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=

ULTOMIRIS is indicated for:

• The treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH).
• The treatment of adults and pediatric patients one month of age and older with atypical hemolytic

uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).

Limitations of Use

• ULTOMIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic

uremic syndrome (STEC-HUS).

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.

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

• For patients switching from eculizumab to ULTOMIRIS, administer the loading dose of ULTOMIRIS 2

weeks after the last eculizumab infusion, and then administer maintenance doses once every 8 weeks or every 4 weeks (depending on body weight), starting 2 weeks after loading dose administration.

• Administration of PE/PI (plasmapheresis or plasma exchange, or fresh frozen plasma infusion) may

reduce ULTOMIRIS serum levels. There is no experience with administration of supplemental doses of ULTOMIRIS.

Preparation of ULTOMIRIS

• 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

|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=

• Patients with unresolved Neisseria meningitidis infection.
• Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying

ULTOMIRIS treatment outweigh the risks of developing a meningococcal infection

|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.

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.

|==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

|drugInteractions= There is limited information regarding Ravulizumab Drug Interactions in the drug label.

|useInPregnancyFDA= 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. |useInLaborDelivery= 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. |useInNursing= |useInPed= The safety and efficacy of Revefenacin for the treatment of PNH in pediatric patients have not been established. |useInGeri= Clinical studies of Revefenacin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. |useInGender= There is no FDA guidance on the use of Revefenacin with respect to specific gender populations. |useInRace= There is no FDA guidance on the use of Revefenacin with respect to specific racial populations. |useInRenalImpair= There is no FDA guidance on the use of Revefenacin in patients with renal impairment. |useInHepaticImpair= There is no FDA guidance on the use of Ultomiris in patients with hepatic impairment. |useInReproPotential= There is no FDA guidance on the use of Ultomiris in women of reproductive potentials and males. |useInImmunocomp= There is no FDA guidance one the use of Ultomiris in patients who are immunocompromised.

|useInOthers=(Description) |administration=

• Injection: 300 mg/30 mL (10 mg/mL) as a clear to translucent, slight whitish color solution in a single-

dose vial. |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.

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

|drugBox=

<!--Clinical data-->
Systematic (IUPAC) name
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CAS number	1803171-55-2
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Mol. mass	188303.705 Da
Pharmacokinetic data
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Excretion	<!--Identifiers-->
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Routes	<!--Pharmacokinetic data-->

|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 Ultomiris 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.

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

Distribution

The mean (%CV) volume of distribution at steady state was 5.34 (17.2) L and 5.22 (35.4) L in patients with PNH and aHUS, respectively.

Elimination

The mean (%CV) terminal elimination half-life of ravulizumab-cwvz in patients with PNH and aHUS are 49.7 (18.0) days and 51.8 (31.3) days, respectively. The mean (%CV) clearance of ravulizumab-cwvz in patients with PNH and aHUS are 0.08 (29.5) L/day and 0.08 (53.3) L/day, respectively.

Specific Populations

No clinically significant differences in the pharmacokinetics of ravulizumab-cwvz were observed based on sex, age (10 months to 83 years), race, hepatic impairment, or any degree of renal impairment, including patients with proteinuria or receiving dialysis. Body weight was a clinically significant covariate on the pharmacokinetics of ravulizumab-cwvz. |nonClinToxic=

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.

|clinicalStudies=

Paroxysmal Nocturnal Hemoglobinuria (PNH)

• The safety and efficacy of ULTOMIRIS in patients with PNH was assessed in two openlabel, randomized,

active-controlled, non-inferiority Phase 3 studies: PNH Study 301 and PNH Study 302.

• ULTOMIRIS was dosed intravenously in accordance with the weightbased dosing (4 infusions of

ULTOMIRIS over 26 weeks). Eculizumab was administered on Days 1, 8, 15, and 22, followed by maintenance treatment with 900 mg of eculizumab on Day 29 and every 2 weeks (q2w) thereafter for a total of 26 weeks of treatment, according to the approved dosing regimen of eculizumab which was the standard-of-care for PNH at the time of studies.

• Patients were vaccinated against meningococcal infection prior to or at the time of initiating treatment

with ULTOMIRIS or eculizumab, or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination.

• There was no observable difference in fatigue between ULTOMIRIS and eculizumab after 26 weeks of

treatment compared to baseline as measured by the FACIT-fatigue instrument. Patient-reported fatigue may be an under-or over-estimation, because patients were not blinded to treatment assignment.

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

• enrolled patients with PNH who were complement inhibitor naïve and had active hemolysis
• 26-week, multicenter, open-label, randomized, active-controlled, non-inferiority Phase 3 study

conducted in 246 patients naïve to complement inhibitor treatment prior to study entry

• Patients with PNH with flow cytometric confirmation of at least 5% PNH cells were randomized 1:1 to

either ULTOMIRIS or eculizumab.

This image is provided by the National Library of Medicine.

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