Detrol LA

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Detrol LA

Classes

Antimuscarinics

Administration

For storage information, see specific product information within the How Supplied section.

Oral Administration

May be administered without regard to meals.

Oral Solid Formulations

Extended-release capsules: Swallow whole, do not crush, cut, or chew.

Adverse Reactions
Severe

visual impairment / Early / 1.0-2.0
Stevens-Johnson syndrome / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known

Moderate

constipation / Delayed / 6.0-7.0
dysuria / Early / 1.0-2.0
chest pain (unspecified) / Early / 2.0-2.0
blurred vision / Early / 1.0-2.0
urinary retention / Early / Incidence not known
hallucinations / Early / Incidence not known
sinus tachycardia / Rapid / Incidence not known
palpitations / Early / Incidence not known
peripheral edema / Delayed / Incidence not known
confusion / Early / Incidence not known
memory impairment / Delayed / Incidence not known
QT prolongation / Rapid / Incidence not known

Mild

xerostomia / Early / 23.0-35.0
headache / Early / 6.0-7.0
dizziness / Early / 2.0-5.0
abdominal pain / Early / 4.0-5.0
vertigo / Early / 2.0-5.0
dyspepsia / Early / 3.0-4.0
fatigue / Early / 2.0-4.0
diarrhea / Early / 0-4.0
xerophthalmia / Early / 3.0-3.0
drowsiness / Early / 3.0-3.0
influenza / Delayed / 3.0-3.0
sinusitis / Delayed / 2.0-2.0
arthralgia / Delayed / 2.0-2.0
xerosis / Delayed / 1.0-1.0
infection / Delayed / 1.0-1.0
anxiety / Delayed / 1.0-1.0
weight gain / Delayed / 1.0-1.0

Common Brand Names

Detrol, Detrol LA

Dea Class

Rx

Description

Oral competitive selective antimuscarinic agent; reduces incontinence episodes and urinary urgency
Used for treatment of overactive bladder (OAB) in adults; used as monotherapy or in combination with a beta-3 adrenoreceptor agonist if needed
Extensive study in elderly

Dosage And Indications
For the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urinary urgency, and urinary frequency. Oral dosage (immediate-release) Adults

2 mg PO twice daily. May decrease dose to 1 mg PO twice daily based on clinical response and tolerability. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Oral dosage (extended-release) Adults

4 mg PO once daily. May decrease dose to 2 mg PO once daily based on clinical response or tolerability. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Dosing Considerations
Hepatic Impairment

Immediate-release products:
Significant hepatic impairment: Reduce dosage to 1 mg PO twice daily.
 
Extended-release capsules:
Mild to Moderate hepatic impairment (Child Pugh Class A or B): Reduce dose to 2 mg once daily.
Severe hepatic impairment (Child Pugh Class C): Use not recommended.

Renal Impairment

Immediate-release products:
CrCl 30 mL/minute or less: Reduce dosage to 1 mg PO twice daily.
 
Extended-release capsules:
CrCl 10 to 30 mL/minute: Reduce dose to 2 mg once daily.
CrCl less than 10 mL/minute: Use not recommended.

Drug Interactions

Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Beverages containing caffeine may aggravate bladder symptoms and counteract the effectiveness of tolterodine to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements, or beverages.
Acetaminophen; Caffeine: (Minor) Beverages containing caffeine may aggravate bladder symptoms and counteract the effectiveness of tolterodine to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements, or beverages.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when dihydrocodeine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of dihydrocodeine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. (Minor) Beverages containing caffeine may aggravate bladder symptoms and counteract the effectiveness of tolterodine to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements, or beverages.
Acetaminophen; Caffeine; Pyrilamine: (Minor) Beverages containing caffeine may aggravate bladder symptoms and counteract the effectiveness of tolterodine to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements, or beverages.
Acetaminophen; Codeine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when codeine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of codeine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Acetaminophen; Hydrocodone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Acetaminophen; Oxycodone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when oxycodone is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of oxycodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Acetazolamide: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Adagrasib: (Major) Avoid concomitant use of adagrasib and tolterodine due to the potential for increased tolterodine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily. Additionally, consider taking steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Tolterodine is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. In CYP2D6 poor metabolizers, the CYP3A pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A inhibitors. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Alfentanil: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when alfentanil is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of alfentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Alfuzosin: (Moderate) Use caution when administering alfuzosin with tolterodine due to the potential for QT prolongation. Alfuzosin may prolong the QT interval in a dose-dependent manner. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Amantadine: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like tolterodine are used concomitantly with other drugs with moderate to significant anticholinergic effects such as amantadine. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the interacting agent.
Amiodarone: (Major) Avoid the concomitant use of amiodarone with other agents that prolong the QT interval, such as tolterodine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Amiodarone is an inhibitor of CYP3A4 and CYP2D6, and tolterodine is a CYP3A4 and CYP2D6 substrate; administering these drugs together may result in increased tolterodine concentrations.
Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with tolterodine. Amisulpride causes dose- and concentration- dependent QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Amlodipine; Celecoxib: (Moderate) Monitor patients closely for tolterodine-related adverse reactions and consider a dosage reduction of tolterodine if coadministration with celecoxib is necessary. Celecoxib may enhance the systemic exposure and toxicity of tolterodine. In vitro studies indicate that celecoxib is an inhibitor of CYP2D6. Tolterodine is a CYP2D6 substrate.
Amoxapine: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like tolterodine are used concomitantly with psychiatric medications with anticholinergic effects such as amoxapine. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily and monitor for evidence of QT prolongation if coadministered with clarithromycin. Concurrent use may increase tolterodine exposure. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with anagrelide include tolterodine.
Anticholinergics: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Apomorphine: (Moderate) Exercise caution when administering apomorphine concomitantly with tolterodine since concurrent use may increase the risk of QT prolongation. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Aprepitant, Fosaprepitant: (Moderate) Use caution if tolterodine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in tolterodine-related adverse effects for several days after administration of a multi-day aprepitant regimen. Tolterodine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of tolterodine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Moderate) Caution is advised when administering aripiprazole with tolterodine, as use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP). Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. QT prolongation has also occurred during therapeutic use of aripiprazole and following overdose.
Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with arsenic trioxide include tolterodine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. This should be taken into consideration when prescribing tolterodine to patients taking other drugs that are associated with QT prolongation.
Artemether; Lumefantrine: (Major) Artemether; lumefantrine is an inhibitor and tolterodine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased tolterodine concentrations. Concomitant use warrants caution due to the potential for increased side effects. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as tolterodine, should be avoided. Consider ECG monitoring if tolterodine must be used with or after artemether; lumefantrine treatment.
Asenapine: (Major) Concurrent use of asenapine and tolterodine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Asenapine has also been associated with QT prolongation.
Aspirin, ASA; Butalbital; Caffeine: (Minor) Beverages containing caffeine may aggravate bladder symptoms and counteract the effectiveness of tolterodine to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements, or beverages.
Aspirin, ASA; Caffeine: (Minor) Beverages containing caffeine may aggravate bladder symptoms and counteract the effectiveness of tolterodine to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements, or beverages.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when orphenadrine is used concomitantly with other drugs known to possess anticholinergic properties including tolterodine. Clinicians should note that anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Minor) Beverages containing caffeine may aggravate bladder symptoms and counteract the effectiveness of tolterodine to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements, or beverages.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when codeine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of codeine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Aspirin, ASA; Oxycodone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when oxycodone is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of oxycodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Atazanavir: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with atazanavir. Concurrent use may increase tolterodine exposure. Atazanavir is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Atazanavir; Cobicistat: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with atazanavir. Concurrent use may increase tolterodine exposure. Atazanavir is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers. (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with cobicistat. Concurrent use may increase tolterodine exposure. Cobicistat is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Atomoxetine: (Moderate) Use caution when coadministering atomoxetine and tolterodine as concurrent use may increase the risk of QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
Atropine: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Atropine; Difenoxin: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined. (Moderate) Antidiarrheals (e.g., atropine; diphenoxylate, atropine; difenoxin, and loperamide) decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been rarely reported to induce toxic megacolon. Tolterodine has been reported to cause dry mouth and constipation as potential side effects. Other anticholinergic and CNS effects may also be additive.
Azithromycin: (Major) Avoid coadministration of azithromycin with tolterodine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with tolterodine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Belladonna; Opium: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when opium is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of opium and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Benzhydrocodone; Acetaminophen: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when benzhydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of benzhydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Benztropine: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and tolterodine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and tolterodine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Buprenorphine: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as tolterodine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Additionally, monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of buprenorphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Buprenorphine; Naloxone: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as tolterodine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Additionally, monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of buprenorphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Bupropion: (Moderate) Bupropion exhibits moderate anticholinergic effects. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with bupropion.
Bupropion; Naltrexone: (Moderate) Bupropion exhibits moderate anticholinergic effects. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with bupropion.
Butalbital; Acetaminophen; Caffeine: (Minor) Beverages containing caffeine may aggravate bladder symptoms and counteract the effectiveness of tolterodine to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements, or beverages.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when codeine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of codeine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. (Minor) Beverages containing caffeine may aggravate bladder symptoms and counteract the effectiveness of tolterodine to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements, or beverages.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when codeine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of codeine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. (Minor) Beverages containing caffeine may aggravate bladder symptoms and counteract the effectiveness of tolterodine to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements, or beverages.
Butorphanol: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when butorphanol is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of butorphanol and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Cabotegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with tolterodine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Caffeine: (Minor) Beverages containing caffeine may aggravate bladder symptoms and counteract the effectiveness of tolterodine to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements, or beverages.
Caffeine; Sodium Benzoate: (Minor) Beverages containing caffeine may aggravate bladder symptoms and counteract the effectiveness of tolterodine to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements, or beverages.
Celecoxib: (Moderate) Monitor patients closely for tolterodine-related adverse reactions and consider a dosage reduction of tolterodine if coadministration with celecoxib is necessary. Celecoxib may enhance the systemic exposure and toxicity of tolterodine. In vitro studies indicate that celecoxib is an inhibitor of CYP2D6. Tolterodine is a CYP2D6 substrate.
Celecoxib; Tramadol: (Moderate) Monitor patients closely for tolterodine-related adverse reactions and consider a dosage reduction of tolterodine if coadministration with celecoxib is necessary. Celecoxib may enhance the systemic exposure and toxicity of tolterodine. In vitro studies indicate that celecoxib is an inhibitor of CYP2D6. Tolterodine is a CYP2D6 substrate. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of tramadol and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Ceritinib: (Major) Avoid coadministration of ceritinib with tolterodine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily. Periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation. Tolterodine is a CYP3A4 substrate that can also cause concentration-dependent QT prolongation, especially in CYP2D6 poor metabolizers. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Chloramphenicol: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with chloramphenicol. Concurrent use may increase tolterodine exposure. Chloramphenicol is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Chlordiazepoxide; Clidinium: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Chloroquine: (Major) Avoid coadministration of chloroquine with tolterodine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Chlorpheniramine; Codeine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when codeine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of codeine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Chlorpheniramine; Hydrocodone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Chlorpromazine: (Major) Depending on the specific agent, additive anticholinergic effects may be seen when drugs with antimuscarinic properties like tolterodine are used concomitantly with other antimuscarinics like most phenothiazines. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the interacting agent. In addition, tolterodine is associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6. Chlorpromazine is specifically associated with an established risk of QT prolongation and TdP; case reports have included patients receiving therapeutic doses of chlorpromazine and should be used cautiously and with close monitoring with tolterodine.
Ciprofloxacin: (Moderate) Tolterodine is associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6. Drugs that are also associated with QT prolongation and have antimuscarinic properties that should be used cautiously and with close monitoring with tolterodine include ciprofloxacin.
Cisapride: (Contraindicated) Coadministration of cisapride and tolterodine is contraindicated due to the risk for serious adverse events, such as torsade de pointes (TdP). QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Citalopram: (Major) Concurrent use of citalopram and tolterodine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If concurrent therapy is considered essential, ECG monitoring is recommended. Citalopram causes dose-dependent QT interval prolongation. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In addition, citalopram may inhibit the CYP2D6 metabolism of tolterodine in extensive metabolizers.
Clarithromycin: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily and monitor for evidence of QT prolongation if coadministered with clarithromycin. Concurrent use may increase tolterodine exposure. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Clofazimine: (Moderate) Concomitant use of clofazimine and tolterodine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers.
Clozapine: (Major) Depending on the specific agent, additive anticholinergic effects may be seen when drugs with antimuscarinic properties like tolterodine are used concomitantly with other antimuscarinics. Other commonly used drugs with moderate to significant anticholinergic effects include clozapine. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the interacting agent. In addition, tolterodine is associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6. Drugs that are also associated with QT prolongation and have antimuscarinic properties that should be used cautiously and with close monitoring with tolterodine include clozapine.
Cobicistat: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with cobicistat. Concurrent use may increase tolterodine exposure. Cobicistat is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Codeine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when codeine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of codeine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Codeine; Guaifenesin: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when codeine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of codeine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when codeine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of codeine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of promethazine and tolterodine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when codeine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of codeine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Codeine; Promethazine: (Moderate) Concomitant use of promethazine and tolterodine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when codeine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of codeine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Crizotinib: (Major) Avoid coadministration of crizotinib with tolterodine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Cyclobenzaprine: (Moderate) Additive anticholinergic effects may be seen when tolterodine is concomitantly with other drugs with antimuscarinic activity such as cyclobenzaprine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive hypotension or CNS effects such as drowsiness may also occur.
Darunavir: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with darunavir. Concurrent use may increase tolterodine exposure. Darunavir is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Darunavir; Cobicistat: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with cobicistat. Concurrent use may increase tolterodine exposure. Cobicistat is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers. (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with darunavir. Concurrent use may increase tolterodine exposure. Darunavir is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with cobicistat. Concurrent use may increase tolterodine exposure. Cobicistat is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers. (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with darunavir. Concurrent use may increase tolterodine exposure. Darunavir is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Dasatinib: (Moderate) Monitor for evidence of QT prolongation during concurrent use of dasatinib and tolterodine as concurrent use may increase the risk of QT prolongation. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving tolterodine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Delavirdine: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with delavirdine. Concurrent use may increase tolterodine exposure. Delavirdine is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Desvenlafaxine: (Major) Although clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 inhibition at doses of 100 mg/day, the manufacturer recommends that primary substrates of CYP2D6, such as tolterodine, be dosed at the original level when co-administered with desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued. The dose of these CYP2D6 substrates should be reduced by up to one-half if co-administered with desvenlafaxine 400 mg/day.
Deutetrabenazine: (Moderate) The risk of QT prolongation may be increased with coadministration of deutetrabenazine and tolterodine. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Dexmedetomidine: (Moderate) Concomitant use of dexmedetomidine and tolterodine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers.
Dextromethorphan; Bupropion: (Moderate) Bupropion exhibits moderate anticholinergic effects. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with bupropion.
Dextromethorphan; Quinidine: (Major) Use tolterodine and quinidine concomitantly with caution and close monitoring. Quinidine can inhibit the hepatic CYP2D6 isoenzyme, which may decrease the metabolism of tolterodine. It is not known if dosage adjustments in tolterodine would be needed as the result of this interaction. In addition, tolterodine is associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6, and quinidine (including dextromethorphan; quinidine) is associated with an established risk of QT prolongation. In addition, the anticholinergic effects of quinidine may be significant and may be enhanced when combined with tolterodine. Anticholinergic agents administered concurrently with quinidine may produce additive antivagal effects on AV nodal conduction.
Dicyclomine: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Digoxin: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
Diltiazem: (Moderate) In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. CYP3A4 inhibitors include diltiazem.
Diphenoxylate; Atropine: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined. (Moderate) Antidiarrheals (e.g., atropine; diphenoxylate, atropine; difenoxin, and loperamide) decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been rarely reported to induce toxic megacolon. Tolterodine has been reported to cause dry mouth and constipation as potential side effects. Other anticholinergic and CNS effects may also be additive.
Disopyramide: (Major) Tolterodine should be used cautiously and with close monitoring with disopyramide. Disopyramide administration is associated with QT prolongation and torsades de pointes (TdP). Tolterodine is associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6. In addition to its electrophysiologic effects, disopyramide exhibits clinically significant antimuscarinic anticholinergic properties. These can be additive with tolterodine. Clinicians should be aware that urinary retention, particularly in males, and aggravation of glaucoma are realistic possibilities of using disopyramide with other anticholinergic agents.
Dofetilide: (Major) Coadministration of dofetilide and tolterodine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Dolasetron: (Moderate) Administer dolasetron with caution in combination with tolterodine as concurrent use may increase the risk of QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Dolutegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with tolterodine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Donepezil: (Major) The therapeutic benefits of donepezil, a cholinesterase inhibitor, may be diminished during chronic co-administration with antimuscarinics/medications with anticholinergic activity. When concurrent use is not avoidable, the patient should be monitored for cognitive decline and anticholinergic side effects. Clinicians should generally avoid multiple medications with anticholinergic activity in the patient with dementia. Some of the common selective antimuscarinic drugs for bladder problems, (such as oxybutynin, darifenacin, trospium, fesoterodine), do not routinely cause problems with medications used for dementia, but may cause anticholinergic side effects in some patients. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Antimuscarinic drugs for bladder problems with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include solifenacin and tolterodine. Atropine may be used therapeutically to offset bradycardia in cholinesterase inhibitor overdose.
Donepezil; Memantine: (Major) The therapeutic benefits of donepezil, a cholinesterase inhibitor, may be diminished during chronic co-administration with antimuscarinics/medications with anticholinergic activity. When concurrent use is not avoidable, the patient should be monitored for cognitive decline and anticholinergic side effects. Clinicians should generally avoid multiple medications with anticholinergic activity in the patient with dementia. Some of the common selective antimuscarinic drugs for bladder problems, (such as oxybutynin, darifenacin, trospium, fesoterodine), do not routinely cause problems with medications used for dementia, but may cause anticholinergic side effects in some patients. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Antimuscarinic drugs for bladder problems with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include solifenacin and tolterodine. Atropine may be used therapeutically to offset bradycardia in cholinesterase inhibitor overdose.
Dronedarone: (Contraindicated) Because of the potential for torsades de pointes (TdP), concurrent use of tolterodine and dronedarone is contraindicated. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce TdP and is contraindicated.
Droperidol: (Major) Concurrent use of droperidol and tolterodine should be avoided due to an increased risk for Q

T prolongation and torsade de pointes (TdP). Droperidol administration is associated with an established risk for QT prolongation and TdP. In December 2001, the FDA issued a black box warning regarding the use of droperidol and its association with QT prolongation and potential for cardiac arrhythmias based on post-marketing surveillance data. According to the revised 2001 labeling for droperidol, any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Efavirenz: (Moderate) Consider alternatives to efavirenz when coadministering with tolterodine due to increased risk for QT prolongation. QTc prolongation has been observed with the use of efavirenz. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as tolterodine.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with tolterodine due to increased risk for QT prolongation. QTc prolongation has been observed with the use of efavirenz. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as tolterodine.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with tolterodine due to increased risk for QT prolongation. QTc prolongation has been observed with the use of efavirenz. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as tolterodine.
Elbasvir; Grazoprevir: (Moderate) Administering tolterodine with elbasvir; grazoprevir may result in elevated tolterodine plasma concentrations. Tolterodine is a substrate of CYP3A in people who are poor CYP2D6 metabolizers; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Eliglustat: (Major) Coadministration of tolterodine and eliglustat may result in increased tolterodine concentrations and an increased risk of QT prolongation. If coadministration is necessary, use caution and monitor closely for both cardiac and anticholinergic adverse effects. No empiric dosage adjustment is required for either drug. Tolterodine is CYP2D6 substrate associated with dose-dependent prolongation of the QT interval, especially in CYP2D6 poor metabolizers (PMs). Eliglustat is CYP2D6 inhibitor that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Coadministration of tolterodine and eliglustat may result in additive effects on the QT interval and increased plasma concentrations of tolterodine, further increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with cobicistat. Concurrent use may increase tolterodine exposure. Cobicistat is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with cobicistat. Concurrent use may increase tolterodine exposure. Cobicistat is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Caution is advised when administering rilpivirine with tolterodine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering rilpivirine with tolterodine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Encorafenib: (Major) Avoid coadministration of encorafenib and tolterodine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Entrectinib: (Major) Avoid coadministration of entrectinib with tolterodine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Ergotamine; Caffeine: (Minor) Beverages containing caffeine may aggravate bladder symptoms and counteract the effectiveness of tolterodine to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements, or beverages.
Eribulin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with eribulin. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Eribulin has also been associated with QT prolongation.
Erythromycin: (Major) Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Tolterodine should be used cautiously and with close monitoring in patients taking erythromycin. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Furthermore, patients receiving strong CYP3A4 inhibitors, such as erythromycin, concomitantly with tolterodine should not receive > 2 mg/day of tolterodine. Because it is difficult to assess which patients will be poor metabolizers of tolterodine via CYP2D6, those patients receiving CYP3A4 inhibitors should not receive > 2 mg/day of tolterodine. In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed.
Escitalopram: (Moderate) Use escitalopram with caution in combination with tolterodine as concurrent use may increase the risk of QT prolongation. Escitalopram has been associated with a risk of QT prolongation and torsade de pointes (TdP). Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Etrasimod: (Moderate) Concomitant use of etrasimod and tolterodine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Fentanyl: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Fexinidazole: (Major) Concomitant use of fexinidazole and tolterodine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers.
Fingolimod: (Moderate) Exercise caution when administering fingolimod concomitantly with tolterodine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Flavoxate: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Flecainide: (Moderate) Tolterodine is associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6. Drugs that are also associated with QT prolongation and have antimuscarinic properties that should be used cautiously and with close monitoring with tolterodine include flecainide.
Fluconazole: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering fluconazole with tolterodine. Fluconazole is associated with QT prolongation and rare cases of TdP. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess who are poor CYP2D6 metabolizers, patients receiving CYP3A4 inhibitors, such as fluconazole, should not receive > 2 mg/day of tolterodine. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed.
Fluoxetine: (Moderate) Coadministration of fluoxetine and tolterodine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Fluphenazine: (Moderate) Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fluphenazine include tolterodine. Additive anticholinergic effects may also be seen with any of the antimuscarinics. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur in some patients.
Fluvoxamine: (Moderate) Both fluvoxamine and tolterodine have been associated with QT prolongation, and torsade de pointes (TdP) has been reported with fluvoxamine. In addition, there is a possibility that fluvoxamine may increase the exposure to tolterodine. In patients who are CYP2D6 poor metabolizers (CYP2D6 PMs), the CYP3A4 pathway becomes important in tolterodine elimination. Because it can be difficult to assess which patients will be CYP2D6 PMs of tolterodine, those patients receiving CYP3A4 inhibitors, such as fluvoxamine, should generally not receive greater than 2 mg/day of tolterodine.
Fosamprenavir: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with fosamprenavir. Concurrent use may increase tolterodine exposure. Fosamprenavir is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as tolterodine. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fostemsavir: (Moderate) Use tolterodine and fostemsavir together with caution due to the potential for QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Galantamine: (Moderate) The therapeutic benefits of the cholinesterase inhibitors for dementia or other neurologic conditions may be diminished during chronic co-administration with antimuscarinics or medications with potent anticholinergic activity. Some of the common selective antimuscarinic drugs for bladder problems, (such as tolterodine), do not routinely cause problems with medications used for dementia, but may cause anticholinergic side effects in some patients. When concurrent use is not avoidable, the patient should be monitored for cognitive decline and anticholinergic side effects. Clinicians should generally avoid multiple medications with anticholinergic activity in the patient with dementia.
Gemifloxacin: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with gemifloxacin. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Gemifloxacin may also prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and tolterodine together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Gilteritinib: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and tolterodine is necessary. Gilteritinib has been associated with QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Givosiran: (Major) Avoid concomitant use of givosiran and tolterodine due to the risk of increased tolterodine-related adverse reactions. If use is necessary, consider reducing the tolterodine dose. Tolterodine is a sensitive CYP2D6 substrate. Givosiran may moderately reduce hepatic CYP2D6 enzyme activity because of its pharmacological effects on the hepatic heme biosynthesis pathway.
Glasdegib: (Major) Avoid coadministration of glasdegib with tolterodine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Glycopyrrolate; Formoterol: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Glycopyrronium: (Moderate) Although glycopyrronium is minimally absorbed into the systemic circulation after topical application, there is the potential for glycopyrronium to have additive anticholinergic effects when administered with tolterodine. Per the manufaturer, avoid concomitant administration of glycopyrronium with other anticholinergic medications.
Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving tolterodine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Androgen deprivation therapy may also prolong the QT/QTc interval.
Granisetron: (Moderate) Use granisetron with caution in combination with tolterodine due to increased risk for QT prolongation and torsade de pointes (TdP). Granisetron has been associated with QT prolongation. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Grapefruit juice: (Minor) In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. Grapefruit and grapefruit juice inhibit CYP3A4 metabolism in gut enterocytes. Patients should not significantly adjust their intake of grapefruit or grapefruit juice while taking tolterodine. Consideration should be given to limiting tolterodine dosage to 2 mg/day in some patients.
Green Tea: (Minor) Beverages containing caffeine may aggravate bladder symptoms and counteract the effectiveness of tolterodine to some degree. Patients may wish to limit their intake of caffeinatedgbhy beverages like green tea.
Guaifenesin; Hydrocodone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with tolterodine. Halogenated anesthetics can prolong the QT interval. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. This should be taken into consideration when prescribing tolterodine to patients taking other drugs that are associated with QT prolongation.
Haloperidol: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with haloperidol. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. QT prolongation and TdP have also been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving tolterodine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Androgen deprivation therapy may also prolong the QT/QTc interval.
Homatropine; Hydrocodone: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Hydrocodone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Hydrocodone; Ibuprofen: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Hydrocodone; Pseudoephedrine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Hydromorphone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydromorphone is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of hydromorphone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Hydroxychloroquine: (Major) Concomitant use of tolterodine and hydroxychloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers.
Hydroxyzine: (Moderate) Caution is recommended if hydroxyzine is administered with tolterodine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Additive anticholinergic effects may also occur. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Hyoscyamine: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Ibuprofen; Oxycodone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when oxycodone is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of oxycodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Ibutilide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with ibutilide. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Ibutilide administration can also cause QT prolongation and TdP; proarrhythmic events should be anticipated.
Idelalisib: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with idelalisib. Concurrent use may increase tolterodine exposure. Idelalisib is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Iloperidone: (Major) Concurrent use of iloperidone and tolterodine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Iloperidone has also been associated with QT prolongation.
Imatinib: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 CYP2D6 and 3A4. Tolterodine is metabolized primarily by CYP2D6 and alternatively, CYP3A4 in those patients who are poor metabolizers of tolterodine via CYP2D6. It is not known if dosage adjustments are required in patients requiring concurrent therapy, but patients should be monitored for increased anticholinergic effects.
Indacaterol; Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Indinavir: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with indinavir. Concurrent use may increase tolterodine exposure. Indinavir is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with tolterodine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Isavuconazonium: (Moderate) The plasma concentrations of tolterodine may be elevated when administered concurrently with isavuconazonium, and a decreased dose may be warranted. Clinical monitoring for adverse effects, such as dry mouth or QT prolongation, is recommended during coadministration. Tolterodine is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme.
Itraconazole: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily and monitor for evidence of QT prolongation if coadministered with itraconazole. Concurrent use may increase tolterodine exposure. Itraconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with tolterodine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and tolterodine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse effects. If concomitant use is necessary, reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily. Tolterodine is a CYP3A substrate and ketoconazole is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. Coadministration with ketoconazole increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily and monitor for evidence of QT prolongation if coadministered with clarithromycin. Concurrent use may increase tolterodine exposure. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Lapatinib: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with tolterodine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Lefamulin: (Major) Avoid coadministration of lefamulin with tolterodine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with tolterodine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Letermovir: (Moderate) An increase in the plasma concentration of tolterodine may occur if given with letermovir. Do not exceed tolterodine 2 mg per day in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. Tolterodine is metabolized by CYP3A4 in patients who are poor metabolizers of CYP2D6. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study involving poor CYP2D6 metabolizers, concurrent administration of tolterodine with another strong CYP3A4 inhibitor increased the mean maximum plasma concentration and exposure of tolterodine by 2- and 2.5-fold, respectively.
Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving tolterodine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Androgen deprivation therapy may also prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving tolterodine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Androgen deprivation therapy may also prolong the QT/QTc interval.
Levofloxacin: (Moderate) Levofloxacin should be used cautiously with tolterodine as concurrent use may increase the risk for QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Levofloxacin has been associated with a risk of QT prolongation and TdP. Although extremely rare, torsade de pointes (TdP) has been reported during postmarketing surveillance of levofloxacin.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and tolterodine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse effects. If concomitant use is necessary, reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily. Tolterodine is a CYP3A substrate and ketoconazole is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. Coadministration with ketoconazole increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Levorphanol: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when levorphanol is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of levorphanol and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Lithium: (Moderate) Lithium should be used cautiously with tolterodine. Lithium has been associated with QT prolongation and tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. This should be taken into consideration when prescribing tolterodine to patients taking other drugs that are associated with QT prolongation.
Lofexidine: (Moderate) Monitor ECG if lofexidine is coadministered with tolterodine due to the potential for additive QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Lonafarnib: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with lonafarnib. Concurrent use may increase tolterodine exposure as lonafarnib is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Loop diuretics: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Loperamide: (Moderate) Loperamide should be used cautiously and with close monitoring with tolterodine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. High doses of loperamide have been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Coadministration may further increase the risk of QT prolongation and TdP.
Loperamide; Simethicone: (Moderate) Loperamide should be used cautiously and with close monitoring with tolterodine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. High doses of loperamide have been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Coadministration may further increase the risk of QT prolongation and TdP.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with tolterodine due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with ritonavir. Concurrent use may increase tolterodine exposure. Ritonavir is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A inhibitors. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Lurasidone: (Moderate) Antipsychotic agents may disrupt core temperature regulation; therefore, caution is recommended during concurrent use of lurasidone and medications with anticholinergic activity such as antimuscarinics. Concurrent use of lurasidone and medications with anticholinergic activity may contribute to heat-related disorders. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if lurasidone is used with antimuscarinics.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as tolterodine. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Mannitol: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Maprotiline: (Major) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with maprotiline include tolterodine. Also, additive anticholinergic effects may be seen when maprotiline is used concomitantly with other drugs with moderate to significant anticholinergic effects including tolterodine.
Mefloquine: (Moderate) Mefloquine should be used with caution in patients receiving tolterodine as concurrent use may increase the risk of QT prolongation. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Meperidine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when meperidine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of meperidine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Methadone: (Major) The need to coadminister methadone with drugs known to prolong the QT interval should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Additionally, monitor patients for signs of urinary retention or reduced gastric motility when methadone is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of methadone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Methazolamide: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Methscopolamine: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Metronidazole: (Moderate) Concomitant use of metronidazole and tolterodine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers.
Midostaurin: (Major) The concomitant use of midostaurin and tolterodine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Mifepristone: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily and monitor for evidence of QT prolongation if coadministered with chronic mifepristone therapy. Concurrent use may increase tolterodine exposure. Mifepristone has been associated with dose-dependent prolongation of the QT interval and when administered chronically is a strong CYP3A4 inhibitor. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as tolterodine may be increased when administered with mirabegron. Tolterodine is primarily metabolized by CYP2D6. Mirabegron should also be used with caution in patients taking antimuscarinic medications for the treatment of overactive bladder because of the risk of urinary retention. Appropriate monitoring and dose adjustment may be necessary. Monitor for symptoms of urinary difficulties or urinary retention. Patients may note constipation or dry mouth with use of these drugs together.
Mirtazapine: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and tolterodine. Coadminister with caution. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Mirtazapine exhibits weak anticholinergic activity that may be additive with the anticholinergic effects of tolterodine.
Mitotane: (Moderate) Use caution if mitotane and tolterodine are used concomitantly, and monitor for decreased efficacy of tolterodine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer. CYP2D6 is primarily responsible for converting tolterodine to its active metabolite is CYP2D6; however, in the roughly 7% of the Caucasian population devoid of this isozyme ('poor metabolizers'), the drug is metabolized via CYP3A4 to N-dealkylated tolterodine. Coadministration could result in decreased plasma concentrations of tolterodine.
Mobocertinib: (Major) Concomitant use of mobocertinib and tolterodine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers.
Morphine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Morphine; Naltrexone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when morphine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of morphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Moxifloxacin: (Major) Concurrent use of moxifloxacin and tolterodine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Prolongation of the QT interval has also been reported with moxifloxacin. Post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
Nalbuphine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Nefazodone: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with nefazodone. Concurrent use may increase tolterodine exposure. Nefazodone is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Nelfinavir: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with nelfinavir. Concurrent use may increase tolterodine exposure. Nelfinavir is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Neostigmine; Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Nilotinib: (Major) Avoid coadministration of nilotinib with tolterodine due to an increased risk for QT prolongation. Systemic exposure of tolterodine may also be increased resulting in increase in treatment-related adverse reactions. Nilotinib is a moderate CYP3A4 inhibitor; sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Tolterodine is a CYP3A4 substrate that has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Concomitant use may increase the risk for QT prolongation.
Nirmatrelvir; Ritonavir: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with ritonavir. Concurrent use may increase tolterodine exposure. Ritonavir is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A inhibitors. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Ofloxacin: (Moderate) Ofloxacin should be used cautiously with tolterodine as concurrent use may increase the risk of QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
Olanzapine: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with olanzapine. Tolterodine is associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, olanzapine exhibits anticholinergic effects that may be clinically significant; additive anticholinergic effects may be seen when drugs with antimuscarinic properties like tolterodine are used concomitantly. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the interacting agent.
Olanzapine; Fluoxetine: (Moderate) Coadministration of fluoxetine and tolterodine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with olanzapine. Tolterodine is associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, olanzapine exhibits anticholinergic effects that may be clinically significant; additive anticholinergic effects may be seen when drugs with antimuscarinic properties like tolterodine are used concomitantly. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the interacting agent.
Olanzapine; Samidorphan: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with olanzapine. Tolterodine is associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, olanzapine exhibits anticholinergic effects that may be clinically significant; additive anticholinergic effects may be seen when drugs with antimuscarinic properties like tolterodine are used concomitantly. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the interacting agent.
Ondansetron: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with ondansetron. If these drugs must be coadministered, ECG monitoring is recommended. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis.
Oritavancin: (Minor) Tolterodine is metabolized by CYP3A4 and CYP2D6; oritavancin is a weak CYP3A4 and CYP2D6 inducer. Plasma concentrations and efficacy of tolterodine may be reduced if these drugs are administered concurrently.
Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when orphenadrine is used concomitantly with other drugs known to possess anticholinergic properties including tolterodine. Clinicians should note that anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
Osilodrostat: (Moderate) Monitor ECGs in patients receiving osilodrostat with tolterodine. Osilodrostat is associated with dose-dependent QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Osimertinib: (Major) Avoid coadministration of tolterodine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of tolterodine with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
Oxybutynin: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Oxycodone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when oxycodone is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of oxycodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Oxymorphone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when oxymorphone is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of oxymorphone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking tolterodine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Pacritinib: (Major) Concomitant use of pacritinib and tolterodine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers.
Paliperidone: (Major) Concurrent use of paliperidone and tolterodine should be avoided if possible due to an increased risk for QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Paliperidone has also been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose.
Panobinostat: (Major) The co-administration of panobinostat with tolterodine is not recommended; QT prolongation has been reported with both agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of tolterodine toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and tolterodine is a CYP2D6 substrate. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Paroxetine: (Moderate) Paroxetine, a potent CYP2D6 inhibitor, may inhibit the metabolism of tolterodine, a CYP2D6 substrate. In a study assessing another potent CYP2D6 inhibitor (fluoxetine) and tolterodine, the metabolism of tolterodine immediate release was significantly decreased in CYP2D6 extensive metabolizers, resulting in a 4.8-fold increase in tolterodine AUC. There was a 52% decrease in Cmax and a 20% decrease in AUC of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of tolterodine. The sums of unbound serum concentrations of tolterodine and 5-HMT were only 25% higher during the interaction. Although the manufacturer requires no dose adjustment during concurrent use of tolterodine and fluoxetine, the kinetic and clinical effects of paroxetine use are unknown. Both drugs exhibit anticholinergic effects that may be additive. In addition, because tolterodine is a primary substrate of CYP2D6 and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events.
Pasireotide: (Moderate) Use caution when using pasireotide in combination with tolterodine as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Pazopanib: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering pazopanib with tolterodine. Pazopanib is associated with QT prolongation. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor metabolizers of tolterodine via CYP2D6, those patients receiving CYP3A4 inhibitors, such as pazopanib, should be monitored closely for adverse events. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed.
Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to tolterodine if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while tolterodine is a CYP2D6 substrate.
Pentamidine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with pentamidine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Pentamidine has also been associated with QT prolongation.
Pentazocine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when pentazocine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of pentazocine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Pentazocine; Naloxone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when pentazocine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of pentazocine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Perphenazine: (Moderate) Use caution if coadministration of tolterodine with perphenazine is necessary, and closely monitor for possible QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Perphenazine is associated with a possible risk for QT prolongation and may theoretically increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Additive anticholinergic effects may also be seen when phenothiazines are used concomitantly with any antimuscarinics. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Drowsiness or other additive CNS effects may also occur in some patients.
Perphenazine; Amitriptyline: (Moderate) Use caution if coadministration of tolterodine with perphenazine is necessary, and closely monitor for possible QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Perphenazine is associated with a possible risk for QT prolongation and may theoretically increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Additive anticholinergic effects may also be seen when phenothiazines are used concomitantly with any antimuscarinics. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Drowsiness or other additive CNS effects may also occur in some patients.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Phentermine; Topiramate: (Moderate) Through an additive effect, the use of topiramate (a weak carbonic anhydrase inhibitor) with agents that may increase the risk for heat-related disorders, such as antimuscarinics, may lead to oligohidrosis, hyperthermia and/or heat stroke.
Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, tolterodine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Coadministration may increase the risk for QT prolongation. This should be taken into consideration when prescribing tolterodine to patients taking other drugs that are associated with QT prolongation.
Pimozide: (Contraindicated) Because of the potential for torsade de pointes (TdP), concurrent use of tolterodine and pimozide is contraindicated. Pimozide is associated with a well-established risk of QT prolongation and TdP and tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Pitolisant: (Major) Avoid coadministration of pitolisant with tolterodine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking tolterodine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Posaconazole: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily and monitor for evidence of QT prolongation if coadministered with posaconazole. Concurrent use may increase tolterodine exposure. Posaconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Potassium-sparing diuretics: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Primaquine: (Moderate) Exercise caution when administering primaquine in combination with tolterodine as concurrent use may increase the risk of QT prolongation. Primaquine is associated with QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Procainamide: (Major) Tolterodine should be used cautiously and with close monitoring with procainamide. Procainamide is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. This should be taken into consideration when prescribing tolterodine to patients taking other drugs that are associated with QT prolongation. In addition, the anticholinergic effects of procainamide may be significant and may be enhanced when combined with tolterodine. Anticholinergic agents administered concurrently with procainamide may produce additive antivagal effects on AV nodal conduction, although this is not as well documented for procainamide as for quinidine.
Prochlorperazine: (Moderate) Prochlorperazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, the risk may be increased if coadministered with drugs with a possible risk for QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with prochlorperazine include tolterodine. Additive anticholinergic effects may be seen with any antimuscarinics. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. With many antimuscarinics, additive drowsiness, hypotension or other additive CNS effects may also occur.
Promethazine: (Moderate) Concomitant use of promethazine and tolterodine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers.
Promethazine; Dextromethorphan: (Moderate) Concomitant use of promethazine and tolterodine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers.
Promethazine; Phenylephrine: (Moderate) Concomitant use of promethazine and tolterodine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers.
Propafenone: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with propafenone. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
Propantheline: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Proton pump inhibitors: (Moderate) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
Quetiapine: (Major) Concurrent use of quetiapine and tolterodine should be avoided if possible due to an increased risk for QT prolongation, torsade de pointes (TdP), and anticholinergic effects. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Limited data, including some case reports, suggest that quetiapine may also be associated with a significant prolongation of the QTc interval in rare instances. If concurrent use is required, also monitor for additive anticholinergic effects such as constipation, blurred vision, urinary retention, xerostomia, and tachycardia. Constipation is a commonly reported adverse effect of quetiapine and anticholinergic agents, such as tolterodine. Constipation in some cases may lead to ileus. Intestinal obstruction has been reported with quetiapine, including fatal cases in patients who were receiving multiple concomitant medications that decrease intestinal motility. Anticholinergic effects observed during therapeutic use of quetiapine are thought to be associated with norquetiapine, the active metabolite of quetiapine which has demonstrated a moderate to strong in vitro binding affinity for several muscarinic receptor subtypes.
Quinidine: (Major) Use tolterodine and quinidine concomitantly with caution and close monitoring. Quinidine can inhibit the hepatic CYP2D6 isoenzyme, which may decrease the metabolism of tolterodine. It is not known if dosage adjustments in tolterodine would be needed as the result of this interaction. In addition, tolterodine is associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6, and quinidine (including dextromethorphan; quinidine) is associated with an established risk of QT prolongation. In addition, the anticholinergic effects of quinidine may be significant and may be enhanced when combined with tolterodine. Anticholinergic agents administered concurrently with quinidine may produce additive antivagal effects on AV nodal conduction.
Quinine: (Major) Concurrent use of quinine and tolterodine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Quinine has been associated with prolongation of the QT interval and rare cases of TdP. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. Quinine is an inhibitor of both CYP2D6 and CYP3A4; coadministation may result in increased tolterodine concentrations.
Quizartinib: (Major) Concomitant use of quizartinib and tolterodine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers.
Ranolazine: (Moderate) Use caution if ranolazine is administered with tolterodine as concurrent use may increase the risk of QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs concurrent use may result in additive QT prolongation.
Relugolix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., relugolix) may prolong the QT/QTc interval. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Relugolix; Estradiol; Norethindrone acetate: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., relugolix) may prolong the QT/QTc interval. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Remifentanil: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Ribociclib: (Major) Avoid coadministration of ribociclib with tolterodine due to an increased risk for QT prolongation. Systemic exposure of tolterodine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Tolterodine is a CYP3A4 substrate that has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Concomitant use may increase the risk for QT prolongation.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with tolterodine due to an increased risk for QT prolongation. Systemic exposure of tolterodine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Tolterodine is a CYP3A4 substrate that has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Concomitant use may increase the risk for QT prolongation.
Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with tolterodine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Risperidone: (Moderate) Use risperidone and tolterodine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Ritonavir: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with ritonavir. Concurrent use may increase tolterodine exposure. Ritonavir is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A inhibitors. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Rivastigmine: (Moderate) The therapeutic benefits of the cholinesterase inhibitors for dementia or other neurologic conditions may be diminished during chronic co-administration with antimuscarinics or medications with potent anticholinergic activity. Some of the common selective antimuscarinic drugs for bladder problems, (such as tolterodine), do not routinely cause problems with medications used for dementia, but may cause anticholinergic side effects in some patients. When concurrent use is not avoidable, the patient should be monitored for cognitive decline and anticholinergic side effects. Clinicians should generally avoid multiple medications with anticholinergic activity in the patient with dementia.
Rolapitant: (Major) Use caution if tolterodine and rolapitant are used concurrently, and monitor for tolterodine-related adverse effects. Tolterodine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
Romidepsin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with tolterodine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Saquinavir: (Major) Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval such as tolterodine. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and reduce tolterodine doses. Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with saquinavir. Concurrent use may increase tolterodine exposure. Saquinavir is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Scopolamine: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Selpercatinib: (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with tolterodine is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Sertraline: (Moderate) Use caution and monitor patients for QT prolongation when administering tolterodine with sertraline. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Sertraline's FDA-approved labeling recommends avoiding concomitant use with drugs known to prolong the QTc interval; however, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving tolterodine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Sodium Stibogluconate: (Moderate) Concomitant use of sodium stibogluconate and tolterodine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers.
Solifenacin: (Moderate) Tolterodine should be used cautiously with solifenacin. Solifenacin has been associated dose-dependent prolongation of the QT interval. Torsades de pointes (TdP) has been reported with post-marketing use, although causality was not determined. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In addition, additive anticholinergic effects may be seen when drugs with antimuscarinic properties like solifenacin are used concomitantly with other antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the interacting agent.
Sorafenib: (Major) Avoid coadministration of sorafenib with tolterodine due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Sotalol: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with sotalol. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Sotalol administration is also associated with QT prolongation and TdP. Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
Sufentanil: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when sufentanil is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of sufentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Sunitinib: (Moderate) Monitor for evidence of QT prolongation if sunitinib is administered with tolterodine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Sunitinib can prolong the QT interval.
Tacrolimus: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with tolterodine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Tolterodine has been asociated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Tamoxifen: (Moderate) Caution is advised with the concomitant use of tamoxifen and tolterodine due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Tapentadol: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tapentadol is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of tapentadol and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Tegaserod: (Major) Tolterodine is an antagonist at muscarinic cholinergic receptors; the anticholinergic actions of the drug are most potent on the urinary bladder, with less activity on GI and salivary muscarinic cholinergic receptors. Tolterodine, as an antimuscarinic, may slow GI motility and thus may potentially antagonize the actions of drugs that enhance gastrointestinal motility, like metoclopramide or tegaserod. However, the clinical significance of this potential interaction is uncertain.
Telavancin: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with telavancin. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Telavancin has also been associated with QT prolongation.
Tetrabenazine: (Major) Concurrent use of tetrabenazine and tolterodine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Tetrabenazine also causes a small increase in the corrected QT interval (QTc).
Thiazide diuretics: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Thioridazine: (Contraindicated) Thioridazine is considered contraindicated for use along with tolterodine. Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Coadministration wirh tolterodine may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Additionally, additive anticholinergic effects may also be seen when phenothiazines are used concomitantly with antimuscarinic agents. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Tipranavir: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with tipranavir. Concurrent use may increase tolterodine exposure. Tipranavir is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Topiramate: (Moderate) Through an additive effect, the use of topiramate (a weak carbonic anhydrase inhibitor) with agents that may increase the risk for heat-related disorders, such as antimuscarinics, may lead to oligohidrosis, hyperthermia and/or heat stroke.
Toremifene: (Major) Avoid coadministration of tolterodine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Tramadol: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of tramadol and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Tramadol; Acetaminophen: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when tramadol is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of tramadol and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Trandolapril; Verapamil: (Moderate) In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. Verapamil is a CYP3A4 inhibitor. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed. Because it is difficult to assess which patients will be poor metabolizers of tolterodine via CYP2D6, those patients receiving CYP3A4 inhibitors should not receive more than 2 mg/day of tolterodine.
Trazodone: (Major) Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers and should be avoided in combination with trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
Triclabendazole: (Moderate) Concomitant use of triclabendazole and tolterodine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The risk for tolterodine-associated QT/QTc prolongation may be increased in poor CYP2D6 metabolizers.
Tricyclic antidepressants: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously and with close monitoring with tolterodine. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Tolterodine is also associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6. In addition, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other antimuscarinics. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when tolterodine is combined with tricyclic antidepressants.
Trifluoperazine: (Moderate) Trifluoperazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with trifluoperazine include solifenacin and tolterodine. Additive anticholinergic effects may be seen with any antimuscarinics. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Drowsiness or other additive CNS effects may also occur in some patients.
Trihexyphenidyl: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Triptorelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving tolterodine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Androgen deprivation therapy may also prolong the QT/QTc interval.
Tucatinib: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with tucatinib. Concurrent use may increase tolterodine exposure. Tucatinib is a strong CYP3A inhibitor. In CYP2D6 poor metabolizers, the CYP3A pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A inhibitors. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Urea: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Vandetanib: (Major) Avoid coadministration of vandetanib with tolterodine due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Vardenafil: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with vardenafil. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil also produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction).
Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as tolterodine, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, concomitant use of vemurafenib and tolterodine may result in altered concentrations of tolterodine. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Tolterodine is metabolized primarily by CYP2D6 and alternatively, CYP3A4 in those patients who are poor metabolizers of tolterodine via CYP2D6. Use caution and monitor patients for toxicity and efficacy.
Venlafaxine: (Moderate) Venlafaxine may inhibit the CYP2D6 metabolism of tolterodine in extensive metabolizers. In addition, tolterodine is associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6. Venlafaxine is also associated with QT prolongation. Use tolterodine and venlafaxine concomitantly with caution.
Verapamil: (Moderate) In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. Verapamil is a CYP3A4 inhibitor. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed. Because it is difficult to assess which patients will be poor metabolizers of tolterodine via CYP2D6, those patients receiving CYP3A4 inhibitors should not receive more than 2 mg/day of tolterodine.
Vibegron: (Moderate) Vibegron should be administered with caution in patients taking antimuscarinic medications for the treatment of overactive bladder, such as tolterodine, because of the risk of urinary retention. Monitor for symptoms of urinary difficulties or urinary retention. Patients may note constipation or dry mouth with use of these drugs together.
Viloxazine: (Moderate) Monitor for an increase in tolterodine-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase tolterodine exposure; viloxazine is a weak CYP2D6 inhibitor and tolterodine is a CYP2D6 substrate.
Voclosporin: (Moderate) Concomitant use of voclosporin and tolterodine may increase the risk of QT prolongation. Consider interventions to minimize the risk of progression to torsades de pointes (TdP), such as ECG monitoring and correcting electrolyte abnormalities, particularly in patients with additional risk factors for TdP. Voclosporin has been associated with QT prolongation at supratherapeutic doses. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily and monitor for evidence of QT prolongation if coadministered with clarithromycin. Concurrent use may increase tolterodine exposure. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Voriconazole: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily and monitor for evidence of QT prolongation if coadministered with voriconazole. Concurrent use may increase tolterodine exposure. Voriconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Vorinostat: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with vorinostat. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Vorinostat therapy is also associated with a risk of QT prolongation.
Warfarin: (Moderate) Increased INR values have been reported with concurrent use of warfarin and tolterodine. In two case reports, patients stabilized on warfarin experienced elevated INR values 10-14 days after beginning tolterodine treatment. Careful monitoring of the INR should be considered.
Zafirlukast: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as tolterodine.
Ziprasidone: (Major) Concomitant use of ziprasidone and tolterodine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.

How Supplied

Detrol LA/Tolterodine/Tolterodine Tartrate Oral Cap ER: 2mg, 4mg
Detrol/Tolterodine/Tolterodine Tartrate Oral Tab: 1mg, 2mg

Maximum Dosage
Adults

4 mg/day PO.

Geriatric

4 mg/day PO.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Mechanism Of Action

Mechanism of Action: Tolterodine and its active metabolite, 5-hydroxymethyltolterodine, are competitive muscarinic receptor antagonists. Actions on the bladder include inhibition of bladder contraction, a decrease in detrusor pressure, and an incomplete emptying of the bladder. Antimuscarinic effects on the salivary gland are much less pronounced than the effects on the urinary bladder. Neither tolterodine nor its active metabolite exert clinically significant effects on other neurotransmitter receptors or other pharmacologic targets such as calcium channels.Tolterodine and its active metabolite have a lipophilicity 30 and > 350 times lower than oxybutynin, respectively, which limits the drugs entry into the CNS and therefore would be expected to limit the drug's CNS antimuscarinic activity. In healthy volunteers, only minor EEG changes were noted after tolterodine administration. In clinical trials of normal volunteers and patients, QT interval prolongation was not observed at doses up to 4 mg PO twice daily of tolterodine. Higher doses were not evaluated for cardiac conduction changes.

Pharmacokinetics

Tolterodine is administered orally. Once in the systemic circulation, it is extensively metabolized by the liver to an active metabolite (5-hydroxymethyltolterodine) which has essentially the same antimuscarinic effects as tolterodine. It is highly bound to plasma proteins, primarily to alpha1-acid glycoprotein; the 5-hydroxymethyl metabolite is not extensively protein bound. Neither tolterodine or the active metabolite distributes significantly to erythrocytes. In animal models, tolterodine exhibited greater tissue distribution in the bladder versus the central nervous system. In mice, the highest concentrations were seen in elimination organs, such as the bladder, kidney, gallbladder, and liver. The lowest concentrations were seen in the central nervous system (brain and spinal cord) and skeletal muscles.
 
Affected cytochrome P450 isoenzymes and drug transporters:  CYP2D6, CYP3A4
The hepatic enzyme responsible for converting tolterodine to its active metabolite is CYP2D6; roughly 7% of the Caucasian population is devoid of this isozyme. In this group (referred to as "poor metabolizers"), the drug is metabolized via CYP3A4 to N-dealkylated tolterodine. Pharmacokinetic studies show that tolterodine is metabolized at a slower rate in poor metabolizers than in extensive metabolizers; this results in significantly higher serum concentrations of tolterodine and in negligible concentrations of the 5-hydroxymethyl metabolite. Because of differences in the protein-binding characteristics of tolterodine and the active metabolite, the sum of unbound serum concentrations of tolterodine and the 5-hydroxymethyl metabolite is similar in extensive and poor metabolizers at steady state. The net antimuscarinic activity is expected to be similar in both extensive and poor metabolizers. The 5-hydroxymethyl metabolite is further metabolized to 5-carboxylic acid and N-dealkylated 5-carboxylic acid metabolites. Approximately 77% of an administered dose is excreted in the urine and 17% in feces, primarily as metabolites.
 
The elimination half-life of immediate-release tolterodine after multiple dosing ranges from 2—4 hours in extensive metabolizers to 9.6 hours in poor metabolizers. The half life of the extended-release product ranges from 6.9 hours in extensive metabolizers to 18 hours in poor metabolizers.

Oral Route

Tolterodine is rapidly absorbed with peak serum concentrations (Cmax) occurring within 1—2 hours after oral administration of the immediate-release product. Maximum serum concentrations of tolterodine extended-release capsules are observed 2—6 hours after administration. Approximately 77% of the dose is absorbed. The pharmacokinetics of tolterodine are dose-proportional over the range of 1—4 mg of an immediate-release tablet. The AUC of the 4 mg dose of tolterodine extended-release once daily is equivalent to tolterodine immediate release 2 mg twice per day. Cmax and Cmin levels of tolterodine extended-release are about 75% and 150% of tolterodine immediate-release, respectively. Concomitant administration with food increases the bioavailability of tolterodine immediate-release by roughly 53%, however, the increase does not appear to be clinically significant. There is no effect of food on the pharmacokinetics of tolterodine extended-release capsules. Tolterodine may be administered with food.

Pregnancy And Lactation
Pregnancy

There are no adequate studies of tolterodine use during pregnancy. Tolterodine should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. In animal reproduction studies, oral administration of tolterodine at doses of 20 mg/kg/day (approximately 9 to 12 times the clinical exposure) during organogenesis did not produce adverse developmental outcomes; however, higher doses did produce adverse developmental outcomes. At doses of 30 to 40 mg/kg/day (14 to 18 times the clinical exposure), 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). Pregnant rabbits administered tolterodine subcutaneously at about 0.3 to 2.5 times the clinical exposure (dose of 0.8 mg/kg/day) did not show any embryotoxicity or teratogenicity.

Use tolterodine with caution during breast-feeding. Animal data show that tolterodine is excreted into the milk of mice in low amounts, however, it is not known whether tolterodine is excreted in human milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.