Revefenacin

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

|genericName=generic name |aOrAn=a |drugClass= anticholinergics |indicationType= treatment |hasBlackBoxWarning=Yes |adverseReactions Side Effects

• Headache
• Cough
• Problems regarding the upper respiratory system
• Back Pain

|blackBoxWarningTitle= WARNING: SERIOUS MENINGOCOCCAL INFECTIONS |blackBoxWarningBody=<i><span style="color:#FF0000;"></span></i> 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.

|fdaLIADAdult=

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

Dosage

• The agreed dosage is 175 micrograms per day
  • Taken via a standard jet nebulizer (turns liquid medication into mist) connected to an air compressor
  • Makes it easy for patients with pulmonary problems

• 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.

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

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

|offLabelAdultGuideSupport=

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

|offLabelAdultNoGuideSupport=

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

|contraindications= There is limited information regarding Revefenacin Contraidications

|warnings =

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.

Clinical Studies

Trials:

• Revefenacin proved to have long duration of action and low systemic exposure (doesn't affect the whole body) for patients struggling with Chronic Obstructive Pulmonary Disease or COPD
• 88 mcg of this drug can result in constructive bronchodilation (to helps patients breathe better)

Pharmacology trials:

• Evaluted human recombitance mAChRs (muscarinic cholinergic receptor) by testing it on airway tissues from rats, guinea pigs, and humans
  • Revefenacin proved high affinity for the human tissue and competed against those five human recombinant mAChRs
  • This drug attacked "mAChRs mediated contractile responses"
  • This shows that revefenacin produces long-lasting attacking effects on this tissue from rats, guinea pigs, and humans

=overdose = There is limited information regarding Revefenacin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

|mechAction= *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 Revefenacin Structure in the drug label. |PD=

• 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.

Use in Specific Populations

• Revefencin is not affected majorly by age, weight, or gender
• Hepatic impariment has not been studied to see if there are necessary precautions to take
• Patients with renal impariment
  • Mesure for antimuscarinic adverse events or the inhibitting of acetocholine, a neurotransmitter in the PNS

Carcinogenesis, Mutagenesis, Impairment of Fertility

• No animal studies were performed to evaluate the effects of ravulizumab-cwvz on carcinogenesis, or

mutagenesis.

• Effects of ravulizumab-cwvz upon fertility have not been studied in animals.
  • Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 0.8-2.2 times

the equivalent of the clinical dose of ULTOMIRIS had no adverse effects on mating or fertility.

Clinical Studies

Trials:

• Revefenacin proved to have long duration of action and low systemic exposure (doesn't affect the whole body) for patients struggling with Chronic Obstructive Pulmonary Disease or COPD
• 88 mcg of this drug can result in constructive bronchodilation (to helps patients breathe better)

Pharmacology trials:

• Evaluted human recombitance mAChRs (muscarinic cholinergic receptor) by testing it on airway tissues from rats, guinea pigs, and humans
  • Revefenacin proved high affinity for the human tissue and competed against those five human recombinant mAChRs
  • This drug attacked "mAChRs mediated contractile responses"
  • This shows that revefenacin produces long-lasting attacking effects on this tissue from rats, guinea pigs, and humans

Conclusion:

• Revefenacin has the potential to be a daily dose broncholdilator for patients struggling from COPD

PNH Study 302 [ALXN1210-PNH-302; NCT03056040]

• Enrolled patients with PNH who were clinically stable after having been treated with eculizumab for at

least the past 6 months.

• Patients who demonstrated clinically stable disease after being treated with eculizumab for at least the

prior 6 months were randomized 1:1 to either continue eculizumab or to switch to ULTOMIRIS.

This image is provided by the National Library of Medicine.

Atypical Hemolytic Uremic Syndrome (aHUS)

• The efficacy of ULTOMIRIS in patients with aHUS was assessed in 2 open-label,single-arm studies.

Study ALXN1210-aHUS-311 and ALXN1210-aHUS-312.

• In order to qualify for enrollment, patients were required to have a platelet count ≤150 x109/L,

evidence of hemolysis such as an elevation in serum LDH, and serum creatinine level ≥97.5% percentile at screening or required dialysis.

• Enrollment criteria excluded patients presenting with TMA due to a disintegrin and metalloproteinase

with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency, Shiga toxin Escherichia coli related hemolytic uremic syndrome (STEC-HUS) and genetic defect in cobalamin C metabolism.

Study in Adult Patients with aHUS [ALXN1210-aHUS-311; NCT02949128]

• Conducted in patients who were naïve to complement inhibitor treatment prior to study entry.
• The study consisted of a 26-week Initial Evaluation Period and patients were allowed to enter an

extension period for up to 4.5 years.

• A total of 56 patients with aHUS were evaluated for efficacy.
• Ninety-three percent of patients had extra-renal signs (cardiovascular, pulmonary, central nervous

system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline.

• At baseline,71.4% (n = 40) of patients had Stage 5 chronic kidney disease (CKD). Fourteen percent had a

medical history of kidney transplant and 51.8% were on dialysis at study entry. Eight patients entered the study with evidence of TMA for > 3 days after childbirth (ie, postpartum).

• Renal function, as measured by eGFR, was improved or maintained during ULTOMIRIS therapy.

This image is provided by the National Library of Medicine.

Study in Pediatric Patients with aHUS [ALXN1210-aHUS-312; NCT03131219]

• A total of 14 eculizumab-naïve patients with documented diagnosis of aHUS were enrolled and

included in this interim analysis.

• Complete TMA Response was observed in 10 of the 14 patients (71%) during the 26-week Initial

Evaluation Period.

• Four of the 5 patients who required dialysis at study entry were able to discontinue dialysis after the

first month in study and for the duration of ULTOMIRIS treatment.

This image is provided by the National Library of Medicine.

|howSupplied=

• ULTOMIRIS (ravulizumab-cwvz) injection is a clear to translucent, slight whitish color preservative-free,

solution supplied as one 300 mg/30 mL (10 mg/mL) single-dose vial per carton. NDC 25682-022-01.

|storage=

• Store ULTOMIRIS vials refrigerated at 2°C - 8°C (36°F - 46°F) in the original carton to protect from light.

Do not freeze. Do not shake.

|packLabel=

This image is provided by the National Library of Medicine.

|fdaPatientInfo=

Meningococcal Infection

• Inform patients that they are required to receive meningococcal vaccination at least 2 weeks prior to

receiving the first dose of ULTOMIRIS, if they have not previously been vaccinated.

• They are required to be revaccinated according to current medical guidelines for meningococcal

vaccines use while on ULTOMIRIS therapy.

• Inform patients about the signs and symptoms of meningococcal infection/sepsis, and strongly advise

patients to seek immediate medical attention if these signs or symptoms occur. These signs and symptoms are as follows:

• • headache with nausea or vomiting
  • headache and a fever
  • headache with a stiff neck or stiff back
  • fever
  • fever and a rash
  • confusion
  • muscle aches with flu-like symptoms
  • eyes sensitive to light
• Inform patients that they will be given an ULTOMIRIS Patient Safety Card that they should carry with

them at all times.

Other Infections

• Counsel patients of the increased risk of infections, particularly those due to encapsulated bacteria,

especially Neisseria species.

• Counsel patients about gonorrhea prevention and advise regular testing for patients at risk.

Discontinuation

• Inform patients with PNH or aHUS that they may develop hemolysis or TMA, respectively, when

ULTOMIRIS is discontinued and that they will be monitored by their healthcare professional for at least 16 weeks for PNH or at least 12 months for aHUS following ULTOMIRIS discontinuation.

• Inform patients who discontinue ULTOMIRIS to keep the ULTOMIRIS Patient Safety Card with them for

eight months after the last ULTOMIRIS dose.

Infusion reactions

• Advise patients that administration of Revefenacin may result in infusion reactions.

|nlmPatientInfo=(Link to patient information page) |lookAlike= There is limited information regarding Revefenacin Look-Alike Drug Names in the drug label.

brandNames

• Yupelri