Safety and Tolerability of Tolterodine for the Treatment of Overactive Bladder in Adults

This article evaluates the safety and tolerability oftolterodine for the treatment of overactive bladder(OAB), which is defined as urinary urgency with orwithout urgency incontinence, usually with frequencyand nocturia, but without infection or pathology.OAB affects tens of millions of people worldwide.Data are summarized from clinical trials and frompostmarketing surveillance studies.

(Am J Manag Care. 2005;11:S158-S162)

The International Continence Society(ICS) has defined overactive bladder(OAB) as urinary urgency with orwithout urge incontinence, usually with frequencyand nocturia, in the absence ofproven infection or obvious pathology.¹ TheICS has recognized OAB as a significantsymptom syndrome affecting millions of peopleworldwide.

Tolterodine is a competitive, nonselectivepure muscarinic receptor antagonist² thatwas developed specifically for the treatmentof OAB. Tolterodine is indicated for symptomsof urinary frequency, urgency, andurge incontinence associated with OAB.

The agent has been shown to reduce micturitionfrequency and the number ofepisodes of urge incontinence and toincrease the volume voided per micturition.³

Tolterodine is available in immediate-release(IR) and extended-release (ER) formulations,which have been shown to bebioequivalent in their pharmacologic profile.⁴ The ER formulation has improved efficacyand tolerability compared with the IRformulation.⁵

OAB: Scope of the Problem

Recent studies have demonstrated thatOAB affects tens of millions of people worldwide.In the United States, the NationalOveractive Bladder Evaluation (NOBLE) programshowed that 16.5% of the adult populationhad symptoms of OAB, including 16% ofmen and 16.9% of women.⁶ The percentagetranslates to almost 35 million people.

OAB is not unique to the United States. Astudy of 6 European countries showed anOAB prevalence of 16.6% among adults aged40 years and older,⁷ virtually identical tothe prevalence found in the NOBLE programin the United States. The prevalenceof OAB increases with age and was estimatedto affect 22 million people in the 6European countries. Because the prevalenceof OAB increases with age, the overallburden of the condition will almost certainlygrow with the continued aging of the populationin the United States and otherWestern countries.

OAB affects all aspects of quality of life(QOL), including physical, social, psychological,occupational, domestic, and sexualfunctioning. Patients with OAB have to usethe toilet more frequently than unaffectedindividuals because of urgency, and incontinencehas been associated with an increasedrisk of falls and fractures.^8,9

OAB has a significant economic impact.In the United States for the year 2000, thetotal cost of OAB was estimated to be $12.6billion, which is similar to the costs associatedwith asthma and osteoporosis.¹⁰Approximately 90% of the costs come inthe form of direct expenses that includediagnosis, treatment, and consequences,such as skin infection and irritation.¹¹However, OAB involves substantial indirectcosts that include lost wages, as wellas intangible costs associated with decreasedQOL.

Evidence of Tolterodine Efficacy in

OAB.

Tolterodine improves objective urodynamicvariables in patients with OAB. Twodouble-blind, placebo-controlled trials evaluateddoses of tolterodine ranging from 0.5mg to 4 mg twice daily.^12,13 The trials showeda dose-response relationship for volume atfirst contraction, maximum cystometriccapacity, and volume at normal desire tovoid. One of the studies showed a doseresponserelationship for micturition diaryparameters, including frequency, leakage,and the number of incontinence pads used.¹⁴The dose-response effect on urodynamicvariables was confirmed in a pooled analysisof 4 randomized, double-blind, placebo-controlledstudies.³

Double-blind, placebo-controlled trialshave demonstrated improvement in micturitiondiary parameters for tolterodine IR 2 mgtwice daily or 1 mg twice daily and tolterodineER 4 mg once daily.^15-22 In the 2 largesttrials, improvement from baseline was significantlygreater with tolterodine IR 2 mg twicedaily and tolterodine ER 4 mg once daily thanwith placebo for all micturition variables.^5,16

The efficacy of tolterodine was maintainedduring open-label follow-up for aslong as 12 months for both tolterodine IR 2mg twice daily^22,23 and tolterodine ER 4 mgonce daily.²⁴ Studies that included subjectiveassessments of improvement have providedadditional confirmation of tolterodineefficacy.^17,22-24

Tolterodine Safety and Tolerability.

The following tolterodine safety and tolerabilitydata came from clinical trials providedby the pharmaceutical company forFDA approval as well as peer-reviewed publishedstudies and a prescription event monitoring(PEM) study. Much of the data areincluded in the manufacturer's full prescribinginformation.^25,26 In the remainder ofthis article, the tolerability and safety profilesof tolterodine IR, tolterodine ER, oxybutyninIR, and oxybutynin transdermal delivery system(TDS) are compared. Other pharmacologictreatments for OAB are now available,including trospium, solifenacin, and darifenacin.However, these agents are not discussedas they are relatively new, andhead-to-head trials have not been conducted.

Antimuscarinic Effects.

The most commonlyreported adverse event associatedwith tolterodine has been dry mouth. Inphase 3 clinical trials, dry mouth occurredin 35% of 986 patients receiving tolterodineIR 2 mg twice daily for 12 weeks comparedwith 10% of 683 patients who receivedplacebo. Additionally, 24% of 505 patientstreated with tolterodine ER 4 mg once dailyreported dry mouth compared with 8% of507 patients who received placebo.^25,26Severe dry mouth occurred in only 1% to 5%of patients treated with tolterodine IR ortolterodine ER in several large trials.^{5,10,16,18,21} Moreover, severe dry mouthwas reported in 2% to 3% of patients duringopen-label follow-up for as long as 12months.^22-24

Dry mouth appears to be less commonwith tolterodine than with oxybutynin.Several large, randomized, double-blindstudies and a pooled analysis of 4 trialsdemonstrated significantly less dry mouthwith tolterodine IR 2 mg twice daily comparedwith oxybutynin IR 5 mg 2 or 3 timesdaily.^19,20,27,28 The incidence of moderate tosevere dry mouth was 3 to 5 times greaterwith oxybutynin IR 5 mg 2 or 3 times dailycompared with tolterodine IR 2 mg twicedaily.^19,27,28 The incidence of severe drymouth was increased 5-fold with oxybutyninIR 5 mg 2 or 3 times daily compared withtolterodine IR 2 mg twice daily.²⁸ One recentstudy comparing tolterodine ER 4 mg oncedaily with oxybutynin transdermal patch(TDS) 3.9 mg daily did find that the incidenceof dry mouth was significantly greaterthan placebo (1.7%) in the tolterodine ERcohort (7.3%), but not in the oxybutyninTDS cohort (4.1%).²⁹ However, oxybutyninTDS was also associated with skin irritation,which resulted in a higher discontinuationrate in the oxybutynin TDS cohort (10.7%)than in the tolterodine ER cohort (1.6%).

In a comparison of different formulationsof the 2 drugs, tolterodine IR 2 mg twice dailywas associated with a similar incidence ofmoderate to severe dry mouth compared withoxybutynin ER 10 mg once daily.³⁰ When ERformulations of the 2 drugs were compared,tolterodine ER 4 mg caused significantly lessdry mouth than oxybutynin ER 10 mg, andthe dry mouth was less severe.^30,31

According to the manufacturer, otherantimuscarinic effects include dry eyes andabnormal vision. These effects were reportedby ²10% of patients treated with tolterodinein clinical trials.^25,26 A PEM study in theUnited Kingdom (N = 14 526) found thatvisual defects attributable to adverse drugreaction occurred in 0.6% of patients treatedwith tolterodine.³² Tolterodine is contraindicatedin patients with uncontrolled narrowangleglaucoma.^25,26

Gastrointestinal (GI) Events.

Dyspepsia,constipation, abdominal pain, and flatulencewere reported by 1% to 10% of patients whoreceived tolterodine in clinical trials.^25,26 TheIR and ER formulations are associated witha similar incidence of GI adverse events.⁵A multicenter, randomized, double-blindstudy demonstrated an incidence of abdominalpain that was similar between patientstreated with tolterodine IR 2 mg twice dailyor placebo. The incidence of constipationwith tolterodine IR was double that of theplacebo group.²¹

During open-label administration of tolterodineIR 2 mg twice daily for as long as 12months, abdominal pain was reported by 6%of patients in 2 different studies, and constipationoccurred in 7% of patients.^22,23 Longtermfollow-up of patients treated withtolterodine ER 4 mg once daily demonstrateda 3% incidence of constipation and a 2%incidence of dyspepsia.²⁴

The incidence of GI events tends to belower in patients treated with tolterodinecompared with those treated with oxybutynin.For example, a randomized, doubleblind,placebo-controlled trial showed thatdyspepsia occurred in 5% of patients givenplacebo, 9% of those treated with tolterodineIR 2 mg twice daily, and 23% ofpatients treated with oxybutynin IR 5 mg3 times daily.²⁰ A pooled analysis of 4 double-blind, placebo-controlled, randomizedtrials demonstrated a 6% incidence of dyspepsiawith tolterodine IR 2 mg twice dailyand 11% with oxybutynin IR 5 mg 3 timesdaily.²⁷

Labeling of tolterodine includes decreasedintestinal motility and hemorrhage.Both types of events have been reportedinfrequently.^25,26

The PEM study from the United Kingdomshowed that dyspepsia and constipationwere reported in <2% of patients during thefirst 6 months after tolterodine becameavailable.³² Tolterodine is contraindicated inpatients with gastric outlet obstruction andshould be used with caution in patients withGI obstructive disorders.^25,26

Nervous System Events.

According to themanufacturer, nervous system adverseevents have occurred in 1% to 10% ofpatients treated with tolterodine in clinicaltrials. The events include headache, dizziness/vertigo, somnolence, and fatigue.^25,26Placebo-controlled studies of tolterodine IR2 mg twice daily and tolterodine ER 4 mgonce daily showed the incidence of headachedid not exceed 6% and was similar tothat in placebo patients.^5,10,16,21 Duringopen-label administration for up to 12months, headache was reported by 6% to 7%of patients treated with tolterodine 2 mgtwice daily^23,24 and by 2.4% of patients treatedwith tolterodine ER 4 mg once daily.²⁴

In the UK PEM study, the incidence ofheadache, dizziness, fatigue, and somnolencewas <2% each during the first 6months after the launch of tolterodine.³²

Direct comparisons between tolterodineand oxybutynin have generally shown similarrates of nervous system events. Theonly notable differences relate to somnolenceand dizziness, both of which favortolterodine.^19,27,28,33

Confusion and hallucinations have beenreported in <1% of patients receiving tolterodinein clinical trials. In the UK PEM study,which documented 9 probably or possiblyrelated events among 14 526 patients, hallucinations,predominantly visual andoccurring mostly in elderly women, werean unexpected finding.³²

Urinary Events.

According to the manufacturer,dysuria occurs in <10% of patientstreated with tolterodine.^25,26 The UK PEMstudy found a 2% reported incidence of micturitiondisorder and a 0.5% reported incidenceof urinary retention.³²

Other Events.

Edema associated withtolterodine is almost always mild and peripheral.^25,26 A multicenter, double-blind trialdemonstrated a 1% incidence of peripheraledema in patients randomized to tolterodineIR 2 mg twice daily, tolterodine ER 4 mg oncedaily, or placebo.⁵

Tachycardia is a class effect of antimuscarinicdrugs. The UK PEM study reported17 cases of tachycardia or palpitationsand 21 cases of chest pain with use oftolterodine.³²

Other postmarketing cardiovascularevents discussed in the manufacturer's labelinclude ventricular arrhythmia, atrial fibrillation,cardiac failure, palpitations, bradycardia,collapse, transient ischemic attacks,and hypertension. Each of those events isreported infrequently, and insufficient evidenceexists to conclude that a causalrelationship exists with tolterodine.^25,26Tolterodine is contraindicated in patientswith urinary retention and impaired gastricemptying. It should be used with caution inpatients with clinically significant bladderoutflow obstruction.

Safety in Special Populations

Older Patients.

Age does not appear toinfluence the safety profile of tolterodine.Randomized, double-blind studies showedno clinically important changes in clinicalchemistry, hematologic parameters, or electrocardiogramrecordings in older patientstreated with tolterodine.^15,34

One placebo-controlled trial assessedtolterodine IR 1 mg and 2 mg twice daily inpatients 65 years of age and older,¹⁴ andanother placebo-controlled trial assessedtolterodine ER 4 mg once daily for 12 weeksin patients aged 65 years of age and oldercompared with younger patients.¹⁵ Drymouth occurred in a similar incidence ofolder patients compared with youngerpatients and was the only adverse event thatoccurred significantly more often withtolterodine than placebo in older patients.Most instances of dry mouth were mild tomoderate in intensity. All adverse eventsoccurred at a similar frequency in youngerand older patients, except for headache,which was more common in youngerpatients.¹⁵

The incidence of dry mouth is lower withtolterodine than with oxybutynin. A randomizedtrial compared tolterodine IR 2 mg twicedaily for 10 weeks and oxybutynin IR 2 mg 3times daily, increasing to 5 mg for theremaining 8 weeks. The mean age of thestudy population was 65 years. A higher proportionof patients receiving oxybutynin haddry mouth, severe dry mouth, and drymouth resulting in withdrawal from thestudy.³⁴

Hepatic and Renal Impairment

.

TolterodineIR achieved a higher serum concentrationand a prolonged eliminationhalf-life when volunteers with liver cirrhosiswere compared with healthy volunteers.³⁵Urine is the major excretion route of tolterodine.As a consequence, the maximum recommendeddosage is 1 mg twice daily for theIR formulation and 2 mg once daily for theER formulation for patients with hepatic orrenal impairment.

Pregnancy and Lactation.

Tolterodine isa US Food and Drug Administration pregnancycategory C drug and should be used duringpregnancy only if the potential benefitjustifies the potential risk to the fetus. Nodata are available on excretion of tolterodinein breast milk, so use during lactation shouldbe avoided.^25,26

In the UK PEM study, 6 women tooktolterodine during the first trimester. Thereported outcomes of the pregnancies were5 live births with no congenital abnormalitiesand 1 spontaneous abortion.³²

Conclusion

Tolterodine is associated with few adverseevents, and most adverse events associatedwith tolterodine are of mild or moderateseverity. Data accumulated since the launchof the drug in September 1997 indicate thattolterodine is well tolerated in the treatmentof OAB. Dry mouth is associated withantimuscarinics and is the most commonlyreported adverse drug reaction associatedwith tolterodine. This condition is usuallymild to moderate in intensity. Clinical studieshave shown that dry mouth occurs lessfrequently with tolterodine than with oxybutynin.The safety profile of tolterodine inolder adults is similar to that in youngeradults.

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