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  • CLASSES

    Antimuscarinics

    DEA CLASS

    Rx

    DESCRIPTION

    Oral muscarinic receptor antagonist for overactive bladder or urinary incontinence.

    COMMON BRAND NAMES

    Detrol, Detrol LA

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    For the treatment of an overactive bladder (OAB) with symptoms of urinary frequency, urinary urgency, or urge-related urinary incontinence.
    Oral dosage (immediate-release tablets)
    Adults

    2 mg PO twice daily. The dose may be lowered to 1 mg PO twice daily based on individual response and tolerability. If significant renal or hepatic disease is present or if concurrently taking CYP3A4-inhibiting drugs, reduce to 1 mg PO twice daily.

    Oral dosage (extended-release capsules)
    Adults

    4 mg PO once daily. The dose may be lowered depending on individual response or tolerability. If significant renal or hepatic disease is present or if concurrently taking CYP3A4-inhibiting drugs, reduce to 2 mg PO once daily.

    MAXIMUM DOSAGE

    Adults

    4 mg/day PO.

    Elderly

    4 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Reduce dosage by 50% to 1 mg PO twice daily, or, if using extended-release capsules, to 2 mg PO once daily.

    Renal Impairment

    CrCl > 30 ml/min: Follow initial dosage guidelines; adjust based on response and tolerance.
    CrCl <= 30 ml/min: Reduce dosage by 50% to 1 mg PO twice daily, or, if using extended-release capsules, to 2 mg PO once daily.

    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.

    STORAGE

    Detrol:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Detrol LA:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Tolterodine is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. Also, do not use in any patient who has had fesoterodine hypersensitivity. Tolterodine and fesoterodine are chemically related and both share the same active metabolite, 5-HMT. Cases of anaphylaxis and angioedema have been reported following administration of initial or subsequent doses of tolterodine. The drug should be discontinued and appropriate medical intervention should be instituted if signs and symptoms of a severe hypersensitivity reaction occur including breathing difficulties, upper airway obstruction, or a fall in blood pressure.

    Prostatic hypertrophy, renal disease, renal failure, renal impairment, urinary retention, urinary tract obstruction

    Due to the anticholinergic effects, tolterodine is contraindicated in patients with urinary retention. Anticholinergics may precipitate urinary retention in patients with preexisting urinary tract obstruction or prostatic hypertrophy, so caution is warranted. Altered pharmacokinetics of tolterodine occur in renal impairment (CrCl <= 30 ml/min) and renal failure; dosages should be adjusted (see Dosage). Use with caution in other patients with significant renal disease.

    Closed-angle glaucoma, contact lenses

    Tolterodine is contraindicated in patients with uncontrolled narrow or closed-angle glaucoma. Tolterodine may increase intraocular pressure and aqueous outflow resistance in patients with closed-angle glaucoma so caution is advised in patients with treated disease. Tolterodine is not contraindicated in patients with chronic open-angle glaucoma. The anticholinergic effects of tolterodine may make the eyes dry and this can cause irritation for wearers of contact lenses.

    Anticholinergic medications, gastroesophageal reflux disease (GERD), gastroparesis, GI obstruction, ileus, pyloric stenosis, toxic megacolon, ulcerative colitis

    Tolterodine has a direct antispasmodic effect on smooth muscle that can delay gastric emptying and is therefore contraindicated for use in patients with gastric retention (e.g., gastroparesis, GI obstruction, pyloric stenosis). Caution is advisable when tolterodine is used in patients with decreased gastrointestinal motility. Tolterodine is not recommended for use in the setting of ileus, toxic megacolon, or severe ulcerative colitis. In general, gastroesophageal reflux disease (GERD) may be aggravated by the use of anticholinergic medications.

    Hepatic disease

    Hepatic disease (e.g., cirrhosis) can significantly alter the disposition of tolterodine. Patients with significantly reduced hepatic function should dosage reductions (see Dosage). Also, dosage reductions may be required in patients receiving medications that reduce the hepatic metabolism of tolterodine (see Drug Interactions).

    Driving or operating machinery

    Patients should be advised to use caution when driving or operating machinery while receiving tolterodine until the effects of the drug are known. Anticholinergic drugs in general can cause blurred vision, dizziness, or somnolence in some patients. However, EEG data show no significant difference with tolterodine vs placebo in psychiatric events reported, even in elderly patients, so continued precautions with driving or other tasks are not expected.

    Autonomic neuropathy, myasthenia gravis

    Anticholinergics in general may exacerbate the clinical symptoms of patients with myasthenia gravis or autonomic neuropathy. Caution is advisable during use of the drug in patients with myasthenia gravis.

    Pregnancy

    Tolterodine is classified as FDA pregnancy risk category C. There are no studies of tolterodine in pregnant women. Tolterodine should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.

    Breast-feeding

    The manufacturer recommends discontinuation of tolterodine during breast-feeding. Animal data show that tolterodine is excreted into the milk of mice, however, it is not known whether tolterodine is excreted in human milk. In addition, chronic use of tolterodine may decrease milk production.

    Children, infants, neonates

    The safe and effective use of tolterodine in neonates, infants, and children has not been established. As might be expected, ingestion of tolterodine in unintentional overdose in children has resulted in characteristic anticholinergic actions like dry mouth. Although pharmacokinetic studies have been performed in children 11—15 years of age, the therapeutic use of tolterodine in clinical studies has failed to demonstrate safety and efficacy in children. A total of 710 pediatric patients, aged 5—10 years with urinary frequency and urge incontinence were studied in two phase 3 randomized, placebo-controlled, double blind, 12 week studies. The percentage of children with urinary tract infections was higher (6.6%) in patients treated with Detrol LA (tolterodine extended-release tablets) compared to children who received placebo (4.5%). Aggressive, abnormal and hyperactive behavior and attention disorders occurred in 2.9% of children treated with Detrol LA compared to 0.9% of children treated with placebo.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT p...

    In a study of the effect of tolterodine immediate release tablets on the QT interval, the effect on the QT interval appeared greater for 8 mg/day (2 times the therapeutic dose) compared to 4 mg/day and was more pronounced in CYP2D6 poor metabolizers. The effect of tolterodine 8 mg/day was not as large as that observed after 4 days of therapeutic dosing with the active control moxifloxacin. However, the confidence intervals overlapped. The 4 mg twice daily dose of tolterodine immediate-release (2 times the highest recommended dose) was chosen to be studied in QT prolongation studies because this dose results in tolterodine exposure similar to that observed upon co-administration of tolterodine at the recommended dosages in combination with CYP3A4 inhibitors in patients who are CYP2D6 poor metabolizers. There has been no association of torsade de pointes in the international post-marketing experience with tolterodine dosage forms. These observations should be considered in clinical decisions to prescribe tolterodine for patients with a known history of QT prolongation, those with congenital QT prolongation syndrome, or for patients who are taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications. Use tolterodine with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, elderly patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.

    Geriatric

    During pre-marketing evaluation of tolterodine, no overall differences in safety were observed between older and younger adult patients. Studies included patients up to 91 years of age, and 42% of patients were 65 years or older in clinical trials. However, geriatric patients have a greater risk of experiencing anticholinergic effects (e.g., dry mouth, constipation, confusion) and toxicity than younger adults. According to the Beers Criteria, antimuscarinics with strong anticholinergic properties, such as tolterodine, are considered potentially inappropriate medications (PIMs) in geriatric patients with dementia/cognitive impairment (adverse CNS effects) or delirium/high risk of delirium (possible new-onset or worsening delirium), and it is recommended that use in these patient populations be avoided.

    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

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: 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; Butalbital; Caffeine: 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; Butalbital; Caffeine; Codeine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists. 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: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists. 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; Magnesium Salicylate; Phenyltoloxamine: 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; Phenyltoloxamine; Salicylamide: 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: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Acetaminophen; Hydrocodone: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Acetaminophen; Oxycodone: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Acetaminophen; Propoxyphene: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Acetazolamide: Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Alfentanil: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Alfuzosin: Due to a possible risk for QT prolongation and torsade de pointes (TdP), alfuzosin and tolterodine should be used together cautiously. Based on electrophysiology studies performed by the manufacturer, alfuzosin has a slight effect to prolong the QT interval. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg. The manufacturer warns that the QT effect of alfuzosin should be considered prior to administering the drug to patients taking other medications known to 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.
    Amantadine: 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.
    Ambenonium Chloride: The therapeutic benefits of ambenonium may be diminished when coadministered with the antimuscarinics. When concurrent use cannot be avoided, monitor the patient for reduced ambenonium efficacy.
    Amiodarone: Use tolterodine with caution in a patient receiving amiodarone, a class III antiarrhythmic agent. Amiodarone can inhibit hepatic CYP2D6 and CYP3A4 isoenzymes, which may impair both pathways for metabolism of tolterodine. Tolterodine dosage should be reduced to 2 mg/day in adult patients receiving potent CYP3A4 inhibitors, especially if CYP2D6 metabolism is also impaired. The potential side effects of tolterodine when its elimination pathways are impaired can include increased anticholinergic effects and the prolongation of the QT interval.
    Amoxapine: 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; Lansoprazole: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with tolterodine. Clarithromycin is associated with an established risk for QT prolongation and 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 clarithromycin, should not receive > 2 mg/day of tolterodine. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed.
    Amoxicillin; Clarithromycin; Omeprazole: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with tolterodine. Clarithromycin is associated with an established risk for QT prolongation and 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 clarithromycin, should not receive > 2 mg/day of tolterodine. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed.
    Anagrelide: 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: 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: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with apomorphine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Limited data indicate that QT prolongation is also possible with apomorphine. The change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines; however, large increases (> 60 msecs from pre-dose) have occurred in two patients receiving 6 mg doses. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended.
    Aprepitant, Fosaprepitant: 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: 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: 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: 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: 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: 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; Butalbital; Caffeine; Codeine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists. 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; Dihydrocodeine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists. 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: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Aspirin, ASA; Oxycodone: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Atazanavir: 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. CYP3A4 inhibitors include anti-retroviral protease inhibitors. In addition, ritonavir and delavirdine inhibit CYP2D6. 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.
    Atazanavir; Cobicistat: 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. CYP3A4 inhibitors include anti-retroviral protease inhibitors. In addition, ritonavir and delavirdine inhibit CYP2D6. 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. The plasma concentrations of tolterodine may be elevated when administered concurrently with cobicistat. A decreased dose may be warranted. Clinical monitoring for adverse effects, such as dry mouth or QT prolongation, is recommended during coadministration. Cobicistat is a CYP3A4 and CYP2D6 inhibitor, while tolterodine is a CYP3A4 and CYP2D6 substrate.
    Atomoxetine: 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. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously with tolterodine include atomoxetine. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of TdP.
    Atropine: 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; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: 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: 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. 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.
    Atropine; Diphenoxylate: 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. 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.
    Atropine; Edrophonium: 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; Hyoscyamine; Phenobarbital; Scopolamine: 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.
    Azithromycin: 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 azithromycin.
    Bedaquiline: 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 Alkaloids; Ergotamine; Phenobarbital: 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.
    Belladonna; Opium: 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.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: 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: 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: Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include tolterodine.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include tolterodine.
    Boceprevir: Close clinical monitoring is advised when administering tolterodine with boceprevir due to an increased potential for tolterodine-related adverse events. If tolterodine dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of tolterodine. Tolterodine is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated tolterodine plasma concentrations.
    Bosentan: Bosentan is a significant inducer of CYP2C9 and CYP3A4 hepatic isoenzymes. Theoretically, bosentan can increase the hepatic clearance of tolterodine, a CYP2C9 and CYP3A4 substrate. However, this interaction has not been studied.
    Brompheniramine; Guaifenesin; Hydrocodone: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Brompheniramine; Hydrocodone; Pseudoephedrine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Buprenorphine: Buprenorphine 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. 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. Coadministration may further increase the risk of QT prolongation and TdP.
    Buprenorphine; Naloxone: Buprenorphine 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. 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. Coadministration may further increase the risk of QT prolongation and TdP.
    Bupropion: 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: Bupropion exhibits moderate anticholinergic effects. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with bupropion.
    Caffeine: 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; Ergotamine: 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.
    Carbinoxamine; Hydrocodone; Phenylephrine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Ceritinib: Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with ceritinib include tolterodine. Periodically monitor electrocardiograms (EGCs) and electrolytes; therapy interruption, dose reduction, or discontinuation may be required.
    Chlordiazepoxide; Clidinium: 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: Concurrent use of chloroquine and tolterodine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). The need to coadminister these drugs should be done with a careful assessment of risks versus benefits. Chloroquine administration is associated with an increased risk of QT prolongation and TdP. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Chlorpheniramine; Codeine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Chlorpheniramine; Hydrocodone: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Chlorpheniramine; Hydrocodone; Phenylephrine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Chlorpromazine: 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.
    Chondroitin; Glucosamine: Drugs that decrease GI motility may increase the risk of GI irritation from sustained-release solid oral dosage forms of potassium salts. Examples of drugs that significantly decrease GI motility include the antimuscarinics. In one study, healthy subjects were examined for GI irritation following the administration of oral potassium for at least 7 days. Glycopyrrolate was coadministered to some subjects in order to study the additional effects of delayed gastric emptying. Results indicated that subjects administered wax-matrix tablets had the highest incidence of erosions (43%) and ulcers (11%). Evidence of GI irritation was less frequent among subjects receiving liquid (0%) and microencapsulated (10.5% erosions, 1.2% ulcers) formulations. Therefore, if oral potassium supplementation is necessary in a patient taking antimuscarinics, a liquid formulation should be considered. If a solid formulation is being prescribed, the patient should be counseled on strategies that can be used to avoid GI irritation such as taking potassium products only while seated or standing, remaining upright for 10 minutes after each dose, and ingesting each dose with plenty of fluids.
    Ciprofloxacin: 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: 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: 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.
    Citric Acid; Potassium Citrate: Drugs that decrease GI motility may increase the risk of GI irritation from sustained-release solid oral dosage forms of potassium salts. Examples of drugs that significantly decrease GI motility include the antimuscarinics. In one study, healthy subjects were examined for GI irritation following the administration of oral potassium for at least 7 days. Glycopyrrolate was coadministered to some subjects in order to study the additional effects of delayed gastric emptying. Results indicated that subjects administered wax-matrix tablets had the highest incidence of erosions (43%) and ulcers (11%). Evidence of GI irritation was less frequent among subjects receiving liquid (0%) and microencapsulated (10.5% erosions, 1.2% ulcers) formulations. Therefore, if oral potassium supplementation is necessary in a patient taking antimuscarinics, a liquid formulation should be considered. If a solid formulation is being prescribed, the patient should be counseled on strategies that can be used to avoid GI irritation such as taking potassium products only while seated or standing, remaining upright for 10 minutes after each dose, and ingesting each dose with plenty of fluids.
    Citric Acid; Potassium Citrate; Sodium Citrate: Drugs that decrease GI motility may increase the risk of GI irritation from sustained-release solid oral dosage forms of potassium salts. Examples of drugs that significantly decrease GI motility include the antimuscarinics. In one study, healthy subjects were examined for GI irritation following the administration of oral potassium for at least 7 days. Glycopyrrolate was coadministered to some subjects in order to study the additional effects of delayed gastric emptying. Results indicated that subjects administered wax-matrix tablets had the highest incidence of erosions (43%) and ulcers (11%). Evidence of GI irritation was less frequent among subjects receiving liquid (0%) and microencapsulated (10.5% erosions, 1.2% ulcers) formulations. Therefore, if oral potassium supplementation is necessary in a patient taking antimuscarinics, a liquid formulation should be considered. If a solid formulation is being prescribed, the patient should be counseled on strategies that can be used to avoid GI irritation such as taking potassium products only while seated or standing, remaining upright for 10 minutes after each dose, and ingesting each dose with plenty of fluids.
    Clarithromycin: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with tolterodine. Clarithromycin is associated with an established risk for QT prolongation and 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 clarithromycin, should not receive > 2 mg/day of tolterodine. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed.
    Clozapine: 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: The plasma concentrations of tolterodine may be elevated when administered concurrently with cobicistat. A decreased dose may be warranted. Clinical monitoring for adverse effects, such as dry mouth or QT prolongation, is recommended during coadministration. Cobicistat is a CYP3A4 and CYP2D6 inhibitor, while tolterodine is a CYP3A4 and CYP2D6 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: The plasma concentrations of tolterodine may be elevated when administered concurrently with cobicistat. A decreased dose may be warranted. Clinical monitoring for adverse effects, such as dry mouth or QT prolongation, is recommended during coadministration. Cobicistat is a CYP3A4 and CYP2D6 inhibitor, while tolterodine is a CYP3A4 and CYP2D6 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: The plasma concentrations of tolterodine may be elevated when administered concurrently with cobicistat. A decreased dose may be warranted. Clinical monitoring for adverse effects, such as dry mouth or QT prolongation, is recommended during coadministration. Cobicistat is a CYP3A4 and CYP2D6 inhibitor, while tolterodine is a CYP3A4 and CYP2D6 substrate.
    Codeine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Codeine; Guaifenesin: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Codeine; Phenylephrine; Promethazine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists. Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include tolterodine,
    Codeine; Promethazine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists. Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include tolterodine,
    Crizotinib: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering crizotinib with tolterodine. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Crizotinib 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 who are poor CYP2D6 metabolizers, patients receiving CYP3A4 inhibitors, such as crizotinib, should be monitored closely for adverse events. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed.
    Cyclobenzaprine: Tolterodine should be used cautiously with cyclobenzaprine. Cyclobenzaprine is structurally similar to tricyclic antidepressants. Tricyclic antidepressants have been reported to prolong the QT interval, especially when given in excessive doses (or in overdosage settings). Cyclobenzaprine is associated with a possible risk of QT prolongation and torsades de pointes (TdP), particularly in the event of acute overdose. In addition, additive anticholinergic effects may be seen during coadministration. 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.
    Darifenacin: 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.
    Darunavir: 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. CYP3A4 inhibitors include anti-retroviral protease inhibitors. In addition, ritonavir and delavirdine inhibit CYP2D6. 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.
    Darunavir; Cobicistat: 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. CYP3A4 inhibitors include anti-retroviral protease inhibitors. In addition, ritonavir and delavirdine inhibit CYP2D6. 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. The plasma concentrations of tolterodine may be elevated when administered concurrently with cobicistat. A decreased dose may be warranted. Clinical monitoring for adverse effects, such as dry mouth or QT prolongation, is recommended during coadministration. Cobicistat is a CYP3A4 and CYP2D6 inhibitor, while tolterodine is a CYP3A4 and CYP2D6 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: 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. CYP3A4 inhibitors include anti-retroviral protease inhibitors. In addition, ritonavir and delavirdine inhibit CYP2D6. 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 addition, both ritonavir and tolterodine are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
    Dasatinib: Due to a possible risk for QT prolongation and torsade de pointes (TdP), dasatinib and tolterodine should be used together cautiously. In vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval). Tolterodine has 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. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed. Drugs with a possible risk of QT prolongation that are also CYP3A4 inhibitors include dasatinib.
    Daunorubicin: Tolterodine has been associated dose-dependent prolongation of the QT interval. This should be taken into consideration when prescribing tolterodine to patients taking other drugs that are associated with QT prolongation. Tolterodine should be used cautiously with other drugs that may prolong the QT interval. Acute cardiotoxicity can occur during administration of daunorubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Degarelix: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with degarelix. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Degarelix can also cause QT prolongation. Prescribers need to weigh the potential benefits and risks of degarelix use in patients with prolonged QT syndrome or in patients taking other QT prolonging drugs.
    Delavirdine: Delavirdine is a potent inhibitor of the CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as tolterodine, should be expected with concurrent use of delavirdine.
    Desvenlafaxine: 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.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: Drugs that decrease GI motility may increase the risk of GI irritation from sustained-release solid oral dosage forms of potassium salts. Examples of drugs that significantly decrease GI motility include the antimuscarinics. In one study, healthy subjects were examined for GI irritation following the administration of oral potassium for at least 7 days. Glycopyrrolate was coadministered to some subjects in order to study the additional effects of delayed gastric emptying. Results indicated that subjects administered wax-matrix tablets had the highest incidence of erosions (43%) and ulcers (11%). Evidence of GI irritation was less frequent among subjects receiving liquid (0%) and microencapsulated (10.5% erosions, 1.2% ulcers) formulations. Therefore, if oral potassium supplementation is necessary in a patient taking antimuscarinics, a liquid formulation should be considered. If a solid formulation is being prescribed, the patient should be counseled on strategies that can be used to avoid GI irritation such as taking potassium products only while seated or standing, remaining upright for 10 minutes after each dose, and ingesting each dose with plenty of fluids.
    Dextromethorphan; Promethazine: Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include tolterodine,
    Dextromethorphan; Quinidine: 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: 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: 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.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Diltiazem: In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. CYP3A4 inhibitors include diltiazem.
    Diphenhydramine; Hydrocodone; Phenylephrine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Disopyramide: 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: Because of the potential for torsades de pointes (TdP), use of tolterodine and dofetilide is contraindicated. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP.
    Dolasetron: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with dolasetron. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Dolasetron has also been associated with a dose-dependant prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Use of dolasetron injection for the prevention of chemotherapy-induced nausea and vomiting is contraindicated because the risk of QT prolongation is higher with the doses required for this indication; when the injection is used at lower doses (i.e., those approved for post-operative nausea and vomiting) or when the oral formulation is used, the risk of QT prolongation is lower and caution is advised.
    Donepezil: 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: 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.
    Doxorubicin: Tolterodine has been associated dose-dependent prolongation of the QT interval. This should be taken into consideration when prescribing tolterodine to patients taking other drugs that are associated with QT prolongation. Tolterodine should be used cautiously with other drugs that may prolong the QT interval. Acute cardiotoxicity can occur during administration of doxorubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Dronedarone: 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: Concurrent use of droperidol and tolterodine should be avoided due to an increased risk for QT 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: Although data are limited, coadministration of efavirenz and tolterodine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with 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: Although data are limited, coadministration of efavirenz and tolterodine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with 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: 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: 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).
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with rilpivirine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with rilpivirine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Epirubicin: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with epirubicin. Tolterodine has been associated dose-dependent prolongation of the QT interval. Acute cardiotoxicity can also occur during administration of epirubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Eribulin: 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: 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.
    Erythromycin; Sulfisoxazole: 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: Escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as tolterodine, should be done with caution and close monitoring.
    Ethanol: Beverages containing ethanol may aggravate bladder symptoms and counteract the effectiveness of tolterodine to some degree. Patients may wish to limit their intake of alcoholic beverages.
    Ezogabine: Tolterodine should be used cautiously and with close monitoring with ezogabine. Ezogabine has been associated with QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In addition, caution is advisable during concurrent use of ezogabine and medications that may affect voiding such as antimuscarinics. Ezogabine has caused urinary retention requiring catheterization in some cases. Additive drowsiness or other CNS effects may also occur.
    Fentanyl: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Fesoterodine: 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.
    Fingolimod: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering fingolimod with tolterodine. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of TdP. 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: 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: 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: 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: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Tolterodine is associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6. In addition, a pharmacokinetic interaction does occur with coadministration but no dosage adjustment is required. Fluoxetine is a potent inhibitor of CYP2D6 and significantly inhibits the metabolism of tolterodine in extensive metabolizers. In a pharmacokinetic interaction study, there was a 4.8 fold increase in tolterodine AUC following concomitant administration with fluoxetine. The sums of unbound serum concentrations of tolterodine and the 5-hydroxymethyl metabolite of tolterodine are only 25% higher during the interaction, however.
    Fluoxetine; Olanzapine: Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Tolterodine is associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6. In addition, a pharmacokinetic interaction does occur with coadministration but no dosage adjustment is required. Fluoxetine is a potent inhibitor of CYP2D6 and significantly inhibits the metabolism of tolterodine in extensive metabolizers. In a pharmacokinetic interaction study, there was a 4.8 fold increase in tolterodine AUC following concomitant administration with fluoxetine. The sums of unbound serum concentrations of tolterodine and the 5-hydroxymethyl metabolite of tolterodine are only 25% higher during the interaction, however. 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 addtion, 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.
    Fluphenazine: 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: 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 should not receive greater than 2 mg per day of tolterodine.
    Fosamprenavir: 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. CYP3A4 inhibitors include anti-retroviral protease inhibitors. In addition, ritonavir and delavirdine inhibit CYP2D6. 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.
    Galantamine: 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.
    Gallium Ga 68 Dotatate: Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Gefitinib: Monitor for an increased incidence of tolterodine-related adverse effects if gefitinib and tolterodine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of tolterodine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); however, the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated.
    Gemifloxacin: 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.
    Glucosamine: Drugs that decrease GI motility may increase the risk of GI irritation from sustained-release solid oral dosage forms of potassium salts. Examples of drugs that significantly decrease GI motility include the antimuscarinics. In one study, healthy subjects were examined for GI irritation following the administration of oral potassium for at least 7 days. Glycopyrrolate was coadministered to some subjects in order to study the additional effects of delayed gastric emptying. Results indicated that subjects administered wax-matrix tablets had the highest incidence of erosions (43%) and ulcers (11%). Evidence of GI irritation was less frequent among subjects receiving liquid (0%) and microencapsulated (10.5% erosions, 1.2% ulcers) formulations. Therefore, if oral potassium supplementation is necessary in a patient taking antimuscarinics, a liquid formulation should be considered. If a solid formulation is being prescribed, the patient should be counseled on strategies that can be used to avoid GI irritation such as taking potassium products only while seated or standing, remaining upright for 10 minutes after each dose, and ingesting each dose with plenty of fluids.
    Glycopyrrolate: 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: 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.
    Goserelin: Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with goserelin include tolterodine.
    Granisetron: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering granisetron with tolterodine. 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: 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: 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: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Guaifenesin; Hydrocodone; Pseudoephedrine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Guaifenesin; Potassium Guaiacolsulfonate: Drugs that decrease GI motility may increase the risk of GI irritation from sustained-release solid oral dosage forms of potassium salts. Examples of drugs that significantly decrease GI motility include the antimuscarinics. In one study, healthy subjects were examined for GI irritation following the administration of oral potassium for at least 7 days. Glycopyrrolate was coadministered to some subjects in order to study the additional effects of delayed gastric emptying. Results indicated that subjects administered wax-matrix tablets had the highest incidence of erosions (43%) and ulcers (11%). Evidence of GI irritation was less frequent among subjects receiving liquid (0%) and microencapsulated (10.5% erosions, 1.2% ulcers) formulations. Therefore, if oral potassium supplementation is necessary in a patient taking antimuscarinics, a liquid formulation should be considered. If a solid formulation is being prescribed, the patient should be counseled on strategies that can be used to avoid GI irritation such as taking potassium products only while seated or standing, remaining upright for 10 minutes after each dose, and ingesting each dose with plenty of fluids.
    Guarana: Caffeine is an active constituent of guarana. Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms and counteract the effectiveness of drugs used to treat overactive bladder (i.e., darifenacin, oxybutynin, trospium, or tolterodine) to some degree.
    Halogenated Anesthetics: 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: 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.
    Hetastarch; Dextrose; Electrolytes: Drugs that decrease GI motility may increase the risk of GI irritation from sustained-release solid oral dosage forms of potassium salts. Examples of drugs that significantly decrease GI motility include the antimuscarinics. In one study, healthy subjects were examined for GI irritation following the administration of oral potassium for at least 7 days. Glycopyrrolate was coadministered to some subjects in order to study the additional effects of delayed gastric emptying. Results indicated that subjects administered wax-matrix tablets had the highest incidence of erosions (43%) and ulcers (11%). Evidence of GI irritation was less frequent among subjects receiving liquid (0%) and microencapsulated (10.5% erosions, 1.2% ulcers) formulations. Therefore, if oral potassium supplementation is necessary in a patient taking antimuscarinics, a liquid formulation should be considered. If a solid formulation is being prescribed, the patient should be counseled on strategies that can be used to avoid GI irritation such as taking potassium products only while seated or standing, remaining upright for 10 minutes after each dose, and ingesting each dose with plenty of fluids.
    Homatropine; Hydrocodone: 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. Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Hydrocodone: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Hydrocodone; Ibuprofen: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Hydrocodone; Phenylephrine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Hydrocodone; Potassium Guaiacolsulfonate: Drugs that decrease GI motility may increase the risk of GI irritation from sustained-release solid oral dosage forms of potassium salts. Examples of drugs that significantly decrease GI motility include the antimuscarinics. In one study, healthy subjects were examined for GI irritation following the administration of oral potassium for at least 7 days. Glycopyrrolate was coadministered to some subjects in order to study the additional effects of delayed gastric emptying. Results indicated that subjects administered wax-matrix tablets had the highest incidence of erosions (43%) and ulcers (11%). Evidence of GI irritation was less frequent among subjects receiving liquid (0%) and microencapsulated (10.5% erosions, 1.2% ulcers) formulations. Therefore, if oral potassium supplementation is necessary in a patient taking antimuscarinics, a liquid formulation should be considered. If a solid formulation is being prescribed, the patient should be counseled on strategies that can be used to avoid GI irritation such as taking potassium products only while seated or standing, remaining upright for 10 minutes after each dose, and ingesting each dose with plenty of fluids. Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: Drugs that decrease GI motility may increase the risk of GI irritation from sustained-release solid oral dosage forms of potassium salts. Examples of drugs that significantly decrease GI motility include the antimuscarinics. In one study, healthy subjects were examined for GI irritation following the administration of oral potassium for at least 7 days. Glycopyrrolate was coadministered to some subjects in order to study the additional effects of delayed gastric emptying. Results indicated that subjects administered wax-matrix tablets had the highest incidence of erosions (43%) and ulcers (11%). Evidence of GI irritation was less frequent among subjects receiving liquid (0%) and microencapsulated (10.5% erosions, 1.2% ulcers) formulations. Therefore, if oral potassium supplementation is necessary in a patient taking antimuscarinics, a liquid formulation should be considered. If a solid formulation is being prescribed, the patient should be counseled on strategies that can be used to avoid GI irritation such as taking potassium products only while seated or standing, remaining upright for 10 minutes after each dose, and ingesting each dose with plenty of fluids. Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Hydrocodone; Pseudoephedrine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Hydroxyzine: Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include tolterodine.
    Hyoscyamine: 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: 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.
    Ibritumomab Tiuxetan: Drugs that decrease GI motility may increase the risk of GI irritation from sustained-release solid oral dosage forms of potassium salts. Examples of drugs that significantly decrease GI motility include the antimuscarinics. In one study, healthy subjects were examined for GI irritation following the administration of oral potassium for at least 7 days. Glycopyrrolate was coadministered to some subjects in order to study the additional effects of delayed gastric emptying. Results indicated that subjects administered wax-matrix tablets had the highest incidence of erosions (43%) and ulcers (11%). Evidence of GI irritation was less frequent among subjects receiving liquid (0%) and microencapsulated (10.5% erosions, 1.2% ulcers) formulations. Therefore, if oral potassium supplementation is necessary in a patient taking antimuscarinics, a liquid formulation should be considered. If a solid formulation is being prescribed, the patient should be counseled on strategies that can be used to avoid GI irritation such as taking potassium products only while seated or standing, remaining upright for 10 minutes after each dose, and ingesting each dose with plenty of fluids.
    Ibuprofen; Oxycodone: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Ibutilide: 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.
    Idarubicin: Tolterodine has been associated dose-dependent prolongation of the QT interval. This should be taken into consideration when prescribing tolterodine to patients taking other drugs that are associated with QT prolongation. Tolterodine should be used cautiously with other drugs that may prolong the QT interval. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Idelalisib: Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with tolterodine, a CYP3A substrate, as tolterodine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: 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, STI-571: 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: 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: 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. CYP3A4 inhibitors include anti-retroviral protease inhibitors. In addition, ritonavir and delavirdine inhibit CYP2D6. 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.
    Iodine; Potassium Iodide, KI: Drugs that decrease GI motility may increase the risk of GI irritation from sustained-release solid oral dosage forms of potassium salts. Examples of drugs that significantly decrease GI motility include the antimuscarinics. In one study, healthy subjects were examined for GI irritation following the administration of oral potassium for at least 7 days. Glycopyrrolate was coadministered to some subjects in order to study the additional effects of delayed gastric emptying. Results indicated that subjects administered wax-matrix tablets had the highest incidence of erosions (43%) and ulcers (11%). Evidence of GI irritation was less frequent among subjects receiving liquid (0%) and microencapsulated (10.5% erosions, 1.2% ulcers) formulations. Therefore, if oral potassium supplementation is necessary in a patient taking antimuscarinics, a liquid formulation should be considered. If a solid formulation is being prescribed, the patient should be counseled on strategies that can be used to avoid GI irritation such as taking potassium products only while seated or standing, remaining upright for 10 minutes after each dose, and ingesting each dose with plenty of fluids.
    Isavuconazonium: 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: Itraconazole is a potent inhibitor of CYP3A4. Coadministration of itraconazole with drugs that are CYP3A4 substrates that also prolong the QT interval, such as tolterodine, may result in an elevated plasma concentrations of that substrate and an increased risk for adverse events, including QT prolongation. In addition, itraconazole has been associated with QT prolongation. The manufacturer of itraconazole states that concomitant use of drugs that are known to prolong that QT interval and are metabolized by CYP3A4 may be contraindicated with itraconazole; however, the manufacturer of posaconazole, another systemic azole with potent inhibitory activity against CYP3A4, contraindicates the use of posaconazole with drugs that prolong the QT interval and are metabolized by CYP3A4. Because itraconazole also is a potent inhibitor of CYP3A4, it would be prudent to follow the same recommendations. It also is prudent to not use tolterodine for up to 2 weeks after discontinuation of itraconazole treatment unless benefits of treatment outweigh the potentially increased risk of side effects.
    Ivacaftor: Use caution when administering ivacaftor and tolterodine concurrently. Ivacaftor is an inhibitor of CYP3A and tolterodine is partially metabolized by CYP3A. Co-administration can theoretically increase tolterodine exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Ketoconazole: Coadministration of ketoconazole with drugs that are CYP3A4 substrates that also prolong the QT interval may result in an elevated plasma concentrations of that substrate and an increased risk for adverse events, including QT prolongation. Ketoconazole in itself can prolong the QT interval. In addition, ketoconazole is a potent inhibitor of CYP3A4. The manufacturer of ketoconazole states that concomitant use of drugs that are known to prolong that QT interval and are metabolized by CYP3A4 may be contraindicated with ketoconazole; however, the manufacturer of posaconazole, another systemic azole with potent inhibitory activity against CYP3A4, contraindicates the use of posaconazole with drugs that prolong the QT interval and are metabolized by CYP3A4. Because ketoconazole also is a potent inhibitor of CYP3A4, it would be prudent to follow the same recommendations. Drugs that prolong QT and are substrates for CYP3A4 include tolterodine. In addition, ketoconazole requires an acidic pH for oral absorption. Medications that increase gastric pH or decrease acid output can cause a notable decrease in the bioavailability of ketoconazole. Medications that have this effect include antimuscarinics.
    Lapatinib: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering lapatinib with tolterodine. Lapatinib 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 who are poor CYP2D6 metabolizers, patients receiving CYP3A4 inhibitors, such as lapatinib, should be monitored closely for adverse events. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed.
    Lenvatinib: Tolterodine should be used cautiously and with close monitoring with lenvatinib. 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. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 tmes the recommended daily dose) in healthy subjects.
    Leuprolide: Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with leuprolide include tolterodine.
    Leuprolide; Norethindrone: Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with leuprolide include tolterodine.
    Levofloxacin: Concurrent use of levofloxacin 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. Levofloxacin has also been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Rare cases of TdP have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin.
    Levorphanol: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Lithium: 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.
    Long-acting beta-agonists: 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. Drugs with a possible risk for QT prolongation that should be used cautiously with tolterodine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Loop diuretics: Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Loperamide: 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: 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: 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. CYP3A4 inhibitors include anti-retroviral protease inhibitors. In addition, ritonavir and delavirdine inhibit CYP2D6. 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 addition, both ritonavir and tolterodine are associated with QT prolongation; concomitant use increases the risk of QT prolongation. Tolterodine should be used cautiously and with close monitoring with lopinavir; ritonavir. Lopinavir; ritonavir administration is associated with QT prolongation. Coadministration of lopinavir; ritonavir with other drugs that prolong the QT interval may result in additive QT prolongation. In addition, lopinavir; ritonavir inhibits CYP3A4 metabolism. Coadministration with drugs that are substrates of CYP3A4, such as tolterodine, may result in elevated plasma concentrations and an added risk of adverse reactions such as QT prolongation.
    Luliconazole: Theoretically, luliconazole may increase the side effects of tolterodine. Tolterodine is metabolized primarily by CYP2D6 and, alternatively, CYP3A4 in those patients who are poor CYP2D6 metabolizers; however, it is difficult to assess which patients will be poor CYP2D6 metabolizers. Monitor patients for adverse effects of tolterodine, such as QT prolongation which is dose-dependent, especially in poor CYP2D6 metabolizers. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP (2C19 or 3A4) and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
    Lumacaftor; Ivacaftor: Use caution when administering ivacaftor and tolterodine concurrently. Ivacaftor is an inhibitor of CYP3A and tolterodine is partially metabolized by CYP3A. Co-administration can theoretically increase tolterodine exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Lurasidone: 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.
    Magnesium Sulfate; Potassium Sulfate; Sodium Sulfate: Drugs that decrease GI motility may increase the risk of GI irritation from sustained-release solid oral dosage forms of potassium salts. Examples of drugs that significantly decrease GI motility include the antimuscarinics. In one study, healthy subjects were examined for GI irritation following the administration of oral potassium for at least 7 days. Glycopyrrolate was coadministered to some subjects in order to study the additional effects of delayed gastric emptying. Results indicated that subjects administered wax-matrix tablets had the highest incidence of erosions (43%) and ulcers (11%). Evidence of GI irritation was less frequent among subjects receiving liquid (0%) and microencapsulated (10.5% erosions, 1.2% ulcers) formulations. Therefore, if oral potassium supplementation is necessary in a patient taking antimuscarinics, a liquid formulation should be considered. If a solid formulation is being prescribed, the patient should be counseled on strategies that can be used to avoid GI irritation such as taking potassium products only while seated or standing, remaining upright for 10 minutes after each dose, and ingesting each dose with plenty of fluids.
    Mannitol: Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Maprotiline: 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: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with mefloquine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. There is also 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. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
    Mepenzolate: 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.
    Meperidine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Meperidine; Promethazine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists. Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include tolterodine,
    Methadone: The need to coadminister methadone with tolterodine should be done with extreme caution and a careful assessment of treatment risks versus benefits. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. 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. In addition, coadministration may result in additive depressive effects on GI motility or bladder function. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use.
    Methazolamide: Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: 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: 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.
    Metoclopramide: Tolterodine has antimuscarinic activity and may slow GI motility.in some patients and thus may potentially reduce the actions of drugs that enhance gastrointestinal motility, like metoclopramide. Monitor patients for an increase in gastrointestinal complaints, such as reflux or constipation. Additive drowsiness may occur rarely. The clinical significance of this potential interaction is uncertain.
    Metronidazole: Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include tolterodine.
    Mifepristone, RU-486: Due to a possible risk for QT prolongation and torsade de pointes (TdP), mifepristone and tolterodine should be used together cautiously. Mifepristone has been associated with dose-dependent prolongation of the QT interval. There is no experience with high exposure or concomitant use with other QT prolonging drugs. To minimize the risk of QT prolongation, the lowest effective dose should always be used. Drugs with a possible risk for QT prolongation and torsades de pointes that should be used cautiously with mifepristone include tolterodine.
    Mirabegron: Mirabegron is a moderate CYP2D6 inhibitor and substrate. Exposure of drugs metabolized by CYP2D6 such as tolterodine may be increased when co-administered with mirabegron. Tolterodine is primarily metabolized by CYP2D6. In vitro data show that while tolterodine is a competitive inhibitor of CYP2D6 at high concentrations; clinically relevant drug interactions from the in vivo inhibition of CYP2D6 do not occur. Mirabegron should also be administered with caution in patients taking antimuscarinic medications for the treatment of overactive bladder and in bladder obstruction because of the risk of urinary retention. Appropriate monitoring and dose adjustment may be necessary.
    Mitotane: 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.
    Morphine: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Morphine; Naltrexone: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Moxifloxacin: 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.
    Nefazodone: In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. CYP3A4 inhibitors include nefazodone.
    Nelfinavir: 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. CYP3A4 inhibitors include anti-retroviral protease inhibitors. In addition, ritonavir and delavirdine inhibit CYP2D6. 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.
    Nilotinib: Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Nilotinib is an inhibitor of CYP3A4 and CYP2D6 and tolterodine is a CYP3A4 and CYP2D6 substrate; administering these drugs together may result in increased tolterodine levels. If the use of tolterodine is required, hold nilotinib therapy. If the use of nilotinib and tolterodine cannot be avoided, a tolterodine dose reduction may be necessary; close monitoring of the QT interval is recommended.
    Norfloxacin: 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 norfloxacin.
    Octreotide: Administer octreotide cautiously in patients receiving drugs that prolong the QT interval. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy, warranting more cautious monitoring during octreotide administration in higher risk patients with cardiac disease. Since bradycardia is a risk factor for development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval. Until further data are available, it is suggested to use octreotide cautiously in patients receiving drugs which prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with octreotide include tolterodine. Also, antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. Other drugs that also decrease GI motility, such as tolterodine, may produce additive effects with antidiarrheals if used concomitantly.
    Ofloxacin: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with ofloxacin. Some quinolones, including ofloxacin, have been associated with QT prolongation and infrequent cases of arrhythmia. Post-marketing surveillance for ofloxacin has identified very rare cases of TdP. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Olanzapine: 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 addtion, 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.
    Ombitasvir; Paritaprevir; Ritonavir: 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. CYP3A4 inhibitors include anti-retroviral protease inhibitors. In addition, ritonavir and delavirdine inhibit CYP2D6. 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 addition, both ritonavir and tolterodine are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
    Ondansetron: 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: 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: 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.
    Osimertinib: Osimertinib should be used cautiously and with close monitoring with tolterodine. Osimertinib causes concentration dependent prolongation of the QT interval at recommended dosing. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Coadministration may further increase the risk of QT prolongation.
    Oxaliplatin: 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. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with tolterodine include oxaliplatin. QT prolongation and ventricular arrhythmias including fatal Torsade de Pointes have been reported with oxaliplatin use in post-marketing experience.
    Oxybutynin: 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: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Oxymorphone: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Paliperidone: Concurrent use of paliperidone and tolterodine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If coadministration is considered necessary by the practitioner, and the patient has known risk factors for cardiac disease or arrhythmia, then 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.
    Panobinostat: 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: Paroxetine may inhibit the CYP2D6 metabolism of tolterodine in extensive metabolizers.
    Pasireotide: Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers and should be used cautiously and with close monitoring with pasireotide as coadministration may have additive effects on the prolongation of the QT interval.
    Pazopanib: 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: 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: 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.
    Perflutren Lipid Microspheres: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with perflutren lipid microspheres. 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. Perflutren lipid microspheres has also been associated with QT prolongation.
    Perflutren Protein-Type A Microspheres: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with perflutren lipid microspheres. 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. Perflutren lipid microspheres has also been associated with QT prolongation.
    Perphenazine: Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.Theoretically, perphenazine 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 perphenazine include tolterodine. 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: Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.Theoretically, perphenazine 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 perphenazine include tolterodine. 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.
    Phentermine; Topiramate: 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.
    Phenylephrine; Promethazine: Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include tolterodine,
    Pimavanserin: 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: 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.
    Posaconazole: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering posaconazole with tolterodine. Posaconazole 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 who are poor CYP2D6 metabolizers, patients receiving CYP3A4 inhibitors, such as posaconazole, should not receive > 2 mg/day of tolterodine. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed.
    Potassium Citrate: Drugs that decrease GI motility may increase the risk of GI irritation from sustained-release solid oral dosage forms of potassium salts. Examples of drugs that significantly decrease GI motility include the antimuscarinics. In one study, healthy subjects were examined for GI irritation following the administration of oral potassium for at least 7 days. Glycopyrrolate was coadministered to some subjects in order to study the additional effects of delayed gastric emptying. Results indicated that subjects administered wax-matrix tablets had the highest incidence of erosions (43%) and ulcers (11%). Evidence of GI irritation was less frequent among subjects receiving liquid (0%) and microencapsulated (10.5% erosions, 1.2% ulcers) formulations. Therefore, if oral potassium supplementation is necessary in a patient taking antimuscarinics, a liquid formulation should be considered. If a solid formulation is being prescribed, the patient should be counseled on strategies that can be used to avoid GI irritation such as taking potassium products only while seated or standing, remaining upright for 10 minutes after each dose, and ingesting each dose with plenty of fluids.
    Potassium Iodide, KI: Drugs that decrease GI motility may increase the risk of GI irritation from sustained-release solid oral dosage forms of potassium salts. Examples of drugs that significantly decrease GI motility include the antimuscarinics. In one study, healthy subjects were examined for GI irritation following the administration of oral potassium for at least 7 days. Glycopyrrolate was coadministered to some subjects in order to study the additional effects of delayed gastric emptying. Results indicated that subjects administered wax-matrix tablets had the highest incidence of erosions (43%) and ulcers (11%). Evidence of GI irritation was less frequent among subjects receiving liquid (0%) and microencapsulated (10.5% erosions, 1.2% ulcers) formulations. Therefore, if oral potassium supplementation is necessary in a patient taking antimuscarinics, a liquid formulation should be considered. If a solid formulation is being prescribed, the patient should be counseled on strategies that can be used to avoid GI irritation such as taking potassium products only while seated or standing, remaining upright for 10 minutes after each dose, and ingesting each dose with plenty of fluids.
    Potassium Phosphate; Sodium Phosphate: Drugs that decrease GI motility may increase the risk of GI irritation from sustained-release solid oral dosage forms of potassium salts. Examples of drugs that significantly decrease GI motility include the antimuscarinics. In one study, healthy subjects were examined for GI irritation following the administration of oral potassium for at least 7 days. Glycopyrrolate was coadministered to some subjects in order to study the additional effects of delayed gastric emptying. Results indicated that subjects administered wax-matrix tablets had the highest incidence of erosions (43%) and ulcers (11%). Evidence of GI irritation was less frequent among subjects receiving liquid (0%) and microencapsulated (10.5% erosions, 1.2% ulcers) formulations. Therefore, if oral potassium supplementation is necessary in a patient taking antimuscarinics, a liquid formulation should be considered. If a solid formulation is being prescribed, the patient should be counseled on strategies that can be used to avoid GI irritation such as taking potassium products only while seated or standing, remaining upright for 10 minutes after each dose, and ingesting each dose with plenty of fluids.
    Potassium Salts: Drugs that decrease GI motility may increase the risk of GI irritation from sustained-release solid oral dosage forms of potassium salts. Examples of drugs that significantly decrease GI motility include the antimuscarinics. In one study, healthy subjects were examined for GI irritation following the administration of oral potassium for at least 7 days. Glycopyrrolate was coadministered to some subjects in order to study the additional effects of delayed gastric emptying. Results indicated that subjects administered wax-matrix tablets had the highest incidence of erosions (43%) and ulcers (11%). Evidence of GI irritation was less frequent among subjects receiving liquid (0%) and microencapsulated (10.5% erosions, 1.2% ulcers) formulations. Therefore, if oral potassium supplementation is necessary in a patient taking antimuscarinics, a liquid formulation should be considered. If a solid formulation is being prescribed, the patient should be counseled on strategies that can be used to avoid GI irritation such as taking potassium products only while seated or standing, remaining upright for 10 minutes after each dose, and ingesting each dose with plenty of fluids.
    Potassium: Drugs that decrease GI motility may increase the risk of GI irritation from sustained-release solid oral dosage forms of potassium salts. Examples of drugs that significantly decrease GI motility include the antimuscarinics. In one study, healthy subjects were examined for GI irritation following the administration of oral potassium for at least 7 days. Glycopyrrolate was coadministered to some subjects in order to study the additional effects of delayed gastric emptying. Results indicated that subjects administered wax-matrix tablets had the highest incidence of erosions (43%) and ulcers (11%). Evidence of GI irritation was less frequent among subjects receiving liquid (0%) and microencapsulated (10.5% erosions, 1.2% ulcers) formulations. Therefore, if oral potassium supplementation is necessary in a patient taking antimuscarinics, a liquid formulation should be considered. If a solid formulation is being prescribed, the patient should be counseled on strategies that can be used to avoid GI irritation such as taking potassium products only while seated or standing, remaining upright for 10 minutes after each dose, and ingesting each dose with plenty of fluids.
    Potassium-sparing diuretics: Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Primaquine: Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include tolterodine.
    Procainamide: 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: 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: Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with promethazine include tolterodine,
    Propafenone: 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: 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.
    Propoxyphene: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Proton pump inhibitors: 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: Concurrent use of quetiapine 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. Limited data, including some case reports, suggest that quetiapine may also be associated with a significant prolongation of the QTc interval in rare instances.
    Quinidine: 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: 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.
    Ranolazine: Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation, such as tolterodine. 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 other drugs that are associated with QT prolongation. 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; however, ranolazine is a CYP3A4 inhibitor. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes and tolterodine is a CYP2D6 substrate. Coadministration may result in increased tolterodine serum concentrations.
    Regadenoson: Regadenoson has been associated with QT prolongation. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with regadenoson include tolterodine.
    Remifentanil: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Rilpivirine: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with rilpivirine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Risperidone: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with risperidone. If coadministration is chosen, and the patient has known risk factors for cardiac disease or arrhythmia, then the patient should be closely monitored clinically. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Risperidone has also been associated with a possible risk for QT prolongation and/or TdP; however, data are currently lacking to establish causality in association with TdP. Reports of QT prolongation and TdP during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting.
    Ritonavir: 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. CYP3A4 inhibitors include anti-retroviral protease inhibitors. In addition, ritonavir and delavirdine inhibit CYP2D6. 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 addition, both ritonavir and tolterodine are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
    Rivastigmine: 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: 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 lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration.
    Romidepsin: Due to a possible risk for QT prolongation and torsade de pointes (TdP), romidepsin and tolterodine should be used together cautiously. Romidepsin has been reported to prolong the QT interval. If romidepsin must be coadministered with another drug that prolongs the QT interval, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. 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.
    Saquinavir: 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 other drugs that are associated with QT prolongation, such as saquinavir. Furthermore, saquinavir is a strong CYP3A4 inhibitor and patients should not receive > 2 mg/day of tolterodine during concurrent use. 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.
    Scopolamine: 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.
    Sertraline: 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. There have been post-marketing reports of QT prolongation and Torsade de Pointes (TdP) during treatment with sertraline; therefore, caution is advisable when using sertraline in patients with risk factors for QT prolongation, including concurrent use of other drugs that prolong the QTc interval.
    Short-acting beta-agonists: 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. Drugs with a possible risk for QT prolongation that should be used cautiously with tolterodine include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Simeprevir: Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of tolterodine, which is a CYP3A4 substrate.Tolterodine is metabolized primarily by CYP2D6 and, alternatively, CYP3A4 in those patients who are poor CYP2D6 metabolizers; however, it is difficult to assess which patients will be poor CYP2D6 metabolizers. Monitor patients for adverse effects of tolterodine, such as QT prolongation which is dose-dependent, especially in poor CYP2D6 metabolizers.
    Solifenacin: 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: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with sorafenib. 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. Sorafenib has also been associated with QT prolongation.
    Sotalol: 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: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. Opioids 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: QT prolongation resulting in ventricular tachycardia and torsade de pointes (TdP) have been reported during post-marketing use of sulfamethoxazole; trimethoprim. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with sulfamethoxazole; trimethoprim include tolterodine.
    Sunitinib: Due to a possible risk for QT prolongation and torsade de pointes (TdP), sunitinib and tolterodine should be used together cautiously. Sunitinib 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.
    Tacrine: 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.
    Tacrolimus: Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tolterodine should be used together cautiously. Tacrolimus causes QT prolongation. 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.
    Tegaserod: 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.
    Telaprevir: Close clinical monitoring is advised when administering tolterodine with telaprevir due to an increased potential for tolterodine-related adverse events. If tolterodine dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of tolterodine. Tolterodine is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated tolterodine plasma concentrations.
    Telavancin: 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.
    Telithromycin: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telithromycin with tolterodine. Telithromycin 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 who are poor CYP2D6 metabolizers, patients receiving CYP3A4 inhibitors, such as telithromycin, should not receive > 2 mg/day of tolterodine. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed.
    Tetrabenazine: 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: Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Thioridazine: 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: 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. CYP3A4 inhibitors include anti-retroviral protease inhibitors. In addition, ritonavir and delavirdine inhibit CYP2D6. 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.
    Tizanidine: Tizanidine should be used cautiously and with close monitoring with tolterodine. Tizanidine administration may result in QT prolongation. 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.
    Topiramate: 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: Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with toremifene. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Trandolapril; Verapamil: 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: 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.
    Tricyclic antidepressants: 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: 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: 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: Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with triptorelin include tolterodine.
    Urea: Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Vandetanib: Concurrent use of vandetanib and tolterodine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If tolterodine is given to a patient already taking vandetanib and no alternative therapy exists, perform more frequent monitoring of the QT interval with an ECG. If QTcF is > 500 ms, interrupt vandetanib dosing until the QTcF is < 450 ms - vandetanib may be resumed at a reduced dose. 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: 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: 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: 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: 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.
    Voriconazole: Voriconazole has been associated with QT prolongation and rare cases of torsades de pointes and also is an inhibitor of CYP3A4 isoenzyme. Drugs that are substrates for CYP3A4, when combined with voriconazole, may theoretically have reduced metabolism, and therefore higher serum concentrations resulting in toxicity. The manufacturer of posaconazole, another systemic azole with potent inhibitory activity against CYP3A4, contraindicates the use of posaconazole with drugs that prolong the QT interval and are metabolized by CYP3A4. Because voriconazole also is a potent inhibitor of CYP3A4, it would be prudent to follow the same recommendations. Drugs that prolong QT and are substrates for CYP3A4 include tolterodine.
    Vorinostat: 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: 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: Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as tolterodine.
    Ziprasidone: According to the manufacturer, ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsades de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation. In one study, ziprasidone increased the QT interval 10 msec more than placebo at the maximum recommended dosage. Comparative data with other antipsychotics have shown that the mean QTc interval prolongation occurring with ziprasidone exceeds that of haloperidol, quetiapine, olanzapine, and risperidone, but is less than that which occurs with thioridazine. Given the potential for QT prolongation, ziprasidone is contraindicated for use with drugs that are known to cause QT prolongation with potential for torsades de pointes including tolterodine.

    PREGNANCY AND LACTATION

    Pregnancy

    Tolterodine is classified as FDA pregnancy risk category C. There are no studies of tolterodine in pregnant women. Tolterodine should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.

    The manufacturer recommends discontinuation of tolterodine during breast-feeding. Animal data show that tolterodine is excreted into the milk of mice, however, it is not known whether tolterodine is excreted in human milk. In addition, chronic use of tolterodine may decrease milk production.

    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.