CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATIQ LN: NDA 20-771
`
`CONTENTS
`
`
`
`Included
`
`Pending
`Comgletion
`
`Not
`Not
`Pregared Reguired
`
`Amgroval Letter
`Tenative Amgroval Letter
`Aggrovable Letter
`Final Printed Labeling
`Medical Review! s Q
`Chemist Review s
`
`X
`
`X
`X
`
`X
`
`
`EA/FONSI
`
`Pharmacolo Review 5
`
`Statistical Review! s !
`Microbiology Reviewgsl
`Clinical Pharmacology
`Biogharmaceutics Reviewgsg
`Bioeguivalence Review; 5!
`Administrative Documentgsg
`Corresgondence
`
`X
`
`X
`
`X
`
`X
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`X
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`ETRR
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`EALATI
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`A DRE EAR H
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`Apprgvgl Pggkggg fgr:
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`Appligatign Num !1_c;r: NDA 20-771
`
`Trad: Name: DETROL 1 & 2 MG TABLETS
`
`n' m'lrinL-rr
`
` : Pharmacia & Upjohn Company
`
`Approval Date: March 25, 1998
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`E RFRR EALA
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`ANDREE
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`H
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`Appljgatign Numbg:r:NDA 20-771
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`APPRQ QVAL LETTER
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`
`
`Public Health Service
`
`Food and Drug Administration
`Boclwillo MD 20867
`
`MAR 2 5 998
`
`. IIIVICII"0.
`{I
`g C DEPARTMENT or HEALTH at HUMAN settvtces
`‘I‘~..~"
`
`NDA 20-771
`
`Pharrnacia & Upjohn Co.
`Attention: Susan M. Mondebaugh. Ph.D.
`Director. U.S. Regulatory Affairs
`Unit 063$-298-113
`
`7000 Portage Road
`Kalamazoo, Michigan 4900!
`
`Dear Dr. Mondabaugh:
`
`Please refer to your new drug application dated March 24, 1997, received March 25, 1997, submitted
`under section 505 (b) of the Federal Food, Drug, and Cosmetic Act for DETROL” (tolterodine tartrate
`tablets).
`
`We acknowledge receipt of your submissions dated April 14, 17. and 22, July 9 and 24. August 8, 12,
`and 29. September 12, October 31, November 18(2) and 24, and December S, 23, and 31(2), 1997; and
`January 16. 27, 28, and 29(2), February 9, 11(2), 19, 24, and 25, and March 4. 6. ll, 12. 13, 19, 20. 24
`and 25. I998. The User Fee goal date for this application is March 25, 1998.
`
`This new drug application provides for the use of Deuol Tablets for the treatment of patients with an
`overactive bladder with symptoms of urinary frequency, urgency. or urge incontinence.
`
`We have completed the review of this application, as amended, and have concluded that adequate
`information has been presented to demonstrate that the drug product is safe and effective for use as
`recommended in the draft labeling. Accordingly, the application is approved effective on the date of this
`letter.
`-
`
`The final printed labeling (FPL) must be identical to the draft labeling in the submissions dated February
`25, I998 (carton and container labels), March 6, 1998 (sample may for blisters), and March 25, I998
`(physician package insert). Marketing the product with FPL that is not identical to this draft labeling
`may render the product misbruuded and an tutapproved new drug.
`
`A‘
`
`'.
`
`Please submit 20 copies of the FPL as soon as it is available, in no case more than 30 days after it is
`printed. Please individually mount ten of the copies on heavy-weight paper or similar material. For
`administrative purposes. this submission should be designated "FINAL PRINTED LABELING" for
`approved NDA 20-771. Approval of submission by FDA is not required before the labeling is used.
`
`We remind you of the Phase 4 commitment specified in your March 12, 1998, submission to conduct a
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`NDA 20-771
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`Page 2
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`Protocol, data. and final reports should be submitted to your IND for this product and a copy of the cover
`letter sent to this NDA. In addition, under 21 CPR 314.8 l(b)(2)(vii), we request that you include a status
`summary of each commitment in your annual report to this application. The status summary should
`include the number of patients entered in the study, expected completion and submission dates, and any
`changes in plans since the last annual report. For administrative purposes, all submissions, including
`labeling supplements, relating to this Phase 4 cominitincnt should be clearly designated "Phase 4
`Commitment."
`
`In addition, please submit three copies of the introductory promotional material that you propose to use
`for this product. All proposed materials should be submitted in draft or mock-up form, not final print.
`Please submit one copy to the Division of Reproductive and Urologic Drug Products and two copies of
`both the promotional material and the package insert directly to:
`
`Food and Drug Adrriinislntion
`Division of Drug Marketing, Advertising and Communications, HFD-40
`5600 Fishers Lane
`
`Rookville. Maryland 2085?
`
`Validation of the regulatory methods has not been completed. At the present time, it is the policy of the
`Center not to withhold approval because the methods are being validated. Nevertheless. we expect your
`continued cooperation to resolve any problems that may be identified.
`
`Please submit one market package of the drug product when it is available.
`
`We remind you that you must comply with the requirements for an approved NDA set forth under
`21 CFR 314.80 and 314.81.
`
`If you have any questions, please contact Alvis Dunson. Project Manager, at (301) 827-4260.
`
`Sincerely,
`
`James Bilstad. MD.
`Director
`
`Office of Drug Evaluation 11
`Center for Drug Evaluation and Research
`
`

`
`F RDR
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`EVAL ATI NA
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`RE EAR H
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`APELIQATIL IN N[]MBER:NDA 20-771
`
`MEDIQ ZAL REVIEW( S)
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`NDA 20-771
`
`Date NDA Submitted: March 24, 1997
`Date NDA received: March 26, 1997
`Date assigned: March 26,1997
`Review completed: January 20,1998
`Revisions completed: _?/(/ 78
`
`Medical Officer Review
`
`Sponsor: Pharmacia and Upjohn
`
`Drug:
`
`Generic: Tolterodine
`Trade: Detrusitol Tablets
`
`.
`
`(R)_-N, N- Diisopropyl-3—( 2-hydroxy-5-methylphenyl)-3—phenyl
`Chemical:
`propanamine L- hydrogen tartrate
`‘
`
`Route: Oral
`
`Dosage Form: Tablets BID
`
`Strength:
`
`1 mg and 2 mg
`
`Proposed indication: Treatment of patients with overactive bladder with symptoms of
`urinary frequency, urgency, or urge incontinence, or any combination of these symptoms.
`
`Related INDs:
`
`1.0 Resume
`
`Safety: The safety review of the submitted NDA was based on two data bases- The short
`
`term experience (up to 12 weeks) is presented on approximately 1600 patients who took
`tolterodine during phase 2 and 3 trials and long term experience included patients
`reported in the I '
`submitted with the NDA and a 4-month safety update submitted on
`7/24/97 which inc udes data through 4/30/97. The long term data base involved 1645 .
`patients who took tolterodine for 6 months and 812 patients with 12 months of drug
`exposure.
`
`The reviewer believes that there are three areas of concern regarding the safety of
`tolterodine. These are exaggerated antimuscarinic effects, cardiac abnormalities and
`adverse events related to distuibances or deficiencies of the cytochrome P450 system.
`The incidence of constipation, abnormal accommodation, constipation and urinary
`retention was quite low and in some cases exceeded background rates but this was not
`clearly demonstrated. The most common antimuscarinic adverse event was dry mouth.
`In the controlled studies, the incidence of dry mouth tended to be higher in the tolterodine
`groups than in placebo groups and highest in the oxybutynin groups. The incidence of
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`dry mouth in the long term studies was approximately 40%. Because of the subjective
`nature, lack of definition of the event and insufficient evidence as to what constituted a
`clinically meaningfizl difference, comparisons between tolterodine and oxybutynin are not
`appropriate for this parameter. In addition, the incidence of dry mouth with oxybutynin
`was similarly ill-defined.
`
`Cardiac safety of tolterodine was extensively studied because of its structural similarity to
`terodiline. Terodiline is a drug that was intended for use in patients with detrusor
`overactivity because of its antimuscarinic activity. However, it also had calcium channel
`blocking and other effects that increased the QT interval in human beings which may
`have resulted in ventricular dysrhythmias including torsades de pointes.
`.These problems
`were not found with tolterodine. Extensive cardiac studies in dogs indicated a wide
`margin of safety with respect to prolongation of QT interval (see
`pharmacology/toxicology report by Dr. Alex Jordan). Careful cardiac monitoring took
`place during all phases of development. Special subgroups such as the elderly and poor
`metabolizers were monitored in short term trials. In phase 3 (12 week) and long term
`studies (6-12 months), patients were monitored for QT interval, other EKG changes,
`arrhythmias, as well as clinical signs and symptoms of cardiac disease. There were no
`data from these studies that indicated that tolterodine precipitated cardiac events.
`
`As described in section 2.2, tolterodine is metabolized by the cytochrome P450 system.
`Poor metabolizers were deficient in the 2D6 portion of the system. About 6% of the
`Caucasian population have this deficiency. In these cases, tolterodine was metabolized
`via the 3A4 enzyme route. In an analysis of adverse events by poor and extensive
`(nonnal) metabolizers within individual studies and by all studies, there appeared to be a
`higher incidence of dry mouth in the extensive metabolizers with more accommodation
`problems and urinary retention in the poor metabolizers. The reviewer did not consider
`this to be clinically significant because of the small numbers involved. The general
`adverse event profile was similar between the two groups. Problems might arise in
`individual patients who are poor metabolizers and are taking medications that block the '
`3A4 enzyme or patients who are extensive metabolizers taking medications that block
`2D6 and 3A4.# This area is further discussed in the Clinical Pharmacology and
`-Biopharmaceutickreview by Dr. Gary Bamette.
`
`Clinical
`
`The primary endpoint for the central efficacy studies submitted in this NDA
`(008,009,0l0) was the change in mean number of micturitions per 24 hours from baseline
`to end of study (12 weeks). Important secondary endpoints were changes in mean
`number of incontinence episodes per 24 hours and mean volume voided per micturition.
`As the analysis of the individtial studies indicated. tolterodine. was superior to placebo in
`two of the three central studies (008,009) with regard to changes in mean micturitions per
`24 hours. In none of the individual studies (008,009,0l0) was tolterodine found to be
`superior to placebo for changes in mean number of incontinence episodes per 24 hours.
`Although in each study tolterodine was more efficacious than placebo for the
`incontinence parameter, this difference did not reach statistical significance. The change
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`in mean volume voided was considered by the reviewer to be an important physiologic
`indicator of the antimuscarinic effect of the tested drugs. Tolterodine was superior to
`placebo in all three studies (008,009,0I0) for this parameter.
`
`The sponsor submitted an analysis of the pooled data for the three central studies
`(0O8,009,0l0). The reviewer believes that the “pooled” analysis can be supportive as the
`protocols of the three “pooled" studies were very similar. In the pooled analysis,
`tolterodine both 1 and 2 mg are superior to placebo ‘for the change in mean episodes of
`incontinence per 24 hours. The reviewer believes that when the data from both the
`individual and “pooled” studies are considered, superiority of tolterodine 1 and 2 mg to
`placebo with regard to change in mean number of incontinent episodes per 24 hours is
`demonstrated.
`'l11e “pooled” data also confirmed superiority of tolterodine I and 2 mg to
`placebo for the micturition and voided volmne parameters. In should be noted that in
`phase 3 clinical studies no efficacy or safety differences between tolterodine 1 and 2 mg
`were demonstrated. On 12/5/97, the sponsor submitted, individual and pooled analysis of
`the three central studies (008,009,0 10) using changes in the median values for each
`endpoint rather that the mean values. The reviewer believes that this approach may have
`some validity especially for the incontinence data which tends to have a nonparametric
`distribution. The median analysis supported the conclusions noted above regarding the
`efficacy of tolterodine 1 and 2 mg for the micturition, incontinence and voided volume
`parameters.
`
`In two of the central studies (008,010), oxybutynin 5 mg tid was used as an active
`comparator. In these individual studies as well as the two “pooled” analyses, oxybutynin
`-tended to demonstrate increased efficacy compared to tolterodine. For this reason, the
`reviewer believes that the decreased “dry mouth” observed in patients taking tolterodine
`compared to oxybutynin during these trials was a result of reduced antirnuscarinic effect
`of tolterodine and does not represent a superior therapeutic ratio.
`
`In conclusion, tolterodine (1 and 2 mg‘ po bid) is safe and effective therapy for the
`treatment of bladder overactivity with symptoms of urinarygfrequency, urgency or
`urge incontimnce.
`7
`2.0 Backgroundk
`
`_ was submitted to The Division
`2.1 Regulatory History:__ On 9/2/94 IND -
`of Medical Imaging and Radiopharmaceutical Drug Products (HFD-160). On 4/24/95,
`the sponsor held a meeting with HFD-160 to discuss the results of their phase 2 trials
`(end-of-phase 2 meeting) and proposed plans for phase 3 trials. Another end-of-phase 2
`meeting was held with the sponsor and The Division of Metabolic and Endocrine Drug
`Products (I-IFD-510) on 2/20/96 as tolterodine had been transferred to this division. The
`pre-NDA meeting was held with The Division of Reproductive and Urologic Drug
`products (HFD-580) on 9/24/96 as a result of formation of this new division from HFD-
`
`SIO. On 3/24/97, The NDA for tolterodine was submitted to HFD-580.
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`2.2 Clinical Baclgground and Scientific Rationale
`Clinical Background: Urinary incontinence, which is the involuntary loss of urine, is
`estimated to effect in some form 10- 35% of the adult US population and half of nursing
`home residents. The incidence increases with age and urinary incontinence is one of the
`major cause of institutionalization of the elderly. A recent estimate of the direct cost of
`caring for all incontinent patients in the community is $11.2 billion and $5.2 billion in
`nursing homes.’
`
`The two most common types of incontinence are stress and urge incontinence. They can
`often coexist and this is called mixed incontinence. Stress incontinence is manifested by
`loss of urine during an activity that increase imra-abdominal pressure such as coughing or
`sneezing. This type of incontinence is caused by one of two abnormalities of the urinary
`sphincter. The most common type is urethral hyper-mobility which is a weakness in the
`pelvic floor musculature. The second type in caused by an intrinsic malfunction of the
`sphincter itself.
`
`Urge incontinence is the involuntary loss of urine associated with a strong desire to void.
`_ This type of incontinence is attributed to an involuntary contraction of the detrusor
`muscle, although this often cannot be demonstrated on a cystometrogram. According to
`the recommendations of the Urodynamic Society,’ the generic term for an involuntary
`detrusor contraction is Detrusor Overactivity. This is the term that is used when the
`etiology of the involuntary contraction is unclear. When the contraction is caused by
`neurologic pathology, the condition is called Detrusor Hyperreflexia. In the absence of
`a neurologic lesion the condition is called Detrusor Instability.
`
`Physiology and Metabolism:
`Detrusor muscle contractions are mainly mediated through cholinergic muscarinic
`receptor stimulation. Inappropriate detrusor contraction can lead to a sensation of
`urgency (an exaggerated sense of the need to micturate). Increased urgency can lead to
`urinary frequency, nocturia and “urge incontinence," if the urge to void cannot be
`resisted. The main pharmacologic therapy for this problem is directed at reducing the
`activity of the dc"
`sor muscle with antimuscarinic drugs. The therapy must generally be
`given long-term drug therapy only controls the condition and does not offer cure.
`.
`
`' Urinag Incontinence in Adults: Acute and Chronic Management, Agency for Health Care Policy
`and Research, 1992 Update.
`_
`2 Blaivas, Appeil et al, Definition and Classification of Urinagy incontinence: Recommendation of
`the Urodynarnic Society, Neurourpiogy and Urodynamics 16:149-151 (1997)
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`Oxybutynin is currently the most commonly used therapy, pharmacologic or otherwise,
`for urgency incontinence. Over 70% of urologists recently stated that oxybutynin was
`their first treatment option in the management of this condition.’ The sponsor believes
`that although oxybutynin has a favorable efficacy profile, it does not have selectivity for
`bladder smooth muscle over tissues such as salivary glands. Thus the usefulness of
`oxybutynin is limited by the severity of adverse events, mainly dry mouth. The Division
`recognizes that many patients discontinue the use of this medication and similar drugs
`because of dry mouth and related anti- cholinergic adverse events such as reduced visual
`accommodation and constipation. The sponsor believes that tolterodine is a competitive
`muscarinic antagonist that exhibited seiective antimuscarinic activity for bladder
`compared to salivary gland. Therefore, tolterodine was expected to be at least as effective
`as oxybutynin with reduced adverse events especially dry moth. The sponsor hoped that
`this would result in improved tolerability and compliance.
`
`Tolterodine is primarily metabolized to the 5-hydroxymetabolite (DD 01), an active
`metabolite, by the isoenzyme CYP2D6 (see figure 1). Subjects that are deficient in
`CYPZD6 (about 7% of the caucasian population) are considered poor metabolizers. In
`these individuals, higher concentrations of tolterodine are exhibited with non-measurable
`DD 0]. Extensive metabolizers are not deficient in CYPZD6. In poor metaboiizers an
`alternative metabolic pathway involving CYP3A is active (the resultant metabolite does
`not contribute to the clinical effect). DD 01 exhibits antimuscarinic activity similar to
`tolterodine. This metabolite is believed to contribute significantly to the therapeutic
`effect in extensive metabolizers. Metabolism is finther discussed in the Pharmacology
`review by Dr. Gary Bamette. No gender dependent difierences in the pharmacokinetic
`profile of tolterodine or DD 01 were observed.
`
`3 Survey conducted at the 1997 annual meeting of the American Urologic Association of a total of
`155 US and 264 non-US urologists.
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`Figure 1
`The Metabolism of Tolterodine
`Hydroxylated tolterodine
`(DD 01)
`OH \/
`
`_
`
`ADH
`
`_
`
`Tolterodine acid
`
`/
`
`OH \/
`
`ALDH
`
`o
`
`0
`
`I
`
`©IVa
`‘cram
`OH
`ti
`/\_, N\/
`I
`IV!)
`
`1 CYPBA
`0H
`v
`N\/
`I
`
`cvpzos
`
`H0
`
`In
`
`_
`
`ADH'
`
`ALDH'
`
`H
`
`Tolterodine
`
`OH \/ CYP2D6
`
`/
`
`xi
`
`, I
`\
`
`ilk!/-_"--DH
`"IK/—-»H°\/fl
`(57.
`1 CYPEA
`,. I OH
`,I_,
`'\
`NY
`III:
`
`Dealkylated tolterodine
`.
`
`Dealkylated hydroxylated
`tolterodine
`
`Dealkylated tolterodine acid
`
`Figure 6.4 Identified urinary metabolites in human beings and proposed metabolic pathways.
`‘Indicates tentative enzyme.
`
`Tolterodine is hydroxylated to a pharmacologically active metabolite DD 01, which
`subsequently is oxidised to the corresponding acid which is dealkylated. The metabolites
`shown in Figure 6.3 have been identified in urine after ['4C]-tolterodine administration
`(90-126-00, Norén et al., 1991 and Edlund et al., 1993).
`
`Reviewer’s Comment: A potential safety problem could arise in a poor metabolizer
`who is on a drug that interferes with CYP3A activity (e.g., Ketoconazole,
`erythromyein). This issue is examined closely in the Clinical Pharmacology Review.
`
`Dose Selection: During phase I and 2 studies, it was determined that a dose of 0.5 mg
`bid was the no-effect dose and a dose of 4 mg bid dose was the maximally tolerated dose.
`The intermediate doses of 1 and 2 mg bid were chosen for the phase 3 trials. At these
`dosage levels and schedule the sponsor believes that accumulation of tolterodine and DD
`01 would be low" 'nce the half life of tolterodine is 2-3 hours and 3-4 hours for DD 01.
`
`In poor metaboliz rs, accumulation would also be low.
`
`During efficacy evaluation in 4 phase 2 trials, it was demonstrated that tolterodine l and 2
`mg bid resulted in “clinically relevant” improvements in the symptoms of urge
`incontinence without significant increases in residual post-void bladder volume. The 4
`mg bid dosing regime, however, resulted in an increase in post void residual volume.
`Despite a relatively short halfilife, the twice daily regimen was shown to be adequate for
`a sustained pharmacodynamic efiect.
`
`I
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`Approval of tolterodine was accomplished during the last several months in Sweden. The
`sponsor will seek European approval on this basis. No data from use in Sweden is
`available to the reviewer.
`
`3.0 Summafl of NDA clinical section
`The clinical section of this application contains the study reports of the three controlled
`“core” studies and a supportive study; all reviewed below. These studies were 12 week
`studies. In addition, the submission includes four randomized controlled 4 week studies.
`
`Phase 2 and safety follow-up studies are also included.
`
`3.1 Summary of submitted controlled trials of tnlterodine-“Core studies”
`
`CTN 94-OATA-008 (Part A)
`This was a multicenter, randomized, double—blind, double-dummy, controlled trial
`comparing tolterodine 2mg. b.i.d. with oxybutynin 5 mg. t.i.d. and placebo in patients
`with detrusor instability. Two hundred and ninety-three patients were randomized to
`treatment at 42 centers (23 in the United Kingdom, 4 in Ireland and 15 in Sweden). The
`first patient was recruited on July 14, 1995. and the last patient completed the study on
`July l5, 1996. Patients were randomized after a two week wash—out period to a twelve‘
`week study. Those who completed the 12 week study were invited to participate in an
`open label long term follow up study which was to last 9 months (CTN 94-OATA-O08
`[Part B]).The primag efficag variable was the change in mean number of micturitions
`per 24 hours. The important secondag efficag variables were the changes in mean
`number of incontinence episodes per 24 hours and the mean volume voided per
`micturition.
`
`CTN 94-OATA-009 {Part A)
`This was a multicenter, multinational, randomized, double-blind, placebo controlled trial
`comparing tolterodine lmg. b.i.d., tolterodine 2mg. and placebo in patients with detrusor
`overactivity. Three hundred sixteen patients were randomized to treatment at 25 centers
`(18 in the USA and 7 in Australia). The first patient was recruited on 11 September 1995 '
`and last patient completed assessments on Oct. 8, 1996. Patients were randomized after a
`two week wash-out period to a twelve week study. Those who complete the 12 week
`study are invited
`participate in an open label long term follow up study involving
`treatment with tolterodine 2mg. bid for 9 months (CTN 94 OATA—O09 Part B). The
`primary efficagy variable was the change in mean number of micturitions per 24 hours.
`The important secondag efficacy variables were the changes in mean number of
`incontinence episodes per 24 hours and the mean "volume voided per micturition.
`
`CTN 94-OATA-010 (Part A] , "
`This was a multicenter, randomized, double-blind, double-dummy, controlled trial
`comparing tolterodine 2mg. b.i.d. with oxybutynin 5 mg. t.i.d. and placebo in patients
`with detrusor overactivity. Two hundred and seventy-seven patients were randomized to
`treatment at 25 centers (15 in the United States, 10 in Canada). The first patient was
`recruited on October 2, 1995, and the last patient completed the study on June 13, 1996.
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`Patients were randomized afier a two week wash-out period to a twelve week study.
`Those who completed the 12 week study were invited to participate in an open label long
`term follow up study which lasted 9 months (CTN 94-OATA-010 [Part B]). The primagy
`efficacy variable was the change in mean number of micturitions per 24 hours. The
`secondagy efficagy variables were the changes mean number of incontinence episodes
`per 24 hours and the mean volume voided per micturition.
`
`3.2 Summary of other clinical trials of tolterodine
`The four-week, controlled, phase 2 studies and safety extensions presented in the
`submission do not add data that altered conclusions that were reached after reviewing the
`four submitted 12 week studies. Two brief (2 week) controlled studies (92-OATA-003,
`93—OATA-005) were specifically designed for patients with detrusor hyperreflexia.
`These studies involved a total of about 175 patients with neurologic disease failed to
`demonstrate any statistically significant drug effect in the clinical endpoints.
`
`4.0 Clinical trial CTN 94-OATA-008 {Part A)
`4.1 Design and conduct of trial: This was a multicenter, randomized, double-blind,
`double-dummy, controlled trial comparing tolterodine 2mg. b.i.d. with oxybutynin 5 mg.
`t.i.d. and placebo. Two hundred and ninety-three patients were randomized to treatment
`at 42 centers (23 in the United Kingdom, 4 in Ireland and 15 in Sweden). The first patient
`was recruited on July 14, 1995, and the last patient completed the study on July 15, 1996.
`Patients were randomized afier a two week wash-out period to a twelve week study.
`Those who complete the 12 week study were invited to participate in an open label long
`term follow up study which was to last 9 months (CTN 94-OATA-008 [Part B]).
`
`Male and female patients over 18 years of age with detrusor instability were included in
`the study. Detrusor instability was demonstrated urodynamically by a detrusor
`contraction of equal to or more than 10 cm. of water during cystometry. No drugs
`effecting bladder function were permitted within 7 days of urodynamic investigation.
`During the run-in period, patients were required to have symptoms of urinary frequency
`defined as at least 8 micturitions on average per 24 hours. In addition patients were
`required to have symptoms of urge incontinence (at least one episode of incontinence on
`average per 24 hkirs) during the run-in period or urinary urgency or both. Patients were
`excluded if they had significant stress incontinence or neurological disease or injury that"
`could affect the lower urinary tract or its nerve supply. Patients were additionally
`T
`excluded if they had residual volumes of more than 200 ml, had a history of interstitial
`cystitis or had a total voided volume of more than 3000 ml on average per 24 hours.
`Reviewer’s comment:
`_ .
`1. Tolterodine was not testedin patients with detrusor hypcrreflexia and therefore
`this trial does not support a claim for patients with neurologic disease.
`
`Following completion of a washout/run-in period (one week for naive patients and two
`weeks for patients who had been on anti-incontinence medication), patients were
`randomized at visit 2 (day 1) to one of the following:
`
`NDA 20-715/Shames
`
`aen wner, I
`
`3
`
`' arma m-
`
`3
`
`X II
`
`

`
`One tolterodine 2 mg tablet bid (morning and evening) and one placebo tolterodine
`tablet once daily (midday). These patients also took one placebo oxybutynin tablet
`tid.
`
`2. One oxybutynin 5 mg tablet tid and one placebo tolterodine tablet tid.
`
`3. One placebo tolterodine tablet tid and one placebo oxybutynin tablet tid.
`
`The study period lasted 12 weeks. Patients were seen and evaluated at week 2 (visit 3),
`week 4 (visit 4), week 8 (visit 5) and week 12 (visit 6). There was a follow-up visit at
`least 2 weeks after visit 6 for assessment of adverse events. At the termination of the
`controlled study the patients were given the option to enter an open label safety study
`(94-OATA-O08 part B).
`
`-
`
`There were two circumstances in which dose reduction could occur. In the first situation,
`in order to comply with the labeling of oxybutynin in the UK, investigators were given
`the option of starting patients over 65 years of age on a reduced dose of study medication
`(tolterodine 1 mg bid or oxybutynin 2.5 mg tid). After one week the dosage was
`increased to the normal study dose (tolterodine 2 mg bid or oxybutynin 5mg tid). If
`these patients did not tolerate the “normal” dose then the dose could be reduced as an
`alternative to withdrawal and only during the second week of the study. In the second
`situation, in the case of study medication intolerance, a patient could be placed on a
`reduced dose only as an alternative to withdrawal and only within 14 days of
`randomization. In both cases the following dose reduction was permitted:
`
`1. One tolterodine 1 mg tablet bid (moming and evening) plus -one placebo tolterodine
`tablet once daily (midday). One placebo oxybutynin tablet tid.
`
`2. One oxybutynin 2.5 mg tablet tid and one placebo tolterodine tablet tid.
`
`3. One placebo tolterodine tablet tid and one placebo oxybutynin tablet tid.
`
`A computer generated randomization list was prepared by the sponsor using the method "
`of random permuted blocks within centers. The block size was five. Patients who
`completed the wash-out/ rim-in period and were eligible for the study were randomized
`to treatment with tolterodine, oxybutynin of placebo in the ratio 2:2:l in accordance with
`the randomization list. The patient numbers had five digits. The first three digits
`identified the center and the lasfitwo digits identified patients randomized consecutively
`at the center. Informed consent was obtained before randomization. The codes could
`only be broken for medical necessity and in this case the situation had to be reported to
`the sponsor within 24 hours. A double—dummy design was used to maintain blinding.
`All patients took the same number of tablets in the morning, midday and evening.
`Tolterodine placebo tablets were indistinguishable from tolterodine tablets and
`
`NDA 20-715/Shames
`
`

`
`oxybutynin placebo tablets were indistinguishable from oxybutynin. There were two
`types of medication packages labeled “study dose” or “reduced dose.”
`
`The primary efficacy variable was the mean number of micturitions per 24 hours. A
`micturition chart printed in intervals of one hour was used to collect efficacy data.
`During the 7 day period preceding visit 2, 3, 4, 5, and 6 patients recorded the time of each
`spontaneous micturition, each incontinent episode and the number of pads used per 24
`hours. The volume voided at each micturition was noted during 2 of the 7 day recording
`period. The secondary efficag variables were the mean number of incontinence
`episodes per 24 hours, the mean volume voided per micturition, and the number of pads
`used per 24 hours. Only complete data for full 24 hour days were included in the
`calculation of the micturition parameters. Data obtained during any period of a
`confirmed urinary tract infection were excluded from the data.
`
`Other efficacy parameters measured were a global assessment of the patient’s perception
`of bladder function, a psychological well-being index, and a quality of life questionnaire.
`
`Clinical safety assessments included ECG (measured at baseline and during part B of
`the study), §P_within 6 hours of drug intake at visit 2,4 and 6 and residual urine measured
`at baseline and if the patient experienced symptoms of retention during the study.
`
`. Reviewer’s comment:
`
`1. Residual urine should have been measured at some point during the study
`period.
`
`Adverse events were monitored in the routine fashion.
`
`Laboratory safety assessments for routine blood laboratory tests were obtained at visit
`1, 4, and 6 or at withdrawal. Samples were analyzed at a central laboratory. A midstream
`specimen of urine was obtained at visit 1.
`_
`Reviewer’s comment: A urine specimen should have been obtained during the
`study period to determine if asymptomatic urinary tract infection is more common
`in the drug grows.
`_
`
`Drug serum concentrations of tolterodine and DD 01 (major active metabolite) along
`with oxybutynin and its desethylated metabolite were obtained at visit 1, 4, 6 or
`withdrawal within 6 hours of ingestion of the study drug. Analysis was done at a central
`laboratory.
`
`/"l
`
`4.2 Study Population: The intent-to-treat (ITT) population included all patients
`randomized to the study. The per-protocol population (PP) included all randomized
`patients who had completed the study without violating any major eligibility or protocol
`criteria. Patients who were withdrawn from treatment or who had dose reductions were
`
`excluded from the PP population. The safety population included those patients that were
`
`NDA 20-715/Shamcs
`
`

`
`randomized and received at least one dose of study medication(the same as the ITT
`population). Table 1 illustrates the relationship between