Brriirfi Journal of Uro.'og)' (1938), 62. 319-322
`@ I088 British J ournal of Urology
`
`Oxybutynin: is it Safe?
`
`R. J. BAIGFIIE, J. P. KELLEHER, D. P. FAWCETT and A. W. PENGELLY
`
`Department of Uroiogy, Barrie Hospitaf. Reading
`
`Summary——0xybutynin has been widely prescribed in the United Kingdom for more than 5 years on
`a named patient basis. Complete knowledge of its side effects is therefore particularly important.
`The literature contains remarkably little data on this topic. We therefore reviewed 192 consecutive
`patients for whom the drug had been prescribed in a district general hospital; 57% derived benefit
`while 76% noted side effects, none of which was dangerous or irreversible. Oxybutynin obtained
`from the two principal suppliers did not appear to differ either in efficacy or side effects. We discuss
`the uncertain medicolegal implications of named patient prescriptions.
`
`Oxybutynin has been widely used in the UK in the
`treatment of detrusor instability for more than 5
`years. In this country, however, unlike Europe and
`the United States of America,
`it has never been
`granted a full product licence and is available only
`on a named patient basis. The legal liability of a
`doctor using this method of prescription is not
`clear. It is therefore particularly important that the
`prescribing doctor is fully aware of any possible
`side ellects. A comprehensive review of the litera-
`ture revealed remarkably little information on
`Oxybutynin in general and its side effects
`in
`particular. We have therefore reviewed our own
`series of l92 consecutive patients who have received
`Oxybutynin over the last 5 years and report on both
`its elficacy and side effects.
`
`Review of the Literature
`
`Three independent computer searches of interna-
`tional journals produced 17 references to Oxybu-
`tynin (sec References). Only 4 studies contained 20
`or more patients to whom the drug was administered
`for 2 or more weeks (Moisey et a!., 1980; Riva and
`Casolati, 1984; Gajewski and Awad, 1986; Milani
`er £11., 1986).
`
`the 43rd Annual Meeting of the British
`Read at
`Association of Urological Surgeons in Edinburgh, July
`1987
`
`The indications, dosage and duration of treat-
`ment varied widely. Indications included spasm
`after transurethral surgery, enuresis, detrusor inst-
`ability, neuropathic bladder, ureteric colic and
`bacterial cystitis. Many patients received only a
`single dose of Oxybutynin and in others the drug
`was administered for only a few days.
`Almost all of the authors concluded that Oxybu-
`tynin was effective. the one exception being a study
`of bladder spasm after transurethral surgery (Wein
`er at'., 1978).
`Only 5 of the i7 studies reported significant side
`effects, which were predominately anticholinergic
`(Brooks and Braf, 1980; Moisey at all, 1980; Riva
`and Casolati, 1984; Bouwmeister er al., 1986;
`Gajewski and Awad, 1986). Although these were a
`minority of the papers, in each the incidence of side
`effects was high (65—75f‘/,,) and they were sulficiently
`unpleasant to justify discontinuation (intolerance)
`in 20 to 38% of patients.
`
`Patients and Methods
`
`Since Oxybutynin is available only on a named
`patient basis, our hospital pharmacy has been
`obliged to keep a record of each prescription: 192
`new patients received the drug after it was first
`prescribed in 1982. We have inadequate data on 12
`of these, leaving 180 patients whose records have
`been reviewed.
`
`319
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2037 - 0001
`
`

`
`BRITISH JOURNAL OF UROLOGY
`
`EABLE 1§%
`
`Primary Enurusis
`
`10%
`
`Neurological
`9%
`
`Idiopathic
`85%
`
`
`
`Fig. 2
`
`Indications For Oxybutynin.
`
`5 mg tds, and for enuresis 5 mg nncre. However, in
`elderly patients and those of small stature the dose
`was frequently reduced. Patients were initially
`prescribed 100 tablets and treatment was continued
`if the drug proved helpful and was well tolerated;
`35 patients took the drug for more than 1 year and
`13 of these took the drug for more than 3 years.
`
`Efiicacy
`
`Figure 3 illustrates the number of patients who
`benefited from Oxybutynin. Those described as
`cured had a complete remission ofsymptoms which
`was maintained after the drug was stopped. The
`improved category includes all ofthose who derived
`any benefit from the drug; however, they relapsed
`when treatment was stopped.
`
`Side Effects
`
`Side effects were noted in 137 patients (76%) (Fig.
`4). Forty—one patients (23%) had side effects so
`unpleasant
`that
`they stopped taking the drug
`(intolerance). The Table lists the various side effects
`which occurred, by far the commonest being dry
`mouth. However, a wide variety of side effects was
`reported, many related to the anticholincrgic
`properties of Oxybutynin.
`
` UNCHANGED
`
`OR WORSE
`43%
`
`IMPROVED
`52%
`
`320
`
`Results
`
`Age and Sex
`
`Figure 1 shows that the majority of our patients
`were female, between 40 and 70 years of age. The
`one patient under the age of 10 had a myelomenin-
`gocelc. Most of the patients under the age of 30
`were given the drug for either primary enuresis or
`a neurological disorder.
`
`Iridr'c'an'ons_fnr Trmtrnent
`
`Detrusor instability is the most widely accepted
`indication for Oxybutynin and this was the diag-
`nosis in 151 (84%) of our patients. In 103 (57‘{’«Q)_it
`was urodynamically proven. It was idiopathic III
`117 (65%). associated with primary enuresis in 18
`l0‘,’{,'d'h
`l'll.'.'16
`Em’ 8?ir;”’§9 §¥ff§n?f?i§o9i‘f5im‘§;‘;'$Z.»L‘li to
`/0 -
`/0
`‘
`have stable bladders. the majority suffered unex-
`plained urgency {Fig. 2).
`
`Dosage
`
`The initial dose for detrusor instability was usually
`
`28%d‘
`
`72% 9
`
`
`
`35
`
`30
`
`M 01
`
`NUMBEROFPATIENTS 5P3
`
`10
`
`10
`
`20 30 40 50 60 ?O 60
`PATIENT AGE
`
`Fig. I Number and age of patients.
`
`Fig. 3 Eilicacy ol'0xybutynin.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2037 - 0002
`
`

`
`OXYBUTYNIN: IS IT SAFE?
`
`321
`
`were intolerant of the drug. The presence of side
`effects was the most
`important cause of non-
`compliance and the major limitation to Oxybutynin
`being more widely prescribed. However, none of
`the side effects was dangerous and all reversed
`when the medication was stopped. We were unable
`to find any pre-treatment factors reliably associated
`with either a good or a bad response to the drug.
`It has been suggested that Oxybutynin obtained
`from the two principal suppliers (Tillots, Smith and
`Nephew) may differ in its side effects. Our series
`included I 9 patients who changed from one supplier
`to the other during their treatment and were
`subsequently followed prospectively. Although the
`number was small, we found no evidence of any
`significant differences in side effects or efficacy
`between the two preparations.
`The legal liability of a doctor prescribing a drug
`on a named patient basis is not Clear.
`In the
`Pharmaceutical Journal (1986), one of the com-
`panies supplying Oxybutynin stated that until the
`drug was licensed, the prescriber had to take full
`responsibility for its use. However, one of the
`medical defence organisations stated in correspond-
`ence with the authors, “We do not believe that you
`will be placing yourselves in a vulnerable position
`if you continue to prescribe this drug on a named
`patient basis." They went on to state, “If any claim
`for damages were to be made against a doctor, the
`doctor will be covered by his indemnity insurance
`with a medical defence organisation in the same
`way as any other aspect of his professional work
`would be covered.”
`
`This study has highlighted the importance of side
`effects as a limitation to the use of Oxybutynin.
`Nevertheless, it has revealed no good reason why
`this drug should not be available under the normal
`method of prescription in this country. In view of
`this and the uncertain liability of the prescribing
`doctor, every effort should be made to encourage
`the suppliers of this drug to submit the necessary
`data to satisfy the Committee of Safety of Medi-
`cine’s criteria for full registration.
`
`References
`
`Bouwmeister, P. P. M., van Waalwijk van Doorn, E. S. C.. van
`Oostendorp. M. E. et cl. (1936). 24-hour ambulant monitoring
`of the efficacy of Oxybutynin chloride in patients with proven
`motor urge incontinence. In Proceedings of the Third Joint
`Meeting of the International Continence Society and the
`Urod_1'narm'r'.r Sor'r'e(y, Boston.
`Brooks, M. E. and Brnf. Z. F. (1980). Oxybntynin chloride
`(Ditropan)—clinical uses and limitations. Paraplegic, 18, 64"
`68.
`
`
`
`"\-._No SIDE arrears
`\
`24%
`
`
`
`
`
`\
`
`
`
`Fig. 4
`
`Side effects and intolerance.
`
`Scrutiny of the many haematological and bio-
`chemical screening tests did not reveal any worrying
`trends or changes.
`
`Discussion
`
`study of
`retrospective adult
`the first
`is
`This
`Oxybutynin reported in the literature. The number
`of patients and duration of treatment and study are
`far greater than in previous reports.
`Only 577}; pf our patients derived benefit from
`the drug and in many cases this was only at modest
`improvement. This compares poorly with the results
`reported in the literature, where efficacy was never
`below 69% (Moisey at at, 1980). However, the long
`duration of this study revealed a number of patients
`initially helped by Oxybutynin who subsequently
`abandoned it because worthwhile benefit was no
`
`longer obtained. It is probable that these patients
`were not detected in many of the short prospective
`trials previously reported.
`Seventy-six per cent of our patients reported side
`effects which were usually anticholinergic and 23"/.,
`
`Table Side Effects
`
`Oral
`(144 patients)
`
`Visual
`(10 patients)
`Gastrointestinal tract
`(23 patients)
`
`Central nervous system
`(19 patients)
`
`Other
`(5 patients)
`
`Dry mouth
`Dysphagia
`Stoinal ulcers
`
`Dry eyes
`Blurred vision
`Diarrhoea
`Constipation
`Distcnsion
`Nausea
`
`Headache
`Dizziness
`Drowsiness
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2037 - 0003
`
`

`
`322
`
`BRITISH JOURNAL OF UROLOGY
`
`Buttarazzi, P. J. ([977). Oxybutynin chloride (Ditropan) in
`enuresis. J. Urui'., I18. 46.
`De Castro. R., Casolari, E. and Ricci, S. (1984). Combination of
`Oxybutynin chloride with intermittent cathetcrization in the
`treatment of neurogenic bladder in childhood: results on
`continence. Paediatr. Med CJ'.!ir.. 6. 795-803.
`Dioltno, A. C. and Lapides, J. U972). Oxyhutyninz ‘it. new drug
`with analgesic and anticholinergic properties. J. Urol.. 108,
`3074410.
`Cajewski, J. B. and Amid. S. A. (1986). Oxybutynin versus
`Propantheline in patients with multiple sclerosis and detrusor
`hyperrcflexia. J. Urol., 135,966 968.
`Hchtr. M. and Fitzpatrick. J. M. (1985). Oxyhutynin and the
`prevention of urinary incontinence in spina bifida. Eur. Urol.,
`11. 254-256.
`Marconi, A. M., Feliei, E., Reggie. A4-mi. ( I985). Anticholinergie
`treatment in the therapy of primary enuresis. Put-«Hair. Med.
`Ch1'r.. 7. 573-576.
`(1986). A
`Milanl, R.. Scalnmbrino, S., Carrcra. S. et al.
`randomised trial of bladder retraining versus Oxybutynirt in
`the treatment of idiopathic urge syndrome: Early results. In
`Prm:‘eed.I'rtgs of the Third Join! Mrwmg of the Irmwiariorial
`Conrirzerzce Society and the Urodynarrrics Society, Ba_s'!0rr.
`Moiscy. C. U., Stephenson, T. P. and Brendler, C. B. (I 980). The
`urudynamic and subjective results of treatment of dctrusor
`instability with osybutynin chloride. Br. J. Urol., 52. 472-475.
`Mulcahy. J. J., James, II. E. and Mclloberts, J. W. (1977).
`Oxyhutynin chloride combined with intermittent clean cath-
`
`cteiisstion in the treatment of myelumcningocclc patients. J’.
`Urol., 118, 95 96.
`Pattlson. D. F. (1976). Oxyhutynin chloride in control of post-
`transurethrall vesical pain and spasm. Urology, II, 237 2.18.
`Paulson. D. F. (1979). Oxybutynin chloride in the management
`ofidiopathic detrusor instability. South. Med. J., 72, 37-#375.
`Pharmaceutical Journal (1986). Cystin (Oxybutyitittl prescribing
`“unusually high". Pharm. J.. l November. p. 548.
`Riva, D. and Casolati, E. (I984). Oxybutynin chloride in the
`treatment of female idiopathic bladder instability. Clirr. F_'.\'p.
`Obit. Cr‘_w1eco."., 11, 37—42.
`Takimoto, Y.. Kiyotaki, S., Kawayoc, K. at at‘. (1985). Clinical
`etfectivcness of Oxybutynin chloride in urinary disorders.
`H1'n_vnk:'ka Kim. 31, 2234-2301.
`Thompson, 1. M. and Lauvelz, R. (1976). Oxybutynin in bladder
`spasm, neurogenie bladder. and enuresis. Um1og_;».8,452—454.
`Wein, A. .l., Haimo, P. M., Raeyer, D. M. 91 ml. (1978). Effect of
`Oitybutynin chloride on bladdcrspasan following lritnsurcthral
`surgery. Urology, 12. 184 l86.
`
`The Authors
`
`R. J. Baigrie, MB. Chli, Senior House Olticer.
`J. P. Kellcher, FRCS. Registrar.
`D. P. Fawcctt. FRCS, Consultant Urologist.
`A. W. Pengelly, FRCS. Consultant Urologist.
`
`Requests for reprints to : A.W. Pcngclly, Departmentofurology.
`Battle Hospital, Oxford Road, Reading RG3 IAG.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2037 - 0004