Advice for healthcare professionals:
- communicating hydrocephalus has been rarely reported during treatment with nusinersen; most cases developed after 2 to 4 loading doses
- discuss the risk of communicating hydrocephalus and its clinical features with patients and their caregivers
- advise them to seek urgent medical attention if any possible symptoms or signs develop including: persistent vomiting or headache, decreased consciousness, or a rapid increase in head size in children
- consider communicating hydrocephalus in the differential diagnosis of any patient with suggestive symptoms and signs and investigate them urgently
- refer patients with hydrocephalus to a neurosurgeon as soon as possible as they may require treatment with a CSF shunt
- if a CSF shunt is considered necessary, prescribers should inform patients and their carers that the benefits and risks of continued nusinersen treatment in patients with CSF shunts are not known (see below)
- report any suspected adverse drug reactions to nusinersen on a Yellow Card, including hydrocephalus or any problems after insertion of a CSF shunt
Nusinersen (Spinraza▼) is an antisense oligonucleotide indicated for the treatment of 5q spinal muscular atrophy that was first authorised in December 2016. Nusinersen is given intrathecally by lumbar puncture as 4 loading doses on days 0, 14, 28, and 63 of therapy, followed by maintenance doses every 4 months.
Reports of communicating hydrocephalus
Worldwide, 5 cases of communicating hydrocephalus have been reported up to 6 July 2018 during routine clinical use of nusinersen. Of the 5 cases, 4 were children with spinal muscular atrophy type 1 who presented with signs of hydrocephalus after receiving 2 to 4 loading doses and one was an adult with scoliosis. Three of the children required cerebrospinal fluid (CSF) drainage procedures and continued nusinersen treatment (2 had ventriculoperitoneal shunts). One child did not require a CSF shunt and is being monitored after nusinersen was discontinued.
There is no known association between spinal muscular atrophy and communicating hydrocephalus and investigations did not reveal an underlying cause such as intracranial haemorrhage or infection.
Worldwide, up to 30 September 2017, approximately 1,437 patients have received nusinersen in routine clinical practice (439 patient-years). We have not received any reports of hydrocephalus associated with nusinersen treatment in the UK, although usage is currently very limited.
Discuss with patients, and their caregivers if necessary, the risk of hydrocephalus and advise them to seek urgent medical attention if any signs or symptoms of hydrocephalus develop including persistent vomiting or headache, seizures, decreased consciousness, or a rapid increase in head size in children.
Hydrocephalus should be considered in any patient with suggestive clinical features and confirmed cases should be referred urgently to a neurosurgeon for advice on further management.
The effectiveness and safety of nusinersen in patients with CSF shunts has not been determined. If nusinersen is continued, prescribers should continue to monitor the response to therapy. There are no data on the complication rate of CSF shunts with continued nusinersen treatment and the elimination rate of nusinersen from the central nervous system following CSF shunt insertion has not been determined. If a CSF shunt is required, patients and their carers should be informed that the risks and benefits of nusinersen in patients with CSF shunts are not known.
Next steps and continued monitoring
The risk of hydrocephalus has been added to the product information for nusinersen and prescribing clinicians were informed of this risk by letter in August 2018. As a new medicine, the benefits and risks of this medicine are being reviewed regularly, including any further data about the risk of hydrocephalus and the effectiveness and safety of nusinersen in patients with CSF shunts. The marketing authorisation holder is also conducting additional studies into the safety of nusinersen.
Report any suspected adverse drug reactions
As for all medicines, MHRA will continue to closely monitor the safety of nusinersen. As a black triangle drug under the additional monitoring scheme, any suspected adverse drug reactions associated with nusinersen should be reported on a Yellow Card, including signs or symptoms of hydrocephalus or any problems developing after insertion of a CSF shunt such as lack of efficacy or shunt dysfunction.
Article citation: Drug Safety Update volume 12, issue 2; September 2018: 4.