Detrol LA

Drug Interactions

Cytochrome P450 3A4 inhibitors

Drug-Food Interactions

Oral Contraceptives

Drug-Laboratory Test Interactions

Other Drugs Metabolized by P450 2D6

Effects of Other Drugs on DETROL LA

Patient Counselling

Drug-Herb Interactions

Effects of DETROL LA on Other Drugs

Drug-Drug Interactions

Fluoxetine

Drugs Which Prolong the QT/QTc Interval

Diuretics

Warfarin

Overview

Information for the Patient

Detrol LA

Special Handling Instructions

Not applicable.

Dosage and Administration

Dosing Considerations

Recommended Dose and Dosage Adjustment

Administration

Adverse Reactions

Post-Market Adverse Drug Reactions

Cholinesterase Inhibitors

DETROL LA

Less Common Clinical Trial Adverse Drug Reactions (1% to <5%)

DETROL LA

Adverse Events Considered to Be Related to Treatment with DETROL LA, Tolterodine Immediate Release Tablets, Versus Placebo

Indications and Clinical Use

DETROL LA (tolterodine L-tartrate extended release capsules) is indicated for:

• the symptomatic management of patients with an overactive bladder with symptoms of urinary frequency, urgency, or urge incontinence, or any combination of these symptoms (see Warnings and Precautions).

  Overdosage

  Management of Overdosage

  Treatment of overdosage with DETROL LA (tolterodine L-tartrate extended release capsules) should consist of gastric lavage and activated charcoal. Treatments for symptoms are recommended as follows. For severe central anticholinergic effects (hallucinations, severe excitation), an anticholinesterase agent, such as physostigmine, may be used. If excitation and convulsions occur, administer an anticonvulsant, such as diazepam. Patients with respiratory insufficiency should be given respiratory assistance. If respiratory arrest occurs, patients should be given artificial respiration. Patients with tachycardia may be treated with a beta-blocker, and those with urinary retention may be catheterized. Patients with troublesome mydriasis may be placed in a dark room or treated with pilocarpine eye drops, or both. ECG should be monitored. In clinical trials of normal volunteers, QT interval prolongation was observed with tolterodine immediate release at doses of 8 mg (4 mg BID). The risk of torsade de pointes with a QT/QTc-prolonging drug is usually dose-dependent. It is recommended that continuous ECG monitoring may be appropriate in cases of overdose with Detrol (or Detrol LA). Concomitant therapy should be immediately reviewed and stopped if potential for drug-drug interaction and exacerbation of the QT prolongation effect is possible (see Warnings and Precautions, Drug Interactions, Drug-Drug Interactions).

  
  
  

  Dosage Forms, Composition and Packaging

  4 mg

  Each blue extended release capsule, with symbol and “4” printed in white ink, contains: tolterodine L-tartrate 4 mg. Nonmedicinal ingredients: ammonium hydroxide, ethylcellulose, FD&C Blue 2, gelatin, hypromellose, medium chain triglycerides, oleic acid, Opacode White S-1-7085 (shellac glaze, titanium dioxide, ammonium hydroxide, propylene glycol and simethicone), starch and sucrose. Blisters of 30, cartons of 3 cards.

  2 mg

  Each blue-green extended release capsule, with symbol and “2” printed in white ink, contains: tolterodine L-tartrate 2 mg. Nonmedicinal ingredients: ammonium hydroxide, ethylcellulose, FD&C Blue 2, gelatin, hypromellose, medium chain triglycerides, oleic acid, Opacode White S-1-7085 (shellac glaze, titanium dioxide, ammonium hydroxide, propylene glycol and simethicone), starch, sucrose and yellow iron oxide. Blisters of 30, cartons of 3 cards.

  
  
  

  Warnings and Precautions

  Geriatrics (65-93 years of age)

  Of the 1120 patients who were treated in the four, phase III, 12-week clinical studies of DETROL LA, 474 (42%) were 65 to 91 years of age. No overall differences in safety were observed between the older and younger patients.

  
  

  Of the 1526 patients who were treated in the 12-week clinical study comparing DETROL LA and tolterodine immediate release tablets versus placebo, 642 (42%) were 65 to 93 years of age. No overall differences in safety were observed between the older and younger patients (see Warnings and Precautions).

  Special Populations

  
  
  

  Hepatic/Biliary/Pancreatic/Renal

  Patients with impaired hepatic function and patients with renal impairment should not receive doses of DETROL LA greater than 2 mg daily.

  Gastrointestinal and Genitourinary

  
  
  

  Neurologic

  DETROL LA should be used with caution in patients with myasthenia gravis.

  Monitoring and Laboratory Tests

  Monitoring of the QT/QTc interval and/or serum electrolyte levels may be appropriate in high risk patients who are being treated with DETROL LA, such as: patients with known congenital or acquired QT/QTc prolongation or electrolyte disturbances; patients with impaired hepatic or renal function or other comorbid conditions that may increase tolterodine exposure or cause QT/QTc prolongation; patients who are taking drugs that have been associated with QT/QTc prolongation and/or torsade de pointes such as Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, or those taking potent CYP3A4 inhibitors.

  
  

  (See Warnings and Precautions, Cardiovascular, Drug Interactions, Drug-Drug Interactions and Dosage and Administration.)

  
  

  Discontinuation of the drug should be considered if symptoms suggestive of arrhythmia occur or if the QT/QTc interval becomes markedly prolonged.

  Patients with Congenital or Acquired QT Prolongation

  In a clinical QT study, the QT prolonging effect of two times the highest labeled dose of tolterodine (8 mg/per day in divided doses, given as DETROL immediate release tablets) was 50% to 60% less than that of the active control moxifloxacin (400 mg) at its labeled dose. At the recommended therapeutic dose (4 mg daily) of DETROL (tolterodine L-tartrate tablets), the effect was lower. Since the QT prolongation effect is in linear relationship with exposure, any QT effect of DETROL LA (tolterodine L-tartrate extended release capsules) would also be expected to be similarly lower. This study, however, was not designed to make direct statistical comparisons between drugs, tolterodine formulations, or dose levels.

  
  

  The clinical relevance of these findings will depend on individual patient risk factors and susceptibilities present. Particular care should be exercised in patients who are at an increased risk of experiencing torsade de pointes during treatment with QT/QTc-prolonging drugs. This especially holds true in patients with abnormally long baseline QT/QTc intervals or when taking potent CYP3A4 inhibitors (see Drug Interactions, Drug-Drug Interactions and Dosage and Administration).

  
  

  In the general population, the risk factors for torsade de pointes include, but are not limited to, the following: female; elderly (65 years); genetic variants affecting cardiac ion channels or regulatory proteins, especially congenital long QT syndrome; family history of sudden cardiac death at <50 years; cardiac disease (e.g., myocardial ischemia or infarction, congestive heart failure, left ventricular hypertrophy, cardiomyopathy); demonstrated history of arrhythmias (especially ventricular arrhythmias, atrial fibrillation, or recent conversion from atrial fibrillation); bradycardia (<50 beats per minute); acute neurological events (e.g., intracranial or subarachnoid haemorrhage, stroke, intracranial trauma; electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia); nutritional deficits (e.g., eating disorders, extreme diets); diabetes mellitus; autonomic neuropathy; hepatic or renal dysfunction if relevant to the elimination of the drug.

  
  

  Approximately 7% of Caucasians are poor metabolizers of CYP2D6 substrates. A pharmacokinetic/pharmacodynamic model estimated that QTc interval increases in poor metabolizers treated with tolterodine 2 mg BID are comparable to those observed in extensive metabolizers receiving 4 mg BID.

  
  

  Discontinuation of the drug should be considered if symptoms suggestive of arrhythmia occur.

  Controlled Narrow Angle Glaucoma

  DETROL LA should be used with caution in patients being treated for narrow angle glaucoma.

  Ophthalmologic

  
  
  

  Pediatrics

  The safety and effectiveness of DETROL LA in pediatric patients have not been established.

  Pregnant Women

  Studies in mice have shown that at doses of 30 to 40 mg/kg/day, tolterodine caused embryolethality, reduced fetal weight, and increased incidence of fetal abnormalities (cleft palate, digital abnormalities, intra-abdominal hemorrhage, various skeletal abnormalities, primarily reduced ossification in mice). At these doses, AUC values were about 20- to 25-fold higher than in humans. At doses of 20 mg/kg/day (AUC value was about 15-fold higher than in humans), no anomalies or malformations were seen in mice. 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 for the fetus. Women of childbearing potential should be considered for treatment only if using adequate contraception.

  Patients at Risk of Urinary Retention and Gastric Retention

  DETROL LA (tolterodine L-tartrate extended release capsules) should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention, to patients at risk of decreased gastrointestinal motility, and to patients with gastrointestinal obstructive disorders, such as pyloric stenosis, because of the risk of gastric retention (see Contraindications).

  Information to Be Provided to the Patient

  The ability to drive and use machinery may be negatively affected. Patients should be advised to exercise caution.

  Nursing Women

  Tolterodine is excreted into the milk in mice. It is not known whether tolterodine is excreted in human milk. Because many drugs are excreted into human milk, administration of DETROL LA should be avoided during nursing.

  Cardiovascular

  
  
  

  
  
  

  Storage and Stability

  Store at room temperature 15 to 30°C. Protect from light.

  Action and Clinical Pharmacology

  Hepatic Insufficiency

  Subjects with hepatic cirrhosis exhibit higher serum concentrations and longer half-lives of tolterodine and DD 01 compared to young healthy subjects given the same dose.

  Distribution

  Tolterodine is highly bound to plasma proteins, primarily α 1-acid glycoprotein. Unbound concentrations of tolterodine average 3.7%±0.13% over the concentration range achieved in clinical studies. The 5-hydroxymethyl metabolite (DD 01) is not extensively protein bound, with unbound fraction concentrations averaging 36%±4.0%. The blood to serum ratio of tolterodine and DD 01 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.

  Pharmacokinetics

  
  
  

  Age

  No overall differences were observed in safety between older and younger patients on tolterodine immediate release tablets in Phase III, 12 week, controlled clinical studies; and therefore, no dosage adjustment for elderly patients is recommended.

  Special Populations and Conditions

  
  
  

  Absorption

  In a study of ¹⁴C tolterodine in healthy volunteers who received a 5 mg oral dose, at least 77% of the radiolabeled dose was absorbed. Tolterodine immediate release tablets are rapidly absorbed, and maximum serum concentrations (C_max) occur within 1 to 2 hours after dose administration. The pharmacokinetics of tolterodine immediate release tablets, based on C_max and area under the concentration time curve (AUC) determinations, are dose proportional over the range of 1 to 4 mg. Based on the sum of unbound serum concentrations of tolterodine and DD 01, the AUC of tolterodine extended release capsules, 4 mg once daily, is equivalent to tolterodine immediate release tablets, 2 mg twice daily. C_max and C_min levels of the extended release capsule are about 75% and 150% of the immediate release tablet, respectively, with maximum serum concentrations observed 2 to 6 hours after dose administration. Food intake does not result in clinically relevant changes in the pharmacokinetic profile of either the tolterodine immediate release tablets or extended release capsules.

  Mechanism of Action

  Tolterodine L-tartrate, is a competitive muscarinic receptor antagonist, which has been shown to inhibit carbachol-induced contraction of isolated bladder preparations from rats, guinea pigs, and man. Tolterodine L tartrate (henceforth referred to as tolterodine) inhibits contractions of the detrusor muscle from the guinea pig, and electrically induced contractions of human detrusor muscle from stable and overactive bladders ex vivo. Tolterodine is significantly more active in inhibiting acetylcholine-induced urinary bladder contractions than electrically induced salivation in the anesthetized cat.

  Race

  Pharmacokinetic differences due to race have not been identified.

  Excretion

  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 in urine and feces as intact tolterodine; 5% to 14% (<1% in poor metabolizers) was recovered as DD 01 within the first 24 hours. This is consistent with the apparent half life of tolterodine: 1.9 to 3.7 hours. The levels of the serum metabolites other than DD 01 determined in four poor metabolizers and four extensive metabolizers, were comparable for the tolterodine extended release capsule and immediate release tablet.

  Renal Insufficiency

  Potential pharmacologic effects and also the toxicological significance of metabolite levels should be taken into account if exposing subjects with renal impairment (GFR <30 mL/min) to repeated doses of tolterodine.

  Gender

  There are no sex dependent differences in the pharmacokinetic profile of tolterodine or DD 01.

  Metabolism

  Tolterodine is extensively metabolized by the liver following oral dosing, and is converted to DD 01 by the isozyme cytochrome P450 2D6. 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.

  
  

  The potential effect of tolterodine on the pharmacokinetics of other drugs also metabolized by P450 2D6, such as tricyclic antidepressants, some antiarrhythmics and selective serotonin reuptake inhibitors, and neuroleptics has not been formally evaluated.

  
  

  Variability in Metabolism: A subset (about 7%) of the population is devoid of the drug metabolizing isoenzyme cytochrome P450 2D6, the enzyme responsible for the formation of DD 01. The identified pathway of metabolism for these individuals, referred to as “poor metabolizers” (PMs), is dealkylation via cytochrome P450 3A4 to N dealkylated tolterodine. The remainder of the population is referred to as “extensive metabolizers” (EMs). Pharmacokinetic studies revealed that tolterodine is metabolized at a slower rate in PMs than in EMs. Since tolterodine and DD 01 have similar antimuscarinic effects, the net activity of DETROL LA is expected to be similar in EMs and PMs.

  Pharmacodynamics

  Tolterodine has a pronounced effect on bladder function in healthy volunteers. The main effects following a 6.4 mg single dose of tolterodine were an increase in residual urine, reflecting an incomplete emptying of the bladder, and a decrease in detrusor pressure. These findings are consistent with antimuscarinic action on the lower urinary tract.

  
  

  In patients with an overactive bladder who received recommended therapeutic doses of the tolterodine immediate release tablets, urodynamic measurements have shown that tolterodine increased the volume at first contraction and maximum cystometric capacity.

  
  

  Tolterodine is converted to a pharmacologically active 5-hydroxymethyl metabolite (DD 01) by the isozyme cytochrome P450 2D6 (debrisoquine hydroxylase). This metabolite exhibits an antimuscarinic profile similar to that of tolterodine, both in vitro and in vivo. In view of the antimuscarinic activity of DD 01 and pharmacokinetic data from both humans and animals, it has been concluded that this metabolite contributes significantly to the therapeutic effect in extensive metabolizers (see Metabolism).

  
  

  A dose-effect relationship was established in a Phase II study for the tolterodine extended release capsule (002) for mean residual volume per micturition during 12 hours. The dose of the tolterodine extended release capsule that has the same effect as the tolterodine immediate release tablets, 2 mg twice daily, was estimated to be 4.7 mg (3.7 mg after correction for relative exposure to the active moiety). A dose-effect relationship was also observed for the inhibition of salivation.

  
  
  

  Contraindications

  DETROL LA (tolterodine L-tartrate extended release capsules) is contraindicated in patients with:

  
  

  • urinary retention,

    
    

  • gastric retention,

    
    

  • uncontrolled narrow angle glaucoma,

    
    

  • a known hypersensitivity to this drug or to any ingredient in the formulation or component of the container.