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    Respiratory Long-Acting Muscarinic Antagonists (LAMA)

    DEA CLASS

    Rx

    DESCRIPTION

    Inhaled long-acting muscarinic antagonist (LAMA); used once per day
    Used in adults for maintenance treatment of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema
    NOT indicated for the relief of acute bronchospasm or for the treatment of asthma

    COMMON BRAND NAMES

    INCRUSE ELLIPTA

    HOW SUPPLIED

    INCRUSE ELLIPTA Respiratory (Inhalation) Inhalant: 1actuation, 62.5mcg

    DOSAGE & INDICATIONS

    For the maintenance treatment of chronic obstructive pulmonary disease (COPD) (e.g., chronic bronchitis or emphysema).
    Oral Inhalation dosage (inhalation powder; i.e., Incruse Ellipta)
    Adults

    62.5 mcg (1 actuation) via oral inhalation once daily, at the same time every day, is the recommended and max dosage. Not indicated for the relief of acute bronchospasm. Use an inhaled short-acting beta-2 agonist (SABA) for immediate relief of acute symptoms. Do not use other long-acting muscarinic antagonists (LAMAs) concurrently.[57100] According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, umeclidinium may be used as initial monotherapy in all groups of COPD patients; however, combination therapy with a long-acting beta-agonist (LABA) or inhaled corticosteroid (ICS) may be needed in patients in Group D or those patients still experiencing dyspnea or exacerbations upon follow-up.[63765]

    MAXIMUM DOSAGE

    Adults

    62.5 mcg/day via oral inhalation.

    Geriatric

    62.5 mcg/day via oral inhalation.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustments are needed.

    Renal Impairment

    No dosage adjustments are needed.

    ADMINISTRATION

    Inhalation Administration
    Oral Inhalation Administration

    Instruct the patient to open and prepare mouthpiece of the umeclidinium inhaler and slide the cover down to activate the first dose (see package instructions). The counter counts down by 1 dose each time the patient opens the cover.
    Holding the inhaler mouthpiece level to, but away from, the mouth, the patient should exhale. Then, put the mouthpiece to the lips and have patient breathe in the dose deeply and slowly. Remove the inhaler from the mouth, hold breath for about 3 to 4 seconds, and then exhale slowly. Instruct patient to close the inhaler.
    If the cover is opened and closed without inhaling the medicine, the dose will be lost. The lost dose will be held in the inhaler, but it will no longer be available to be inhaled. It is not possible to accidentally take a double dose or an extra dose in one inhalation.
    Routine cleaning of the inhaler is not required; the patient can clean the mouthpiece if needed, using a dry tissue, before the cover is closed.
    Discard inhaler after 30 sprays or when the counter reads "0", or when the expiration date has passed.

    STORAGE

    INCRUSE ELLIPTA:
    - Avoid direct heat and sunlight
    - Product should always be stored in the blister and only removed immediately before use
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in a dry place

    CONTRAINDICATIONS / PRECAUTIONS

    Angioedema, milk protein hypersensitivity

    Umeclidinium is contraindicated in patients with a known hypersensitivity to any ingredient in the preparation and in patients with a severe milk protein hypersensitivity since the product contains lactose, which contains milk proteins. Hypersensitivity reactions may also occur after the administration of umeclidinium and may present as anaphylactic reaction, urticaria, angioedema, rash, and pruritus.

    Acute bronchospasm

    Umeclidinium should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. The drug has not been studied in patients with acutely deteriorating COPD. Umeclidinium should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute bronchospasm. Umeclidinium has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta-2 agonist. Warn patients that increasing inhaled short-acting beta-agonist use is a signal of deteriorating disease. Loss of symptom control with umeclidinium is also a marker of deterioration of disease; in this setting a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dose of umeclidinium beyond the recommended dose is not appropriate in this situation.

    Paradoxical bronchospasm

    Like other inhaled medications, umeclidinium can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, it should be treated immediately with a short-acting, inhaled bronchodilator, and umeclidinium should be discontinued immediately and alternative therapy instituted.

    Closed-angle glaucoma, contact lenses, ocular exposure, ophthalmic administration

    All anticholinergics should be used with caution in patients with closed-angle glaucoma. Significant systemic absorption may aggravate this condition. Umeclidinium may increase intraocular pressure and aqueous outflow resistance in patients with closed-angle glaucoma, particularly if the medication gets into the eyes (i.e., inadvertent ocular exposure). Temporary pain, mydriasis, cycloplegia, blurred vision, conjunctivitis, or visual impairment may result from inadvertent ophthalmic administration; care should be taken not to get umeclidinium in the eyes. The anticholinergic effects of umeclidinium may make the eyes dry and this can cause irritation or blurred vision for wearers of contact lenses. The use of lubricating drops may be necessary.

    Anticholinergic medications, bladder obstruction, prostatic hypertrophy

    Anticholinergics like umeclidinium should be used with caution in patients with preexisting bladder obstruction (of the bladder neck) or other urinary tract obstruction, or in patients with prostatic hypertrophy. Umeclidinium may precipitate urinary retention in patients with these conditions. The effects of umeclidinium may be additive to other concomitantly administered anticholinergic medications.

    Pregnancy

    Adequate and well-controlled studies regarding the use of umeclidinium inhalation during pregnancy have not been perfromed. When umeclidinium was administered to rats and rabbits at approximately 50 and 200 times, respectively, the MRHDID (maximum recommended human daily inhaled dose), teratogenic effects were not evident. Umeclidinium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women who become pregnant while stabilized on umeclidinium therapy should contact a qualified health care professional.

    Breast-feeding

    The manufacturer recommends caution when administering umeclidinium inhalation to women who are breast-feeding. It is unknown whether umeclidinium is excreted in human breast milk. However, subcutaneous administration of umeclidinium to lactating rats at approximately 25 times the MRHDID in adults resulted in a quantifiable level of umeclidinium in 2 pups, which may indicate transfer of umeclidinium in milk. A decision should be made whether to discontinue nursing or to discontinue treatment with umeclidinium. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    Umeclidinium inhalation is not indicated for use in children. The safety and efficacy of umeclidinium inhalation have not been established in infants, neonates, children, and adolescents.

    Geriatric

    Based on available data, no adjustment of the dosage of inhaled umeclidinium in geriatric patients is necessary, but greater sensitivity to the drug in some older individuals cannot be ruled out. Clinical trials included 810 subjects aged 65 years of age and older, and, of those, 183 subjects were aged 75 years and older. Safety and efficacy in clinical trials, as well as other reported clinical experience, has not identified differences in the elderly vs. younger adult patient. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities (LTCFs). The OBRA guidelines caution that inhaled anticholinergic drugs, such as umeclidinium, can cause xerostomia.

    ADVERSE REACTIONS

    Severe

    atrial fibrillation / Early / 0-1.0
    bronchospasm / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    ocular hypertension / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 0-1.0
    depression / Delayed / 1.0
    sinus tachycardia / Rapid / 1.0
    supraventricular tachycardia (SVT) / Early / 1.0
    wheezing / Rapid / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    urinary retention / Early / Incidence not known
    blurred vision / Early / Incidence not known

    Mild

    pharyngitis / Delayed / 1.0-8.0
    infection / Delayed / 1.0-5.0
    cough / Delayed / 3.0-3.0
    arthralgia / Delayed / 2.0-2.0
    myalgia / Early / 1.0-1.0
    ecchymosis / Delayed / 1.0-1.0
    abdominal pain / Early / 1.0-1.0
    xerostomia / Early / 0-1.0
    vertigo / Early / 1.0
    headache / Early / 1.0
    dizziness / Early / 1.0
    rhinitis / Early / 1.0
    nausea / Early / 1.0
    diarrhea / Early / 1.0
    dyspepsia / Early / 1.0
    rash / Early / 1.0
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Aclidinium: (Moderate) Although aclidinium is minimally absorbed into the systemic circulation after inhalation, there is the potential for aclidinium to have additive anticholinergic effects when administered with other anticholinergics or antimuscarinics. Per the manufaturer, avoid concomitant administration of aclidinium with other anticholinergic medications, when possible.
    Aclidinium; Formoterol: (Moderate) Although aclidinium is minimally absorbed into the systemic circulation after inhalation, there is the potential for aclidinium to have additive anticholinergic effects when administered with other anticholinergics or antimuscarinics. Per the manufaturer, avoid concomitant administration of aclidinium with other anticholinergic medications, when possible.
    Anticholinergics: (Moderate) There is the potential for umeclidinium to have additive anticholinergic effects when administered with other anticholinergics or antimuscarinics. Per the manufaturer, avoid concomitant administration of umeclidinium with other anticholinergic medications when possible.
    Brigatinib: (Moderate) Monitor for an increase in umeclidinium-related adverse reactions if coadministration with brigatinib is necessary. Umeclidinium is a P-glycoprotein (P-gp) substrate. Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates. Coadministration with a P-gp inhibitor increased umeclidinium exposure by 1.4-fold.
    Daclatasvir: (Moderate) Systemic exposure of umeclidinium; vilanterol, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of umeclidinium; vilanterol; monitor patients for potential adverse effects.
    Darunavir: (Moderate) Caution is warranted when darunavir is administered with umeclidinium; vilanterol as there is a potential for elevated umeclidinium; vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Umeclidinium; vilanterol is a substrate of CYP3A4 and CYP2D6. Darunavir is an inhibitor of CYP3A4 and CYP2D6.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when darunavir is administered with umeclidinium; vilanterol as there is a potential for elevated umeclidinium; vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Umeclidinium; vilanterol is a substrate of CYP3A4 and CYP2D6. Darunavir is an inhibitor of CYP3A4 and CYP2D6.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when darunavir is administered with umeclidinium; vilanterol as there is a potential for elevated umeclidinium; vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Umeclidinium; vilanterol is a substrate of CYP3A4 and CYP2D6. Darunavir is an inhibitor of CYP3A4 and CYP2D6.
    Fosamprenavir: (Moderate) Concomitant use of umeclidinium and fosamprenavir may result in decreased umeclidinium plasma concentrations. Umeclidinium is a substrate of the drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is an inducer of P-gp.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and umeclidinium as coadministration may increase serum concentrations of umeclidinium and increase the risk of adverse effects. Umeclidinium is a substrate of P-glycoprotein (P-gp); glecaprevir is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and umeclidinium as coadministration may increase serum concentrations of umeclidinium and increase the risk of adverse effects. Umeclidinium is a substrate of P-glycoprotein (P-gp); pibrentasvir is a P-gp inhibitor.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with umeclidinium; vilanterol may result in increased serum concentrations of umeclidinium; vilanterol. Umeclidinium; vilanterol is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4 and P-gp. Caution and close monitoring are advised if these drugs are used together.
    Lumacaftor; Ivacaftor: (Minor) Lumacaftor; ivacaftor may alter the exposure of umeclidinium. Umeclidinium is a substrate for P-glycoprotein (P-gp); in vitro data suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport and its effect on umeclidinium is not clear. Monitor the patient for therapeutic efficacy and increased or prolonged anticholinergic effects.
    Methacholine: (Major) Discontinue use of umeclidinium 168 hours or more before a methacholine challenge test. Umeclidinium inhibits the airway response to methacholine.
    Mirabegron: (Minor) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as umeclidinium may be increased when co-administered with mirabegron. Umeclidinium is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary. Monitor for dry mouth, constipation, blurred vision or urinary retention.
    Osimertinib: (Moderate) Monitor for an increase in umeclidinium-related adverse reactions if coadministration with osimertinib is necessary. Umeclidinium is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased umeclidinium exposure by 1.4-fold.
    Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to umeclidinium if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while umeclidinium is a CYP2D6 substrate.
    Rolapitant: (Major) Use caution if umeclidinium and rolapitant are used concurrently, and monitor for umeclidinium-related adverse effects. Umeclidinium is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of umeclidinium, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently.
    Sorafenib: (Moderate) Monitor for an increase in umeclidinium-related adverse reactions if coadministration with sorafenib is necessary. Umeclidinium is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor in vitro. Coadministration with another P-gp inhibitor increased umeclidinium exposure by 1.4-fold.
    Temsirolimus: (Minor) Monitor for an increase in umeclidinium-related adverse reactions if coadministration with temsirolimus is necessary. Umeclidinium is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of umeclidinium.
    Trandolapril; Verapamil: (Moderate) Umeclidinium is a P-gp substrate. When verapamil, a moderate P-gp transporter inhibitor, was given to healthy adult subjects at a dose of 240 mg once daily in combination with umeclidinium, no effect on umeclidinium Cmax was observed. However, an approximately 1.4-fold increase in umeclidinium AUC was observed.
    Verapamil: (Moderate) Umeclidinium is a P-gp substrate. When verapamil, a moderate P-gp transporter inhibitor, was given to healthy adult subjects at a dose of 240 mg once daily in combination with umeclidinium, no effect on umeclidinium Cmax was observed. However, an approximately 1.4-fold increase in umeclidinium AUC was observed.

    PREGNANCY AND LACTATION

    Pregnancy

    Adequate and well-controlled studies regarding the use of umeclidinium inhalation during pregnancy have not been perfromed. When umeclidinium was administered to rats and rabbits at approximately 50 and 200 times, respectively, the MRHDID (maximum recommended human daily inhaled dose), teratogenic effects were not evident. Umeclidinium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women who become pregnant while stabilized on umeclidinium therapy should contact a qualified health care professional.

    The manufacturer recommends caution when administering umeclidinium inhalation to women who are breast-feeding. It is unknown whether umeclidinium is excreted in human breast milk. However, subcutaneous administration of umeclidinium to lactating rats at approximately 25 times the MRHDID in adults resulted in a quantifiable level of umeclidinium in 2 pups, which may indicate transfer of umeclidinium in milk. A decision should be made whether to discontinue nursing or to discontinue treatment with umeclidinium. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Umeclidinium is a respiratory antimuscarinic or long-acting muscarinic antagonist (LAMA), which is often referred to as an anticholinergic. Umeclidinium has similar affinity to the subtypes of muscarinic receptors M1 thru M5. Bronchodilation occurs through inhibition of the M3 receptor in the smooth muscle of the airways. The competitive and reversible nature of antagonism was exhibited with human and animal origin receptors and isolated organ preparations. Prevention of acetylcholine-induced bronchoconstriction was shown to be dose-dependent in preclinical in vitro and in vivo studies. The effect lasted longer than 24 hours. The clinical relevance of these findings is unknown. After inhalation, bronchodilation is predominantly a site-specific effect.

    PHARMACOKINETICS

    Umeclidinium is administered by oral inhalation. Linear pharmacokinetics are observed for umeclidinium (62.5 to 500 mcg). Following IV administration to healthy subjects, the mean volume of distribution was 86 liters. In vitro plasma protein binding in human plasma was on average 89%. In vitro data showed that umeclidinium is primarily metabolized by CYP2D6 and is a P-gp substrate. Umeclidinium is metabolized via oxidative metabolism (hydroxylation, O-dealkylation) followed by conjugation (e.g., glucuronidation); metabolites have either low or no pharmacological activity. Systemic exposure to the metabolites is low. Following IV dosing with radio-labeled umeclidinium, mass balance showed 58% of the radio-label in the feces and 22% in the urine. Bile elimination was also evident. Following oral dosing to healthy male subjects, 92% of the total dose was recovered in feces, and in urine recovery was less than 1% of the total dose, suggesting negligible oral absorption. The effective half-life after once-daily inhalation dosing is 11 hours.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2D6, P-glycoprotein (P-gp)
    In vitro data showed that umeclidinium is primarily metabolized by CYP2D6 and is a substrate for the P-glycoprotein (P-gp) transporter. However, no clinically meaningful difference in systemic exposure (AUC) to umeclidinium (500 mcg) (8 times the approved dose) was observed following repeat daily inhaled dosing in CYP2D6 normal (ultrarapid, extensive, and intermediate metabolizers) and poor metabolizer subjects. In a clinical study with a strong P-gp inhibitor, an approximately 1.4-fold increase in umeclidinium AUC was observed but no increase in Cmax occurred.

    Inhalation Route

    Plasma levels of umeclidinium after oral inhalation are not predictive of therapeutic effect. Following inhaled administration of umeclidinium in healthy subjects, Cmax occurred at 5 to 15 minutes. Umeclidinium is mostly absorbed from the lung after inhaled doses with minimum contribution from oral absorption. Following repeat dosing of inhaled umeclidinium steady state was achieved within 14 days with up to 1.8-fold accumulation.