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  • CLASSES

    Antimuscarinics

    DEA CLASS

    Rx

    DESCRIPTION

    Oral competitive selective antimuscarinic (M3); reduces incontinence episodes and urinary urgency
    Used for treatment of overactive bladder (OAB) in adults; used as monotherapy or in combination with a beta-3 adrenoreceptor agonist if needed
    Comparable to oxybutynin in efficacy; less dry mouth and CNS side effects

    COMMON BRAND NAMES

    Enablex

    HOW SUPPLIED

    Darifenacin/Enablex Oral Tab ER: 7.5mg, 15mg

    DOSAGE & INDICATIONS

    For the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urinary urgency, and urinary frequency.
    Oral dosage
    Adults

    7.5 mg PO once daily, initially. May increase dose to 15 mg PO once daily after 2 weeks if needed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    MAXIMUM DOSAGE

    Adults

    15 mg/day PO.

    Geriatric

    15 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild hepatic impairment (Child-Pugh A): No dosage adjustment needed.
    Moderate liver impairment (Child-Pugh class B): Do not exceed 7.5 mg PO once daily.
    Severe hepatic impairment (Child-Pugh class C): Use is not recommended.

    Renal Impairment

    No dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Extended-release tablets:
    Have the patient swallow the extended-release tablets whole with water; do not chew, divide, or crush.
    May take with or without food. Administer at approximately the same time daily.

    STORAGE

    Enablex:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    History of angioedema

    Darifenacin is contraindicated in patients who have demonstrated darifenacin hypersensitivity or a history of angioedema with the drug. Reports of angioedema of the face, lips, tongue, and/or larynx have been associated with darifenacin use. Angioedema has occurred, in some cases, after a single dose. Patients taking darifenacin should be informed of the risk of this adverse reaction and instructed to immediately discontinue the drug if swelling of the tongue, hypopharynx, or larynx occurs. Because upper airway swelling could be life threatening, patients may need emergent care to ensure a patent airway is promptly provided.

    Bladder obstruction, prostatic hypertrophy, urinary retention, urinary tract obstruction

    Due to the anticholinergic effects, darifenacin is contraindicated in patients with urinary retention. Anticholinergics may precipitate urinary retention in patients with preexisting urinary tract obstruction or bladder obstruction. Use cautiously in patients with potential risk for urinary retention, including prostatic hypertrophy.

    Anticholinergic medications, autonomic neuropathy, constipation, gastroparesis, GI obstruction, ileus, myasthenia gravis, pyloric stenosis, ulcerative colitis

    Darifenacin should be administered with caution to patients with gastrointestinal (GI) obstructive disorders because of the risk of gastric retention. Darifenacin may delay gastric emptying and is contraindicated in patients with gastric retention (i.e., GI obstruction, ileus, gastroparesis, pyloric stenosis). Darifenacin, like other anticholinergic drugs, may decrease GI motility and should be used with caution in patients with conditions such as severe constipation, ulcerative colitis, and myasthenia gravis. Anticholinergics may in general aggravate conditions such as myasthenia gravis and autonomic neuropathy. Patients receiving darifenacin in combination with other anticholinergic medications may experience an increased frequency or severity of dry mouth, constipation, blurred vision, or other anticholinergic effects.

    Closed-angle glaucoma, contact lenses

    Darifenacin is contraindicated in patients with uncontrolled narrow-angle or closed-angle glaucoma. Darifenacin may increase intraocular pressure and aqueous outflow resistance in patients with controlled closed-angle glaucoma and caution is advised; initiate treatment with darifenacin only if the potential benefits outweigh risks. The anticholinergic effects of darifenacin may make the eyes dry, and dry eyes can cause irritation for wearers of contact lenses.

    Driving or operating machinery

    Darifenacin is associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported, including headache, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients to use caution with driving or operating machinery, or performing other hazardous tasks, until they know how darifenacin affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

    Hepatic disease

    The daily dose of darifenacin should not exceed 7.5 mg for patients with moderate hepatic disease (Child-Pugh B). Darifenacin has not been studied in patients with severe hepatic impairment (Child-Pugh C) and therefore is not recommended for use in this patient population.

    Pregnancy

    There are no data available regarding the use of darifenacin during human pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriages, or other adverse maternal or fetal outcomes. In animal studies, doses of 50 mg/kg per day in rats (59-times the AUC at the maximum recommended human dose or MRHD) caused delays in the ossification of the sacral and caudal vertebrae. In rabbits, doses of 30 mg/kg per day (28-times the AUC at MRHD) resulted in increased post-implantation loss; also at this dose, dilated ureters and kidney pelvis' were observed in the rabbit offspring along with urinary bladder dilation consistent with the pharmacological action of darifenacin. Finally, in pre- and post-natal development studies in rats, decreased weight gain and dystocia were observed in dams and slight developmental delays were noted in pups at doses equivalent to 17-times the AUC at the MRHD (10 mg/kg per day).

    Breast-feeding

    There are no data available on the presence of darifenacin in human milk, the effects on the breast-fed infant, or the effects on milk production. However, anticholinergic medications have been found to inhibit lactation in animals and decrease serum prolactin concentrations in non-lactating women. Therefore, chronic use of darifenacin may decrease milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for darifenacin and any potential adverse effects on the breast-fed child from the drug or the underlying maternal condition.

    Geriatric

    During clinical trials, no overall difference in safety or efficacy was observed in geriatric adults relative to younger adult patients; dosage adjustments in geriatric patients are not recommended based on age alone. However, geriatric patients may be more sensitive to the anticholinergic effects of darifenacin; monitor and consider dosage adjustments if anticholinergic effects are experienced.[30711] According to the Beers Criteria, antimuscarinics with strong anticholinergic properties, such as darifenacin, are considered potentially inappropriate medications (PIMs) in geriatric patients with dementia/cognitive impairment (adverse CNS effects) or delirium/high risk of delirium (new-onset or worsening delirium), and it is recommended that use in these patient populations be avoided.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, darifenacin has specific and limited uses for urinary incontinence based on the cause and categorization of incontinence. According to the OBRA guidelines, assessment of the underlying causes and identification of the type/category of urinary incontinence needs to be documented before or soon after the time of initiating treatment with a urinary incontinence medication. Patients should be assessed periodically for medication effects on urinary incontinence as well as lower urinary tract symptoms and treatment tolerability.[60742]

    Children, infants

    The safe and effective use of darifenacin in adolescents, children, or infants has not been established.

    ADVERSE REACTIONS

    Severe

    anaphylactoid reactions / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    constipation / Delayed / 14.8-21.3
    vaginitis / Delayed / 1.0
    peripheral edema / Delayed / 1.0
    hypertension / Early / 1.0
    urinary retention / Early / Incidence not known
    palpitations / Early / Incidence not known
    hallucinations / Early / Incidence not known
    confusion / Early / Incidence not known

    Mild

    xerostomia / Early / 18.7-35.5
    dyspepsia / Early / 2.7-8.4
    headache / Early / 6.7-6.7
    nausea / Early / 1.5-4.1
    vomiting / Early / 1.5-4.1
    abdominal pain / Early / 2.4-3.9
    asthenia / Delayed / 1.5-2.7
    diarrhea / Early / 0.9-2.1
    xerophthalmia / Early / 1.5-2.1
    drowsiness / Early / 0-2.0
    dizziness / Early / 0-2.0
    back pain / Delayed / 1.0
    rhinitis / Early / 1.0
    pharyngitis / Delayed / 1.0
    rash / Early / 1.0
    weight gain / Delayed / 1.0
    pruritus / Rapid / 1.0
    arthralgia / Delayed / 1.0

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms, increase urination, and counteract the effectiveness of darifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas).
    Acetaminophen; Caffeine: (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms, increase urination, and counteract the effectiveness of darifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas).
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with darifenacin may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Consider alternative therapy to dihydrocodeine when the opioid is used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of darifenacin could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If darifenacin is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine has similar pharmacokinetics to codeine and is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known. (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms, increase urination, and counteract the effectiveness of darifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas).
    Acetaminophen; Caffeine; Pyrilamine: (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms, increase urination, and counteract the effectiveness of darifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas).
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with darifenacin may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Avoid this combination when codeine is being used for cough; consider alternative therapy for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of darifenacin could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If darifenacin is discontinued, monitor the patient carefully and consider reducing the codeine dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Acetaminophen; Dextromethorphan: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Doxylamine: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with darifenacin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including a risk for hypotension, respiratory depression, profound sedation, coma, and death. Avoid use of hydrocodone when it is being used for cough; consider alternative agents for cough treatment. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of darifenacin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If darifenacin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Acetaminophen; Oxycodone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Adagrasib: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with adagrasib due to increased darifenacin exposure. Darifenacin is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor.
    Alfentanil: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Amantadine: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like darifenacin are used concomitantly with amantadine.
    Amiloride: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Amiloride; Hydrochlorothiazide, HCTZ: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Amiodarone: (Moderate) Amiodarone, an inhibitor of both CYP3A4 and CYP2D6, may decrease the metabolism of darifenacin and increase serum concentrations. Patients should be monitored for increased anticholinergic effects if these drugs are used concomitantly; dosage adjustments of darifenacin may be necessary.
    Amitriptyline: (Moderate) The exposure to tricyclic antidepressants (TCAs) may be increased when coadministered with darifenacin. Appropriate monitoring and dose adjustment may be necessary. Darifenacin is a moderate CYP2D6 inhibitor; TCAs are CYP2D6 substrates.
    Amlodipine; Celecoxib: (Moderate) Monitor patients closely for darifenacin-related adverse reactions and consider a dosage reduction of darifenacin if coadministration with celecoxib is necessary. Celecoxib may enhance the systemic exposure and toxicity of darifenacin. In vitro studies indicate that celecoxib is an inhibitor of CYP2D6. Darifenacin is a CYP2D6 substrate.
    Amobarbital: (Minor) Barbiturates (e.g., phenobarbital or primidone) may induce the CYP3A4 metabolism of darifenacin. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers.
    Amoxapine: (Moderate) Monitor for increased toxicity of amoxapine, such as increased anticholinergic effects, if coadministered with darifenacin. Coadministration may increase serum concentrations of amoxapine. Amoxapine is a CYP2D6 substrate; darifenacin is a moderate CYP2D6 inhibitor.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with clarithromycin due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor.
    Apalutamide: (Moderate) Monitor for decreased efficacy of darifenacin if coadministration with apalutamide is necessary; coadministration may result in decreased plasma concentrations of darifenacin. Apalutamide is a strong CYP3A4 inducer and darifenacin is a CYP3A4 substrate.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if darifenacin and aprepitant, fosaprepitant are used concurrently and monitor for an increase in darifenacin-related adverse effects for several days after administration of a multi-day aprepitant regimen. Darifenacin 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 darifenacin. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aripiprazole: (Moderate) Carefully monitor for aripiprazole-related adverse reactions if coadministered with darifenacin. Darifenacin is a moderate CYP2D6 inhibitor and may increase exposure to aripiprazole, a CYP2D6 substrate. In addition, because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor.
    Artemether; Lumefantrine: (Moderate) Lumefantrine is an inhibitor and darifenacin is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased darifenacin concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Aspirin, ASA; Butalbital; Caffeine: (Minor) Barbiturates (e.g., phenobarbital or primidone) may induce the CYP3A4 metabolism of darifenacin. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers. (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms, increase urination, and counteract the effectiveness of darifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas).
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with darifenacin may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Avoid this combination when codeine is being used for cough; consider alternative therapy for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of darifenacin could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If darifenacin is discontinued, monitor the patient carefully and consider reducing the codeine dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known. (Minor) Barbiturates (e.g., phenobarbital or primidone) may induce the CYP3A4 metabolism of darifenacin. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers. (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms, increase urination, and counteract the effectiveness of darifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas).
    Aspirin, ASA; Caffeine: (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms, increase urination, and counteract the effectiveness of darifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas).
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like darifenacin are used concomitantly with orphenadrine. (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms, increase urination, and counteract the effectiveness of darifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas).
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with darifenacin may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Avoid this combination when codeine is being used for cough; consider alternative therapy for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of darifenacin could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If darifenacin is discontinued, monitor the patient carefully and consider reducing the codeine dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Atazanavir: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with atazanavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor.
    Atazanavir; Cobicistat: (Major) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with cobicistat due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with atazanavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor.
    Atropine; Difenoxin: (Moderate) Antidiarrheals (e.g. atropine; diphenoxylate, atropine; difenoxin, or loperamide) decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been rarely reported to induce toxic megacolon. Constipation and dry mouth are reported side effects of darifenacin. Additive GI, CNS, or other anticholinergic effects may occur if used concomitantly.
    Barbiturates: (Minor) Barbiturates (e.g., phenobarbital or primidone) may induce the CYP3A4 metabolism of darifenacin. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers.
    Belladonna; Opium: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Benzhydrocodone; Acetaminophen: (Moderate) Use of darifenacin with benzhydrocodone may increase hydrocodone concentrations. Benzhydrocodone is a prodrug of hydrocodone. Use together may prolong opioid adverse reactions, including a risk for hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of benzhydrocodone until stable drug effects are achieved. Discontinuation of darifenacin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence. If darifenacin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug that is converted to hydrocodone, and hydrocodone is a substrate for CYP2D6. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Berotralstat: (Moderate) Monitor for increased toxicity of darifenacin if coadministered with berotralstat. Coadministration may increase the exposure of darifenacin. Darifenacin is a sensitive CYP3A substrate; berotralstat is a moderate CYP3A inhibitor.
    Bosentan: (Minor) Bosentan may induce the CYP3A4 metabolism of darifenacin and thereby reduce its oral bioavailability. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers.
    Brexpiprazole: (Moderate) Use caution if coadministration of darifenacin with brexpiprazole is necessary, as the systemic exposure of brexpiprazole may be increased resulting in an increase in brexpiprazole-related adverse reactions. Reduce the dose of brexpiprazole to one-quarter (25%) of the usual dose if brexpiprazole and darifenacin are coadministered with a moderate to strong inhibitor of CYP3A4. If darifenacin is discontinued, adjust the brexpiprazole dosage to its original level. darifenacin is a moderate CYP2D6 inhibitor. Brexpiprazole is a CYP3A4 and CYP2D6 substrate. Concomitant use of moderate CYP2D6 inhibitors with a strong or moderate CYP3A4 inhibitor increased the exposure of brexpiprazole compared to use of brexpiprazole alone.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Bumetanide: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Bupropion: (Moderate) Bupropion, an inhibitor of CYP2D6 may inhibit the metabolism of darifenacin. In addition, bupropion is associated with moderate anticholinergic effects which could be additive when coadministered with darifenacin. Patients should be monitored for increased anticholinergic effects or other adverse effects when these two drugs are coadministered. Dosage adjustments may be necessary.
    Bupropion; Naltrexone: (Moderate) Bupropion, an inhibitor of CYP2D6 may inhibit the metabolism of darifenacin. In addition, bupropion is associated with moderate anticholinergic effects which could be additive when coadministered with darifenacin. Patients should be monitored for increased anticholinergic effects or other adverse effects when these two drugs are coadministered. Dosage adjustments may be necessary.
    Butabarbital: (Minor) Barbiturates (e.g., phenobarbital or primidone) may induce the CYP3A4 metabolism of darifenacin. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers.
    Butalbital; Acetaminophen: (Minor) Barbiturates (e.g., phenobarbital or primidone) may induce the CYP3A4 metabolism of darifenacin. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers.
    Butalbital; Acetaminophen; Caffeine: (Minor) Barbiturates (e.g., phenobarbital or primidone) may induce the CYP3A4 metabolism of darifenacin. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers. (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms, increase urination, and counteract the effectiveness of darifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas).
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with darifenacin may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Avoid this combination when codeine is being used for cough; consider alternative therapy for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of darifenacin could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If darifenacin is discontinued, monitor the patient carefully and consider reducing the codeine dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known. (Minor) Barbiturates (e.g., phenobarbital or primidone) may induce the CYP3A4 metabolism of darifenacin. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers. (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms, increase urination, and counteract the effectiveness of darifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas).
    Caffeine: (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms and counteract the effectiveness of darifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas). (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms, increase urination, and counteract the effectiveness of darifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas).
    Caffeine; Sodium Benzoate: (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms, increase urination, and counteract the effectiveness of darifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas).
    Carbamazepine: (Minor) Carbamazepine may induce the CYP3A4 metabolism of darifenacin and thereby reduce its oral bioavailability. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers.
    Carbidopa; Levodopa: (Minor) Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. Antimuscarinics, by slowing GI transit, may also decrease levodopa bioavailability; however, this mechanism appears to be of modest clinical significance. Antimuscarinic agents targeted specifically for urinary incontinence may be less likely to produce pronounced effects on levodopa response than those with more pronounced systemic action.
    Carbidopa; Levodopa; Entacapone: (Minor) Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. Antimuscarinics, by slowing GI transit, may also decrease levodopa bioavailability; however, this mechanism appears to be of modest clinical significance. Antimuscarinic agents targeted specifically for urinary incontinence may be less likely to produce pronounced effects on levodopa response than those with more pronounced systemic action.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Celecoxib: (Moderate) Monitor patients closely for darifenacin-related adverse reactions and consider a dosage reduction of darifenacin if coadministration with celecoxib is necessary. Celecoxib may enhance the systemic exposure and toxicity of darifenacin. In vitro studies indicate that celecoxib is an inhibitor of CYP2D6. Darifenacin is a CYP2D6 substrate.
    Celecoxib; Tramadol: (Moderate) Coadministration of darifenacin with tramadol may decrease tramadol metabolism resulting in decreased tramadol efficacy and/or increased tramadol-induced risks for respiratory depression, serotonin syndrome, or seizures. Tramadol is a CYP2D6 substrate; darifenacin is a moderate CYP2D6 inhibitor. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 metabolism is expected to result in reduced metabolic clearance of tramadol that may increase the risk of tramadol-related adverse events including respiratory depression, serotonin syndrome, and seizures. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates such as tramadol 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. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known. (Moderate) Monitor patients closely for darifenacin-related adverse reactions and consider a dosage reduction of darifenacin if coadministration with celecoxib is necessary. Celecoxib may enhance the systemic exposure and toxicity of darifenacin. In vitro studies indicate that celecoxib is an inhibitor of CYP2D6. Darifenacin is a CYP2D6 substrate.
    Cenobamate: (Moderate) Monitor for decreased efficacy of darifenacin if coadministration with cenobamate is necessary; coadministration may result in decreased plasma concentrations of darifenacin. Cenobamate is a moderate CYP3A4 inducer and darifenacin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of darifenacin.
    Ceritinib: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with ceritinib due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor.
    Chloramphenicol: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with chloramphenicol due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor.
    Chlordiazepoxide; Amitriptyline: (Moderate) The exposure to tricyclic antidepressants (TCAs) may be increased when coadministered with darifenacin. Appropriate monitoring and dose adjustment may be necessary. Darifenacin is a moderate CYP2D6 inhibitor; TCAs are CYP2D6 substrates.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with darifenacin may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Avoid this combination when codeine is being used for cough; consider alternative therapy for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of darifenacin could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If darifenacin is discontinued, monitor the patient carefully and consider reducing the codeine dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Chlorpheniramine; Dextromethorphan: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with darifenacin may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Consider alternative therapy to dihydrocodeine when the opioid is used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of darifenacin could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If darifenacin is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine has similar pharmacokinetics to codeine and is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with darifenacin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including a risk for hypotension, respiratory depression, profound sedation, coma, and death. Avoid use of hydrocodone when it is being used for cough; consider alternative agents for cough treatment. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of darifenacin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If darifenacin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Cimetidine: (Moderate) The mean Cmax and AUC of darifenacin 30 mg once daily at steady state were 42 percent and 34 percent higher, respectively, in the presence of cimetidine. Monitor patients receiving these two drugs concomitantly for increased anticholinergic effects; dosage adjustments may be necessary.
    Ciprofloxacin: (Moderate) Clinical monitoring for adverse effects, such as anticholinergic effects, is recommended during coadministration of darifenacin and ciprofloxacin. The plasma concentrations of darifenacin may be elevated when administered concurrently with ciprofloxacin. Ciprofloxacin is a CYP3A4 inhibitor, while darifenacin is a CYP3A4 substrate.
    Cisapride: (Moderate) Because darifenacin antagonizes GI muscarinic cholinergic receptors, it decreases gastrointestinal motility. Darifenacin, therefore, may potentially antagonize the actions of drugs that enhance gastrointestinal motility, like cisapride.
    Citalopram: (Moderate) Clinicians should monitor patients for increased anticholinergic effects when darifenacin, a CYP2D6 substrate, is coadministered with citalopram, a mild CYP2D6 inhibitor; the dosage of darifenacin may need to be adjusted.
    Clarithromycin: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with clarithromycin due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor.
    Clomipramine: (Moderate) The exposure to tricyclic antidepressants (TCAs) may be increased when coadministered with darifenacin. Appropriate monitoring and dose adjustment may be necessary. Darifenacin is a moderate CYP2D6 inhibitor; TCAs are CYP2D6 substrates.
    Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with darifenacin and monitor for adverse reactions including anticholinergic effects. If darifenacin is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP2D6. Darifenacin is a moderate CYP2D6 inhibitor. Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like darifenacin are used concomitantly with other drugs with moderate to significant anticholinergic effects including clozapine.
    Cobicistat: (Major) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with cobicistat due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor.
    Codeine: (Moderate) Concomitant use of codeine with darifenacin may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Avoid this combination when codeine is being used for cough; consider alternative therapy for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of darifenacin could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If darifenacin is discontinued, monitor the patient carefully and consider reducing the codeine dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with darifenacin may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Avoid this combination when codeine is being used for cough; consider alternative therapy for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of darifenacin could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If darifenacin is discontinued, monitor the patient carefully and consider reducing the codeine dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with darifenacin may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Avoid this combination when codeine is being used for cough; consider alternative therapy for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of darifenacin could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If darifenacin is discontinued, monitor the patient carefully and consider reducing the codeine dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with darifenacin may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Avoid this combination when codeine is being used for cough; consider alternative therapy for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of darifenacin could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If darifenacin is discontinued, monitor the patient carefully and consider reducing the codeine dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with darifenacin may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Avoid this combination when codeine is being used for cough; consider alternative therapy for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of darifenacin could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If darifenacin is discontinued, monitor the patient carefully and consider reducing the codeine dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Conivaptan: (Moderate) Monitor for increased toxicity of darifenacin if coadministered with conivaptan. Coadministration may increase the exposure of darifenacin. Darifenacin is a sensitive CYP3A substrate; conivaptan is a moderate CYP3A inhibitor.
    Dabrafenib: (Major) The concomitant use of dabrafenib and darifenacin may lead to decreased darifenacin concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of darifenacin efficacy. Dabrafenib is a moderate CYP3A4 inducer and darifenacin is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 65%.
    Darunavir: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with darunavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor.
    Darunavir; Cobicistat: (Major) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with cobicistat due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with darunavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with cobicistat due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with darunavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with ritonavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor.
    Delavirdine: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with delavirdine due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor.
    Desipramine: (Moderate) The exposure to tricyclic antidepressants (TCAs) may be increased when coadministered with darifenacin. Appropriate monitoring and dose adjustment may be necessary. Darifenacin is a moderate CYP2D6 inhibitor; TCAs are CYP2D6 substrates.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Bupropion: (Moderate) Bupropion, an inhibitor of CYP2D6 may inhibit the metabolism of darifenacin. In addition, bupropion is associated with moderate anticholinergic effects which could be additive when coadministered with darifenacin. Patients should be monitored for increased anticholinergic effects or other adverse effects when these two drugs are coadministered. Dosage adjustments may be necessary. (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Guaifenesin: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Quinidine: (Moderate) Clinicians should monitor patients for increased anticholinergic effects when CYP2D6 inhibitors, such as quinidine, are coadministered with darifenacin; the dosage of darifenacin should be adjusted, if necessary. (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Digoxin: (Moderate) Oral formulations of digoxin can produce higher serum concentrations when administered concurrently with antimuscarinics because of decreased GI motility induced by the antimuscarinic agent. Darifenacin coadministered with digoxin resulted in a 16 percent increase in digoxin exposure. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
    Diltiazem: (Moderate) Darifenacin is a substrate for CYP3A4 and, theoretically, plasma concentrations could be increased via CYP3A4 inhibition by diltiazem, a moderate inhibitor.
    Diphenoxylate; Atropine: (Moderate) Antidiarrheals (e.g. atropine; diphenoxylate, atropine; difenoxin, or loperamide) decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been rarely reported to induce toxic megacolon. Constipation and dry mouth are reported side effects of darifenacin. Additive GI, CNS, or other anticholinergic effects may occur if used concomitantly.
    Doxepin: (Moderate) The exposure to tricyclic antidepressants (TCAs) may be increased when coadministered with darifenacin. Appropriate monitoring and dose adjustment may be necessary. Darifenacin is a moderate CYP2D6 inhibitor; TCAs are CYP2D6 substrates.
    Doxorubicin Liposomal: (Major) Avoid coadministration of darifenacin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Darifenacin is a moderate CYP2D6 inhibitor and doxorubicin is a major substrate of CYP2D6. Concurrent use of CYP2D6 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Doxorubicin: (Major) Avoid coadministration of darifenacin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Darifenacin is a moderate CYP2D6 inhibitor and doxorubicin is a major substrate of CYP2D6. Concurrent use of CYP2D6 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Dronedarone: (Moderate) Dronedarone is metabolized by CYP3A and is an inhibitor of CYP2D6 and CYP3A. Darifenacin is a substrate for CYP2D6 and CYP3A4. The concomitant administration of dronedarone with CYP2D6 and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Duloxetine: (Moderate) Duloxetine, a CYP2D6 inhibitor, may decrease the metabolism of darifenacin, a CYP2D6 substrate. Clinicians should monitor patients for increased anticholinergic effects when CYP2D6 inhibitors are coadministered with darifenacin; dosage adjustments of darifenacin may be necessary.
    Dutasteride; Tamsulosin: (Moderate) Use caution if coadministration of darifenacin with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP2D6 substrate and darifenacin is a moderate CYP2D6 inhibitor. The effects of concomitant administration of a moderate CYP2D6 inhibitor on the pharmacokinetics of tamsulosin have not been evaluated, but tamsulosin exposure may increase based on the effects of strong CYP2D6 inhibition.
    Duvelisib: (Moderate) Monitor for increased toxicity of darifenacin if coadministered with duvelisib. Coadministration may increase the exposure of darifenacin. Darifenacin is a sensitive CYP3A substrate; duvelisib is a moderate CYP3A inhibitor.
    Efavirenz: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as darifenacin.
    Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as darifenacin.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as darifenacin.
    Elbasvir; Grazoprevir: (Moderate) Administering darifenacin with elbasvir; grazoprevir may result in elevated darifenacin plasma concentrations. Darifenacin is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of darifenacin and eliglustat is not recommended. In extensive or intermediate CYP2D6 metabolizers (EMs or IMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with both darifenacin and a moderate or strong CYP3A inhibitor is contraindicated in all patients. darifenacin is a moderate CYP2D6 inhibitor; eliglustat is a CYP2D6 and CYP3A substrate. Coadministration of eliglustat with CYP2D6 inhibitors, such as darifenacin, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with cobicistat due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with cobicistat due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor.
    Encorafenib: (Moderate) Coadministration of encorafenib with darifenacin may result in increased toxicity or decreased efficacy of darifenacin. Darifenacin is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Enzalutamide: (Moderate) Monitor for decreased efficacy of darifenacin if coadministration with enzalutamide is necessary; coadministration may result in decreased plasma concentrations of darifenacin. Enzalutamide is a strong CYP3A4 inducer and darifenacin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of darifenacin.
    Ergotamine; Caffeine: (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms, increase urination, and counteract the effectiveness of darifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas).
    Escitalopram: (Moderate) Escitalopram, a modest CYP2D6 inhibitor, may decrease the metabolism of darifenacin, a CYP2D6 substrate. Clinicians should monitor patients for increased anticholinergic effects; dosage adjustments of darifenacin may be necessary.
    Ethacrynic Acid: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Fedratinib: (Moderate) Monitor for increased toxicity of darifenacin if coadministered with fedratinib. Coadministration may increase the exposure of darifenacin. Darifenacin is a sensitive CYP3A substrate; fedratinib is a moderate CYP3A inhibitor.
    Fentanyl: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Fesoterodine: (Major) Coadministration of fesoterodine and other antimuscarinics may increase the frequency and/or severity of anticholinergic effects such as blurred vision, constipation, xerostomia, and urinary retention. Additive antimuscarinic effects may be seen on GI smooth muscle, bladder function, the CNS, the eye, and temperature regulation.
    Flecainide: (Moderate) Caution should be exercised when darifenacin is used in combination with medications that are predominantly metabolized by CYP2D6 with narrow therapeutic windows, such as flecainide, as the serum concentrations of such drugs could be greatly increased in the presence of darifenacin.
    Fluconazole: (Moderate) Fluconazole, an inhibitor of CYP3A4, may decrease the metabolism of darifenacin and increase serum concentrations. Patients should be monitored for increased anticholinergic effects if these drugs are used concomitantly; dosage adjustments of darifenacin may be necessary.
    Fluoxetine: (Moderate) Fluoxetine inhibits CYP2D6 and CYP3A4. Serum concentrations of darifenacin, a CYP2D6 and CYP3A4 substrate, may increase when used in combination with fluoxetine. Patients should be monitored for increased anticholinergic effects if these drugs are coadministered.
    Fosamprenavir: (Moderate) Monitor for increased toxicity of darifenacin if coadministered with fosamprenavir. Coadministration may increase the exposure of darifenacin. Darifenacin is a sensitive CYP3A substrate; fosamprenavir is a moderate CYP3A inhibitor.
    Fosphenytoin: (Minor) Fosphenytoin may induce the CYP3A4 metabolism of darifenacin and thereby reduce its oral bioavailability. Depending on the individual clinical situation and the indication for the interacting medication, enzyme-induction interactions may not always produce reductions in treatment efficacy.
    Furosemide: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Grapefruit juice: (Moderate) Advise patients that grapefruit juice may increase darifenacin plasma concentrations resulting in increased adverse effects. Darifenacin is a CYP3A4 substrate; grapefruit juice is a strong CYP3A4 inhibitor. The manufacturer of darifenacin recommends a maximum daily dose of 7.5 mg of darifenacin if coadministered with a strong CYP3A4 inhibitor.
    Green Tea: (Minor) Some green tea products contain caffeine, which may aggravate bladder symptoms and counteract the effectiveness of drugs used to treat overactive bladder like darifenacin.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with darifenacin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including a risk for hypotension, respiratory depression, profound sedation, coma, and death. Avoid use of hydrocodone when it is being used for cough; consider alternative agents for cough treatment. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of darifenacin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If darifenacin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with darifenacin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including a risk for hypotension, respiratory depression, profound sedation, coma, and death. Avoid use of hydrocodone when it is being used for cough; consider alternative agents for cough treatment. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of darifenacin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If darifenacin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Haloperidol: (Moderate) Haloperidol inhibits CYP2D6. Serum concentrations of darifenacin, a CYP2D6 substrate, may increase when used in combination with haloperidol. Patients should be monitored for increased anticholinergic side effects if these drugs are coadministered.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with darifenacin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including a risk for hypotension, respiratory depression, profound sedation, coma, and death. Avoid use of hydrocodone when it is being used for cough; consider alternative agents for cough treatment. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of darifenacin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If darifenacin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with darifenacin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including a risk for hypotension, respiratory depression, profound sedation, coma, and death. Avoid use of hydrocodone when it is being used for cough; consider alternative agents for cough treatment. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of darifenacin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If darifenacin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with darifenacin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including a risk for hypotension, respiratory depression, profound sedation, coma, and death. Avoid use of hydrocodone when it is being used for cough; consider alternative agents for cough treatment. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of darifenacin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If darifenacin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with darifenacin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including a risk for hypotension, respiratory depression, profound sedation, coma, and death. Avoid use of hydrocodone when it is being used for cough; consider alternative agents for cough treatment. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of darifenacin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If darifenacin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Hydromorphone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Ibuprofen; Oxycodone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Idelalisib: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with idelalisib due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor.
    Imatinib: (Moderate) Clinicians should monitor patients for increased anticholinergic effects when CYP2D6 inhibitors, such as imatinib, are coadministered with darifenacin; the dosage of darifenacin should be adjusted, if necessary.
    Imipramine: (Moderate) The exposure to tricyclic antidepressants (TCAs) may be increased when coadministered with darifenacin. Appropriate monitoring and dose adjustment may be necessary. Darifenacin is a moderate CYP2D6 inhibitor; TCAs are CYP2D6 substrates.
    Indinavir: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with indinavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with darifenacin may result in increased serum concentrations of darifenacin. Darifenacin is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Itraconazole: (Major) Avoid use of darifenacin during and for 2 weeks after discontinuation of itraconazole treatment due to the potential for increased darifenacin exposure. If concurrent use cannot be avoided, do not exceed 7.5 mg/day PO darifenacin. Darifenacin is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Additionally, antimuscarinic drugs can raise intragastric pH, which can decrease the oral bioavailability of itraconazole.
    Ivosidenib: (Moderate) Monitor for loss of efficacy of darifenacin during coadministration of ivosidenib; a darifenacin dose adjustment may be necessary. Darifenacin is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased darifenacin concentrations.
    Ketoconazole: (Moderate) Do not exceed a dose of 7.5 mg/day of darifenacin when administered with ketoconazole due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with clarithromycin due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor.
    Lefamulin: (Moderate) Monitor for increased toxicity of darifenacin if coadministered with oral lefamulin. Coadministration may increase the exposure of darifenacin. Darifenacin is a sensitive CYP3A substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
    Lenacapavir: (Moderate) Monitor for increased toxicity of darifenacin if coadministered with lenacapavir. Coadministration may increase the exposure of darifenacin. Darifenacin is a sensitive CYP3A substrate; lenacapavir is a moderate CYP3A inhibitor.
    Letermovir: (Moderate) An increase in the plasma concentration of darifenacin is expected when given with letermovir. Do not exceed a maximum daily darifenacin dose of 7.5 mg in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. No dosing adjustments are required when darifenacin and letermovir are given together without cyclosporine. Darifenacin is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. The mean Cmax and AUC of darifenacin were increased by 128% and 95%, respectively, when in the presence of another moderate CYP3A4 inhibitor.
    Levodopa: (Minor) Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. Antimuscarinics, by slowing GI transit, may also decrease levodopa bioavailability; however, this mechanism appears to be of modest clinical significance. Antimuscarinic agents targeted specifically for urinary incontinence may be less likely to produce pronounced effects on levodopa response than those with more pronounced systemic action.
    Levoketoconazole: (Moderate) Do not exceed a dose of 7.5 mg/day of darifenacin when administered with ketoconazole due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Lonafarnib: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with lonafarnib due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor.
    Loop diuretics: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Lopinavir; Ritonavir: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with ritonavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor.
    Lorlatinib: (Moderate) Monitor for decreased efficacy of darifenacin if coadministration with lorlatinib is necessary. Lorlatinib is a moderate CYP3A4 inducer and darifenacin is a sensitive CYP3A4 substrate; coadministration may result in decreased plasma concentrations of darifenacin.
    Lumacaftor; Ivacaftor: (Minor) Lumacaftor; ivacaftor may reduce the efficacy of darifenacin by decreasing its systemic exposure; if used together, monitor patients for clinical efficacy and increase the darifenacin dosage if needed. Darifenacin is a substrate of CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Maprotiline: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like darifenacin are used concomitantly with maprotiline.
    Mavacamten: (Moderate) Monitor for decreased efficacy of darifenacin if coadministration with mavacamten is necessary; coadministration may result in decreased plasma concentrations of darifenacin. Darifenacin is a CYP3A substrate and mavacamten is a moderate CYP3A inducer; coadministration may result in decreased plasma concentrations of darifenacin.
    Meperidine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Meperidine; Promethazine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of darifenacin is necessary. If darifenacin is discontinued, consider increasing the methadone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Methadone is a CYP2D6 substrate, and coadministration with CYP2D6 inhibitors like darifenacin can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If darifenacin is discontinued, methadone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Darifenacin has anticholinergic actions that may produce additive effects. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Methohexital: (Minor) Barbiturates (e.g., phenobarbital or primidone) may induce the CYP3A4 metabolism of darifenacin. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers.
    Mexiletine: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with darifenacin. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP2D6 substrate and darifenacin is a moderate CYP2D6 inhibitor.
    Midazolam: (Moderate) Darifenacin 30 mg daily coadministered with a single, oral dose of midazolam 7.5 mg resulted in a 17 percent increase is midazolam exposure.
    Mifepristone: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg/day PO in adults receiving mifepristone chronically for the treatment of hormonal conditions. The exposure of darifenacin, a sensitive CYP3A4 substrate, is expected to increase significantly with the administration of mifepristone when mifepristone is used chronically for hormonal conditions, such as Cushing's syndrome. Mifepristone is a CYP3A4 inhibitor. Due to the slow elimination of mifepristone from the body, any drug interactions that occur may be prolonged.
    Mirabegron: (Moderate) Mirabegron should be administered with caution in patients taking antimuscarinic medications for the treatment of overactive bladder, such as darifenacin, because of the risk of urinary retention. In addition, mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as darifenacin may be increased when administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary. Monitor for symptoms of urinary difficulties or urinary retention. Patients may note constipation or dry mouth with use of these drugs together.
    Mitotane: (Moderate) Use caution if mitotane and darifenacin are used concomitantly, and monitor for decreased efficacy of darifenacin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and darifenacin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of darifenacin.
    Morphine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Morphine; Naltrexone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Nebivolol: (Moderate) Monitor patients closely and adjust the nebivolol dose according to blood pressure response if coadministered with darifenacin. Nebivolol plasma concentrations may be increased during concurrent use. Darifenacin is a moderate CYP2D6 inhibitor; nebivolol is a sensitive CYP2D6 substrate.
    Nebivolol; Valsartan: (Moderate) Monitor patients closely and adjust the nebivolol dose according to blood pressure response if coadministered with darifenacin. Nebivolol plasma concentrations may be increased during concurrent use. Darifenacin is a moderate CYP2D6 inhibitor; nebivolol is a sensitive CYP2D6 substrate.
    Nefazodone: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with nefazodone due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor.
    Nelfinavir: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with nelfinavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor.
    Nirmatrelvir; Ritonavir: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with ritonavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor.
    Nortriptyline: (Moderate) The exposure to tricyclic antidepressants (TCAs) may be increased when coadministered with darifenacin. Appropriate monitoring and dose adjustment may be necessary. Darifenacin is a moderate CYP2D6 inhibitor; TCAs are CYP2D6 substrates.
    Olanzapine: (Moderate) Olanzapine exhibits anticholinergic effects that may be enhanced when combined with other drugs with anticholinergic activity like darifenacin. 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.
    Olanzapine; Fluoxetine: (Moderate) Fluoxetine inhibits CYP2D6 and CYP3A4. Serum concentrations of darifenacin, a CYP2D6 and CYP3A4 substrate, may increase when used in combination with fluoxetine. Patients should be monitored for increased anticholinergic effects if these drugs are coadministered. (Moderate) Olanzapine exhibits anticholinergic effects that may be enhanced when combined with other drugs with anticholinergic activity like darifenacin. 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.
    Olanzapine; Samidorphan: (Moderate) Olanzapine exhibits anticholinergic effects that may be enhanced when combined with other drugs with anticholinergic activity like darifenacin. 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.
    Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and darifenacin is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and darifenacin may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If darifenacin is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP2D6 substrate and darifenacin is a moderate CYP2D6 inhibitor.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with ritonavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor.
    Oritavancin: (Minor) Darifenacin is metabolized by CYP3A4 and CYP2D6; oritavancin is a weak CYP3A4 and CYP2D6 inducer. Plasma concentrations and efficacy of darifenacin may be reduced if these drugs are administered concurrently. Darifenacin dosage adjustment may be necessary.
    Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like darifenacin are used concomitantly with orphenadrine.
    Oxycodone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Oxymorphone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Paroxetine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with darifenacin is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and darifenacin is a moderate CYP2D6 inhibitor.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and darifenacin, a CYP3A4 substrate, may cause an increase in systemic concentrations of darifenacin. Use caution when administering these drugs concomitantly.
    Peginterferon Alfa-2b: (Moderate) The plasma concentrations of darifenacin may be elevated when administered concurrently with peginterferon alfa-2b. Clinical monitoring for adverse effects, such as anticholinergic effects, is recommended during coadministration. Peginterferon alfa-2b is a CYP2D6 inhibitor, while darifenacin is a CYP2D6substrate.
    Pentobarbital: (Minor) Barbiturates (e.g., phenobarbital or primidone) may induce the CYP3A4 metabolism of darifenacin. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers.
    Perphenazine; Amitriptyline: (Moderate) The exposure to tricyclic antidepressants (TCAs) may be increased when coadministered with darifenacin. Appropriate monitoring and dose adjustment may be necessary. Darifenacin is a moderate CYP2D6 inhibitor; TCAs are CYP2D6 substrates.
    Pexidartinib: (Moderate) Monitor for decreased efficacy of darifenacin if coadministration with pexidartinib is necessary; coadministration may result in decreased plasma concentrations of darifenacin. pexidartinib is a moderate CYP3A4 inducer and darifenacin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of darifenacin.
    Phenobarbital: (Minor) Barbiturates (e.g., phenobarbital or primidone) may induce the CYP3A4 metabolism of darifenacin. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Minor) Barbiturates (e.g., phenobarbital or primidone) may induce the CYP3A4 metabolism of darifenacin. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers.
    Phenytoin: (Minor) Phenytoin may induce the CYP3A4 metabolism of darifenacin and thereby reduce its oral bioavailability. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers.
    Pimozide: (Moderate) Caution is advisable during concurrent use of pimozide and moderate CYP2D6 inhibitors such as darifenacin. Pimozide is metabolized primarily through CYP3A4, and to a lesser extent CYP1A2 and CYP2D6. While the manufacturer has provided no guidance regarding pimozide use with mild or moderate CYP2D6 inhibitors, concurrent use of the drug with more potent inhibitors of CYP2D6 is contraindicated. Elevated concentrations of pimozide can lead to QT prolongation, ventricular arrhythmias, and sudden death.
    Posaconazole: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with posaconazole due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; posaconazole is a strong CYP3A4 inhibitor.
    Potassium-sparing diuretics: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Primidone: (Minor) Barbiturates (e.g., phenobarbital or primidone) may induce the CYP3A4 metabolism of darifenacin. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers.
    Promethazine; Dextromethorphan: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Propafenone: (Moderate) Monitor for increased toxicity of propafenone if coadministered with darifenacin. Coadministration may increase serum concentrations of propafenone. Increased exposure to propafenone may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity. Propafenone is a CYP2D6 substrate; darifenacin is a moderate CYP2D6 inhibitor. Because of its metabolism, the combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition in users of propafenone is potentially hazardous. Therefore, avoid simultaneous use of propafenone with both a CYP2D6 inhibitor and a CYP3A4 inhibitor.
    Propranolol: (Moderate) Monitor for increased toxicity of propranolol if coadministered with darifenacin. Coadministration may increase serum concentrations of propranolol. Propranolol is a CYP2D6 substrate; darifenacin is a moderate CYP2D6 inhibitor.
    Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased toxicity of propranolol if coadministered with darifenacin. Coadministration may increase serum concentrations of propranolol. Propranolol is a CYP2D6 substrate; darifenacin is a moderate CYP2D6 inhibitor.
    Protriptyline: (Moderate) The exposure to tricyclic antidepressants (TCAs) may be increased when coadministered with darifenacin. Appropriate monitoring and dose adjustment may be necessary. Darifenacin is a moderate CYP2D6 inhibitor; TCAs are CYP2D6 substrates.
    Quetiapine: (Moderate) When coadministering quetiapine and darifenacin, monitor for additive anticholinergic effects such as constipation, blurred vision, urinary retention, xerostomia, and tachycardia. Constipation is a commonly reported adverse effect of quetiapine and anticholinergic agents such as darifenacin. Constipation may lead to ileus. Intestinal obstruction has been reported with quetiapine, including fatal cases in patients who were receiving multiple concomitant medications that decrease intestinal motility. Anticholinergic effects observed during therapeutic use of quetiapine are thought to be associated with norquetiapine, the active metabolite of quetiapine which has demonstrated a moderate to strong in vitro binding affinity for several muscarinic receptor subtypes.
    Quinidine: (Moderate) Clinicians should monitor patients for increased anticholinergic effects when CYP2D6 inhibitors, such as quinidine, are coadministered with darifenacin; the dosage of darifenacin should be adjusted, if necessary.
    Remifentanil: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Ribociclib: (Major) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with ribociclib due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor.
    Ribociclib; Letrozole: (Major) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with ribociclib due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor.
    Rifamycins: (Moderate) Monitor for decreased efficacy of darifenacin if coadministration with rifamycins is necessary; coadministration may result in decreased plasma concentrations of darifenacin. Rifamycins are CYP3A4 inducers and darifenacin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of darifenacin.
    Ritonavir: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with ritonavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor.
    Rolapitant: (Major) Use caution if darifenacin and rolapitant are used concurrently, and monitor for darifenacin-related adverse effects. Darifenacin is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Saquinavir: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with saquinavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor.
    Secobarbital: (Minor) Barbiturates (e.g., phenobarbital or primidone) may induce the CYP3A4 metabolism of darifenacin. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers.
    Sertraline: (Moderate) Sertraline, an inhibitor of CYP3A4, may decrease the metabolism of darifenacin and increase serum concentrations. Patients should be monitored for increased anticholinergic effects if these drugs are used concomitantly; dosage adjustments of darifenacin may be necessary.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of darifenacin, which is a CYP3A4 substrate. Monitor patients for adverse effects of darifenacin, such as anticholinergic effects.
    Sotorasib: (Moderate) Monitor for decreased efficacy of darifenacin if coadministration with sotorasib is necessary; coadministration may result in decreased plasma concentrations of darifenacin. Darifenacin is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer; coadministration may result in decreased plasma concentrations of darifenacin.
    Spironolactone: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Spironolactone; Hydrochlorothiazide, HCTZ: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Stiripentol: (Moderate) Consider a dose adjustment of darifenacin when coadministered with stiripentol. Coadministration may alter plasma concentrations of darifenacin resulting in an increased risk of adverse reactions and/or decreased efficacy. Darifenacin is a sensitive CYP3A4 substrate. In vitro data predicts inhibition or induction of CYP3A4 by stiripentol potentially resulting in clinically significant interactions.
    Sufentanil: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Tamsulosin: (Moderate) Use caution if coadministration of darifenacin with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP2D6 substrate and darifenacin is a moderate CYP2D6 inhibitor. The effects of concomitant administration of a moderate CYP2D6 inhibitor on the pharmacokinetics of tamsulosin have not been evaluated, but tamsulosin exposure may increase based on the effects of strong CYP2D6 inhibition.
    Tapentadol: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Telithromycin: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with telithromycin due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; telithromycin is a strong CYP3A4 inhibitor.
    Terbinafine: (Minor) Terbinafine inhibits hepatic isoenzyme CYP2D6, and thus may inhibit the clearance of drugs metabolized by this isoenzyme including darifenacin. Monitor patients for increased anticholinergic effects when CYP2D6 inhibitors are coadministered with darifenacin.
    Thioridazine: (Contraindicated) Coadministration of thioridazine and darifenacin is contraindicated due to the potential for increased thioridazine exposure. Increased plasma concentrations of thioridazine are expected to increase the prolongation of the QTc interval associated with thioridazine and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes type arrhythmias. Thioridazine is a CYP2D6 substrate; darifenacin is a moderate CYP2D6 inhibitor.
    Tipranavir: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with tipranavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor.
    Torsemide: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Tramadol: (Moderate) Coadministration of darifenacin with tramadol may decrease tramadol metabolism resulting in decreased tramadol efficacy and/or increased tramadol-induced risks for respiratory depression, serotonin syndrome, or seizures. Tramadol is a CYP2D6 substrate; darifenacin is a moderate CYP2D6 inhibitor. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 metabolism is expected to result in reduced metabolic clearance of tramadol that may increase the risk of tramadol-related adverse events including respiratory depression, serotonin syndrome, and seizures. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates such as tramadol 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. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Tramadol; Acetaminophen: (Moderate) Coadministration of darifenacin with tramadol may decrease tramadol metabolism resulting in decreased tramadol efficacy and/or increased tramadol-induced risks for respiratory depression, serotonin syndrome, or seizures. Tramadol is a CYP2D6 substrate; darifenacin is a moderate CYP2D6 inhibitor. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of CYP2D6 metabolism is expected to result in reduced metabolic clearance of tramadol that may increase the risk of tramadol-related adverse events including respiratory depression, serotonin syndrome, and seizures. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates such as tramadol 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. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Trandolapril; Verapamil: (Moderate) Verapamil is an inhibitor of CYP3A4 isoenzymes. Co-administration with verapamil may lead to an increase in serum levels of drugs that are CYP3A4 substrates, including darifenacin.
    Triamterene: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Triamterene; Hydrochlorothiazide, HCTZ: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Tricyclic antidepressants: (Moderate) The exposure to tricyclic antidepressants (TCAs) may be increased when coadministered with darifenacin. Appropriate monitoring and dose adjustment may be necessary. Darifenacin is a moderate CYP2D6 inhibitor; TCAs are CYP2D6 substrates.
    Trimipramine: (Moderate) The exposure to tricyclic antidepressants (TCAs) may be increased when coadministered with darifenacin. Appropriate monitoring and dose adjustment may be necessary. Darifenacin is a moderate CYP2D6 inhibitor; TCAs are CYP2D6 substrates.
    Tucatinib: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with tucatinib due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and darifenacin may result in altered concentrations of darifenacin. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Darifenacin is a substrate of CYP2D6 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Verapamil: (Moderate) Verapamil is an inhibitor of CYP3A4 isoenzymes. Co-administration with verapamil may lead to an increase in serum levels of drugs that are CYP3A4 substrates, including darifenacin.
    Vibegron: (Moderate) Vibegron should be administered with caution in patients taking antimuscarinic medications for the treatment of overactive bladder, such as darifenacin, because of the risk of urinary retention. Monitor for symptoms of urinary difficulties or urinary retention. Patients may note constipation or dry mouth with use of these drugs together.
    Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with clarithromycin due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor.
    Voriconazole: (Major) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with voriconazole due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor.
    Voxelotor: (Moderate) Monitor for increased toxicity of darifenacin if coadministered with voxelotor. Coadministration may increase the exposure of darifenacin. Darifenacin is a sensitive CYP3A substrate; voxelotor is a moderate CYP3A inhibitor.
    Zafirlukast: (Moderate) Zafirlukast inhibits CYP3A4 and may increase the serum concentration of darifenacin, a CYP3A4 substrate.
    Zileuton: (Moderate) The serum concentration of darifenacin may be increased if coadministered with CYP3A4 inhibitors including zileuton.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no data available regarding the use of darifenacin during human pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriages, or other adverse maternal or fetal outcomes. In animal studies, doses of 50 mg/kg per day in rats (59-times the AUC at the maximum recommended human dose or MRHD) caused delays in the ossification of the sacral and caudal vertebrae. In rabbits, doses of 30 mg/kg per day (28-times the AUC at MRHD) resulted in increased post-implantation loss; also at this dose, dilated ureters and kidney pelvis' were observed in the rabbit offspring along with urinary bladder dilation consistent with the pharmacological action of darifenacin. Finally, in pre- and post-natal development studies in rats, decreased weight gain and dystocia were observed in dams and slight developmental delays were noted in pups at doses equivalent to 17-times the AUC at the MRHD (10 mg/kg per day).

    There are no data available on the presence of darifenacin in human milk, the effects on the breast-fed infant, or the effects on milk production. However, anticholinergic medications have been found to inhibit lactation in animals and decrease serum prolactin concentrations in non-lactating women. Therefore, chronic use of darifenacin may decrease milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for darifenacin and any potential adverse effects on the breast-fed child from the drug or the underlying maternal condition.

    MECHANISM OF ACTION

    Darifenacin is a competitive muscarinic receptor antagonist that has a greater affinity for the M3 receptor than for other known muscarinic receptors. Darifenacin has a 9-fold greater affinity for M3 when compared to M1, a 12-fold greater affinity for M3 when compared to M5, and a 59-fold greater affinity for M3 when compared to M2 and M4 receptors. In general, muscarinic receptors play an important role in several functions, including contractions of the urinary bladder smooth muscle. Both M2 and M3 receptors are found in the human detrusor muscle; even though there are a greater number of M2 receptors located in the detrusor muscle, it appears that M3 receptors are primarily responsible for bladder function and direct contraction of the detrusor muscle. Darifenacin has been shown to increase bladder capacity and diminish the frequency of unstable detrusor contractions in patients with involuntary detrusor contractions. The M3 receptors are involved in contraction of human bladder and gastrointestinal smooth muscle, saliva production, and iris sphincter function. Adverse drug effects such as dry mouth, constipation and abnormal vision may be mediated through effects on M3 receptors in these organs.

    PHARMACOKINETICS

    Darifenacin is administered orally. It is 98% protein-bound, primarily to alpha-1-acid-glycoprotein, with a volume of distribution of 163 L. Darifenacin is extensively metabolized by the liver after oral dosing; the three main routes of metabolism are monohydroxylation in the dihydrobenzofuran ring, dihydrobenzofuran ring opening, and N-dealkylation of the pyrrolidine nitrogen. Metabolism is mediated by CYP3A4 and CYP2D6. The elimination half-life following chronic dosing is 13 to 19 hours.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4, CYP2D6
    CYP3A4 and CYP2D6 are the primary mediators of darifenacin metabolism. Metabolism is significantly affected by potent CYP3A4 inhibitors, and darifenacin dosing limits are recommended in patients receiving potent CYP3A4 inhibitors concomitantly. Darifenacin exposure is 33% higher in the presence of a potent CYP2D6 inhibitor, so caution is recommended in patients receiving potent CYP2D6 inhibiting drugs concomitantly. Finally, darifenacin is an inhibitor of CYP2D6, and may increase the concentrations of drugs that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic window.

    Oral Route

    The mean oral bioavailability at steady-state is estimated to be 15% and 19% for 7.5 mg and 15 mg tablets, respectively. After oral administration, peak plasma concentrations of darifenacin are reached approximately 7 hours after multiple dosing and steady state plasma concentrations are achieved by the sixth day of dosing. Approximately 60% of an orally administered dose is recovered in the urine and 40% in the feces with 3% of the dose excreted in the urine as unchanged drug.