Drug Class Description
Immunomodulators

Generic Name
Eculizumab

Drug Description
Each vial of 30 ml contains 300 mg of eculizumab (10 mg/ml).Eculizumab is a humanised monoclonal IgG2/4? antibody produced in NS0 cell line by recombinant DNA technology.After dilution, the final concentration of the solution to be infused is 5mg/ml.Excipients: Sodium (5.00 mmol per dose (1 vial))

Presentation
Concentrate for Solution for Infusion.Clear, colorless, pH 7.0 solution.

Indications
Soliris (eculizumab) is indicated for the treatment of patients with paroxysmal nocturnal haemoglobinuria (PNH).Evidence of clinical benefit of Soliris in the treatment of patients with PNH is limited to patients with history of transfusions.

Adult Dosage
To reduce the risk of meningococcal infection (Neisseria meningitidis), all patients must be vaccinated at least 2 weeks prior to receiving Soliris and must be re-vaccinated according to current medical guidelines for vaccination use.Soliris should be administered by a healthcare professional and under the supervision of a physician experienced in the management of patients with haematological disorders.The dosing regimen consists of a 5-week initial phase followed by a maintenance phase:• Initial phase: 600 mg of eculizumab via a 25 - 45 minute intravenous infusion every week for the first 4 weeks, followed by 900 mg of eculizumab for the fifth week of the initial phase.• Maintenance phase: 900 mg of Soliris administered via a 25 - 45 minute intravenous infusion every 14 ± 2 days.Instructions for preparation of the diluted solutions are described in section 6.6.Do not administer as an intravenous push or bolus injection. Soliris should only be administered via intravenous infusion as described below.The diluted solution of Soliris should be administered by intravenous infusion over 25 – 45 minutes 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.Renal impairment:The safety and efficacy of Soliris have not been studied in patients with renal impairment.Hepatic impairment: The safety and efficacy of Soliris have not been studied in patients with hepatic impairment.

Child Dosage
There is no experience in children

Elderly Dosage
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.

Contra Indications
Hypersensitivity to eculizumab, murine proteins or to any of the excipients.Do not initiate Soliris therapy in patients:• with unresolved Neisseria meningitidis infection.• who are not currently vaccinated against Neisseria meningitidis.• who have known or suspected hereditary complement deficiencies.

Special Precautions
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). These patients might be at risk of disease by uncommon serogroups (particularly Y, W135 and X), although 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 and must be re-vaccinated according to current medical guidelines for vaccination use. Tetravalent vaccines against serotypes A, C, Y and W135 are strongly recommended, preferably conjugated ones. Vaccination may not be sufficient to prevent meningococcal infection. Consideration should be given to official guidance on the appropriate use of antibacterial agents. There have been 3 reported cases of meningococcal infection in Soliris treated patients: two in vaccinated PNH patients and one in an unvaccinated patient with idiopathic membranous glomerulonephropathy. All patients should be monitored for early signs of meningococcal infection, eva luated immediately if infection is suspected, and treated with antibiotics if necessary. Patients should be informed of these signs and symptoms and steps taken to seek medical care immediately (see Patient Information 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. The overall severity and frequency of infections in Soliris treated patients was similar to placebo treated patients in clinical studies, although an increase in the number and severity of infections, particularly due to encapsulated bacteria, cannot be excluded. Patients should be provided with information from the Patient Information Leaflet to increase their awareness of potential serious infections and the signs and symptoms of them.Infusion Reactions:As with all therapeutic proteins, 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 and non-PNH studies conducted with Soliris. In clinical trials, no PNH 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, low titre antibody responses have been detected in Soliris treated patients across all PNH and non-PNH studies with a frequency (3.4%) similar to that of placebo (4.8%). No patients have been reported to develop neutralizing antibodies following therapy with Soliris, and 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 patients should receive immunizations according to current immunization guidelines. Additionally, all patients must be vaccinated against meningococcus at least 2 weeks prior to receiving Soliris. If available, tetravalent, conjugated vaccines are recommended (see meningococcal disease).Anticoagulant therapy: Treatment with Soliris should not alter anticoagulant management.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).Treatment Discontinuation: Patients who discontinue treatment with Soliris should be 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 gm/dL or a decrease of>4 gm/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 Soliris for at least 8 weeks to detect serious haemolysis and other reactions.If serious haemolysis occurs after Soliris 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 Soliris. In PNH clinical studies, 16 patients discontinued the Soliris treatment regimen. Serious haemolysis was not observed.Excipients : This medicinal product contains 5.00 mmol sodium per dose (1 vial). To be taken into consideration by patients on a controlled sodium diet.

Interactions
No interaction studies have been performed. Pregnancy: For Soliris, no clinical data on exposed pregnancies are available. Animal reproduction studies have not been conducted with eculizumab.Human IgG are known to cross 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. Woman of childbearing potential have to use adequate contraception methods during treatment and up to 5 months after treatment.Lactation: It is not known whether eculizumab is secreted into human milk. Since many medicinal products and immunoglobulins are secreted into human milk, and because of the potential for serious adverse reactions in nursing infants, lactation should be discontinued during treatment and up to 5 months after treatment.

Adverse Reactions
Eculizumab for the treatment of PNH was studied in three clinical studies that included 195 eculizumab-treated patients and most of these patients have been enrolled in the E05-001 extension study. There was one pivotal trial comparing the eculizumab-treatment arm to a placebo-treatment arm.The most commonly reported adverse reactions are headache, nasopharyngitis, nausea, pyrexia, myalgia, fatigue, and herpes simplex, each occurring in 5 or more out of 100 patients.Adverse events reported at a very common (1/10) or common (>5/100 and < 10/100) frequency with eculizumab in a total of 140 patients in C04-001 and C04-002 are listed by system organ class and preferred term in Table 1. Adverse events were mostly mild to moderate in severity. Uncommon or rare events cannot be estimated due to limited patient exposure (195 PNH patients).Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.Table 1: Adverse Events Reported in Studies C04-001 and C04-002Adverse EventPreferred TermSystem Organ ClassVery Common ( >1/10)Common (5/100 – 1/10)Infections and infestationsUrinary tract infection NasopharyngitisUpper Respiratory Tract InfectionRespiratory Tract InfectionHerpes SimplexSinusitisViral InfectionGastroenteritisPsychiatric disordersInsomniaNervous System DisordersDizzinessHeadacheRespiratory, Thoracic and Mediastinal DisordersEpistaxisPharyngolaryngeal painCoughGastrointestinal DisordersDiarrhoeaNauseaVomitingAbdominal PainAbdominal Pain UpperConstipationSkin and Subcutaneous Tissue DisordersRashPruritisMusculoskeletal and Connective Tissue DisordersBack PainMyalgiaPain in extremityMuscle crampArthralgiaGeneral Disorders and Administration Site ConditionsPyrexiaInfluenza-Like IllnessFatigueInjury, Poisoning and Procedural ComplicationsContusionIn the C04-001 study, headache was the most common adverse event observed with eculizumab. Headaches were observed in 44.2% (19/43 patients) of patients treated with eculizumab and 27.3% (12/44 patients) in placebo-treated patients and were mild/moderate in all but 1 eculizumab treated and 1 placebo-treated patients. Most headaches were mild and did not persist after the initial administration phase of Soliris. In addition, the following adverse events were increased in frequency by 5% or more with Soliris as compared to placebo: nasopharyngitis (25.0%), nausea (17.1%), pyrexia (14.3%), myalgia (7.9%), fatigue (7.9%), and herpes simplex (5.7%). There was no evidence of an increased incidence of infection across PNH studies with eculizumab as compared to placebo, including serious infections, severe infections or multiple infections.The most serious adverse event was meningococcal septicaemia in two vaccinated PNH patients.Low titres of antibodies were detected in 2% patients with PNH treated with Soliris. As with all proteins there is a potential for immunogenicity.Safety Data From Other Clinical StudiesSupportive safety data were obtained in 11 clinical studies that included 716 patients exposed to eculizumab in six disease populations other than PNH. There was an un-vaccinated patient diagnosed with idiopathic membranous glomerulonephropathy who experienced meningococcal meningitis. With regard to other AEs and considering all double-blind, placebo-controlled studies in patients diagnosed with diseases other than PNH (N=526 patients with Soliris; N=221 patients with placebo), AEs reported with Soliris at a frequency of 2% or greater than the frequency reported with placebo were: upper respiratory tract infection, rash, and injury.

Manufacturer
Alexion Pharma

Drug Availability
(POM)

Updated
12 August 2009