Fesoterodine Fumarate Er (fesoterodine fumarate)

For the management of overactive bladder, the recommended initial dosage of fesoterodine fumarate in adults is 4 mg once daily. Depending on individual response and tolerability, dosage may be increased to 8 mg once daily.

Fesoterodine fumarate is administered orally once daily without regard to meals. Fesoterodine fumarate extended-release tablets should be administered with liquids and swallowed whole; the tablets should not be chewed, crushed, or divided.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Agents Affecting Growth Hormone/Macimorelin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

CLINICAL EFFECTS: Concurrent use of agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of macimorelin states concurrent use with agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test. Discontinue growth hormone products at least 1 week before administering the macimorelin diagnostic test. Sufficient washout time of drugs affecting growth hormone release prior to administration of macimorelin is recommended.(1) Agents affecting growth hormone include: - Drugs that directly affect the pituitary secretion of growth hormone (e.g. somatostatin, insulin, glucocorticoids, cyclooxygenase inhibitors) - Drugs that may transiently elevate growth hormone concentrations (e.g. clonidine, levodopa, insulin) - Drugs that may blunt the growth hormone response (e.g. muscarinic antagonists, anti-thyroid medications, growth hormone products)

DISCUSSION: Concurrent use of agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

Anticholinergics/Secretin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Anticholinergic drugs may result in an incorrect secretin stimulation test result.(1)

CLINICAL EFFECTS: Concurrent use of anticholinergic drugs may impact the accuracy of the secretin stimulation test.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of human secretin states concurrent use of anticholinergic drugs at the time of stimulation testing may cause the patient to be hyporesponsive to the testing and suggest false positive results for pancreatic disease. The manufacturer recommends discontinuing anticholinergic drugs at least 5 half-lives prior to stimulation testing. Consider additional testing and clinical assessment for diagnosis.(1)

DISCUSSION: Concurrent use of anticholinergic drugs may impact the accuracy of the secretin stimulation test.(1)

Anticholinergics; Antispasmodics/Pramlintide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Pramlintide slows gastric emptying. Anticholinergics and antispasmodics may result in additive or synergistic effects on gastric emptying.

CLINICAL EFFECTS: Concurrent use of pramlintide and anticholinergics or antispasmodics may result in additive or synergistic effects on gastric emptying.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of pramlintide states that pramlintide therapy should not be considered in patients requiring the use of drugs that alter gastrointestinal motility.(1) Patients receiving anticholinergics and antispasmodics should be evaluated for signs of systemic effects which may include constipation.

DISCUSSION: Patients using drugs that alter gastrointestinal motility have not been studied in clinical trials for pramlintide.(1) Constipation has been reported as a side effect of anticholinergics and antispasmodics.

Slt High Strength Antimuscarinics/Strong Cyp3a4 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of darifenacin(1) and fesoterodine.(2)

CLINICAL EFFECTS: The concurrent administration of a strong inhibitor of CYP3A4 may result in elevated levels of and signs of toxicity from darifenacin(1) and fesoterodine.(2)

PREDISPOSING FACTORS: The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)

PATIENT MANAGEMENT: The US manufacturer of darifenacin states that the daily dose of darifenacin should not exceed 7.5 mg in patients receiving potent CYP3A4 inhibitors.(1) The US manufacturer of fesoterodine states that the daily dose of fesoterodine should not exceed 4 mg in adult patients receiving potent CYP3A4 inhibitors. In pediatric patients, the daily dose of fesoterodine in patients taking strong CYP3A4 inhibitors should be reduced to 4 mg in patients weighing greater than 35 kilograms. Use of fesoterodine in pediatric patients weighing greater than 25 kilograms and up to 35 kilograms is not recommended.(2) The US manufacturer of itraconazole states that concurrent use with fesoterodine is contraindicated in patients with severe renal or hepatic impairment during and two weeks after itraconazole treatment.(4)

DISCUSSION: In a study in 10 extensive CYP2D6 metabolizers and 1 poor CYP2D6 metabolizer, concurrent administration of ketoconazole (400 mg) increased the area-under-curve (AUC) and maximum concentration (Cmax) of darifenacin (7.5 mg daily) by 3.9-fold and 4.6-fold, respectively, in extensive metabolizers and by 12.9-fold and 12-fold, respectively, in the poor metabolizer, compared to historical controls. The concurrent administration of ketoconazole (400 mg) and darifenacin (15 mg daily) increased darifenacin AUC and Cmax by 11.5-fold and 10.73-fold, respectively, in extensive metabolizers and by 4.9-fold and 4.9-fold, respectively, in the poor metabolizer, compared to historical controls.(1) Concurrent administration of darifenacin (30 mg daily) and erythromycin, a moderate CYP3A4 inhibitor, increased darifenacin AUC and Cmax by 128% and 95%, respectively. Administration of darifenacin (30 mg daily) and fluconazole, another moderate CYP3A4 inhibitor, increased darifenacin AUC and Cmax by 84% and 88%, respectively. No dosage adjustment is recommended during concurrent therapy with moderate inhibitors of CYP3A4.(1) In a study, co-administration of ketoconazole (200 mg twice a day) increased the Cmax and AUC of the active metabolite of fesoterodine 2.0 and 2.3-fold in CYP2D6 extensive metabolizers and 2.1 and 2.5-fold in CYP2D6 poor metabolizers, respectively. Fesoterodine Cmax and AUC were 4.5-fold and 5.7-fold higher in subjects who were CYP2D6 poor metabolizers and taking ketoconazole when compared to extensive CYP2D6 metabolizers not taking ketoconazole.(2) In another study, ketoconazole (200 mg daily) increased the Cmax and AUC of the active metabolite of fesoterodine 2.2-fold in CYP2D6 extensive metabolizers and 1.5-fold and 1.9-fold in CYP P-450-2D6 poor metabolizers, respectively.(1,2) Fesoterodine Cmax and AUC were 3.4-fold and 4.2-fold higher in subjects who were CYP2D6 poor metabolizers and taking ketoconazole when compared to extensive CYP2D6 metabolizers not taking ketoconazole.(2) Based on a controlled randomized study in 28 healthy adults, oral fluconazole (200 mg daily) taken with oral fesoterodine (8 mg daily) was generally well tolerated in patients. A slightly non-clinically significant rise in plasma fesoterodine levels did occur. No clinically significant side effects were reported. The most common side effects reported by patients include: dizziness, blurred vision and abdominal distension when fluconazole was taken with fesoterodine.(5) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(6)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Anticholinergics/Clozapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clozapine has potent anticholinergic properties and inhibits serotonin receptors, including 5-HT3.(1-4) Both of these properties may cause inhibition of gastrointestinal (GI) smooth muscle contraction, resulting in decreased peristalsis.(3,4) These effects may be compounded by concurrent use of anticholinergic agents.(1-6)

CLINICAL EFFECTS: Concurrent use of clozapine with other anticholinergic agents may increase the risk of constipation (common) and serious bowel complications (uncommon), including complete bowel obstruction, fecal impaction, paralytic ileus and intestinal ischemia or infarction.(1-6)

PREDISPOSING FACTORS: The risk for serious bowel complications is higher with increasing age, higher frequency of constipation, and in patients on higher doses of clozapine or multiple anticholinergic agents.(1,5)

PATIENT MANAGEMENT: Avoid the use of other anticholinergic agents with clozapine.(1-6) If concurrent use is necessary, evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(2) Consider a prophylactic laxative in those with a history of constipation or bowel obstruction.(2) Review patient medication list for other anticholinergic agents. When possible, decrease the dosage or number of prescribed anticholinergic agents, particularly in the elderly. Counsel the patient about the importance of maintaining adequate hydration. Encourage regular exercise and eating a high-fiber diet.(2)

DISCUSSION: In a prospective cohort study of 26,720 schizophrenic patients in the Danish Central Psychiatric Research Registry, the odds ratio (OR) for ileus was 1.99 with clozapine and 1.48 with anticholinergics. The OR for fatal ileus was 6.73 with clozapine and 5.88 with anticholinergics. Use of anticholinergics with 1st generation antipsychotics (FGA) increased the risk of ileus compare to FGA alone, but this analysis was not done with clozapine.(5) A retrospective cohort study of 24,970 schizophrenic patients from the Taiwanese National Health Insurance Research Database found that the hazard ratio (HR) for clozapine-induced constipation increased from 1.64 when clozapine is used alone, to 2.15 when used concomitantly with anticholinergics. However, there was no significant difference in the HR for ileus when clozapine is used with and without anticholinergics (1.95 and 2.02, respectively).(6) In the French Pharmacovigilance Database, 7 of 38 cases of antipsychotic-associated ischemic colitis or intestinal necrosis involved clozapine, and 5 of these cases involved use of concomitant anticholinergic agents. Three patients died, one of whom was on concomitant anticholinergics.(3) In a case series, 4 of 9 cases of fatal clozapine-associated GI dysfunction involved concurrent anticholinergic agents.(4)

Anticholinergics/Glucagon (DIAGNOSTIC)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Glucagon and anticholinergic agents may have additive effects on inhibition of gastrointestinal motility.(1)

CLINICAL EFFECTS: Concurrent use of glucagon with anticholinergic agents may increase the risk of gastrointestinal hypomotility, including constipation and bowel complications.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of glucagon as a diagnotic aid is not recommended with the use of anticholinergic agents.(1) If concurrent use is necessary, evaluate the patient's bowel function. Monitor for symptoms of constipation and gastrointestinal hypomotility.

DISCUSSION: Both glucagon and anticholinergic agents may have additive effects on inhibition of gastrointestinal motility and increase the risk of gastrointestinal adverse effects.(1)

Anticholinergics/Solid Oral Potassium Capsules

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concentrated potassium may damage the lining of the GI tract. Anticholinergics delay gastric emptying, resulting in the potassium product remaining in the gastrointestinal tract for a longer period of time.(1-16))

CLINICAL EFFECTS: Use of solid oral dosage forms of potassium in patients treated with anticholinergics may result in gastrointestinal erosions, ulcers, stenosis and bleeding.(1-16)

PREDISPOSING FACTORS: Diseases or conditions which may increase risk for GI damage include: preexisting dysphagia, strictures, cardiomegaly, diabetic gastroparesis, elderly status, or insufficient oral intake to allow dilution of potassium.(1-10,21) Other drugs which may add to risk for GI damage include: nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines.(21)

PATIENT MANAGEMENT: Regulatory agency and manufacturer recommendations regarding this interaction: - In the US, all solid oral dosage forms (including tablets and extended release capsules) of potassium are contraindicated in patients receiving anticholinergics at sufficient dosages to result in systemic effects.(2-8) Patients receiving such anticholinergic therapy should use a liquid form of potassium chloride.(2) - In Canada, solid oral potassium is contraindicated in any patient with a cause for arrest or delay in tablet/capsule passage through the gastrointestinal tract and the manufacturers recommend caution with concurrent anticholinergic medications.(1,9-10) Evaluate each patient for predisposing factors which may increase risk for GI damage. In patients with multiple risk factors for harm, consider use of liquid potassium supplements, if tolerated. For patients receiving concomitant therapy, assure any potassium dose form is taken after meals with a large glass of water or other fluid. To decrease potassium concentration in the GI tract, limit each dose to 20 meq; if more than 20 meq daily is required, give in divided doses.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Patients should be instructed to immediately report any difficulty swallowing, abdominal pain, distention, severe vomiting, or gastrointestinal bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In clinical trials, there was a higher incidence of gastric and duodenal lesions in patients receiving a high dose of a wax-matrix controlled-release formulation with a concurrent anticholinergic agent. The lesions were asymptomatic and not accompanied by bleeding, as shown by a lack of positive Hemoccult tests.(1-17) Several studies suggest that the incidence of gastric and duodenal lesions may be less with the microencapsulated formulation of potassium chloride.(14-17)

Anticholinergics/Solid Oral Potassium Tablets

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concentrated potassium may damage the lining of the GI tract. Anticholinergics delay gastric emptying, resulting in the potassium product remaining in the gastrointestinal tract for a longer period of time.(1-16)

CLINICAL EFFECTS: Use of solid oral dosage forms of potassium in patients treated with anticholinergics may result in gastrointestinal erosions, ulcers, stenosis and bleeding.(1-16)

PREDISPOSING FACTORS: Diseases or conditions which may increase risk for GI damage include: preexisting dysphagia, strictures, cardiomegaly, diabetic gastroparesis, elderly status, or insufficient oral intake to allow dilution of potassium.(1-10,21) Other drugs which may add to risk for GI damage include: nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines.(21)

PATIENT MANAGEMENT: Regulatory agency and manufacturer recommendations regarding this interaction: - In the US, all solid oral dosage forms (including tablets and extended release capsules) of potassium are contraindicated in patients receiving anticholinergics at sufficient dosages to result in systemic effects.(2-8) Patients receiving such anticholinergic therapy should use a liquid form of potassium chloride.(2) - In Canada, solid oral potassium is contraindicated in any patient with a cause for arrest or delay in tablet/capsule passage through the gastrointestinal tract and the manufacturers recommend caution with concurrent anticholinergic medications.(1,9-10) Evaluate each patient for predisposing factors which may increase risk for GI damage. In patients with multiple risk factors for harm, consider use of liquid potassium supplements, if tolerated. For patients receiving concomitant therapy, assure any potassium dose form is taken after meals with a large glass of water or other fluid. To decrease potassium concentration in the GI tract, limit each dose to 20 meq; if more than 20 meq daily is required, give in divided doses.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Patients should be instructed to immediately report any difficulty swallowing, abdominal pain, distention, severe vomiting, or gastrointestinal bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In clinical trials, there was a higher incidence of gastric and duodenal lesions in patients receiving a high dose of a wax-matrix controlled-release formulation with a concurrent anticholinergic agent. Some lesions were asymptomatic and not accompanied by bleeding, as shown by a lack of positive Hemoccult tests.(1-17) Several studies suggest that the incidence of gastric and duodenal lesions may be less with the microencapsulated formulation of potassium chloride.(14-17)

Anticholinergics; Opioids/Eluxadoline

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Eluxadoline is a mixed mu-opioid and kappa-opioid agonist and delta-opioid antagonist and may alter or slow down gastrointestinal transit.(1)

CLINICAL EFFECTS: Constipation related adverse events that sometimes required hospitalization have been reported, including the development of intestinal obstruction, intestinal perforation, and fecal impaction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid use with other drugs that may cause constipation. If concurrent use is necessary, evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(1) Instruct patients to stop eluxadoline and immediately contact their healthcare provider if they experience severe constipation. Loperamide may be used occasionally for acute management of severe diarrhea, but must be discontinued if constipation develops.(1)

DISCUSSION: In phase 3 clinical trials, constipation was the most commonly reported adverse reaction (8%). Approximately 50% of constipation events occurred within the first 2 weeks of treatment while the majority occurred within the first 3 months of therapy. Rates of severe constipation were less than 1% in patients receiving eluxadoline doses of 75 mg and 100 mg.(1)

Fesoterodine/Rifampin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Rifampicin may induce the metabolism of fesoterodine by CYP3A4.(1,2)

CLINICAL EFFECTS: Administering rifampicin with fesoterodine may result in decreased levels of fesoterodine, as well as its active metabolites, and decreased clinical effectiveness.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent or recent use may lead to subtherapeutic levels of fesoterodine. Monitor patients for decreased effectiveness. The UK manufacturer of fesoterodine suggests that the concomitant use of these agents is not recommended;(1) however, the US manufacturer states no dosage adjustment is necessary.(2)

DISCUSSION: In one clinical study, the induction of CYP3A4 by co-administration of rifampicin (600 mg once a day), maximum concentration (Cmax) and area-under-curve (AUC) of the active metabolite of fesoterodine decreased by 70% and 75%, respectively, following the oral administration of 8mg of fesoterodine.(1,2)

Fesoterodine/Selected Anticonvulsants; Barbiturates

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Barbiturates, carbamazepine, phenobarbital, phenytoin, and primidone may induce the metabolism of fesoterodine by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of barbiturates, carbamazepine, phenobarbital, phenytoin, or primidone with fesoterodine may result in decreased levels of fesoterodine as well as their active metabolites, and decreased clinical effectiveness.

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Concurrent or recent use may lead to subtherapeutic levels of fesoterodine. Monitor patients for decreased effectiveness. The UK manufacturer of fesoterodine suggests that the concomitant use of these agents is not recommended;(1) however, the US manufacturer states no dosage adjustment is necessary.(2)

DISCUSSION: In one clinical study, the induction of CYP3A4 by co-administration of rifampicin (600 mg once a day), another inducer of CYP3A4, maximum concentration (Cmax) and area-under-curve (AUC) of the active metabolite of fesoterodine decreased by 70% and 75%, respectively, following the oral administration of 8 mg of fesoterodine.(1,2)

Fesoterodine/St. John's Wort

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: St. John's Wort may induce the metabolism of fesoterodine by CYP3A4.(1,2)

CLINICAL EFFECTS: St. John's Wort with fesoterodine may result in decreased levels of fesoterodine as well as their active metabolites, and decreased clinical effectiveness.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent or recent use may lead to subtherapeutic levels of fesoterodine. Monitor patients for decreased effectiveness. The UK manufacturer of fesoterodine suggests that the concomitant use of these agents is not recommended;(1) however, the US manufacturer states no dosage adjustment is necessary.(2)

DISCUSSION: In one clinical study, the induction of CYP3A4 by co-administration of rifampicin (600 mg once a day), another inducer of CYP3A4, Cmax and AUC of the active metabolite of fesoterodine decreased by 70% and 75%, respectively, following the oral administration of 8mg of fesoterodine.(1,2)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Anticholinergics/Topiramate

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Topiramate can cause decreased sweating and elevated body temperature. Agents with anticholinergic activity can predispose patients to heat-related disorders.(1-2)

CLINICAL EFFECTS: Concurrent use of topiramate with agents with anticholinergic activity may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death.

PREDISPOSING FACTORS: Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1)

PATIENT MANAGEMENT: The manufacturer of topiramate states that caution should be used when topiramate is prescribed with other medicinal products that predispose to heat-related disorders, such as agents with anticholinergic activity (e.g. clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin) concurrently with zonisamide.(1) Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of dehydration, oligohidrosis, or elevated body temperature occur, discontinuation of zonisamide should be considered.

DISCUSSION: Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment.(1) A 64-year old woman developed non-exertional hyperthemia while taking multiple psychiatric medications with topiramate.(2)

Anticholinergics/Zonisamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Zonisamide can cause decreased sweating and elevated body temperature. Agents with anticholinergic activity can predispose patients to heat-related disorders.(1-2)

CLINICAL EFFECTS: Concurrent use of zonisamide with agents with anticholinergic activity may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death.

PREDISPOSING FACTORS: Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1)

PATIENT MANAGEMENT: The UK and US manufacturers of zonisamide state that caution should be used in adults when zonisamide is prescribed with other medicinal products that predispose to heat-related disorders, such as agents with anticholinergic activity.(1-2) Pediatric and adolescent patients must not take anticholinergic agents (e.g. clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin) concurrently with zonisamide.(1) Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of dehydration, oligohidrosis, or elevated body temperature occur, discontinuation of zonisamide should be considered.

DISCUSSION: Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment and resulted in death.(1)

Slt Low Strength Antimuscarinics/Strong Cyp3a4 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of darifenacin(1) and fesoterodine.(2)

CLINICAL EFFECTS: The concurrent administration of a strong inhibitor of CYP3A4 may result in elevated levels of and signs of toxicity from darifenacin(1) and fesoterodine.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of darifenacin states that the daily dose of darifenacin should not exceed 7.5 mg in patients receiving potent CYP3A4 inhibitors.(1) The US manufacturer of fesoterodine states that the daily dose of fesoterodine should not exceed 4 mg in adult patients receiving potent CYP3A4 inhibitors. In pediatric patients, the daily dose of fesoterodine taking strong CYP3A4 inhibitors should be reduced to 4 mg in patients weighing greater than 35 kilograms. Use of fesoterodine in pediatric patients weighing greater than 25 kilograms and up to 35 kilograms is not recommended.(2)

DISCUSSION: In a study in 10 extensive CYP2D6 metabolizers and 1 poor CYP2D6 metabolizer, concurrent administration of ketoconazole (400 mg) increased the area-under-curve (AUC) and maximum concentration (Cmax) of darifenacin (7.5 mg daily) by 3.9-fold and 4.6-fold, respectively, in extensive metabolizers and by 12.9-fold and 12-fold, respectively, in the poor metabolizer, compared to historical controls. The concurrent administration of ketoconazole (400 mg) and darifenacin (15 mg daily) increased darifenacin AUC and Cmax by 11.5-fold and 10.73-fold, respectively, in extensive metabolizers and by 4.9-fold and 4.9-fold, respectively, in the poor metabolizer, compared to historical controls.(1) Concurrent administration of darifenacin (30 mg daily) and erythromycin, a moderate CYP3A4 inhibitor, increased darifenacin AUC and Cmax by 128% and 95%, respectively. Administration of darifenacin (30 mg daily) and fluconazole, another moderate CYP3A4 inhibitor, increased darifenacin AUC and Cmax by 84% and 88%, respectively. No dosage adjustment is recommended during concurrent therapy with moderate inhibitors of CYP3A4.(1) In a study, co-administration of ketoconazole (200 mg twice a day) increased the Cmax and AUC of the active metabolite of fesoterodine 2.0 and 2.3-fold in CYP2D6 extensive metabolizers and 2.1 and 2.5-fold in CYP2D6 poor metabolizers, respectively. Fesoterodine Cmax and AUC were 4.5-fold and 5.7-fold higher in subjects who were CYP2D6 poor metabolizers and taking ketoconazole when compared to extensive CYP2D6 metabolizers not taking ketoconazole.(2) In another study, ketoconazole (200 mg daily) increased the Cmax and AUC of the active metabolite of fesoterodine 2.2-fold in CYP2D6 extensive metabolizers and 1.5-fold and 1.9-fold in CYP2D6 poor metabolizers, respectively.(1,2) Fesoterodine Cmax and AUC were 3.4-fold and 4.2-fold higher in subjects who were CYP2D6 poor metabolizers and taking ketoconazole when compared to extensive CYP2D6 metabolizers not taking ketoconazole.(2) Based on a controlled randomized study in 28 healthy adults, oral fluconazole (200 mg daily) taken with oral fesoterodine (8 mg daily) was generally well tolerated in patients. A slightly non-clinically significant rise in plasma fesoterodine levels did occur. No clinically significant side effects were reported. The most common side effects reported by patients include: dizziness, blurred vision and abdominal distension when fluconazole was taken with fesoterodine.(3) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(4)

Urinary retention, gastric retention, or uncontrolled angle-closure glaucoma.

Known hypersensitivity to fesoterodine fumarate or any ingredient in the formulation.

• Gastric retention
• Urinary retention

• Angle-closure glaucoma
• Bladder outflow obstruction
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Gastrointestinal hypomotility
• Severe constipation

• CYp2d6 poor metabolizer
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Myasthenia gravis

The most common adverse effects in patients with overactive bladder receiving fesoterodine include dry mouth and constipation, which occurred in about 19 and 4%, respectively, of patients receiving the 4-mg daily dosage and in 35 and 6%, respectively, of patients receiving the 8-mg daily dosage.

Rare or Very Rare

• Angina
• Angioedema
• Chest pain
• Diverticulitis of gastrointestinal tract
• Facial edema
• Gastroenteritis
• Gastrointestinal hypomotility
• Hypersensitivity drug reaction
• Irritable bowel syndrome
• Secondary angle-closure glaucoma

More Frequent

• Constipation
• Xerostomia

Less Frequent

• Abnormal hepatic function tests
• Acute abdominal pain
• Acute cognitive impairment
• Diarrhea
• Dizziness
• Drowsy
• Dry eye
• Dry throat
• Dyspepsia
• Dysuria
• Headache disorder
• Nausea
• Oral hypoesthesia
• Peripheral edema
• Skin rash
• Upper respiratory infection
• Urinary retention
• Urinary tract infection

Rare or Very Rare

• Accidental fall
• Anticholinergic toxicity
• Back pain
• Blurred vision
• Cough
• Fatigue
• Insomnia
• Palpitations
• Pruritus of skin
• Urticaria

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Safety and efficacy of fesoterodine have not been established in pediatric patients.

Category C. (See Users Guide.)

It is not known whether fesoterodine is distributed into milk in humans. The manufacturer states that the drug should not be used during breast-feeding unless the benefit to the woman outweighs the potential risk to the infant.

In the phase 2 and 3, placebo-controlled, efficacy and safety studies of fesoterodine, approximately 33% of patients were 65 years of age or older and 9% were 75 years of age or older. In patients with overactive bladder, no difference was found in safety or efficacy in those patients 65 years of age or older relative to younger adults; however, the incidence of adverse antimuscarinic events, including dry mouth, constipation, dyspepsia, increase in residual urine, dizziness (only at a dosage of 8 mg daily) and urinary tract infection, was higher in patients 75 years of age or older compared with younger patients. The pharmacokinetics of fesoterodine are not substantially influenced by age. (See Dosage and Administration: Special Populations.)