Revefenacin: Difference between revisions

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__NOTOC__
{{DrugProjectFormSinglePage
{{CMG}} {{AE}} {{Uma}}
|authorTag= {{Uma}}
 


|genericName=generic name
|genericName=generic name
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|drugClass= anticholinergics
|drugClass= anticholinergics
|indicationType= treatment
|indicationType= treatment
|indication= 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]]
|hasBlackBoxWarning=Yes
|hasBlackBoxWarning=Yes
|adverseReactions
|adverseReactions= Headache, Cough, Problems regarding the upper respiratory system, Back Pain
Side Effects
*Headache
*Cough
*Problems regarding the upper respiratory system
*Back Pain


|blackBoxWarningTitle= WARNING: SERIOUS MENINGOCOCCAL INFECTIONS
|blackBoxWarningTitle= WARNING: Serious Case of Paradoxical Bronchospasm
|blackBoxWarningBody=<i><span style="color:#FF0000;"></span></i> Life-threatening meningococcal
|blackBoxWarningBody=<i><span style="color:#FF0000;"></span></i> Life-threatening paradoxical bronchospasm
infections/sepsis
*Contact doctor immediately if you are experiencing shortness of breath, severe cough, or wheezing after taking a dose of Revefenacin
*Comply with the most current Advisory Committee on Immunization Practices (ACIP)
*Treat immediately with “inhaled, short-acting bronchodilator”
recommendations for meningococcal vaccination in patients with complement deficiencies
*Should not be administered to patients with acutely deteriorating COPD (Chronic Obstructive Pulmonary Disease)
*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=
|fdaLIADAdult=
 
====Revefenacin is indicated for:====
====ULTOMIRIS is indicated for:====
*The treatment of patients with chronic obstructive pulmonary disorder
* The treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH).
**Should not be given to patients experiencing life threatening episodes
* The treatment of adults and pediatric patients one month of age and older with atypical hemolytic
**In other words, Revefenacin should not be used as a rescue drug
uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).
*Discontinue the drug if patients appears to suffer from [[paradoxical bronchospasm]] or hypersensitivity reactions


====Limitations of Use====
====Limitations of Use====
*ULTOMIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic
*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"
uremic syndrome (STEC-HUS).
**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.
 
==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====
====Dosing Considerations====
*For patients switching from eculizumab to ULTOMIRIS, administer the loading dose of ULTOMIRIS 2
*Patients are not allowed to use nephrotoxic or hepatotoxic medications for 4 weeks before drug administration
weeks after the last eculizumab infusion, and then administer maintenance doses once every 8 weeks or
**They may use the following medications: [[acetaminophen]], [[ibuprofen]], milk of magnesia ([[magnesium hydroxide]]), and routine vitamins and minerals
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.


====Administration of Revefenacin====
====Administration of Revefenacin====
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**54% came out as solid waste
**54% came out as solid waste
**27% came out as liquid waste
**27% came out as liquid waste


|offLabelAdultGuideSupport=
|offLabelAdultGuideSupport=


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


|offLabelAdultNoGuideSupport=
|offLabelAdultNoGuideSupport=


There is limited information regarding Revefenacin Off-Label Non-Guideline-Supported Use and Dosage
There is limited information regarding Revefenacin Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
(Adult) in the drug label.
 
 
|fdaLIADPed=
Children are not administered Revefenacin because of the strength and long-lasting effects it has with on daily dose.
 
|offLabelPedGuideSupport=
There is limited information regarding Revefenacin Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
 
|offLabelPedNoGuideSupport=
 
There is limited information regarding Revefenacin Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
 


|contraindications=
|contraindications=
*Patients with unresolved Neisseria meningitidis infection.
*Revefenacin is contraindicated in patients with hypersensitivity to revefenacin or any component of this product.
*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======
|warnings =  
======Deterioration of Disease and Acute Episodes======
*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.


*ULTOMIRIS blocks terminal complement activation; therefore, patients may have increased
====Worsening of Narrow-Angle Glaucoma====
susceptibility to encapsulated bacteria infections, especially infections caused by Neisseria meningitidis
*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.


but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria
====Worsening of Urinary Retention====
gonorrhoeae.
*Patients with urinary retention should be monitored carefully while being treated with Revefenacin.
* Children treated with ULTOMIRIS may be at increased risk of developing serious infections due to
*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.
Streptococcus pneumoniae and Haemophilus influenzae type b (Hib).
*If these signs and symptoms show up, patients are heavily advised to call their doctor.  
** Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus
influenzae type b (Hib) infections accordingto ACIP guidelines.


====Infusion Reactions====
====Immediate Hypersensitivity Reactions====
*In clinical trials, 5 out of 296 patients treated with ULTOMIRIS experienced infusion reactions (lower
*Patients may be allergic or sensitive to some of the ingredients, and if hypersensitivity arises, their treatment with Revefenacin should be discontinued immediately.  
back pain, drop in blood pressure, infusion-related pain, elevation in blood pressure and limb
*Patients should consult their doctors to consider alternative treatments.  
discomfort) during ULTOMIRIS administration.
*Interrupt ULTOMIRIS infusion and institute appropriate supportive measures if signs of cardiovascular
instability or respiratory compromise occur.


|==Clinical Studies==
|clinicalTrials =
Trials:
*Some Adverse Reactions include cough,[[nasopharyngitis]], upper respiratory tract infection, headache, and back pain
*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
*These reactions were present in at least 2% of patients in the clinical trials, and they were much more common that placebo reactions.
*88 mcg of this drug can result in constructive bronchodilation (to helps patients breathe better)
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.


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
|postmarketing= There is limited information regarding Yupelri Postmarketing Experience in the drug label.
label.


|useInPregnancyFDA= There are no available data on Revefencain use in pregnant women to inform a
|drugInteractions=
drugassociated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
*Anticholinergic medicines coadministered with Yupelri (Revefenacin) can cause heightened [[Anticholinergic]] Adverse effects.
|useInLaborDelivery= The estimated background risk of major birth defects and miscarriage for the
*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
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
|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.  
and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
|useInLaborDelivery= 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.
|useInNursing=
|useInNursing= 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.
|useInPed= The safety and efficacy of Revefenacin for the treatment of PNH in pediatric patients have not
|useInPed= Revefenacin is not administered to children. Therefore, the safety and well-being of children administered this medication is unknown.  
been established.
|useInGeri= Clinical studies have shown no need to alter doses in older patients.  
|useInGeri= Clinical studies of Revefenacin did not include sufficient numbers of subjects aged 65 and over
|useInGender= There is no FDA guidance on the use of Revefenacin with respect to specific gender populations.
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.
|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.
|useInRenalImpair= Patients with renal impairment should be monitored on the side, but there is no need of dose adjustment for patients with renal impairment.  
|useInHepaticImpair= There is no FDA guidance on the use of Ultomiris in patients with hepatic
|useInHepaticImpair= 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.  
impairment.
|useInReproPotential= There is no FDA guidance on the use of Revefenacin in women of reproductive potentials and males.
|useInReproPotential= There is no FDA guidance on the use of Ultomiris in women of reproductive
|useInImmunocomp= There is no FDA guidance one the use of Revefenacin in patients who are immunocompromised.
potentials and males.
|useInImmunocomp= There is no FDA guidance one the use of Ultomiris in patients who are
immunocompromised.


|useInOthers=(Description)
|useInOthers=(Description)
|administration=
|administration=  
*Injection: 300 mg/30 mL (10 mg/mL) as a clear to translucent, slight whitish color solution in a single-
*After intravenous administration of revefenacin, the reported volume of distribution is 218 L which suggests an extensive distribution to the tissues
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
|overdose =  
poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
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.


|drugBox={{Drugbox2
|drugBox={{Drugbox2
| verifiedrevid =
| verifiedrevid =  
| IUPAC_name =
| IUPAC_name =  
| image =
| image =  
| drug_name =
| drug_name = Yupelri


&lt;!--Clinical data--&gt;
<!--Clinical data-->
| tradename =
| tradename =  
| MedlinePlus =
| MedlinePlus =  
| licence_US =
| licence_US =  
| pregnancy_AU =
| pregnancy_AU =  
| pregnancy_US =
| pregnancy_US =  
| legal_status =
| legal_status =  
| routes_of_administration =
| routes_of_administration = orally inhale


&lt;!--Pharmacokinetic data--&gt;
<!--Pharmacokinetic data-->
| bioavailability =
| bioavailability =  
| metabolism =
| metabolism =  
| elimination_half-life =
| elimination_half-life = the half-life of a dose of 350 mcg of Revefenacin was 22.3-70 hours
| excretion =
| excretion = 54% of the dose is recovered in feces and 27% was recovered in urine


&lt;!--Identifiers--&gt;
<!--Identifiers-->
| CAS_number_Ref =
| CAS_number_Ref =  
| CAS_number = 1803171-55-2
| CAS_number = 864750-70-9
| ATC_prefix =


| ATC_suffix =
 
| PubChem =
| ATC_prefix =
| IUPHAR_ligand =
| ATC_suffix =  
| DrugBank_Ref =
| PubChem =  
| DrugBank =
| IUPHAR_ligand =  
| ChemSpiderID_Ref =
| DrugBank_Ref =  
| ChemSpiderID =
| DrugBank =  
| UNII_Ref =
| ChemSpiderID_Ref =  
| ChemSpiderID =  
| UNII_Ref =  
| UNII = C3VX249T6L
| UNII = C3VX249T6L
| KEGG_Ref =
| KEGG_Ref =  
| KEGG = Intravenous
| KEGG = Intravenous
| ChEBI_Ref =
| ChEBI_Ref =  
| ChEBI =
| ChEBI =  
| ChEMBL_Ref =
| ChEMBL_Ref =  
| ChEMBL =
| ChEMBL =  


&lt;!--Chemical data--&gt;
<!--Chemical data-->
| C= | H= | N= | O=
| C= | H= | N= | O=  
| molecular_weight = 188303.705 Da
| molecular_weight = 597.7 g/mol
| smiles =
| smiles =  
| InChI =
| InChI = 1S/C35H43N5O4/c1-38(34(42)29-13-11-26(12-14-29)25-40-19-15-28(16-20-40)33(36)41)23-24-39-21-17-30(18-22-39)44-35(43)37-32-10-6-5-9-31(32)27-7-3-2-4-8-27/h2-14,28,30H,15-25H2,1H3,(H2,36,41)(H,37,43)
| InChIKey =
| InChIKey = FYDWDCIFZSGNBU-UHFFFAOYSA-N
| StdInChI_Ref =
| StdInChI_Ref =  
| StdInChI =
| StdInChI =  
| StdInChIKey_Ref =
| StdInChIKey_Ref =  
| StdInChIKey =
| StdInChIKey =  
| melting_point =
| melting_point =  
}}
}}
|mechAction= 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]].


|mechAction= *Ravulizumab-cwvz is a terminal complement inhibitor that specifically binds to the
|structure= *
complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the proinflammatory
|PD=  
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 &lt;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=====
=====Distribution=====
The mean (%CV) volume of distribution at steady state was 5.34 (17.2) L and 5.22 (35.4) L in patients
The reported volume of distribution is 218 L which suggests an extensive distribution to the tissues
with PNH and aHUS, respectively.
=====Elimination=====
=====Elimination=====
The mean (%CV) terminal elimination half-life of ravulizumab-cwvz in patients with
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.  
PNH and aHUS are 49.7 (18.0) days and 51.8 (31.3) days, respectively. The mean (%CV)
Following the IV administration, 54% of dose is recovered in feces and 27* in urine
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=====
=====Specific Populations=====
No clinically significant differences in the pharmacokinetics of ravulizumab-cwvz were observed based
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.  
on sex, age (10 months to 83 years), race, hepatic impairment, or any degree of renal impairment,
|nonClinToxic=  
including patients with proteinuria or receiving dialysis. Body weight was a clinically significant covariate
====Impairment of Fertility====
on the pharmacokinetics of ravulizumab-cwvz.
*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.
|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=
|clinicalStudies=
====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.


=====Paroxysmal Nocturnal Hemoglobinuria (PNH)=====
====Study in Pediatric Patients with Chronic Obstructive Pulmonary Disease [ALXN1210-aHUS-312; NCT03131219]====
*The safety and efficacy of ULTOMIRIS in patients with PNH was assessed in two openlabel, randomized,
*There is limited information regarding Revefenacin Studies in Pediatric Patients
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.
[[Image:Clinical Trials Results PNH Study 301.png|none|thumb|400px|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.
[[Image:Clinical Trials Results PNH Study 302.png|none|thumb|400px|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 &gt; 3 days after childbirth (ie, postpartum).
*Renal function, as measured by eGFR, was improved or maintained during ULTOMIRIS therapy.
[[Image:Clinical Trials Results aHUS Adults.png|none|thumb|400px|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.
[[Image:Clinical Trials Results aHUS Pediatric.png|none|thumb|400px|This image is provided by the
National Library of Medicine.]]


|howSupplied=
|howSupplied=
*ULTOMIRIS (ravulizumab-cwvz) injection is a clear to translucent, slight whitish color preservative-free,
*YUPELRI inhalation solution: as a sterile, clear, colorless, aqueous solution for nebulization in low-density polyethylene unit-dose vials
solution supplied as one 300 mg/30 mL (10 mg/mL) single-dose vial per carton. NDC 25682-022-01.
*Each vial: 175 mcg of revefenacin in 3 mL of aqueous solution.
 
|storage=
|storage=
*Store ULTOMIRIS vials refrigerated at 2°C - 8°C (36°F - 46°F) in the original carton to protect from light.
*Revefenacin is stored as a preservative-free aqueous solution product
Do not freeze. Do not shake.
*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)


|packLabel=
|packLabel=
[[Image:ULTOMIRIS Drug Label ravulizumab.jpeg|none|thumb|400px|This image is provided by the
*
National Library of Medicine.]]
 
|fdaPatientInfo=
|fdaPatientInfo=
=====Meningococcal Infection=====
=====Serious Side Effects=====
* Inform patients that they are required to receive meningococcal vaccination at least 2 weeks prior to
* Get medical help right away if these symptoms show up
receiving the first dose of ULTOMIRIS, if they have not previously been vaccinated.
** Wheezing
* They are required to be revaccinated according to current medical guidelines for meningococcal
**Choking
vaccines use while on ULTOMIRIS therapy.
** Blurred Vision
* Inform patients about the signs and symptoms of meningococcal infection/sepsis, and strongly advise
**Tunnel Vision
patients to seek immediate medical attention if these signs or symptoms occur. These signs and
**Eye Pain, Redness
symptoms are as follows:
** Difficulty Urinating or Emptying your bladder
**headache with nausea or vomiting
**headache and a fever
**headache with a stiff neck or stiff back
**fever


**fever and a rash
*Inform Patients to report side effects to the FDA at: 1-800-FDA-1088
**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====
====Other Infections====
*Counsel patients of the increased risk of infections, particularly those due to encapsulated bacteria,
*Counsel patients of the increased risk of infections, particularly those due to encapsulated bacteria, especially Neisseria species.
especially Neisseria species.
*Counsel patients about gonorrhea prevention and advise regular testing for patients at risk.


====Discontinuation====
====Discontinuation====
*Inform patients with PNH or aHUS that they may develop hemolysis or TMA, respectively, when
*Patients who express Paradoxical Bronchospasm, which means breathing or wheezing will worsen, should discontinue Revefenacin and initiate therapy with another agent
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====
====Infusion reactions====
*Advise patients that administration of Revefenacin may result in 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


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


=brandNames=
|brandNames=
*Yupelri
Ultomiris
|drugShortage=
Drug Shortage
 
}}

Latest revision as of 23:18, 14 December 2020

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]

Disclaimer

WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.

Black Box Warning

WARNING: Serious Case of Paradoxical Bronchospasm
See full prescribing information for complete Boxed Warning.
Life-threatening paradoxical bronchospasm
  • Contact doctor immediately if you are experiencing shortness of breath, severe cough, or wheezing after taking a dose of Revefenacin
  • Treat immediately with “inhaled, short-acting bronchodilator”
  • Should not be administered to patients with acutely deteriorating COPD (Chronic Obstructive Pulmonary Disease)

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

Dosing Considerations

  • Patients are not allowed to use nephrotoxic or hepatotoxic medications for 4 weeks before drug administration

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)

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.

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 Case of Paradoxical Bronchospasm
See full prescribing information for complete Boxed Warning.
Life-threatening paradoxical bronchospasm
  • Contact doctor immediately if you are experiencing shortness of breath, severe cough, or wheezing after taking a dose of Revefenacin
  • Treat immediately with “inhaled, short-acting bronchodilator”
  • Should not be administered to patients with acutely deteriorating COPD (Chronic Obstructive Pulmonary Disease)
Deterioration of Disease and Acute Episodes
  • 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

Yupelri
Systematic (IUPAC) name
?
Identifiers
CAS number 864750-70-9
ATC code ?
PubChem ?
Chemical data
Formula ?
Mol. mass 597.7 g/mol
Pharmacokinetic data
Bioavailability ?
Metabolism ?
Half life the half-life of a dose of 350 mcg of Revefenacin was 22.3-70 hours
Excretion 54% of the dose is recovered in feces and 27% was recovered in urine
Therapeutic considerations
Pregnancy cat.

?

Legal status
Routes orally inhale

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

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.

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 [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

{{#ask: Page Name::Revefenacin |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Revefenacin |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

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 Revefenacin 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.

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