Urinary antispasmodics
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Detrol Prescribing Information

Drug Detail:Detrol (Tolterodine [ tol-ter-oh-deen ])

Drug Class: Urinary antispasmodics

Contents
Uses Warnings Before Taking Dosage Side effects Interactions

Detrol - 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

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
Tolterodine5-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)
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.
*
Parameter was dose-normalized from 4 mg to 2 mg.
†
= not applicable.
Single-dose
EM1.6±1.51.6±1.20.50±0.352.0±0.7534±6971.8±1.41.8±0.70.62±0.263.1±0.7
PM1.4±0.510±4.98.3±4.36.5±1.617±7.3††††
Multiple-dose
EM1.2±0.52.6±2.80.58±0.542.2±0.4415±3771.2±0.52.4±1.30.92±0.462.9±0.4
PM1.9±1.019±7.512±5.19.6±1.511±4.2††††

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 (e.g., itraconazole, miconazole) or macrolide antibiotics (e.g., 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/DoseNQTcF
(msec)
(manual)		QTcF
(msec)
(machine)		QTcP
(msec)
(manual) 		QTcP
(msec)
(machine)
*
At Tmax of 1 hr; 95% Confidence Interval
†
At Tmax of 2 hr; 90% Confidence Interval
‡
The 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.
Tolterodine
2 mg BID*		485.01
(0.28, 9.74)		1.16
(-2.99, 5.30)		4.45
(-0.37, 9.26)		2.00
(-1.81, 5.81)
Tolterodine
4 mg BID*		4811.84
(7.11, 16.58)		 5.63
(1.48, 9.77)		10.31
(5.49, 15.12)		8.34
(4.53, 12.15)
Moxifloxacin
400 mg QD†		4519.26‡
(15.49, 23.03)		8.90
(4.77, 13.03)		19.10‡
(15.32, 22.89)		9.29
(5.34, 13.24)

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).

Related/similar drugs

oxybutynin, Myrbetriq, solifenacin, tolterodine, mirabegron, Botox, Ditropan

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
(SD)
N=514		Placebo
(SD)
N=508		Difference
(95% CI)
SD = Standard Deviation.
*
The difference between DETROL and placebo was statistically significant.
Number of Incontinence Episodes per Week
Mean baseline23.223.3
Mean change from baseline-10.6 (17)-6.9 (15)-3.7 (-5.7, -1.6)
Number of Micturitions per 24 Hours
Mean baseline11.111.3
Mean change from baseline-1.7 (3.3)-1.2 (2.9)-0.5* (-0.9, -0.1)
Volume Voided per Micturition (mL)
Mean baseline137136
Mean change from baseline29 (47)14 (41)15* (9, 21)
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
StudyDETROL
(SD)		Placebo
(SD) 		Difference
(95% CI)
SD = Standard Deviation.
*
The difference between DETROL and placebo was statistically significant.
Number of Incontinence Episodes per 24 Hours
008Number of patients9340
Mean baseline2.9 3.3
Mean change from baseline-1.3 (3.2) -0.9 (1.5)0.5 (-1.3,0.3)
009Number of patients11655
Mean baseline 3.6 3.5
Mean change from baseline -1.7 (2.5) -1.3 (2.5)-0.4 (-1.0,0.2)
010Number of patients9050
Mean baseline 3.7 3.5
Mean change from baseline-1.6 (2.4)-1.1 (2.1) -0.5 (-1.1,0.1)
Number of Micturitions per 24 Hours
008Number of patients11856
Mean baseline 11.511.7
Mean change from baseline -2.7 (3.8)-1.6 (3.6)-1.2* (-2.0,-0.4)
009Number of patients12864
Mean baseline 11.211.3
Mean change from baseline -2.3 (2.1)-1.4 (2.8)-0.9* (-1.5,-0.3)
010Number of patients10856
Mean baseline 11.611.6
Mean change from baseline -1.7 (2.3)-1.4 (2.8)-0.38 (-1.1,0.3)
Volume Voided per Micturition (mL)
008Number of patients11856
Mean baseline166157
Mean change from baseline38 (54)6 (42)32* (18,46)
009Number of patients12964
Mean baseline155158
Mean change from baseline36 (50)10 (47)26* (14,38)
010Number of patients10856
Mean baseline155160
Mean change from baseline31 (45)13 (52)18* (4,32)

Precautions

General

Risk of Urinary Retention and Gastric Retention

DETROL Tablets should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention and to patients with gastrointestinal obstructive disorders, such as pyloric stenosis, because of the risk of gastric retention (see CONTRAINDICATIONS).

Decreased Gastrointestinal Motility

DETROL, like other antimuscarinic drugs, should be used with caution in patients with decreased gastrointestinal motility.

Controlled Narrow-Angle Glaucoma

DETROL should be used with caution in patients being treated for narrow-angle glaucoma.

Central Nervous System (CNS) Effects

Detrol is associated with anticholinergic central nervous system (CNS) effects including dizziness and somnolence (see Adverse Reactions). Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until the drug's effects have been determined. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

Reduced Hepatic and Renal Function

For patients with significantly reduced hepatic function or renal function, the recommended dose of DETROL is 1 mg twice daily (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations).

Myasthenia Gravis

DETROL should be used with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.

Patients with Congenital or Acquired QT Prolongation

In a study of the effect of tolterodine immediate release tablets on the QT interval (see CLINICAL PHARMACOLOGY, Cardiac Electrophysiology), the effect on the QT interval appeared greater for 8 mg/day (two times the therapeutic dose) compared to 4 mg/day and was more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers (EMs). 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. These observations should be considered in clinical decisions to prescribe DETROL for patients with a known history of QT prolongation or patients who are taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications (see PRECAUTIONS, Drug Interactions). There has been no association of Torsade de Pointes in the international post-marketing experience with DETROL or DETROL LA.

Adverse Reactions/Side Effects

The Phase 2 and 3 clinical trial program for DETROL Tablets included 3071 patients who were treated with DETROL (N=2133) or placebo (N=938). The patients were treated with 1, 2, 4, or 8 mg/day for up to 12 months. No differences in the safety profile of tolterodine were identified based on age, gender, race, or metabolism.

The data described below reflect exposure to DETROL 2 mg bid in 986 patients and to placebo in 683 patients exposed for 12 weeks in five Phase 3, controlled clinical studies. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and approximating rates.

Sixty-six percent of patients receiving DETROL 2 mg bid reported adverse events versus 56% of placebo patients. The most common adverse events reported by patients receiving DETROL were dry mouth, headache, constipation, vertigo/dizziness, and abdominal pain. Dry mouth, constipation, abnormal vision (accommodation abnormalities), urinary retention, and xerophthalmia are expected side effects of antimuscarinic agents.

Dry mouth was the most frequently reported adverse event for patients treated with DETROL 2 mg bid in the Phase 3 clinical studies, occurring in 34.8% of patients treated with DETROL and 9.8% of placebo-treated patients. One percent of patients treated with DETROL discontinued treatment due to dry mouth.

The frequency of discontinuation due to adverse events was highest during the first 4 weeks of treatment. Seven percent of patients treated with DETROL 2 mg bid discontinued treatment due to adverse events versus 6% of placebo patients. The most common adverse events leading to discontinuation of DETROL were dizziness and headache.

Three percent of patients treated with DETROL 2 mg bid reported a serious adverse event versus 4% of placebo patients. Significant ECG changes in QT and QTc have not been demonstrated in clinical-study patients treated with DETROL 2 mg bid. Table 5 lists the adverse events reported in 1% or more of the patients treated with DETROL 2 mg bid in the 12-week studies. The adverse events are reported regardless of causality.

Table 5. Incidence* (%) of Adverse Events Exceeding Placebo Rate and Reported in >1% of Patients Treated with DETROL Tablets (2 mg bid) in 12-week, Phase 3 Clinical Studies
Body SystemAdverse Event% DETROL
N=986 		% Placebo
N=683
*
in nearest integer.
Autonomic Nervousaccommodation abnormal2 1
dry mouth35 10
Generalchest pain2 1
fatigue4 3
headache7 5
influenza-like symptoms3 2
Central/Peripheral Nervousvertigo/dizziness5 3
Gastrointestinalabdominal pain5 3
constipation7 4
diarrhea4 3
dyspepsia4 1
Urinarydysuria2 1
Skin/Appendagesdry skin1 0
Musculoskeletalarthralgia2 1
Visionxerophthalmia3 2
Psychiatricsomnolence3 2
Metabolic/Nutritionalweight gain1 0
Resistance Mechanisminfection1 0

Post-marketing Surveillance

The following events have been reported in association with tolterodine use in worldwide post-marketing experience: General: anaphylaxis and angioedema; Cardiovascular: tachycardia, palpitations, peripheral edema; Central/Peripheral Nervous: confusion, disorientation, memory impairment, hallucinations.

Reports of aggravation of symptoms of dementia (e.g., confusion, disorientation, delusion) have been reported after tolterodine therapy was initiated in patients taking cholinesterase inhibitors for the treatment of dementia.

Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of tolterodine in their causation cannot be reliably determined.

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.

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LAB-0257-11.0
October 2016

PATIENT INFORMATION DETROL® (DE-trol)(tolterodine tartrate tablets)

Read the Patient Information that comes with DETROL before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your condition or your treatment. Only your doctor can determine if treatment with DETROL is right for you.

What is DETROL?

DETROL is a prescription medicine for adults used to treat the following symptoms due to a condition called overactive bladder:

  • Urge urinary incontinence: a strong need to urinate with leaking or wetting accidents
  • Urgency: a strong need to urinate right away
  • Frequency: urinating often

DETROL LA (tolterodine tartrate extended release capsules) did not help the symptoms of overactive bladder when studied in children.

What is overactive bladder?

Overactive bladder happens when you cannot control your bladder muscle. When the muscle contracts too often or cannot be controlled, you get symptoms of overactive bladder, which are leakage of urine (urge urinary incontinence), needing to urinate right away (urgency), and needing to urinate often (frequency).

Who should not take DETROL?

Do not take DETROL if you:

  • Are not able to empty your bladder (urinary retention)
  • Have delayed or slow emptying of your stomach (gastric retention)
  • Have an eye problem called "uncontrolled narrow-angle glaucoma"
  • Are allergic to DETROL or to any of its ingredients. See the end of this leaflet for a complete list of ingredients
  • Are allergic to TOVIAZ which contains fesoterodine.

What should I tell my doctor before starting DETROL?

Before starting DETROL, tell your doctor about all of your medical and other conditions that may affect the use of DETROL, including:

  • Stomach or intestinal problems or problems with constipation
  • Problems emptying your bladder or if you have a weak urine stream
  • Treatment for an eye problem called narrow-angle glaucoma
  • Liver problems
  • Kidney problems
  • A condition called myasthenia gravis
  • If you or any family members have a rare heart condition called QT prolongation (long QT syndrome)
  • If you are pregnant or trying to become pregnant. It is not known if DETROL could harm your unborn baby.
  • If you are breastfeeding. It is not known if DETROL passes into your breast milk or if it can harm your baby. Talk to your doctor about the best way to feed your baby if you take DETROL.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Other medicines can affect how your body handles DETROL. Your doctor may use a lower dose of DETROL if you are taking:

  • Certain medicines for fungus or yeast infections
  • Certain medicines for bacterial infections
  • Sandimmune® (cyclosporine) or Velban® (vinblastine)

Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take. Keep a list of them with you to show your doctor or pharmacist each time you get a new medicine.

How should I take DETROL?

  • Take DETROL exactly as your doctor tells you to take it.
  • Your doctor will tell you how many DETROL Tablets to take and when to take them.
  • Do not change your dose unless told to do so by your doctor.
  • You can take DETROL with or without food.
  • Take DETROL at the same times each day.
  • If you miss a dose of DETROL, just take your next regular dose at your next regular time. Do not try to make up for your missed dose.
  • If you take too much DETROL, call your doctor, or go to the hospital emergency room right away.

What should I avoid while taking DETROL?

Medicines like DETROL can cause blurred vision, dizziness, and drowsiness. Do not drive, operate machinery, or do other dangerous activities until you know how DETROL affects you.

What are possible side effects of DETROL?

DETROL may cause allergic reactions that may be serious. Symptoms of a serious allergic reaction may include swelling of the face, lips, throat or tongue. If you experience these symptoms, you should stop taking DETROL and get emergency medical help right away.

The most common side effects with DETROL are:

  • Dry mouth
  • Dizziness
  • Headache
  • Stomach pain
  • Constipation

Tell your doctor if you have any side effects that bother you or that do not go away.

These are not all the side effects with DETROL. For a complete list, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

How do I store DETROL?

  • Store DETROL at room temperature (59 to 86° F).
  • Keep it in a dry place.

Keep DETROL and all medicines out of the reach of children.

General Information about DETROL

Medicines are sometimes prescribed for conditions that are not mentioned in the patient information leaflet. Only use DETROL the way your doctor tells you. Do not give DETROL to other people even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about DETROL. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about DETROL that is written for health professionals.

What are the ingredients in DETROL?

Active ingredients: tolterodine tartrate

Inactive ingredients: 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.

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.

Logo

LAB-0329-8.0
October 2016

PRINCIPAL DISPLAY PANEL - 1 mg Tablet Blister

Detrol®1mg
tolterodine tartrate tablets
EXP MM/YYYY LOT XXXXXXX

PRINCIPAL DISPLAY PANEL - 1 mg Tablet Blister

PRINCIPAL DISPLAY PANEL - 1 mg Tablet Unit Dose Carton

NDC 0009-4541-01

Pfizer
Detrol®
1 mg
tolterodine tartrate
tablets

For in-institution use only
UNIT DOSE

140 Tablets
Rx only

PRINCIPAL DISPLAY PANEL - 1 mg Tablet Unit Dose Carton

PRINCIPAL DISPLAY PANEL - 2 mg Tablet Bottle Label

Pfizer

NDC 0009-4544-03

Detrol®
tolterodine tartrate
2 mg
tablets

500 Tablets
Rx only

PRINCIPAL DISPLAY PANEL - 2 mg Tablet Bottle Label

PRINCIPAL DISPLAY PANEL - 2 mg Tablet Blister

Detrol®2mg
tolterodine tartrate tablets
EXP MM/YYYY LOT XXXXXXX

PRINCIPAL DISPLAY PANEL - 2 mg Tablet Blister

PRINCIPAL DISPLAY PANEL - 2 mg Tablet Unit Dose Carton

NDC 0009-4544-01

Pfizer
Detrol®
2 mg
tolterodine tartrate
tablets

For in-institution use only
UNIT DOSE

140 Tablets
Rx only

PRINCIPAL DISPLAY PANEL - 2 mg Tablet Unit Dose Carton
DETROL
tolterodine tartrate tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0009-4541
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
TOLTERODINE TARTRATE (UNII: 5T619TQR3R) (TOLTERODINE - UNII:WHE7A56U7K) TOLTERODINE TARTRATE1 mg
Inactive Ingredients
Ingredient NameStrength
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
MAGNESIUM STEARATE (UNII: 70097M6I30)
STEARIC ACID (UNII: 4ELV7Z65AP)
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
Product Characteristics
ColorWHITEScoreno score
ShapeROUNDSize6mm
FlavorImprint CodeTO
Contains
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:0009-4541-0260 in 1 BOTTLE; Type 0: Not a Combination Product03/25/1998
2NDC:0009-4541-03500 in 1 BOTTLE; Type 0: Not a Combination Product03/25/199808/01/2015
3NDC:0009-4541-01140 in 1 CARTON03/25/199805/01/2015
31 in 1 BLISTER PACK; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02077103/25/1998
DETROL
tolterodine tartrate tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0009-4544
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
TOLTERODINE TARTRATE (UNII: 5T619TQR3R) (TOLTERODINE - UNII:WHE7A56U7K) TOLTERODINE TARTRATE2 mg
Inactive Ingredients
Ingredient NameStrength
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
MAGNESIUM STEARATE (UNII: 70097M6I30)
STEARIC ACID (UNII: 4ELV7Z65AP)
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
Product Characteristics
ColorWHITEScoreno score
ShapeROUNDSize6mm
FlavorImprint CodeDT
Contains
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:0009-4544-0260 in 1 BOTTLE; Type 0: Not a Combination Product03/25/1998
2NDC:0009-4544-03500 in 1 BOTTLE; Type 0: Not a Combination Product03/25/199803/11/2017
3NDC:0009-4544-01140 in 1 CARTON03/25/199805/01/2015
31 in 1 BLISTER PACK; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02077103/25/1998
Labeler - Pharmacia & Upjohn Company LLC (618054084)
Registrant - Pfizer Inc (113480771)
Establishment
NameAddressID/FEIBusiness Operations
Pfizer Pharmaceuticals LLC829084545ANALYSIS(0009-4541, 0009-4544) , API MANUFACTURE(0009-4541, 0009-4544)
Establishment
NameAddressID/FEIBusiness Operations
NEOLPHARMA, INC.078709787ANALYSIS(0009-4541, 0009-4544) , LABEL(0009-4541, 0009-4544) , MANUFACTURE(0009-4541, 0009-4544) , PACK(0009-4541, 0009-4544)
Establishment
NameAddressID/FEIBusiness Operations
Pharmacia & Upjohn Company LLC618054084ANALYSIS(0009-4541, 0009-4544) , API MANUFACTURE(0009-4541, 0009-4544) , PACK(0009-4541, 0009-4544)
Establishment
NameAddressID/FEIBusiness Operations
Pfizer Italia S.r.l.458521908ANALYSIS(0009-4541, 0009-4544) , MANUFACTURE(0009-4541, 0009-4544) , PACK(0009-4541, 0009-4544)

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