Revefenacin

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# Black Box Warning

# Overview
Revefenacin is a anticholinergics that is FDA approved for the treatment of The treatment of patients with chronic obstructive pulmonary disorder
- Should not be given to patients experiencing life threatening episodes
- In other words, Revefenacin should not be used as a rescue drug
- Discontinue the drug if patients appears to suffer from paradoxical bronchospasm or hypersensitivity reactions. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include Headache, Cough, Problems regarding the upper respiratory system, Back Pain.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Revefenacin is indicated for:
- The treatment of patients with chronic obstructive pulmonary disorder
Should not be given to patients experiencing life threatening episodes
In other words, Revefenacin should not be used as a rescue drug
- Should not be given to patients experiencing life threatening episodes
- In other words, Revefenacin should not be used as a rescue drug
- Discontinue the drug if patients appears to suffer from paradoxical bronchospasm or hypersensitivity reactions

### Limitations of Use
- Revefenacin delivered via jet nebulizer can result in "longer administration time, variability in residual volume and particle size, daily cleaning requirements, limited portability, and need for device assembly"
The benefits may outweigh this because some patients are required to use nebulizers
- The benefits may outweigh this because some patients are required to use nebulizers

### Dosing Considerations
- Patients are not allowed to use nephrotoxic or hepatotoxic medications for 4 weeks before drug administration
They may use the following medications: acetaminophen, ibuprofen, milk of magnesia (magnesium hydroxide), and routine vitamins and minerals
- They may use the following medications: acetaminophen, ibuprofen, milk of magnesia (magnesium hydroxide), and routine vitamins and minerals

### Administration of Revefenacin
- Only administer as an intravenous infusion.
- Intravenous solution in healthy volunteers
Volume of distribution was 218 L
Intravenous solution radioactivity:
54% came out as solid waste
27% came out as liquid waste
- Volume of distribution was 218 L
- Intravenous solution radioactivity:
- 54% came out as solid waste
- 27% came out as liquid waste

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Revefenacin Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding Revefenacin Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
Children are not administered Revefenacin because of the strength and long-lasting effects it has with on daily dose.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Revefenacin Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding Revefenacin Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
- Revefenacin is contraindicated in patients with hypersensitivity to revefenacin or any component of this product.

# Warnings
- Revefenacin should not be given to patients during an acutely deteriorating or potentially life-threatening episode of COPD
- Revefenacin is a one dose daily medication to treat patients with Chronic Obstructive Pulmonary Disease, and it should not be used as a bronchodilator to relieve acute symptoms. An extra dose should not be administered at any given time unless a doctor prescribes it. Instead, acute symptoms should be relieved with "an inhaled, short-acting beta2-agonist."
- If the beta2-agonist and the daily-dose of Revefenacin are becoming increasingly less effective, patients should be re-evaluated as it may be a sign of COPD deteriorating. Patients should talk to their medical examiner to determine the next steps.

### Worsening of Narrow-Angle Glaucoma
- If patients have narrow-angle glaucoma, they should be closely monitored while on treatment with Revefenacin.
- Some signs and symptoms of worsening of narrow-angle glaucoma include eye pain/ discomfort of the eye, blurry vision, visual halos, or "colored images in association with red eyes from conjunctival congestion and corneal edema"
- If these symptoms arise, patients should immediately contact their healthcare provider.

### Worsening of Urinary Retention
- Patients with urinary retention should be monitored carefully while being treated with Revefenacin.
- Signs and symptoms patients, prescribers, and doctors should watch out for include having difficulty passing urine and/or painful urination. This should be monitored extremely carefully and thoroughly in patients with prostatic hyperplasia or bladder-neck obstruction.
- If these signs and symptoms show up, patients are heavily advised to call their doctor.

### Immediate Hypersensitivity Reactions
- Patients may be allergic or sensitive to some of the ingredients, and if hypersensitivity arises, their treatment with Revefenacin should be discontinued immediately.
- Patients should consult their doctors to consider alternative treatments.

# Adverse Reactions

## Clinical Trials Experience
- Some Adverse Reactions include cough,nasopharyngitis, upper respiratory tract infection, headache, and back pain
- These reactions were present in at least 2% of patients in the clinical trials, and they were much more common that placebo reactions.
If there is a suspicion surrounding the adverse reactions, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800 FDA-1088 or visit www.fda.gov/medwatch.

## Postmarketing Experience
There is limited information regarding Yupelri Postmarketing Experience in the drug label.

# Drug Interactions
- Anticholinergic medicines coadministered with Yupelri (Revefenacin) can cause heightened Anticholinergic Adverse effects.
- Additionally, OATP1B1 and OATP1B3 inhibitors could potentially harm and increase the exposure of a metabolite, so it is not recommended that these be coadministered with Yupelri

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
There are no available data on Revefencain use in pregnant women to inform a drugassociated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Revefenacin in women who are pregnant.

### Labor and Delivery
Patients are advised to contact their physician if they become pregnant during treatment with Revefenacin. It is important to converse and address all the effect it could have on a fetus. Since there are no adequate information from studies indicating the effect on pregnant women and people who can become pregnant, patients should contact their doctor immediately.

### Nursing Mothers
Patients should be aware that the active metabolite of Revefenacin was present for rats producing breast-feeding milk. Patients should consider the developmental effects that the active metabolite in the milk can have on the baby.

### Pediatric Use
Revefenacin is not administered to children. Therefore, the safety and well-being of children administered this medication is unknown.

### Geriatic Use
Clinical studies have shown no need to alter doses in older patients.

### Gender
There is no FDA guidance on the use of Revefenacin with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Revefenacin with respect to specific racial populations.

### Renal Impairment
Patients with renal impairment should be monitored on the side, but there is no need of dose adjustment for patients with renal impairment.

### Hepatic Impairment
It is recommended that patients with any level of hepatic impairment should not take this medication. Studies have shown there is an increased exposure in metabolite of Revefenacin for patients with mild hepatic impairment. Therefore, it is advised that patients with any level of impairment stay away from this medication.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Revefenacin in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Revefenacin in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- After intravenous administration of revefenacin, the reported volume of distribution is 218 L which suggests an extensive distribution to the tissues

### Monitoring
There is limited information regarding Revefenacin Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Revefenacin and IV administrations.

# Overdosage
Common signs and symptoms of overdosage of Revefenacin:
- nausea, vomiting, dizziness, lightheadedness, blurred vision, increased intraocular pressure, obstipation and difficulties in voiding
- If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology

## Mechanism of Action
Revefenacin is a bronchodilator taken through inhalation that is a muscarinic antagonist with a long-lasting bronchodilation activity. Through studies and monitoring, it has been found to have a high affinity and it behaves as a competitive antagonist to the five muscarinic cholinergic receptors. Revefenacin is shown to dissociate slower from the receptor M3 compared to the receptor M2. That shows a kinetic selectivity for this subtype of receptors. It produces a suppressive action of the acetocholine evoked calcium mobilization and contractile responses in the airway tissue. Revefenacin is a long-lasting muscarinic antagonist, so it can only be administered one dose daily. The activity of Revefenacin produces a long-lasting protection against the bronchoconstrictor response acetylcholine and methacholine.

## Structure

## Pharmacodynamics
The reported volume of distribution is 218 L which suggests an extensive distribution to the tissues
There are two phases of elimination: Kinetics Elimination: rapid declining plasma concentration followed by slow bi-exponential elimination. Renal Elimination: the amount excreted in urine is the unchanged drug, <0.2% of the administered dose. 
Following the IV administration, 54% of dose is recovered in feces and 27- in urine
In clinical trials that tested Yupelri effect on pregnant rats and rabbits at exposures that would be 209 times the maximum exposure compared to the maximum human dose, it produced no birth defects or harm.

## Pharmacokinetics
There is limited information regarding Revefenacin Pharmacokinetics in the drug label.

## Nonclinical Toxicology

### Impairment of Fertility
- There are no studies performed on humans and the harm rate is unknown for pregnant women. However, studies performed on pregnant rats and rabbits resulted in slim to 0 fetal harm.

# Clinical Studies

### Study in Adult Patients with Chronic Obstructive Pulmonary Disease 
- The clinical trials are secured and conducted in many different conditions, so it cannot be compared to other drugs undergoing clinical trials
- There were two 12-week trials and one 52-week trial
- The patients received a total of 175 mcg of Yupelri one-time daily
- 12-week trials: There were two 12-week trials. They are replicated trials that use placebo.
These trials were conducted on patients with moderate to severe COPD. There were a total of 395 patients, ages ranging from 41-88. The demographics are 50% male, and 90% Caucasian out of the total patients. 13% of the Yupelri treated patients discontinued the trial due to adverse reactions, and 19% of the placebo patients.
- These trials were conducted on patients with moderate to severe COPD. There were a total of 395 patients, ages ranging from 41-88. The demographics are 50% male, and 90% Caucasian out of the total patients. 13% of the Yupelri treated patients discontinued the trial due to adverse reactions, and 19% of the placebo patients.
- 52-week trial: This was one 52-week length trial that provided the subjects with a 18 mcg dose of tiotropium daily once. There were 335 subjects treated with 175 mcg of Yupelri daily, and 356 patients with the dose of tiotropium mentioned above.

### Study in Pediatric Patients with Chronic Obstructive Pulmonary Disease 
- There is limited information regarding Revefenacin Studies in Pediatric Patients

# How Supplied
- YUPELRI inhalation solution: as a sterile, clear, colorless, aqueous solution for nebulization in low-density polyethylene unit-dose vials
- Each vial: 175 mcg of revefenacin in 3 mL of aqueous solution.

## Storage
- Revefenacin is stored as a preservative-free aqueous solution product
- The storage condition is dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years)

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Get medical help right away if these symptoms show up
Wheezing
Choking
Blurred Vision
Tunnel Vision
Eye Pain, Redness
Difficulty Urinating or Emptying your bladder
- Wheezing
- Choking
- Blurred Vision
- Tunnel Vision
- Eye Pain, Redness
- Difficulty Urinating or Emptying your bladder
- Inform Patients to report side effects to the FDA at: 1-800-FDA-1088

### Other Infections
- Counsel patients of the increased risk of infections, particularly those due to encapsulated bacteria, especially Neisseria species.

### Discontinuation
- Patients who express Paradoxical Bronchospasm, which means breathing or wheezing will worsen, should discontinue Revefenacin and initiate therapy with another agent

### Infusion reactions
- Advise patients that administration of Revefenacin may result in infusion reactions.
- Headache, Cough, Problems regarding the upper respiratory system, Back Pain are all examples of infusion reactions

# Precautions with Alcohol
Alcohol-Revefenacin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
Ultomiris

# Look-Alike Drug Names
There is limited information regarding Revefenacin Look-Alike Drug Names in the drug label.

# Drug Shortage Status
Drug Shortage

# Price