Incruse Ellipta (umeclidinium bromide)

Dosage of umeclidinium bromide is expressed in terms of umeclidinium.

Each foil-wrapped blister in the Incruse(R) Ellipta(R) inhaler device contains 74.2 mcg of umeclidinium bromide (equivalent to 62.5 mcg of umeclidinium). After the inhaler is activated, the powder within the blister is exposed and dispersed into the air stream created by the patient's inhalation. Using standardized in vitro testing at a flow rate of 60 L/minute for 4 seconds, the inhaler delivered 55 mcg of umeclidinium per blister. The precise amount of drug delivered to the lungs with each activation of the inhaler device depends on factors such as the patient's inspiratory flow. The commercially available inhaler delivers 30 doses (or 7 doses from the sample or institutional package).

Umeclidinium bromide is administered by oral inhalation using a specific preloaded inhaler (Incruse(R) Ellipta(R)) that delivers powdered drug from foil-wrapped blisters. Umeclidinium should be administered once daily at the same time every day.

Before first use of the Incruse(R) Ellipta(R) inhaler, the device should be removed from the foil tray and the enclosed desiccant should be discarded out of reach of children and pets. The date the tray is opened and the discard date (6 weeks after opening) should be written on the inhaler label. The number of doses remaining in the inhaler is displayed on the counter located on the front of the device. The cover of the inhaler should not be opened until immediately before use; to avoid wasting doses, the inhaler cover should not be closed again until the dose has been inhaled. When the cover of the inhaler is opened fully to expose the mouthpiece, a click should be heard. If the dose counter does not advance when the click is heard, the dose has not been properly prepared, and the patient should contact the clinician.

Before inhaling the dose, the patient should exhale completely, but should not exhale into the mouthpiece of the inhaler. The patient should then place the mouthpiece between the lips and inhale deeply through the inhaler with a steady, even breath; the patient should not inhale through the nose. The air vent on the inhaler should not be blocked while the dose is administered. The patient should remove the inhaler from the mouth, hold the breath for about 3-4 seconds (or as long as comfortable), and then exhale slowly and gently. While some patients may taste or feel a dose of drug delivered from the inhaler, patients should be instructed not to use another dose even if they do not perceive that the dose has been delivered. After the dose is administered, the inhaler should be closed by sliding the cover up and over the mouthpiece as far as possible.

The inhaler does not need to be cleaned after use. However, if desired, the mouthpiece can be cleaned with a dry tissue. The inhaler should be discarded when every blister has been used or 6 weeks after removal of the inhaler from the foil tray, whichever comes first.

Umeclidinium is a substrate of cytochrome P-450 (CYP) isoenzyme 2D6 and P-glycoprotein (P-gp).

There are no contraindication interactions for this drug.

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

Inhaled Anticholinergics/Pramlintide

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)

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

Beta-Agonists; Anticholinergics; Theophylline/Methacholine

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.

Inhaled Anticholinergics/Solid Oral Potassium Capsules

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)

Inhaled Anticholinergics/Solid Oral Potassium Tablets

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)

*Hypersensitivity to umeclidinium or any ingredient in the formulation.

*Severe hypersensitivity to milk proteins.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

• Angle-closure glaucoma
• Benign prostatic hyperplasia
• Bladder outflow obstruction
• Urinary retention

Adverse events occurring in 2% or more of patients with COPD receiving umeclidinium and at an incidence greater than placebo include nasopharyngitis, upper respiratory tract infection, cough, and arthralgia.

Less Frequent

• Urinary retention

Rare or Very Rare

• Abnormal ECG
• Anaphylaxis
• Angioedema
• Atrial fibrillation
• Ocular hypertension
• Secondary angle-closure glaucoma
• Supraventricular premature beats

More Frequent

• Arthralgia
• Cough
• Pharyngitis
• Upper respiratory infection

Less Frequent

• Chest pain
• Constipation
• Diarrhea
• Dyspepsia
• Lower respiratory infection
• Myalgia
• Neck pain
• Toothache
• Upper abdominal pain
• Urinary tract infection

Rare or Very Rare

• Blurred vision
• Conjunctivitis
• Dysgeusia
• Dysuria
• Ocular pain
• Pain in oropharynx
• Pruritus of skin
• Sinusitis
• Urticaria
• Voice change
• Xerostomia

No enhanced messaging available.

Safety and efficacy of umeclidinium have not been established in children. The drug is not indicated for use in pediatric patients.

There are insufficient data on the use of umeclidinium in pregnant women to inform a drug-associated risk. When administered via inhalation or subcutaneously to pregnant rats and rabbits, umeclidinium was not associated with adverse effects on embryofetal development at exposures approximately 50 and 200 times, respectively, the human exposure at the maximum recommended human daily inhaled dose.

Umeclidinium may be distributed into milk in rats; it is not known whether the drug is distributed into milk in humans or whether the drug has any effects on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for umeclidinium and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition..

No dosage adjustment required in geriatric patients.

When the total number of patients studied in clinical trials of umeclidinium is considered, about 49% were 65 years of age or older, while 11% were 75 years of age or older. Although no overall differences in efficacy or safety were observed between geriatric and younger patients in clinical trials, and other clinical experience revealed no evidence of age-related differences, 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.