Epysqli 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).

Epysqli must be administered by a healthcare professional and under the supervision of a physician experienced in the management of patients with haematological 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

Adult patients in PNH

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

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

Paediatric patients in PNH

Paediatric patients with body weight ≥ 40 kg are treated with the adult dosing recommendations.

In paediatric patients with body weight below 40 kg, Epysqli dosing regimen consists of:

Table 1: Epysqli dose for paediatric patients

Duration of use

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

Special populations

Elderly

Epysqli 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 5.1).

Hepatic impairment

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

Method of administration

Epysqli should not be administered as an intravenous push or bolus injection. Epysqli 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 Epysqli 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.

Patients should be monitored for one hour following infusion. If an adverse event occurs during the administration of Epysqli, 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 SPC.

Hypersensitivity to the active substance, CHO cell products or to any of the excipients listed in section 6.1.

Eculizumab 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.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Eculizumab 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 eculizumab 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 eculizumab unless the risk of delaying eculizumab therapy outweighs the risks of developing a meningococcal infection. Patients who initiate eculizumab 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, 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, may experience increased signs and symptoms of their underlying disease, such as haemolysis. Therefore, patients should be closely monitored for disease symptoms after recommended vaccination.

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 eculizumab 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, eculizumab 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 eculizumab may result in infusion reactions or immunogenicity that could cause allergic or hypersensitivity reactions (including anaphylaxis). In clinical trials of the reference medicinal product, 1 (0.9%) refractory generalised myasthenia gravis (gMG) patient experienced an infusion reaction which required discontinuation of eculizumab. No PNH patients experienced an infusion reaction which required discontinuation of eculizumab. Eculizumab administration should be interrupted in all patients experiencing severe infusion reactions and appropriate medical therapy administered.

Immunogenicity

Anti-eculizumab antibodies may develop during eculizumab treatment. No apparent correlation of antibody development with clinical response or adverse events has been observed.

Immunisation

Prior to initiating eculizumab therapy, it is recommended that patients initiate immunisations according to current immunisation guidelines. Additionally, all patients must be vaccinated against meningococcal infections at least 2 weeks prior to receiving eculizumab unless the risk of delaying eculizumab therapy outweighs the risks of developing a meningococcal infection. Patients who initiate eculizumab 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, 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 may experience increased signs and symptoms of their underlying disease, such as haemolysis. Therefore, patients should be closely monitored for disease symptoms after recommended vaccination.

Anticoagulant therapy

Treatment with eculizumab should not alter anticoagulant management.

PNH Laboratory Monitoring

Patients should be monitored for signs and symptoms of intravascular haemolysis, including serum lactate dehydrogenase (LDH) levels. Patients receiving eculizumab 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).

Treatment Discontinuation for PNH

If patients discontinue treatment with eculizumab 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 eculizumab for at least 8 weeks to detect serious haemolysis and other reactions.

If serious haemolysis occurs after eculizumab 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 eculizumab. In PNH clinical trials, 16 patients discontinued the eculizumab treatment regimen. Serious haemolysis was not observed.

Educational materials

All physicians who intend to prescribe eculizumab must ensure they are familiar with the physician's guide to prescribing. Physicians must discuss the benefits and risks of eculizumab 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.

Sodium content

Once diluted with sodium chloride 9 mg/mL (0.9 %) solution for injection, this medicinal product contains 0.35 g sodium per 180 mL at the maximal dose, equivalent to 17.5 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Once diluted with sodium chloride 4.5 mg/mL (0.45 %) solution for injection, this medicinal product contains 0.19 g sodium per 180 mL at the maximal dose, equivalent to 9.5 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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.

Chronic intravenous human immunoglobulin (IVIg) treatment may interfere with the endosomal neonatal Fc receptor (FcRn) recycling mechanism of monoclonal antibodies such as eculizumab and thereby decrease serum eculizumab concentrations.

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, eculizumab should be given to a pregnant woman only if clearly needed.

Breast-feeding

No effects on the breastfed newborn / 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 breastfeeding should be considered along with the mother's clinical need for eculizumab and any potential adverse events on the breastfed child from eculizumab or from the underlying maternal condition.

Fertility

No specific study of eculizumab on fertility has been conducted.

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

Summary of the safety profile

Supportive safety data were obtained from 31 completed clinical trials that included 1 503 patients exposed to eculizumab in complement-mediated disease populations, including PNH, atypical Haemolytic Uremic Syndrome (aHUS), 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 sepsis.

Tabulated list of adverse reactions

Table 2 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 2: 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), gMG (C08-001, ECU-MG-301, ECU-MG-302), Neuromyelitis Optica Spectrum Disorder (ECU-NMO-301), 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 21.0.

*See paragraph 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.

^cADRs identified in post marketing reports

Description of selected adverse reactions

In all clinical trials, 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.

Antibodies to eculizumab were detected in patients. As with all proteins there is a potential for immunogenicity.

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.

Paediatric population

In children and adolescent 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 patients. The most common adverse reaction reported in paediatric patients was headache.

Other special populations

Elderly

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

Patients with other diseases

Safety Data from Other Clinical trials

Supportive safety data were obtained in 12 completed clinical trials 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 2 above). No specific adverse reactions have emerged from these clinical trials.

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 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.

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code: L04AA25

Eculizumab 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 eculizumab antibody contains human constant regions and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. Eculizumab 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.

Epysqli is produced in a CHO cell line expression system and purified by affinity and ion exchange chromatography. The bulk active substance manufacturing process also includes specific viral inactivation and removal steps.

Epysqli is a biosimilar medicinal product.

Mechanism of action

Eculizumab, the active substance in Epysqli, 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 patients, uncontrolled terminal complement activation and the resulting complement-mediated intravascular haemolysis are blocked with eculizumab treatment.

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

Chronic administration of eculizumab resulted in a rapid and sustained reduction in complement- mediated haemolytic activity.

Clinical efficacy and safety

Paroxysmal Nocturnal Haemoglobinuria

The safety and efficacy of eculizumab 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 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 characterize 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 /microliter were randomized 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 3).

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 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 3.

Table 3: 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 4). 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 4.

Table 4: 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 x 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; Table 5). 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 5: 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

Paediatric population

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) (Table 4 and 6).

Table 6: Efficacy outcomes in paediatric PNH study M07-005

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 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. 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 microgram/mL results in essentially complete blockade of haemolytic activity in the majority of PNH patients.

Pharmacodynamic activity measured by free C5 concentrations of < 0.5 ug/mL, is correlated with essentially complete blockade of terminal complement activity in PNH 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 studies in patients 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 paediatric patients (aged from 11 to less than 18 years) with body-weight based dose regimen in study M07-005.

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

Sodium dihydrogen phosphate monohydrate

Disodium hydrogen phosphate heptahydrate

Trehalose dihydrate

Polysorbate 80 (E 433)

Water for injections

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

Before dilution

3 years at 2 ° C – 8 ° C.

Epysqli may be stored at temperature up to a maximum of 30 ° C for a single period of up to 2 months, but not exceeding the original expiry date. At the end of this period the product can be put back in the refrigerator.

After dilution

Chemical and physical in-use stability of the diluted solution has been demonstrated for each diluent as following:

• Sodium chloride 9 mg/ml (0.9 %) solution for injection, sodium chloride 4.5 mg/ml (0.45 %) solution for injection as diluent: 3 months at 2 ° C to 8 ° C followed by up to 72 hours at room temperature (up to 30° C)

• 5 % glucose in water as diluent: 24 hours at 2 ° C to 8 ° C and at room temperature (up to 30 ° C) after removal from refrigeration

From a microbiological point of view, the infusion solution should be administered 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 – 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.

For storage conditions up to 30 ° C before dilution of the medicinal product, see section 6.3.

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

30 ml of concentrate in a vial (Type I glass) with a stopper (coated chlorinated butyl rubber), and a seal (aluminium) with flip-off cap (polypropylene).

Pack size of one vial.

Prior to administration, Epysqli solution should be visually inspected for particulate matter and discolouration. Do not use if there is evidence of particulate matter or 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 Epysqli from the vial(s) using a sterile syringe.

Transfer the recommended dose to an infusion bag.

Dilute Epysqli 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 % glucose 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 and 180 ml for 900 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 (up to 30 ° C) 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.