TOLTERODINE TARTRATE tablet, film coated

United States - English - NLM (National Library of Medicine)

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Active ingredient:
TOLTERODINE TARTRATE (UNII: 5T619TQR3R) (TOLTERODINE - UNII:WHE7A56U7K)
Available from:
Proficient Rx LP
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Tolterodine tablets are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. Tolterodine tablets are contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Tolterodine tablets are also contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients, or to fesoterodine fumarate extended-release tablets which, like tolterodine tablets, are metabolized to 5-hydroxymethyl tolterodine.
Product summary:
Tolterodine Tartrate Tablets, 1 mg, are available as white, round, unscored, biconvex, film-coated tablets, debossed with “93” on one side and “0010” on the other side containing 1 mg tolterodine tartrate, packaged in bottles of 30 (NDC 71205-319-30), 60 (NDC 71205-319-60) and 90 (NDC 71205-319-90) tablets. PHARMACIST: Dispense in a tight container as defined in the USP, with a child-resistant closure (as required). Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature]. KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. Manufactured In India By: Cipla Ltd. Goa, India Manufactured For: TEVA PHARMACEUTICALS USA, INC. North Wales, PA 19454 Rev. D 4/2015
Authorization status:
Abbreviated New Drug Application
Authorization number:
71205-319-30, 71205-319-60, 71205-319-90

TOLTERODINE TARTRATE- tolterodine tartrate tablet, film coated

Proficient Rx LP

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TOLTERODINE TARTRATE TABLETS

DESCRIPTION

This product contains 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). It has the following

structural formula:

H NO M.W. 475.6

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.

Each tolterodine tartrate tablet, for oral administration, contains 1 mg or 2 mg of tolterodine tartrate. In

addition, each tablet contains the following inactive ingredients: corn starch, croscarmellose sodium,

hypromellose, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, sodium stearyl

fumarate, 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

Abs orption

In a study with

C-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 (C

) typically occur within 1 to 2 hours after dose administration.

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.

Dis tribution

Tolterodine is highly bound to plasma proteins, primarily α -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%. 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.

Metabolis m

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

C-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) t

(h) C

(mcg/L) C

(mcg/L) t

(h) CL/F(L/h) t

(h) C

(mcg/L) C

(mcg/L) t

(h)

Single-dose

EM

1.6±1.5

1.6±1.2

0.50±0.35

2±0.7

534±697 1.8±1.4

1.8±0.7

0.62±0.26

3.1±0.7

PM

1.4±0.5

10±4.9

8.3±4.3

6.5±1.6

17±7.3

Multiple-dose

EM

1.2±0.5

2.6±2.8

0.58±0.54

2.2±0.4 415±377

1.2±0.5

2.4±1.3

0.92±0.46

2.9±0.4

PM

1.9±1

19±7.5

12±5.1

9.6±1.5

11±4.2

= Maximum plasma concentration; t

= Time of occurrence of C

= Average plasma concentration; t

= Terminal elimination half-life; CL/F = Apparent oral

clearance.

EM = Extensive metabolizers; PM = Poor metabolizers.

Pharmacokinetics in Special Populations

Parameter was dose-normalized from 4 mg to 2 mg.

= not applicable

max

max

avg

1/2

max

max

avg

1/2

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 C

of tolterodine (1.6 mcg/L in males versus 2.2 mcg/L in females) and

the active 5-hydroxymethyl metabolite (2.2 mcg/L in males versus 2.5 mcg/L in females) are similar in

males and females who were administered tolterodine immediate-release 2 mg. Mean AUC values of

tolterodine (6.7 mcgh/L in males versus 7.8 mcgh/L in females) and the 5-hydroxymethyl metabolite

(10 mcgh/L in males versus 11 mcgh/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 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 to 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 to 30 fold) in

renally impaired patients as compared to the healthy volunteers. The recommended dosage for patients

with significantly reduced renal function is tolterodine 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 ± 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 tolterodine 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 C

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 tolterodine

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 C

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 mcg/levonorgestrel 150 mcg) 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 to 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 (T

) 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 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 T

(Relative to Placebo)

Drug/Dos e

N

QTcF

(ms ec)

QTcF

(ms ec)

QTcP

(ms ec)

QTcP

(ms ec)

max

(manual)

(machine)

(manual)

(machine)

Tolterodine

2 mg BID

5.01

(0.28, 9.74)

1.16

(-2.99, 5.30)

4.45

(-0.37, 9.26)

(-1.81, 5.81)

Tolterodine

4 mg BID

11.84

(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

19.26

(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 postmarketing experience with

tolterodine tablets or tolterodine extended-release capsules (see PRECAUTIONS, Patients with

Congenital or Acquired QT Prolongation).

CLINICAL STUDIES

Tolterodine 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 tolterodine 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:

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 Tolterodine (2 mg BID) and

Placebo for the Mean Change at Week 12 From Baseline in Study 007

Tolterodine(SD) N = 514

Placebo(SD) N =

508

Difference(95%

CI)

Number of Incontinence

Episodes per Week

Mean baseline

23.2

23.3

Mean change from baseline

-10.6 (17)

-6.9 (15)

-3.7 (-5.7, -1.6)

Number of Micturitions per 24

Hours

Mean baseline

11.1

11.3

Mean change from baseline

-1.7 (3.3)

-1.2 (2.9)

-0.5 (-0.9, -0.1)

Volume Voided per

Micturition (mL)

Mean baseline

At T

of 1 hr; 95% Confidence Interval

At T

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.

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)

Mean change from baseline

29 (47)

14 (41)

15 (9, 21)

SD = Standard Deviation

Table 4: 95% Confidence Intervals (CI) for the Difference Between Tolterodine (2 mg BID) and

Placebo for the Mean Change at Week 12 From Baseline in Studies 008, 009, 010

Study

Tolterodine(SD)

Placebo(SD)

Difference (95% CI)

Number of Incontinence Episodes per 24 Hours

Number of patients

Mean baseline

Mean change from baseline

-1.3 (3.2)

-0.9 (1.5)

0.5 (-1.3, 0.3)

Number of patients

Mean baseline

Mean change from baseline

-1.7 (2.5)

-1.3 (2.5)

-0.4 (-1, 0.2)

Number of patients

Mean baseline

Mean change from baseline

-1.6 (2.4)

-1.1 (2.1)

-0.5 (-1.1, 0.1)

Number of Micturitions per 24 Hours

Number of patients

Mean baseline

11.5

11.7

Mean change from baseline

-2.7 (3.8)

-1.6 (3.6)

-1.2 (-2, -0.4)

Number of patients

Mean baseline

11.2

11.3

Mean change from baseline

-2.3 (2.1)

-1.4 (2.8)

-0.9 (-1.5, -0.3)

Number of patients

Mean baseline

11.6

11.6

Mean change from baseline

-1.7 (2.3)

-1.4 (2.8)

-0.38 (-1.1, 0.3)

Volume Voided per Micturition (mL)

Number of patients

Mean baseline

Mean change from baseline

38 (54)

6 (42)

32 (18, 46)

Number of patients

Mean baseline

Mean change from baseline

36 (50)

10 (47)

26 (14, 38)

Number of patients

Mean baseline

Mean change from baseline

31 (45)

13 (52)

18 (4, 32)

SD = Standard Deviation

INDICATIONS AND USAGE

Tolterodine tablets are indicated for the treatment of overactive bladder with symptoms of urge urinary

incontinence, urgency, and frequency.

CONTRAINDICATIONS

Tolterodine tablets are contraindicated in patients with urinary retention, gastric retention, or

uncontrolled narrow-angle glaucoma. Tolterodine tablets are also contraindicated in patients who have

demonstrated hypersensitivity to the drug or its ingredients, or to fesoterodine fumarate extended-

release tablets which, like tolterodine tablets, are metabolized to 5-hydroxymethyl tolterodine.

WARNINGS

Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred

with the first or subsequent doses of tolterodine tablets. In the event of difficulty in breathing, upper

airway obstruction, or fall in blood pressure, tolterodine tablets should be discontinued and appropriate

The difference between tolterodine and placebo was statistically significant

The difference between tolterodine and placebo was statistically significant.

therapy promptly provided.

PRECAUTIONS

General

Risk of Urinary Retention and Gastric Retention

Tolterodine 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

Tolterodine, like other antimuscarinic drugs, should be used with caution in patients with decreased

gastrointestinal motility.

Controlled Narrow-Angle Glaucoma

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

Central Nervous System (CNS) Effects

Tolterodine tablets are 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

tolterodine is 1 mg twice daily (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special

Populations ).

Myasthenia Gravis

Tolterodine 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 (PMs) 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 tolterodine 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 postmarketing experience with tolterodine tablets or tolterodine extended-

release capsules.

Information for Patients

Patients should be informed that antimuscarinic agents such as tolterodine may produce the following

effects: blurred vision, dizziness, or drowsiness. Patients should be advised to exercise caution in

decisions to engage in potentially dangerous activities until the drug's effects have been determined.

Drug Interactions

CYP3A4 Inhibitors

Ketoconazole, an inhibitor of the drug-metabolizing enzyme CYP3A4, significantly increased plasma

concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see

CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For

patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (e.g.,

itraconazole, miconazole) or macrolide antibiotics (e.g., erythromycin, clarithromycin) or cyclosporine

or vinblastine, the recommended dose of tolterodine is 1 mg twice daily (see DOSAGE AND

ADMINISTRATION).

Drug-Laboratory Test Interactions

Interactions between tolterodine and laboratory tests have not been studied.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with tolterodine were conducted in mice and rats. At the maximum tolerated

dose in mice (30 mg/kg/day), female rats (20 mg/kg/day), and male rats (30 mg/kg/day), AUC values

obtained for tolterodine were 355, 291, and 462 mcgh/L, respectively. In comparison, the human AUC

value for a 2 mg dose administered twice daily is estimated at 34 mcgh/L. Thus, tolterodine exposure

in the carcinogenicity studies was 9 to 14 fold higher than expected in humans. No increase in tumors

was found in either mice or rats.

No mutagenic effects of tolterodine were detected in a battery of in vitro tests, including bacterial

mutation assays (Ames test) in 4 strains of Salmonella typhimurium and in 2 strains of Escherichia coli, a

gene mutation assay in L5178Y mouse lymphoma cells, and chromosomal aberration tests in human

lymphocytes. Tolterodine was also negative in vivo in the bone marrow micronucleus test in the mouse.

In female mice treated for 2 weeks before mating and during gestation with 20 mg/kg/day

(corresponding to AUC value of about 500 mcgh/L), neither effects on reproductive performance or

fertility were seen. Based on AUC values, the systemic exposure was about 15 fold higher in animals

than in humans. In male mice, a dose of 30 mg/kg/day did not induce any adverse effects on fertility.

Pregnancy

Teratogenic Effects

Pregnancy Category C

At oral doses of 20 mg/kg/day (approximately 14 times the human exposure), no anomalies or

malformations were observed in mice. When given at doses of 30 to 40 mg/kg/day, tolterodine has been

shown to be embryolethal, reduce fetal weight, and increase the incidence of fetal abnormalities (cleft

palate, digital abnormalities, intra-abdominal hemorrhage, and various skeletal abnormalities, primarily

reduced ossification) in mice. At these doses, the AUC values were about 20 to 25 fold higher than in

humans. Rabbits treated subcutaneously at a dose of 0.8 mg/kg/day achieved an AUC of 100 mcgh/L,

which is about 3 fold higher than that resulting from the human dose. This dose did not result in any

embryotoxicity or teratogenicity. There are no studies of tolterodine in pregnant women. Therefore,

tolterodine should be used during pregnancy only if the potential benefit for the mother justifies the

potential risk to the fetus.

Nursing Mothers

Tolterodine is excreted into the milk in mice. Offspring of female mice treated with tolterodine 20

mg/kg/day during the lactation period had slightly reduced body weight gain. The offspring regained

the weight during the maturation phase. It is not known whether tolterodine is excreted in human milk;

therefore, tolterodine should not be administered during nursing. A decision should be made whether to

discontinue nursing or to discontinue tolterodine in nursing mothers.

Pediatric Use

Efficacy in the pediatric population has not been demonstrated.

Two pediatric phase 3 randomized, placebo-controlled, double-blind, 12 week studies were conducted

using tolterodine extended-release capsules. A total of 710 pediatric patients (486 on tolterodine

extended-release capsules and 224 on placebo) aged 5 to 10 years with urinary frequency and urge

urinary incontinence were studied. The percentage of patients with urinary tract infections was higher in

patients treated with tolterodine extended-release capsules (6.6%) compared to patients who received

placebo (4.5%). Aggressive, abnormal, and hyperactive behavior and attention disorders occurred in

2.9% of children treated with tolterodine extended-release capsules compared to 0.9% of children

treated with placebo.

Geriatric Use

Of the 1120 patients who were treated in the four Phase 3, 12 week clinical studies of tolterodine, 474

(42%) were 65 to 91 years of age. No overall differences in safety were observed between the older

and younger patients (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special

Populations ).

ADVERSE REACTIONS

The Phase 2 and 3 clinical trial program for tolterodine tablets included 3071 patients who were treated

with tolterodine (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 tolterodine 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 tolterodine 2 mg BID reported adverse events versus 56% of

placebo patients. The most common adverse events reported by patients receiving tolterodine 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 tolterodine 2 mg

BID in the Phase 3 clinical studies, occurring in 34.8% of patients treated with tolterodine and 9.8% of

placebo-treated patients. One percent of patients treated with tolterodine 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 tolterodine 2 mg BID discontinued treatment due to

adverse events versus 6% of placebo patients. The most common adverse events leading to

discontinuation of tolterodine were dizziness and headache.

Three percent of patients treated with tolterodine 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 tolterodine 2 mg BID. Table 5 lists the adverse events reported in 1% or

more of the patients treated with tolterodine 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 Tolterodine Tablets (2 mg BID) in 12 week, Phase 3 Clinical Studies

Body System

Adverse Event

% TolterodineN = 986

% PlaceboN = 683

Autonomic Nervous

Accommodation abnormal

Dry mouth

General

Chest pain

Fatigue

Headache

Influenza-like symptoms

Central/Peripheral

Nervous

Vertigo/dizziness

Gastrointestinal

Abdominal pain

Constipation

Diarrhea

Dyspepsia

Urinary

Dysuria

Skin/Appendages

Dry skin

Musculoskeletal

Arthralgia

Vision

Xerophthalmia

Psychiatric

Somnolence

Metabolic/Nutritional

Weight gain

Resistance Mechanism

Infection

*

in nearest integer

Postmarketing Surveillance

The following events have been reported in association with tolterodine use in worldwide

postmarketing 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 postmarketing experience, the

frequency of events and the role of tolterodine in their causation cannot be reliably determined.

OVERDOSAGE

A 27 month-old child who ingested 5 to 7 tolterodine tablets 2 mg was treated with a suspension of

activated charcoal and was hospitalized overnight with symptoms of dry mouth. The child fully

recovered.

Management of Overdosage

Overdosage with tolterodine can potentially result in severe central anticholinergic effects and should

be treated accordingly.

ECG monitoring is recommended in the event of overdosage. In dogs, changes in the QT interval (slight

prolongation of 10% to 20%) were observed at a suprapharmacologic dose of 4.5 mg/kg, which is

about 68 times higher than the recommended human dose. In clinical trials of normal volunteers and

patients, QT interval prolongation was observed with tolterodine immediate-release at doses up to 8 mg

(4 mg BID) and higher doses were not evaluated (see PRECAUTIONS, Patients With Congenital or

Acquired QT Prolongation).

DOSAGE AND ADMINISTRATION

The initial recommended dose of tolterodine tartrate tablets is 2 mg twice daily. The dose may be

lowered to 1 mg twice daily based on individual response and tolerability. For patients with

significantly reduced hepatic or renal function or who are currently taking drugs that are potent

inhibitors of CYP3A4, the recommended dose of tolterodine tartrate is 1 mg twice daily (see

PRECAUTIONS, General; PRECAUTIONS, Reduced Hepatic and Renal Function, and

PRECAUTIONS, Drug Interactions).

HOW SUPPLIED

Tolterodine Tartrate Tablets, 1 mg, are available as white, round, unscored, biconvex, film-coated

tablets, debossed with “93” on one side and “0010” on the other side containing 1 mg tolterodine

tartrate, packaged in bottles of 30 (NDC 71205-319-30), 60 (NDC 71205-319-60) and 90 (NDC 71205-

319-90) tablets.

PHARMACIST: Dispense in a tight container as defined in the USP, with a child-resistant closure (as

required).

Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature].

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Manufactured In India By:

Cipla Ltd.

Goa, India

Manufactured For:

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. D 4/2015

TOLTERODINE TARTRATE TABLETS

PATIENT INFORMATION

TOLTERODINE (Tol-TER-oh-deen) TARTRATE (TAHR-trat) TABLETS

Read the Patient Information that comes with tolterodine tartrate tablets before you start using

them 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 tolterodine tartrate tablets is right for you.

What are tolterodine tartrate tablets?

Tolterodine tartrate tablets are a prescription medicine for adults used to treat the following symptoms

due to a condition called overactive bladder:

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 tolterodine tartrate tablets?

Do not take tolterodine tartrate tablets if you:

What should I tell my doctor before starting tolterodine tartrate tablets?

Before starting tolterodine tartrate tablets, tell your doctor about all of your medical and other

conditions that may affect the use of tolterodine tartrate tablets, including:

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

tolterodine tartrate tablets. Your doctor may use a lower dose of tolterodine tartrate tablets if you are

taking:

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

Urge urinary incontinence: a strong need to urinate with leaking or wetting accidents

Urgency: a strong need to urinate right away

Frequency: urinating often

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 tolterodine tartrate tablets or to any of its ingredients. See the end of this leaflet

for a complete list of ingredients

Are allergic to Toviaz

(fesoterodine fumarate) which contains fesoterodine

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 tolterodine tartrate tablets

could harm your unborn baby.

If you are breastfeeding. It is not known if tolterodine tartrate tablets pass into your breast milk or

if they can harm your baby. Talk to your doctor about the best way to feed your baby if you take

tolterodine tartrate tablets.

Certain medicines for fungus or yeast infections

Certain medicines for bacterial infections

Sandimmune

(cyclosporine) or Velban (vinblastine)

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 tolterodine tartrate tablets?

What should I avoid while taking tolterodine tartrate tablets?

Medicines like tolterodine tartrate tablets can cause blurred vision, dizziness, and drowsiness. Do not

drive, operate machinery, or do other dangerous activities until you know how tolterodine tartrate

tablets affect you.

What are possible side effects of tolterodine tartrate tablets?

Tolterodine tartrate tablets 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 tolterodine tartrate tablets and get emergency medical help right away.

The most common side effects with tolterodine tartrate tablets are:

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 tolterodine tartrate tablets. 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 tolterodine tartrate tablets?

Keep tolterodine tartrate tablets and all medicines out of the reach of children.

General information about tolterodine tartrate tablets

Medicines are sometimes prescribed for conditions that are not mentioned in the Patient Information

leaflet. Only use tolterodine tartrate tablets the way your doctor tells you. Do not give tolterodine

tartrate tablets to other people even if they have the same symptoms you have. They may harm them.

This leaflet summarizes the most important information about tolterodine tartrate tablets. If you would

like more information, talk with your doctor. You can ask your doctor or pharmacist for information

about tolterodine tartrate tablets that is written for health professionals. For more information about

tolterodine tartrate tablets, call Teva Pharmaceuticals Medical Affairs at 1-888-838-2872.

What are the ingredients in tolterodine tartrate tablets?

Active ingredients: tolterodine tartrate

Inactive ingredients: corn starch, croscarmellose sodium, hypromellose, lactose monohydrate,

microcrystalline cellulose, polyethylene glycol, sodium stearyl fumarate, and titanium dioxide.

Manufactured In India By:

Take tolterodine tartrate tablets exactly as your doctor tells you to take them.

Your doctor will tell you how many tolterodine tartrate tablets to take and when to take them.

Do not change your dose unless told to do so by your doctor.

You can take tolterodine tartrate tablets with or without food.

Take tolterodine tartrate tablets at the same times each day.

If you miss a dose of tolterodine tartrate tablets, 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 many tolterodine tartrate tablets, call your doctor, or go to the hospital emergency

room right away.

Dry mouth

Dizziness

Headache

Stomach pain

Constipation

Store tolterodine tartrate tablets at 20º to 25ºC (68º to 77ºF).

Keep them in a dry place.

Cipla Ltd.

Goa, India

Manufactured For:

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Repackaged by:

Proficient Rx LP

Thousand Oaks, CA 91320

Rev. B 4/2015

All brand names listed are the registered trademarks of their respective owners and are not trademarks

of Teva Pharmaceuticals USA.

Package/Label Display Panel

NDC 71205-319-90

Tolterodine Tartrate

Tablets, 1 mg

PHARMACIST: PLEASE DISPENSE

WITH ATTACHED PATIENT

INFORMATION LEAFLET

Rx only

90 TABLETS

TOLTERODINE TARTRATE

tolterodine tartrate tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:7120 5-319 (NDC:0 0 9 3-0 0 10 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

TO LTERO DINE TARTRATE (UNII: 5T6 19 TQR3R) (TOLTERODINE - UNII:WHE7A56 U7K)

TOLTERODINE TARTRATE 1 mg

Proficient Rx LP

Inactive Ingredients

Ingredient Name

Stre ng th

STARCH, CO RN (UNII: O8 232NY3SJ)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

HYPRO MELLO SE 2 9 10 ( 15 MPA.S) (UNII: 36 SFW2JZ0 W)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

PO LYETHYLENE GLYCO L 6 0 0 0 (UNII: 30 IQX730 WE)

SO DIUM STEARYL FUMARATE (UNII: 7CV7WJK4UI)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

ROUND

S iz e

6 mm

Flavor

Imprint Code

9 3;0 0 10

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:7120 5-319 -30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 1/20 19

2

NDC:7120 5-319 -6 0

6 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 1/20 19

3

NDC:7120 5-319 -9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 1/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 770 0 6

11/0 1/20 15

Labeler -

Proficient Rx LP (079196022)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Pro ficient Rx LP

0 79 19 6 0 22

REPACK(7120 5-319 ) , RELABEL(7120 5-319 )

Revised: 10/2019

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