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Detrol LA
Overview
What is Detrol LA?
DETROL LA Capsules contain tolterodine tartrate. The active moiety, tolterodine,
is a muscarinic receptor antagonist. The chemical name of tolterodine tartrate
is (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine
L-hydrogen tartrate. The empirical formula of tolterodine tartrate is CHNO. Its
structure is:
Tolterodine tartrate is a white, crystalline powder with a molecular weight
of 475.6.. The pK 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 LA 4 mg capsule for oral administration contains 4 mg of tolterodine
tartrate. Inactive ingredients are sucrose, starch, hypromellose,
ethylcellulose, medium chain triglycerides, oleic acid, gelatin, and FD&C
Blue #2.
DETROL LA 2 mg capsule for oral administration contains 2 mg of tolterodine
tartrate, and the following inactive ingredients: sucrose, starch, hypromellose,
ethylcellulose, medium chain triglycerides, oleic acid, gelatin, yellow iron
oxide, and FD&C Blue #2.
Both the 2 mg and 4 mg capsule strengths are imprinted with a pharmaceutical
grade printing ink that contains shellac glaze, titanium dioxide, propylene
glycol, and simethicone.
What does Detrol LA look like?
What are the available doses of Detrol LA?
The 2 mg capsules are blue-green with symbol and 2 printed in
white ink.
The 4 mg capsules are blue with symbol and 4 printed in white ink.
What should I talk to my health care provider before I take Detrol LA?
Pregnancy Category C.
At approximately 9–12 times the clinical exposure to the pharmacologically
active components of DETROL® LA, no anomalies or malformations were observed in
mice (based on the AUC of tolterodine and its 5-HMT metabolite at a dose of 20
mg/kg/day). At 14–18 times the exposure (doses of 30 to 40 mg/kg/day) in mice,
tolterodine has been shown to be embryolethal and reduce fetal weight, and
increase the incidence of fetal abnormalities (cleft palate, digital
abnormalities, intra-abdominal hemorrhage, and various skeletal abnormalities,
primarily reduced ossification). Pregnant rabbits treated subcutaneously at
about 0.3 – 2.5 times the clinical exposure (dose of 0.8 mg/kg/day) did not show
any embryotoxicity or teratogenicity. There are no studies of tolterodine in
pregnant women. Therefore, DETROL LA should be used during pregnancy only if the
potential benefit for the mother justifies the potential risk to the fetus.
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,
DETROL LA should not be administered during nursing. A decision should be made
whether to discontinue nursing or to discontinue DETROL LA in nursing
mothers.
Efficacy in the pediatric population has not been
demonstrated.
The pharmacokinetics of tolterodine extended release capsules have been
evaluated in pediatric patients ranging in age from 11–15 years. The dose-plasma
concentration relationship was linear over the range of doses assessed.
Parent/metabolite ratios differed according to CYP2D6 metabolizer status [
]. CYP2D6 extensive
metabolizers had low serum concentrations of tolterodine and high concentrations
of the active metabolite 5-HMT, while poor metabolizers had high concentrations
of tolterodine and negligible active metabolite concentrations.
A total of 710 pediatric patients (486 on DETROL LA, 224 on placebo) aged
5–10 with urinary frequency and urge incontinence were studied in two
randomized, placebo-controlled, double-blind, 12-week studies. The percentage of
patients with urinary tract infections was higher in patients treated with
DETROL LA (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 DETROL LA compared to 0.9% of children treated with
placebo.
No overall differences in safety were observed between the older
and younger patients treated with tolterodine.
In multiple-dose studies in which tolterodine immediate release 4 mg (2 mg
bid) was administered, serum concentrations of tolterodine and of 5-HMT were
similar in healthy elderly volunteers (aged 64 through 80 years) and healthy
young volunteers (aged less than 40 years). In another clinical 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 5-HMT in
these elderly volunteers were approximately 20% and 50% higher, respectively,
than concentrations reported in young healthy volunteers. However, no overall
differences were observed in safety between older and younger patients on
tolterodine in the Phase 3, 12-week, controlled clinical studies; therefore, no
tolterodine dosage adjustment for elderly patients is recommended.
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 and
5-HMT 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, -dealkylated
tolterodine acid, -dealkylated tolterodine and -dealkylated hydroxy tolterodine) were significantly
higher (10–30 fold) in renally impaired patients as compared to the healthy
volunteers. The recommended dose for patients with severe renal impairment (CCr:
10–30 mL/min) is DETROL LA 2 mg daily. Patients with CCr less than 10 mL/min have not
been studied and use of DETROL LA in this population is not recommended [ and
DETROL LA has not been studied in patients with mild to
moderate renal impairment [CCr 30–80 mL/min].
Liver impairment can significantly alter the disposition of
tolterodine immediate release. In a study of tolterodine immediate release
conducted in cirrhotic patients (Child-Pugh Class A and B), 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 immediate release 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 mild to
moderate hepatic impairment (Child-Pugh Class A or B) is DETROL LA 2 mg once
daily. DETROL LA is not recommended for use in patients with severe hepatic
impairment (Child-Pugh Class C) [and
The pharmacokinetics of tolterodine immediate release and 5-HMT
are not influenced by gender. Mean Cof tolterodine
immediate release (1.6 µg/L in males versus 2.2 µg/L in females) and the active
5-HMT (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 µgh/L in males versus 7.8
µgh/L in females) and 5-HMT (10 µgh/L in males versus 11 µgh/L in
females) are also similar. The elimination half-life of tolterodine immediate
release for both males and females is 2.4 hours, and the half-life of 5-HMT is
3.0 hours in females and 3.3 hours in males.
Pharmacokinetic differences due to race have not been
established.
How should I use Detrol LA?
DETROL LA Capsules is indicated for the treatment of overactive
bladder with symptoms of urge urinary incontinence, urgency, and frequency [see
].
The recommended dose of DETROL LA Capsules is 4 mg once daily
with water and swallowed whole.. The dose may be lowered to 2 mg daily based on
individual response and tolerability; however, limited efficacy data are
available for DETROL LA 2 mg [].
For patients with mild to moderate hepatic impairment (Child-Pugh
Class A or B) or severe renal impairment (CCr 10 – 30 mL/min), the recommended
dose of DETROL LA is 2 mg once daily. DETROL LA is not recommended for use in
patients with severe hepatic impairment (Child-Pugh Class C). Patients with
CCr less than 10 mL/min have not been studied and use of DETROL LA in this population
is not recommended [
For patients who are taking drugs that are potent inhibitors of
CYP3A4 [e.g. ketoconazole, clarithromycin, ritonavir], the recommended dose of
DETROL LA is 2 mg once daily [see
What interacts with Detrol LA?
Sorry No Records found
What are the warnings of Detrol LA?
Sorry No Records found
What are the precautions of Detrol LA?
Sorry No Records found
What are the side effects of Detrol LA?
Sorry No records found
What should I look out for while using Detrol LA?
[.
What might happen if I take too much Detrol LA?
Overdosage with DETROL LA Capsules 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 [].
A 27-month-old child who ingested 5 to 7 tolterodine immediate release 2 mg
tablets was treated with a suspension of activated charcoal and was hospitalized
overnight with symptoms of dry mouth. The child fully recovered.
How should I store and handle Detrol LA?
Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP/NF with a child-resistant closure.A Schedule CIII Narcotic.Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP/NF with a child-resistant closure.A Schedule CIII Narcotic.Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP/NF with a child-resistant closure.A Schedule CIII Narcotic.DETROL LA Capsules are supplied as follows:2 mg Capsules:Bottles of 30 NDC 54868-5126-0Bottles of 90 NDC 54868-5126-14 mg Capsules:Bottles of 30 NDC 54868-4514-0Bottles of 90 NDC 54868-4514-1 Store at 20°–25°C (68°–77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from light.DETROL LA Capsules are supplied as follows:2 mg Capsules:Bottles of 30 NDC 54868-5126-0Bottles of 90 NDC 54868-5126-14 mg Capsules:Bottles of 30 NDC 54868-4514-0Bottles of 90 NDC 54868-4514-1 Store at 20°–25°C (68°–77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from light.DETROL LA Capsules are supplied as follows:2 mg Capsules:Bottles of 30 NDC 54868-5126-0Bottles of 90 NDC 54868-5126-14 mg Capsules:Bottles of 30 NDC 54868-4514-0Bottles of 90 NDC 54868-4514-1 Store at 20°–25°C (68°–77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from light.DETROL LA Capsules are supplied as follows:2 mg Capsules:Bottles of 30 NDC 54868-5126-0Bottles of 90 NDC 54868-5126-14 mg Capsules:Bottles of 30 NDC 54868-4514-0Bottles of 90 NDC 54868-4514-1 Store at 20°–25°C (68°–77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from light.DETROL LA Capsules are supplied as follows:2 mg Capsules:Bottles of 30 NDC 54868-5126-0Bottles of 90 NDC 54868-5126-14 mg Capsules:Bottles of 30 NDC 54868-4514-0Bottles of 90 NDC 54868-4514-1 Store at 20°–25°C (68°–77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from light.DETROL LA Capsules are supplied as follows:2 mg Capsules:Bottles of 30 NDC 54868-5126-0Bottles of 90 NDC 54868-5126-14 mg Capsules:Bottles of 30 NDC 54868-4514-0Bottles of 90 NDC 54868-4514-1 Store at 20°–25°C (68°–77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from light.DETROL LA Capsules are supplied as follows:2 mg Capsules:Bottles of 30 NDC 54868-5126-0Bottles of 90 NDC 54868-5126-14 mg Capsules:Bottles of 30 NDC 54868-4514-0Bottles of 90 NDC 54868-4514-1 Store at 20°–25°C (68°–77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from light.DETROL LA Capsules are supplied as follows:2 mg Capsules:Bottles of 30 NDC 54868-5126-0Bottles of 90 NDC 54868-5126-14 mg Capsules:Bottles of 30 NDC 54868-4514-0Bottles of 90 NDC 54868-4514-1 Store at 20°–25°C (68°–77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from light.
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Tolterodine acts as a competitive antagonist of acetylcholine at
postganglionic muscarinic receptors. 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 5-hydroxymethyl tolterodine (5-HMT), the major
pharmacologically active metabolite. 5-HMT, which exhibits an antimuscarinic
activity similar to that of tolterodine, contributes significantly to the
therapeutic effect. Both tolterodine and 5-HMT 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.
Cardiac
Electrophysiology
The effect of 2 mg BID and 4 mg BID of DETROL immediate release (tolterodine
IR) tablets 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 [
]. 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 (QT) relative to placebo at the time of peak
tolterodine (1 hour) and moxifloxacin (2 hour) concentrations. Both Fridericia's
(QTF) and a population-specific (QTP) 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.
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 QT 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 ].
Absorption:
Effect of Food:
Distribution:
N
Variability in Metabolism:
N
Excretion:
A summary of mean (± standard deviation) pharmacokinetic parameters of
tolterodine extended release and 5-HMT in extensive (EM) and poor (PM)
metabolizers is provided in Table 3. These data were obtained following single
and multiple doses of tolterodine extended release administered daily to 17
healthy male volunteers (13 EM, 4 PM).
Drug
Interactions:
Potent CYP2D6 inhibitors
Potent CYP3A4 inhibitors
For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as
itraconazole, miconazole, clarithromycin, ritonavir, the recommended dose of
DETROL LA is 2 mg daily [
].
Warfarin
Oral Contraceptives
Diuretics
Effect of tolterodine on other drugs
metabolized by Cytochrome P450 enzymes
In vivo
In vitro
Non-Clinical Toxicology
[.Administer DETROL LA Capsules with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention. [].
Administer DETROL LA with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention.
DETROL LA, like other antimuscarinic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions associated with decreased gastrointestinal motility (e.g. intestinal atony) [see ].
Administer DETROL LA with caution in patients being treated for narrow-angle glaucoma [see ].
The clearance of orally administered tolterodine immediate release was substantially lower in cirrhotic patients than in the healthy volunteers. For patients with mild to moderate hepatic impairment (Child-Pugh Class A or B), the recommended dose for DETROL LA is 2 mg once daily. DETROL LA is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C)
Renal impairment can significantly alter the disposition of tolterodine and its metabolites. The dose of DETROL LA should be reduced to 2 mg once daily in patients with severe renal impairment (CCr: 10–30 mL/min). Patients with CCr less than 10 mL/min have not been studied and use of DETROL LA in this population is not recommended [see ].
Administer DETROL LA with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction
In a study of the effect of tolterodine immediate release tablets on the QT interval [] 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 LA to patients with a known history of QT prolongation or to patients who are taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications. There has been no association of Torsade de Pointes in the international post-marketing experience with DETROL or DETROL LA.
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 efficacy and safety of DETROL LA Capsules was evaluated in 1073 patients (537 assigned to DETROL LA; 536 assigned to placebo) who were treated with 2, 4, 6, or 8 mg/day for up to 15 months. These include a total of 1012 patients (505 randomized to DETROL LA 4 mg once daily and 507 randomized to placebo) enrolled in a randomized, placebo-controlled, double-blind, 12-week clinical efficacy and safety study.
Adverse events were reported in 52% (n=263) of patients receiving DETROL LA and in 49% (n=247) of patients receiving placebo. The most common adverse events reported by patients receiving DETROL LA were dry mouth, headache, constipation, and abdominal pain. Dry mouth was the most frequently reported adverse event for patients treated with DETROL LA occurring in 23.4% of patients treated with DETROL LA and 7.7% of placebo-treated patients. Dry mouth, constipation, abnormal vision (accommodation abnormalities), urinary retention, and dry eyes are expected side effects of antimuscarinic agents. A serious adverse event was reported by 1.4% (n=7) of patients receiving DETROL LA and by 3.6% (n=18) of patients receiving placebo.
Table 1 lists the adverse events, regardless of causality, that were reported in the randomized, double-blind, placebo-controlled 12-week study at an incidence greater than placebo and in greater than or equal to 1% of patients treated with DETROL LA 4 mg once daily.
The frequency of discontinuation due to adverse events was highest during the first 4 weeks of treatment. Similar percentages of patients treated with DETROL LA or placebo discontinued treatment due to adverse events. Dry mouth was the most common adverse event leading to treatment discontinuation among patients receiving DETROL LA [n=12 (2.4%) vs. placebo n=6 (1.2%)].
The following events have been reported in association with tolterodine use in worldwide post-marketing experience:
;
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.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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