Detrol La Information
Detrol la (Tolterodine l-tartrate) Indications And Usage
Detrol la (Tolterodine l-tartrate) Capsules is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency [see ].
Detrol la (Tolterodine l-tartrate) Dosage Forms And Strengths
The 2 mg capsules are blue-green with symbol and 2 printed in white ink.
The 4 mg capsules are blue with symbol and 4 printed in white ink.
Detrol la (Tolterodine l-tartrate) Contraindications
Detrol la (Tolterodine l-tartrate) is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Detrol la (Tolterodine l-tartrate) is also contraindicated in patients with known hypersensitivity to the drug or its ingredients, or to fesoterodine fumarate extended-release tablets which, like Detrol la (Tolterodine l-tartrate) , are metabolized to 5-hydroxymethyl tolterodine [
Detrol la (Tolterodine l-tartrate) Warnings And Precautions
Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with the first or subsequent doses of Detrol la (Tolterodine l-tartrate) . In the event of difficulty in breathing, upper airway obstruction, or fall in blood pressure, Detrol la (Tolterodine l-tartrate) should be discontinued and appropriate therapy promptly provided.
Administer Detrol la (Tolterodine l-tartrate) with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention.
Detrol la (Tolterodine l-tartrate) , like other antimuscarinic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions associated with decreased gastrointestinal motility (e.g., intestinal atony) [see ].
In a study of the effect of tolterodine immediate release tablets on the QT interval [], 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 la (Tolterodine l-tartrate) to patients with a known history of QT prolongation or to patients who are taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications. There has been no association of Torsade de Pointes in the international post-marketing experience with DETROL or Detrol la (Tolterodine l-tartrate) .
Detrol la (Tolterodine l-tartrate) Adverse Reactions
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 efficacy and safety of Detrol la (Tolterodine l-tartrate) Capsules was evaluated in 1073 patients (537 assigned to Detrol la (Tolterodine l-tartrate) ; 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 (Tolterodine l-tartrate) 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 (Tolterodine l-tartrate) and in 49% (n=247) of patients receiving placebo. The most common adverse events reported by patients receiving Detrol la (Tolterodine l-tartrate) were dry mouth, headache, constipation, and abdominal pain. Dry mouth was the most frequently reported adverse event for patients treated with Detrol la (Tolterodine l-tartrate) , occurring in 23.4% of patients treated with Detrol la (Tolterodine l-tartrate) 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 (Tolterodine l-tartrate) 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, double-blind, 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 (Tolterodine l-tartrate) 4 mg once daily.
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 l-tartrate) 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 (Tolterodine l-tartrate) [n=12 (2.4%) vs. placebo n=6 (1.2%)].
The following events have been reported in association with tolterodine use in worldwide post-marketing experience:
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.
Detrol la (Tolterodine l-tartrate) Drug Interactions
Ketoconazole (200 mg daily), a potent CYP3A4 inhibitor, increased the mean Cand AUC of tolterodine by 2- and 2.5-fold, respectively, in CYP2D6 poor metabolizers.
For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as itraconazole, clarithromycin, or ritonavir, the recommended dose of Detrol la (Tolterodine l-tartrate) is 2 mg once daily [ ].
In vivo
[see ].
Detrol la (Tolterodine l-tartrate) Use In Specific Populations
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 la (Tolterodine l-tartrate) should not be administered during nursing. A decision should be made whether to discontinue nursing or to discontinue Detrol la (Tolterodine l-tartrate) in nursing mothers.
Efficacy in the pediatric population has not been demonstrated.
The pharmacokinetics of tolterodine extended release capsules have been evaluated in pediatric patients ranging in age from 11–15 years. The dose-plasma concentration relationship was linear over the range of doses assessed. Parent/metabolite ratios differed according to CYP2D6 metabolizer status [ ]. CYP2D6 extensive metabolizers had low serum concentrations of tolterodine and high concentrations of the active metabolite 5-HMT, while poor metabolizers had high concentrations of tolterodine and negligible active metabolite concentrations.
A total of 710 pediatric patients (486 on Detrol la (Tolterodine l-tartrate) , 224 on placebo) aged 5–10 with urinary frequency and urge incontinence were studied in two randomized, placebo-controlled, double-blind, 12-week studies. The percentage of patients with urinary tract infections was higher in patients treated with Detrol la (Tolterodine l-tartrate) (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 (Tolterodine l-tartrate) compared to 0.9% of children treated with placebo.
No overall differences in safety were observed between the older and younger patients treated with tolterodine.
In multiple-dose studies in which tolterodine immediate release 4 mg (2 mg bid) was administered, serum concentrations of tolterodine and of 5-HMT were similar in healthy elderly volunteers (aged 64 through 80 years) and healthy young volunteers (aged less than 40 years). In another clinical 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 5-HMT in these elderly volunteers were approximately 20% and 50% higher, respectively, than concentrations reported in young healthy volunteers. However, no overall differences were observed in safety between older and younger patients on tolterodine in the Phase 3, 12-week, controlled clinical studies; therefore, no tolterodine dosage adjustment for elderly patients is recommended.
Detrol la (Tolterodine l-tartrate) Overdosage
Overdosage with Detrol la (Tolterodine l-tartrate) Capsules 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 [].
A 27-month-old child who ingested 5 to 7 tolterodine immediate release 2 mg tablets was treated with a suspension of activated charcoal and was hospitalized overnight with symptoms of dry mouth. The child fully recovered.
Detrol la (Tolterodine l-tartrate) Description
Detrol la (Tolterodine l-tartrate) Capsules contain tolterodine tartrate. The active moiety, tolterodine, is a muscarinic receptor antagonist. The chemical name of tolterodine tartrate is (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine L-hydrogen tartrate. The empirical formula of tolterodine tartrate is CHNO. Its structure is:
Tolterodine tartrate is a white, crystalline powder with a molecular weight of 475.6. The pK 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 la (Tolterodine l-tartrate) 4 mg capsule for oral administration contains 4 mg of tolterodine tartrate. Inactive ingredients are sucrose, starch, hypromellose, ethylcellulose, medium chain triglycerides, oleic acid, gelatin, and FD&C Blue #2.
Detrol la (Tolterodine l-tartrate) 2 mg capsule for oral administration contains 2 mg of tolterodine tartrate, and the following inactive ingredients: sucrose, starch, hypromellose, ethylcellulose, medium chain triglycerides, oleic acid, gelatin, yellow iron oxide, and FD&C Blue #2.
Both the 2 mg and 4 mg capsule strengths are imprinted with a pharmaceutical grade printing ink that contains shellac glaze, titanium dioxide, propylene glycol, and simethicone.
Detrol la (Tolterodine l-tartrate) Clinical Pharmacology
Tolterodine acts as a competitive antagonist of acetylcholine at postganglionic muscarinic receptors. 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 5-hydroxymethyl tolterodine (5-HMT), the major pharmacologically active metabolite. 5-HMT, which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and 5-HMT 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.
Detrol la (Tolterodine l-tartrate) Clinical Studies
Detrol la (Tolterodine l-tartrate) Capsules 2 mg were evaluated in 29 patients in a Phase 2 dose-effect study. Detrol la (Tolterodine l-tartrate) 4 mg was evaluated for the treatment of overactive bladder with symptoms of urge urinary incontinence and frequency in a randomized, placebo-controlled, multicenter, double-blind, Phase 3, 12-week study. A total of 507 patients received Detrol la (Tolterodine l-tartrate) 4 mg once daily in the morning and 508 received placebo. The majority of patients were Caucasian (95%) and female (81%), with a mean age of 61 years (range, 20 to 93 years). In the study, 642 patients (42%) were 65 to 93 years of age. The study included patients known to be responsive to tolterodine immediate release and other anticholinergic medications, however, 47% of patients never received prior pharmacotherapy for overactive bladder. At study entry, 97% of patients had at least 5 urge incontinence episodes per week and 91% of patients had 8 or more micturitions per day.
The primary efficacy assessment was change in mean number of incontinence episodes per week at week 12 from baseline. Secondary efficacy measures included change in mean number of micturitions per day and mean volume voided per micturition at week 12 from baseline.
Patients treated with Detrol la (Tolterodine l-tartrate) experienced a statistically significant decrease in number of urinary incontinence per week from baseline to last assessment (week 12) compared with placebo as well as a decrease in the average daily urinary frequency and an increase in the average urine volume per void.
Mean change from baseline in weekly incontinence episodes, urinary frequency, and volume voided between placebo and Detrol la (Tolterodine l-tartrate) are summarized in Table 4.
Detrol la (Tolterodine l-tartrate) How Supplied/storage And Handling
Detrol la (Tolterodine l-tartrate) Capsules are supplied as follows:
Detrol la (Tolterodine l-tartrate) Patient Counseling Information
See .
LAB-0256-8.0September 2011
Detrol la (Tolterodine l-tartrate)
Detrol la (Tolterodine l-tartrate)
Detrol la (Tolterodine l-tartrate)
Detrol la (Tolterodine l-tartrate)
