- How does this medication work? What will it do for me?
- What form(s) does this medication come in?
- How should I use this medication?
- Who should NOT take this medication?
- What side effects are possible with this medication?
- Are there any other precautions or warnings for this medication?
- What other drugs could interact with this medication?
- Side effects
- Further help
- Before taking tolterodine,
- CLINICAL PHARMACOLOGY
- Pharmacokinetics In Special Populations
- Drug-Drug Interactions
- Cardiac Electrophysiology
- Clinical Studies
- Detrol LA
How does this medication work? What will it do for me?
Tolterodine belongs to a group of medications known as antispasmodics and anticholinergics. It is used to treat people with overactive bladders who have symptoms including frequent urination, urgency, or involuntary loss of urine. Tolterodine helps these symptoms by preventing contractions or spasms of the bladder.
Relief from symptoms may not be seen until about 2 weeks after starting treatment with tolterodine, and more improvement is seen after 8 weeks.
Your doctor may have suggested this medication for conditions other than those listed in these drug information articles. As well, some forms of this medication may not be used for all of the conditions discussed here. If you have not discussed this with your doctor or are not sure why you are taking this medication, speak to your doctor. Do not stop taking this medication without consulting your doctor.
Do not give this medication to anyone else, even if they have the same symptoms as you do. It can be harmful for people to take this medication if their doctor has not prescribed it.
What form(s) does this medication come in?
Each white, round, biconvex, film-coated tablet, engraved with arcs above and below the letters “TO”, contains tolterodine L-tartrate 1 mg. Nonmedicinal ingredients: calcium hydrogen phosphate dihydrate, cellulose microcrystalline, colloidal anhydrous silica, hypromellose, magnesium stearate, sodium starch glycolate (pH 3.0-5.0), stearic acid, and titanium dioxide.
Each white, round, biconvex, film-coated tablet, engraved with arcs above and below the letters “DT”, contains tolterodine L-tartrate 2 mg. Nonmedicinal ingredients: calcium hydrogen phosphate dihydrate, cellulose microcrystalline, colloidal anhydrous silica, hypromellose, magnesium stearate, sodium starch glycolate (pH 3.0-5.0), stearic acid, and titanium dioxide.
How should I use this medication?
The recommended adult starting dose for tolterodine is 2 mg twice daily, with or without food. The dose may be reduced to 1 mg twice daily based on individual response and needs.
For people with reduced liver or kidney function, and people taking certain medications, the recommended dose is 1 mg twice daily. Check with your doctor or pharmacist.
Many things can affect the dose of medication that a person needs, such as body weight, other medical conditions, and other medications. If your doctor has recommended a dose different from the ones listed here, do not change the way that you are using the medication without consulting your doctor.
It is important to take this medication regularly and exactly as prescribed by your doctor. If you miss a dose, take it as soon as possible and continue with your regular schedule. If it is almost time for your next dose, skip the missed dose and continue with your regular dosing schedule. Do not take a double dose to make up for a missed one. If you are not sure what to do after missing a dose, contact your doctor or pharmacist for advice.
Store this medication at room temperature, protect it from light and moisture, and keep it out of the reach of children.
Do not dispose of medications in wastewater (e.g. down the sink or in the toilet) or in household garbage. Ask your pharmacist how to dispose of medications that are no longer needed or have expired.
Who should NOT take this medication?
Tolterodine should not be used by anyone who:
- is allergic to tolterodine or any of the ingredients of the medication
- has gastric retention (stomach obstruction)
- has uncontrolled narrow-angle glaucoma
- has urinary retention
What side effects are possible with this medication?
Many medications can cause side effects. A side effect is an unwanted response to a medication when it is taken in normal doses. Side effects can be mild or severe, temporary or permanent. The side effects listed below are not experienced by everyone who takes this medication. If you are concerned about side effects, discuss the risks and benefits of this medication with your doctor.
The following side effects have been reported by at least 1% of people taking this medication. Many of these side effects can be managed, and some may go away on their own over time.
Contact your doctor if you experience these side effects and they are severe or bothersome. Your pharmacist may be able to advise you on managing side effects.
- abdominal pain
- dry eyes
- dry mouth
- vision changes, including difficulty adjusting to distances
Although most of the side effects listed below don’t happen very often, they could lead to serious problems if you do not check with your doctor or seek medical attention.
Check with your doctor as soon as possible if any of the following side effects occur:
- bloody or cloudy urine
- difficult, burning, or painful urination
- swelling of the lower legs
Stop taking this medication and seek immediate medical attention if any of the following occur:
- chest pain
- symptoms of an abnormal heart rhythm such as dizziness, heart palpitations (fast, pounding or irregular heartbeat), fainting, or seizures
- symptoms of an allergic reaction (such as difficulty breathing, hives, swelling of the fact or throat)
Some people may experience side effects other than those listed. Check with your doctor if you notice any symptom that worries you while you are taking this medication.
Are there any other precautions or warnings for this medication?
Before you being using a medication, be sure to inform your doctor of any medical conditions or allergies you may have, any medications you are taking, whether you are pregnant or breast-feeding, and any other significant facts about your health. These factors may affect how you should use this medication.
Abnormal heart rhythm: This medication may cause or increase the risk for a certain type of abnormal heart rhythm called QT prolongation. Other medications can also increase the risk of QT prolongation when taken together with tolterodine. This abnormal heart rhythm is more likely to occur in women, seniors, and people with certain risk factors such as:
- heart disease
- other heart rhythm problems (such as atrial fibrillation)
- a history of stroke
- a family history of sudden cardiac death
- blood electrolyte disturbances
- abnormally slow heartbeat
- eating disorders
- nerve disorders
If you experience symptoms of an abnormal heart rhythm such as dizziness, heart palpitations (fast, pounding, or irregular heartbeat), fainting, or seizures, stop taking this medication and get immediate medical attention.
Bladder problems: People with conditions that significantly block or obstruct the bladder should be closely monitored by their doctor for urinary retention while taking this medication.
Driving/using machinery: Tolterodine may cause fatigue or blurred vision. Avoid activities requiring mental alertness, such as driving, operating machinery, or performing hazardous work, if the medication affects you in this way. Alcohol and other medications that cause drowsiness may increase the drowsiness caused by tolterodine.
Glaucoma: People who have controlled narrow-angle glaucoma should discuss the benefits and risks of this medication with their doctor. Tolterodine may worsen this condition.
Kidney or liver disease: People with liver disease or kidney disease may be more at risk of experiencing side effects and may require lower doses of this medication.
Stomach problems: People with stomach problems affecting passage and digestion of food should discuss with their doctor how this medication may affect their medical condition, how their medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.
Pregnancy: This medication should not be used during pregnancy unless the benefits outweigh the risks. If you are or may be pregnant, talk to your doctor about the benefits and risks of using this medication. Women who may become pregnant should use adequate contraception (birth control) while taking this medication.
Breast-feeding: It is not known if tolterodine passes into breast milk. If you are a breast-feeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding.
Children: The safety and effectiveness of using this medication have not been established for children.
What other drugs could interact with this medication?
There may be an interaction between tolterodine and any of the following:
If you are taking any of these medications, speak with your doctor or pharmacist. Depending on your specific circumstances, your doctor may want you to:
- stop taking one of the medications,
- change one of the medications to another,
- change how you are taking one or both of the medications, or
- leave everything as is.
An interaction between two medications does not always mean that you must stop taking one of them. In many cases, interactions are intended or are managed by close monitoring. Speak to your doctor about how any drug interactions are being managed or should be managed.
Medications other than those listed above may interact with this medication. Tell your doctor or prescriber about all prescription, over-the-counter (non-prescription), and herbal medications that you are taking. Also tell them about any supplements you take. Since caffeine, alcohol, the nicotine from cigarettes, or street drugs can affect the action of many medications, you should let your prescriber know if you use them.
All material copyright MediResource Inc. 1996 – 2020. Terms and conditions of use. The contents herein are for informational purposes only. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Source: www.medbroadcast.com/drug/getdrug/Detrol
Tolterodine is a medicine used to treat people who have urinary problems such as urinary incontinence or frequency which are caused by an overactive bladder. It works by preventing spasms of the bladder muscle which can help to reduce the episodes of urinary incontinence or reduce the feeling of urgency that bladder spasms can cause.
Tolterodine is not suitable for everyone so it’s important that the person prescribing this medicine knows your full medical history
You may not be suitable for this medication if you:
- are allergic or sensitive to or have had a reaction to any of the ingredients in the medicine
- have a hiatus hernia
- have autonomic neuropathy
- have certain types of gastrointestinal problems
- have kidney problems
- have liver problems
- have mega colon
- have myasthenia gravis
- have narrow angle glaucoma
- have risk factors which affect the heart’s activity such as having certain types of heart problems, metabolic problems, abnormal heart beats or a slow heart rate
- have ulcerative colitis
- have urinary retention or have risk factors for urinary retention
Everyone’s reaction to a medicine is different. You may experience some of the side effects listed below or none at all. If you are having problems with this medicine, it’s important to tell your GP immediately.
Some very common side effects experienced by users of this medication are:
- dry mouth
Common side effects of taking Tolterodine are:
- chest pain
- difficult or painful urination
- dry eyes
- dry skin
- eye or eyesight problems
- feeling dizzy
- oedema of the extremities
- stomach pain
- urinary retention
- weight gain
If you feel unwell or if you have concerns about a side-effect, you will need to seek advice. If you feel very ill, get medical help straight away. Contact your prescriber, pharmacist, nurse or call NHS non-emergency number on 111 (You should use the NHS 111 service if you urgently need medical help or advice but it’s not a life-threatening situation)
Before taking tolterodine,
- tell your doctor and pharmacist if you are allergic to tolterodine, fesoterodine fumarate (Toviaz), any other medications, or any of the ingredients in tolterodine tablets or extended-release capsules. Ask your pharmacist for a list of the ingredients.
- tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: amiodarone (Nexterone, Pacerone); antihistamines; atazanavir (Reyataz, in Evotaz); clarithromycin; cyclosporine (Gengraf, Neoral, Sandimmune); donepezil (Aricept, in Namzaric); erythromycin (E.E.S., Ery-Tab, others); galantamine (Razadyne); itraconazole (Onmel, Sporanox. Tolsura); medications for irritable bowel disease, motion sickness, or Parkinson’s disease; ketoconazole; procainamide; quinidine (in Nuedexta); ritonavir (Norvir, in Kaletra, Technivie, Viekira); rivastigmine (Exelon); saquinavir (Invirase); sotalol (Betapace, Sorine, Sotylize); and vinblastine . Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
- tell your doctor if you have or have ever had glaucoma (increased pressure in the eye that may cause vision loss), urinary retention (inability to empty your bladder completely or at all), or gastric retention (slow emptying of your stomach).Your doctor may tell you not to take tolterodine.
- tell your doctor if you or anyone in your family has or has ever had a prolonged QT interval (a rare heart problem that may cause irregular heartbeat, fainting, or sudden death), or if you have or have ever had bladder problems, stomach or bowel problems including problems with constipation, myasthenia gravis (a disorder of the nervous system that causes muscle weakness), or kidney or liver disease..
- tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking tolterodine, call your doctor.
- you should know that tolterodine may make you dizzy or drowsy, or cause blurred vision or other vision problems. Do not drive a car or operate machinery until you know how this medication affects you.
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.
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. Tolterodine immediate release is rapidly absorbed, and maximum serum concentrations (Cmax) typically occur within 1 to 2 hours after dose administration. Cmax and area under the concentration-time curve (AUC) determined after dosage of tolterodine immediate release are doseproportional 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.
Tolterodine is highly bound to plasma proteins, primarily α1 -acid glycoprotein. Unbound concentrations of tolterodine average 3.7% ± 0.13% over the concentration range achieved in clinical studies. The 5- hydroxymethyl metabolite is not extensively protein bound, with unbound fraction concentrations averaging 36% ± 4.0%. The blood to serum ratio of tolterodine and the 5-hydroxymethyl metabolite averages 0.6 and 0.8, respectively, indicating that these compounds do not distribute extensively into erythrocytes. The volume of distribution of tolterodine following administration of a 1.28 mg intravenous dose is 113 ± 26.7 L.
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.
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
Pharmacokinetics In Special Populations
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).
The pharmacokinetics of tolterodine have not been established in pediatric patients.
The pharmacokinetics of tolterodine immediate release and the 5-hydroxymethyl metabolite are not influenced by gender. Mean Cmax of tolterodine (1.6 μg/L in males versus 2.2 μg/L in females) and the active 5- hydroxymethyl metabolite (2.2 μg/L in males versus 2.5 μg/L in females) are similar in males and females who were administered tolterodine immediate release 2 mg. Mean AUC values of tolterodine (6.7 μg•h/L in males versus 7.8 μg•h/L in females) and the 5-hydroxymethyl metabolite (10 μg•h/L in males versus 11 μg•h/L in females) are also similar. The elimination half-life of tolterodine for both males and females is 2.4 hours, and the half-life of the 5-hydroxymethyl metabolite is 3.0 hours in females and 3.3 hours in males.
Pharmacokinetic differences due to race have not been established.
Renal impairment can significantly alter the disposition of tolterodine immediate release and its metabolites. In a study conducted in patients with creatinine clearance between 10 and 30 mL/min, tolterodine immediate release and the 5-hydroxymethyl metabolite levels were approximately 2-3 fold higher in patients with renal impairment than in healthy volunteers. Exposure levels of other metabolites of tolterodine (e.g., tolterodine acid, N-dealkylated tolterodine acid, N-dealkylated tolterodine, and N-dealkylated hydroxylated tolterodine) were significantly higher (10-30 fold) in renally impaired patients as compared to the healthy volunteers. The recommended dosage for patients with significantly reduced renal function is DETROL 1 mg twice daily (see PRECAUTIONS, General and DOSAGE AND ADMINISTRATION).
Liver impairment can significantly alter the disposition of tolterodine immediate release. In a study conducted in cirrhotic patients, the elimination half-life of tolterodine immediate release was longer in cirrhotic patients (mean, 7.8 hours) than in healthy, young, and elderly volunteers (mean, 2 to 4 hours). The clearance of orally administered tolterodine was substantially lower in cirrhotic patients (1.0 ± 1.7 L/h/kg) than in the healthy volunteers (5.7 ± 3.8 L/h/kg). The recommended dose for patients with significantly reduced hepatic function is DETROL 1 mg twice daily (see PRECAUTIONS, General and DOSAGE AND ADMINISTRATION).
Fluoxetine is a selective serotonin reuptake inhibitor and a potent inhibitor of CYP2D6 activity. In a study to assess the effect of fluoxetine on the pharmacokinetics of tolterodine immediate release and its metabolites, it was observed that fluoxetine significantly inhibited the metabolism of tolterodine immediate release in extensive metabolizers, resulting in a 4.8-fold increase in tolterodine AUC. There was a 52% decrease in Cmax and a 20% decrease in AUC of the 5-hydroxymethyl metabolite. Fluoxetine thus alters the pharmacokinetics in patients who would otherwise be extensive metabolizers of tolterodine immediate release to resemble the pharmacokinetic profile in poor metabolizers. The sums of unbound serum concentrations of tolterodine immediate release and the 5-hydroxymethyl metabolite are only 25% higher during the interaction. No dose adjustment is required when DETROL and fluoxetine are coadministered.
Other Drugs Metabolized By Cytochrome P450 Isoenzymes
Tolterodine immediate release does not cause clinically significant interactions with other drugs metabolized by the major drug metabolizing CYP enzymes. In vivo drug-interaction data show that tolterodine immediate release does not result in clinically relevant inhibition of CYP1A2, 2D6, 2C9, 2C19, or 3A4 as evidenced by lack of influence on the marker drugs caffeine, debrisoquine, S-warfarin, and omeprazole. In vitro data show that tolterodine immediate release is a competitive inhibitor of CYP2D6 at high concentrations (Ki 1.05 μM), while tolterodine immediate release as well as the 5-hydroxymethyl metabolite are devoid of any significant inhibitory potential regarding the other isoenzymes.
The effect of 200 mg daily dose of ketoconazole on the pharmacokinetics of tolterodine immediate release was studied in 8 healthy volunteers, all of whom were poor metabolizers (see Pharmacokinetics, Variability in Metabolism for discussion of poor metabolizers). In the presence of ketoconazole, the mean Cmax and AUC of tolterodine increased by 2 and 2.5 fold, respectively. Based on these findings, other potent CYP3A inhibitors such as other azole antifungals (e.g., itraconazole, miconazole) or macrolide antibiotics (e.g., erythromycin, clarithromycin) or cyclosporine or vinblastine may also lead to increases of tolterodine plasma concentrations (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
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/levonorgestrel 150 μg) as evidenced by the monitoring of ethinyl estradiol and levonorgestrel over a 2-month cycle 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.
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 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 DRUG INTERACTIONS). QT interval was measured over a 12-hour period following dosing, including the time of peak plasma concentration (Tmax) of tolterodine and at steady state (Day 4 of dosing).
Table 2 summarizes the mean change from baseline to steady state in corrected QT interval (QTc) relative to placebo at the time of peak tolterodine (1 hour) and moxifloxacin (2 hour) concentrations. Both Fridericia’s (QTcF) and a population-specific (QTcP) method were used to correct QT interval for heart rate. No single QT correction method is known to be more valid than others. QT interval was measured manually and by machine, and data from both are presented. The mean increase of heart rate associated with a 4 mg/day dose of tolterodine in this study was 2.0 beats/minute and 6.3 beats/minute with 8 mg/day tolterodine. The change in heart rate with moxifloxacin was 0.5 beats/minute.
Table 2: Mean (CI) change in QTc from baseline to steady state (Day 4 of dosing) at Tmax (relative to placebo)
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).
DETROL Tablets were evaluated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency in four randomized, double-blind, placebo-controlled, 12-week studies. A total of 853 patients received DETROL 2 mg twice daily and 685 patients received placebo. The majority of patients were Caucasian (95%) and female (78%), with a mean age of 60 years (range, 19 to 93 years). At study entry, nearly all patients perceived they had urgency and most patients had increased frequency of micturitions and urge incontinence. These characteristics were well balanced across treatment groups for the studies.
The efficacy endpoints for study 007 (see Table 3) included the change from baseline for:
- Number of incontinence episodes per week
- Number of micturitions per 24 hours (averaged over 7 days)
- Volume of urine voided per micturition (averaged over 2 days)
The efficacy endpoints for studies 008, 009, and 010 (see Table 4) were identical to the above endpoints with the exception that the number of incontinence episodes was per 24 hours (averaged over 7 days).
Table 3: 95% Confidence Intervals (CI) for the Difference between DETROL (2 mg bid) and Placebo for the Mean Change at Week 12 from Baseline in Study 007
Table 4: 95% Confidence Intervals (CI) for the Difference between DETROL (2 mg bid) and Placebo for the Mean Change at Week 12 from Baseline in Studies 008, 009, 010
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.
Clinical Trials Experience
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
|Body System||Adverse Event||% DETROL LA
|Autonomic Nervous||dry mouth||23||8|
|*in nearest integer.|
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 .
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 post-marketing experience, the frequency of events and the role of tolterodine in their causation cannot be reliably determined.
Read the entire FDA prescribing information for Detrol LA (Tolterodine Tartrate)