Detrol™ LA

Tolterodine L-tartrate

Anticholinergic--Antispasmodic

Pfizer

http://www.pfizer.com/pfizer/main.jsp

Detrol1 Monograph PDF download here.

 

CPS:PIS_m160550

Date of Preparation: September 5, 2003

Date of Revision: July 14, 2004

 

 

Pharmacology

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. 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 (DD 01), which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and DD 01 exhibit a high affinity for muscarinic receptors and have a very weak affinity for α -adrenoreceptors, histamine receptors, neuromuscular junction, and calcium channels.

     Preclinical studies have shown that tolterodine is as active as oxybutynin in inhibiting contractions of the detrusor muscle from the guinea pig; it has a potency similar to that of oxybutynin in inhibiting electrically induced contractions of human detrusor muscle from stable and overactive bladders ex vivo.

     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.

     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. Preclinical studies have shown that DD 01 exhibits a similar antimuscarinic profile to that of tolterodine, and a greater antimuscarinic activity on the bladder relative to the salivary gland in vivo.

     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.

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

 

Pharmacokinetics

Special Populations: 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.

Race: Pharmacokinetic differences due to race have not been identified.

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.

Renal Impairment: 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.

 

Indications

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.

 

Contraindications

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

•  urinary retention,

•  gastric retention,

•  uncontrolled narrow angle glaucoma,

•  known hypersensitivity to the drug or its ingredients.

 

 

Warnings

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).

Controlled Narrow Angle Glaucoma

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

Pregnancy

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, intraabdominal 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.

Lactation

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.

Children

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

 

Precautions

Impaired Hepatic and Renal Function

Patients with impaired hepatic function and patients with renal impairment should not receive doses of DETROL LA (tolterodine L-tartrate extended release capsules) greater than 2 mg daily.

Geriatrics

Of the 1120 patients who were treated in the four, phase III, 12-week clinical studies of tolterodine immediate release tablets, 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.

 

Drug Interactions

Concomitant medication with other drugs that possess antimuscarinic properties may result in more pronounced therapeutic and/or adverse effects. Conversely, the therapeutic effect of tolterodine may be reduced by concomitant administration of muscarinic receptor agonists.

     Fluoxetine, a potent inhibitor of P450 2D6, inhibits significantly the metabolism of tolterodine immediate release tablets in extensive metabolizers. The sum of unbound serum concentrations of tolterodine and the 5-hydroxymethyl derivative (DD 01) is 25% higher when the two drugs are administered concomitantly. No dose adjustment is required.

     The potential effect of DETROL LA on the pharmacokinetics of drugs that are metabolized by P450 2D6 (such as flecainide, vinblastine, carbamazepine, tricyclic antidepressants) has not been formally evaluated.

     Patients treated with ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (e.g., itraconazole, miconazole) or macrolide antibiotics (e.g., erythromycin, clarithromycin) or cyclosporine or vinblastine, should not receive doses of DETROL LA greater than 2 mg daily.

     Coadministration of diuretics (such as indapamide, hydrochlorothiazide, triamterene, bendroflumethiazide, chlorothiazide, methylchlorothiazide, or furosemide) with tolterodine immediate release tablets (2 mg, twice daily) did not cause any adverse ECG effects.

     Clinical drug interaction studies have shown that there are no known interactions between tolterodine immediate release tablets and warfarin or oral contraceptives (ethinyl estradiol/levonorgestrel).

Drug-Laboratory Test Interactions

Interactions between tolterodine and laboratory tests have not been studied.

Information to Be Provided to the Patient

Patients should be informed that antimuscarinic agents such as DETROL LA may produce blurred vision or dizziness.

 

Adverse Effects

In a large randomized, multicenter, double-blind, 12-week study, patients treated with DETROL LA (tolterodine L-tartrate extended release capsules), 4 mg once daily (N=505), tolterodine immediate release tablets, 2 mg twice daily (N=512), or placebo (N=507), were evaluated for safety.

     DETROL LA, 4 mg once daily, was generally well tolerated, with an overall incidence of adverse events comparable to tolterodine immediate release tablets, 2 mg twice daily, and placebo. 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, 30.5% in patients treated with tolterodine immediate release tablets and 7.7% of placebo-treated patients. The overall dry mouth rate for patients taking DETROL LA, in this single pivotal trial, was 23% lower than for tolterodine immediate release tablets (P<0.02) (see Table 1).

CPS:DetrolLA_t1Click here for Table 1

Table 1: DETROL LA

Adverse events considered to be related to treatment with DETROL LA, tolterodine immediate release tablets, versus placebo

 

	DETROL LA   (tolterodine extended release capsules)	Tolterodine immediate release tablets	Placebo
Dry Mouth	23.4%	30.5%	7.7%
Abdominal Pain	3.8%	2.5%	1.6%
Dyspepsia	3.0%	3.1%	1.4%
Dizziness/Vertigo	2.2%	1.8%	1.0%
Fatigue	2.2%	1.2%	0.8%
Sinusitis	1.8%	0.6%	0.6%
Abnormal Vision	1.2%	0.8%	0.4%
Dysuria	1.0%	1.6%	0.2%

 

     Dry mouth, constipation, abnormal vision (accommodation abnormalities), urinary retention, and dry eyes are expected side effects of antimuscarinic agents.

     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, tolterodine immediate release tablets or placebo, discontinued treatment due to adverse events; the most common adverse events associated with discontinuation were dry mouth (1.6%), headache (1.0%), and constipation (0.7%).

      Table 2 lists the adverse events reported in ≥  5% or more of patients treated with DETROL LA, 4 mg once daily, in the 12-week study. The adverse events were reported regardless of causality.

CPS:DetrolLA_t2Click here for Table 2

Table 2: DETROL LA

Incidence (%) of Adverse Events that Occurred in ≥  5% of Patients Treated with DETROL LA and tolterodine immediate release tablets in a 12-week Controlled Clinical Trial

 

	DETROL LA  (tolterodine extended release capsules)  4 mg Once Daily N=505	Placebo  N=507	Tolterodine immediate release tablets 2 mg twice daily  N=512
% Patients Reporting Serious Events	1.4	3.6	2.3
% Patients Discontinuing due to Adverse Events	5.3	6.5	5.4
Dry mouth	23.4	7.7	30.5
Headache	6.3	4.5	3.7
Constipation	5.9	4.3	6.6

 

 

 

 

 

     Other events reported by 1% to < 5% of patients treated with DETROL LA and numerically greater than those reported for patients receiving placebo are listed in order of descending frequency: abdominal pain, dry eyes, urinary tract infection, dyspepsia, upper respiratory tract infection, somnolence, dizziness, fatigue, flatulence, sinusitis, edema, pain, abnormal vision, and dysuria.

     Over 400 patients treated for up to 6 months with DETROL LA, 4 mg once daily, had an overall incidence and adverse event profile similar to those patients treated with DETROL LA for 12 weeks.

     The following events have been reported in association with tolterodine use in clinical practice: anaphylactoid reactions, including angioedema, tachycardia, palpitations, peripheral edema, and hallucinations.

 

Overdose

 

 

Symptoms

The highest dose of tolterodine tartrate given to human volunteers was 12.8 mg as single dose. The most severe adverse events observed were accommodation disturbances and micturition difficulties. One case of overdose has been reported prior to the marketing of the tolterodine immediate release tablets that involved a 27-month-old child who ingested 5 to 7 tablets of tolterodine immediate release 2 mg. He was hospitalized overnight with symptoms of dry mouth and was treated with a suspension of activated charcoal. The child recovered fully.

 

 

Treatment

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.

 

Dosage

The initial recommended dose of DETROL LA (tolterodine L- tartrate extended release capsules) is 4 mg once daily. The dose may be reduced to 2 mg once daily based on individual response and tolerability. However, limited efficacy data is available for DETROL LA 2 mg once daily. For patients with impaired hepatic function and patients with renal impairment, the recommended dose is 2 mg once daily (see Precautions).

     Patients treated with potent CYP3A4 inhibitors should not receive doses of DETROL LA greater than 2 mg once daily (see Precautions).

     DETROL LA can be taken with food. It should be swallowed whole.

 

Supplied

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. Bottles of 30, 90, 100 and 500. Blisters of 30, cartons of 3 cards. Blisters of 100, cartons of 10 cards. Store at room temperature 15 to 30°C. Protect from light.

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