Detrol®

Tolterodine L-tartrate

Anticholinergic--Antispasmodic

Pfizer

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

Detrol Monograph PDF download here.

 

CPS:PIS_m160500

 

 

 

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 is rapidly absorbed, and maximum serum concentrations (C_max) occur within 1 to 2 hours after dose administration. The pharmacokinetics of tolterodine, based on C_max and area under the concentration time curve (AUC) determinations, are dose-proportional over the range of 1 to 4 mg. Food intake does not result in clinically relevant changes in the pharmacokinetic profile.

     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%, 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.

     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 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

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

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: Tolterodine 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: Tolterodine 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, 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, tolterodine 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 tolterodine should be avoided during nursing.

Children

The safety and effectiveness of tolterodine 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 tolterodine greater than 1 mg, twice daily.

Geriatrics

Of the 1120 patients who were treated in the 4, phase III, 12-week clinical studies of tolterodine, 474 (42%) were 65 to 91 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 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 tolterodine 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 vinblatine, should not receive doses of tolterodine greater than 1 mg twice daily.

     Coadministration of diuretics (such as indapamide, hydrochlorothiazide, triamterene, bendroflumethiazide, chlorothiazide, methylchlorothiazide, or furosemide) with tolterodine (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 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 tolterodine may produce blurred vision or dizziness.

 

Adverse Effects

The clinical trial program for tolterodine comprised 2398 patients who were treated with either tolterodine (N=1619), oxybutynin (N=349), or placebo (N=430). No differences in the safety profile of tolterodine were identified based on age, gender, race, or metabolism.

     A total of 1120 patients were treated in 4, phase III, 12-week, controlled clinical studies with either tolterodine 2 mg twice daily (N=474), tolterodine 1 mg twice daily (N=121), oxybutynin 5 mg 3 times daily (N=349), or placebo (N=176). The percentage of patients reporting any adverse event in the 12-week studies was similar for tolterodine 2 mg twice daily (75.5%), tolterodine 1 mg twice daily (74.4%), and placebo (77.8%). The overall incidence rates for these treatment groups were lower than that reported for oxybutynin 5 mg 3 times daily (93.1%); these rates were significantly less for tolterodine 2 mg and placebo compared with oxybutynin (P<0.0001). The incidence of serious adverse events was similar among treatment groups (tolterodine 1 and 2 mg twice daily, 3.7%; oxybutynin 5 mg 3 times daily, 3.7%; placebo, 3.4%).

     Dry mouth was the most frequently reported adverse event across all treatment groups. However, the incidence was significantly less for patients treated with either dose of tolterodine or placebo compared with oxybutynin 5 mg 3 times daily (P=0.001). Dry mouth, constipation, abnormal vision (accommodation abnormalities), urinary retention, and xerophthalmia are all expected side effects of antimuscarinic agents.

      Table 1 lists all adverse events that occurred in ≥ 5% of patients in either of the tolterodine treatment groups in the 12-week studies.

CPS:Detrol_t1Click here for Table 1

Table 1: Detrol

Incidence of Adverse Events that Occurred in ≥% Tolterodine-treated Patients (1 or 2 mg b.i.d.) in the 12-week Controlled Clinical Studies

 

	Placebo		Tolterodine 1 mg b.i.d.		Tolterodine 2 mg b.i.d.			Oxybutynin 5 mg t.i.d.
Number Treated	176		121		474			349
Reported AE n (%)	137	(77.8)	90	(74.4)	358	(75.5)	325	(93.1)
Adverse Event by Body System	n	%	n	%	n	%	n	%
Autonomic Nervous System
Mouth Dry	28	(15.9)	29	(24.0)	187	(39.5)	273	(78.2)
Palpitation	5	(2.8)	8	(6.6)	2	(0.4)	8	(2.3)
General
Headache	13	(7.4)	8	(6.6)	52	(11.0)	24	(6.9)
Fatigue	13	(7.4)	9	(7.4)	32	(6.8)	16	(4.6)
Central/Peripheral Nervous Systems
Vertigo/Dizziness	16	(9.1)	11	(9.1)	42	(8.9)	30	(8.6)
Gastrointestinal
Abdominal Pain	11	(6.3)	7	(5.8)	36	(7.6)	22	(6.3)
Constipation	8	(4.5)	7	(5.8)	31	(6.5)	33	(9.5)
Dyspepsia	3	(1.7)	2	(1.7)	28	(5.9)	39	(11.2)
Diarrhea	11	(6.3)	7	(5.8)	19	(4.0)	18	(5.2)
Respiratory
Upper Respiratory Tract Infection	16	(9.1)	3	(2.5)	28	(5.9)	11	(3.2)
Sinusitis	10	(5.7)	7	(5.8)	5	(1.1)	8	(2.3)
Urinary
Urinary Tract Infection	13	(7.4)	6	(5.0)	26	(5.5)	27	(7.7)

 

 

     Other adverse events observed in patients during the 12-week clinical trials were chest pain (3.4%), somnolence (3.0%), dysuria (2.5%), bronchitis (2.1%), dry skin (1.7%), increased weight (1.3%), and flatulence (1.3%). Adverse events observed in <1% of patients were confusion, gastroesophageal reflux, flushed skin, and allergic reactions. 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 tolterodine that involved a 27-month-old child who ingested 5 to 7 tablets of tolterodine 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 tolterodine 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 is 2 mg twice daily. The dose may be reduced to 1 mg twice daily based on individual response and tolerability. For patients with impaired hepatic function and patients with renal impairment, the recommended dose is 1 mg twice daily (see Precautions).

     Patients treated with potent CYP3A4 inhibitors should not receive doses of tolterodine greater than 1 mg twice daily (see Precautions).

     Administration of tolterodine at the recommended dosage for a minimum of 2 weeks may be required before relief of overactive bladder can be expected/detected. Further improvement is seen after 8 weeks.

     Tolterodine can be taken with food.

 

Supplied

1 mg

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, stearic acid and titanium dioxide. Bottles of 60 and 500.

2 mg

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, stearic acid and titanium dioxide. Bottles of 60 and 500.

     Store at room temperature 15 to 30°C.