-
`
`Secondary actions of tolterodine in the conscious dog and mouse have only been recorded
`alter oral administration of high doses. resulting in high serum levels of both tolterodine and
`DD 01.
`
`o
`
`In the conscious dog. an increased heart rate was recorded at unbound semm concentrations
`
`of tolterodine and DD 01 that were 17 and 7 times, respectively. higher than those expected to
`be reached in most patien_ts treated with tolterodine 2 mg bid. The corresponding rati_os for
`effects on the EGG (QT-prolongation) were 100 for tolterodine and 40 for DD 01. Almost the
`same ratios (>100 and >30) were found for the unbound concentrations at which effects on the
`
`central nervous system, gastrointestinal tract and renal function were recorded in the mouse.
`
`0
`
`Poor metabolizers of
`
`tolterodine will get higher concentrations of
`
`tolterodine, but no
`
`measurable levels of DD 01. Similarly, the serum levels of tolterodine and DD 01 may be
`affected by drug interactions. This issue cannot be adequately addressed in animal studies
`
`and has therefore been studied in humans.
`
`- Most of the secondary effects are of an antimuscarinic nature. Thus, increased heart rate.
`
`increased looomotor activity, mydriasis. decreased intestinal motitity and development of
`
`residual urine can all be attributed to blockade of muscarinic receptors.
`
`PHARMACOKINETICSITOXICOKINEITCS
`
`Summary of PKITK:
`Phannacokinetics of tolterodine has been studied in rat, mouse and dog.
`
`Differences between species were seen in systemic exposure. At similar oral doses. the serum
`concentrations of tolterodine in the dog were more than 50 and 30 times higher compared to rat
`and mouse respectively. The serum concentration in man was. after adjustment to the much
`higher dose given in the animals, in the same range as seen in the dog. With increasing dose.
`there was an non-proportional increase in Cmax and AUC in mouse and dog. The differences
`seen between species in the exposure of tolterodine was reduced when a comparison was based
`on unbound concentration in semm.
`
`The binding to semm proteins varied between the species. The unbound fraction was in dog and
`cat less than 1% but in rodents between 7.9-20.1%. In man the unbound fraction was 2.1%.
`Orosomucoid was kind to be a major binding protein.
`-
`
`Tolterodine was extensively metabolized. The metabolic pathway in dog and mouse was similar
`to that in man. The main metabolic pathway was
`In rat another metabolic pathway involving hydroxylation of the unsubstituted
`aromatic ring was found.
`
`In dog
`The 5-hydroxymethyl metabolite (DD 01) has been shown to be phamiacologically active.
`and mouse the semm concentration of the metabolite ranged from the same to four times
`lower the concentration of the parent molecule; in man the metabolite ranged from about
`equal concentrations to not measurable concentrations.
`The protein binding of the
`metabolite was however much lower than that of tolterodine, resulting in a higher unbound
`concentration in serum of the metabolite compared with tolterodine (4-10 fold) in dog and
`mouse.
`
`[1
`
`aen wner,
`
`3
`
`' arma m— X II
`
`

`
`The excretion of radioactive material in urine was. after an oral dose of radioactively labeled
`tolterodine (4 mglkg bw) 9% in the rat. 50% in the dog, and in man 75% of a dose of 5 mg.
`Most of the radioactivity represented metabolites, mainly the carboxylated metabolite. while
`the parent molecule was present only in low amounts. After an iv dose in the rat. the main
`part of the radioactivity was found in feces (75%) indicating a high biliary excretion in this
`species.
`
`In conclusion, mouse and in particular dog, exhibit similarities to man regarding
`pharmacokinetic profile and metabolite pattern.
`
`Systemic exposure: At the no-observed-adverse effect doses in general toxicology studies
`
`Dose
`
`tolterodine
`Cmax
`Cmax u
`AUC
`AUC u
`
`DDD1
`Cmax
`Cmax u
`AUC
`AUG u
`
`Mouse
`10 mglkg
`
`fu=16%
`83
`13
`238
`38
`
`fu=72%
`63
`45
`166
`119
`
`Dog
`0.5 mglkg
`
`fu=2.1%
`65
`1.4
`166
`3.5
`
`fu=32%
`12
`3.8
`52
`17
`
`Man
`2 mg bid
`
`fu=3.T%
`3.6
`0.13
`17
`0.63
`
`fu=36%
`2.9
`1.0
`14
`5.0
`
`Concentrations in ugll, fu = unbound fraction in serum. u = unbound concentration, n.d. =
`undetectable. AUC is estimated fora dose interval of 24 hrs in animals and 12 hrs in man. To
`compare exposures between humans and animals, the human AUC should be doubled.
`
`Systemic exposure: At the highest doses in the carcinogenicity studies.
`
`Mouse
`
`Rat
`
`Man
`
`Dose
`
`30 mglkg
`
`20 mgikg (F)
`
`30 mgfkg (M)
`
`2 mg bid
`
`g
`
`totterodine
`Cmax
`Cmax u
`AUC
`AUG u
`
`fu=16%
`18
`'
`2.9
`3% , 355
`" 57
`
`14
`3.1
`291
`64
`
`fu=22%
`23
`5.1
`452
`102
`
`fu=3.7%
`3.5
`0.13
`17
`0.63
`
`fu=63%
`n.d.
`
`n.d.
`
`'
`
`fLl=36°/o
`fu=72%
`DD01
`2.9
`10
`Cmax
`1.0
`7.2
`Cmax u
`14
`198
`AUC
`5.0~
`.
`143
`AUG u
`concentrations in ugll; u=unbound concentration; fu=fraction unbound; n.d.=not detectable; AUC
`in animals over 24 hrs, man over 12 hrs.
`
`,
`
`Pharmacokinetic parameters of tolterodine
`
`Species
`
`fu %
`
`t1l2 h
`
`Vd l/kg
`
`Vdu
`
`CL
`
`Bioavail
`
`

`
`16
`Mouse
`s 2.1
`Dog
`22
`Rat
`3.7
`Man
`fu=l'raction unbound
`
`I .0
`0.8
`L8
`3.7
`
`16
`1.5
`25
`L6
`
`I00
`7|
`
`43
`
`l/hxkg
`
`13
`1.4
`l0
`0.64
`
`Excretion
`14C
`43
`50
`I7
`77
`
`Excretion
`14C
`51
`34
`81
`i7
`
`Vdu= volume of distribution (unbound concentration)
`CL=clearance; Clu= clearance (unbound concentration)
`
`Metabolism
`
`Metabolite screening for urinary metabolites of tolterodine has been performed in mouse, rat, dog
`and man. The urine was analyzed by
`The
`isolated metabolites in the
`
`Tolterodine was extensively metabolized. The rnetabotite pattern in dog and mouse urine was
`similar to that of human urine while rat urine exhibited a markedly different pattern. Totterodine is
`primarily metabolized by
`The
`major metabolites that were identified in both mouse. dog and man were the
`
`The rat appears to metabolize tolterodine along a different route
`
`metabolites were observed.
`
`Excretion of radioactivity in urine and feces after administration of 14C-labelled toiterodine was
`studied in rat and in dog. The total recovery in the studies was >95% in the rat and > 80% in the
`dog.
`
`In the rat, both intravenous (0.4 mgll-cg bw) and oral doses (4. 12 and 40 mgfkg bw) were given.
`After the iv dose. an average of 75% of the dose was found in feces indicating a high biliary
`excretion. After the oral doses the main part, 90%. was excreted after the first 24 hours, mainly in
`the feces. An average of 9-24% was found in the urine; increasing amount with increasing dose
`in the interval 4-40 mglkg bw. In the dog, only oral doses (0.5 and 4.5 mglkg) were studied. A
`larger amount, about 50% of the dose, was excreted in the urine.
`In man. 75% of a tracer dose of
`14C-labeiled tolterodine (total dose 5 mg) was excreted in urine and 20% in feces.
`
`Most of the radioactivity in urine represented metabolites, mainly the
`man and dog. The parent molecule was present only in low amounts.
`
`metabolite in
`
`The pharrnaookinetics of tolterodine was studied in rat. mouse and dog. There were large
`- differences in sys
`ic exposure between the species investigated. These differences were
`.
`eliminated when
`ed on unbound fraction of tolterodine in serum. as there were large
`differences in protein binding between the species. The rat differed from the other species by a_
`different metabolic pathway.
`
`Mouse and in particular dog exhibited similarities to man regarding pharmacokinetic profile and
`metabolite pattern.
`
`

`
`TOXICOLOGY
`
`Single and repeat dose toxicology: Acute Toxicity in mice and rats after single oral
`administration of Tolterodine.
`
`Study sponsor:
`Study report number: 89-22
`Date: 1990
`
`Specieslstrain:
`Route: Oral gavage
`Numberlsexldosez 5
`
`mice and Sprague-Dawley rats
`
`Doses: 150 and 300 mglkg for mice and 150. 300 or 375 rnglkg for rats
`Duration: single dose with 14 day observation period.
`
`There were no deaths in L0 mice and 60% mortality at the high close. All deaths occurred within
`24 hrs of dosing. There was no morality in the rat study. There was a reduction in food
`consumption and body weight loss in the first few days alter treatment in both mice and rats at all
`dose levels.
`
`Acute intravenous toxicity study in the mouse.
`
`Testing facility: Phannacia Therapeutics Uppsala
`Study number.
`number 93059
`- Date: 1994
`
`Specieslstrain:
`Route:
`intravenous
`Numberlsexldose: 5
`
`mice
`
`Doses: 8. 16 and 24 mglkg
`Duration: single administration with 14 day observation period.
`
`In males treated with 16 mglkg increased motor activity,
`No reaction to treatment at B mglkg.
`increased respiratory frequency, piloerection and ventral recumbency was observed for short
`periods after dosing. One male died after having convulsions. No effects in females at this dose.
`Both males and females treated with 24 mgfkg showed ataxia, ventral recumbency and
`convulsions. An 80% mortality was recorded at this dose level.
`
`Acute intravenous toxicity study In the rat
`
`Testing facility: ‘Phannacia Therapeutics Uppsala
`Study number.
`number 93058
`Date: 1994
`Specieslstrainr Sprague-Dawley rats
`Route:
`intravenous
`.
`Numberlsexldose: 5
`
`Doses: 8. 16 and 24 mglkg
`Duration: single administration with 14 day observation period.
`
`No effects of treatment with 8 mgifkg At 16 mglkg. only short-lived ataxia. At 24 mglkg there
`were deaths (25 males and 1/5 females) which occurred during or immediately after dosing. The
`most prominent clinical findings at 24 mglkg were reversible ataxia. ventral recumbency and
`convulsions.
`
`

`
`Repeated Dose Toxicology
`
`Toxicity to mice by‘ repeated oral administration for 13 weeks followed by a 4-week
`recovery period.
`
`Study sponsor
`Study report numben
`Date: 1993
`
`document 20817F
`
`;CD-1(lCR)BR mice
`Specieslstrainz
`Route: Oral gavage
`Numberlsex: 16. with an additional Slsex for recovery and 24-30Isex for toxlcokinetics and
`metabotisrn studies.
`
`‘
`
`Doses: 4. 12 or 40 mglkg
`Duration: 13 weeks with 4 week recovery
`
`Mortality: Significant increase in the HD gps. No consistent findings to account for the deaths.
`Sponsor concludes that deaths due to phannacological (anticholinergic) effect of the drug.
`
`Clinical signs: None
`
`S Bodyweight changes: A significant reduction in bw gain at the HD for males and females.
`Sponsor did not consider the reduction to be toxicologically significant and simply reflected normal
`variability for mice of their age and strain at these labs.
`
`Food consumption: No treatment related effect.
`
`Water consumption: During wks 8 and 12. the HD animals consumed more water than controls.
`
`Hematotcgy: No treatment related effects.
`
`Clin chem: No toxicologically significant changes.
`
`Urinalysis: No toxicologically significant changes.
`
`Gross path: No treatment related effects.
`
`Organ wts: No toxicologically significant findings.
`
`Histopathology: Abnormal round spermatids in 6113 HD males compared to 3l16 control rnales.
`LD and MD were similar to controls. Testicular atrophy, prominent interstitial cells and minimal
`reduction of spe
`ogenesis was seen in low incidence in treated males but not in controls.
`Sponsor states that these changes are occasionally seen in controls and believe the changes are
`unrelated to treatment.
`
`General toxicity in rats of tolterodine administered orally for two weeks.
`
`Study sponsoi".
`Study number
`Date: 1990
`
`document 819/9.6 616
`
`Specieslstrain: Sprague-Dawley rats
`Route: Oral gavage
`Numberlsex/dose: 10
`
`Doses: 4, 12 or 40 mg/kg
`Duration: 2 weeks
`
`I5
`
`aen wner,
`
`3
`
`' arma m— X II
`
`

`
`Mortality: None treatment related.
`
`Clinical signs: Salivation, occasionally red-stained, showed a dose related incidence and
`appeared usually within 5-15 minutes of dosing.
`It continued throughout the study.
`
`_ Body weight: No effect
`
`Food consumption: No effect.
`
`'
`
`Hematology: Slight stimulation of erythropoiesis in males only. Increased platelet counts in HD
`males and females.
`increase in WBC counts in HD males and females as well as LD females.
`
`Clinical chemistry: No toxicologically significant changes.
`
`Urinalysis: Reduced volume of urine and increased osmolality. density and protein concentration
`were seen in MD and HD males. HD females had a slightly increased volume of urine when
`compared to controls.
`
`Organ wts: Small but significant increase in absolute and rel liver wts for HD males and females
`and MD females.
`
`Gross pathology: No effects.
`
`Histopathology: No toxioologically significant changes.
`
`Toxicity to rats by repeated oral administration for 13 weeks followed by a 4-week recovery
`period.
`
`Study sponsor:
`Study number:
`Date: 1991
`
`'90
`
`CD(SD) BR rats
`Speciesistrain:
`Route: Oral gavage
`Numberlsexldosez 15
`
`Doses: 4. 12 or 40
`Duration: 13 weeks with a 4 week recovery period.
`
`Mortality: Ten flD females died during the study. All died approximately 20 hrs after dosing.
`P‘
`dth
`hdd‘taed
`b‘ cl"|'
`fdb'l'ty
`'t'ti
`N'th
`nor to ea noni a
`rsp y
`any o vrous
`rmca signs o
`e ll or in oxlca on.
`er er
`macroscopic post V
`rtern exam nor histopath exam revealed any changes that could account for
`the deaths.
`'
`h
`
`Clinical signs: Dose related salivation together with brown staining on the muzzle and wetting of
`the coat.
`‘
`
`Body weight: HD females gained _less than controls. No other effects.
`
`Food consumption: No significant effects.
`
`Ophthalmoscopy: No effects.
`
`Hematology: MD and HD females had a significantly lower \NBC count than controls.
`
`16
`
`aen wner,
`
`3
`
`' arma m— X II
`
`

`
`Clinical chem: Dose related increase in plasma cholesterol in HD rats. Some increase in plasma
`triglycerides also noted. All-r Phos increased in MD and HD females.
`
`Urinalysis: HD males had more dilute urine with lower sp gravity and osmolality. Females also
`affected but to a lesser degree.
`
`Gross path: No treatment related changes.
`
`increased liver wts for MD and HD females and HD males. Increased lung M5
`Organ weights:
`for HD rats and increased kidney wts for HD males.
`-
`
`Histopathology: Thyroid - Increased height of follicular epithelium and decrease colloid in HD rats.
`Liver - centrilobular andfor diffuse hepatocyte enlargement in MD and HD males and females.
`Lungs - Prominent, pigmented (iron positive) alveolar macrophages in MD and HD males and HD
`females.
`
`Only the lung pathology was apparent after the 4 week recovery period.
`
`General toxicity in dogs of tolterodine administered orally for two weeks.
`
`Study sponsor:
`Study number 89 96 631
`Date: 1990
`
`Specieslstrainz Beagle dogs
`Route: Oral capsules
`Numberlsexldose: 2
`
`Doses: 0.5. 2 or 8 mgfkg
`Duration: 2 weeks
`
`Mortality: None.
`
`Clinical signs: Main clinical signs were those related to the anticholinergic effects of the drug;
`inhibition of salivation. pupil dilation and discharge from the eyes. Ataxia and drowsiness were
`also observed on the first day of treatment in one HD dog. Also. a low frequency of vomiting was
`noted among the treated dogs.
`
`Body wts: Reduction in body wt was seen for one male and one female of the HD.
`
`Food consumption: Reduced in HD dogs.
`
`Ophthalmoscopic-exam: No effects.
`
`Electrocardiography: No significant effects.
`
`Hematology: No significant effects.
`
`Clin chem: No significant effects.
`Urinalysis: Increased vol with decreased osmolality in HD dogs.
`
`Organ wts: No effects.
`
`Histopathology: Conjunctivitis in all HD dogs. No other treatment related effects.
`
`l7
`
`aen wner,
`
`3
`
`' arma m— X II
`
`

`
`Toxicity to dogs by repeated oral administration for 13 weeks.
`
`Study sponsor:
`Study number.
`Date: 1991
`
`document 91 96 112
`
`Specieslstrain: Beagle dogs
`Route: Oral capsules
`Numberlsexldosez 4
`Doses: 0.5, 1.5‘or 4.5
`Duration 13 weeks
`
`Mortality: None
`
`Clinical signs: Dry mouth, pupil dilation and discharge from the eyes. All HD dogs developed
`conjunctivitis. Some ptosis and ataxia in 2 HD dogs on day 1 of treatment only.
`
`Body weight: No changes.
`
`Foodfwater consumption: No effects.
`
`Ophthalmoscopy: No effects other than conjunctivitis.
`
`EKG: No effects.
`
`Hematology: No effects.
`
`_ Clin chem: No effects.
`
`Urinalysis: No effects.
`
`Gross path: No effects.
`
`Organ weights: No effects.
`
`Histopathotogy: No treatment related findings.
`
`Toxicity to Beagle dogs by repeated oral administration for 26 weeks.
`
`Study sponson _
`Study number: 9f084
`Date: 1991-2
`'
`
`Specieslstrain: Beagle dogs
`Route: Oral capsules
`Numberlsexldose: 5
`
`Doses: 0.5, 1.5 or 4.5 mglkg
`Duration: 26 weeks
`
`Mortality: One LD and one MD female were sacrificed moribund with pyometra and chronic disc
`prolapse, respectively. Neither were treatment related.
`a
`
`increased pupillary response (dilation) to direct light with the MD and HD.
`Clinical signs:
`high dose the effect was moderate to pronounced and persisted for 24 hrs.
`
`in the
`
`

`
`Slight depression of salivation in the MD and slight to moderate in the HD. This occurred within
`the first 3-6 hrs after dosing particularly during the first week of treatment and sporadically after
`that.
`
`There was dose-related decrease in tear flow: dry nose; increase in dry oral mucosa and corneal
`spotslulcers. Corneal changes regressed with appropriate treatment. The HD dogs on the first
`day of dosing showed ataxia. sedation. sensitivity towards light and trembling which subsided by
`the following day. Thereafter only occasional ataxia and tremor were seen.
`In the HD. there were
`occasional distended abdomen and blood in the urine.
`‘
`
`Bodyweight: No effect
`
`Food consumption: No effect
`
`Hematology: No treatment related effects.
`
`Clinical chemistry: There were sporadic changes in LFT's which were not dose and probably not
`treatment related.
`
`Urinalysis: Some increase in urine volume in the MD and HD females.
`
`Ophthalrnoiogic exam: There was unilateral focal, superficial keratitis at 12 weeks in one control
`_and 3 MD dogs. This was not seen in any dogs at 26 wks.
`
`ECG: During the first hour after dosing, there was an increase in heart rate in most dogs. The
`lowest dose producing this effect was 1.5 mgfkg in males and 0.5 mglkg in males. During the
`course of the study the dogs adapted and no treatment related effect on heart rate was noted.
`
`The duration of the T wave was increased in HD males 1 hr after dosing. This effect was also
`seen in females and occurred about 1-5 hrs after dosing.
`
`Organ weights: Statistically significant increased liver wt in HD males and non significant increase
`in HD females.
`
`Gross path: Distended gall bladder with a large amount of bile was seen in one male and one
`female in the HD. Another HD female had a distended gall bladder with slightly increased amount
`of bile.
`
`Histopathology' There were no histopath correlates to the enlarged livers. Aside from the two
`animals killed uring the study, there were no toxicolo-gically significant histopath changes.
`
`52-week oral toxicity study in the beagle dog followed by an eight-week recovery period T
`
`1'
`
`Testing facility: Pharmacia & Upjohn. Heisingborg, Sweden
`Study number. Study no. 95009
`Date: 1996
`
`Specieslstrainz Beagle
`-
`_
`Route: Oral gelatin capsules
`Nurnberlsexldosez 7 dogslsex in the control and high dose and 5 dogslsex in the low and mid
`doses. The extra two animals in the control and HD were assigned for an 8- week recovery
`period.
`Doses: 0.5, 1.5 and 4.5 mgrkglday
`Duration: 52 weeks
`
`[9
`
`aen wner,
`
`3
`
`' arma m— X II
`
`

`
`Systemic Exposure
`
`Dose
`mgfkg
`
`Week
`No.
`
`0.5
`
`1.5
`
`4.5
`
`Male
`
`T
`72.8
`87.9
`135
`
`125
`190
`249
`
`516
`695
`771
`
`-
`
`2
`26
`52
`
`2
`26
`52
`
`2
`26
`52
`
`Cmax (nglml)
`
`AUC (ngxhlml)
`
`1
`Female
`
`Male
`
`Female
`
`DD01
`12.0
`15.3
`15.6
`
`41.9
`49.3
`54.3
`
`137
`148
`166
`
`T
`50.7
`61.9
`46.8
`
`105
`136
`164
`
`420
`574
`401
`
`DD01
`9.2
`12.8
`12.2
`
`28.2
`35.1
`38.2
`
`100
`127
`126
`
`T
`161
`178
`393
`
`405
`538
`565
`
`5989
`4648
`4276
`
`DD01
`43.1
`52.1
`66.6
`
`T
`103
`- 160
`116
`
`169
`212
`221
`
`1857
`1975
`2117
`
`294
`363
`380
`
`2894
`3217
`3981
`
`DD01
`27.5
`47.0
`35.5
`
`107
`125
`149
`
`1149
`1349
`1845
`
`Mortality: Two high dose males showed subdued behavior. urinating difficulties, dilated tensed
`urinary bladder. blood-stained urine. distended abdomen and pain reaction at palpation of the
`abdomen caused by urolithiasis and were killed. One HD female showed a chronic purulent
`conjunctivitis, keratitis and half-closed eyes. The signs disappeared during a 27-days (days 163-
`210) dose free period but returned within a few days after start of dosing despite continuous
`moistening of the eyes. The dog was killed for ethical reasons on day 225.
`
`Clinical signs: Dose related decreased pupillary response to directed light was seen from the LD
`upward. At the MD. pronounced dilation was observed in several dogs on several occasions. At
`the HD, slight to total dilation was seen in most dogs on most occasions. This effect nonnalized
`during the recovery period.
`
`There was a dose-related decrease in salivary secretion and lacnmation starting at the LD.
`
`At the HD. conjunctivitis and occasional comeal lesions due to dry eyes were seen in several
`dogs. pronounced in some dogs. After 2 months, daily moistening of the eyes of HD dogs was
`initiated.
`
`Body Weight: Nio effects were seen.
`
`Food Consumptiorhslight decrease in HD females throughout the study and during recovery.
`
`Ophthalmoscopy: Higher frequency of keratitis andlor oomeal opacities and conjunctivitis in HD
`animals compared to controls or the other gps. Pupillary reflex was absent in several HD dogs
`after 6 or 12 months of dosing.
`-
`
`ECG-Recordings: On day 1 and 7. treated animals of both sexes showed increased heart rate
`one hr after drug administration. The lowest dose giving a significant increase was 0.5 mkd.
`During the course of the study the dogs adapted but treatment related effects on heart rate
`continued sporadically until the end of the study.
`
`A decrease in the PQ—interval was seen in both sexes primarily after treatment with the MD and
`HD. The QRS-interval was unchanged.
`In both sexes given the MD and HD_ the QT—intervaI
`
`20
`
`aen wner, 3' arma m— X II
`
`3 H:
`
`

`
`as.
`
`decreased after the first dose (which may have been mused by the marked increase in heart
`rate). Both males and females showed changes in Cm: during the treatment.
`
`Hematology: No significant treatment related changes.
`
`Clinical Chemistry: No treatment related changes.
`Urinalysis: No treatment related changes.
`
`Macroscopic Pathology: Two HD males had marked occlusive urolithiasis in the bladder and
`urethra along with mucosa! hemorrhage and edema. Distention of the gall bladder with
`macroscopically nonnal bile was seen in some of the MD and HD male and female animals.
`Mucosal petechiation in the urinary bladder was seen in ‘U3 and 215 HD males.
`
`Organ Weights: No treatment related changes in absolute or relative organ weights were
`observed.
`
`Histopathology: Two HD male dogs that were sacrificed had marked urolithiasis in the bladder
`and urethra which was the reason for the eady sacrifice of these dogs. Mucosat and mural
`hemonhage. necrosis and inflammation were seen in the urinary bladder and urethra. Both dogs
`had marked purulent hemorrhagic prostatitis along with inflammatory edema and congestion in the
`retroperitoneal soft tissues.
`
`One HD female had corneal inflammatory cell infiltrate in both eyes and slight multifocal corneal
`epithelial degeneration in one eye. These changes were considered by the sponsor to be
`treatment related.
`
`There was an inflammatory reaction in the urethra of both males and females which was possibly
`dose related. Foci of epididymal vascular and perivascular inflammation were seen in 115 males
`at the LD. 215 at the MD and 213 at the HD. Moderate chronic epididymitis was seen in another
`MD male.
`
`No changes in the testis. epididymis, urinary bladder or urethra were seen in the recovery
`animals.
`
`Discussion: The main adverse effects were due to tolterodine's phamtacological (antimuscarinic)
`effects. i.e. dry mouth. decreased tear how and pupillary dilation. The ophthalmologic findings
`(keratitis. corneal opacities and conjunctivitis). seen mainly in the HD were most likely secondary
`to xerophthatmia induced by the antimuscarinic effects. ‘lite urolithiasis seen in two HD males
`was most likely secondary to increased residual urine, which predisposes to urinary infection.
`concrement forp1ation and traumatic cystitislurethritis.
`
`increase in heart fie was seen early in the study with some adaptation during the progress of the
`study but there was significant heart rate elevations in some dogs at various time points until the"
`end of the study. Moreover, there was a general increase in heart rate (not reaching statistical
`significance) in almost all treated dogs at all time points throughout the study. There was no. no
`effect dose. Decreases in the PQ interval were probably the result of the increased heart rate.
`
`Sub-Acute Toxicity to Mice by Dietary Administration for 13 Weeks.
`
`Testing facility:
`Study number: 9610715
`Date: 10196
`
`.CD-1 (ICR) BR mice
`Specieslstrain:
`Route: oral; mixed with diet
`
`2|
`
`aen wner,
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`3
`
`' arma m— X II
`
`

`
`Nurnberisexldosez 221sex in control; 42Isex in treated. Only 10 animalslgp were used for
`toxicological evaluation. The remaining animals were used for toxicokinetics.
`Doses: 4. 16. and 60 mgfkglday
`Duration: 13 weeks
`
`Mortality: None treatment related.
`
`Clinical signs: None related to treatment
`
`Bodyweight: There was a non-significant decrease in BW gain in males and females.
`
`Group and Dosage (mglkglday)
`
`male
`
`female
`
`week 0-13
`SD
`
`0
`11.0
`2.74
`
`4
`15.3
`5.05
`
`16
`10.8
`2.04
`
`60
`8.0
`1.99
`
`0
`7.9
`2.93
`
`4
`7.5
`2.36
`
`16
`6.7
`2.23
`
`60
`6.0
`2.38
`
`Food Consumption; No significance compared to controls.
`
`Clinical chernlhematologyr Some early morning elevations of T3 for HD males and females and
`elevations of T4 for HD males.
`
`Organ weights: Slight increase in relative liver and pituitary weight for HD males. Mean thymus
`wts were decrease in HD females.
`
`Gross pathology: No treatment related effects.
`
`Histopathology: No changes correlated with the organ wt changes except for a minimal
`centrilobular hepatocyte enlargement in 1110 LD. 1110 MD and 3110 HD male mice.
`
`Sub-Acute Toxicity to Rats by Dietary Administration for 13 Weeks.
`
`0
`Testing facility:
`Study nurnbeq: 9610716
`Date: 10196
`;,
`Specleslstrain:
`_ CD Sprague-Dawley BR Rats
`Route: oral: mixed with diet
`
`Numberlsexldosez 181sex in control; 26Isex in treated. Only 10 animalslgp were used for
`toxicological evaluation. The remaining animals were used for toxicokinetics.
`Doses: 4. 12, 40 mglkglday (M) and 4. 12, 24 mg1kg1day(F)
`Duration: 13 weeks
`'
`
`Mortality: None
`
`Clinical signs: No treatment related signs.
`
`Bodyweight: Significant decrease in BW gain for HD males and females. At 13 weeks for males
`controls had gained 393 g vs 287 g for HD (p< 0.01). Control females gained 137 g vs 98 g for
`HD (p< 0.01}.
`
`22
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`aen wner, =' arma m— XII
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`I H:
`
`

`
`Food consumption: There was a significant (p < 0.05) decrease in F0 for HD males only.
`
`Clinical ChernfHematoIogy: No treatment related effects.
`
`Organ weights: Increase in rel but not absolute liver wts for HD males and females. Mean lung
`wts were significantly increased for HD males and females.
`
`Gross path: Congestion of the lungs was seen in 6110 males and 4110 females in the HD groups.
`Lung congestion was not seen in the controls. There was a decrease in adipose tissue for males
`and females that was dose related.
`
`Histopathology: Lungs: Increased number of alveolar macrophages, some staining for iron, in
`1110 MD and 3110 HD females. Increased incidence of vascular congestion in HD males and
`females.
`
`Liver: Increased incidence of centrilobular hepatocyte enlargement in HD males and females.
`
`Thyroid: Slightly higher incidence of increased height of follicular epithelium associated with
`decreased colloid in MD and HD males.
`
`Sub-Acute Toxicity to Hamsters by Dietary Administration for 13 Weeks.
`
`_
`Testing facility:
`Study number: 9610717
`Date: 1OI96
`
`Hamsters
`Speciesfstrain:
`Route: oral; mixed with diet
`Numberlsexldose: 16Isex in control; 26Isex in treated
`Doses: 4, 12, 40 and 60 mglkglday
`Duration: 13 weeks
`
`Mortality: One male in the HD, considered unrelated to treatment
`
`Clinical signs: None attributable to treatment
`
`Bodyweight: There was a significant decrease in bw gain in males at the LMD, HMD and HD.
`There was a slight, and nonsignificant decrease in bw gain in females.
`1
`Food consumption
`
`' There was a significant decrease in fc in males at the HD only.
`it
`Biochemistry: No /treatment related changes.
`
`Organ weights: There was a dose-related increase in relative lung weights for all treated males
`and females which was statistically significant starting at the LD. Group mean relative liver
`weights were increased for females.
`-'
`
`Macroscopic Pathology: Dose related increase in lung congestion.
`
`Histopathologyz Increased incidence of lung congestion in the two highest dose gps.
`
`Toxicokinetics: Hamsters were studied to determine if they would be a suitable species for
`carcinogenicity testing since rats metabolize tolterodine differently than humans. DDD1 was not
`produced to a great extent in hamsters but at the 60 mglkg dose, serum DD01 levels (AUC) were
`
`23
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`aen wner, 3' arma m— X II
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`3
`
`‘H:
`
`

`
`39.4 (males) and 47.6 (females) ug.hIl. The concentration of DD01 was about 20% of the
`concentration of the parent tolterodine. Apparently the sponsors felt that this metabolite pattem
`was not sufficiently different from the rat to warrant use of the hamster in the carcinogenicity
`studies.
`
`Toxicity to mice by repeated oral administration for 26 weeks followed by an 8-week
`recovery period.
`
`Testing facility:
`Study number. Pharrnacia document 21744F
`Date: 1994
`
`CD-1(lCR)BR mice
`Specieslstrain:
`Route: Oral gavage
`Numberfsexldosez 30; a subgroup of 9-10 were sacrificed after 13 wks. Another gp of controls
`(9-10) and high dose (5-6) were treated for 26 wks then maintained for a recovery period. An
`additional 56lsex were treated at each dose and used for toxicokinetic sampling.
`Doses: 3, 10 and 30 mglkg
`Duration: 26 weeks
`
`Mortality: There was an increase in mortality in the high dose. Death occurred within a short time
`after dosing most within 1 hr. These animals had previously not shown any effects of treatment
`and there were no consistent abnormalities to account for the deaths and no cause of death was
`identified pathologically. The sponsor considers the deaths to be the result of the
`pharmacological action of the drug. Four HD animals died with convulsions which was considered
`treatment related.
`
`Clinical signs: convulsions prior to death in a few HD animals.
`
`Bodyweight: Decrease in BW gain in HD females.
`
`Food consumption: No effect.
`
`Water consumption: Increase in water consumption in HD males and females.
`
`Ophthalmoscopy: No effects.
`
`Hematology: Slight but statistically significant reductions in PCV and Hb were seen for all treated '
`female gps in comparison to controls. A decrease in PCV alone was noted for HD males.
`Associated witzthese changes were minor reductions in MCV for MD and HD animals, and
`increases in M Hgfor HD mice. These changes were not seen after the recovery period.
`Clinical chemistry: At 14 weeks, there was a slight but significant increase in BUN for MD and HD
`males and females and for.LD males. At 26 wks, BUN was elevated in MD and HD females
`compared to controls but the control values were unusually low.
`
`Urinalysis: Slight decrease in urine osmolality and so gravity for M0 and HD males. Reduction in
`urinary protein in HD males. Alsoseen in females but not significant No differences were
`apparent alter the recovery period.
`:
`
`Organ weights: Increased lung wt for HD males, increased adrenalwts for HD females and
`reduced liver wts for all treated female gps. All changes were reversed during recovery.
`Gross path: Thickened uterus in HD females at wk 13 but not at wk 26.
`
`Histopath: Liver - Increased incidence of centrilobular hepatocyte enlargement in HD males.
`
`24
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`aen wner,
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`' arma m— X II
`
`

`
`No other toxicologically significant findings were noted. including me cause of the excess deaths
`in the HD animals.
`
`Summary of toxicology:
`
`Carcinogenicity:
`
`24-Month Dietary Carcinogenicity Study in Mice.
`
`Testing facility:
`Study number. N583—Q1345
`Date: 1996
`
`:CD-1 BR mice
`Specieslstrain:
`Route: Oral; mixed with diet
`Numberlsexidose: 60; Satellite groups of 16 were used only for determination of systemic
`exposure to tolterodine and its metabolite DD01.
`Doses: 0, 0, 5, 15 and 30 mgfkg
`Duration: 24 months.
`
`Because of the high mortality rate observed in male mice given the MD and HD, (54% and ?4%,
`respectively, alter 76 wks of dosing), all male gps were terminated on week 79. Females were
`sacrificed after 24 months of study.
`
`Mortality: Progressive dose-related mortality was observed in males given 15 and 30 mglkgfday
`starting from week 41 of study. The mortality rate reached an incidence of 55% and 78%
`beginning at wk 78, compared to a 20% mortality rate in the control gps. No substantial
`differences in mortality were seen in treated females compared to controls except for a slightly
`higher rate in HD females (63% vs 47% in controts after 2 yrs.). The main causes of death were
`due to a marked distention of the large intestine due to an abnonrlal presence of feces a