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Product Name
:
DETROTAC
Chemical Name
:
Tolterodine Tartarate
Therapeutic Category
:
Urinary tract drugs
Pharmacologic Category
:
Anticholinergic Agent
Pharmaceutical Form
:
Tablets
Composition
:
Tolterodine Tartarate 1mg / 2mg
Monitoring Parameters
Dosing
 
Dosing: Adult
Treatment of overactive bladder: Oral:
Immediate release tablet: 2 mg twice daily; the dose may be lowered to 1 mg twice daily based on individual response and tolerability
Dosing adjustment in patients concurrently taking CYP3A4 inhibitors: 1 mg twice daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Use with caution (studies conducted in patients with Clcr 10-30 mL/minute):
Immediate release tablet: 1 mg twice daily

Dosing: Hepatic Impairment

Immediate release tablet: 1 mg twice daily
Use
 
Treatment of patients with an overactive bladder with symptoms of urinary frequency, urgency, or urge incontinence
Adverse Reactions
 
As reported with immediate release tablet, unless otherwise specified
>10%: Gastrointestinal: Dry mouth (35%; extended release capsules 23%)
1% to 10%:
Cardiovascular: Chest pain (2%)
Central nervous system: Headache (7%; extended release capsules 6%), somnolence (3%; extended release capsules 3%), fatigue (4%; extended release capsules 2%), dizziness (5%; extended release capsules 2%), anxiety (extended release capsules 1%)
Dermatologic: Dry skin (1%)
Gastrointestinal: Abdominal pain (5%; extended release capsules 4%), constipation (7%; extended release capsules 6%), dyspepsia (4%; extended release capsules 3%), diarrhea (4%), weight gain (1%)
Genitourinary: Dysuria (2%; extended release capsules 1%)
Neuromuscular & skeletal: Arthralgia (2%)
Ocular: Abnormal vision (2%; extended release capsules 1%), dry eyes (3%; extended release capsules 3%)
Respiratory: Bronchitis (2%), sinusitis (extended release capsules 2%)
Miscellaneous: Flu-like syndrome (3%), infection (1%)
<1% (Limited to important or life-threatening): Anaphylaxis, angioedema, confusion, dementia aggravated, disorientation, hallucinations, memory impairment, palpitation, peripheral edema, QTc prolongation, tachycardia
Contraindications
 
Hypersensitivity to tolterodine or fesoterodine (both are metabolized to 5-hydroxymethyl tolterodine) or any component of the formulation; urinary retention; gastric retention; uncontrolled narrow-angle glaucoma
Warnings / Precautions Drug
 
Concerns related to adverse effects:
• Angioedema: Cases of angioedema have been reported with oral tolterodine; some cases have occurred after a single dose. Discontinue immediately if develops.
• CNS effects: May cause drowsiness and/or blurred vision, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• QT prolongation: Has been associated with QTc prolongation at high (supratherapeutic) doses. The manufacturer recommends caution in patients with congenital prolonged QT or in patients receiving concurrent therapy with QTc-prolonging drugs (class Ia or III antiarrhythmics). However, the extent of QTc prolongation even at supratherapeutic dosages was less than 15 msec. Individuals who are CYP2D6 poor metabolizers or in the presence of inhibitors of CYP2D6 and CYP3A4 may be more likely to exhibit prolongation.
Disease-related concerns:
• Bladder flow obstruction: Use with caution in patients with bladder flow obstruction; may increase the risk of urinary retention.
• Gastrointestinal obstructive disorders: Use with caution in patients with decreased GI motility or gastrointestinal obstructive disorders (ie, pyloric stenosis); may increase the risk of gastric retention.
• Glaucoma: Use with caution in patients with controlled (treated) narrow-angle glaucoma.
• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustment is required.
• Myasthenia gravis: Use with caution in patients with myasthenia gravis.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment is required.
Concurrent drug therapy issues:
• CYP3A4 inhibitors: Dosage adjustment is recommended in patients receiving CYP3A4 inhibitors; a lower dose of tolterodine is recommended. Also see QT prolongation in “Concerns related to adverse effects” above.
Metabolism/Transport Effects
Substrate of CYP2C9 (minor), 2C19 (minor), 2D6 (major), 3A4 (major)
Interactions
 
Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Risk D: Consider therapy modification
AbobotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of AbobotulinumtoxinA. Risk C: Monitor therapy
Acetylcholinesterase Inhibitors (Central): Anticholinergics may diminish the therapeutic effect of Acetylcholinesterase Inhibitors (Central). Acetylcholinesterase Inhibitors (Central) may diminish the therapeutic effect of Anticholinergics. If the anticholinergic action is a side effect of the agent, the result may be beneficial. Risk C: Monitor therapy
Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Levocabastine (Nasal); Paliperidone. Risk C: Monitor therapy
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Tolterodine. This is likely only of concern in CYP2D6-deficient patients (ie, "poor metabolizers") Risk D: Consider therapy modification
Cannabinoids: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoids. Risk C: Monitor therapy
CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Tolterodine. Management: The maximum recommended dose of long-acting tolterodine is 2 mg/day when used together with a strong CYP3A4 inhibitor. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Fluconazole: May decrease the metabolism of Tolterodine. This is likely only of concern in CYP2D6-deficient patients (ie, "poor metabolizers") Risk C: Monitor therapy
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
OnabotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of OnabotulinumtoxinA. Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Risk D: Consider therapy modification
Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification
RimabotulinumtoxinB: Anticholinergic Agents may enhance the anticholinergic effect of RimabotulinumtoxinB. Risk C: Monitor therapy
Secretin: Anticholinergic Agents may diminish the stimulatory effect of Secretin. Risk D: Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
VinBLAStine: May increase the serum concentration of Tolterodine. Management: Reduce tolterodine dose to 1 mg twice daily (regular release formulation) or 2 mg daily (extended release formulation) (adult doses) and monitor for increased levels/effects of tolterodine with initiation of vinblastine therapy. Risk D: Consider therapy modification
Warfarin: Tolterodine may enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy
Pregnancy
 
C
Pregnancy Implications
Teratogenic effects were observed in some animal studies. There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if the potential benefit to the mother outweighs the possible risk to the fetus.
Lactation
 
Excretion in breast milk unknown/not recommended
Mechanism of Action
 
Tolterodine is a competitive antagonist of muscarinic receptors. In animal models, tolterodine demonstrates selectivity for urinary bladder receptors over salivary receptors. Urinary bladder contraction is mediated by muscarinic receptors. Tolterodine increases residual urine volume and decreases detrusor muscle pressure.
Pharmacodynamics / Kinetics
 
Absorption: Immediate release tablet: Rapid; ≥77%
Distribution: I.V.: Vd: 113 ± 27 L
Protein binding: >96% (primarily to alpha1-acid glycoprotein)
Metabolism: Extensively hepatic, primarily via CYP2D6 to 5-hydroxymethyltolterodine (active) and 3A4 usually (minor pathway). In patients with a genetic deficiency of CYP2D6, metabolism via 3A4 predominates.
Bioavailability: Immediate release tablet: Increased 53% with food
Half-life elimination:
Immediate release tablet: Extensive metabolizers: ~2 hours; Poor metabolizers: ~10 hours
Time to peak: Immediate release tablet: 1-2 hours; Extended release tablet: 2-6 hours
Excretion: Urine (77%); feces (17%); primarily as metabolites (<1% unchanged drug) of which the active 5-hydroxymethyl metabolite accounts for 5% to 14% (<1% in poor metabolizers); as unchanged drug (<1%; <2.5% in poor metabolizers)
 
   
 
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