Tolterodine (DB01036): A Comprehensive Pharmacological and Clinical Monograph

I. Executive Summary

Tolterodine is a potent and competitive muscarinic receptor antagonist, pharmacologically classified as a urinary antispasmodic agent. It was specifically developed for the symptomatic management of overactive bladder (OAB), a condition characterized by urinary urgency, frequency, and urge incontinence.[1] The therapeutic rationale for Tolterodine is based on its ability to antagonize M2 and M3 muscarinic receptor subtypes, which are densely expressed in the detrusor smooth muscle of the urinary bladder. This antagonism inhibits acetylcholine-mediated involuntary bladder contractions, leading to a reduction in intravesical pressure, an increase in bladder capacity, and alleviation of OAB symptoms.[3]

A defining characteristic of Tolterodine's pharmacology is the pivotal role of its primary active metabolite, 5-hydroxymethyltolterodine (5-HMT). Following oral administration, Tolterodine undergoes extensive hepatic metabolism, and the resulting 5-HMT possesses an antimuscarinic activity profile that is equipotent to the parent compound, contributing substantially to the overall therapeutic effect.[6] This dual contribution from both the parent drug and its active metabolite is a central feature of its clinical profile.

Clinically, Tolterodine has demonstrated robust efficacy superior to placebo and comparable to the older benchmark agent, oxybutynin, in reducing micturition frequency and incontinence episodes in patients with OAB.[3] The subsequent development and approval of an extended-release (ER) formulation represented a significant therapeutic advance, offering improved efficacy and a more favorable tolerability profile compared to the immediate-release (IR) version by mitigating peak-concentration-related side effects.[11]

The pharmacokinetic profile of Tolterodine is notable for its dependence on the genetically polymorphic cytochrome P450 2D6 (CYP2D6) enzyme for its primary metabolic conversion to 5-HMT. A secondary pathway mediated by CYP3A4 also exists. This dual-pathway metabolism results in significant pharmacokinetic variability between "extensive metabolizers" (the majority of the population) and "poor metabolizers" (individuals with deficient CYP2D6 activity), a critical consideration for predicting drug response and potential for adverse events.[7]

The safety and tolerability profile of Tolterodine is dominated by its mechanism-based anticholinergic effects. Dry mouth is the most frequently reported adverse event and a common reason for treatment discontinuation.[3] Other common side effects include constipation, blurred vision, and dizziness. Important warnings and precautions for its use include the risk of inducing or exacerbating urinary and gastric retention, potential for central nervous system effects such as confusion (particularly in the elderly), and a dose-dependent risk of QT interval prolongation. This cardiac risk is of particular concern in poor metabolizers or when Tolterodine is co-administered with potent inhibitors of the CYP3A4 metabolic pathway.[14]

In conclusion, Tolterodine stands as a significant second-generation antimuscarinic agent for the treatment of OAB. It offers a well-established balance of efficacy and tolerability that represented an improvement over older agents. The ER formulation, in particular, enhances its therapeutic index. Prudent clinical use of Tolterodine necessitates careful patient selection, an awareness of the potential for altered pharmacokinetics due to genetic polymorphisms and drug interactions, and proactive management of its characteristic anticholinergic side effects, which remain the principal challenge to long-term patient adherence and therapeutic success.

II. Drug Identification and Physicochemical Properties

This section provides a definitive and comprehensive summary of the nomenclature, chemical identifiers, and core physicochemical properties of Tolterodine and its commonly used salt form, Tolterodine Tartrate. Accurate identification is foundational for all pharmacological, clinical, and regulatory contexts.

Nomenclature and Identifiers

Tolterodine is a small molecule drug approved for medical use.[4] It is known by a variety of names and is cataloged in numerous international chemical and pharmacological databases.

• [Generic Name (English):] Tolterodine [3]
• [Synonyms and Chemical Names:] The drug is chemically designated as the R-enantiomer. Common synonyms include (+)-(R)-2-(alpha-(2-(Diisopropylamino)ethyl)benzyl)-p-cresol, (R)-(+)-Tolterodine, and developmental codes such as Kabi 2234 and PNU-200583. International nonproprietary names include Tolterodina (Spanish) and Tolterodinum (Latin).[1]
• [Commercial Brand Names:] Tolterodine was originally developed by Pharmacia and Upjohn and is most widely known by the brand names Detrol and its extended-release version, Detrol LA.[3] In the United States, these brands are now marketed by Viatris following the merger of Upjohn with Mylan.[3] Other brand names used internationally include Detrusitol, Neditol, Mariosea, and Inconex XL.[16]
• [Database Identifiers:] A comprehensive list of key database identifiers is provided in Table 1 below. These identifiers ensure unambiguous reference across scientific literature, regulatory filings, and chemical databases.

Chemical Structure and Properties

Tolterodine is structurally classified as a tertiary amine and is functionally related to a p-cresol molecule.[1] Its chemical structure is the basis for its interaction with muscarinic receptors.

• [Chemical Formula:] The empirical formula for the Tolterodine free base is C22​H31​NO.[3]
• [Molecular Weight:] The average molecular weight of the free base is 325.496 g·mol⁻¹, with a monoisotopic mass of 325.240564619 g·mol⁻¹.[3]
• [IUPAC Name:] The systematic IUPAC name is 2--1-phenylpropyl]-4-methylphenol.[16]
• [Chemical Descriptors:] Standardized chemical descriptors are essential for computational chemistry and database searching.
• [SMILES (Simplified Molecular Input Line Entry System):] Cc1ccc(c(c1)[C@H](CCN(C(C)C)C(C)C)c2ccccc2)O [3]
• [InChI (International Chemical Identifier) Key:] OOGJQPCLVADCPB-HXUWFJFHSA-N [3]
• [Chemical Classification:] Based on its structure, Tolterodine belongs to several chemical superclasses, including benzenoids, organooxygen compounds, and organonitrogen compounds. More specific classifications include para-cresols, aralkylamines, and trialkylamines.[5]

Formulations and Salt Forms

While the active moiety is the Tolterodine free base, for pharmaceutical formulation, it is almost exclusively used as a tartrate salt to improve its physical properties, such as stability and solubility.

• [Common Salt Form:] The commercially available product is [Tolterodine Tartrate], which is a 1:1 salt of Tolterodine and L-tartaric acid.[7]
• [CAS Number (Tartrate Salt):] 124937-52-6 [3]
• [Chemical Formula (Tartrate Salt):] C26​H37​NO7​ [7]
• [Molecular Weight (Tartrate Salt):] 475.6 g·mol⁻¹ [7]
• [Physical Properties:] The physical form of the drug substance influences its formulation and handling.
• [Tolterodine (Free Base):] Described as a Pale Yellow Gel.[17]
• [Tolterodine Tartrate (Salt):] A white, crystalline powder.[7] It has a pKa value of 9.87. Its solubility in water is 12 mg/mL at 25°C. It is also soluble in methanol, slightly soluble in ethanol, and practically insoluble in toluene.[7] The partition coefficient (Log D) between n-octanol and water is 1.83 at a physiological pH of 7.3, indicating moderate lipophilicity.[7]
• [Available Pharmaceutical Formulations:] Tolterodine is administered orally and is available in two main formulations to accommodate different dosing strategies:
• [Immediate-Release (IR) Tablets:] Available in strengths of 1 mg and 2 mg of Tolterodine Tartrate.[7]
• [Extended-Release (ER) Capsules:] Available in strengths of 2 mg and 4 mg of Tolterodine Tartrate, designed for once-daily administration.[28]

[Table 1: Tolterodine Identifiers and Physicochemical Properties]

Property Category	Characteristic	Value / Identifier	Source(s)
General	Generic Name	Tolterodine	3
	Drug Type	Small Molecule	4
	Pharmacological Class	Cholinergic Muscarinic Antagonist, Urinary Antispasmodic	1
Identifiers (Free Base)	CAS Number	124937-51-5	1
	DrugBank ID	DB01036	3
	PubChem CID	443879	3
	UNII	WHE7A56U7K	1
Chemical Properties (Free Base)	Chemical Formula	C22​H31​NO	3
	Average Molecular Weight	325.496 g·mol⁻¹	3
	Monoisotopic Molecular Weight	325.240564619 g·mol⁻¹	4
	IUPAC Name	2--1-phenylpropyl]-4-methylphenol	16
	SMILES	Cc1ccc(c(c1)[C@H](CCN(C(C)C)C(C)C)c2ccccc2)O	3
	InChI Key	OOGJQPCLVADCPB-HXUWFJFHSA-N	3
Identifiers (Tartrate Salt)	CAS Number	124937-52-6	3
	DrugBank Salt ID	DBSALT000467	3
	UNII	5T619TQR3R	3
Chemical Properties (Tartrate Salt)	Chemical Formula	C26​H37​NO7​	7
	Molecular Weight	475.6 g·mol⁻¹	7
Physical Properties (Tartrate Salt)	Appearance	White, crystalline powder	7
	pKa	9.87	7
	Water Solubility	12 mg/mL	7

III. Comprehensive Pharmacological Profile

The clinical utility of Tolterodine is a direct consequence of its specific interactions with the cholinergic nervous system and its subsequent pharmacokinetic disposition. This section provides a detailed analysis of its mechanism of action, its physiological effects, and its absorption, distribution, metabolism, and excretion (ADME) profile.

Mechanism of Action (MoA)

Tolterodine is a potent, competitive antagonist of acetylcholine at postganglionic muscarinic receptors.[6] Its therapeutic effect is derived from its ability to block the signaling pathways that mediate bladder contraction. Both urinary bladder contraction and salivation are physiological processes mediated by cholinergic muscarinic receptors, which explains both the therapeutic effects and the primary side effects of the drug.[6]

The drug binds with high affinity to all five subtypes of muscarinic receptors (M1-M5).[4] However, its clinical efficacy in the treatment of overactive bladder is primarily attributed to the blockade of M2 and M3 receptor subtypes, which are prominently expressed on the detrusor smooth muscle of the urinary bladder.[3] The M3 receptor is directly responsible for mediating the contraction of the detrusor muscle upon stimulation by acetylcholine. The M2 receptor, while more abundant than M3 in the bladder, plays a more modulatory role by inhibiting sympathetically-induced relaxation. By antagonizing both receptor subtypes, Tolterodine effectively suppresses involuntary detrusor contractions, which are the pathophysiological hallmark of OAB.[3]

A critical and unique aspect of Tolterodine's mechanism is the significant contribution of its major active metabolite, 5-hydroxymethyltolterodine (5-HMT). Following hepatic metabolism, 5-HMT is formed, and it exhibits an antimuscarinic activity profile that is highly similar and equipotent to the parent drug.[4] Consequently, the overall therapeutic effect observed in patients is the combined result of the actions of both Tolterodine and 5-HMT. Both the parent compound and this active metabolite demonstrate high specificity for muscarinic receptors, with negligible affinity for other neurotransmitter receptors or potential cellular targets such as calcium channels, which contributes to a relatively clean pharmacological profile outside of the cholinergic system.[4]

Pharmacodynamics

The pharmacodynamic effects of Tolterodine are the direct physiological consequences of its muscarinic receptor antagonism. These effects are most pronounced in the lower urinary tract but are also observable in other organ systems with significant muscarinic innervation, such as the salivary glands and gastrointestinal tract.

The primary urodynamic effects of Tolterodine include a dose-dependent decrease in detrusor pressure and an increase in residual urine volume, reflecting a more relaxed bladder state and an incomplete emptying of the bladder.[4] This antagonism of bladder contractility leads to an increase in functional bladder capacity. Clinically, these physiological changes manifest as a reduction in the cardinal symptoms of OAB: urinary frequency (fewer voids per day), urgency (less intense and fewer sudden desires to void), and urge incontinence (fewer episodes of involuntary urine leakage).[33] The onset of these inhibitory effects on bladder function can be observed within one hour of oral administration.[35]

A key pharmacodynamic consideration in the development and clinical positioning of Tolterodine has been its "bladder selectivity." The drug was designed to offer a more favorable tolerability profile, particularly a lower incidence of dry mouth, compared to older, non-selective antimuscarinics like oxybutynin.[3] While clinical trials have consistently supported this improved tolerability, the underlying mechanism is more complex than simple receptor subtype selectivity. In-vitro radioligand binding studies have shown that Tolterodine possesses high affinity for muscarinic receptors in various tissues, not just the bladder. For instance, its binding affinity (

Ki​) for receptors in the human urinary bladder (Ki​ = 3.3 nM) is comparable to its affinity for receptors in the guinea pig parotid gland (Ki​ = 4.8 nM).[6] This suggests that the observed clinical "functional selectivity" does not arise from a significantly lower affinity for salivary gland receptors. Instead, this favorable clinical profile is likely the result of a complex interplay of factors. These may include differential tissue distribution leading to relatively lower drug concentrations at the salivary glands compared to the bladder at therapeutic doses, potential differences in receptor signaling pathways or receptor reserve between the two organs, and the specific pharmacokinetic and pharmacodynamic contributions of the 5-HMT metabolite. This distinction is important, as it highlights that a drug's overall clinical selectivity is an emergent property of its complete pharmacological profile, not just a single molecular interaction.

Pharmacokinetics (ADME)

The absorption, distribution, metabolism, and excretion (ADME) profile of Tolterodine is complex and is a major determinant of its clinical efficacy, safety, and potential for drug interactions. A key feature is the significant inter-individual variability driven by genetic polymorphism in its primary metabolic enzyme.

Absorption

Tolterodine is rapidly and efficiently absorbed from the gastrointestinal tract following oral administration, with at least 77% of an administered dose being absorbed.[14] For the immediate-release (IR) formulation, peak plasma concentrations (

Cmax​) are typically achieved within 1 to 2 hours post-dose.[14] The extended-release (ER) formulation is designed to slow absorption, resulting in a delayed and broader peak, with

Cmax​ occurring between 2 and 6 hours after administration.[35]

The presence of food has a differential effect on the two formulations. Food intake increases the bioavailability of the IR formulation by an average of 53%; however, because this does not significantly alter the total exposure to the active moiety (the sum of unbound Tolterodine and 5-HMT), no dose adjustment is necessary.[14] In contrast, the ER formulation exhibits no significant pharmacokinetic interaction with food, allowing it to be administered without regard to meals, which enhances patient convenience.[38]

Distribution

Once absorbed, Tolterodine distributes extensively into body tissues, as indicated by its large volume of distribution of approximately 113 L.[12] It is highly bound to plasma proteins (96.3%), primarily to alpha-1-acid glycoprotein (AAG).[7] This high degree of protein binding results in a very low fraction of unbound, pharmacologically active drug in the plasma, averaging just 3.7%.[12]

In contrast, the active 5-HMT metabolite is not as extensively protein-bound, with an average unbound fraction of 36%.[7] This higher unbound fraction means that 5-HMT can more readily distribute to target tissues and contribute to the pharmacological effect. The blood-to-serum concentration ratio for Tolterodine is approximately 0.6, indicating that it does not distribute extensively into erythrocytes.[7]

Metabolism

Tolterodine undergoes extensive first-pass metabolism in the liver, a process that is central to its pharmacology and is the primary source of pharmacokinetic variability.[6] The metabolism of Tolterodine is governed by a dual-pathway system dependent on a common genetic polymorphism in the cytochrome P450 enzyme system.

1. [Extensive Metabolizers (EMs):] This phenotype constitutes the majority of the population (approximately 93%). In EMs, the dominant metabolic pathway is the oxidation of the 5-methyl group on the phenol ring, a reaction catalyzed by the [cytochrome P450 2D6 (CYP2D6)] isoenzyme. This reaction leads to the formation of the major, pharmacologically active metabolite, [5-hydroxymethyltolterodine (5-HMT)].[7]
2. [Poor Metabolizers (PMs):] This group, comprising about 7% of the Caucasian population, has deficient or absent CYP2D6 activity due to genetic variations. In these individuals, the primary CYP2D6 pathway is non-functional. Metabolism is therefore shunted to a slower, alternative pathway involving dealkylation at the nitrogen atom, which is mediated by the [cytochrome P450 3A4 (CYP3A4)] isoenzyme, to form N-dealkylated tolterodine.[7]

This genetic polymorphism has profound clinical implications. In PMs, the metabolism of Tolterodine is significantly slower, resulting in substantially higher serum concentrations of the parent drug and negligible concentrations of the 5-HMT metabolite when compared to EMs.[7] While the total exposure to the active moiety (parent drug in PMs vs. parent drug + metabolite in EMs) is designed to be roughly equivalent to ensure similar efficacy, the different pharmacokinetic profiles can lead to different safety considerations. For example, the higher and more sustained levels of the parent drug in PMs contribute to a greater risk of dose-dependent adverse effects, such as QT interval prolongation.[14] This metabolic variability also dictates the nature of drug-drug interactions. For a PM, who relies solely on CYP3A4 for clearance, co-administration of a potent CYP3A4 inhibitor (like ketoconazole) can effectively shut down drug metabolism, leading to a high risk of accumulation and toxicity. This underpins the clinical recommendation to reduce the Tolterodine dose when used with such inhibitors.[6]

Further metabolism of 5-HMT in EMs leads to the formation of inactive metabolites, the 5-carboxylic acid and N-dealkylated 5-carboxylic acid, which are the primary metabolites recovered in the urine.[7]

Excretion

Tolterodine and its metabolites are eliminated from the body primarily via the kidneys. Following administration of a radiolabeled oral dose, approximately 77% of the radioactivity is recovered in the urine and 17% is recovered in the feces over 7 days.[12] In EMs, less than 1% of the dose is excreted as unchanged Tolterodine, while 5% to 14% is excreted as the active 5-HMT metabolite. The majority is excreted as the inactive carboxylic acid metabolites.[14]

The elimination half-life (t1/2​) of the IR formulation of Tolterodine in EMs is approximately 2 to 4 hours, and the half-life of 5-HMT is around 3 hours.[6] As detailed in Table 2, these values are significantly different in PMs.

Pharmacokinetics in Special Populations

• [Renal Impairment:] In patients with significantly reduced renal function (creatinine clearance [CrCl] between 10 and 30 mL/min), the exposure to both Tolterodine and its active 5-HMT metabolite is approximately two- to three-fold higher than in individuals with normal renal function. Therefore, a dose reduction to 1 mg IR twice daily or 2 mg ER once daily is recommended.[6]
• [Hepatic Impairment:] In patients with liver cirrhosis, the clearance of Tolterodine is substantially lower, leading to a prolonged elimination half-life of approximately 7.8 hours. A dose reduction to 1 mg IR twice daily or 2 mg ER once daily is recommended for patients with mild-to-moderate hepatic impairment.[14] The drug is not recommended for use in patients with severe hepatic impairment.[41]
• [Pediatrics:] The efficacy of Tolterodine was not established in pediatric clinical trials, and its use in this population is not recommended.[7]
• [Geriatrics and Gender:] Pharmacokinetic studies have not shown clinically significant differences based on age or gender, and no dose adjustments are required on these bases alone.[7]

[Table 2: Pharmacokinetic Parameters of Tolterodine and 5-HMT by CYP2D6 Phenotype (Immediate-Release Formulation)]

Parameter	Drug / Metabolite	Extensive Metabolizers (EMs)	Poor Metabolizers (PMs)	Source(s)
Elimination Half-life (t1/2​)	Tolterodine	2.0–2.4 hours	6.5–9.6 hours	35
	5-HMT	2.9–3.1 hours	Not Applicable (negligible levels)	35
Plasma Concentration	Tolterodine	Lower	Significantly Higher	7
	5-HMT	Substantial	Negligible	7

IV. Clinical Efficacy and Therapeutic Application

This section translates the fundamental pharmacological properties of Tolterodine into its practical application in clinical medicine. It details the approved indications, provides comprehensive dosing guidelines, and critically evaluates the evidence from clinical trials, including comparisons with other therapeutic agents for overactive bladder.

Approved Therapeutic Indications

The primary, regulatory-approved indication for Tolterodine is the symptomatic treatment of [overactive bladder (OAB)].[1] This condition is defined by a symptom complex that includes:

• [Urinary Urgency:] A sudden, compelling desire to pass urine that is difficult to defer.
• [Urinary Frequency:] The need to urinate more often than is typical for an individual.
• [Urge Urinary Incontinence:] Involuntary leakage of urine accompanied by or immediately preceded by urgency.

Tolterodine is indicated for patients experiencing these symptoms, either individually or in combination.[3] Detrusor overactivity, the underlying urodynamic finding in many OAB patients, is the most common cause of urinary incontinence in older adults, making Tolterodine a cornerstone of therapy in this population, often used in conjunction with non-pharmacological interventions like bladder retraining and pelvic floor muscle therapy.[3] While primarily studied and approved for OAB, Tolterodine is also utilized off-label in the management of male Lower Urinary Tract Symptoms (LUTS), particularly when storage symptoms are predominant.[16]

Dosage, Administration, and Formulations

The safe and effective use of Tolterodine requires adherence to specific dosing regimens, with important adjustments for different formulations, patient-specific factors, and potential drug interactions.

• [Immediate-Release (IR) Tablets (e.g., Detrol):] This formulation requires twice-daily dosing.
• [Initial Recommended Dose:] 2 mg administered orally twice daily.[6]
• [Dose Adjustment:] Based on individual patient response and tolerability, the dose may be reduced to 1 mg twice daily.[6]
• [Extended-Release (ER) Capsules (e.g., Detrol LA):] This formulation allows for convenient once-daily dosing.
• [Initial Recommended Dose:] 4 mg administered orally once daily.[29]
• [Dose Adjustment:] The dose may be lowered to 2 mg once daily depending on response and tolerability.[29]
• [Administration Instructions:] The ER capsules must be swallowed whole with liquid and should not be chewed, divided, or crushed, as this would disrupt the controlled-release mechanism.[44]
• [Dose Adjustments for Special Populations and Concomitant Medications:] Specific dose reductions are mandated for patient groups with altered drug clearance or those taking medications that inhibit Tolterodine's metabolism.
• [Patients with Significantly Reduced Renal Function (CrCl 10–30 mL/min):] The recommended dose is 1 mg IR twice daily or 2 mg ER once daily.[6]
• [Patients with Mild-to-Moderate Hepatic Impairment (Child-Pugh Class A or B):] The recommended dose is 1 mg IR twice daily or 2 mg ER once daily.[6] Use is not recommended in patients with severe hepatic impairment.[41]
• [Patients Taking Concomitant Potent CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin):] The recommended dose is 1 mg IR twice daily or 2 mg ER once daily to mitigate the risk of drug accumulation and toxicity.[6]

[Table 3: Recommended Dosing Regimens and Adjustments for Tolterodine]

Patient Population / Condition	Immediate-Release (IR) Dose	Extended-Release (ER) Dose	Source(s)
Standard Adult	2 mg twice daily (may reduce to 1 mg twice daily)	4 mg once daily (may reduce to 2 mg once daily)	6
Severe Renal Impairment (CrCl 10-30 mL/min)	1 mg twice daily	2 mg once daily	6
Mild-to-Moderate Hepatic Impairment	1 mg twice daily	2 mg once daily	6
Concomitant use of Potent CYP3A4 Inhibitors	1 mg twice daily	2 mg once daily	6

Evidence from Clinical Trials and Comparative Efficacy

The clinical utility of Tolterodine is supported by a large body of evidence from numerous randomized controlled trials that have evaluated its efficacy, safety, and comparative performance against both placebo and other active treatments.

• [Efficacy versus Placebo:] Large-scale, double-blind, placebo-controlled studies have consistently demonstrated that Tolterodine, in both its IR and ER formulations, is significantly more effective than placebo. These trials have shown statistically significant reductions in key micturition diary variables, including the number of incontinence episodes per 24 hours, the frequency of micturitions, and the severity of urinary urgency. Concurrently, Tolterodine treatment leads to a significant increase in the mean volume of urine voided per micturition.[10]
• [Immediate-Release versus Extended-Release Formulation:] The development of the ER formulation was a key step in optimizing Tolterodine therapy. The rationale was to create a smoother pharmacokinetic profile by avoiding the sharp peaks and troughs associated with the IR formulation. This change was hypothesized to improve tolerability without compromising efficacy. A pivotal head-to-head clinical trial confirmed this hypothesis, demonstrating that Tolterodine ER 4 mg once daily was not only clinically effective but was also 18% more effective than Tolterodine IR 2 mg twice daily in reducing incontinence episodes. Critically, this enhanced efficacy was accompanied by a statistically significant reduction in the incidence of dry mouth (23% for ER vs. 30% for IR), the most common dose-limiting side effect.[11] This finding is a clear example of how advanced formulation science can directly improve a drug's therapeutic index—the balance between its beneficial and harmful effects. By optimizing the drug delivery system, the ER formulation provides a more favorable balance, leading to better patient adherence and potentially better long-term outcomes.
• [Comparative Efficacy against Other Antimuscarinics:]
• [Oxybutynin:] Tolterodine was developed as a second-generation agent to improve upon the tolerability of the first-generation standard, oxybutynin. Clinical trials comparing Tolterodine IR (2 mg twice daily) with oxybutynin IR (5 mg three times daily) found that the two drugs had comparable efficacy in improving OAB symptoms. The key differentiator was tolerability; Tolterodine was associated with a significantly lower incidence (40% vs. 78%) and intensity of dry mouth.[10] Subsequent trials comparing the ER formulations of both drugs, such as the OPERA and ACET studies, reported broadly similar efficacy profiles, with some trials showing minor advantages for one agent on specific secondary endpoints, but with a consistent trend toward better overall tolerability for Tolterodine ER.[11]
• [Newer Agents (Solifenacin and Fesoterodine):] Tolterodine has also been compared to newer antimuscarinic agents. The STAR trial, a large head-to-head study, found that solifenacin provided statistically greater improvements in several key endpoints, including episodes of urgency and urge incontinence, compared to Tolterodine ER.[11] Fesoterodine is a prodrug that is metabolized to 5-HMT, the same active metabolite as Tolterodine. Comparative studies have shown that fesoterodine at its higher 8 mg dose can offer greater efficacy than Tolterodine ER 4 mg on some measures, such as achieving complete continence. However, this increased efficacy comes at the cost of a significantly higher rate of dry mouth (e.g., 34% for fesoterodine 8 mg vs. 17% for Tolterodine ER 4 mg).[11]
• [Impact on Health-Related Quality of Life (HRQoL):] The debilitating impact of OAB on a patient's daily life is substantial. Clinical trials have demonstrated that treatment with Tolterodine leads to statistically significant and clinically meaningful improvements in HRQoL. Using validated instruments like the King’s Health Questionnaire (KHQ), studies have shown that long-term treatment with Tolterodine ER improves patient scores across multiple domains, including the impact of incontinence on daily life, role and physical limitations, social interactions, emotional well-being, and sleep quality.[11]

V. Safety, Tolerability, and Risk Management

A thorough understanding of a drug's safety profile is paramount for its responsible clinical use. This section provides a comprehensive evaluation of the adverse reactions, contraindications, warnings, drug interactions, and toxicological data associated with Tolterodine therapy.

Adverse Drug Reactions (ADRs)

The adverse drug reactions associated with Tolterodine are predominantly extensions of its primary pharmacological action as a muscarinic receptor antagonist. These anticholinergic effects are predictable and dose-related.

• [Incidence and Profile:] The overall safety profile of Tolterodine was established in large clinical trials. In 12-week, placebo-controlled Phase 3 studies, adverse events were reported by 66% of patients receiving Tolterodine 2 mg twice daily, compared to 56% of patients receiving placebo.[14] The most common adverse events leading to treatment discontinuation were headache and dizziness/vertigo.[14]
• [Common and Very Common ADRs:]
• [Very Common (>10% incidence):] The most frequently reported adverse event is [Dry Mouth (Xerostomia)]. Incidence rates in clinical trials range from 35% to 40% with the IR formulation, significantly higher than placebo (around 10%).[6] This side effect is a primary driver of non-adherence to therapy.
• [Common (1% to 10% incidence):] Other common anticholinergic effects include [Constipation], [Headache], [Dizziness/Vertigo], and [Abdominal Pain]. Ocular effects such as [Dry Eyes (Xerophthalmia)] and [Blurred Vision] (due to impaired accommodation) are also common. Central nervous system effects like [Somnolence (Drowsiness)] and fatigue are frequently reported.[3]
• [Uncommon and Rare ADRs:]
• [Uncommon (0.1% to 1% incidence):] Neurological effects such as memory impairment, nervousness, and paresthesia have been reported.[13]
• [Rare and Post-marketing Events:] More serious but less frequent events have been identified through clinical use. These include severe hypersensitivity reactions such as [Anaphylaxis and Angioedema] (swelling of the face, lips, tongue, and throat), which can be life-threatening and require immediate medical attention.[3] Cardiovascular events like tachycardia and palpitations, as well as peripheral edema, have been observed. Psychiatric effects, including [Hallucinations, Confusion, and Disorientation], have been reported, particularly in elderly patients. There are also post-marketing reports of an aggravation of dementia symptoms in patients concurrently treated with cholinesterase inhibitors.[3] [Urinary Retention] is a serious potential complication, especially in at-risk patients.[6]

[Table 4: Incidence of Common Adverse Events in 12-Week Phase 3 Trials (Tolterodine 2 mg BID vs. Placebo)]

Adverse Event	Tolterodine 2 mg BID (%)	Placebo (%)	Source(s)
Dry Mouth	34.8	9.8	14
Headache	6.5	5.8	14
Constipation	6.0	3.8	14
Vertigo/Dizziness	4.6	3.2	14
Abdominal Pain	3.7	2.5	14
Dyspepsia	3.6	2.1	14
Somnolence	2.9	2.0	14
Dry Eyes	2.8	1.6	14
Fatigue	2.5	2.2	14

Contraindications, Warnings, and Precautions

Certain patient populations and pre-existing conditions preclude the use of Tolterodine or require significant caution to avoid serious harm.

• [Absolute Contraindications:] Tolterodine is strictly contraindicated in patients with the following conditions:
• [Urinary Retention:] The drug's mechanism can exacerbate the inability to empty the bladder.[3]
• [Gastric Retention:] Tolterodine decreases gastrointestinal motility and is contraindicated in patients with delayed gastric emptying.[3]
• [Uncontrolled Narrow-Angle Glaucoma:] Anticholinergic drugs can increase intraocular pressure and precipitate an acute glaucoma attack.[3]
• [Known Hypersensitivity:] Patients with a known allergy to Tolterodine, its ingredients, or to fesoterodine (which is metabolized to the same active moiety, 5-HMT) should not receive the drug.[29]
• [Warnings and Precautions:]
• [Risk of Retention:] Caution is warranted in patients with clinically significant bladder outflow obstruction (e.g., due to benign prostatic hyperplasia) due to an increased risk of urinary retention. Similarly, caution is needed in patients with gastrointestinal obstructive disorders (e.g., pyloric stenosis).[14]
• [Glaucoma:] Tolterodine should be used with caution in patients being treated for controlled narrow-angle glaucoma.[14]
• [Myasthenia Gravis:] The anticholinergic effects of Tolterodine can antagonize cholinergic therapies and exacerbate the muscle weakness characteristic of myasthenia gravis.[15]
• [Central Nervous System (CNS) Effects:] Tolterodine is associated with anticholinergic CNS effects, including dizziness, somnolence, and confusion. Patients should be monitored for these effects, particularly after initiating therapy or increasing the dose. They should be advised not to drive or operate heavy machinery until they are aware of how the drug affects them. If significant CNS effects occur, dose reduction or discontinuation should be considered.[8]
• [QT Prolongation:] Clinical studies have shown that Tolterodine can prolong the QT interval on an electrocardiogram (ECG) in a dose-dependent manner. This effect is more pronounced at doses higher than recommended (e.g., 8 mg/day) and is more significant in individuals who are CYP2D6 poor metabolizers. Therefore, caution should be exercised when prescribing Tolterodine to patients with a known personal or family history of QT prolongation or to those taking concomitant medications known to prolong the QT interval, such as Class IA (e.g., quinidine) or Class III (e.g., amiodarone, sotalol) antiarrhythmic drugs.[3]

Drug and Food Interactions

Tolterodine's metabolism through the CYP450 system makes it susceptible to a number of clinically significant drug interactions.

• [Pharmacokinetic Interactions:]
• [Potent CYP3A4 Inhibitors:] Co-administration with potent inhibitors of the CYP3A4 enzyme (e.g., azole antifungals like ketoconazole, macrolide antibiotics like clarithromycin) can significantly increase plasma concentrations of Tolterodine. This is particularly dangerous in CYP2D6 poor metabolizers, for whom CYP3A4 is the primary clearance pathway. To prevent potential toxicity, the dose of Tolterodine must be reduced when used with these agents.[6]
• [Potent CYP2D6 Inhibitors:] Drugs that are potent inhibitors of CYP2D6 (e.g., the antidepressant fluoxetine) can inhibit the primary metabolic pathway in extensive metabolizers. This effectively converts their pharmacokinetic profile to that of a poor metabolizer, resulting in a 4.8-fold increase in Tolterodine AUC.[14] While this interaction is significant, the total exposure to the active moiety (unbound Tolterodine + 5-HMT) is only modestly increased (by 25%), and therefore, a dose adjustment is not typically required for this interaction alone.[35]
• [Pharmacodynamic Interactions:]
• [Other Anticholinergic Drugs:] Concomitant use of Tolterodine with other drugs possessing antimuscarinic properties (e.g., some antihistamines, tricyclic antidepressants, antipsychotics) can lead to an additive effect, increasing the frequency and severity of anticholinergic side effects like dry mouth, constipation, blurred vision, and confusion.[35]
• [Food and Lifestyle Interactions:]
• [Grapefruit Juice:] As a known inhibitor of intestinal CYP3A4, grapefruit juice can increase the bioavailability and plasma concentrations of Tolterodine. Patients, particularly those who may be poor metabolizers, should be advised to avoid significant or abrupt changes in their consumption of grapefruit or grapefruit juice.[48]
• [Caffeine:] Beverages containing caffeine can have a diuretic effect and may aggravate the underlying symptoms of OAB, potentially counteracting the therapeutic benefit of Tolterodine to some degree. Patients may benefit from limiting their caffeine intake.[48]

[Table 5: Clinically Significant Drug-Drug Interactions and Management Recommendations]

Interacting Drug / Class	Mechanism of Interaction	Clinical Consequence	Management Recommendation	Source(s)
Potent CYP3A4 Inhibitors (e.g., Ketoconazole, Clarithromycin)	Inhibition of secondary (in EMs) or primary (in PMs) metabolic pathway	Significant increase in Tolterodine plasma concentrations; increased risk of toxicity (e.g., QT prolongation)	Reduce Tolterodine dose: 1 mg IR BID or 2 mg ER QD	6
Potent CYP2D6 Inhibitors (e.g., Fluoxetine, Paroxetine)	Inhibition of primary metabolic pathway in EMs	Converts EM phenotype to PM phenotype; significantly increases Tolterodine concentration	No dose adjustment typically required as total active moiety exposure is only modestly increased	35
Other Anticholinergic Agents (e.g., Diphenhydramine, Amitriptyline)	Additive Pharmacodynamic Effect	Increased frequency and severity of anticholinergic side effects (dry mouth, constipation, confusion, etc.)	Use with caution; monitor closely for additive toxicity. Consider alternative agents if possible.	35
QT-Prolonging Drugs (e.g., Class IA/III Antiarrhythmics)	Additive Pharmacodynamic Effect on Cardiac Repolarization	Increased risk of significant QT prolongation and potentially life-threatening arrhythmias (Torsade de Pointes)	Use with caution, especially in at-risk patients (e.g., PMs, electrolyte imbalance). Consider alternatives.	14

Toxicology Profile and Overdose Management

The non-clinical and clinical toxicology of Tolterodine is consistent with its pharmacology as a potent anticholinergic agent.

• [Reproductive and Developmental Toxicity:] In non-clinical studies and according to safety data sheets (SDS) under the Globally Harmonized System (GHS), Tolterodine is classified with the hazard statement H361: "Suspected of damaging fertility or the unborn child," corresponding to Reproductive Toxicity Category 2.[52] Due to a lack of adequate and well-controlled studies in humans, its safety in pregnancy is unclear, and its use is generally not recommended.[3] It is not known whether Tolterodine or its metabolites are excreted in human breast milk, and caution is advised during lactation.[29]
• [Carcinogenicity and Mutagenicity:] There is no evidence from non-clinical studies to suggest that Tolterodine is carcinogenic or mutagenic.[52] A large retrospective pharmacoepidemiological cohort study was conducted to assess the risk of ten common cancers among users of antimuscarinic medications for OAB, including Tolterodine. The study observed a higher incidence rate of bladder and prostate cancer in the first year after initiating therapy. However, this finding was not indicative of a causal relationship. The incidence rates of these cancers decreased markedly after the first year and also decreased with increasing cumulative dose of the medication. This pattern is a classic signature of "protopathic bias," where the initial symptoms of an undiagnosed cancer (e.g., urinary frequency from prostate or bladder cancer) are misinterpreted as OAB, leading to the prescription of the drug. The subsequent cancer diagnosis is thus temporally associated with the drug but not caused by it. This finding carries a significant clinical implication: physicians should maintain a high index of suspicion and consider the possibility of underlying urogenital malignancy in patients presenting with new-onset OAB symptoms, particularly in older individuals, to avoid a delay in cancer diagnosis.[55]
• [Hepatotoxicity:] Tolterodine therapy has a very low risk of liver injury. In multiple large clinical trials, rates of serum aminotransferase elevations were not significantly different from placebo, occurring in less than 1% of patients. Despite its widespread use for over two decades, there has been only a single published case report of clinically apparent acute liver injury attributed to its use, which resolved upon discontinuation of the drug. The likelihood of liver injury is therefore considered very rare.[34]
• [Overdose Management:] An overdose of Tolterodine would be expected to produce severe manifestations of its anticholinergic effects. Symptoms may include severe peripheral effects (e.g., urinary retention, mydriasis, severe dry mouth, tachycardia) and central effects (e.g., restlessness, confusion, hallucinations, excitement).[44] In severe cases, cardiovascular effects such as arrhythmias and QT prolongation could occur. Management of an overdose is primarily supportive and symptomatic. In case of a suspected overdose, patients should be advised to contact a poison control center or seek immediate emergency medical attention.[15]

VI. Regulatory Status and Future Perspectives

This section outlines the regulatory history of Tolterodine, its current market status, and examines ongoing research and future therapeutic strategies involving this well-established molecule.

Regulatory History and Market Landscape

Tolterodine has been a significant component of the OAB treatment landscape for over two decades, with a well-documented regulatory pathway.

• [Initial FDA Approval:] Tolterodine tartrate, under the brand name [Detrol], was first approved by the United States Food and Drug Administration (FDA) on March 25, 1998. The original New Drug Application (NDA 020771) was sponsored by Pharmacia & Upjohn.[59] This approval marked the introduction of a new generation of antimuscarinic agents for OAB.
• [Approval of Extended-Release Formulation:] Recognizing the therapeutic advantages of a smoother pharmacokinetic profile, the extended-release formulation, [Detrol LA], was developed and subsequently approved by the FDA on December 22, 2000 (NDA 021228).[61]
• [Pediatric Studies and Exclusivity:] In response to a Pediatric Written Request from the FDA, the sponsor conducted a series of clinical trials to evaluate the efficacy and safety of Tolterodine in children with both neurologically impaired and neurologically normal OAB. The studies, which used both a syrup formulation and the ER capsules, ultimately failed to demonstrate efficacy in the pediatric population. This information was incorporated into the drug's labeling, and as a result of conducting the requested studies, the FDA granted an additional six months of marketing exclusivity for both Detrol and Detrol LA in 2004.[42]
• [Market Status and Generic Availability:] Tolterodine is now widely available as a generic medication, following the expiration of its patent protection.[3] Numerous pharmaceutical manufacturers have received FDA approval to market generic versions of both the immediate-release tablets and the extended-release capsules, increasing accessibility and reducing cost.[59] Despite the introduction of newer agents, Tolterodine remains a commonly prescribed medication; in 2020, it was the 271st most prescribed drug in the United States, with over 1 million prescriptions filled.[3] It maintains its status as a prescription-only medicine in major markets, including the United States, the United Kingdom, and the European Union.[3]

Current Research and Future Directions

While Tolterodine is a mature drug, research continues to refine its use and explore novel therapeutic approaches to improve the management of OAB.

• [Ongoing Clinical Trials:] Current research efforts include studies designed to better understand the patient experience and optimize treatment in real-world settings. For example, recent trials have employed innovative web-based methodologies to evaluate the efficacy and safety of Tolterodine ER by focusing on patient-reported outcomes, reflecting a modern approach to clinical trial design.[62] Other studies have focused on its effectiveness on specific OAB symptoms within primary care settings, aiming to provide more practical guidance for clinicians.[63] Tolterodine also continues to be used as an active comparator in clinical trials for new OAB therapies, such as the beta-3 agonist vibegron, underscoring its role as a benchmark treatment.[64]
• [The Next Frontier: Mitigating Side Effects through Combination Therapy:] The most significant and persistent challenge in antimuscarinic therapy for OAB is the high rate of treatment discontinuation due to bothersome side effects, primarily dry mouth.[9] While the search for a novel molecule with perfect bladder selectivity has proven elusive, an innovative therapeutic strategy has emerged: combining an established, effective antimuscarinic with an agent designed specifically to counteract its principal side effect. A prime example of this approach is the clinical development of [Tolenix (THVD-201)], a proprietary, fixed-dose combination of Tolterodine and pilocarpine.[66] Pilocarpine is a muscarinic agonist that acts as a salivary stimulant. The formulation is designed to combine the bladder-relaxing effects of the antagonist (Tolterodine) with the saliva-stimulating effects of the agonist (pilocarpine). The results from a Phase 2, randomized, double-blind, multiple-crossover trial were highly promising. The study demonstrated that the Tolenix combination maintained the efficacy of Tolterodine in reducing micturition frequency and incontinence episodes compared to placebo. Critically, when compared to Tolterodine alone (active control), Tolenix produced a statistically significant and clinically meaningful 60% reduction in the severity of dry mouth. Patients receiving the combination therapy also reported improved saliva production and better quality of sleep.[66] This research represents a potential paradigm shift in the management of OAB. Rather than continuing the incremental search for a more selective single agent, this strategy employs a "pharmacological balancing act." It leverages the known efficacy of a drug like Tolterodine while directly addressing the primary barrier to its long-term use. The success of this approach could pave the way for a new class of combination products that significantly improve the therapeutic index of antimuscarinic therapy, enhance patient adherence, and ultimately lead to better long-term clinical outcomes for patients with OAB.

VII. Concluding Analysis and Recommendations

Tolterodine has firmly established itself as a cornerstone in the pharmacotherapy of overactive bladder. Its development marked a significant step forward from first-generation antimuscarinics, offering a more favorable balance between clinical efficacy and tolerability. This concluding analysis synthesizes the comprehensive data presented in this monograph to position Tolterodine within the current therapeutic landscape and provide actionable recommendations for optimizing its clinical use.

Position in OAB Therapy

Tolterodine, and particularly its extended-release (ER) formulation, remains a highly relevant and widely prescribed first- or second-line agent for the management of OAB. Its extensive clinical trial history provides a robust evidence base supporting its efficacy in reducing urinary frequency, urgency, and urge incontinence. Its primary advantage over older agents like oxybutynin is its improved tolerability profile, most notably a lower incidence and severity of dry mouth, which can translate into better patient adherence.

In the contemporary OAB market, Tolterodine faces competition from newer-generation antimuscarinics (e.g., solifenacin, fesoterodine) and a different class of medication, the beta-3 adrenergic agonists (e.g., mirabegron). Some comparative trials suggest that newer antimuscarinics may offer a modest efficacy advantage in certain patient populations, though often with a similar or sometimes greater side-effect burden. Beta-3 agonists offer a completely different mechanism of action and lack the characteristic anticholinergic side effects, making them an excellent alternative for patients who cannot tolerate antimuscarinics. The final choice of agent should be a result of shared decision-making, individualized to the patient's specific symptom profile, comorbidities, potential for drug interactions, tolerability of side effects, and cost considerations, with generic Tolterodine often being a highly cost-effective option.

Optimizing Therapy: Recommendations for Clinical Practice

To maximize the therapeutic benefit and minimize the risks associated with Tolterodine, clinicians should adopt a strategic approach to its prescription and management.

• [Thorough Patient Selection and Initial Assessment:] Before initiating Tolterodine, a comprehensive clinical evaluation is essential. This should include ruling out other pathologies that can mimic OAB symptoms, such as urinary tract infections, bladder stones, or interstitial cystitis. Critically, especially in older patients or those with red-flag symptoms like hematuria, the possibility of an underlying urogenital malignancy (e.g., bladder or prostate cancer) must be considered. This diligence is necessary to avoid the potential for a delayed cancer diagnosis that could result from attributing symptoms solely to benign OAB, a phenomenon known as protopathic bias.[55] A careful review of the patient's medical history for contraindications (urinary/gastric retention, uncontrolled narrow-angle glaucoma) and risk factors (e.g., history of QT prolongation, cognitive impairment, myasthenia gravis) is mandatory.
• [Prioritize the Extended-Release Formulation:] Whenever possible, the ER formulation (Detrol LA) should be the preferred choice over the IR version. The evidence clearly indicates that the once-daily ER capsule provides a superior therapeutic index, offering at least comparable, and in some studies superior, efficacy with a significantly lower incidence of dry mouth.[11] The improved tolerability and convenient dosing schedule of the ER formulation are likely to enhance long-term patient adherence, which is a major challenge in the chronic management of OAB.
• [Proactive Management of Side Effects:] Patient counseling is a critical component of successful Tolterodine therapy. Clinicians should set realistic expectations regarding the onset of action (which may take several weeks) and the likelihood of experiencing anticholinergic side effects. Patients should be provided with practical strategies to manage the most common adverse events. For dry mouth, this includes recommending sugarless gum or candies, saliva substitutes, and maintaining good oral hygiene. For constipation, advice should focus on adequate hydration, dietary fiber intake, and regular physical activity. If side effects prove intolerable at the initial dose, a dose reduction should be attempted before abandoning the therapy altogether.
• [Vigilance for Drug Interactions and High-Risk Scenarios:] Prescribers must be acutely aware of Tolterodine's metabolic pathways (CYP2D6 and CYP3A4) and the potential for significant drug-drug interactions. A thorough medication reconciliation is necessary to identify any concomitant use of potent CYP3A4 inhibitors, which mandates a dose reduction of Tolterodine. Caution should also be exercised with other anticholinergic medications to avoid additive toxicity, and with QT-prolonging drugs to mitigate cardiac risk.

Final Expert Perspective

Tolterodine represents a mature and well-understood therapeutic tool that continues to play a vital role in the management of overactive bladder. Its clinical utility is maximized when prescribers leverage a deep understanding of its pharmacology—particularly the nuances of its metabolism via the polymorphic CYP2D6 enzyme, its potential for clinically significant drug interactions, and the evidence-based strategies for managing its predictable side-effect profile. While the therapeutic armamentarium for OAB has expanded, Tolterodine's proven efficacy, established safety record, and availability as a cost-effective generic ensure its continued place in therapy. The future evolution of this molecule may not lie in further chemical modification but in innovative formulation strategies, such as the combination therapies currently under investigation, which aim to directly counteract its primary tolerability limitations. This approach could further enhance the value of this established drug, improving the quality of life for the many patients affected by overactive bladder.

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