Umeclidinium

Umeclidinium belongs to the Anti-Cholinergics Pharmacological class.

Umeclidinium has been approved for the treatment and maintenance of COPD (Chronic Obstructive Pulmonary Disease).

Umeclidinium is absorbed with 1.8-fold accumulation. Umeclidinium achieved a mean volume of distribution of 86 L. The Umeclidinium is found to be metabolized by the CYP2D6. Following intravenous radiolabelled Umeclidinium administration, 58% of the Umeclidinium dose is recovered in feces and 22% was recovered in urine

The common side effects associated with Umeclidinium are redness of the eyes, hives, vision changes, dizziness, difficulty in urination, and wheezing and swelling in the eyes.

Umeclidinium is available in the form of Inhalation Powder.

Umeclidinium is available in U.S., Canada, E.U., India

Umeclidinium belongs to the pharmacological class of Anticholinergics. Umeclidinium is a long-acting muscarinic antagonist. Through its long action on Muscarinic receptors. It has an affinity towards the M₁ to M₅ receptor. This M₃ receptor hence acts on the bronchial smooth muscles in the lungs and leads to Bronchodilation.

Umeclidinium has a quick onset of action, and the duration of action is around 4-6 hrs which allows to once a day dosing.

In Umeclidinium treated patients the values ranged from 5–15 min and mean Cmax values ranged from 70 Cmax pg/mL for a dose of 67.5mcg.

Umeclidinium is available in Inhalation Powder:

Inhalation Powder

• The medicine comes in a foil tray.
• Peel the foil and slide the inhaler cover down until the clicking sound is heard.
• The inhaler should not be opened until ready for use.
• Now the head is turned away and breathed out away fully.
• The mouthpiece is put between the lips and the lips are closed around the mouthpiece.
• Now breathe in fully through the mouth.
• And once finished clean the mouthpiece and close the inhaler.

Umeclidinium can be used in the treatment and maintenance of:

• COPD(Chronic Obstructive Pulmonary Disease)

Umeclidinium can help to relieve symptoms and also for the long-term treatment maintenance of COPD (Chronic Obstructive Pulmonary Disease).

Umeclidinium is approved for use in the following clinical indications:

• COPD(Chronic Obstructive Pulmonary Disease)

62.5 mcg/actuation once a day

Inhalation Powder: 62.5 mcg/inhalation

Inhalation Powder

Smoking cessation and maintaining health are a must.

Caffeine should be avoided or limited to use as it might lead to the risk of nausea, palpitations, nervousness, rapid heartbeat, etc.

Milk should be avoided if there is severe hypersensitivity to milk proteins and it should be reported to the treating physician.

Diet containing food with a high glycemic index, saturated and trans fat food, red and processed meat, added sugar, salt, preservatives, refined and high energy-dense foods, low fiber, low antioxidants, and vitamins needs to be restricted.

The dietary restrictions are needed to be individualized as per the patient's requirements.

Umeclidinium may be contraindicated during the co-administration with the following drugs:

• Hypersensitivity to the ingredients of the medication
• Severe hypersensitivity toward milk proteins

The treating physician should closely monitor the patients and keep pharmacovigilance as follows:

Not for Acute Use

Umeclidinium is found to be intended as a once-a-day maintenance treatment for asthma and COPD and it should not be used for the relief of acute symptoms, such as rescue therapy for the treatment of acute episodes of bronchospasm.

Hypersensitivity Reactions

Hypersensitivity reactions might occur after the administration of Umeclidinium. There are reports of anaphylactic reactions in patients who have severe allergies to milk protein after inhalation of other powder products which contain lactose. Hence, patients with severe milk protein allergy should not use Umeclidinium.

Paradoxical Bronchospasm

Inhaled medications, including Umeclidinium, might lead to paradoxical bronchospasm. In such conditions, it should be treated immediately with an inhalation short-acting beta2-agonist such as albuterol. Treatment with Umeclidinium should be withdrawn immediately and other treatments considered.

Worsening of Narrow-Angle Glaucoma

Umeclidinium should be administered with caution in patients suffering from narrow-angle glaucoma. It is advised that patients and prescribers should be alert for signs of acute narrow-angle glaucoma such as eye pain or discomfort, blurred vision, etc. It is advised that the Patients should be instructed to consult a medical practitioner immediately should any of these signs or symptoms develop.

Worsening of Urinary Retention

Umeclidinium should be administered with caution in patients suffering from urinary retention. Physicians and patients should be vigilant for signs and symptoms of urinary retention such as difficulty passing urine, and painful urination, especially in patients suffering from prostatic hyperplasia or bladder-neck obstruction. It is advised that the patients should be advised to consult a medical practitioner immediately should any of these signs or symptoms develop.

Avoid alcohol usage while on Umeclidinium Medication as alcohol can worsen the effects of any underlying disease condition, including conditions such as dizziness, blurred vision, etc.

It is not established whether umeclidinium is excreted in breast milk in humans. As many drugs are excreted in human milk, caution should be taken when administering Umeclidinium to a nursing woman. No data from well-controlled human studies on the use of Umeclidinium by nursing mothers has been found. Hence a decision should be made on whether to continue or discontinue the use of Umeclidinium. In animal studies, subcutaneous administration of umeclidinium in lactating rats which is approximately 25 times the MRHDID in adults has been found to result in a quantifiable level of umeclidinium in 2 pups, which might indicate the transfer of umeclidinium in milk.

Teratogenic Effects

Pregnancy Category C.

There were found to be no adequate and well-controlled trials or data with Umeclidinium in pregnant women. As animal reproduction studies are said to be not always predictive of human response, hence Umeclidinium should be administered during pregnancy only if the potential benefits outweigh the risk associated with the fetus. In animal studies, no teratogenic effects in rats and rabbits at about 50 and 200 times, respectively, have been recorded.

Nonteratogenic Effects

There were found to be no effects on perinatal and postnatal developments in animal studies in rats when administered approximately 80 times the MRHDID in adults.

It is advised that patients with an allergy to milk proteins should report to the physician and its concomitant use with milk might produce allergic reactions.

The adverse reactions related to Umeclidinium can be categorized as:

Less common

• Loss of voice
• Lower back or side pain
• Sneezing
• Sore throat
• Tender, swollen glands in the neck
• Tightness in the chest
• Trouble in swallowing
• Unusual tiredness or weakness
• Voice changes
• Bladder pain
• Bloody or cloudy urine
• Body aches or pain
• Chest pain
• Chills
• Cough
• Difficult, burning, or painful urination
• Difficulty with breathing
• Dryness or soreness of the throat
• Ear congestion
• Fast, pounding, or irregular heartbeat or pulse
• Fever
• Frequent urge to urinate
• Hoarseness

Rare

• Dizziness
• Fainting

The clinically relevant drug interactions of Umeclidinium are briefly summarized here:

Umeclidinium and P-glycoprotein Transporter: Umeclidinium is said to be a substrate of P-GP. The effects of the moderate P-GP transporter inhibitor verapamil of about 240 mg once daily dose on the steady-state pharmacokinetics of umeclidinium was studied and assessed in healthy subjects. No effect on umeclidinium Cmax has been observed. However, an approximately 1.4-fold increase in umeclidinium AUC had been observed.

Umeclidinium and Cytochrome P450 2D6: In-vitro metabolism of umeclidinium is said to be mediated primarily by CYP2D6. However, clinically no meaningful difference in systemic exposure to umeclidinium which is 500 mcg i.e. 8 times the approved dose has been observed following repeat daily inhaled dosing to normal (ultrarapid, extensive, and intermediate metabolizers) and CYP2D6 poor metabolizer subjects.

The common side effects of Umeclidinium include the following:

• Redness of the eye
• Vision changes
• Seeing halos around lights
• Blurred vision
• Severe dizziness
• Difficult or painful urination
• Wheezing
• Eye pain or swelling
• Hives
• Difficulty breathing

Teratogenic Effects

Pregnancy Category C.

There were found to be no adequate and well-controlled trials or data with Umeclidinium in pregnant women. As animal reproduction studies are said to be not always predictive of human response, hence Umeclidinium should be administered during pregnancy only if the potential benefits outweighs the risk associated with the fetus. In animal studies, no teratogenic effects in rats and rabbits at about 50 and 200 times, respectively, have been recorded.

Nonteratogenic Effects

There were found to be no effects on perinatal and postnatal developments in animal studies in rats when administered approximately 80 times the MRHDID in adults.

Nursing Mothers

It is not established whether umeclidinium is excreted in breast milk in humans. As many drugs are excreted in human milk, caution should be taken when administering Umeclidinium to a nursing woman. No data from well-controlled human studies on the use of Umeclidinium by nursing mothers has been found. Hence a decision should be made on whether to continue or discontinue the use of Umeclidinium. In animal studies, subcutaneous administration of umeclidinium in lactating rats which is approximately 25 times the MRHDID in adults has been found to result in a quantifiable level of umeclidinium in 2 pups, which might indicate the transfer of umeclidinium in milk.

Pediatric Use

Umeclidinium is not indicated for use in children. Hence, safety and efficacy in pediatric patients have not been established.

Geriatric Use

Physicians should be knowledgeable and vigilant about the treatment pertaining to the identification and treatment of overdosage of Umeclidinium.

No case of overdose has been studied or reported with Umeclidinium. High doses of umeclidinium might lead to anticholinergic signs and symptoms. There were no systemic anticholinergic adverse effects which were followed by a once-daily inhaled dose of up to 1,000 mcg umeclidinium which is 16 times the maximum recommended daily dose, for 14 days in subjects with COPD (Chronic Obstructive Pulmonary Disease). Treatment of overdosage consists of discontinuation of Umeclidinium along with the institution of appropriate symptomatic and/or supportive therapy.

Pharmacodynamics

Umeclidinium belongs to the long-acting, antimuscarinic agent. It is often referred to as an anticholinergic. It has a similar affinity to the muscarinic subtype receptors i.e.M1 - M5. In the airways, it is found to exhibit pharmacological effects through the inhibition of the M3 receptor at the smooth muscle hence leading to bronchodilation.

Pharmacokinetics

• Absorption

The plasma levels of Umeclidinium may not predict therapeutic effects. After inhaled administration of umeclidinium in healthy subjects, Cmax is found to have occurred at 5 to 15 minutes. Umeclidinium is found to be mostly absorbed from the lung after inhaled doses. After allowing repeat dosing of inhaled Umeclidinium, a steady state was achieved within 14 days with about 1.8-fold accumulation.

• Distribution

After intravenous administration to subjects in good health, the mean volume of distribution was found to be 86 L. The In-vitro plasma protein binding in human plasma on average was 89%.

• Metabolism

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

• Elimination

The intravenous dosing with radiolabeled umeclidinium, mass balance showed around 58% of the radiolabel in the feces and 22% was found in the urine. The excretion of the drug-related material in the feces which was followed by the intravenous dosing indicated elimination in the bile. After oral dosing to healthy male subjects, 92% of the total dose was recovered in the feces and less than 1% of the total dose was recovered in the urine, suggesting that umeclidinium has negligible oral absorption. The half-life after once-daily dosing is 11 hours.

• Shah D, Driessen M, Risebrough N, Baker T, et.al. The Cost-effectiveness of umeclidinium compared with glycopyrronium and tiotropium as monotherapy for chronic obstructive pulmonary disease: a UK perspective. Cost Eff Resour Alloc. 2018 May 10;16:17.
• Feldman G, Maltais F, Khindri S, et.al.Randomized, blinded study to evaluate the efficacy and safety of umeclidinium 62.5 μg in comparison with tiotropium 18 μg in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2016 Apr 7;11:719-30.

• Sousa AR, Riley JH, Church A, Zhu CQ, Punekar YS, Fahy WA. The effect of umeclidinium added to inhaled corticosteroid/long-acting β2-agonist in patients with symptomatic COPD: a randomized, double-blind, parallel-group study. NPJ Prim Care Respir Med. 2016 Jun 23;26:16031.

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