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Published: September 2001
ADR update

Tiaprofenic Acid-Induced Cystitis

Prescriber Update 22: 18-21
September 2001

Dr Ruth Savage, Medical Assessor, CARM, P O Box 913, Dunedin

Tiaprofenic acid (Surgam™, Surgam SA™) is a non-steroidal anti-inflammatory agent which can cause cystitis.  Recent New Zealand case reports suggest that some clinicians may not be familiar with this adverse effect.  In most cases, the cystitis has developed after taking tiaprofenic acid for months or years.  Symptoms are frequency of micturition, urgency, dysuria and suprapubic pain, and are often severe.  Urine microscopy shows sterile pyuria and haematuria.

Prompt withdrawal of tiaprofenic acid usually results in complete recovery.  Failure to withdraw tiaprofenic acid can result in unnecessary surgery, permanent damage to the urinary tract and renal impairment.  Advise patients on tiaprofenic acid to report any urinary symptoms, and also regularly enquire about these.>

Spontaneous case reports indicate a link between cystitis and tiaprofenic acid

In 2000, the Centre for Adverse Reactions Monitoring (CARM) received two reports of tiaprofenic acid-induced cystitis, bringing the total number to 17.  In one patient, recognition of the cause only occurred when her symptoms resolved on withdrawal of tiaprofenic acid prior to cystoscopy.  The Medicines Adverse Reactions Committee (MARC) would like to remind prescribers about this debilitating adverse effect, to assist in early recognition and resolution.

Tiaprofenic acid-induced cystitis was first reported in New Zealand in 1991.  Two patients developed non-bacterial cystitis while taking tiaprofenic acid.  The cystitis resolved when tiaprofenic acid was withdrawn and recurred on re-introduction.  This reaction was bought to the attention of prescribers.1  In subsequent years, similar cases were seen in other countries.  Spontaneous adverse reaction reporting has led to the identification and confirmation of this potentially serious medicine-related disorder.

An analysis of the Committee on Safety of Medicines database in the United Kingdom (UK) showed that the reporting rate for cystitis in the UK was 18 cases per million tiaprofenic acid prescriptions compared with 0.05 - 0.2 per million for other NSAIAs.2  Cystitis occurs coincidentally, or only extremely rarely, with NSAIAs other than tiaprofenic acid.

Symptoms can be severe and disabling, and may become persistent

Tiaprofenic acid-induced cystitis is characterised by urinary frequency, urgency, dysuria and suprapubic pain.  These symptoms are often severe and disabling, and may become persistent if tiaprofenic acid is continued.  Sterile pyuria, haematuria and sometimes proteinuria are found on urine examination.

Cystoscopy typically reveals a diffusely inflamed mucosa, and the bladder is often small and contracted.  Histological features are mucosal erosion, submucosal oedema and diffuse infiltration of inflammatory cells sometimes extending into the muscle layer.  Eosinophils may also be present.  The inflammatory changes can result in fibrosis extending into the ureters, leading to obstruction.2  Postulated mechanisms for tiaprofenic acid-induced cystitis include a delayed hypersensitivity reaction3, or a direct toxic effect on the urothelium.4

Most patients recover on withdrawal of tiaprofenic acid, avoiding unnecessary surgery

In a case series3,5-7 published in 1994, most of the 32 patients experienced significant morbidity over several months, illustrating a lack of awareness by clinicians of the association between tiaprofenic acid and cystitis.  Twenty four of the patients fully recovered upon withdrawal of the tiaprofenic acid.  Two patients were rechallenged and experienced a rapid recurrence of symptoms lasting several weeks.  Four patients underwent cystectomy and urinary diversion into an ileal conduit for presumed intractable interstitial cystitis.  One patient developed hydronephrosis and renal impairment due to ureteric obstruction.

Tiaprofenic acid-induced cystitis usually occurs in older patients on long-term treatment

A case-control study8 showed age was the only clinical variable that increased the risk of cystitis.  There was a three-fold increase in risk for patients aged > 70 years compared with those aged < 55 years.  The median duration of tiaprofenic acid use until onset of symptoms was 6.3 months, and the median time interval from onset of symptoms to cessation of tiaprofenic acid was three months.  Time to recovery after tiaprofenic acid is withdrawn has ranged from one day to five months.2

Tiaprofenic acid-induced cystitis is still under-recognised

Tiaprofenic acid-induced cystitis is rare and the market share of this NSAIA is small.   Recognition of this reaction may be further impeded by a long delay between starting tiaprofenic acid and the onset of symptoms.  It is important to advise patients to contact their doctor if any urinary symptoms develop.  Tiaprofenic acid should be used with caution in patients with recurrent urinary tract infections, cystitis or urinary symptoms from any cause, since the symptoms of tiaprofenic acid-induced urinary problems may be masked.9

Immediate withdrawal of tiaprofenic acid is essential when any urinary symptoms occur.  The longer tiaprofenic acid is continued the greater the likelihood of irreversible damage and unnecessary surgery.  Patients on long-term treatment with this medicine need to be regularly asked about urinary symptoms.

Competing interests (author): none declared

Correspondence to Dr Ruth Savage, CARM, PO Box 913, Dunedin.

References
  1. New Zealand Department of Health (Therapeutics Section). Cystitis associated with non steroidal anti-inflammatory agents. Prescriber Update 1993; May No.1:10.
  2. Crawford MLA, Waller PC, Wood SM. Severe cystitis associated with Tiaprofenic acid. Br J Urol 1997;79:578-584.
  3. Mayall FG, Blewitt RW, Staff WG. Cystitis and ureteric obstruction in patients taking tiaprofenic acid. BMJ 1994;309:599-600.
  4. Bramble FJ, Morley R. Drug-induced cystitis: the need for vigilance. Br J Urol 1997;79:3-7.
  5. Harrison WJ, Willis RG, Neal DE. Adverse reactions to tiaprofenic acid mimicking interstitial cystitis. BMJ 1994;309:574.
  6. O'Neil GFA. Tiaprofenic acid as a cause of non-bacterial cystitis. M J Aust 1994;160:123-125.
  7. Greene GF, Millard OH, Norman RW, et al. Cystitis associated with tiaprofenic acid. J Urol 1994;152:1101-1102.
  8. Buchbinder R, Forbes A, Kobben F, et al. Clinical features of tiaprofenic acid (Surgam) associated cystitis and a study of risk factors for its development. J Clin Epidemiol 2000;53:1013-1019.
  9. Aventis Pharma Ltd. Surgam, Surgam SA data sheet October 1998. www.medsafe.govt.nz/Profs/Datasheet/s/Surgamtab.pdf

 

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