Detrol®
tolterodine tartrate tablets
DESCRIPTION
DETROL Tablets contain tolterodine tartrate. The active moiety, tolterodine, is a
muscarinic receptor antagonist. The chemical name of tolterodine tartrate is (R)-2-[3
[bis(1-methylethyl)-amino]1-phenylpropyl]-4-methylphenol [R-(R*,R*)]
2,3dihydroxybutanedioate (1:1) (salt). The empirical formula of tolterodine tartrate is
C26H37NO7, and its molecular weight is 475.6. The structural formula of tolterodine
tartrate is represented below:
Tolterodine tartrate is a white, crystalline powder. The pKa value is 9.87 and the
solubility in water is 12 mg/mL. It is soluble in methanol, slightly soluble in ethanol, and
practically insoluble in toluene. The partition coefficient (Log D) between n-octanol and
water is 1.83 at pH 7.3.
DETROL Tablets for oral administration contain 1 or 2 mg of tolterodine tartrate. The
inactive ingredients are colloidal anhydrous silica, calcium hydrogen phosphate
dihydrate, cellulose microcrystalline, hypromellose, magnesium stearate, sodium starch
glycolate (pH 3.0 to 5.0), stearic acid, and titanium dioxide.
CLINICAL PHARMACOLOGY
Tolterodine is a competitive muscarinic receptor antagonist. Both urinary bladder
contraction and salivation are mediated via cholinergic muscarinic receptors.
After oral administration, tolterodine is metabolized in the liver, resulting in the
formation of the 5-hydroxymethyl derivative, a major pharmacologically active
metabolite. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity
similar to that of tolterodine, contributes significantly to the therapeutic effect. Both
tolterodine and the 5-hydroxymethyl metabolite exhibit a high specificity for muscarinic
receptors, since both show negligible activity or affinity for other neurotransmitter
receptors and other potential cellular targets, such as calcium channels.
Tolterodine has a pronounced effect on bladder function. Effects on urodynamic
parameters before and 1 and 5 hours after a single 6.4 mg dose of tolterodine immediate
release were determined in healthy volunteers. The main effects of tolterodine at 1 and 5
hours were an increase in residual urine, reflecting an incomplete emptying of the
bladder, and a decrease in detrusor pressure. These findings are consistent with an
antimuscarinic action on the lower urinary tract.
Pharmacokinetics
Absorption: In a study with 14C-tolterodine solution in healthy volunteers who received
a 5-mg oral dose, at least 77% of the radiolabeled dose was absorbed. Tolterodine
immediate release is rapidly absorbed, and maximum serum concentrations (Cmax)
typically occur within 1 to 2 hours after dose administration. Cmax and area under the
concentration-time curve (AUC) determined after dosage of tolterodine immediate
release are dose-proportional over the range of 1 to 4 mg.
Effect of Food: Food intake increases the bioavailability of tolterodine (average
increase 53%), but does not affect the levels of the 5-hydroxymethyl metabolite in
extensive metabolizers. This change is not expected to be a safety concern and
adjustment of dose is not needed.
Distribution: Tolterodine is highly bound to plasma proteins, primarily α1-acid
glycoprotein. Unbound concentrations of tolterodine average 3.7% ± 0.13% over the
concentration range achieved in clinical studies. The 5-hydroxymethyl metabolite is not
extensively protein bound, with unbound fraction concentrations averaging 36% ± 4.0%.
The blood to serum ratio of tolterodine and the 5-hydroxymethyl metabolite averages 0.6
and 0.8, respectively, indicating that these compounds do not distribute extensively into
erythrocytes. The volume of distribution of tolterodine following administration of a
1.28-mg intravenous dose is 113 ± 26.7 L.
Metabolism: Tolterodine is extensively metabolized by the liver following oral dosing.
The primary metabolic route involves the oxidation of the 5-methyl group and is
mediated by the cytochrome P450 2D6 (CYP2D6) and leads to the formation of a
pharmacologically active 5-hydroxymethyl metabolite. Further metabolism leads to
formation of the 5-carboxylic acid and N-dealkylated 5-carboxylic acid metabolites,
which account for 51% ± 14% and 29% ± 6.3% of the metabolites recovered in the urine,
respectively.
Variability in Metabolism: A subset (about 7%) of the population is devoid of CYP2D6,
the enzyme responsible for the formation of the 5-hydroxymethyl metabolite of
tolterodine. The identified pathway of metabolism for these individuals (“poor
metabolizers”) is dealkylation via cytochrome P450 3A4 (CYP3A4) to N-dealkylated
tolterodine. The remainder of the population is referred to as “extensive metabolizers.”
Pharmacokinetic studies revealed that tolterodine is metabolized at a slower rate in poor
metabolizers than in extensive metabolizers; this results in significantly higher serum
concentrations of tolterodine and in negligible concentrations of the 5-hydroxymethyl
metabolite.
Excretion: Following administration of a 5-mg oral dose of 14C-tolterodine solution to
healthy volunteers, 77% of radioactivity was recovered in urine and 17% was recovered
in feces in 7 days. Less than 1% (<2.5% in poor metabolizers) of the dose was recovered
as intact tolterodine, and 5% to 14% (<1% in poor metabolizers) was recovered as the
active 5-hydroxymethyl metabolite.
A summary of mean (± standard deviation) pharmacokinetic parameters of tolterodine
immediate release and the 5-hydroxymethyl metabolite in extensive (EM) and poor (PM)
metabolizers is provided in Table 1. These data were obtained following single and
multiple doses of tolterodine 4 mg administered twice daily to 16 healthy male volunteers
(8 EM, 8 PM).
Table 1. Summary of Mean (±SD) Pharmacokinetic Parameters of Tolterodine and
its Active Metabolite (5-hydroxymethyl metabolite) in Healthy Volunteers
Tolterodine 5-Hydroxymethyl Metabolite
Phenotype
(CYP2D6)
tmax
(h)
Cmax*
(µg/L)
Cavg*
(µg/L)
t1/2
(h)
CL/F
(L/h)
tmax
(h)
Cmax*
(µg/L)
Cavg*
(µg/L)
t1/2
(h)
Single-dose
EM
PM
1.6±1.5
1.4±0.5
1.6±1.2
10±4.9
0.50±0.35
8.3±4.3
2.0±0.7
6.5±1.6
534±697
17±7.3
1.8±1.4
-†
1.8±0.7
-
0.62±0.26
-
3.1±0.7
-
Multiple-dose
EM
PM
1.2±0.5
1.9±1.0
2.6±2.8
19±7.5
0.58±0.54
12±5.1
2.2±0.4
9.6±1.5
415±377
11±4.2
1.2±0.5
-
2.4±1.3
-
0.92±0.46
-
2.9±0.4
-
* Parameter was dose-normalized from 4 mg to 2 mg.
Cmax = Maximum plasma concentration; tmax = Time of occurrence of Cmax;
Cavg = Average plasma concentration; t1/2 = Terminal elimination half-life; CL/F = Apparent oral
clearance.
EM = Extensive metabolizers; PM = Poor metabolizers.
† - = not applicable.
Pharmacokinetics in Special Populations
Age: In Phase 1, multiple-dose studies in which tolterodine immediate release 4 mg (2
mg bid) was administered, serum concentrations of tolterodine and of the 5
hydroxymethyl metabolite were similar in healthy elderly volunteers (aged 64 through 80
years) and healthy young volunteers (aged less than 40 years). In another Phase 1 study,
elderly volunteers (aged 71 through 81 years) were given tolterodine immediate release 2
or 4 mg (1 or 2 mg bid). Mean serum concentrations of tolterodine and the 5
hydroxymethyl metabolite in these elderly volunteers were approximately 20% and 50%
higher, respectively, than reported in young healthy volunteers. However, no overall
differences were observed in safety between older and younger patients on tolterodine in
Phase 3, 12-week, controlled clinical studies; therefore, no tolterodine dosage adjustment
for elderly patients is recommended (see PRECAUTIONS, Geriatric Use).
Pediatric: The pharmacokinetics of tolterodine have not been established in pediatric
patients.
Gender: The pharmacokinetics of tolterodine immediate release and the 5
hydroxymethyl metabolite are not influenced by gender. Mean Cmax of tolterodine (1.6
µg/L in males versus 2.2 µg/L in females) and the active 5-hydroxymethyl metabolite
(2.2 µg/L in males versus 2.5 µg/L in females) are similar in males and females who were
administered tolterodine immediate release 2 mg. Mean AUC values of tolterodine (6.7
µg·h/L in males versus 7.8 µg·h/L in females) and the 5-hydroxymethyl metabolite (10
µg·h/L in males versus 11 µg·h/L in females) are also similar. The elimination half-life of
tolterodine for both males and females is 2.4 hours, and the half-life of the 5
hydroxymethyl metabolite is 3.0 hours in females and 3.3 hours in males.
Race: Pharmacokinetic differences due to race have not been established.
Renal Insufficiency: Renal impairment can significantly alter the disposition of
tolterodine immediate release and its metabolites. In a study conducted in patients with
creatinine clearance between 10 and 30 mL/min, tolterodine immediate release and the 5
hydroxymethyl metabolite levels were approximately 2–3 fold higher in patients with
renal impairment than in healthy volunteers. Exposure levels of other metabolites of
tolterodine (e.g., tolterodine acid, N-dealkylated tolterodine acid, N-dealkylated
tolterodine, and N-dealkylated hydroxylated tolterodine) were significantly higher (10–30
fold) in renally impaired patients as compared to the healthy volunteers. The
recommended dosage for patients with significantly reduced renal function is DETROL 1
mg twice daily (see PRECAUTIONS, General and DOSAGE AND
ADMINISTRATION ).
Hepatic Insufficiency: Liver impairment can significantly alter the disposition of
tolterodine immediate release. In a study conducted in cirrhotic patients, the elimination
half-life of tolterodine immediate release was longer in cirrhotic patients (mean, 7.8
hours) than in healthy, young, and elderly volunteers (mean, 2 to 4 hours). The clearance
of orally administered tolterodine was substantially lower in cirrhotic patients (1.0 ± 1.7
L/h/kg) than in the healthy volunteers (5.7 ± 3.8 L/h/kg). The recommended dose for
patients with significantly reduced hepatic function is DETROL 1 mg twice daily (see
PRECAUTIONS, General and DOSAGE AND ADMINISTRATION).
Drug-Drug Interactions
Fluoxetine: Fluoxetine is a selective serotonin reuptake inhibitor and a potent inhibitor
of CYP2D6 activity. In a study to assess the effect of fluoxetine on the pharmacokinetics
of tolterodine immediate release and its metabolites, it was observed that fluoxetine
significantly inhibited the metabolism of tolterodine immediate release in extensive
metabolizers, resulting in a 4.8-fold increase in tolterodine AUC. There was a 52%
decrease in Cmax and a 20% decrease in AUC of the 5-hydroxymethyl metabolite.
Fluoxetine thus alters the pharmacokinetics in patients who would otherwise be extensive
metabolizers of tolterodine immediate release to resemble the pharmacokinetic profile in
poor metabolizers. The sums of unbound serum concentrations of tolterodine immediate
release and the 5-hydroxymethyl metabolite are only 25% higher during the interaction.
No dose adjustment is required when DETROL and fluoxetine are coadministered.
Other Drugs Metabolized by Cytochrome P450 Isoenzymes: Tolterodine
immediate release does not cause clinically significant interactions with other drugs
metabolized by the major drug metabolizing CYP enzymes. In vivo drug-interaction
data show that tolterodine immediate release does not result in clinically relevant
inhibition of CYP1A2, 2D6, 2C9, 2C19, or 3A4 as evidenced by lack of influence on
the marker drugs caffeine, debrisoquine, S-warfarin, and omeprazole. In vitro data
show that tolterodine immediate release is a competitive inhibitor of CYP2D6 at high
concentrations (Ki 1.05 µM), while tolterodine immediate release as well as the 5
hydroxymethyl metabolite are devoid of any significant inhibitory potential regarding
the other isoenzymes.
CYP3A4 Inhibitors: The effect of 200 mg daily dose of ketoconazole on the
pharmacokinetics of tolterodine immediate release was studied in 8 healthy volunteers,
all of whom were poor metabolizers (see Pharmacokinetics, Variability in Metabolism
for discussion of poor metabolizers). In the presence of ketoconazole, the mean Cmax and
AUC of tolterodine increased by 2 and 2.5 fold, respectively. Based on these findings,
other potent CYP3A inhibitors such as other azole antifungals (eg, itraconazole,
miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine
or vinblastine may also lead to increases of tolterodine plasma concentrations (see
PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Warfarin: In healthy volunteers, coadministration of tolterodine immediate release 4 mg
(2 mg bid) for 7 days and a single dose of warfarin 25 mg on day 4 had no effect on
prothrombin time, Factor VII suppression, or on the pharmacokinetics of warfarin.
Oral Contraceptives: Tolterodine immediate release 4 mg (2 mg bid) had no effect on
the pharmacokinetics of an oral contraceptive (ethinyl estradiol 30 µg/levonorgestrel 150
µg) as evidenced by the monitoring of ethinyl estradiol and levonorgestrel over a 2
month cycle in healthy female volunteers.
Diuretics: Coadministration of tolterodine immediate release up to 8 mg (4 mg bid) for
up to 12 weeks with diuretic agents, such as indapamide, hydrochlorothiazide,
triamterene, bendroflumethiazide, chlorothiazide, methylchlorothiazide, or furosemide,
did not cause any adverse electrocardiographic (ECG) effects.
Cardiac Electrophysiology
The effect of 2 mg BID and 4 mg BID of tolterodine immediate release (IR) on the QT
interval was evaluated in a 4-way crossover, double-blind, placebo- and active-controlled
(moxifloxacin 400 mg QD) study in healthy male (N=25) and female (N=23) volunteers
aged 18–55 years. Study subjects [approximately equal representation of CYP2D6
extensive metabolizers (EMs) and poor metabolizers (PMs)] completed sequential 4-day
periods of dosing with moxifloxacin 400 mg QD, tolterodine 2 mg BID, tolterodine 4 mg
BID, and placebo. The 4 mg BID dose of tolterodine IR (two times the highest
recommended dose) was chosen because this dose results in tolterodine exposure similar
to that observed upon coadministration of tolterodine 2 mg BID with potent CYP3A4
inhibitors in patients who are CYP2D6 poor metabolizers (see PRECAUTIONS, Drug
Interactions). QT interval was measured over a 12-hour period following dosing,
including the time of peak plasma concentration (Tmax) of tolterodine and at steady state
(Day 4 of dosing).
Table 2 summarizes the mean change from baseline to steady state in corrected QT
interval (QTc) relative to placebo at the time of peak tolterodine (1 hour) and
moxifloxacin (2 hour) concentrations. Both Fridericia’s (QTcF) and a population-specific
(QTcP) method were used to correct QT interval for heart rate. No single QT correction
method is known to be more valid than others. QT interval was measured manually and
by machine, and data from both are presented. The mean increase of heart rate associated
with a 4 mg/day dose of tolterodine in this study was 2.0 beats/minute and 6.3
beats/minute with 8 mg/day tolterodine. The change in heart rate with moxifloxacin was
0.5 beats/minute.
Table 2. Mean (CI) change in QTc from baseline to steady state (Day 4 of dosing)
at Tmax (relative to placebo)
Drug/Dose N QTcF QTcF QTcP QTcP
(msec) (msec) (msec) (msec)
(manual) (machine) (manual) (machine)
Tolterodine 2 48 5.01 1.16 4.45 2.00
mg BID1 (0.28, 9.74) (-2.99, 5.30) (-0.37, 9.26) (-1.81, 5.81)
Tolterodine 4 48 11.84 5.63 10.31 8.34
mg BID1 (7.11, 16.58) (1.48, 9.77) (5.49, 15.12) (4.53, 12.15)
Moxifloxacin 45 19.263 8.90 19.103 9.29
400 mg QD 2 (15.49, 23.03) (4.77, 13.03) (15.32, 22.89) (5.34, 13.24)
1At Tmax of 1 hr; 95% Confidence Interval
2At Tmax of 2 hr; 90% Confidence Interval
3The effect on QT interval with 4 days of moxifloxacin dosing in this QT trial may be greater than typically
observed in QT trials of other drugs.
The reason for the difference between machine and manual read of QT interval is
unclear.
The QT effect of tolterodine immediate release tablets appeared greater for 8 mg/day
(two times the therapeutic dose) compared to 4 mg/day. The effect of tolterodine 8
mg/day was not as large as that observed after four days of therapeutic dosing with the
active control moxifloxacin. However, the confidence intervals overlapped.
Tolterodine’s effect on QT interval was found to correlate with plasma concentration of
tolterodine. There appeared to be a greater QTc interval increase in CYP2D6 poor
metabolizers than in CYP2D6 extensive metabolizers after tolterodine treatment in this
study.
This study was not designed to make direct statistical comparisons between drugs or dose
levels. There has been no association of Torsade de Pointes in the international post-
marketing experience with DETROL or DETROL LA (see PRECAUTIONS, Patients
with Congenital or Acquired QT Prolongation).
CLINICAL STUDIES
DETROL Tablets were evaluated for the treatment of overactive bladder with
symptoms of urge urinary incontinence, urgency, and frequency in four randomized,
double-blind, placebo-controlled, 12-week studies. A total of 853 patients received
DETROL 2 mg twice daily and 685 patients received placebo. The majority of patients
were Caucasian (95%) and female (78%), with a mean age of 60 years (range, 19 to 93
years). At study entry, nearly all patients perceived they had urgency and most patients
had increased frequency of micturitions and urge incontinence. These characteristics
were well balanced across treatment groups for the studies.
The efficacy endpoints for study 007 (see Table 3) included the change from baseline
for:
• Number of incontinence episodes per week
• Number of micturitions per 24 hours (averaged over 7 days)
• Volume of urine voided per micturition (averaged over 2 days)
The efficacy endpoints for studies 008, 009, and 010 (see Table 4) were identical to
the above endpoints with the exception that the number of incontinence episodes was per
24 hours (averaged over 7 days).
Table 3. 95% Confidence Intervals (CI) for the Difference between DETROL (2
mg bid) and Placebo for the Mean Change at Week 12 from Baseline in Study 007
DETROL Placebo Difference
(SD) (SD) (95% CI)
N=514 N=508
Number of Incontinence Episodes per Week
Mean baseline
Mean change from baseline
23.2
-10.6 (17)
23.3
-6.9 (15) -3.7 (-5.7, -1.6)
Number of Micturitions per 24 Hours
Mean baseline
Mean change from baseline
11.1
-1.7 (3.3)
11.3
-1.2 (2.9) -0.5* (-0.9, -0.1)
Volume Voided per Micturition (mL)
Mean baseline
Mean change from baseline
137
29 (47)
136
14 (41) 15* (9, 21)
SD = Standard Deviation.
*The difference between DETROL and placebo was statistically significant.
Table 4. 95% Confidence Intervals (CI) for the Difference between DETROL (2
mg bid) and Placebo for the Mean Change at Week 12 from Baseline in Studies 008,
009, 010
Study DETROL Placebo Difference
(SD) (SD) (95% CI)
Number of Incontinence Episodes per 24 Hours
008 Number of patients
Mean baseline
Mean change from baseline
009 Number of patients
Mean baseline
Mean change from baseline
010 Number of patients
Mean baseline
M
本文档为【Detrol (tolterodine tartrate tablets)】,请使用软件OFFICE或WPS软件打开。作品中的文字与图均可以修改和编辑,
图片更改请在作品中右键图片并更换,文字修改请直接点击文字进行修改,也可以新增和删除文档中的内容。
该文档来自用户分享,如有侵权行为请发邮件ishare@vip.sina.com联系网站客服,我们会及时删除。
[版权声明] 本站所有资料为用户分享产生,若发现您的权利被侵害,请联系客服邮件isharekefu@iask.cn,我们尽快处理。
本作品所展示的图片、画像、字体、音乐的版权可能需版权方额外授权,请谨慎使用。
网站提供的党政主题相关内容(国旗、国徽、党徽..)目的在于配合国家政策宣传,仅限个人学习分享使用,禁止用于任何广告和商用目的。