Incruse Ellipta (Umeclidinium)

INCRUSE ELLIPTA is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

The recommended dosage of INCRUSE ELLIPTA for maintenance treatment of COPD is 1 actuation (umeclidinium 62.5 mcg) once daily by oral inhalation.

• •INCRUSE ELLIPTA should be used at the same time every day. Do not use INCRUSE ELLIPTA more than 1 time every 24 hours.
• •No dosage adjustment is required for geriatric patients, patients with renal impairment, or patients with moderate hepatic impairment
  [see Clinical Pharmacology (

  12.3 Pharmacokinetics

  Linear pharmacokinetics was observed for umeclidinium (62.5 to 500 mcg).

  Absorption

  Umeclidinium plasma levels may not predict therapeutic effect. Following inhaled administration of umeclidinium in healthy subjects, C_maxoccurred 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 INCRUSE ELLIPTA, steady state was achieved within 14 days with up to 1.8-fold accumulation.

  Distribution

  Following intravenous administration to healthy subjects, the mean volume of distribution was 86 L. In vitro plasma protein binding in human plasma was on average 89%.

  Elimination

  Metabolism:

  In vitro data showed that umeclidinium is primarily metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (e.g., glucuronidation), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low.

  Excretion:

  The effective half-life after once-daily orally inhaled dosing is 11 hours. Following intravenous dosing with radiolabeled umeclidinium, mass balance showed 58% of the radiolabel in the feces and 22% in the urine. The excretion of the drug-related material in the feces following intravenous dosing indicated elimination in the bile. Following oral dosing to healthy male subjects, radiolabel recovered in feces was 92% of the total dose and that in urine was <1% of the total dose, suggesting negligible oral absorption.

  Specific Populations

  Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age (40 to 93 years) (Figure 1), gender (69% male) (Figure 1), inhaled corticosteroid use (48%), or weight (34 to 161 kg) on systemic exposure of umeclidinium. In addition, there was no evidence of a clinically significant effect of race.

  Patients with Hepatic Impairment:

  The impact of hepatic impairment on the pharmacokinetics of INCRUSE ELLIPTA has been evaluated in subjects with moderate hepatic impairment (Child-Pugh score of 7-9). There was no evidence of an increase in systemic exposure to umeclidinium (C_maxand AUC) (Figure 1). There was no evidence of altered protein binding in subjects with moderate hepatic impairment compared with healthy subjects. INCRUSE ELLIPTA has not been evaluated in subjects with severe hepatic impairment.

  Patients with Renal Impairment:

  The pharmacokinetics of INCRUSE ELLIPTA has been evaluated in subjects with severe renal impairment (CrCl <30 mL/min). There was no evidence of an increase in systemic exposure to umeclidinium (C_maxand AUC) (Figure 1). There was no evidence of altered protein binding in subjects with severe renal impairment compared with healthy subjects.

  Figure 1. Impact of Intrinsic and Extrinsic Factors on the Systemic Exposure of Umeclidinium

  

  Drug Interaction Studies

  Umeclidinium and P-glycoprotein Transporter:

  Umeclidinium is a substrate of P-gp. The effect of the moderate P-gp transporter inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of umeclidinium was assessed in healthy subjects. No effect on umeclidinium C_maxwas observed; however, an approximately 1.4-fold increase in umeclidinium AUC was observed (Figure 1).

  Umeclidinium and Cytochrome P450 2D6:

  In vitro metabolism of umeclidinium is mediated primarily by CYP2D6. However, no clinically meaningful difference in systemic exposure to umeclidinium (500 mcg) (8 times the approved dose) was observed following repeat daily inhaled dosing to normal (ultrarapid, extensive, and intermediate metabolizers) and CYP2D6 poor metabolizer subjects (Figure 1).

  

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Inhalation powder: 62.5 mcg umeclidinium per actuation.

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

The estimated risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

In a perinatal and postnatal developmental study in rats, dams received umeclidinium during late gestation and lactation periods with no evidence of effects on offspring development at doses up to approximately 26 times the MRHDID (on an AUC basis at maternal subcutaneous doses up to 60 mcg/kg/day).

• •Do not initiate in acutely deteriorating COPD. Do not use to treat acute symptoms. (
  5.1 Deterioration of Disease and Acute Episodes

  INCRUSE ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. INCRUSE ELLIPTA has not been studied in subjects with acutely deteriorating COPD. The initiation of INCRUSE ELLIPTA in this setting is not appropriate.

  INCRUSE ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. INCRUSE ELLIPTA 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 beta₂-agonist.

  If INCRUSE ELLIPTA no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting beta₂-agonist becomes less effective; or the patient needs more short-acting beta₂-agonist than usual, these may be markers of deterioration of disease. In this setting re-evaluate the patient and the COPD treatment regimen at once. Increasing the daily dose of INCRUSE ELLIPTA beyond the recommended dose is not appropriate in this situation.
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• •If paradoxical bronchospasm occurs, discontinue INCRUSE ELLIPTA and institute alternative therapy. (
  5.2 Paradoxical Bronchospasm

  As with other inhaled therapies, INCRUSE ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with INCRUSE ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; INCRUSE ELLIPTA should be discontinued immediately; and alternative therapy should be instituted.
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• •Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to contact a healthcare provider immediately if symptoms occur. (
  5.4 Worsening of Narrow-Angle Glaucoma

  INCRUSE ELLIPTA should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should also be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develop.
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• •Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to contact a healthcare provider immediately if symptoms occur. (
  5.5 Worsening of Urinary Retention

  INCRUSE ELLIPTA, like all therapies containing an anticholinergic, should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develop.
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