Yupelri

Drug overview for YUPELRI (revefenacin):

Generic name: REVEFENACIN (REV-e-FEN-a-sin)
Drug class: Anticholinergic Agents Long-Acting (Inhaled)
Therapeutic class: Respiratory Therapy Agents

Revefenacin, a synthetic tertiary amine antimuscarinic agent, is a long-acting orally inhaled bronchodilator.

No enhanced Uses information available for this drug.

DRUG IMAGES

YUPELRI 175 MCG/3 ML SOLUTION

The following indications for YUPELRI (revefenacin) have been approved by the FDA:

Indications:
Chronic obstructive pulmonary disease

Professional Synonyms:
None.

Dosing information for YUPELRI
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
YUPELRI 175 MCG/3 ML SOLUTION	Maintenance	Adults inhale 3 milliliters (175 mcg) by nebulization route once daily

The following drug interaction information is available for YUPELRI (revefenacin):

Contraindicated
Severe
Moderate

There are 0 contraindications.

There are 1 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
Pramlintide/Inhaled Anticholinergics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Pramlintide slows gastric emptying. Anticholinergics may result in additive or synergistic effects.(1) CLINICAL EFFECTS: Concurrent use of pramlintide and anticholinergics may result in additive or synergistic effects.(1) 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 stimulate gastrointestinal motility or in patients taking drugs that alter gastrointestinal motility.(1) Patients receiving inhaled anticholinergics 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 inhaled anticholinergic agents such as ipratropium(2) and tiotropium.(3)	SYMLINPEN 120, SYMLINPEN 60

Drug Interaction

Drug Names

Pramlintide/Inhaled Anticholinergics

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

MECHANISM OF ACTION: Pramlintide slows gastric emptying. Anticholinergics may result in additive or synergistic effects.(1)

CLINICAL EFFECTS: Concurrent use of pramlintide and anticholinergics may result in additive or synergistic effects.(1)

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 stimulate gastrointestinal motility or in patients taking drugs that alter gastrointestinal motility.(1) Patients receiving inhaled anticholinergics 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 inhaled anticholinergic agents such as ipratropium(2) and tiotropium.(3)

SYMLINPEN 120, SYMLINPEN 60

There are 4 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Select Antipsychotics;Select Phenothiazines/Anticholinergics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Multiple mechanisms may be involved: 1. additive peripheral and CNS blockade of muscarinic receptors. 2. anticholinergic-induced inhibition of gastrointestinal absorption of phenothiazines. 3. antagonism of the dopamine blocking effects of selected antipsychotics and phenothiazines. CLINICAL EFFECTS: The dopamine blocking effects of selected antipsychotic agents or phenothiazines may be decreased while anticholinergic adverse effects may be increased. PREDISPOSING FACTORS: The risk for severe anticholinergic toxicities, e.g. delirium, hyperthermia, paralytic ileus is increased in the elderly and in patients on multiple anticholinergic agents. PATIENT MANAGEMENT: Anticholinergic agents may be required to treat or prevent antipsychotic induced extrapyramidal symptoms. When other indications lead to co-prescribing of the combination, assess patient response to the combination. Review patient medication list for other anticholinergic agents. When needed, decrease the dosage or number of prescribed anticholinergic agents, particularly in the elderly. DISCUSSION: Although numerous studies have been published regarding a possible interaction between phenothiazines and anticholinergics, the earlier reports were not double-blind or placebo controlled and patients may have received other drugs concomitantly. These earlier investigations reported increased side effects as well as increased, decreased and no effect on the therapeutic outcome. Double-blind studies have also reported conflicting results. Anticholinergic therapy varied from having no effect on phenothiazine concentration or patient outcome, to increasing phenothiazine levels. The discrepancies reported may be due to interpatient variability including age of the patient, type and duration of illness and treatment setting.	ADASUVE, CHLORPROMAZINE HCL, LOXAPINE, PERPHENAZINE, PERPHENAZINE-AMITRIPTYLINE, PHENERGAN, PROMETHAZINE HCL, PROMETHAZINE HCL-0.9% NACL, PROMETHAZINE VC, PROMETHAZINE-CODEINE, PROMETHAZINE-DM, PROMETHAZINE-PHENYLEPHRINE HCL, PROMETHEGAN, THIORIDAZINE HCL, THIORIDAZINE HYDROCHLORIDE, TRIFLUOPERAZINE HCL
Solid Oral Potassium Tablets/Inhaled Anticholinergics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. 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 inhaled anticholinergics could potentially 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) Constipation has been reported as a side effect of inhaled anticholinergic agents such as ipratropium(22) and tiotropium.(23)	KLOR-CON 10, KLOR-CON 8, KLOR-CON M10, KLOR-CON M15, KLOR-CON M20, POTASSIUM CHLORIDE, POTASSIUM CITRATE ER, UROCIT-K
Solid Oral Potassium Capsules/Inhaled Anticholinergics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. 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 inhaled anticholinergics could potentially 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) Constipation has been reported as a side effect of inhaled anticholinergic agents such as ipratropium(22) and tiotropium.(23)	POTASSIUM CHLORIDE
Methacholine/Beta-Agonists; Anticholinergics; Theophylline SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Beta-agonists, anticholinergics, and theophylline may inhibit the action of methacholine on the airway.(1) CLINICAL EFFECTS: The result of the methacholine challenge test may not be accurate.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The following drugs should be held before a methacholine challenge for the the duration indicated:(1) - short-acting beta-agonists: 6 hours - long-acting beta-agonists: 36 hours - short-acting anti-cholinergics: 12 hours - long-acting anti-cholinergics: at least 168 hours (7 days) - oral theophylline: 12-48 hours DISCUSSION: Beta-agonists, anticholinergics, and theophylline may inhibit the action of methacholine on the airway and cause inaccurate test results.	METHACHOLINE CHLORIDE, PROVOCHOLINE

Severe List
Exacerbation of chronic obstructive pulmonary disease

Moderate List
Angle-closure glaucoma
Benign prostatic hyperplasia
Bladder outflow obstruction

The following adverse reaction information is available for YUPELRI (revefenacin):

Overview
Severe
Less Severe

Adverse reaction overview.

Adverse events occurring in at least 2% of patients receiving revefenacin include cough, nasopharyngitis, upper respiratory tract infection, headache, and back pain.

There are 4 severe adverse reactions.

More Frequent	Less Frequent
None.	Hypertension

Rare/Very Rare
Hypersensitivity drug reaction Paradoxical bronchospasm Secondary angle-closure glaucoma

There are 11 less severe adverse reactions.

More Frequent	Less Frequent
Back pain Cough Headache disorder Pharyngitis Upper respiratory infection	Bronchitis Dizziness Pain in oropharynx Urinary retention

Rare/Very Rare
Anticholinergic toxicity Xerostomia

The following precautions are available for YUPELRI (revefenacin):

Pediatric
Pregnant
Lactation
Geriatric

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

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

There are no adequate and well-controlled studies of orally inhaled revefenacin in pregnant women. Women should be advised to contact their clinician if they become pregnant while using revefenacin. In reproduction studies in pregnant rats receiving subcutaneous revefenacin during the period of organogenesis from gestation days 6 to 17, the drug was not teratogenic and did not affect fetal survival at exposures up to 209 times the maximum recommended human dose.

In pregnant rabbits receiving revefenacin during the period of organogenesis from gestation days 7 to 19, the drug was not teratogenic and did not affect fetal survival at exposures up to 694 times the maximum recommended human dose. Placental transfer of revefenacin and its active metabolite has been observed in pregnant rabbits. In a prenatal and postnatal development study in pregnant rats receiving revefenacin during the periods of organogenesis and lactation from gestation day 6 to lactation day 20, the drug had no adverse developmental effects on pups at exposures up to 196 times the maximum recommended human dose.

Revefenacin and its active metabolite are distributed into milk in rats. Following administration of revefenacin to lactating rats, the drug and its metabolite were distributed into breast milk in concentrations up to 10 times greater than plasma. It is not known whether revefenacin is distributed into human milk following oral inhalation.

Data also are not available on the effects of the drug on the breast-fed child or on milk production. Because revefenacin is less than 3% absorbed orally, it is unlikely to affect the breast-fed child. However, because long-term use of revefenacin has the potential to reduce milk production, it has been suggested that nursing women receiving the drug should be observed for signs of decreased lactation (e.g., insatiety or poor weight gain in the nursing infant). The benefits of breast-feeding should be considered along with the importance of the drug to the woman and any potential adverse effects on the breast-fed child from the drug or underlying maternal condition.

Although no overall differences in efficacy or safety were observed between geriatric and younger patients in revefenacin clinical trials, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out. Dosage adjustment is not necessary in geriatric patients.

Chronic obstructive pulmonary disease
J44	Other chronic obstructive pulmonary disease
J44.8	Other specified chronic obstructive pulmonary disease
J44.89	Other specified chronic obstructive pulmonary disease
J44.9	Chronic obstructive pulmonary disease, unspecified