in children over 5 years old, prescribing algorithm , , trospium, and mirabegron are ‘Amber Initiated’ in paediatrics

Children with symptoms of Success = no side effects, improvement overactive bladder Failure = side effects, no improvement

Oral Oxybutynin standard release Increase dose if

Success necessary Consider (licensed in children aged > modified 5 years) according to release Review in 6 weeks response (BNFc) Review every 3-6 Failure months

Tolterodine standard release Increase dose if (not licensed for use in necessary according Consider Success children) to response (BNFc) modified Refer to BNFc for dosing Review every 3-6 release

advice months

Discuss treatment failure with senior Either / OR treatmentFailure Trospium: Oxybutynin patch (if Increase dose if can’t take whole) Trospium standard necessary Trospium

(Not licensed for use in release (if >12 years Success according to Consider children) or <12 if can swallow response. Max modified adult dose 20mg • 4 – 9 years old ¼ tablet whole) release patch twice weekly (licensed in children BD (BNF) • 10 – 12 years old ½ aged >12 years) patch twice weekly 5mg – 10mg BD Oxybutynin patch: • >12 years old 1 initially Adjust dose patch twice weekly according to Provide Tegaderm and response. Max 1 application advice patch twice weekly Review in 6/52 then 3-6 Review every 3-6 months if tolerated months

Failure

Solifenacin Increase dose if necessary according to (Not licensed for use in children) Success response. Max adult dose Start at 5mg daily 10mg daily (BNF) Review every 3-6 months Failure in 7 years and over treatment on stable is patient the when GP to drug prescribing Transfer Mirabegron

(Not licensed for use in children) Increase dose if Start at 25mg daily Success necessary according to Monitor BP and heart rate 3 response. Max adult monthly dose 50mg daily (BNF) Review every 3-6 months Failure d/w consultant

Add Solifenacin 5mg daily to Mirabegron at 25mg daily (Hospital only) Version: 2.0 Review date: Apr 2022 (or earlier if there is significant new evidence relating to this recommendation) When prescribing antimuscarinics, the specialist who initiated the treatment would have considered the followings:

• antimuscarinics known to cross the blood-brain barrier (for example, oxybutynin) have the potential to cause central nervous system-related side effects (such as confusion)

• antimuscarinic treatment can reduce bladder emptying, which may increase the risk of urinary tract infections

• antimuscarinic treatment may precipitate or exacerbate constipation

Where a patient failed treatment with tolterodine:

• oxybutynin patch is a preferred choice for a child who cannot take tablets whole. Do not prescribe for any patient with ezcema or previous history of skin allergies/sensitive skin.

• trospium should be first option in all children over 12 years who can tolerate tablets as it is licenced and cheaper than the patch, and in children under 12 years who can take tablets. Advise to take tablets on an empty stomach. If problems with compliance, side effects or poor response, consider oxybutynin patch. NB: Not all antimuscarinics have a UK marketing authorisation for use in children.

Please refer to the individual Summary of Product Characteristics for full list of cautions, contraindications, drug interactions and adverse reactions.

Primary Care prescribing • Prescribing will be continued in primary care under amber initiated criteria. • Patients will have been stabilised on treatment by the initiating specialist (including specialist consultants, advanced nurse practitioners) before GP prescribing commences. • The specialist should provide primary care with a diagnosis and treatment plan including review dates. The specialist will inform the patient / carer where a medicine is being used “off-label” and obtain their consent. This will be documented and the GP informed.

• The specialist will continue to monitor and supervise the overall treatment and review of the patient. • The GP would inform the specialist of any concerns or side effects associated with the drug. • If the GP does not feel it is appropriate to take on the prescribing then the prescribing responsibilities will remain with the specialist. The GP should inform the specialist the reason for declining.

Monitoring recommendations:

• Mirabegron: regular monitoring of blood pressure and heart rate at least once every 3 months . See NIH blood pressure tables in paediatrics and adolescents for reference values. • side effects e.g. constipation, , dry mouth, blurred vision, skin flushing, transient bradycardia

How long the medicine should be prescribed for The duration of treatment benefit may vary between individuals. Termination of treatment will be carried out by the specialist.

Ongoing role of specialist Advice of the specialist should be sought if any concerns or if serious adverse effects are reported by the patient. Notify the specialist of any lack of clinical efficacy or non-adherence with the treatment plan or if patient did not attend appointment(s). References

1. British National Formulary for Children November 2016 2. British National Formulary November 2016 3. Medhi B et al. Comparison of tolterodine with standard treatment in pediatric patients with non- neurogenic dysfunctional voiding/overactive bladder: a systematic review. Indian Journal of Physiology and Pharmacology, 2013; 57(4): 343-353 4. Lopez Pereira P et al. for the treatment of detrusor instability in children. Journal of Urology, 2003; 170: 1978-81 5. Bolduc S et al. Prospective open label study of solifenacin for overactive bladder in children. J Urol, 2010; 184(4) Suppl: 1668-1673 6. Kajiwara M et al. Combination treatment with solifenacin plus desmopressin for children with persistent nocturnal incontinence which lasts after obtaining complete cure of urge urinary incontinence. International Urogynecology Journal and Pelvic Floor Dysfunction, 2010; 21: S279- S280 (Conference abstract) 7. Hoebeke P et al. Solifenacin for therapy resistant overactive bladder. J Urol, 2009; 182: 2040-44 8. Gleason JM et al. Single centre experience with oxybutynin transdermal system (patch) for management of symptoms related to non-neuropathic overactive bladder in children: An attractive, well tolerated alternative form of administration. J Pediatr Urol, 2014; 10(4): 753-757 9. Cartwright PC et al. Efficacy and safety of transdermal and oral oxybutynin in children with neurogenic detrusor overactivity. J Urol, 2009; 182(4) Suppl: 1548-1554 10. Blais AS et al. Prospective study of mirabegron in pediatric patients with overactive bladder. Eur Urol, 2016; 70(1): 9-13 11. Abrams P et al. Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging phase 2 study (Symphony). Eur Urology, 2015; 67: 577-588 12. Yamaguchi O et al. Safety and efficacy of mirabegron as ‘add-on’ therapy in patients with overactive bladder treated with solifenacin: a post-marketing, open-label study in Japan (MILAI study). BJU Int, 2015; 116: 612-622