Family Health, Nottingham Children s Hospital Date of submission February 2018

Transcription

1 Nusinersen Title of Guideline Guideline for the prescribing and administration of Nusinersen to patients with Spinal Muscular Atrophy Type 1 Contact Name and Job Title (author) Dr Gabriel Chow- Consultant Paediatric Neurologist Dr Simone Stokley- Consultant Paediatric Haematologist/ Trust Intrathecal Lead Andrew Wignell - Senior Paediatric Pharmacist Directorate & Speciality Family Health, Nottingham Children s Hospital Date of submission February 2018 Date on which guideline must be reviewed (this should be one to three years) Explicit definition of patient group to which it applies (e.g. inclusion and exclusion criteria, diagnosis) Abstract Key Words Statement of the evidence base of the guideline has the guideline been peer reviewed by colleagues? Evidence base: (1-5) 1a meta analysis of randomised controlled trials 1b at least one randomised controlled trial 2a at least one well-designed controlled study without randomisation 2b at least one other type of well-designed quasiexperimental study 3 well designed non-experimental descriptive studies (i.e. comparative / correlation and case studies) 4 expert committee reports or opinions and / or clinical experiences of respected authorities 5 recommended best practise based on the clinical experience of the guideline developer February 2020 Children with Spinal Muscular Atrophy Type 1 This guideline is intended to provide clear guidance on the use of nusinersen in the management of Children with Spinal Muscular Atrophy Type 1 Treatment can only be initiated by a Consultant Paediatric Neurologist. Paediatric, Children, Spinal Muscular Atrophy, Nusinersen 1b. Use is in line with the NHS England (2017) Urgent Clinical Commissioning Policy Statement: Nusinersen for genetically confirmed Spinal Muscular Atrophy (SMA) type 1 for eligible patients under the Expanded Access Programme (EAP). Consultation Process Paediatric Neurology, Paediatric Haematology, Paediatric Oncology, Pharmacy, NUH Drugs and Therapeutics Committee. Target audience Medical, nursing and pharmacy staff working at Nottingham Children s Hospital This guideline has been registered with the trust. However, clinical guidelines are guidelines only. The interpretation and application of clinical guidelines will remain the responsibility of the individual clinician. If in doubt contact a senior colleague or expert. Caution is advised when using guidelines after the review date. Lead Author: Gabriel Chow Page 1 of 8 September 2017

2 Document Control Document Amendment Record Version Issue Date Author V1 Feb 2018 Dr G Chow, Consultant Paediatric Neurologist Dr S Stockley, Consultant Paediatric Haematologist Andrew Wignell, Senior Paediatric Pharmacist Statement of Compliance with Child Health Guidelines SOP This guideline refers to activities of only one specific team and consultation has taken place with relevant members of that team. Therefore this version has not been circulated for wider review. Maria Moran Clinical Guideline Lead 27 th February 2018 Lead Author: Gabriel Chow Page 2 of 8 September 2017

3 Background Spinal Muscular Atrophy Type 1 (SMA1) is the most common fatal genetic disease of infancy; children die in childhood of muscle weakness. Until now there has been no treatment. Nusinersen is an investigational disease-modifying drug, which works by increasing the amount of functional SMN protein, by altering the splicing of pre-mrna from the SMN2 gene. Biogen, the manufacturer of Nusinersen, reported that the drug met the primary endpoint pre-specified for the interim analysis of ENDEAR, the Phase 3 trial evaluating nusinersen in infantile-onset (consistent with Type 1) SMA. The analysis 1 found that infants receiving nusinersen experienced a statistically significant improvement in the achievement of motor milestones compared to those who did not receive treatment. Nusinersen demonstrated an acceptable safety profile in the trial. Nusinersen is now licenced in the UK for the treatment of SMA1. The manufacturer s Summary of Product Characteristics ( data sheet ) can be found here: Commissioning of Nusinersen Treatment Based on a limited scoping of the evidence, NHS England has concluded that there is sufficient evidence to support a proposal for the routine commissioning of this treatment for SMA Type 1 as outlined in the starting criteria below 2. The medicine will be provided free of charge by Biogen under an Early Access Programme (EAP); NHS England will reimburse Trusts for the activity associated with drug administration. Criteria for stopping treatment have also been stipulated by NHS England. Starting Criteria Genetic documentation of 5q SMA homozygous gene deletion, homozygous mutation, or compound heterozygote. SMN2 copy number = 2. Onset of clinical signs and symptoms consistent with SMA at 6 months (180 days) of age. Males and females 7 months (210 days) of age at Screening. Receiving adequate nutrition and hydration (with or without gastrostomy). Body weight 3rd percentile for age using appropriate country-specific guidelines. Medical care, such as routine immunisations (including influenza vaccine, pneumococcus vaccine, and respiratory syncytial virus prophylaxis (palivizumab) if available), meets and is expected to continue to meet guidelines set out in the Consensus Statement for Standard of Care in SMA. Exclusion criteria SMA1A (also called SMA0) is a special category by virtue of its extreme severity, Lead Author: Gabriel Chow Page 3 of 8 September 2017

4 and which requires discussion with the parents on the basis that SMA1A infants are very unlikely to respond to Nusinersen. Thus nusinersen EAP will not be an appropriate intervention for SMA 1A infants. Comorbidities that might preclude lumbar puncture. Hypoxaemia (O2 saturation awake <96% or O2 saturation asleep <96%, without ventilation support) during screening evaluation. Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy. History of brain or spinal cord disease that would interfere with the lumbar puncture procedures, cerebrospinal fluid (CSF) circulation, or safety assessments. Untreated bleeding disorders or any other existing condition which precludes lumbar punctures. Spinal fusion in most instances (needs further assessment with orthopaedic surgeons). Stopping Criteria For patients on 24 hour non-invasive ventilation (NIV), if there is no improvement in motor score, assessed by the Hammersmith Infant Neurological Examination (HINE), or NIV requirement improvement - then treatment should discontinue after the 5th dose of nusinersen treatment. For patients on less than 24 hour NIV, maintenance of respiratory function with NIV (i.e. need for the same number of hours NIV (for example a patient receiving 16 hours NIV per day continues to need 16 hours per day, or one on 22 hours per day continues to need 22 hours) may be viewed as stabilisation and an indication of benefit - so nusinersen treatment will continue. HINE score will also be calculated, and stability or improvement on the HINE score will be considered an indication to continue nusinersen administration. If in the parents view the quality of life is poor because of SMA1 disability progression, or adverse effects of nusinersen administration procedure or drug side effects, then there is a need to discuss nusinersen discontinuation. If the view of the treating physician is that the handling and positioning required for lumbar puncture or a general anaesthetic required for this procedure, impose significant life-threatening risk in a fragile SMA1 infant, this would be considered as an indication to stop nusinersen EAP participation. There may be additional unforeseen circumstances / worsening of clinical status, which may necessitate a discussion with the parents to discontinue nusinersen treatment. Contraindications Nusinersen will not be offered to patients with other life limiting conditions or if it is contraindicated to treatment as set out in the Summary of Product Characteristics. Lead Author: Gabriel Chow Page 4 of 8 September 2017

5 Adverse Effects Most common adverse reactions reported: fever, lower respiratory infection, upper respiratory infection and constipation Other reported adverse reactions: teething, upper respiratory tract congestion, aspiration, ear infection, scoliosis, rash, reduction in growth, respiratory distress, respiratory failure, salivary hypersecretion, atelectasis, nasopharyngitis, nausea and vomiting Reported side effects of intrathecal injections include: headache, back pain, infection, bleeding near the puncture site (rarely into the epidural space) and transient or persistent cerebrospinal fluid leakage (post lumbar puncture syndrome) Dosing The Nusinersen dose is 5ml = 12mg, given by the intrathecal route. This is not age dependent. Four loading doses are given in the first 2 months on days 1, 15, 30 and 60. A maintenance dose is then given every 4 months thereafter. If a loading dose is delayed or missed, administer nusinersen as soon as possible, with at least 14-days between doses and then continue dosing as prescribed. Consent and Planning Once a patient is identified by Dr Chow or another neurologist, they should inform the medical intrathecal lead for Queen s Medical Centre or one of the other paediatric haematologists/oncologists who will decide with Dr Chow when the child should start treatment. The Neurologist would determine whether the procedure was to be completed with or without general anaesthetic. Most children under the age of 2 years should manage well with local anaesthetic. Consent will be taken by the Neurologist for both the lumbar puncture and intrathecal administration of Nusinersen. Prescribing and Administration Nusinersen must be prescribed by a Consultant Paediatric Neurologist. The administrator of the drug will be a Paediatric oncologist/haematologist who is on the Trust Intrathecal Register. This will require annual training and assessment of competence. The medical intrathecal lead for Queen s Medical Centre will advise on the necessary training. Each dose needs to be prescribed separately, but up to a year s worth of doses may be written up at any one time. If a treatment dates change following the initial prescription, the prescription can be re-dated (with the prescriber making Lead Author: Gabriel Chow Page 5 of 8 September 2017

6 the change annotating the prescription with their initials, printed name and the date the change was made). The prescriptions should be written on a specific nusinersen intrathecal drug chart. Administration will take place at the end of an oncology intrathecal list on E39 Day Care. All staff involved in the administration of the drug must be on the Children s Hospital Intrathecal Register. A detailed protocol covering administration is included as Appendix 1 of this guideline. Preparation, Delivery and Storage of Medication The required dose will be drawn up in the Pharmacy Sterile Production Unit into a NRFit Spinal Syringe. After release from the production unit, the dose will be delivered to E39 Day Care following the normal intrathecal procedures. Delivery of Nusinersen to the ward must be separate to the delivery of intrathecal chemotherapy. All personnel involved in delivery and receipt of the prepared dose must be the Children s Hospital Intrathecal Register. Nusinersen must be stored separately to other medicines, including other intrathecals. It must be stored at room temperature in a designated locked cupboard separate to all other medicines. Lead Author: Gabriel Chow Page 6 of 8 September 2017

7 References 1) European Medicines Agency (2017) European Public Assessment Report: Spinraza. _Public_assessment_report/human/004312/WC pdf 2) NHS England (2017) Urgent Clinical Commissioning Policy Statement: Nusinersen for genetically confirmed Spinal Muscular Atrophy (SMA) type 1 for eligible patients under the Expanded Access Programme (EAP). Lead Author: Gabriel Chow Page 7 of 8 September 2017

8 Appendix 1: Protocol for Drug Administration Pre-Procedure Checklist Check Consent for Lumbar puncture and nusinersen intrathecal administration Check that LP needle is available Check that the nurse checking nusinersen, and Doctor due to administer it intrathecally, are on the intrathecal register. Check the patient is fit for procedure Check blood/urine results (clotting, FBC and urine protein)- before start of course of EAP treatment, or taken with last dose, whichever is most recent). This is the responsibility of the Paediatric Neurology Team. Check prescription and treatment protocol Check that oxygen saturations >95% before procedure Protocol for lumbar puncture and intrathecal administration: Wash hands wear sterile gloves before commencing the procedure in a non touch aseptic manner. Strict aseptic technique. Lumbar puncture must be performed with a non-luer NRFit syringe. NRFit intrathecal Kit is obtained from NHS Supply Chain. Once the lumbar puncture needle is in place, approximately 3 5 ml of CSF should be drained (collected and saved if indicated) through the lumbar puncture needle prior to dose administration. If a lumbar puncture (LP) is technically difficult and requires the assistance (doing the LP to obtain successful spinal CSF tap) of someone else whose name does not appear on the register, this is acceptable but these staff must never be involved in any other aspect of the process and must never administer the intrathecal nusinersen. The nusinersen syringe, which has a non-luer NRFit tip, should be directly attached to the hub of the lumbar puncture NRFit needle. The drug solution should be injected slowly, over the course of 1 minute. Once the procedure has been completed, the puncture site should be covered with an adhesive bandage or occlusive dressing. Doctor and IT registered nurse to sign the prescription to record drug administration. Lead Author: Gabriel Chow Page 8 of 8 September 2017