Revefenacin

Revefenacin
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Uma Maveli[2]

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Black Box Warning

WARNING: SERIOUS MENINGOCOCCAL INFECTIONS See full prescribing information for complete Boxed Warning. Life-threatening meningococcal infections/sepsis Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies Immunize patients with meningococcal vaccines at least 2 weeks prior to administering the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS therapy outweigh the risks of developing a meningococcal infection Vaccination reduces, but does not eliminate, the risk of meningococcal infection Monitor patients for early signs of meningococcal infections, and evaluate immediately if infection is suspected ULTOMIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the ULTOMIRIS REMS, prescribers must enroll in the program Enrollment in the ULTOMIRIS REMS program and additional information are available by telephone: 1-888-765-4747 or at www.ultomirisrems.com.

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
• 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

Recommended Vaccination and Prophylaxis

• Provide 2 weeks of antibacterial drug prophylaxis to patients if ULTOMIRIS must be initiated immediately and vaccines are administered less than 2 weeks before starting ULTOMIRIS therapy.

Recommended Weight-Based Dosage Regimen - OCPD

• The recommended dosing regimen in adult patients with PNH weighing 40 kg or greater, consists of a loading dose followed by maintenance dosing, administered by intravenous infusion. Administer the doses based on the patient’s body weight.
• Starting 2 weeks after the loading dose administration, begin maintenance doses at a once every 8-week interval.
• The dosing schedule is allowed to occasionally vary within 7 days of the scheduled infusion day (except for the first maintenance dose of ULTOMIRIS); but the subsequent doses should be administered according to the original schedule.

This image is provided by the National Library of Medicine.

Recommended Weight-Based Dosage Regimen - aHUS

• The recommended dosing regimen in adult and pediatric patients one month of age and older with aHUS weighing 5 kg or greater, consists of a loading dose followed by maintenance dosing, administered by intravenous infusion.
• Administer the doses based on the patient’s body weight
• Starting 2 weeks after the loading dose administration, begin maintenance doses once every 8 weeks or every 4 weeks (depending on body weight).
• The dosing schedule is allowed to occasionally vary within 7 days of the scheduled infusion day (except for the first maintenance dose of ULTOMIRIS); but the subsequent doses should be administered according to the original schedule.

This image is provided by the National Library of Medicine.

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

Preparation of Revefenacin

• Each vial of ULTOMIRIS is intended for single-dose only.
• ULTOMIRIS requires dilution to a final concentration of 5 mg/mL.
• Use aseptic technique to prepare ULTOMIRIS as follows:
  • 1. The number of vials to be diluted is determined based on the individual patient’s weight and the prescribed dose
  • 2. Prior to dilution, visually inspect the solution in the vials; the solution should be free of any particulate matter or precipitation. Do not use if there is evidence of particulate matter or precipitation.
  • 3. Withdraw the calculated volume of ULTOMIRIS from the appropriate number of vials and dilute in an infusion bag using 0.9% Sodium Chloride Injection, USP to a final concentration of 5 mg/mL. The product should be mixed gently. Do not shake. Protect from light. Do not freeze.
  • 4. Administer the prepared solution immediately following preparation. Infusion must be administered through a 0.2 or 0.22 micron filter.
  • 5. If the diluted ULTOMIRIS infusion solution is not used immediately, storage under refrigeration at 2°C - 8°C (36°F - 46°F) must not exceed 24 hours taking into account the expected infusion time. Once removed from refrigeration, administer the diluted ULTOMIRIS infusion solution within 6 hours.

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

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.

Non–Guideline-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)

There is limited information regarding Revefenacin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

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.

Non–Guideline-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

WARNING: SERIOUS MENINGOCOCCAL INFECTIONS See full prescribing information for complete Boxed Warning. Life-threatening meningococcal infections/sepsis Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies Immunize patients with meningococcal vaccines at least 2 weeks prior to administering the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS therapy outweigh the risks of developing a meningococcal infection Vaccination reduces, but does not eliminate, the risk of meningococcal infection Monitor patients for early signs of meningococcal infections, and evaluate immediately if infection is suspected ULTOMIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the ULTOMIRIS REMS, prescribers must enroll in the program Enrollment in the ULTOMIRIS REMS program and additional information are available by telephone: 1-888-765-4747 or at www.ultomirisrems.com.

Serious Meningococcal Infections

• The use of ULTOMIRIS increases a patient’s susceptibility to serious meningococcal infections (septicemia and/or meningitis). Meningococcal disease due to any serogroup may occur.
• Immunize patients without a history of meningococcal vaccination at least 2 weeks prior to receiving the first dose of ULTOMIRIS. If urgent ULTOMIRIS therapy is indicated in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible and provide patients with 2 weeks of antibacterial drug prophylaxis.
• Vaccination reduces, but does not eliminate, the risk of meningococcal infections.
• Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected.
• If ULTOMIRIS therapy is administered to patients with active systemic infections, monitor closely for signs and symptoms of worsening infection.
• In clinical studies, 59 patients with PNH were treated with ULTOMIRIS less than 2 weeks after meningococcal vaccination. All of these patients received antibiotics for prophylaxis of meningococcal infection until at least 2 weeks after meningococcal vaccination. The benefits and risks of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving ULTOMIRIS have not been established.
• In PNH clinical studies, 3 out of 261 PNH patients developed serious meningococcal infections/sepsis while receiving treatment with ULTOMIRIS; all 3 had been vaccinated. These 3 patients recovered while continuing treatment with ULTOMIRIS.

Other Infections

• ULTOMIRIS blocks terminal complement activation; therefore, patients may have increased susceptibility to encapsulated bacteria infections, especially infections caused by Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae.
• Children treated with ULTOMIRIS may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib).
  • Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections accordingto ACIP guidelines.

Monitoring Disease Manifestations after ULTOMIRIS Discontinuation

Treatment Discontinuation for PNH

• After discontinuing treatment with ULTOMIRIS, closely monitor for signs and symptoms of hemolysis, identified by elevated LDH along with sudden decrease in PNH clone size or hemoglobin, or re-appearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction.
  • Monitor any patient who discontinues ULTOMIRIS for at least 16 weeks to detect hemolysis and other reactions.
  • If signs and symptoms of hemolysis occur after discontinuation, including elevated LDH, consider restarting treatment with ULTOMIRIS.

Treatment Discontinuation for aHUS

• ULTOMIRIS treatment of aHUS should be a minimum duration of 6 months.
• Patients should be monitored for clinical symptoms and laboratory signs of TMA complications for at least 12 months.
• TMA complications post-discontinuation can be identified if any of the following is observed:
  • Changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure
  • At least two of the following laboratory signs observed concurrently and results should be confirmed by a second measurement 28 days apart with no interruption:
    • A decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ULTOMIRIS treatment;
    • An increase in serum creatinine of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment
    • An increase in serum LDH of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment
• If TMA complications occur after ULTOMIRIS discontinuation, consider reinitiation of ULTOMIRIS treatment or appropriate organ-specific supportive measures.

Infusion Reactions

• In clinical trials, 5 out of 296 patients treated with ULTOMIRIS experienced infusion reactions (lower back pain, drop in blood pressure, infusion-related pain, elevation in blood pressure and limb discomfort) during ULTOMIRIS administration.
• Interrupt ULTOMIRIS infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur.

Adverse Reactions

Clinical Trials Experience

Paroxysmal Nocturnal Hemoglobinuria (PNH)

• Most common adverse reactions in patients with PNH (incidence ≥10%) were upper respiratory tract infection and headache

Atypical Hemolytic Uremic Syndrome (aHUS)

• Most common adverse reactions in patients with aHUS (incidence ≥20%) were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension and pyrexia

Immunogenicity

• The immunogenicity of ravulizumab-cwvz has been evaluated using an enzyme-linked immunosorbent assay (ELISA) for the detection of binding anti-ravulizumab-cwvz antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.
• In clinical studies, treatment-emergent antibodies to ravulizumab-cwvz were detected in 1 of 206 (0.5%) patients with PNH and 1 of 71 (1.4%) patients with aHUS.
• No apparent correlation of antibody development to altered pharmacokinetic profile, clinical response, or adverse events was observed.

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

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Nursing Mothers

There is no FDA guidance on the use of Revefenacin with respect to nursing.

Pediatric Use

The safety and efficacy of Revefenacin for the treatment of PNH in pediatric patients have not been established.

Geriatic Use

Clinical studies of Ultomiris did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

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

There is no FDA guidance on the use of Revefenacin in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Revefenacin in patients with hepatic impairment.

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

• Monitor patients for early signs and symptoms of meningococcal infection.
• Monitor the patient for at least one hour following completion of the infusion for signs or symptoms of an infusion reaction.
• After discontinuing treatment with ULTOMIRIS, patients should be monitored for clinical symptoms and laboratory signs of TMA complications for at least 12 months.
  • Clinical symptoms of TMA include changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure.

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

Revefenacin
Systematic (IUPAC) name
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CAS number	1803171-55-2
ATC code	?
PubChem	?
Chemical data
Formula	?
Mol. mass	55768.94 Da
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	?
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status
Routes	?

Mechanism of Action

• Ravulizumab-cwvz is a terminal complement inhibitor that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the terminal complement complex [C5b-9]) and preventing the generation of the terminal complement complex C5b9.
• ULTOMIRIS inhibits terminal complement-mediated intravascular hemolysis in patients with PNH and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS.

Structure

There is limited information regarding Ultomiris Structure in the drug label.

Pharmacodynamics

• The extent and duration of the pharmacodynamic response in patients with PNH and aHUS were exposure-dependent for ULTOMIRIS. Free C5 levels of <0.5 mcg/mL were correlated with maximal intravascular hemolysis control and complete terminal complement inhibition in patients with PNH.
• Complete terminal complement inhibition following initiation of ULTOMIRIS treatment led to normalization of serum LDH by week 4 in complement-inhibitor naïve patients with PNH, and maintained LDH normalization in patients previously treated with eculizumab with PNH.

Pharmacokinetics

Ravulizumab-cwvz pharmacokinetics increase proportionally over a dose range of 200 to 5400 mg.

Distribution

The reported volume of distribution is 218 L which suggests an extensive distribution to the tissues

Elimination

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

Specific Populations

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.

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

Chronic Obstructive Pulmonary Disease (COPD)

OCPD Study 301 [ALXN1210-PNH-301; NCT02946463]

OCPD Study [ALXN1210-PNH-302; NCT03056040]

Study in Adult Patients with Chronic Obstructive Pulmonary Disease [ALXN1210-aHUS-311; NCT02949128]

• 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.
• 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 [ALXN1210-aHUS-312; NCT03131219]

• 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

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Package and Label Display Panel

This image is provided by the National Library of Medicine.

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Patient Counseling Information

Serious Side Effects

• 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

• 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 Ultomiris Look-Alike Drug Names in the drug label.

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.