Incruse Ellipta

Incruse Ellipta

umeclidinium bromide

Manufacturer:

GlaxoSmithKline

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Umeclidinium bromide.
Description
Each delivered dose (the dose leaving the mouthpiece of the inhaler) contains 55 micrograms umeclidinium (equivalent to 65 micrograms of umeclidinium bromide).
This corresponds to a pre-dispensed dose of 62.5 micrograms of umeclidinium (equivalent to 74.2 micrograms umeclidinium bromide).
Excipients/Inactive Ingredients: Lactose monohydrate (which contains milk protein) (12.5 milligrams lactose monohydrate per dose), magnesium stearate.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Umeclidinium is a long acting muscarinic receptor antagonist (also referred to as an anticholinergic). It is a quinuclidine derivative that is a muscarinic receptor antagonist with activity across multiple muscarinic cholinergic receptor subtypes. Umeclidinium exerts its bronchodilatory activity by competitively inhibiting the binding of acetylcholine with muscarinic cholinergic receptors on airway smooth muscle. It demonstrates slow reversibility at the human M3 muscarinic receptor subtype in vitro and a long duration of action in vivo when administered directly to the lungs in pre-clinical models.
Pharmacodynamic Effects: In a 24-week, placebo controlled clinical efficacy study INCRUSE ELLIPTA increased forced expiratory volume in one second (FEV1) after the first dose on Day 1 with an improvement of 0.10 litres at 30 minutes compared with placebo (p<0.001*). The increase from baseline to peak FEV1 over the first 6 hours post-dose at Day 1 was 0.23 litres with INCRUSE ELLIPTA compared with 0.11 litres for placebo. The increase from baseline to peak FEV1 over the first 6 hours post-dose at Week 24 was 0.23 litres with INCRUSE ELLIPTA compared with 0.10 litres for placebo.
*A step-down statistical testing procedure was used in this study and this comparison was below a comparison that did not achieve statistical significance. Therefore, statistical significance on this comparison cannot be inferred.
Cardiovascular Effects: The effect of umeclidinium 500 micrograms on the QT interval was evaluated in a placebo- and moxifloxacin-controlled QT trial of 103 healthy volunteers. Following repeat doses of umeclidinium 500 micrograms once daily for 10 days, no clinically relevant effect on prolongation of QT interval (corrected using the Fridericia method) was observed.
Clinical Studies: The clinical efficacy of INCRUSE ELLIPTA administered once daily was evaluated in 904 adult patients who received umeclidinium bromide or placebo from two pivotal Phase III clinical (DB2113373).
Pivotal Efficacy Studies: Effects on Lung Function: In both of the pivotal 12-week and 24-week studies, INCRUSE ELLIPTA demonstrated statistically significant and clinically meaningful improvements in lung function (as defined by change from baseline trough FEV1 at Week 12 and Week 24 respectively, which was the primary efficacy endpoint in each study) compared with placebo (see Table 1). The bronchodilatory effects with INCRUSE ELLIPTA compared with placebo were evident after the first day of treatment in both studies and were maintained over the 12-week and 24-week treatment periods.
There was no attenuation of the bronchodilator effect over time. (See Table 1.)

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INCRUSE ELLIPTA demonstrated a statistically significant greater improvement from baseline in weighted mean FEV1 over 0-6 hours post-dose at Week 12 compared with placebo (166 ml, p<0.001) in the 12-week pivotal study. INCRUSE ELLIPTA demonstrated a greater improvement from baseline in weighted mean FEV1 over 0-6 hours post-dose at Week 24 compared with placebo (150 ml, p<0.001*) in the 24-week pivotal study.
*A step-down statistical testing procedure was used in this study and this comparison was below a comparison that did not achieve statistical significance. Therefore, statistical significance on this comparison cannot be inferred.
Symptomatic Outcomes: Breathlessness: In the 12-week study, a statistically significant improvement compared with placebo in the TDI focal score at Week 12 was not demonstrated for INCRUSE ELLIPTA (1.0 units, p=0.05). A statistically significant improvement compared with placebo in the TDI focal score at Week 24 was demonstrated for INCRUSE ELLIPTA (1.0 units, p<0.001) in the 24-week study.
The proportion of patients who responded with at least the minimum clinically important difference (MCID) of 1 unit TDI focal score at Week 12 was greater for INCRUSE ELLIPTA (38%) compared with placebo (15%) in the 12-week study. Similarly, a greater proportion of patients achieved ≥1 unit TDI focal score for INCRUSE ELLIPTA (53%) compared with placebo (41%) at Week 24 in the 24-week study.
Health-Related Quality of Life: INCRUSE ELLIPTA also demonstrated a statistically significant improvement in health-related quality of life measured using the St. George’s Respiratory Questionnaire (SGRQ) as indicated by a reduction in SGRQ total score at Week 12 compared with placebo (-7.90 units, p<0.001) in the 12-week study. A greater improvement compared with placebo in the change from baseline in SGRQ total score at Week 24 was demonstrated for INCRUSE ELLIPTA (-4.69 units, p<0.001*) in the 24-week study.
The proportion of patients who responded with at least the MCID in SGRQ score (defined as a decrease of 4 units from baseline) at Week 12 was greater for INCRUSE ELLIPTA 55 micrograms (44%) compared with placebo (26%) in the 12-week study. Similarly, a greater proportion of patients achieved at least the MCID for INCRUSE ELLIPTA at Week 24 (44%) compared with placebo (34%) in the 24-week study.
COPD Exacerbations: In the 24-week study, INCRUSE ELLIPTA lowered the risk of a COPD exacerbation compared with placebo (analysis of time to first exacerbation; Hazard Ratio 0.6, p=0.035*). The probability of having an exacerbation in patients receiving INCRUSE ELLIPTA at week 24 was 8.9% compared with 13.7% for placebo. These studies were not specifically designed to evaluate the effect of treatments on COPD exacerbations and patients were withdrawn from the study if an exacerbation occurred.
*A step down statistical testing procedure was used in this study and this comparison was below a comparison that did not achieve statistical significance. Therefore, statistical significance on this comparison cannot be inferred.
Use of Rescue Medicinal Product: In the 12-week study, INCRUSE ELLIPTA statistically significantly reduced the use of rescue medication with salbutamol compared with placebo (on average a reduction of 0.7 puffs per day over Weeks 1-12, p=0.025) and demonstrated a higher percentage of days when no rescue medication was needed (on average 46.3%) compared with placebo (on average 35.2%; no formal statistical analysis was performed on this endpoint). In the 24-week study treatment with INCRUSE ELLIPTA, the mean (SD) change from baseline in the number of puffs of rescue salbutamol over the 24-week treatment period was -1.4 (0.20) for placebo and -1.7 (0.16) for INCRUSE ELLIPTA (Difference = -0.3; 95% CI: -0.8, 0.2, p=0.276). Patients receiving INCRUSE ELLIPTA had a higher percentage of days when no rescue medication was needed (on average 31.1%) compared with placebo (on average 21.7%). No formal statistical testing was performed on this endpoint.
Pharmacokinetics: Absorption: Following inhaled administration of umeclidinium in healthy volunteers, Cmax occurred at 5 to 15 minutes. The absolute bioavailability of inhaled umeclidinium was on average 13% of the dose, with negligible contribution from oral absorption. Following repeat dosing of inhaled umeclidinium, steady state was achieved within 7 to 10 days with 1.5 to 2-fold accumulation. Umeclidinium systemic exposure following inhaled administration was dose proportional between 62.5 mcg and 125 mcg.
Distribution: Following intravenous administration to healthy subjects, the mean volume of distribution was 86 litres. In vitro plasma protein binding in human plasma was on average 89%.
Metabolism: In vitro studies showed that umeclidinium is principally metabolised by the enzyme P450 CYP2D6 and is a substrate for the P-glycoprotein (Pgp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (glucuronidation, etc), 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.
Elimination: Plasma clearance following intravenous administration was 151 litres/hour. Following intravenous administration, approximately 58% of the administered radiolabelled dose (or 73% of the recovered radioactivity) was excreted in faeces by 192 hours post-dose. Urinary elimination accounted for 22% of the administered radiolabelled dose by 168 hours (27% of recovered radioactivity). The excretion of the drug-related material in the faeces following intravenous dosing indicated secretion into the bile. Following oral administration to healthy male subjects, total radioactivity was excreted primarily in faeces (92% of the administered radiolabelled dose or 99% of the recovered radioactivity) by 168 hours post-dose. Less than 1% of the orally administered dose (1% of recovered radioactivity) was excreted in urine, suggesting negligible absorption following oral administration. Umeclidinium plasma half-life following inhaled dosing for 10 days averaged 19 hours, with 3% to 4% drug excreted unchanged in urine at steady-state.
Special Patient Populations: Elderly: A population pharmacokinetic analysis showed that pharmacokinetics of umeclidinium are similar between COPD patients 65 years and older and those younger than 65 years of age.
Renal Impairment: Subjects with severe renal impairment (creatinine clearance <30 millilitres/min) showed no evidence of an increase in systemic exposure to umeclidinium (Cmax and AUC) and no evidence of altered protein binding between subjects with severe renal impairment and healthy volunteers.
Hepatic Impairment: Subjects with moderate hepatic impairment (Child-Pugh Class B) showed no evidence of an increase in systemic exposure to umeclidinium (Cmax and AUC) and no evidence of altered protein binding between subjects with moderate hepatic impairment and healthy volunteers. Umeclidinium has not been evaluated in subjects with severe hepatic impairment.
Other Patient Characteristics: A population pharmacokinetic analysis showed that no dose adjustment is required for umeclidinium based on the effect of age, race, gender, inhaled corticosteroid use or weight. A study in CYP2D6 poor metabolisers showed no evidence of a clinically significant effect of CYP2D6 genetic polymorphism on systemic exposure to umeclidinium.
Toxicology: Preclinical Safety Data: In non-clinical studies with umeclidinium, findings were those typically associated with the primary pharmacology of muscarinic receptor antagonists and/or local irritancy.
Carcinogenesis/Mutagenesis: Umeclidinium was not genotoxic in a standard battery of studies and was not carcinogenic in lifetime inhalation studies in mice or rats at exposures 26 or 22-fold, times the human clinical exposure of umeclidinium, based on AUC, respectively.
Reproductive Toxicology: Umeclidinium had no adverse effects on male or female fertility in rats.
Umeclidinium was not teratogenic in rats or rabbits. In a pre- and post-natal study, subcutaneous administration of umeclidinium to rats resulted in lower maternal body weight gain and food consumption and slightly decreased pre-weaning pup body weights in dams given 180 micrograms/kg/day dose (approximately 80-times the human clinical exposure of umeclidinium, based on AUC).
Indications/Uses
INCRUSE ELLIPTA is indicated for maintenance bronchodilator treatment to relieve symptoms associated with chronic obstructive pulmonary disease (COPD).
Dosage/Direction for Use
Adults: The recommended dose is one inhalation of INCRUSE ELLIPTA once daily.
Children:
Use in patients less than 18 years of age is not relevant given the indication for INCRUSE ELLIPTA.
Elderly:
No dosage adjustment is required in patients over 65 years (see Pharmacology: Pharmacokinetics: Special Patient Populations under Actions).
Renal Impairment: No dosage adjustment is required in patients with renal impairment (see Pharmacology: Pharmacokinetics: Special Patient Populations under Actions).
Hepatic Impairment: No dosage adjustment is required in patients with mild or moderate hepatic impairment.
INCRUSE ELLIPTA has not been studied in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics: Special Patient Populations under Actions).
Administration: INCRUSE ELLIPTA is for oral inhalation only.
INCRUSE ELLIPTA should be administered once daily at the same time of the day each day.
Overdosage
No data from clinical studies are available regarding overdose with INCRUSE ELLIPTA.
An overdose of INCRUSE ELLIPTA will likely produce signs and symptoms consistent with the known inhaled muscarinic antagonist adverse effects (e.g. dry mouth, visual accommodation disturbances and tachycardia).
If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.
Further management should be as clinically indicated or as recommended by the national poisons centre, where available.
Contraindications
INCRUSE ELLIPTA is contraindicated in patients with severe milk-protein allergy.
Hypersensitivity to the umeclidinium bromide or to any of the excipients (see Description).
Special Precautions
INCRUSE ELLIPTA should not be used in patients with asthma since it has not been studied in this patient population.
INCRUSE ELLIPTA is intended for the maintenance treatment of COPD. It should not be used for the relief of acute symptoms, i.e. as rescue therapy for the treatment of acute episodes of bronchospasm. Acute symptoms should be treated with an inhaled short-acting bronchodilator. Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a physician.
As with other inhalation therapies, administration of INCRUSE ELLIPTA may produce paradoxical bronchospasm that may be life threatening. Treatment with INCRUSE ELLIPTA should be discontinued if paradoxical bronchospasm occurs and alternative therapy instituted if necessary.
Cardiovascular effects, such as cardiac arrhythmias e.g. atrial fibrillation and tachycardia, may be seen after the administration of muscarinic receptor antagonists, including INCRUSE ELLIPTA. Therefore, INCRUSE ELLIPTA should be used with caution in patients with severe cardiovascular disorders, especially cardiac arrhythmias.
Consistent with its antimuscarinic activity, INCRUSE ELLIPTA should be used with caution in patients with narrow-angle glaucoma or urinary retention.
Effects on Ability to Drive and Use Machines: There have been no studies to investigate the effect of INCRUSE ELLIPTA on driving performance or the ability to operate machinery. There have been no adverse effects associated with INCRUSE ELLIPTA that would affect the ability to perform tasks that require judgment, motor or cognitive skills.
Use In Pregnancy & Lactation
Pregnancy: There is a limited amount of data from the use of INCRUSE ELLIPTA in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (See Non-clinical Information).
INCRUSE ELLIPTA should be used during pregnancy only if the expected benefit to the mother justifies the potential risk to the fetus.
Lactation: It is unknown whether umeclidinium is excreted in human milk. A risk to breastfed newborns/infants cannot be excluded.
A decision must be made whether to discontinue breastfeeding or to discontinue INCRUSE ELLIPTA therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy of woman.
Fertility: There are no data on the effects of INCRUSE ELLIPTA on human fertility. Animal studies indicate no effects of INCRUSE ELLIPTA on fertility (see Non-clinical information).
Adverse Reactions
Clinical Trial Data: The safety profile of umeclidinium was evaluated from approximately 1,700 patients with COPD who received doses of 62.5 micrograms or greater for up to one year. This includes approximately 600 patients who received the recommended dose of 62.5 micrograms once daily.
The adverse reactions identified from the four efficacy studies and the long-term safety study (which involved approximately 1,400 patients who received umeclidinium) are presented in the table as follows.
Adverse drug reactions (ADRs) are listed as follows by MedDRA system organ class and by frequency. The following convention has been used for the classification of adverse reactions: Very common ≥1/10, common ≥1/100 and <1/10, uncommon ≥1/1,000 and <1/100, rare ≥1/10,000 and <1/1,000, very rare <1/10,000. (See Table 2.)

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Post-marketing Data: (See Table 3)

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Drug Interactions
Available clinical data has revealed no clinically relevant drug interactions (see Clinical Pharmacology).
There is potential for an additive interaction with concomitantly used antimuscarinic medicines. Therefore, avoid coadministration of INCRUSE ELLIPTA with other antimuscarinic-containing drugs as this may lead to an increase in antimuscarinic adverse effects.
Umeclidinium is a substrate of P-glycoprotein transporter (P-gp) and CYP2D6. The effect of the P-gp transporter inhibitor verapamil (240 milligrams once daily) on the steady-state pharmacokinetics of umeclidinium was assessed in healthy volunteers. No effect of verapamil was observed on umeclidinium Cmax. An approximately 1.4-fold increase in umeclidinium AUC was observed. Based on the magnitude of these changes, no clinically relevant interaction is expected when umeclidinium bromide is co-administered with P-gp inhibitors.
The effect of lack of CYP2D6 poor metaboliser genotype on the steady-state pharmacokinetics of umeclidinium was assessed in healthy volunteers (CYP2D6 normal metabolisers and CYP2D6 poor metabolisers). No clinically meaningful difference in systemic exposure to umeclidinium (500 micrograms) was observed following repeat daily inhaled dosing to normal and CYP2D6 poor metaboliser subjects.
Caution For Usage
Instructions for Use/Handling: When the patient first use the Ellipta inhaler the patient do not need to check that it is working properly and the patient do not need to prepare it for use in any special way. Just follow the instructions as follows.
The inhaler is packaged in a tray containing a desiccant packet, to reduce moisture.
Throw packet away-don't eat or inhale.
When the patient take the inhaler out of the sealed tray, it will be in the 'closed' position. Don't open it until the patient are ready to inhale a dose of medicine.
The step-by-step instructions shown as follows for the 30-dose Ellipta inhaler also apply to the 7-dose Ellipta inhaler.
Read Before Initiation of Therapy: If the patient open and close the cover without inhaling the medicine, you will lose the dose.
The lost dose will be securely held inside the inhaler, but it will no longer be available.
It is not possible to accidentally take extra medicine or a double dose in one inhalation.
Prepare a Dose: Wait to open the cover until the patient is ready to take the patient's dose; do not shake the inhaler.
Slide the cover fully down until you hear a "click".
The medicine is now ready to be inhaled.
The dose counter counts down by 1 to confirm. If the dose counter does not count down as you hear the "click", the inhaler will not deliver medicine. Take it back to the patient's pharmacist for advice; do not shake the inhaler at any time.
Inhale Medication: While holding the inhaler away from the patient's mouth, breathe out as far as is comfortable.
Don't breathe out into the inhaler.
Put the mouthpiece between the patient's lips and close the patient's lips firmly around it. Don't block the air vent with the patient's fingers.
Take one long, steady, deep breath in. Hold this breath for as long as possible (at least 3-4 seconds).
Remove the inhaler from the patient's mouth.
Breathe out slowly and gently.
The patient may not be able to taste or feel the medicine, even when you are using the inhaler correctly.
Close the Inhaler: If the patient wants to clean the mouthpiece, use a dry tissue, before the patient closes the cover. Slide the cover upwards as far as it will go, to cover the mouthpiece.
Incompatibilities: No incompatibilities have been identified.
Storage
Special Precautions for Storage: Do not store above 30°C. If stored in the refrigerator, allow the inhaler to return to room temperature for at least an hour before use.
In-Use Shelf-Life: Following removal from the tray, the product may be stored for a maximum period of 6 weeks.
ATC Classification
R03BB07 - umeclidinium bromide ; Belongs to the class of other inhalants used in the treatment of obstructive airway diseases, anticholinergics.
Presentation/Packing
Inhalation powd (pre-dispensed) 62.5 mcg x 30's.
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