349 to 378 h (approximately 14.5 to 15.8 days).

The clearance and half-life of eculizumab were also evaluated during plasma exchange interventions. Plasma exchange resulted in an approximately 50% decline in eculizumab concentrations following a 1 hour intervention and the elimination half-life of eculizumab was reduced to 1.3 hours. Supplemental dosing is recommended when Солирис is administered to aHUS patients receiving plasma infusion or exchange.

All aHUS patients treated with Солирис when administered as recommended demonstrated rapid and sustained reduction in terminal complement activity. In aHUS patients, pharmacodynamic activity correlates directly with eculizumab serum concentrations and maintenance of trough levels of approximately 50-100 microgram/ml results in essentially complete blockade of terminal complement activity in all aHUS patients.

PK parameters observed in the refractory gMG population are consistent with what has been observed in PNH and aHUS populations.

Pharmacodynamic activity measured by free C5 concentrations of <0.5 ug/mL, is correlated with essentially complete blockade of terminal complement activity in PNH, aHUS, and refractory gMG patients.

Special Populations

PNH and refractory gMG

Dedicated studies have not been conducted to evaluate the pharmacokinetics of Солирис in special PNH or refractory gMG patient populations identified by gender, race, age (geriatric), or the presence of renal or hepatic impairment.

Paediatric population

The pharmacokinetics of eculizumab was evaluated in Study M07-005 including 7 PNH paediatric patients (aged from 11 to less than 18 years).

Weight was a significant covariate resulting in a lower eculizumab clearance 0.0105 L/h in the adolescent patients. Dosing for paediatric patients <40 kg is based on paediatric patients with aHUS.

aHUS

The pharmacokinetics of Солирис have been studied in aHUS patients with a range of renal impairment and age. There have been no observed differences in pharmacokinetic parameters noted in these subpopulations of aHUS patients.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Солирис is not expected to affect the aplastic component of anaemia in patients with PNH.

Meningococcal Infection

Due to its mechanism of action, the use of Солирис increases the patient's susceptibility to meningococcal infection (Neisseria meningitidis). Meningococcal disease due to any serogroup may occur. To reduce the risk of infection, all patients must be vaccinated at least 2 weeks prior to receiving Солирис unless the risk of delaying Солирис therapy outweighs the risks of developing a meningococcal infection. Patients who initiate Солирис treatment less than 2 weeks after receiving a meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. Vaccines against serogroups A, C, Y, W 135 and B where available, are recommended in preventing the commonly pathogenic meningococcal serogroups. Patients must receive vaccination according to current national vaccination guidelines for vaccination use.

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

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 have been reported in Солирис-treated patients. All patients should be monitored for early signs of meningococcal infection, evaluated immediately if infection is suspected, and treated with appropriate antibiotics if necessary. Patients should be informed of these signs and symptoms and steps taken to seek medical care immediately. Physicians must discuss the benefits and risks of Солирис therapy with patients and provide them with a patient information brochure and a patient safety card (see Package Leaflet for a description).

Other Systemic Infections

Due to its mechanism of action, Солирис therapy should be administered with caution to patients with active systemic infections. Patients may have increased susceptibility to infections, especially with encapsulated bacteria. Patients should be provided with information from the Package Leaflet to increase their awareness of potential serious infections and the signs and symptoms of them.

Infusion Reactions

Administration of Солирис may result in infusion reactions or immunogenicity that could cause allergic or hypersensitivity reactions (including anaphylaxis), though immune system disorders within 48 hours of Солирис administration did not differ from placebo treatment in PNH, aHUS, refractory gMG, and other studies conducted with Солирис. In clinical trials, no PNH, aHUS, or refractory gMG patients experienced an infusion reaction which required discontinuation of Солирис. Солирис administration should be interrupted in all patients experiencing severe infusion reactions and appropriate medical therapy administered.

Immunogenicity

Infrequent antibody responses have been detected in Солирис-treated patients across all clinical studies. In PNH placebo controlled studies low antibody responses have been reported with a frequency (3.4%) similar to that of placebo (4.8%).

In patients with aHUS treated with Солирис, antibodies to Солирис were detected in 3/100 (3%) by the ECL bridging format assay. 1/100 (1%) aHUS patients had low positive values for neutralizing antibodies.

In a refractory gMG placebo controlled study, none (0/62) of the Солирис treated patients showed antidrug antibody response during the 26 week active treatment.

There has been no observed correlation of antibody development to clinical response or adverse events.

Immunization

Prior to initiating Солирис therapy, it is recommended that PNH, aHUS, and refractory gMG patients initiate immunizations according to current immunization guidelines. Additionally, all patients must be vaccinated against meningococcal infections at least 2 weeks prior to receiving Солирис unless the risk of delaying Солирис therapy outweighs the risks of developing a meningococcal infection. Patients who initiate Солирис treatment less than 2 weeks after receiving a meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. Vaccines against serogroups A, C, Y, W 135 and B where available are recommended in preventing the commonly pathogenic meningococcal serogroups. (see Meningococcal Infection).

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

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

Anticoagulant therapy

Treatment with Солирис should not alter anticoagulant management.

Immunosuppressant and anticholinesterase therapies

Patients in refractory gMG clinical trials continued treatment with immunosuppressant and anticholinesterase therapies while on Солирис treatment. Withdrawal of immunosuppressant and anticholinesterase therapies during Солирис treatment for refractory gMG was not assessed in the placebo-controlled studies.

In the open-label extension trial (Study ECU-MG-302), physicians had the option to adjust background immunosuppressant therapies. In this setting, a decrease of the daily dose of at least 1 immunosuppressant was observed in 47% of patients. The most common reason for change in immunosuppressant therapy was improvement in MG symptoms while on eculizumab treatment. When immunosuppressant and anticholinesterase therapies are decreased or discontinued, patients should be monitored closely for signs of disease exacerbation.

PNH Laboratory Monitoring

PNH patients should be monitored for signs and symptoms of intravascular haemolysis, including serum lactate dehydrogenase (LDH) levels. PNH patients receiving Солирис therapy should be similarly monitored for intravascular haemolysis by measuring LDH levels, and may require dose adjustment within the recommended 14±2 day dosing schedule during the maintenance phase (up to every 12 days).

aHUS Laboratory Monitoring

aHUS patients receiving Солирис therapy should be monitored for thrombotic microangiopathy by measuring platelet counts, serum LDH and serum creatinine, and may require dose adjustment within the recommended 14±2 day dosing schedule during the maintenance phase (up to every 12 days).

Treatment Discontinuation for PNH

If PNH patients discontinue treatment with Солирис they should be closely monitored for signs and symptoms of serious intravascular haemolysis. Serious haemolysis is identified by serum LDH levels greater than the pre-treatment level, along with any of the following: greater than 25% absolute decrease in PNH clone size (in the absence of dilution due to transfusion) in one week or less; a haemoglobin level of <5 g/dL or a decrease of >4 g/dL in one week or less; angina; change in mental status; a 50% increase in serum creatinine level; or thrombosis. Monitor any patient who discontinues Солирис for at least 8 weeks to detect serious haemolysis and other reactions.

If serious haemolysis occurs after Солирис discontinuation, consider the following procedures/treatments: blood transfusion (packed RBCs), or exchange transfusion if the PNH RBCs are >50% of the total RBCs by flow cytometry; anticoagulation; corticosteroids; or reinstitution of Солирис. In PNH clinical studies, 16 patients discontinued the Солирис treatment regimen. Serious haemolysis was not observed.

Treatment Discontinuation for aHUS

Thrombotic microangiopathy (TMA) complications have been observed as early as 4 weeks and up to 127 weeks following discontinuation of Солирис treatment in some patients. Discontinuation of treatment should only be considered if medically justified.

In aHUS clinical studies, 61 patients (21 paediatric patients) discontinued Солирис treatment with a median follow-up period of 24 weeks. Fifteen severe thrombotic microangiopathy (TMA) complications in 12 patients were observed following treatment discontinuation, and 2 severe TMA complications occurred in an additional 2 patients that received a reduced dosing regimen of Солирис outside of the approved dosing regimen. Severe TMA complications occurred in patients regardless of whether they had an identified genetic mutation, high risk polymorphism or auto-antibody. Additional serious medical complications occurred in these patients including severe worsening of kidney function, disease-related hospitalization and progression to end stage renal disease requiring dialysis. Despite Солирис re-initiation following discontinuation, progression to end stage renal disease occurred in one patient.

If aHUS patients discontinue treatment with Солирис, they should be monitored closely for signs and symptoms of severe thrombotic microangiopathy complications. Monitoring may be insufficient to predict or prevent severe thrombotic microangiopathy complications in patients with aHUS after discontinuation of Солирис.

Severe thrombotic microangiopathy complications post discontinuation can be identified by (i) any two, or repeated measurement of any one, of the following: a decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during Солирис treatment; an increase in serum creatinine of 25% or more as compared to baseline or to nadir during Солирис treatment; or, an increase in serum LDH of 25% or more as compared to baseline or to nadir during Солирис treatment; or (ii) any one of the following: a change in mental status or seizures; angina or dyspnoea; or thrombosis.

If severe thrombotic microangiopathy complications occur after Солирис discontinuation, consider reinstitution of Солирис treatment, supportive care with PE/PI, or appropriate organ-specific supportive measures including renal support with dialysis, respiratory support with mechanical ventilation or anticoagulation.

Treatment discontinuation for refractory gMG:

Use of Солирис in refractory gMG treatment has been only studied in the setting of chronic administration. Patients that discontinue Солирис treatment should be carefully monitored for signs and symptoms of deterioration of disease.

Educational materials

All physicians who intend to prescribe Солирис must ensure they are familiar with the physician's guide to prescribing. Physicians must discuss the benefits and risks of Солирис therapy with patients and provide them with a patient information brochure and a patient safety card.

Patients should be instructed that if they develop fever, headache accompanied with fever and/or stiff neck or sensitivity to light, they should immediately seek medical care as these signs may be indicative of meningococcal infection.

Excipients

This medicinal product contains 5 mmol sodium per vial. It should be taken into consideration by patients on a controlled sodium diet.

Effects on ability to drive and use machines

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

Dosage (Posology) and method of administration

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

Posology

Adult Patients:

In Paroxysmal Nocturnal Haemoglobinuria (PNH):

The PNH dosing regimen for adult patients (>18 years of age) consists of a 4-week initial phase followed by a maintenance phase:

- Initial phase: 600 mg of Солирис administered via a 25 - 45 minute intravenous infusion every week for the first 4 weeks.

- Maintenance phase: 900 mg of Солирис administered via a 25 - 45 minute intravenous infusion for the fifth week, followed by 900 mg of Солирис administered via a 25 - 45 minute intravenous infusion every 14 ± 2 days.

In atypical Haemolytic Uremic Syndrome (aHUS) and refractory generalized Myasthenia Gravis (gMG):

The aHUS and refractory gMG dosing regimen for adult patients (>18 years of age) consists of a 4 week initial phase followed by a maintenance phase:

- Initial phase: 900 mg of Солирис administered via a 25 - 45 minute intravenous infusion every week for the first 4 weeks.

- Maintenance phase: 1,200 mg of Солирис administered via a 25 - 45 minute intravenous infusion for the fifth week, followed by 1,200 mg of Солирис administered via a 25 - 45 minute intravenous infusion every 14 ± 2 days.

Paediatric patients in PNH and aHUS:

Paediatric PNH and aHUS patients with body weight > 40 kg are treated with the adult dosing recommendations, respectively.

In paediatric PNH and aHUS patients with body weight below 40 kg, the Солирис dosing regimen consists of:

Солирис has not been studied in patients with PNH who weigh less than 40kg. The posology of Солирис for PNH patients less than 40kg weight is based on the posology used for patients with aHUS and who weigh less than 40kg.

Солирис has not been studied in paediatric patients with refractory gMG.

For adult aHUS and refractory gMG patients and paediatric aHUS patients supplemental dosing of Солирис is required in the setting of concomitant PE/PI (plasmapheresis or plasma exchange, or fresh frozen plasma infusion):

Treatment monitoring

a).

Солирис treatment is recommended to continue for the patient's lifetime, unless the discontinuation of Солирис is clinically indicated.

Elderly

Солирис may be administered to patients aged 65 years and over. There is no evidence to suggest that any special precautions are needed when older people are treated - although experience with Солирис in this patient population is still limited.

Renal impairment

No dose adjustment is required for patients with renal impairment.

Hepatic impairment

The safety and efficacy of Солирис have not been studied in patients with hepatic impairment.

Method of administration

Do not administer as an intravenous push or bolus injection. Солирис should only be administered via intravenous infusion as described below.

The diluted solution of Солирис should be administered by intravenous infusion over 25 - 45 minutes in adults and 1-4 hours in paediatric patients via gravity feed, a syringe-type pump, or an infusion pump. It is not necessary to protect the diluted solution of Солирис from light during administration to the patient.

Patients should be monitored for one hour following infusion. If an adverse event occurs during the administration of Солирис, the infusion may be slowed or stopped at the discretion of the physician. If the infusion is slowed, the total infusion time may not exceed two hours in adults and adolescents (aged 12 years to under 18 years) and four hours in children aged less than 12 years.

Refractory gMG

Available data suggest that clinical response is usually achieved by 12 weeks of Солирис treatment. Discontinuation of the therapy should be considered in a patient who shows no evidence of therapeutic benefit by 12 weeks.

Special precautions for disposal and other handling

Prior to administration, the Солирис solution should be visually inspected for particulate matter and discolouration.

Instructions:

Reconstitution and dilution should be performed in accordance with good practices rules, particularly for the respect of asepsis.

Withdraw the total amount of Солирис from the vial(s) using a sterile syringe.

Transfer the recommended dose to an infusion bag.

Dilute Солирис to a final concentration of 5 mg/ml by addition to the infusion bag using sodium chloride 9 mg/ml (0.9%) solution for injection, sodium chloride 4.5 mg/ml (0.45%) solution for injection, or 5% dextrose in water, as the diluent.

The final volume of a 5 mg/ml diluted solution is 60 ml for 300 mg doses, 120 ml for 600 mg doses, 180 ml for 900 mg doses and 240 ml for 1,200 mg doses. The solution should be clear and colourless.

Gently agitate the infusion bag containing the diluted solution to ensure thorough mixing of the product and diluent.

The diluted solution should be allowed to warm to room temperature prior to administration by exposure to ambient air.

Discard any unused portion left in a vial, as the product contains no preservatives.

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