There are no well-controlled studies in pregnant women treated with eculizumab. In a refractory gMG placebo controlled study, none (0/62) of the Soliris treated patients showed antidrug antibody response during the 26 week active treatment, whereas in a refractory gMG extension study, a total of 2.6% overall were positive for ADAs at any post-baseline visit. SOLIRIS is a medicine that affects your immune system. 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. A total of 22 paediatric and adolescents patients (aged 5 months to 17 years) received Soliris in aHUS Study C10-003. �]��Vyk����C�� /u��^c˹���jV� / ��M��C���,���b���D���~�U�G[��} ��&=�]����dҩ��Nә����(n�b}k�bP�e[u��������0i�E�)A�0���\C���ID�L1�Bx*`J�$�����f���eI@uk��%�$D�*�r X�D�;X"�|U��F(&�hс��F�U �B`�rF!�Z0"=:3@��3:�>XgX�. All patients enrolled in both prospective studies had an ADAMTS-13 level above 5%. 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. The terminal complement protein (C5) inhibitor eculizumab (Soliris ®) is the first agent to be specifically approved in the EU, USA, Canada and Japan for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults who are aquaporin-4 water channel autoantibody (AQP4-IgG) seropositive and (in the EU only) for those with a relapsing course of disease. - Neuromyelitis optica spectrum disorder (NMOSD) in patients who are anti-aquaporin-4 (AQP4) antibody-positive with a relapsing course of the disease (see section 5.1). 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 median patient age was 35 (range: 18 to 80 years). 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). Original Effective Date: 2/1 /2018 - … 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. Does the patient have a contraindication per FDA label or significant intolerance to ALL of the following systemic therapies: A. azathioprine (Azasan, Imuran), Table 17 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in aHUS Study C10-003. The effectiveness of Soliris in aHUS is based on the effects on thrombotic microangiopathy (TMA) and renal function. Infusion reactions are described in Sections 4.4 and 4.8 on the SmPC. The majority (90.9%) of patients were female. SOLIRIS and NMOSD. Table 9 presents the baseline characteristics of the refractory gMG patients enrolled in Study ECU-MG-301. Table 17: Baseline Characteristics of Paediatric and Adolescents Patients Enrolled in aHUS Study C10-003, Time from aHUS diagnosis until first study dose (months) median (min, max ), Time from current clinical TMA manifestation until first study dose (months), median ( min, max), Baseline platelet count (x 109/L), median ( min, max), Baseline eGFR (mL/min/1.73 m2 ), median (min, max). Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system detailed below. A total of 10 patients received PE/PI prior to eculizumab. The European Medicines Agency has deferred the obligation to submit the results of studies with Soliris in one or more subsets of the paediatric population in the treatment of NMOSD (see section 4.2 for information on paediatric use). 1.4 Neuromyelitis Optica Spectrum Disorder (NMOSD) Soliris is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) All rates of efficacy endpoints improved or were maintained through 2 years of treatment. To email a medicine you must sign up and log in. 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. Adverse events should also be reported to Alexion Pharma UK Ltd on [email protected], Freephone (UK): 0800 321 3902, Freephone (Ireland): 1 800 936 544. All patients enrolled in aHUS Study C10-004 had an ADAMTS-13 level above 5%. Chronic administration of Soliris results in immediate, complete, and sustained inhibition of terminal complement activity (eculizumab serum concentrations ≥ 116 microgram/ml). Despite Soliris re-initiation following discontinuation, progression to end stage renal disease occurred in one patient. The clearance and half-life of eculizumab were also evaluated during plasma exchange interventions. Home infusion may be considered for patients who have tolerated infusions well in the clinic. Because of the study sample size and duration, the effects of Soliris on thrombotic events could not be determined. 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. �.N&Y�T��u��#9M��'�rL�b����6R���10In���L1@z"�?aP�10�)��^ R;��\�(cT0 ���! In most PNH patients, eculizumab serum concentrations of approximately 35 microgram/mL are sufficient for essentially complete inhibition of terminal complement-mediated intravascular haemolysis. PNH patients should be monitored for signs and symptoms of intravascular haemolysis, including serum lactate dehydrogenase (LDH) levels. In aHUS C10-003, responses to Soliris were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H. Table 18 summarizes the efficacy results for aHUS C10-003. The bulk drug substance manufacturing process also includes specific viral inactivation and removal steps. In Study ECU-NMO-302, physicians had the option to adjust background immunosuppressant therapies. In the PNH Registry, patients treated with Soliris were observed to have a reduction in haemolysis and associated symptoms. Baseline characteristics are shown in Table 2. Home infusions should be performed by a qualified healthcare professional. In aHUS C10-004, mean (±SD) platelet count increased from 119 ± 66 x109/L at baseline to 200 ± 84 x109/L by one week; this effect was maintained through 26 weeks (mean platelet count (±SD) at week 26: 252 ± 70 x109/L). When immunosuppressant therapy is decreased or discontinued, patients should be monitored closely for signs and symptoms of potential NMOSD relapse. Due to its mechanism of action, the use of Soliris increases the patient's susceptibility to meningococcal infection (Neisseria meningitidis). Patients in aHUS Study C10-004 received Soliris for a minimum of 26 weeks. 30 ml of concentrate in a vial (Type I glass) with a stopper (butyl, siliconised), and a seal (aluminium) with flip-off cap (polypropylene). At least two thirds of cases are associated with aquaporin-4 antibodies (AQP4-IgG) and complement-mediated damage to the central nervous system. 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. Reduction in terminal complement activity was observed in all patients after commencement of Soliris. • Maintenance phase: 1,200 mg of Soliris administered via a 25 – 45 minute (35 minutes ± 10 minutes) intravenous infusion for the fifth week, followed by 1,200 mg of Soliris administered via a 25 – 45 minute (35 minutes ± 10 minutes) intravenous infusion every 14 ± 2 days (see section 5.1). 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). Haematologic normalization was defined as normalization of platelet counts and LDH levels sustained for ≥2 consecutive measurements for ≥4 weeks. Abstract. The PNH registry (M07-001) was used to evaluate the efficacy of Soliris in PNH patients with no history of RBC transfusion. Supplemental dosing is recommended when Soliris is administered to aHUS patients receiving plasma infusion or exchange (see section 4.2). Soliris vials in the original package may be removed from refrigerated storage for only one single period of up to 3 days. Please see full Prescribing Information for Soliris, including Boxed WARNING regarding serious meningococcal infections. However, this finding was shown in non-controlled clinical trials. Patients were randomized to receive Soliris or placebo. All physicians who intend to prescribe Soliris must ensure they are familiar with the physician's guide to prescribing. Table 8: Efficacy Outcomes in Prospective aHUS Study C10-004, Change in platelet count through week 26 (109/L), Median duration of hematologic normalization, weeks (range) 1, Daily TMA Intervention Rate, median (range). No specific study of eculizumab on fertility has been conducted. 2. By continuing to browse the site you are agreeing to our policy on the use of cookies. SOLIRIS® (eculizumab) is indicated for the treatment of patients with atypical hemolytic uremic syndrome (atypical HUS) to reduce complement-mediated thrombotic microangiopathy. Patients suffering from NMOSD, who were anti-AQP4 antibody positive, were treated with Soliris or placebo. There were fewer thrombotic events with Soliris treatment than during the same period of time prior to treatment. The solution should be clear and colourless. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In this setting, the most common change in immunosuppressant therapy was decreased immunosuppressant therapy dose, which occurred in 18.5% of patients. Patients may have increased susceptibility to infections, especially with Neisseria and encapsulated bacteria. Patients who initiate Soliris treatment less than 2 weeks after receiving a tetravalent meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. Vaccination may further activate complement. 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). Positive ADA samples were low titer and transient. Patients either received meningococcal vaccination at least 2 weeks prior to initiating treatment with Soliris or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. 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. Therefore, an individual risk benefit analysis is recommended before starting and during treatment with eculizumab in pregnant women. In normal kidneys, antibodies are not excreted and are excluded from filtration by their size. Soliris has not been studied in paediatric patients with refractory gMG or NMOSD. 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. 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. Table 1: Adverse Reactions reported in eculizumab clinical trials, including patients with PNH, aHUS, refractory gMG and NMOSD as well as from postmarketing experience, Pneumonia, Upper respiratory tract infection, Bronchitis, Nasopharyngitis, Urinary tract infection, Oral Herpes. Fifty percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 2: Patient Demographics and Characteristics in C04-001 and C04-002, Concomitant Steroids/Immunosuppressant Treatments (%), PRBC in previous 12 months (median (Q1,Q3)), Free Haemoglobin at baseline (median, mg/dL). Gently agitate the infusion bag containing the diluted solution to ensure thorough mixing of the product and diluent. Vaccines against serogroups A, C, Y, W 135 and B where available are recommended in preventing the commonly pathogenic meningococcal serogroups. Supportive safety data were obtained from 31 completed clinical studies that included 1,503 patients exposed to eculizumab in complement-mediated disease populations, including PNH, aHUS, refractory gMG and NMOSD. Despite the recent Soliris and Uplizna approvals, about 40% of patients with NMOSD remain untreated. Other cases of Neisseria species have been reported including sepsis with Neisseria gonorrhoeae, Neisseria sicca/subflava, Neisseria spp unspecified. In clinical trials, 1 (0.9%) gMG patient experienced an infusion reaction which required discontinuation of Soliris. The Soliris antibody contains human constant regions and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. When suggestions are available use up and down arrows to review and ENTER to select. Qualitative and quantitative composition, 4.2 Posology and method of administration, 4.4 Special warnings and precautions for use, 4.5 Interaction with other medicinal products and other forms of interaction, 4.7 Effects on ability to drive and use machines, 6.6 Special precautions for disposal and other handling, 9. “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 … In aHUS Study C08-002A/B, the median duration of Soliris therapy was approximately100 weeks (range: 2 weeks to 145 weeks). Soliris was administered as an intravenous infusion over 35 minutes. Table 4: Efficacy Outcomes (LDH level and FACIT-Fatigue) in Patients with PNH with No History of Transfusion in M07-001, FACIT-Fatigue score at last available assessment (median), FACIT-Fatigue is measured on a scale of 0-52, with higher values indicating less fatigue. Administration of Soliris may result in infusion reactions or immunogenicity that could cause allergic or hypersensitivity reactions (including anaphylaxis). Soliris is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord. Continue, 2. Treatment with Soliris should not alter anticoagulant management. 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. Soliris treatment is recommended to continue for the patient's lifetime, unless the discontinuation of Soliris is clinically indicated (see section 4.4). Infrequent antibody responses have been detected in Soliris-treated patients across all clinical studies. When Soliris treatment was continued for more than 26 weeks, three additional patients (63% of patients in total) achieved Complete TMA response and four additional patients (98% of patients in total) achieved hematologic normalization. Table 6 summarizes the efficacy results for aHUS Study C08-003A/B. It is estimated that 73% of all patients with NMOSD have AQP4 auto-antibodies. Responses were similar across all ages from 5 months to 17 years of age. h�bbd```b``� ��A$�� "���J�lf'�ը�Ȗ ɸt���H�{���!�4F�$�/bU�D�g�t�@� ��C The FDA approval of Soliris for neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive was based on a study of 143 patients who were randomized to receive either Soliris treatment or placebo. 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). 3871 0 obj <>/Filter/FlateDecode/ID[<7CBF98507F04CB459DEFE294DE5086BE>]/Index[3858 37]/Info 3857 0 R/Length 88/Prev 777728/Root 3859 0 R/Size 3895/Type/XRef/W[1 3 1]>>stream Dosing for paediatric patients <40 kg is based on paediatric patients with aHUS. 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. Study ECU-NMO-301 was a double-blind, randomized, placebo-controlled, multi-center, Phase 3 study of Soliris in patients with NMOSD. The proportion of clinical responders at Week 26 with no rescue therapy was 45.2% on Soliris compared with 19% on placebo (p=0.0018). After 3 weeks of Soliris treatment, patients reported less fatigue and improved health-related quality of life. Antibodies to Soliris were detected in 2% of patients with PNH using an ELISA assay, 3% of patients with aHUS and 2% of patients with NMOSD using the ECL bridging format assay. However, renal function was not changed due to prior irreversible kidney damage (Table 16). 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. Cases of haemolysis have been reported in the setting of missed or delayed Soliris dose in PNH clinical trials (see also Section 4.4). 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. 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. This approval makes Soliris ® the first FDA approved drug for this indication. Soliris FDA Approval History. Soliris ® (eculizumab) is proven and/or medically necessary for treatment of: 1Atypical hemolytic uremic syndrome (aHUS) Paroxysmal nocturnal hemoglobinuria (PNH)1,12 Generalized myasthenia gravis1,9,11 1,25Neuromyelitis optica spectrum disorder (NMOSD) Soliris ® In this setting, 65.0% of patients decreased their daily dose of at least 1 immunosuppressive therapy (IST); 43.6% of patients stopped an existing IST. 4 Based on a stratified Cox proportional hazards model. In SHEPHERD study, 96 of the 97 enrolled patients completed the study (one patient died following a thrombotic event). 3894 0 obj <>stream Soliris received FDA approval in June 2019 for the treatment of NMOSD with anti-aquaporin-4 (AQP4-IgG) positive antibodies. SOLIRIS increases your chance of getting serious and life-threatening meningococcal infections. In aHUS clinical studies, 61 patients (21 paediatric patients) discontinued Soliris treatment with a median follow-up period of 24 weeks. Chronic administration of Soliris results in immediate, complete, and sustained inhibition of terminal complement activity (eculizumab serum concentrations ≥ 116 microgram/ml). Table 3: Efficacy Outcomes in C04-001 and C04-002, Percentage of patients with stabilized Haemoglobin levels at end of study, PRBC transfused during treatment (median), Transfusion Avoidance during treatment (%), LDH AUC at end of study (median, U/L x Day), Free Haemoglobin at end of study (median, mg/dL). Evidence of clinical benefit is demonstrated in patients with haemolysis The corresponding elimination half-life remained almost unchanged within a range of 349 to 378 h (approximately 14.5 to 15.8 days). hެUmk�0�+��Q�ϲ�����Vֵ[��e���$�.���?�Yr7/kB�{ѝ��ɔ�((4 Reduction in terminal complement activity was observed in all patients after commencement of Soliris. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. %H� A]u� �=BP�B���L`YV U40p�K���̌�+��3q2�i6X�qk To view the changes to a medicine you must sign up and log in. Soliris is indicated in adults and children for the treatment of: - Paroxysmal nocturnal haemoglobinuria (PNH). Soliris was administered as an intravenous infusion over 35 minutes. In PNH placebo controlled studies low antibody responses have been reported with a frequency (3.4%) similar to that of placebo (4.8%). Abbreviations: ARR = annualized relapse rate; CI = confidence interval. FDA Approved: Yes (First approved March 16, 2007) Brand name: Soliris Generic name: eculizumab Dosage form: Injection Company: Alexion Pharmaceuticals, Inc. Thrombotic microangiopathy (TMA) complications have been observed as early as 4 weeks and up to 127 weeks following discontinuation of Soliris treatment in some patients. Renal function, as measured by eGFR, was improved and maintained during Soliris therapy. It allows continued monitoring of the benefit/risk balance of the medicinal product. * Immunosuppressant's included, but are not limited to, corticosteroids, azathioprine, mycophenolate, methotrexate , cyclosporine, tacrolimus, or cyclophosphamide. 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. An interim analysis of Study ECU-NMO-302 demonstrates a significant and clinically meaningful reduction in On-trial ARR (as determined by the Treating Physician) on eculizumab treatment, based on the median (min, max) change (-1.829 [-6.38, 1.63], p<0.0001) from historical ARR (24 months prior to screening in Study ECU-NMO-301). Patients in both prospective studies were treated with Soliris for 26 weeks and most patients enrolled into a long-term, open-label extension study. In Study ECU-MG-301, a clinical responder in the QMG total score was defined as having at least a 5-point improvement. 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.
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