Soliris

Therapeutic indication

Adults and children with Paroxysmal nocturnal haemoglobinuria (PNH)

Mechanism of action

Eculizumab, the active ingredient in Soliris, 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 (Paroxysmal Nocturnal Hemoglobinuria) PNH patients, uncontrolled terminal complement activation and the resulting complement-mediated intravascular haemolysis are blocked with Soliris 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 Soliris resulted in a rapid and sustained reduction in complement-mediated haemolytic activity. In (aTypical Hemolytic Uremic Syndrome) aHUS patients, uncontrolled terminal complement activation and the resulting complement-mediated thrombotic microangiopathy are blocked with Soliris treatment. All patients treated with Soliris 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 Soliris resulted in a rapid and sustained reduction in complement-mediated thrombotic microangiopathy

Therapeutic indication

Soliris 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)

Soliris is indicated in adults for the treatment of Refractory generalized myasthenia gravis (gMG) in patients who are anti-acetylcholine receptor (AChR) antibody-positive (see the European Medicines Agency website for full information: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000791/human_med_001055.jsp&mid=WC0b01ac058001d124

Reimbursement modalities

In Belgium, Soliris is reimbursed for PNH and aHUS with the following criteria:

PNH:

Soliris is reimbursed in Belgium for patients with PNH, diagnosed by flow cytometry, showing a clone of hematopoietic stem cells type III of minimal 10 %, and have received minimal 4 transfusions in the past 2 years.

aHUS:

Soliris is reimbursed in Belgium for patients with aHUS, defined by the simultaneous presence of:

- a microangiopathic hemolytic anemia, with or without thrombocytopenia (<150.000 thrombocytes/mm³ or a decrease of total amount of thrombocytes of >25% from baseline), with a negative direct Coombs test, an increase of LDH, decreased hemoglobin, and/or decreased haptoglobin, and/or reticulocytosis and > 1% schistocytes.

- AND an ADAMTS13 activity > 10%, and the presence of 1 or more of the following factors:

o Neurological symptoms including confusion, CVA, epileptic insults and coma,

o AND/OR renal dysfunction with increased serum creatinine, decreased GFR, and/or proteinuria and/or hematuria,

o AND/OR pathological symptoms of acute thrombotic microangiopathy (TMA) in the kidney biopsy,

o AND/OR gastro-intestinal symptoms including diarrhea, nausea, vomiting, abdominal pain and gastro-enteritis,

o AND/OR cardiovascular dysregulation with cardiomyopathy and/or heart attack

- The diagnose of aHUS can only be retained if other causes of thrombotic microangiopathy (thrombotic thrombocytopenic purpura due to congenital ADAMTS13 deficiency or anti-ADAMTS13 antibodies, HELLP syndrome) or TMA with other forms of HUS (STEC-HUS, HUS in combination with underlying pathology, HUS due to infection with Streptococcus pneumonia or Influenza A /H1N1, HUS due to medication, HUS with cobalamin C deficiency or HUS linked to DGKE mutations) are excluded.

- Proven analysis (or is requested and in process in case of a first request for reimbursement) for a dysfunction of the alternative complement pathway by:

o Genetic mutations in CFH, CFI, MCP, C3, CFB or THBD,

o AND/OR the presence of anti-CFH antibodies

For full details, please refer to www.riziv.fgov.be

Administration and dosage

Soliris 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 Soliris administered via a 25 – 45 minute intravenous infusion every week for the first 4 weeks.

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

In atypical Haemolytic Uremic Syndrome (aHUS):

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 Soliris administered via a 25 – 45 minute intravenous infusion every week for the first 4 weeks.

Maintenance phase: 1,200 mg of Soliris administered via a 25 – 45 minute intravenous infusion for the fifth week, followed by 1,200 mg of Soliris 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 Soliris dosing regimen consists of:

Patient Body Weight	Initial Phase	Maintenance Phase
30 to <40 kg	600 mg weekly x 2	900 mg at week 3; then 900 mg every 2 weeks
20 to <30 kg	600 mg weekly x 2	600 mg at week 3; then 600 mg every 2 weeks
10 to <20 kg	600 mg weekly x 1	300 mg at week 2; then 300 mg every 2 weeks
5 to <10 kg	300 mg weekly x 1	300 mg at week 2; then 300 mg every 3 weeks

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

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

Type of Plasma Intervention	Most Recent Soliris Dose	Supplemental Soliris Dose With Each PE/PI Intervention	Timing of Supplemental Soliris Dose
Plasmapheresis or plasma exchange	300 mg	300 mg per each plasmapheresis or plasma exchange session	Within 60 minutes after each plasmapheresis or plasma exchange
Plasmapheresis or plasma exchange	≥600 mg	600 mg per each plasmapheresis or plasma exchange session
Fresh frozen plasma infusion	≥300 mg	300 mg per infusion of fresh frozen plasma	60 minutes prior to each infusion of fresh frozen plasma

Treatment monitoring

aHUS patients should be monitored for signs and symptoms of thrombotic microangiopathy (TMA).

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

Elderly

Soliris 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 Soliris in this patient population is still limited.

Method of administration

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

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

Transfer the recommended dose to an infusion bag.

Dilute Soliris 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.

The diluted solution of Soliris 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 Soliris 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 Soliris, 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.

Dose modifications

Toxicity

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 Soliris 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.

Hepatic impairment

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

Renal impairment

No dose adjustment is required for patients with renal impairment.

Drug-drug interactions

No interaction studies have been performed.

Drug-food interactions

No interaction studies have been performed.

Adverse events of special interest

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 and aHUS, and refractory gMG. The most common adverse reaction was headache, (occurred mostly in the initial phase), and, of all meningococcal infections^a 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

MedDRA System Organ Class	Very Common (≥1/10)	Common (≥1/100 to <1/10)	Uncommon (≥1/1,000 to <1/100)	Rare (≥1/10,000 to <1/1,000)
Infection and infestations		Pneumonia, Upper respiratory tract infection, Nasopharyngitis, Urinary tract infection, Oral Herpes	Meningococcal infection^a, Sepsis, Septic shock, Peritonitis, Lower respiratory tract infection, Fungal infection, Viral infection, Bronchitis, Abscess, Cellulitis, Influenza, Gastrointestinal infection, Cystitis, Infection, Sinusitis, Tooth infection	Aspergillus infection^b, Arthritis bacterial^b, Genitourinary tract gonococcal infection, Haemophilus influenzae infection, Impetigo, Gingivitis
Neoplasms benign, malignant and unspecified (including cysts and polyps)				Malignant melanoma, Myelodysplastic syndrome
Blood and lymphatic system disorders		Leukopenia, Anaemia	Thrombocytopenia, Lymphopenia	Haemolysis*, Abnormal clotting factor, Red blood cell agglutination, Coagulopathy
Immune system disorders			Anaphylactic reaction, Hypersensitivity
Endocrine disorders				Basedow’s disease
Metabolism and nutrition disorders			Decreased appetite
Psychiatric disorders		Insomnia	Depression, Anxiety, Mood swings	Abnormal dreams, Sleep disorder
Nervous system disorders	Headache	Dizziness, Dysgeusia, Tremor	Paraesthesia	Syncope
Eye disorders			Vision blurred	Conjunctival irritation
Ear and labyrinth disorders			Tinnitus, Vertigo
Cardiac disorders			Palpitation
Vascular disorders		Hypertension	Accelerated hypertension, Hypotension, Hot flush, Vein disorder	Haematoma
Respiratory, thoracic and mediastinal disorders		Cough, Oropharyngeal pain	Dyspnoea, Epistaxis, Throat irritation, Nasal congestion, Rhinorrhoea
Gastrointestinal disorders		Diarrhoea, Vomiting, Nausea, Abdominal pain	Constipation, Dyspepsia, Abdominal distension	Gastroesophageal reflux disease, Gingival pain
Hepatobiliary disorders				Jaundice
Skin and subcutaneous tissue disorders		Rash, Pruritus, Alopecia	Urticaria, Erythema, Petechiae, Hyperhidrosis, Dry skin	Dermatitis, Skin depigmentation
Musculoskeletal and connective tissue disorders		Arthralgia, Myalgia, Pain in extremity	Muscle spasms, Bone pain, Back pain, Neck pain, Joint swelling	Trismus
Renal and urinary disorders			Renal impairment, Dysuria	Haematuria
Reproductive system and breast disorders			Spontaneous penile erection, Menstrual disorder
General disorders and administration site conditions		Pyrexia, Chills, Fatigue, Influenza like illness	Oedema, Chest discomfort, Asthenia, Chest pain, Infusion site pain	Extravasation, Infusion site paraesthesia, Feeling hot
Investigations			Alanine aminotransferase increased, Aspartate aminotransferase increased, Gamma-glutamyltransferase increased, Haematocrit decreased, Haemoglobin decreased	Coombs test positive^b
Injury, poisoning and procedural complication			Infusion related reaction

*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.

Antibodies to Soliris were detected in 2% of patients with PNH using an ELISA assay and 3% of patients with aHUS using the ECL bridging format assay. As with all proteins there is a potential for immunogenicity.

Cases of haemolysis have been reported in the setting of missed or delayed Soliris dose in PNH clinical trials.

Cases of thrombotic microangiopathy complication have been reported in the setting of missed or delayed Soliris dose in aHUS clinical trials.

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.

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:

Federal agency for medicines and health products

Division Vigilance

EUROSTATION II

Victor Hortaplein, 40/ 40

B-1060 Brussels

Website: www.fagg.be

e-mail: adversedrugreactions@fagg-afmps.be

Or directly to the Marketing authorization holder:

Email: MedInfo.EMEA@alexion.com

Phone: +32 (0)2 548 3667

Management of adverse events

Initial work-up before start of treatment

Contraindications

Hypersensitivity to eculizumab, murine proteins or to any of the following excipients: Sodium phosphate, monobasic, Sodium phosphate, dibasic, Sodium chloride, Polysorbate 80, Water for injections.

Soliris 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.

Special warnings and precautions for use

Soliris 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 Soliris 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 Soliris unless the risk of delaying Soliris therapy outweighs the risks of developing a meningococcal infection. Patients who initiate Soliris 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 and aHUS, may experience increased signs and symptoms of their underlying disease, such as haemolysis (PNH) and 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 Soliris-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 Soliris 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, Soliris 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 Soliris may result in infusion reactions or immunogenicity that could cause allergic or hypersensitivity reactions (including anaphylaxis), though immune system disorders within 48 hours of Soliris administration did not differ from placebo treatment in PNH, aHUS, and other studies conducted with Soliris. In clinical trials, no PNH or aHUS, patients experienced an infusion reaction which required discontinuation of Soliris. Soliris administration should be interrupted in all patients experiencing severe infusion reactions and appropriate medical therapy administered.

Immunogenicity

Infrequent antibody responses have been detected in Soliris-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 Soliris, antibodies to Soliris were detected in 3/100 (3%) by the ECL bridging format assay. 1/100 (1%) aHUS patients had low positive values for neutralizing antibodies.

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

Immunization

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

Anticoagulant therapy

Treatment with Soliris 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 Soliris 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 Soliris 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).

Educational materials

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

Fertility, pregnancy and lactation

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, Soliris 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 effects on the breastfed child from eculizumab or from the underlying maternal condition.

Fertility

No specific study of eculizumab on fertility has been conducted.

Concomitant Treatment

No interaction (with other medicinal products and other forms of interaction) studies have been performed.

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 Soliris. 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 ³ 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 Soliris regimen in studies C08-002A/B and C08-003A/B. In this model, the clearance of Soliris 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 Soliris regimen in aHUS C10-003. The clearance and volume of distribution of Soliris are weight dependent, which forms the basis for a weight categorical based dose regimen in paediatric patients (see section 4.2). Clearance values of Soliris 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 Soliris is administered to aHUS patients receiving plasma infusion or exchange (see section 4.2).

All aHUS patients treated with Soliris 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.

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

Special Populations

PNH

Dedicated studies have not been conducted to evaluate the pharmacokinetics of Soliris in special PNH 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 Soliris 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.

Response evaluation

Paroxysmal Nocturnal Haemoglobinuria

The safety and efficacy of Soliris 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 Soliris 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 Soliris. 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. Soliris 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 Soliris 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 Soliris (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 Soliris 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

	C04-001		C04-002
Parameter	Placebo N = 44	Soliris N = 43	Soliris N = 97
Mean Age (SD)	38.4 (13.4)	42.1 (15.5)	41.1 (14.4)
Gender - Female (%)	29 (65.9)	23 (53.5)	49 (50.5)
History of Aplastic Anaemia or MDS (%)	12 (27.3)	8 (18.7)	29 (29.9)
Concomitant Anticoagulants (%)	20 (45.5)	24 (55.8)	59 (61)
Concomitant Steroids/Immunosuppressant Treatments (%)	16 (36.4)	14 (32.6)	46 (47.4)
Discontinued treatment	10	2	1
PRBC in previous 12 months (median (Q1,Q3))	17.0 (13.5, 25.0)	18.0 (12.0, 24.0)	8.0 (4.0, 24.0)
Mean Hgb level (g/dL) at setpoint (SD)	7.7 (0.75)	7.8 (0.79)	N/A
Pre-treatment LDH levels (median, U/L)	2,234.5	2,032.0	2,051.0
Free Haemoglobin at baseline (median, mg/dL)	46.2	40.5	34.9

In TRIUMPH, study patients treated with Soliris 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 Soliris treatment, patients reported less fatigue and improved health-related quality of life. Because of the study sample size and duration, the effects of Soliris 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

	C04-001			C04-002*
	Placebo N = 44	Soliris N = 43	P – Value	Soliris N = 97	P – Value
Percentage of patients with stabilized Haemoglobin levels at end of study	0	49	< 0.001	N/A
PRBC transfused during treatment (median)	10	0	< 0.001	0		< 0.001
Transfusion Avoidance during treatment (%)	0	51	< 0.001	51		< 0.001
LDH levels at end of study (median, U/L)	2,167	239	< 0.001	269		< 0.001
LDH AUC at end of study (median, U/L x Day)	411,822	58,587	< 0.001	-632,264		< 0.001
Free Haemoglobin at end of study (median, mg/dL)	62	5	< 0.001	5		< 0.001
FACIT-Fatigue (effect size)		1.12	< 0.001	1.14		< 0.001

* 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, Soliris-treated PNH patients were enrolled in a long term extension study (E05-001). All patients sustained a reduction in intravascular haemolysis over a total Soliris exposure time ranging from 10 to 54 months. There were fewer thrombotic events with Soliris 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 Soliris 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 Soliris were observed to have a reduction in haemolysis and associated symptoms. At 6 months, patients treated with Soliris 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 Soliris 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

	M07-001
Parameter		Soliris No transfusion
LDH level at baseline (median , U/L)		N=43 1447
LDH level at 6 months (median, U/L)		N=36 305
FACIT-Fatigue score at baseline (median)		N=25 32
FACIT-Fatigue score at last available assessment (median)		N=31 44

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 Soliris 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 Soliris 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 Soliris or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. In all studies, the dose of Soliris 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. Soliris 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

Parameter	C08-002A/B	C08-003A/B
Parameter	Soliris N = 17	Soliris N = 20
Time from first diagnosis until screening in months, median (min, max)	10 (0.26, 236)	48 (0.66, 286)
Time from current clinical TMA manifestation until screening in months, median (min, max)	< 1 (<1, 4)	9 (1, 45)
Number of PE/PI sessions for current clinical TMA manifestation, median (min, max)	17 (2, 37)	62 (20, 230)
Number of PE/PI sessions in 7 days prior to first dose of eculizumab, median (min, max)	6 (0, 7)	2 (1, 3)
Baseline platelet count (× 10⁹/L), mean (SD)	109 (32)	228 (78)
Baseline LDH (U/L), mean (SD)	323 (138)	223 (70)
Patients without identified mutation, n (%)	4 (24)	6 (30)

Patients in aHUS Study C08-002 A/B received Soliris for a minimum of 26 weeks. After completion of the initial 26-week treatment period, most patients continued to receive Soliris by enrolling into an extension study. In aHUS Study C08-002A/B, the median duration of Soliris 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 Soliris. Reduction in terminal complement activity was observed in all