Detrol la

Overdose

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.

Detrol LA price

Contraindications

DETROL LA is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. DETROL LA is also contraindicated in patients with known hypersensitivity to the drug or its ingredients, or to fesoterodine fumarate extended-release tablets which, like DETROL LA, are metabolized to 5-hydroxymethyl tolterodine.

Undesirable effects

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 included 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, doubleblind, 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.

Table 1. Incidence* (%) of Adverse Events Exceeding Placebo Rate and Reported in ≥1% of Patients Treated with DETROL LA (4 mg daily) in a 12- week, Phase 3 Clinical Trial

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 postmarketing experience:

General: anaphylaxis and angioedema; Cardiovascular: tachycardia, palpitations, peripheral edema; Gastrointestinal: diarrhea; 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.

Therapeutic indications

DETROL LA Capsules is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

Pharmacodynamic properties

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.

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 (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 T (relative to placebo)

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.

Pharmacokinetic properties

In a study with 14C-tolterodine solution in healthy volunteers who received a 5 mg oral dose, at least 77% of the radiolabeled dose was absorbed. Cmax and area under the concentration-time curve (AUC) determined after dosage of tolterodine immediate release are dose-proportional over the range of 1 to 4 mg. Based on the sum of unbound serum concentrations of tolterodine and 5-HMT ("active moiety"), the AUC of tolterodine extended release 4 mg daily is equivalent to tolterodine immediate release 4 mg (2 mg bid). Cmax and Cmin levels of tolterodine extended release are about 75% and 150% of tolterodine immediate release, respectively. Maximum serum concentrations of tolterodine extended release are observed 2 to 6 hours after dose administration.

There is no effect of food on the pharmacokinetics of tolterodine extended release.

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. 5-HMT is not extensively protein bound, with unbound fraction concentrations averaging 36% ± 4.0%. The blood to serum ratio of tolterodine and 5-HMT 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.

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 metabolite, 5-HMT. 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 of individuals (approximately 7% of Caucasians and approximately 2% of African Americans) are poor metabolizers for CYP2D6, the enzyme responsible for the formation of 5-HMT from 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 5-HMT.

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 5-HMT.

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).

Table 3. Summary of Mean (±SD) Pharmacokinetic Parameters of Tolterodine Extended Release and its Active Metabolite (5-Hydroxymethyl Tolterodine) in Healthy Volunteers

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Fertility, pregnancy and lactation

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.

Qualitative and quantitative composition

The 2 mg capsules are blue-green with symbol and 2 printed in white ink. Sections or subsections omitted from the full prescribing information are not listed. The 4 mg capsules are blue with symbol and 4 printed in white ink.

DETROL LA Capsules are supplied as follows:

Store at 20°–25°C (68°–77°F); excursions permitted to 15–30°C (59–86°F). Protect from light.

Distributed by: Pharmacia & Upjohn Co, Division of Pfizer Inc, NY, NY 10017. Revised: Aug 2012

Special warnings and precautions for use

Included as part of the "PRECAUTIONS" Section

Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with the first or subsequent doses of DETROL LA. In the event of difficulty in breathing, upper airway obstruction, or fall in blood pressure, DETROL LA should be discontinued and appropriate therapy promptly provided.

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).

Administer DETROL LA with caution in patients being treated for narrow-angle glaucoma.

Detrol LA is associated with anticholinergic central nervous system (CNS) effects including dizziness and somnolence. 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.

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<10 mL/min have not been studied and use of DETROL LA in this population is not recommended.

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.

See FDA-Approved Patient Labeling.

Patients should be informed that antimuscarinic agents such as DETROL LA 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.

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), exposure margins were approximately 6–9 times, 7 times, and 11 times the clinical exposure to the pharmacologically active components of DETROL® LA (based on AUC of tolterodine and its 5-HMT metabolite). At these exposure margins, no increase in tumors was found in either mice or rats.

No mutagenic or genotoxic 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 (about 9–12 times the clinical exposure via AUC), neither effects on reproductive performance or fertility were seen. In male mice, a dose of 30 mg/kg/day did not induce any adverse effects on fertility.

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, Ndealkylated tolterodine acid, N-dealkylated tolterodine, and N-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<10 mL/min have not been studied and use of DETROL LA in this population is not recommended. 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).

The pharmacokinetics of tolterodine immediate release and 5-HMT are not influenced by gender. Mean C of 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 μg·h/L in males versus 7.8 μg·h/L in females) and 5-HMT (10 μg·h/L in males versus 11 μg·h/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.

Dosage (Posology) and method of administration

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<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.

Interaction with other medicinal products and other forms of interaction

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 5- hydroxymethyl tolterodine (5-HMT, the pharmacologically active metabolite of tolterodine). Fluoxetine thus alters the pharmacokinetics in patients who would otherwise be CYP2D6 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 5-HMT are only 25% higher during the interaction. No dose adjustment is required when tolterodine and fluoxetine are coadministered.

The effect of a 200 mg daily dose of ketoconazole on the pharmacokinetics of tolterodine immediate release was studied in 8 healthy volunteers, all of whom were CYP2D6 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 CYP3A4 inhibitors may also lead to increases of tolterodine plasma concentrations.

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.

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.

Tolterodine immediate release 4 mg (2 mg bid) had no effect on the pharmacokinetics of an oral contraceptive (ethinyl estradiol 30 μg/levo-norgestrel 150 μg) as evidenced by the monitoring of ethinyl estradiol and levo-norgestrel over a 2-month period in healthy female volunteers.

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.

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 (K 1.05 μM), while tolterodine immediate release as well as the 5-HMT are devoid of any significant inhibitory potential regarding the other isoenzymes.