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Detrol®
tolterodine tartrate tablets
DESCRIPTION
DETROL Tablets contain tolterodine tartrate. The active moiety, tolterodine, is a muscarinic receptor antagonist. The chemical name of tolterodine tartrate is (R)-2-[3-[bis(1-methylethyl)-amino]1-phenylpropyl]-4-methylphenol [R-(R*,R*)]-2,3dihydroxybutanedioate (1:1) (salt). The empirical formula of tolterodine tartrate is C26H37NO7, and its molecular weight is 475.6. The structural formula of tolterodine tartrate is represented below:
Tolterodine tartrate is a white, crystalline powder. The pKa value is 9.87 and the solubility in water is 12 mg/mL. It is soluble in methanol, slightly soluble in ethanol, and practically insoluble in toluene. The partition coefficient (Log D) between n-octanol and water is 1.83 at pH 7.3.
DETROL Tablets for oral administration contain 1 or 2 mg of tolterodine tartrate. The inactive ingredients are colloidal anhydrous silica, calcium hydrogen phosphate dihydrate, cellulose microcrystalline, hypromellose, magnesium stearate, sodium starch glycolate (pH 3.0 to 5.0), stearic acid, and titanium dioxide.
CLINICAL PHARMACOLOGY
Tolterodine is a competitive muscarinic receptor antagonist. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors.
After oral administration, tolterodine is metabolized in the liver, resulting in the formation of the 5-hydroxymethyl derivative, a major pharmacologically active metabolite. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and the 5-hydroxymethyl metabolite exhibit a high specificity for muscarinic receptors, since both show negligible activity or affinity for other neurotransmitter receptors and other potential cellular targets, such as calcium channels.
Tolterodine has a pronounced effect on bladder function. Effects on urodynamic parameters before and 1 and 5 hours after a single 6.4-mg dose of tolterodine immediate release were determined in healthy volunteers. The main effects of tolterodine at 1 and 5 hours were an increase in residual urine, reflecting an incomplete emptying of the bladder, and a decrease in detrusor pressure. These findings are consistent with an antimuscarinic action on the lower urinary tract.
Pharmacokinetics
Metabolism
Tolterodine is extensively metabolized by the liver following oral dosing. The primary metabolic route involves the oxidation of the 5-methyl group and is mediated by the cytochrome P450 2D6 (CYP2D6) and leads to the formation of a pharmacologically active 5-hydroxymethyl metabolite. Further metabolism leads to formation of the 5-carboxylic acid and N-dealkylated 5-carboxylic acid metabolites, which account for 51%± 14% and 29%± 6.3% of the metabolites recovered in the urine, respectively.
Pharmacokinetics in Special Populations
Drug-Drug Interactions
Cardiac Electrophysiology
The effect of 2 mg BID and 4 mg BID of tolterodine immediate release (IR) on the QT interval was evaluated in a 4-way crossover, double-blind, placebo- and active-controlled (moxifloxacin 400 mg QD) study in healthy male (N=25) and female (N=23) volunteers aged 18–55 years. Study subjects [approximately equal representation of CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs)] completed sequential 4-day periods of dosing with moxifloxacin 400 mg QD, tolterodine 2 mg BID, tolterodine 4 mg BID, and placebo. The 4 mg BID dose of tolterodine IR (two times the highest recommended dose) was chosen because this dose results in tolterodine exposure similar to that observed upon co-administration of tolterodine 2 mg BID with potent CYP3A4 inhibitors in patients who are CYP2D6 poor metabolizers (see PRECAUTIONS, Drug Interactions). QT interval was measured over a 12-hour period following dosing, including the time of peak plasma concentration (Tmax) of tolterodine and at steady state (Day 4 of dosing).
Table 2 summarizes the mean change from baseline to steady state in corrected QT interval (QTc) relative to placebo at the time of peak tolterodine (1 hour) and moxifloxacin (2 hour) concentrations. Both Fridericia's (QTcF) and a population specific (QTcP) method were used to correct QT interval for heart rate. No single QT correction method is known to be more valid than others. QT interval was measured manually and by machine, and data from both are presented. The mean increase of heart rate associated with a 4 mg/day dose of tolterodine in this study was 2.0 beats/minute and 6.3 beats/minute with 8 mg/day tolterodine. The change in heart rate with moxifloxacin was 0.5 beats/minute.
| Drug/Dose | N | QTcF (msec) (manual) | QTcF (msec) (machine) | QTcP (msec) (manual) | QTcP (msec) (machine) |
|---|---|---|---|---|---|
| Tolterodine 2 | 48 | 5.01 | 1.16 | 4.45 | 2.00 |
| mg BID | (0.28, 9.74) | (-2.99, 5.30) | (-0.37, 9.26) | (-1.81, 5.81) | |
| Tolterodine 4 | 48 | 11.84 | 5.63 | 10.31 | 8.34 |
| mg BID | (7.11, 16.58) | (1.48, 9.77) | (5.49, 15.12) | (4.53, 12.15) | |
| Moxifloxacin | 45 | 19.26 | 8.90 | 19.10 | 9.29 |
| 400 mg QD | (15.49, 23.03) | (4.77, 13.03) | (15.32, 22.89) | (5.34, 13.24) |
The reason for the difference between machine and manual read of QT interval is unclear.
The QT effect of tolterodine immediate release tablets appeared greater for 8 mg/day (two times the therapeutic dose) compared to 4 mg/day. The effect of tolterodine 8 mg/day was not as large as that observed after four days of therapeutic dosing with the active control moxifloxacin. However, the confidence intervals overlapped.
Tolterodine's effect on QT interval was found to correlate with plasma concentration of tolterodine. There appeared to be a greater QTc interval increase in CYP2D6 poor metabolizers than in CYP2D6 extensive metabolizers after tolterodine treatment in this study.
This study was not designed to make direct statistical comparisons between drugs or dose levels. There has been no association of Torsade de Pointes in the international post-marketing experience with DETROL or DETROL LA (see PRECAUTIONS, Patients with Congenital or Acquired QT Prolongation.)
CLINICAL STUDIES
DETROL Tablets were evaluated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency in four randomized, double-blind, placebo controlled, 12-week studies. A total of 853 patients received DETROL 2 mg twice daily and 685 patients received placebo. The majority of patients were Caucasian (95%) and female (78%), with a mean age of 60 years (range, 19 to 93 years). At study entry, nearly all patients perceived they had urgency and most patients had increased frequency of micturitions and urge incontinence. These characteristics were well balanced across treatment groups for the studies.
The efficacy endpoints for study 007 (see Table 3) included the change from baseline for:
- Number of incontinence episodes per week
- Number of micturitions per 24 hours (averaged over 7 days)
- Volume of urine voided per micturition (averaged over 2 days)
The efficacy endpoints for studies 008, 009, and 010 (see Table 4) were identical to the above endpoints with the exception that the number of incontinence episodes was per 24 hours (averaged over 7 days).
| DETROL (SD) N=514 | Placebo (SD) N=508 | Difference (95% CI) | |
|---|---|---|---|
| SD = Standard Deviation. | |||
| 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 |
| Volume Voided per Micturition (mL) | |||
| Mean baseline | 137 | 136 | |
| Mean change from baseline | 29 (47) | 14 (41) | 15 |
| Study | DETROL (SD) | Placebo (SD) | Difference (95% CI) | |
|---|---|---|---|---|
| SD = Standard Deviation. | ||||
| Number of Incontinence Episodes per 24 Hours | ||||
| 008 | Number of patients | 93 | 40 | |
| Mean baseline | 2.9 | 3.3 | ||
| Mean change from baseline | -1.3 (3.2) | -0.9 (1.5) | 0.5 (-1.3,0.3) | |
| 009 | Number of patients | 116 | 55 | |
| Mean baseline | 3.6 | 3.5 | ||
| Mean change from baseline | -1.7 (2.5) | -1.3 (2.5) | -0.4 (-1.0,0.2) | |
| 010 | Number of patients | 90 | 50 | |
| Mean baseline | 3.7 | 3.5 | ||
| Mean change from baseline | -1.6 (2.4) | -1.1 (2.1) | -0.5 (-1.1,0.1) | |
| Number of Micturitions per 24 Hours | ||||
| 008 | Number of patients | 118 | 56 | |
| Mean baseline | 11.5 | 11.7 | ||
| Mean change from baseline | -2.7 (3.8) | -1.6 (3.6) | -1.2 | |
| 009 | Number of patients | 128 | 64 | |
| Mean baseline | 11.2 | 11.3 | ||
| Mean change from baseline | -2.3 (2.1) | -1.4 (2.8) | -0.9 | |
| 010 | Number of patients | 108 | 56 | |
| 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) | ||||
| 008 | Number of patients | 118 | 56 | |
| Mean baseline | 166 | 157 | ||
| Mean change from baseline | 38 (54) | 6 (42) | 32 | |
| 009 | Number of patients | 129 | 64 | |
| Mean baseline | 155 | 158 | ||
| Mean change from baseline | 36 (50) | 10 (47) | 26 | |
| 010 | Number of patients | 108 | 56 | |
| Mean baseline | 155 | 160 | ||
| Mean change from baseline | 31 (45) | 13 (52) | 18 | |
INDICATIONS AND USAGE
DETROL Tablets are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.
CONTRAINDICATIONS
DETROL Tablets are contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. DETROL is also contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.
PRECAUTIONS
General
Patients with Congenital or Acquired QT Prolongation
In a study of the effect of tolterodine immediate release tablets on the QT interval (SeeCLINICAL PHARMACOLOGY, Cardiac Electrophysiology), the effect on the QT interval appeared greater for 8 mg/day (two times the therapeutic dose) compared to 4 mg/day and was more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers (EMs). The effect of tolterodine 8 mg/day was not as large as that observed after four days of therapeutic dosing with the active control moxifloxacin. However, the confidence intervals overlapped. These observations should be considered in clinical decisions to prescribe DETROL for patients with a known history of QT prolongation or patients who are taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications (see PRECAUTIONS, Drug Interactions). There has been no association of Torsade de Pointes in the international post-marketing experience with DETROL or DETROL LA.
Information for Patients
Patients should be informed that antimuscarinic agents such as DETROL 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
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 µg∙h/L, respectively. In comparison, the human AUC value for a 2-mg dose administered twice daily is estimated at 34 µg∙h/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 µg∙h/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
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, DETROL should not be administered during nursing. A decision should be made whether to discontinue nursing or to discontinue DETROL 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 (DETROL LA) capsules. A total of 710 pediatric patients (486 on DETROL LA and 224 on placebo) aged 5–10 years with urinary frequency and urge urinary incontinence were studied. The percentage of patients with urinary tract infections was higher in patients treated with 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.
Geriatric Use
Of the 1120 patients who were treated in the four Phase 3, 12-week clinical studies of DETROL, 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 DETROL Tablets included 3071 patients who were treated with DETROL (N=2133) or placebo (N=938). The patients were treated with 1, 2, 4, or 8 mg/day for up to 12 months. No differences in the safety profile of tolterodine were identified based on age, gender, race, or metabolism.
The data described below reflect exposure to DETROL 2 mg bid in 986 patients and to placebo in 683 patients exposed for 12 weeks in five Phase 3, controlled clinical studies. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and approximating rates.
Sixty-six percent of patients receiving DETROL 2 mg bid reported adverse events versus 56% of placebo patients. The most common adverse events reported by patients receiving DETROL were dry mouth, headache, constipation, vertigo/dizziness, and abdominal pain. Dry mouth, constipation, abnormal vision (accommodation abnormalities), urinary retention, and xerophthalmia are expected side effects of antimuscarinic agents.
Dry mouth was the most frequently reported adverse event for patients treated with DETROL 2 mg bid in the Phase 3 clinical studies, occurring in 34.8% of patients treated with DETROL and 9.8% of placebo-treated patients. One percent of patients treated with DETROL discontinued treatment due to dry mouth.
The frequency of discontinuation due to adverse events was highest during the first 4 weeks of treatment. Seven percent of patients treated with DETROL 2 mg bid discontinued treatment due to adverse events versus 6% of placebo patients. The most common adverse events leading to discontinuation of DETROL were dizziness and headache.
Three percent of patients treated with DETROL 2 mg bid reported a serious adverse event versus 4% of placebo patients. Significant ECG changes in QT and QTc have not been demonstrated in clinical-study patients treated with DETROL 2 mg bid. Table 5 uls the adverse events reported in 1% or more of the patients treated with DETROL 2 mg bid in the 12-week studies. The adverse events are reported regardless of causality.
| Body System | Adverse Event | % DETROL N=986 | % Placebo N=683 |
| Autonomic Nervous | accommodation abnormal | 2 | 1 |
| dry mouth | 35 | 10 | |
| General | chest pain | 2 | 1 |
| fatigue | 4 | 3 | |
| headache | 7 | 5 | |
| influenza-like symptoms | 3 | 2 | |
| Central/Peripheral Nervous | vertigo/dizziness | 5 | 3 |
| Gastrointestinal | abdominal pain | 5 | 3 |
| constipation | 7 | 4 | |
| diarrhea | 4 | 3 | |
| dyspepsia | 4 | 1 | |
| Urinary | dysuria | 2 | 1 |
| Skin/Appendages | dry skin | 1 | 0 |
| Musculoskeletal | arthralgia | 2 | 1 |
| Vision | xerophthalmia | 3 | 2 |
| Psychiatric | somnolence | 3 | 2 |
| Metabolic/Nutritional | weight gain | 1 | 0 |
| Resistance Mechanism | infection | 1 | 0 |
Post-marketing Surveillance
The following events have been reported in association with tolterodine use in worldwide post-marketing experience: General: anaphylactoid reactions, including 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 DETROL 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 DETROL 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 DETROL 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 DETROL is 1 mg twice daily (see PRECAUTIONS, General and PRECAUTIONS, Drug Interactions).
HOW SUPPLIED
DETROL Tablets 1 mg (white, round, biconvex, film-coated tablets engraved with arcs above and below the letters "TO") and DETROL Tablets 2 mg (white, round, biconvex, film-coated tablets engraved with arcs above and below the letters "DT") are supplied as follows:
Bottles of 60
1 mg NDC 0009-4541-02
2 mg NDC 0009-4544-02
Bottles of 500
1 mg NDC 0009-4541-03
2 mg NDC 0009-4544-03
Unit Dose Pack of 140
1 mg NDC 0009-4541-01
2 mg NDC 0009-4544-01
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature] (DTL).
Rx only
LAB-0257-7.0
December 2006
PATIENT INFORMATION
DETROL® (DE-trol)
(tolterodine tartrate tablets)
Read the Patient Information that comes with DETROL before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your condition or your treatment. Only your doctor can determine if treatment with DETROL is right for you.
What is DETROL?
DETROL is a prescription medicine for adults used to treat the following symptoms due to a condition called overactive bladder:
- having a strong need to urinate with leaking or wetting accidents (urge urinary incontinence)
- having a strong need to urinate right away (urgency)
- having to urinate often (frequency)
DETROL LA (tolterodine tartrate extended release capsules) did not help the symptoms of overactive bladder when studied in children.
What is overactive bladder?
Overactive bladder happens when you cannot control your bladder muscle. When the muscle contracts too often or cannot be controlled, you get symptoms of overactive bladder, which are leakage of urine (urge urinary incontinence), needing to urinate right away (urgency), and needing to urinate often (frequency).
Who should not take DETROL?
Do not take DETROL if:
- you have trouble emptying your bladder (also called "urinary retention")
- your stomach empties slowly (also called "gastric retention")
- you have an eye problem called "uncontrolled narrow-angle glaucoma"
- you are allergic to DETROL or to any of its ingredients. See the end of this leaflet for a complete ul of ingredients.
What should I tell my doctor before starting DETROL?
Before starting DETROL, tell your doctor about all of your medical conditions, including if you:
- have any stomach or intestinal problems
- have trouble emptying your bladder or you have a weak urine stream
- have an eye problem called narrow-angle glaucoma
- have liver problems
- have kidney problems
- or any family members have a rare heart condition called QT prolongation (long QT syndrome)
- are pregnant or trying to become pregnant. It is not known if DETROL could harm your unborn baby.
- are breastfeeding. It is not known if DETROL passes into your milk and if it can harm your child.
Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Other drugs can affect how your body handles DETROL. Your doctor may use a lower dose of DETROL if you are taking:
- Certain medicines for fungus or yeast infections such as Nizoral® (ketoconazole), Sporanox® (itraconazole), and Monistat® (miconazole)
- Certain medicines for bacteria infections such as Biaxin® (clarithromycin), and erythromycin
- Sandimmune® (cyclosporine) or Velban® (vinblastine)
Know the medicines you take. Keep a ul of them with you to show your doctor or pharmacist each time you get a new medicine.
How should I take DETROL?
- Take DETROL exactly as prescribed. Your doctor will prescribe the dose that is right for you. Do not change your dose unless told to do so by your doctor.
- Take DETROL tablets two times a day.
- DETROL can be taken with or without food.
- Take DETROL the same time each day.
- If you miss a dose of DETROL, begin taking DETROL again the next day. Do not take 2 doses of DETROL in the same day.
- If you took more than your prescribed dose of DETROL, call your doctor, or poison control center, or go to the hospital emergency room.
What are possible side effects of DETROL?
The most common side effects with DETROL are:
- dry mouth
- headache
- dizziness
- constipation
- stomach pain
Medicines like DETROL can cause blurred vision or drowsiness.
Use caution while driving or doing other dangerous activities until you know how DETROL affects you.
These are not all the side effects with DETROL. For a complete ul, ask your doctor or pharmacist.
How do I store DETROL?
- Store DETROL room temperature (59 to 86° F). Keep it in a dry place.
- Keep DETROL and all medicines out of the reach of children.
General Information about DETROL
Medicines are sometimes prescribed for conditions that are not in the patient information leaflet. Only use DETROL the way your doctor tells you. Do not share it with other people even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about DETROL. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about DETROL that is written for health professionals. You can also visit www.DETROL.com on the Internet, or call 1-888-4-DETROL (1-888-433-8765).
What are the ingredients in DETROL?
Active ingredients: tolterodine tartrate
Inactive ingredients: colloidal anhydrous silica, calcium hydrogen phosphate dihydrate, cellulose microcrystalline, hypromellose, magnesium stearate, sodium starch glycolate (pH 3.0 to 5.0), stearic acid, and titanium dioxide.
LAB-0329-2.0
March 2006
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