Other cases of Neisseria species have been reported including sepsis with Neisseria gonorrhoeae, Neisseria sicca/subflava, Neisseria spp unspecified. Table 16: Efficacy Outcomes in Paediatric Patients in Study C09-001r according to duration of current severe clinical thrombotic microangiopathy (TMA) manifestation, Duration of current severe clinical TMA manifestation, *One patient achieved eGFR improvement after renal transplant. 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. h�bbd```b``� ��A$�� "���J�lf'�ը�Ȗ ɸt���H�{���!�4F�$�/bU�D�g�t�@� ��C The steady state is achieved by 4 weeks using the PNH adult dosing regimen. Data from 139 patients in two prospective controlled studies (Studies C08-001 and ECU-MG-301), and one open-label extension trial (Study ECU-MG-302) were used to evaluate the efficacy of Soliris in the treatment of patients with refractory gMG. 0 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. Patients should be informed of these signs and symptoms and steps taken to seek medical care immediately. * Results from study C04-002 refer to pre- versus post-treatment comparisons. Monitor any patient who discontinues Soliris for at least 8 weeks to detect serious haemolysis and other reactions. Patients who discontinue Soliris treatment should be carefully monitored for signs and symptoms of disease exacerbation. All patients enrolled in aHUS Study C10-004 had an ADAMTS-13 level above 5%. The median patient age was 6.5 years (range: 5 months to 17 years). There are three FDA-approved medications for maintenance in NMOSD, but anything else that is prescribed is done off-label. However, this finding was shown in non-controlled clinical trials. The solution should be clear and colourless. 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 section 5.1). Soliris (eculizumab) has not been studied for the treatment of acute relapses in NMOSD patients. • Soliris is the first FDA-approved treatment for NMOSD. Meningococcal infections may quickly become life-threatening and cause death if not recognized and treated early. Soliris was administered as an intravenous infusion over 25 – 45 minutes (35 minutes ± 10 minutes). No patient required new dialysis with Soliris. Soliris is not expected to affect the aplastic component of anaemia in patients with PNH. Archila, who initiated coverage on Viela earlier this week with a "hold" rating, said he is anticipating a net price of around $175,000 a year. 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. No overall differences in safety were reported between elderly (≥ 65 years) and younger refractory gMG patients (< 65 years) (see section 5.1). Treatment discontinuation for refractory gMG: Use of Soliris in refractory gMG treatment has been studied only in the setting of chronic administration. In refractory gMG placebo-controlled studies, no antidrug antibodies were observed. The corresponding elimination half-life remained almost unchanged within a range of 349 to 378 h (approximately 14.5 to 15.8 days). • The approval of Soliris for the new indication was based on a double -blind study in 143 patients with NMOSD who were anti-AQP4 antibody positive. SOLIRIS increases your chance of getting serious and life-threatening meningococcal infections. 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). On June 27, 2019, the FDA approved Soliris ® for the additional indication of neuromyelitis optica spectrum disorder (NMOSD). In aHUS, chronic administration of Soliris resulted in a rapid and sustained reduction in complement-mediated thrombotic microangiopathy. Baseline characteristics are shown in Table 5. It should be taken into consideration by patients on a controlled sodium diet. 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). Positive ADA samples were low titer and transient. After dilution, the final concentration of the solution to be infused is 5 mg/ml. In Studies ECU-MG-301 and ECU-MG-302, the dose of Soliris in adult refractory gMG patients was 900 mg every 7 ± 2 days for 4 weeks, followed by 1200 mg at Week 5± 2 days, then 1,200 mg every 14 ± 2 days for the study duration. Based on the potential inhibitory effect of eculizumab on complement-dependent cytotoxicity of rituximab, eculizumab may reduce the expected pharmacodynamic effects of rituximab. Soliris must be administered by a healthcare professional and under the supervision of a physician experienced in the management of patients with haematological, renal, neuromuscular or neuro-inflammatory disorders. Administration of Soliris may result in infusion reactions or immunogenicity that could cause allergic or hypersensitivity reactions (including anaphylaxis). aHUS patients should be monitored for signs and symptoms of thrombotic microangiopathy (TMA) (see section 4.4 aHUS laboratory monitoring). In clinical trials, Soliris reduced NMOSD relapses significantly, also reducing the need for hospitalizations. The primary analysis of the QMG was a Worst-Rank ANCOVA with a mean rank of 54.7 for Soliris and 70.7 for placebo, based on 125 study patients (p=0.0129). 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 Soliris in study M07-005. Table 12: Patient Disease History and Baseline Characteristics in Study ECU-NMO-301, Age at NMOSD Initial Clinical Presentation (years), Time from NMOSD initial clinical presentation to first dose of study drug (years), Historical Annualized Relapse Rate within 24 months prior to Screening. These studies included assessment of fertility and early embryonic development, developmental toxicity, and pre and post-natal development. • Maintenance phase: 900 mg of Soliris administered via a 25 – 45 minute (35 minutes ± 10 minutes) intravenous infusion for the fifth week, followed by 900 mg of Soliris administered via a 25 – 45 minute (35 minutes ± 10 minutes) intravenous infusion every 14 ± 2 days (see section 5.1). In the eculizumab NMOSD clinical development program, the dose of Soliris in adult patients with NMOSD was 900 mg every 7 ± 2 days for 4 weeks, followed by 1200 mg at Week 5 ± 2 days, then 1200 mg every 14 ± 2 days for the study duration. Neuromyelitis optica spectrum disorder (NMOSD) in patients who are anti-aquaporin-4 (AQP4) antibody-positive with a relapsing course of the disease. It also resulted in a marked decrease or elimination of blood transfusions, and a trend towards an overall improvement in general function. Table 11 presents an overview of the patients reporting clinical deterioration and patients requiring rescue therapy over the 26 weeks. 4 Based on a stratified Cox proportional hazards model. 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 pediatric patients (aged 2 months to less than 18 years) with body-weight based dose regimen. This approval makes Soliris ® the first FDA approved drug for this indication. Dedicated studies have not been conducted to evaluate the pharmacokinetics of Soliris in special patient populations identified by gender, race, age (geriatric), or the presence of renal or hepatic impairment. 1 Through data cut-off (October 12, 2012), with median duration of Soliris therapy of 44 weeks (range: 1 dose to 88 weeks). Soliris has not been studied in paediatric patients with refractory gMG or NMOSD. In all aHUS patients, eculizumab serum concentrations of approximately 50 - 100 microgram/mL are sufficient for essentially complete inhibition of terminal complement activity. 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. At least two thirds of cases are associated with aquaporin-4 antibodies (AQP4-IgG) and … 2) Failed at least one immunosuppressant therapy and required chronic plasma exchange or IVIg to control symptoms, ie, patients require PE or IVIg on a regular basis for the management of muscle weakness at least every 3 months over previous 12 months. Patients who discontinue Soliris treatment should be carefully monitored for signs and symptoms of potential NMOSD relapse. Additional serious medical complications occurred in these patients including severe worsening of kidney function, disease-related hospitalization and progression to end stage renal disease requiring dialysis. Patients enrolled in aHUS C10-003 had an ADAMTS-13 level above 5%. 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. The median patient age was 35 (range: 18 to 80 years). SOLIRIS can lower the ability of your immune system to fight infections. Evidence of clinical benefit is demonstrated in patients with haemolysis Reporting suspected adverse reactions after authorisation of the medicinal product is important. “The phase 3 study of Soliris in NMOSD was the first ever randomized controlled study in NMOSD and was based on promising results from a single-center 14-patient open-label … Patients received meningococcal vaccination prior to receipt of Soliris. Cases of thrombotic microangiopathy complication have been reported in the setting of missed or delayed Soliris dose in aHUS clinical trials (see also Section 4.4). 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 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 (35 minutes ± 10 minutes) intravenous infusion every week for the first 4 weeks. Twenty-two (22) (17.6%) elderly refractory gMG patients (> 65 years of age) were treated with Soliris in the clinical trials. 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. 1 Based on the Kaplan-Meier product limit method. Monitoring may be insufficient to predict or prevent severe thrombotic microangiopathy complications in patients with aHUS after discontinuation of Soliris. 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. The clearance and half-life of eculizumab were also evaluated during plasma exchange interventions. Dosing for paediatric patients <40 kg is based on paediatric patients with aHUS. hެUmk�0�+��Q�ϲ�����Vֵ[��e���$�.���?�Yr7/kB�{ѝ��ɔ�((֋4 The primary analysis of the MG-ADL was a Worst-Rank ANCOVA with a mean rank of 56.6 for Soliris and 68.3 for placebo, based on 125 study patients (p=0.0698). There has been no observed correlation of antibody development to clinical response or adverse events. Meningococcal infections may quickly become life-threatening and cause death if not recognized and treated early. There were fewer thrombotic events with Soliris treatment than during the same period of time prior to treatment. For patients who received placebo in Study ECU-MG-301 (placebo/eculizumab arm of Study ECU-MG-302), improvement occurred after initiating treatment with eculizumab and was maintained for more than 130 weeks in Study ECU-MG-302. 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. All patients sustained a reduction in intravascular haemolysis over a total Soliris exposure time ranging from 10 to 54 months. The primary endpoint for Study ECU-MG-301 was the change from baseline in the MG Activities of Daily Living Profile (MG-ADL – a patient reported outcome measure validated in gMG) total score at Week 26. In SHEPHERD study, 96 of the 97 enrolled patients completed the study (one patient died following a thrombotic event). After completion of the initial 26-week treatment period, most patients continued to receive Soliris by enrolling into an extension study. Serious haemolysis was not observed. Patients reported improved health-related quality of life (QoL). Soliris therapy must not be initiated in patients (see section 4.4): - with unresolved Neisseria meningitidis infection. Table 15: Efficacy Results in Paediatric Patients Enrolled in aHUS C09-001r, Patients with platelet count normalization, n (%), Daily TMA intervention rate, median (range), Patients with eGFR improvement ≥15 mL/min/1.73 m2, n (%). 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. The most common side effects in people with NMOSD treated with SOLIRIS include: common cold (upper respiratory infection), pain or swelling of your nose or throat (nasopharyngitis), diarrhea, back pain, dizziness, flu like symptoms (influenza) including fever, headache, tiredness, cough, sore throat, and body aches, joint pain (arthralgia), throat irritation (pharyngitis), and bruising (contusion). 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. 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. Original Effective Date: 2/1 /2018 - … Patients were permitted to receive background immunosuppressant therapies at stable dose during the study, with the exclusion of rituximab and mitoxantrone. Infrequent antibody responses have been detected in Soliris-treated patients across all clinical studies. The proportion of clinical responders at Week 26 with no rescue therapy was 59.7% on Soliris compared with 39.7% on placebo (p=0.0229). Baseline characteristics are shown in Table 2. The diluted solution of Soliris 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. Soliris 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. 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). Soliris has not been evaluated in paediatric patients with NMOSD. 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). Discard any unused portion left in a vial, as the product contains no preservatives. In patients with aHUS treated with Soliris, antibodies to Soliris were detected in 3/100 (3%) by the ECL bridging format assay. One hundred and eighteen (118) of the 125 (94%) patients completed the 26-week treatment period and 117 (94%) patients subsequently enrolled in Study ECU-MG-302, an open-label, multi-center long-term safety and efficacy extension study in which all patients received Soliris treatment.
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