BEKEMV 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 (see section 5.1).

• Atypical haemolytic uraemic syndrome (aHUS) (see section 5.1).

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

Home infusion may be considered for patients who have tolerated infusions well in the clinic. The decision of a patient to receive home infusions should be made after evaluation and recommendation from the treating physician. Home infusions should be performed by a qualified healthcare professional.

Posology

PNH in adults

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 BEKEMV administered via a 25 – 45 minute (35 minutes ± 10 minutes) intravenous infusion every week for the first 4 weeks.

• Maintenance phase: 900 mg of BEKEMV administered via a 25 – 45 minute (35 minutes ± 10 minutes) intravenous infusion for the fifth week, followed by 900 mg of BEKEMV administered via a 25 – 45 minute (35 minutes ± 10 minutes) intravenous infusion every 14 ± 2 days (see section 5.1).

aHUS in adults

The aHUS 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 BEKEMV administered via a 25 – 45 minute (35 minutes ± 10 minutes) intravenous infusion every week for the first 4 weeks.

• Maintenance phase: 1,200 mg of BEKEMV administered via a 25 – 45 minute (35 minutes ± 10 minutes) intravenous infusion for the fifth week, followed by 1,200 mg of BEKEMV administered via a 25 – 45 minute (35 minutes ± 10 minutes) intravenous infusion every 14 ± 2 days (see section 5.1).

Paediatric patients in PNH and aHUS

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

BEKEMV is contraindicated in babies and young children below 2 years of age (see section 4.3).

In paediatric PNH and aHUS patients above 2 years of age and with body weight below 40 kg, the BEKEMV dosing regimen consists of:

Eculizumab has not been studied in patients with PNH who weigh less than 40 kg. The posology of eculizumab to be used in paediatric patients with PNH patients weighing less than 40 kg is identical to the weight-based dose recommendation provided for paediatric patients with aHUS. Based on the pharmacokinetic (PK)/pharmacodynamic (PD) data available in patients with aHUS and PNH treated with eculizumab, this body-weight based dose regimen for paediatric patients is expected to result in an efficacy and safety profile similar to that in adults.

Supplemental dosing of BEKEMV is required in the setting of concomitant plasmapheresis (PP), plasma exchange (PE), or fresh frozen plasma infusion (PI), as described below:

Abbreviations: PP/PE/PI = plasmapheresis/plasma exchange/plasma infusion

Supplemental dose of BEKEMV is required in the setting of concomitant intravenous immunoglobulin (IVIg) treatment as described below (see also section 4.5):

Abbreviation: IVIg = intravenous immunoglobulin

Treatment monitoring

aHUS patients should be monitored for signs and symptoms of thrombotic microangiopathy (TMA) (see section 4.4 aHUS laboratory monitoring).

BEKEMV treatment is recommended to continue for the patient's lifetime, unless the discontinuation of BEKEMV is clinically indicated (see section 4.4).

Elderly

BEKEMV 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 eculizumab in this patient population is still limited.

Renal impairment

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

Hepatic impairment

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

Method of administration

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

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

The diluted solution of BEKEMV should be administered by intravenous infusion over 25 - 45 minutes (35 minutes ± 10 minutes) in adults and 1 - 4 hours in paediatric patients under 18 years of age via gravity feed, a syringe-type pump, or an infusion pump. It is not necessary to protect the diluted solution of BEKEMV 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 BEKEMV, 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 four hours in paediatric patients under 18 years of age.

There is limited safety data supporting home-based infusions, additional precautions in the home setting such as availability of emergency treatment of infusion reactions or anaphylaxis are recommended.

Infusion reactions are described in sections 4.4 and 4.8 on the SmPC.

Hypersensitivity to eculizumab or to any of the excipients listed in section 6.1.

BEKEMV is contraindicated in babies and young children below 2 years of age since they may not yet be diagnosed with hereditary fructose intolerance (HFI). Medicines containing sorbitol/fructose given intravenously may therefore be life-threatening, and are contraindicated in this population (see section 4.4).

BEKEMV therapy must not be initiated in patients (see section 4.4):

- 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.

BEKEMV 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 BEKEMV 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 BEKEMV unless the risk of delaying BEKEMV therapy outweighs the risks of developing a meningococcal infection. Patients who initiate BEKEMV treatment less than 2 weeks after receiving a tetravalent meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. Vaccines against serogroups A, C, Y andW 135, are recommended in preventing the commonly pathogenic meningococcal serogroups. Vaccine against serogroup B where available is also recommended. 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 and aHUS, may experience increased signs and symptoms of their underlying disease, such as haemolysis (PNH) or TMA (aHUS). 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 eculizumab-treated patients. Sepsis is a common presentation of meningococcal infections in patients treated with eculizumab (see section 4.8). 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 BEKEMV 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, BEKEMV therapy should be administered with caution to patients with active systemic infections. Patients may have increased susceptibility to infections, especially with Neisseria and encapsulated bacteria. Serious infections with Neisseria species (other than Neisseria meningitidis), including disseminated gonococcal infections, have been reported.

Patients should be provided with information from the package leaflet to increase their awareness of potential serious infections and the signs and symptoms of them. Physicians should advise patients about gonorrhoea prevention.

Infusion reactions

Administration of BEKEMV may result in infusion reactions or immunogenicity that could cause allergic or hypersensitivity reactions (including anaphylaxis). In clinical trials, no PNH or aHUS patients experienced an infusion reaction which required discontinuation of eculizumab. BEKEMV administration should be interrupted in all patients experiencing severe infusion reactions and appropriate medical therapy administered.

Immunisation

Prior to initiating BEKEMV therapy, it is recommended that PNH and aHUS patients initiate immunisations according to current immunisation guidelines. Additionally, all patients must be vaccinated against meningococcal infections at least 2 weeks prior to receiving BEKEMV unless the risk of delaying BEKEMV therapy outweighs the risks of developing a meningococcal infection. Patients who initiate BEKEMV treatment less than 2 weeks after receiving a tetravalent meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. Vaccines against serogroups A, C, Y and W 135 are recommended in preventing the commonly pathogenic meningococcal serogroups. Vaccine against serogroup B where available is also recommended (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 and aHUS may experience increased signs and symptoms of their underlying disease, such as haemolysis (PNH) or TMA (aHUS). Therefore, patients should be closely monitored for disease symptoms after recommended vaccination.

Anticoagulant therapy

Treatment with BEKEMV should not alter anticoagulant management.

PNH laboratory monitoring

PNH patients should be monitored for signs and symptoms of intravascular haemolysis, including serum lactate dehydrogenase (LDH) levels. PNH patients receiving BEKEMV 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 BEKEMV 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 BEKEMV 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 BEKEMV for at least 8 weeks to detect serious haemolysis and other reactions.

If serious haemolysis occurs after BEKEMV 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 BEKEMV. In PNH clinical studies, 16 patients discontinued the eculizumab 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 eculizumab treatment in some patients. Discontinuation of treatment should only be considered if medically justified.

In aHUS clinical studies, 61 patients (21 paediatric patients) discontinued eculizumab 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 eculizumab outside of the approved dosing regimen (see section 4.2). 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 hospitalisation and progression to end stage renal disease requiring dialysis. Despite eculizumab re-initiation following discontinuation, progression to end stage renal disease occurred in one patient.

If aHUS patients discontinue treatment with BEKEMV, 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 BEKEMV.

Severe thrombotic microangiopathy complications post discontinuation can be identified by (i) any two, or repeated measurement of anyone, of the following: a decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during BEKEMV treatment; an increase in serum creatinine of 25% or more as compared to baseline or to nadir during BEKEMV treatment; or, an increase in serum LDH of 25% or more as compared to baseline or to nadir during BEKEMV 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 BEKEMV discontinuation, consider reinstitution of BEKEMV treatment, supportive care with PE/PI, or appropriate organ-specific supportive measures including renal support with dialysis, respiratory support with mechanical ventilation or anticoagulation.

Educational materials

All physicians who intend to prescribe BEKEMV must ensure they are familiar with the physician's guide to prescribing. Physicians must discuss the benefits and risks of BEKEMV 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 medicine contains 50 mg sorbitol (E420) in each mL. Patients with HFI must not be given this medicine unless strictly necessary.

Babies and young children (below 2 years of age) may not yet be diagnosed with HFI. Medicines (containing sorbitol/fructose) given intravenously may be life-threatening and should be contraindicated in this population (see sections 4.2 and 4.3).

A detailed history with regard to HFI symptoms has to be taken of each patient prior to being given this medicinal product.

This medicinal product contains less than 1 mmol of sodium (23 mg) per dose, that is to say essentially “ sodium free” .

Traceability

In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

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

Plasma exchange (PE), plasmapheresis (PP), fresh frozen plasma infusion (PI) and intravenous immunoglobulin (IVIg) have been shown to reduce eculizumab serum levels. A supplemental dose of eculizumab is required in these settings. See section 4.2 for guidance in case of concomitant PE, PP, PI, or IVIg treatment.

Concomitant use of eculizumab with intravenous immunoglobulin (IVIg) may reduce effectiveness of eculizumab. Closely monitor for reduced effectiveness of eculizumab.

Concomitant use of eculizumab with neonatal Fc receptor (FcRn) blockers may lower systemic exposures and reduce effectiveness of eculizumab. Closely monitor for reduced effectiveness of eculizumab.

The use of adequate contraception to prevent pregnancy and for at least 5 months after the last dose of treatment with eculizumab should be considered for women of childbearing potential.

Pregnancy

There are no well-controlled studies in pregnant women treated with eculizumab. Data on a limited number of pregnancies exposed to eculizumab (less than 300 pregnancy outcomes) indicate there is no increased risk of foetal malformation or foetal-neonatal toxicity. However, due to the lack of well-controlled studies, uncertainties remain. Therefore, an individual risk benefit analysis is recommended before starting and during treatment with eculizumab in pregnant women. Should such a treatment be considered necessary during pregnancy, a close maternal and foetal monitoring according to local guidelines is recommended.

Animal reproduction studies have not been conducted with eculizumab (see section 5.3).

Human IgG are known to cross the human placental barrier, and thus eculizumab may potentially cause terminal complement inhibition in the foetal circulation. Therefore, BEKEMV should be given to a pregnant woman only if clearly needed.

Breast-feeding

No effects on the breastfed new-born/infant are anticipated as limited data available suggest that eculizumab is not excreted in human breast milk. However, due to the limitations of the available data, the developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for eculizumab and any potential adverse effects on the breastfed child from eculizumab or from the underlying maternal condition.

Fertility

No specific study of eculizumab on fertility has been conducted.

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

Summary of the safety profile

Supportive safety data were obtained from 33 clinical studies that included 1,555 patients exposed to eculizumab in complement-mediated disease populations, including PNH, aHUS, refractory generalised myasthenia gravis (gMG) and neuromyelitis optica spectrum disorder (NMOSD). The most common adverse reaction was headache, (occurred mostly in the initial phase of dosing), and the most serious adverse reaction was meningococcal infection .

Tabulated list of adverse reactions

Table 1 gives the adverse reactions observed from spontaneous reporting and in eculizumab completed clinical trials, including PNH, aHUS, refractory gMG and NMOSD 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 eculizumab clinical trials, including patients with PNH, aHUS, refractory gMG and NMOSD as well as from post marketing experience

Included studies: asthma (C07-002), aHUS (C08-002, C08-003, C10-003, C10-004), dermatomyositis (C99-006), refractory gMG (C08-001, ECU-MG-301, ECU-MG-302, ECU-MG-303), Neuromyelitis Optica Spectrum Disorder (ECU-NMO-301, ECU-NMO-302), IMG (C99-004, E99-004), PNH (C02-001, C04-001, C04-002, C06-002, C07-001, E02-001, E05-001, E07-001, M07-005, X03-001, X03-001A), psoriasis (C99-007), RA (C01-004, C97-001, C99-001, E01-004, E99-001), STEC-HUS (C11-001), SLE (C97-002). MedDRA version 24.1.

* See 'Description of selected adverse reactions.'

^a Abscess includes the following group of PTs: abscess limb, colonic abscess, renal abscess, subcutaneous abscess, tooth abscess, hepatosplenic abscess, perirectal abscess, rectal abscess.

^b Meningococcal infection includes the following group of PTs: meningococcal infection, meningococcal sepsis, meningitis meningococcal, Neisseria infection.

^c ADRs identified in post marketing reports.

Description of selected adverse reactions

In all clinical studies, the most serious adverse reaction was meningococcal sepsis which is a common presentation of meningococcal infections in patients treated with eculizumab (see section 4.4).

Other cases of Neisseria species have been reported including sepsis with Neisseria gonorrhoeae, Neisseria sicca/subflava, Neisseria spp unspecified.

Cases of haemolysis have been reported in the setting of missed or delayed eculizumab dose in PNH clinical trials (see also section 4.4).

Cases of thrombotic microangiopathy complication have been reported in the setting of missed or delayed eculizumab dose in aHUS clinical trials (see also section 4.4).

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 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.

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 12 completed clinical studies that included 934 patients exposed to eculizumab in other disease populations other than PNH, aHUS, refractory gMG or NMOSD. 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, refractory gMG or NMOSD were similar to those reported in patients with PNH, aHUS, refractory gMG or NMOSD (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:

Yellow Card Scheme

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

No case of overdose has been reported in any of the clinical studies.

Pharmacotherapeutic group: Selective immunosuppressants, ATC code: L04AA25

BEKEMV is a biosimilar medicinal product. Detailed information is available on the MHRA website https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency.

BEKEMV is a recombinant humanised monoclonal IgG_2/4k antibody that binds to the human C5 complement protein and inhibits the activation of terminal complement. The BEKEMV antibody contains human constant regions and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. BEKEMV 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.

BEKEMV is produced in a CHO cell line 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 BEKEMV, 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 opsonisation of microorganisms and clearance of immune complexes.

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

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

In PNH, chronic administration of eculizumab 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 eculizumab treatment.

All patients treated with eculizumab 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 eculizumab resulted in a rapid and sustained reduction in complement-mediated thrombotic microangiopathy.

Clinical efficacy and safety

Paroxysmal nocturnal haemoglobinuria

The safety and efficacy of eculizumab in PNH patients with haemolysis were assessed in a randomised, double-blind, placebo-controlled 26 week study (C04-001). PNH patients were also treated with eculizumab 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 eculizumab. 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. Eculizumab was administered as an intravenous infusion over 25 – 45 minutes (35 minutes ± 10 minutes). An observational non-interventional registry in patients with PNH (M07-001) was also initiated to characterise the natural history of PNH in untreated patients and the clinical outcomes during eculizumab 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/microlitre were randomised to either eculizumab (n = 43) or placebo (n = 44). Prior to randomisation, 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 stabilisation 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 stabilisation (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/microlitre received eculizumab 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 eculizumab had significantly reduced (p < 0.001) haemolysis resulting in improvements in anaemia as indicated by increased haemoglobin stabilisation 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 eculizumab treatment, patients reported less fatigue and improved health-related quality of life. Because of the study sample size and duration, the effects of eculizumab 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, eculizumab -treated PNH patients were enrolled in a long-term extension study (E05-001). All patients sustained a reduction in intravascular haemolysis over a total eculizumab exposure time ranging from 10 to 54 months. There were fewer thrombotic events with eculizumab 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 eculizumab in PNH patients with no history of RBC transfusion. These patients had high disease activity as defined by elevated haemolysis (LDH ≥ 1.5 × 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 eculizumab were observed to have a reduction in haemolysis and associated symptoms. At 6 months, patients treated with eculizumab with no history of RBC transfusion had significantly (p < 0.001) reduced LDH levels (median LDH of 305 U/L; see table 4). Furthermore, 74% of the patients without a history of transfusion and treated with eculizumab 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 uraemic 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 eculizumab 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 eculizumab 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 eculizumab or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. In all studies, the dose of eculizumab 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. Eculizumab 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 (see section 4.2).

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 normalisation, 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 normalisation was defined as normalisation of platelet counts and LDH levels sustained for ≥ 2 consecutive measurements for ≥ 4 weeks. Complete TMA response was defined as haematologic normalisation 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 eculizumab for a minimum of 26 weeks. After completion of the initial 26 - week treatment period, most patients continued to receive eculizumab by enrolling into an extension study. In aHUS study C08-002A/B, the median duration of eculizumab therapy was approximately 100 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 eculizumab. Reduction in terminal complement activity was observed in all patients after commencement of eculizumab. 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 normalisation of LDH (1 patient) and a decrease in serum creatinine (2 patients).

Renal function, as measured by eGFR, was improved and maintained during eculizumab therapy. Four of the five patients who required dialysis at study entry were able to discontinue dialysis for the duration of eculizumab 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 eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins.

Patients in aHUS study C08-003A/B received eculizumab for a minimum of 26 weeks. After completion of the initial 26-week treatment period, most patients continued to receive eculizumab by enrolling into an extension study. In aHUS study C08-003A/B, the median duration of eculizumab 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 eculizumab 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 eculizumab. 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 eculizumab. Renal function, as measured by median eGFR, increased during eculizumab 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 eculizumab 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 eculizumab. Eculizumab 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 x 10⁹/L at baseline to 200 ± 84 x 10⁹/L by one week; this effect was maintained through 26 weeks (mean platelet count (± SD) at week 26: 252 ± 70 x 10⁹/L). Renal function, as measured by eGFR, was improved during eculizumab therapy. Twenty of the 24 patients who required dialysis at baseline were able to discontinue dialysis during eculizumab 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 eculizumab therapy of 50 weeks (range: 13 weeks to 86 weeks).

Longer term treatment with eculizumab (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 eculizumab 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) achieved haematologic normalisation. At the last evaluation, 25 of 41 patients (61%) achieved eGFR improvement of ≥ 15 mL/min/1.73m² from baseline.

Immunogenicity

Infrequent antibody responses have been detected in eculizumab-treated patients across all clinical studies.

Paediatric population

Paroxysmal nocturnal haemoglobinuria

A total of 7 PNH paediatric patients, with a median weight of 57.2 kg (range of 48.6 to 69.8 kg) and aged from 11 to 17 years (median age: 15.6 years), received eculizumab in study M07-005.

Treatment with eculizumab at the proposed dosing regimen in the paediatric population was associated with a reduction of intravascular haemolysis as measured by serum LDH level. It also resulted in a marked decrease or elimination of blood transfusions, and a trend towards an overall improvement in general function. The efficacy of eculizumab treatment in paediatric PNH patients appears to be consistent with that observed in adult PNH patients enrolled in PNH pivotal studies (C04-001 and C04-002) (see tables 3 and 9).

Table 9. Efficacy outcomes in paediatric PNH study M07-005

Atypical haemolytic uraemic syndrome

A total of 15 paediatric patients (aged 2 months to 12 years) received eculizumab in aHUS Study C09-001r. Forty seven percent of patients had an identified complement regulatory factor mutation or auto-antibody. The median time from aHUS diagnosis to first dose of eculizumab was 14 months (range <1,110 months). The median time from current thrombotic microangiopathy manifestation to first dose of eculizumab was 1 month (range <1 to 16 months). The median duration of eculizumab therapy was 16 weeks (range 4 to 70 weeks) for children < 2 years of age (n=5) and 31 weeks (range 19 to 63 weeks) for children 2 to <12 years of age (n=10).

Overall, the efficacy results for these paediatric patients appeared consistent with what was observed in patients enrolled in aHUS pivotal studies C08-002 and C08-003 (table 6). No paediatric patient required new dialysis during treatment with eculizumab.

Table 10: Efficacy results in paediatric patients enrolled in aHUS C09-001r

In paediatric patients with shorter duration of current severe clinical thrombotic microangiopathy (TMA) manifestation prior to eculizumab, there was TMA control and improvement of renal function with eculizumab treatment (table 10).

In paediatric patients with longer duration of current severe clinical TMA manifestation prior to eculizumab, there was TMA control with eculizumab treatment. However, renal function was not changed due to prior irreversible kidney damage (table 11).

Table 11. Efficacy outcomes in paediatric patients in study C09-001r according to duration of current severe clinical thrombotic microangiopathy (TMA) manifestation

*One patient achieved eGFR improvement after renal transplant

A total of 22 paediatric and adolescents patients (aged 5 months to 17 years) received eculizumab in aHUS study C10-003.

In study C10-003, patients who enrolled in the study were required to have a platelet count < lower limit of normal range (LLN), evidence of haemolysis such as an elevation in serum LDH above the upper limits of normal and serum creatinine level ≥ 97 percentile for age without the need for chronic dialysis. The median patient age was 6.5 years (range: 5 months to 17 years). Patients enrolled in aHUS C10-003 had an ADAMTS-13 level above 5%. Fifty percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 10 patients received PE/PI prior to eculizumab. Table 12 summarises the key baseline clinical and disease-related characteristics of patients enrolled in aHUS study C10-003.

Table 12. Baseline characteristics of paediatric and adolescents patients enrolled in aHUS study C10-003

Patients in aHUS C10-003 received eculizumab 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 was observed in all patients after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. The mean (± SD) platelet count increased from 88 ± 42 x10⁹/L at baseline to 281 ± 123 x10⁹/L by one week; this effect was maintained through 26 weeks (mean platelet count (± SD) at week 26: 293 ± 106 x10⁹/L). Renal function, as measured by eGFR, was improved during eculizumab therapy. Nine of the 11 patients who required dialysis at baseline no longer required dialysis after study day 15 of eculizumab treatment. Responses were similar across all ages from 5 months to 17 years of age. In aHUS C10-003, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H.

Table 13 summarises the efficacy results for aHUS C10-003.

Table 13. Efficacy outcomes in prospective aHUS study C10-003

Longer term treatment with eculizumab (median 55 weeks ranging from 1 day to 107 weeks) was associated with an increased rate of clinically meaningful improvements in paediatric and adolescent patients with aHUS. When eculizumab treatment was continued for more than 26 weeks, one additional patient (68% of patients in total) achieved Complete TMA response and two additional patients (91% of patients in total) achieved haematologic normalisation. At the last evaluation, 19 of 22 patients (86%) achieved eGFR improvement of ≥ 15 mL/min/1.73m² from baseline. No patient required new dialysis with eculizumab.

Pharmacokinetics and active substance 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 catabolised 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 eculizumab. In normal kidneys, antibodies are not excreted and are excluded from filtration by their size.

Pharmacokinetic/pharmacodynamic relationship(s)

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. The steady state is achieved by 4 weeks using the PNH adult dosing regimen.

In PNH patients, pharmacodynamic activity correlates directly with eculizumab serum concentrations and maintenance of trough levels above ≥ 35 micrograms/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 eculizumab regimen in studies C08-002A/B and C08-003A/B. In this model, the clearance of eculizumab 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 eculizumab regimen in aHUS C10-003. The clearance and volume of distribution of eculizumab are weight dependent, which forms the basis for a weight categorical based dose regimen in paediatric patients (see section 4.2). Clearance values of eculizumab 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 eculizumab is administered to aHUS patients receiving plasma infusion or exchange (see section 4.2).

All aHUS patients treated with eculizumab 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 are consistent across PNH and aHUS patient populations.

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

Special Populations

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

Population PK analysis on data collected across eculizumab studies showed that gender, race, age (geriatric), or the presence of renal or hepatic impairment function do not influence the PK of eculizumab. Body weight was a significant covariate resulting in a lower eculizumab clearance in paediatric patients requiring body weight-based dosing in paediatric patients.

Paediatric population

The pharmacokinetics of eculizumab was evaluated in study M07-005 in PNH paediatric patients (aged from 11 to less than 18 years) and in Studies C08-002, C08-003, C09-001r and C10-003 in aHUS paediatric patients (aged 2 months to less than 18 years) with body-weight-based dose regimen.

Weight was a significant covariate resulting in a lower eculizumab clearance 0.0105 L/h in the adolescent PNH patients.

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 utilised 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 eculizumab 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.

Acetic acid

Sodium hydroxide

Disodium edetate (EDTA)

Sorbitol (E420)

Polysorbate 80

Water for injections

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

36 months.

After dilution, chemical, physical, and microbiological in-use stability has been demonstrated for:

• 96 hours at 2° C to 8° C

• 48 hours at room temperature

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2° C to 8° C, unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2° C – 8° C). Do not freeze.

Store in the original package in order to protect from light.

BEKEMV vials in the original package may be removed from refrigerated storage for only one single period of up to 7 days. At the end of this period the product can be put back in the refrigerator.

For storage conditions after dilution of the medicinal product, see section 6.3.

30 mL of concentrate in a 30 mL vial (type I glass) with an elastomeric stopper with fluoropolymer laminated plug, and an aluminium seal with attached dust cover (elastomeric).

Pack size of one vial.

Prior to administration, the BEKEMV 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 BEKEMV from the vial(s) using a sterile syringe.

Transfer the recommended dose to an infusion bag.

Dilute BEKEMV 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.

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