tolterodine tartrate 4 MG 24 HR Extended Release Oral Capsule
Generic Name: TOLTERODINE TARTRATE
Brand Name: Tolterodine Tartrate Extended Release
- Substance Name(s):
- TOLTERODINE TARTRATE
DRUG INTERACTIONS
7 Potent CYP3A4 Inhibitors: Coadministration may increase systemic exposure to tolterodine tartrate extended – release capsules.
Reduce tolterodine tartrate extended – release capsules dose to 2 mg once daily.
( 7.2 ) Other Anticholinergics (antimuscarinics): Concomitant use with other anticholinergic agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision, and other anticholinergic pharmacological effects.
( 7.6 ) 7.1 Potent CYP2D6 Inhibitors Fluoxetine, a potent inhibitor of CYP2D6 activity, significantly inhibited the metabolism of tolterodine immediate – release in CYP2D6 extensive metabolizers, resulting in a 4.8-fold increase in tolterodine AUC.
There was a 52% decrease in C max and a 20% decrease in AUC of 5-hydroxymethyl tolterodine (5-HMT), the pharmacologically active metabolite of tolterodine [ see CLINICAL PHARMACOLOGY (12.1) ].
The sums of unbound serum concentrations of tolterodine and 5-HMT are only 25% higher during the interaction.
No dose adjustment is required when tolterodine and fluoxetine are co-administered [ see CLINICAL PHARMACOLOGY (12.3) ] .
7.2 Potent CYP3A4 Inhibitors Ketoconazole (200 mg daily), a potent CYP3A4 inhibitor, increased the mean C max and 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 tolterodine tartrate extended – release capsules is 2 mg once daily [ see DOSAGE AND ADMINISTRATION (2.2) and CLINICAL PHARMACOLOGY (12.3) ].
7.3 Other Interactions No clinically relevant interactions have been observed when tolterodine was co-administered with warfarin, with a combined oral contraceptive drug containing ethinyl estradiol and levonorgestrel, or with diuretics [ see CLINICAL PHARMACOLOGY (12.3) ] 7.4 Other Drugs Metabolized by Cytochrome P450 Isoenzymes 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 [ see CLINICAL PHARMACOLOGY (12.3) ] .
7.5 Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied.
7.6 Other Anticholinergics The concomitant use of tolterodine tartrate extended – release capsules with other anticholinergic (antimuscarinic) agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision, somnolence, and other anticholinergic pharmacological effects.
OVERDOSAGE
10 Overdosage with tolterodine tartrate extended – release 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 [ see WARNINGS AND PRECAUTIONS (5.9) and CLINICAL PHARMACOLOGY (12.2) ].
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.
DESCRIPTION
11 Tolterodine tartrate extended – release 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 C 26 H 37 NO 7 .
Its structure is: Tolterodine tartrate is a white, crystalline powder with a molecular weight of 475.6.
The pK a 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.
Tolterodine tartrate extended-release capsules 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.
Tolterodine tartrate extended – release capsules 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.
Chemical Structure
CLINICAL STUDIES
14 Tolterodine tartrate extended – release capsules 2 mg were evaluated in 29 patients in a Phase 2 dose-effect study.
Tolterodine tartrate extended – release capsules 4 mg were 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 tolterodine tartrate extended – release capsules 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 tolterodine tartrate extended – release capsules 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 tolterodine tartrate extended – release capsules are summarized in Table 4.
Table 4.
95% Confidence Intervals (CI) for the Difference between Tolterodine Tartrate Extended-Release Capsules (4 mg daily) and Placebo for Mean Change at Week 12 from Baseline Intent-to-treat analysis.
Tolterodine Tartrate Extended-Release Capsules (n=507) Placebo (n=508) 1 to 2 patients missing in placebo group for each efficacy parameter.
Treatment Difference, vs.
Placebo (95% Cl) SD = Standard Deviation.
Number of incontinence episodes/ week Mean Baseline 22.1 23.3 -4.8 The difference between tolterodine tartrate extended – release capsules and placebo was statistically significant.
Mean Change from Baseline –11.8 (SD 17.8) –6.9 (SD 15.4) (–6.9, –2.8) Number of micturitions/day Mean Baseline 10.9 11.3 -0.6 Mean Change from Baseline –1.8 (SD 3.4) –1.2 (SD 2.9) (–1.0, –0.2) Volume voided per micturition (mL) Mean Baseline 141 136 20 Mean Change from Baseline 34 (SD 51) 14 (SD 41) (14, 26)
HOW SUPPLIED
16 /STORAGE AND HANDLING Tolterodine tartrate extended – release capsules are supplied as follows: Bottles of 30 Bottles of 500 2 mg Capsules NDC 59762-0047-1 2 mg Capsules NDC 59762-0047-3 4 mg Capsules NDC 59762-0048-1 4 mg Capsules NDC 59762-0048-3 Bottles of 90 2 mg Capsules NDC 59762-0047-2 4 mg Capsules NDC 59762-0048-2 Store at 20°–25°C (68°–77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].
Protect from light.
GERIATRIC USE
8.5 Geriatric Use 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.
DOSAGE FORMS AND STRENGTHS
3 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.
Capsules: 2 mg and 4 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action 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.
INDICATIONS AND USAGE
1 Tolterodine tartrate extended-release capsules are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency [ see CLINICAL STUDIES (14) ].
Tolterodine tartrate extended – release capsules are an antimuscarinic indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.
( 1 )
PEDIATRIC USE
8.4 Pediatric Use The effectiveness of tolterodine tartrate extended – release capsules has not been established in pediatric patients.
Efficacy was not established in two randomized, placebo-controlled, double-blind, 12-week studies that enrolled 710 pediatric patients (486 on tolterodine tartrate extended – release capsules, 224 on placebo) aged 5–10 years with urinary frequency and urge incontinence.
The percentage of patients with urinary tract infections was higher in patients treated with tolterodine tartrate extended – release capsules (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 tolterodine tartrate extended – release capsules compared to 0.9% of children treated with placebo.
PREGNANCY
8.1 Pregnancy Risk Summary There are no available data with tolterodine tartrate extended – release capsules use in pregnant women to inform drug-associated risks.
In animal reproduction studies, oral administration of tolterodine and its 5-HMT metabolite to pregnant mice during organogenesis did not produce adverse developmental outcomes at doses approximately 9 to 12 times the clinical exposure at a dose of 20 mg/kg/day; however, higher doses produced adverse developmental outcomes (see Data ) .
In the U.S.
general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Data Animal Data No anomalies or malformations were observed after oral administration of tolterodine to pregnant mice during organogenesis at approximately 9–12 times the clinical exposure to the pharmacologically active components of tolterodine tartrate extended – release capsules (based on the AUC of tolterodine and its 5-HMT metabolite at a dose of 20 mg/kg/day).
At 14–18 times the clinical exposure (doses of 30 to 40 mg/kg/day) in mice, tolterodine was embryo-lethal, caused reduced fetal weight, and increased the incidence of fetal abnormalities (cleft palate, digital abnormalities, intra-abdominal hemorrhage, and various skeletal abnormalities, primarily reduced ossification).
Pregnant rabbits administered tolterodine subcutaneously at about 0.3–2.5 times the clinical exposure (dose of 0.8 mg/kg/day) did not show any embryotoxicity or teratogenicity.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with the first or subsequent doses of tolterodine tartrate extended – release capsules.
( 5.1 ) Urinary Retention: use caution in patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.
( 5.2 ) Gastrointestinal Disorders: use caution in patients with gastrointestinal obstructive disorders or decreased gastrointestinal motility because of the risk of gastric retention.
( 5.3 ) Controlled Narrow-Angle Glaucoma: use caution in patients being treated for narrow-angle glaucoma.
( 5.4 ) Central Nervous System Effects: Somnolence has been reported with tolterodine tartrate extended – release capsules.
Advise patients not to drive or operate heavy machinery until they know how tolterodine tartrate extended – release capsules affect them ( 5.5 ).
Myasthenia Gravis: use caution in patients with myasthenia gravis.
( 5.8 ) QT Prolongation : consider observations from the thorough QT study in clinical decisions to prescribe tolterodine tartrate extended – release capsules 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.
( 5.9 ) 5.1 Angioedema Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with the first or subsequent doses of tolterodine tartrate extended – release capsules.
In the event of difficulty in breathing, upper airway obstruction, or fall in blood pressure, tolterodine tartrate extended-release capsules should be discontinued and appropriate therapy promptly provided.
5.2 Urinary Retention Administer tolterodine tartrate extended – release capsules with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [ see CONTRAINDICATIONS (4) ].
5.3 Gastrointestinal Disorders Administer tolterodine tartrate extended – release capsules with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention.
Tolterodine tartrate extended – release capsules, 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 CONTRAINDICATIONS (4) ].
5.4 Controlled Narrow-Angle Glaucoma Administer tolterodine tartrate extended – release capsules with caution in patients being treated for narrow-angle glaucoma [ see CONTRAINDICATIONS (4) ].
5.5 Central Nervous System Effects Tolterodine tartrate extended – release capsules are associated with anticholinergic central nervous system (CNS) effects [ see Adverse Reactions (6.2) ] including dizziness and somnolence [ see Adverse Reactions (6.1) ].
Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose.
Advise patients not to drive or operate heavy machinery until the drug’s effects have been determined.
If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.
5.6 Hepatic Impairment The clearance of orally administered tolterodine immediate – release was substantially lower in cirrhotic patients than in the healthy volunteers.
For patients with mild to moderate hepatic impairment (Child-Pugh Class A or B), the recommended dose for tolterodine tartrate extended – release capsules is 2 mg once daily.
Tolterodine tartrate extended – release capsules are not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) [ see DOSAGE AND ADMINISTRATION (2.2) and USE IN SPECIFIC POPULATIONS (8.6) ] .
5.7 Renal Impairment Renal impairment can significantly alter the disposition of tolterodine and its metabolites.
The dose of tolterodine tartrate extended – release capsules should be reduced to 2 mg once daily in patients with severe renal impairment (CCr: 10–30 mL/min).
Patients with CCr<10 mL/min have not been studied and use of tolterodine tartrate extended – release capsules in this population is not recommended [ see DOSAGE AND ADMINISTRATION (2.2) and USE IN SPECIFIC POPULATIONS (8.7) ].
5.8 Myasthenia Gravis Administer tolterodine tartrate extended – release capsules with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.
5.9 Use in Patients with Congenital or Acquired QT Prolongation In a study of the effect of tolterodine immediate – release tablets on the QT interval [ see CLINICAL PHARMACOLOGY (12.2) ], 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 tolterodine tartrate extended – release capsules 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 tolterodine tartrate extended – release capsules.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).
Antimuscarinic Effects Inform patients that antimuscarinic agents such as tolterodine tartrate extended – release capsules may have side effects including blurred vision, dizziness, or drowsiness.
Advise patients not to drive, operate machinery, or do other potentially dangerous activities until they know how tolterodine tartrate extended-release capsules affects them.
This product’s label may have been updated.
For current full prescribing information, please visit www.greenstonellc.com.
DOSAGE AND ADMINISTRATION
2 4 mg capsules taken orally once daily with water and swallowed whole.
( 2.1 ) 2 mg capsules taken orally once daily with water and swallowed whole in the presence of: mild to moderate hepatic impairment (Child-Pugh class A or B) ( 2.2 ) severe renal impairment [Creatinine Clearance (CCr) 10–30 mL/min] ( 2.2 ) drugs that are potent CYP3A4 inhibitors.
( 2.2 ) Tolterodine tartrate extended – release capsules are not recommended for use in patients with CCr <10 mL/min.
( 2.2 ) Tolterodine tartrate extended – release capsules are not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C).
( 2.2 ) 2.1 Dosing Information The recommended dose of tolterodine tartrate extended – release capsules is 4 mg once daily with water and swallowed whole.
The dose may be lowered to 2 mg daily based on individual response and tolerability; however, limited efficacy data are available for tolterodine tartrate extended – release capsules 2 mg [ see CLINICAL STUDIES (14) ].
2.2 Dosage Adjustment in Specific Populations For patients with mild to moderate hepatic impairment (Child-Pugh Class A or B) or severe renal impairment (CCr 10–30 mL/min), the recommended dose of tolterodine tartrate extended-release capsules is 2 mg once daily.
Tolterodine tartrate extended – release capsules are not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C).
Patients with CCr<10 mL/min have not been studied and use of tolterodine tartrate extended – release capsules in this population is not recommended [ see WARNINGS AND PRECAUTIONS (5.6) and USE IN SPECIFIC POPULATIONS (8.6 , 8.7) ] .
2.3 Dosage Adjustment in Presence of Concomitant Drugs For patients who are taking drugs that are potent inhibitors of CYP3A4 [e.g., ketoconazole, clarithromycin, ritonavir], the recommended dose of tolterodine tartrate extended – release capsules is 2 mg once daily [ see DRUG INTERACTIONS (7.2) ] .