Revefenacin

Revefenacin belongs to the Long Acting Anti-Cholinergics Pharmacological class.

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

Revefenacin is absorbed and the bioavailability is found to be less than 3%. Revefenacin achieved a volume of distributions of 218 L. Revefenacin is found to be metabolized by the CYP2D6 to its major hydrolytic metabolite THRX-195518. Following intravenous Revefenacin administration, 54% of the Revefenacin dose is recovered in feces and 27% was recovered in urine

The common side effects associated with Revefenacin are dry mouth, constipation, upset stomach, vomiting, cold symptoms, nosebleed, and muscle pain.

Revefenacin is available in the form of an Inhalation Solution.

Revefenacin is available in the U.S.

Revefenacin belongs to the pharmacological class of Anticholinergics. Through its long action on Muscarinic receptors, Revefenacin appears to inhibit the muscarinic receptors especially M₂ and M₃ receptors. It has slower activity towards the M₂ receptor than the M₃ receptor. This M₃ receptor hence acts on the bronchial smooth muscles in the lungs and leads to Bronchodilation.

Revefenacin has a quick onset of action, and the duration of action is around 24 hrs which allows to once a day dosing. Hence, it is used in the treatment and maintenance of COPD (Chronic Obstructive Pulmonary Disease).

In Revefenacin-treated patients, who received 44 88, 175, or 350ug for 48 days, the median Tmax values ranged from 0.483 to 0.517 h, and mean Cmax values ranged from 0.0203 to 0.146 ng/mL.

Revefenacin is available Inhalation Solution:

Inhalation Solution

1. The cap is kept closed.
2. The clear base is removed and the safety catch is pressed while firmly pulling off the base with the other hand.
3. The cartridge is inserted into the haler.
4. The inhaler is placed on a firm surface until a click sound is heard.
5. The checkbox is marked on the inhaler label.
6. The clear base is put back until it is clicked.
7. Now the clear base is turned in the direction of arrows on the label until it clicks (half a turn).
8. The cap is fully opened.
9. The inhaler is pointed toward the ground, the dose-release button is pressed.
10. The cap is closed
11. Steps 7-10 are repeated until a cloud is visible.
12. Steps 7-10 are repeated three more times.
13. Now the inhaler is held upright with the cap closed.
14. The base is turned in the direction of arrows on the label until it clicks (half a turn).
15. The cap is opened fully.
16. Now breathe out gently away from the inhaler
17. The mouthpiece is put near the mouth and inhaled deeply at the same time releasing the dose-release button.
18. The breath is held for 5 seconds.
19. Now the inhaler is removed away from the mouth while keeping the inhaler intact.
20. Breathe out gently and close the cap.

Revefenacin can be used in the treatment of:

• COPD(Chronic Obstructive Pulmonary Disease)

Revefenacin can help to relieve symptoms of COPD (Chronic Obstructive Pulmonary Disease).

Revefenacin is approved for use in the following clinical indications:

• COPD(Chronic Obstructive Pulmonary Disease)

88 mcg once daily

Inhalation Solution: 175 mcg/3 mL (3 mL)

Inhalation Solution

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.

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.

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

• Hypersensitivity to the ingredients of the medication

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

Not for Acute Use

Revefenacin 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 in the acute episodes of bronchospasm.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions such as urticaria, angioedema, rashes, bronchospasm, anaphylaxis, or itching may occur after the administration of Revefenacin. The therapy with Revefenacin should be stopped at once and alternative treatments should be considered when such a reaction occurs. Atropine and Revefenacin have a similar structural formula, therefore its is advised that the patients with a history of hypersensitivity effect to atropine or its derivatives should be closely monitored if similar hypersensitivity reactions to that of Revefenacin is noted.

Paradoxical Bronchospasm

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

Worsening of Narrow-Angle Glaucoma

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

Worsening of Urinary Retention

Revefenacin should be administered with caution in patients suffering from urinary retention. Physicians and patients should be alert 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 instructed to consult a physician immediately should any of these signs or symptoms develop.

There are no studies regarding the presence of revefenacin in human milk or its effects on the breastfed infant. However, revefenacin was found to be present in the milk of lactating rats followed by the dosing during pregnancy and lactation. Animal Data In a PPND study revefenacin and its active metabolite were found to be present in the milk of lactating rats on the 22nd lactation day. For revefenacin and its active metabolite, Milk-to-plasma concentration ratios were up to 10.

There are no well-controlled and adequate studies of the use of Revefenacin in pregnant women. Patients should be advised to contact their medical practitioner if they become pregnant while taking Revefenacin. In animal reproduction studies, it was found that subcutaneous administration of revefenacin in pregnant rabbits and rats during the period of organogenesis, no reported fetal adverse effects at respective exposures approximately which is 209 times the exposure at the maximum recommended human dose (MRHD) (on an area under the curve [AUC] basis. In the U.S. population in general, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies involving Revefenacin is 2-4% and 15-20%, respectively.

No sufficient scientific evidence is traceable regarding the use and safety of Revefenacin is concurrent use with any particular food.

The adverse reactions related to Revefenacin can be categorized as:

Less common

• Blurred vision
• Body aches or pains
• Usual tiredness or weakness
• Tightness of the chest
• Fever
• Headache
• Loss of voice
• Dizziness
• Muscle aches
• Sneezing
• Slow or fast heartbeat
• Ear congestion
• Difficulty in breathing
• Cough with mucus

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

Anticholinergics: There is a potential for an additive interaction of Revefenacin along with concomitant usage with anticholinergic medicines. Therefore, avoid coadministration of Revefenacin with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects

Transporter-related drug interactions: OATP1B1 and OATP1B3 inhibitors e.g. rifampicin, cyclosporine, etc. might lead to an increase in the systemic exposure of the active metabolite. Therefore, coadministration with Revefenacin is not recommended.

The common side effects of Revefenacin include the following:

• Hypertension
• Dizziness
• Mouth or throat pain
• Bronchitis
• Cough
• Runny or stuffy nose
• Upper respiratory tract infection
• Headache
• Back pain

Pregnancy

There are no well-controlled and adequate studies of the use of Revefenacin in pregnant women. Patients should be advised to contact their medical practitioner if they become pregnant while taking Revefenacin. In animal reproduction studies, it was found that subcutaneous administration of revefenacin in pregnant rats and rabbits during the period of organogenesis produced no evidence of fetal adverse effects at respective exposures approximately which is 209 times the exposure at the maximum recommended human dose (MRHD) (on an area under the curve [AUC] basis. In the U.S. population in general, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies involving Revefenacin is 2-4% and 15-20%, respectively.

Nursing Mothers

There is no data regarding the presence of revefenacin in human milk or its effects on the breastfed infant. However, revefenacin was found to be present in the milk of lactating rats followed by the dosing during pregnancy and lactation. Animal Data In a PPND study revefenacin and its active metabolite were found to be present in the milk of lactating rats on the 22nd lactation day. For revefenacin and its active metabolite, Milk-to-plasma concentration ratios were up to 10.

Pediatric Use

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

Geriatric Use

Based on available data, no dosage adjustment of Revefenacin in geriatric patients is warranted. No overall differences in effectiveness have been observed among these groups of people.

Physician should be knowledgeable and vigilant about the treatment pertaining to the identification and treatment of overdosage of Revefenacin.

An overdose of Revefenacin may lead to anticholinergic signs and symptoms including nausea, vomiting, dizziness, lightheadedness, blurred vision, increased intraocular pressure i.e.causing pain, vision disturbances, or reddening of the eye, obstipation or difficulties in voiding. In COPD patients, orally inhaled administration of Revefenacin at a once a day dose of up to 700 mcg i.e.4 times the maximum recommended daily dose for 7 days was well tolerated. Treatment of overdosage consists of discontinuation of Revefenacin along with institution of appropriate symptomatic and/or supportive therapy..

Pharmacodynamics

Revefenacin said to produce a sustained, long-acting bronchodilation with low anti-muscarinic-related side effects. In clinical trials, revefenacin has demonstrated to be of a long duration of action and low systemic exposure in patients suffering with COPD. Also, it was found that a dose of 88 mcg can produce a clinically effective bronchodilation measured through forced expiratory volume in 1s and also serial spirometric assessments.

In a placebo-controlled trials, it was found that revefenacin showed a decrease in the use of albuterol rescue inhalers and also resulted in sustained increase in the peak expiratory flow rate that reached a steady state at a maximum in day 7. As well, there was a reported superior lung selectivity index when compared with other LAMAs such as glycopyrronium and Revefenacin which produced a decreased sialagogue effect.

Pharmacokinetics

• Absorption

Followed by the inhalation administration of Revefenacin in healthy subjects or patients with COPD, Cmax of revefenacin and its active metabolite was found to be occuring at the first postdose sampling time ranged from 14 to 41 minutes after the initiation of nebulization. The absolute bioavailability following an oral administration of revefenacin is low i.e.<3%.

• Distribution

Followed by the intravenous administration to healthy subjects, the mean steady-state volume of distribution of revefenacin was found to be 218 L suggesting an extensive distribution to the tissues. The In-vitro protein binding of revefenacin and its active metabolite in human plasma was on average 71% and 42%, respectively

• Metabolism

In-vitro and in-vivo data showed that revefenacin is primarily metabolized to a carboxylic acid via hydrolysis of the primary amide forming its major active metabolite. Followed by the inhaled administration of Revefenacin in COPD patients, conversion to its active metabolite has found to be occurred rapidly, and plasma exposures of the active metabolite exceeded those of revefenacin by approximately 4- to 6-fold which is based on AUC. The active metabolite is said to be formed by hepatic metabolism and possesses an activity at target muscarinic receptors that is lower i.e. approximately one-third to one-tenth than that of Revefenacin. It said to potentially contribute to systemic antimuscarinic effects at therapeutic doses

• .Elimination

Followed by the administration of a single intravenous dose of radiolabeled revefenacin in healthy male subjects, around 54% of total radioactivity was recovered in the feces and 27% was found to be excreted in the urine. Approximately 19% of the administered radioactive dose was recovered in the feces in the form of active metabolite. After administration of single radiolabeled oral dose of revefenacin intravenously, 88% of total radioactivity was recovered in the feces and < 5% was found in urine, suggesting a low oral absorption of Revefenacin. There was found to be a minimal renal excretion (<1%) of revefenacin and its active metabolite followed by the inhaled administration of Revefenacin in COPD patients.

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