YUPELRI inhalation solution is indicated for the maintenance treatment of patients
with chronic obstructive pulmonary disease (COPD).

The recommended dose of YUPELRI inhalation solution is one 175 mcg unit-dose vial
administered once daily by nebulizer using a mouthpiece.
YUPELRI should be administered by the orally inhaled route via a standard jet
nebulizer connected to an air compressor. The safety and efficacy of YUPELRI have
been established in clinical trials when administered using the PARI LC® Sprint
nebulizer with a mouthpiece and the PARI Trek® S compressor. The safety and
efficacy of YUPELRI delivered from non-compressor-based nebulizer systems have
not been established. The YUPELRI unit-dose vial should only be removed from the
foil pouch and opened IMMEDIATELY BEFORE USE. The vial and any residual
content should be discarded after use.
No dosage adjustment is required for geriatric patients, or patients with renal
impairment. The drug compatibility (physical and chemical), efficacy, and safety of
YUPELRI when mixed with other drugs in a nebulizer have not been established.
Method of Administration:
YUPELRI is used only in a standard Jet nebulizer machine with a mouth piece
connected to an air compressor.

Make sure to know how to use nebulizer machine before used to breathe in YUPELRI
or other medicines.
Patient’s Instructions for use and handling:
Step 1. Open Pouch: Open the foil pouch by tearing along the seam of the pouch.
Remove the vial of YUPELRI form the foil pouch (Figure 1)

Step 2. Open Vial: Carefully twist open the top of the vial and use it right away
(Figure 2).

Step 3. Add Medicine: Squeeze all of the medicine from the vial into the nebulizer
cup (reservoir) (Figure 3).

Step 4. Attach Mouthpiece: Connect the mouthpiece to the nebulizer cup (reservoir)
with the expiratory valve facing up (Figure 4).

Step 5. Connect the nebulizer to the compressor: Firmly insert one end of the
tubing to the compressor. Firmly insert the other end of the tubing to the bottom of
the nebulizer cup (reservoir) (Figure 5).

Step 6. Prepare for treatment: Sit in a comfortable upright position. Place the
mouthpiece in your mouth and close lips around the mouthpiece.

Step 7. Begin Treatment: Turn on the compressor to begin your treatment (Figure
6).

Step 8. Breathe in medicine: Breathe as calmly, deeply, and evenly as possible until
no more mist is seen in nebulizer reservoir. Your treatment will take about 8 minutes.
When you do not see any mist in the nebulizer, your treatment is finished. Turn the
compressor off.
Step 9. Clean Nebulizer: Clean and store your nebulizer. See the manufacturer’s
instructions that come with your nebulizer for how to clean and store your nebulizer.

Deterioration of Disease and Acute Episodes
YUPELRI should not be initiated in patients during acutely deteriorating or potentially
life-threatening episodes of COPD. YUPELRI has not been studied in subjects with
acutely deteriorating COPD. The initiation of YUPELRI in this setting is not
appropriate.
YUPELRI is intended as a once-daily maintenance treatment for COPD and should not
be used for relief of acute symptoms, i.e. as rescue therapy for the treatment of acute
episodes of bronchospasm, and extra doses should not be used for that purpose. Acute
symptoms should be treated with an inhaled, short-acting beta2-agonist.
COPD may deteriorate acutely over a period of hours or chronically over several days
or longer. If YUPELRI no longer controls symptoms of bronchoconstriction, the
patient's inhaled, short-acting beta2-agonist becomes less effective, or the patient needs
more inhalations of a short-acting beta2-agonist than usual, these may be markers of
deterioration of disease. In this setting, a re-evaluation of the patient and the COPD
treatment regimen should be undertaken at once. Increasing the daily dose of YUPELRI
beyond the recommended dose is not appropriate in this situation.

Paradoxical Bronchospasm
As with other inhaled medicines, YUPELRI can produce paradoxical bronchospasm
that may be life-threatening. If paradoxical bronchospasm occurs following dosing with
YUPELRI, it should be treated immediately with an inhaled, short-acting
bronchodilator; YUPELRI should be discontinued immediately and alternative therapy
should be instituted.
Worsening of Narrow-Angle Glaucoma
YUPELRI should be used with caution in patients with narrow-angle glaucoma.
Prescribers and patients should be alert for signs and symptoms of acute narrow-angle
glaucoma (e.g. eye pain or discomfort, blurred vision, visual halos or colored images
in association with red eyes from conjunctival congestion and corneal edema). Instruct
patients to consult a physician immediately if any of these signs or symptoms develops.
Worsening of Urinary Retention
YUPELRI should be used with caution in patients with urinary retention. Prescribers
and patients should be alert for signs and symptoms of urinary retention (e.g. difficulty
passing urine, painful urination), especially in patients with prostatic hyperplasia or
bladder-neck obstruction. Instruct patients to consult a healthcare provider immediately
if any of these signs or symptoms develops.

Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions may occur after administration of YUPELRI. If
such a reaction occurs, therapy with YUPELRI should be stopped at once and
alternative treatments should be considered.

Anticholinergics:
There is potential for an additive interaction with concomitantly used anticholinergic
medicines. Therefore, avoid coadministration of YUPELRI with other anti-cholinergic
containing drugs as this may lead to an increase in anticholinergic adverse effects.
Transporter-related drug interactions:
OATP1B1 and OATP1B3 inhibitors (e.g. rifampicin, cyclosporine, etc.) could lead to
an increase in systematic exposure of the active metabolite. Therefore, coadministration
with YULERPI is not recommended.

4.6.1 Pregnancy
Risk Summary
There are no adequate and well-controlled studies with YUPELRI in pregnant women.
Women should be advised to contact their physician if they become pregnant while
taking YUPELRI. In animal reproduction studies, subcutaneous administration of
revefenacin to pregnant rats and rabbits during the period of organogenesis produced
no evidence of fetal harm at respective exposures approximately 209 times the exposure
at the maximum recommended human dose (MRHD) (on an area under the curve
[AUC] basis).
The estimated background risk of major birth defects and miscarriage for the indicated
population is unknown. 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.
Data
Animal Data
In an embryo-fetal development study in pregnant rats dosed during the period of
organogenesis from gestation days 6 to 17, revefenacin was not teratogenic and did not
affect fetal survival at exposures up to 209 times the MRHD (based upon summed
AUCs for revefenacin and its active metabolite at maternal subcutaneous doses up to
500 mcg/kg/day).
In an embryo-fetal development study in pregnant rabbits dosed during the period of
organogenesis from gestation days 7 to 19, revefenacin was not teratogenic and did not
affect fetal survival at exposures up to 694 times the MRHD (based upon summed AUCs for revefenacin and its active metabolite at maternal subcutaneous doses up to
500 mcg/kg/day).
Placental transfer of revefenacin and its active metabolite was observed in pregnant
rabbits. In a pre-and postnatal development (PPND) study in pregnant rats dosed
during the periods of organogenesis and lactation from gestation day 6 to lactation day
20, revefenacin had no adverse developmental effects on pups at exposures up to 196
times the MRHD (based upon summed AUCs for revefenacin and its active metabolite
at maternal subcutaneous doses up to 500 mcg/kg/day).
4.6.2 Lactation
Risk Summary
There is no information regarding the presence of revefenacin in human milk, the
effects on the breastfed infant, or the effects on milk production. However, revefenacin
was present in the milk of lactating rats following dosing during pregnancy and
lactation.
The developmental and health benefits of breastfeeding should be considered along
with the mother’s clinical need for YUPELRI and any potential adverse effects on the
breastfed infant from YUPELRI or from the underlying maternal condition.

Data
Animal Data
In a PPND study revefenacin and its active metabolite were present in milk of lactating
rats on lactation day 22. Milk-to-plasma concentration ratios were up to 10 for
revefenacin and its active metabolite.
4.6.3 Pediatric Use
YUPELRI is not indicated for use in children. The safety and efficacy in pediatric
patients have not been established.
4.6.4 Geriatric Use
Based on available data, no adjustment of the dosage of YUPELRI in geriatric patients
is necessary.
Clinical trials of YUPELRI included 441 subjects aged 65 years and older, and, of
those, 101 subjects were aged 75 years and older. No overall differences in safety or
effectiveness were observed between these subjects and younger subjects, and other
reported clinical experience has not identified differences in responses between the
elderly and younger patients, but greater sensitivity of some older individuals cannot
be ruled out.

4.6.5 Hepatic Impairment
The systemic exposure of revefenacin is unchanged while that of its active metabolite
is increased in subjects with moderate hepatic impairment. The safety of YUPELRI has
not been evaluated in COPD patients with mild-to-severe hepatic impairment.
YUPELRI is not recommended in patients with any degree of hepatic impairment.
4.6.6 Renal Impairment
No dosage adjustment is required in patients with renal impairment. Monitor for
systemic antimuscarinic side effects in COPD patients with severe renal impairment.

Not Applicable.

The following potential adverse reactions are described in greater detail in other
sections:
• Paradoxical Bronchospasm
• Worsening of Narrow-Angle Glaucoma
• Worsening of Urinary Retention
• Immediate Hypersensitivity Reactions
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials of a drug cannot be directly compared to
rates in the clinical trials of another drug and may not reflect the rates observed in
practice.
The YUPELRI safety database included 2,285 subjects with COPD in two 12-week
efficacy studies and one 52-week long-term safety study. A total of 730 subjects
received treatment with YUPELRI 175 mcg once daily. The safety data described
below are based on the two 12-week trials and the one 52-week trial.

12-Week Trials
YUPELRI was studied in two 12-week replicate placebo-controlled trials in patients
with moderate to very severe COPD (Trials 1 and 2). In these trials, 395 patients were
treated with YUPELRI at the recommended dose of 175 mcg once daily.
The population had a mean age of 64 years (range from 41 to 88 years), with 50%
males, 90% Caucasian, and had COPD with a mean post-bronchodilator forced
expiratory volume in one second (FEV1) percent predicted of 55%. Of subjects
enrolled in the two 12-week trials, 37% were taking concurrent LABA or ICS/LABA therapy. Patients with unstable cardiac disease, narrow-angle glaucoma, or
symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from
these trials.
Table 1 shows the most common adverse reactions that occurred with a frequency of
greater than or equal to 2% in the YUPELRI group and higher than placebo in the two
12-week placebo-controlled trials.
The proportion of subjects who discontinued treatment due to adverse reactions was
13% for the YUPELRI-treated subjects and 19% for placebo-treated subjects.
Table 1: Adverse Events with YUPELRI ≥2% Incidence and Higher than Placebo

Other adverse reactions defined as events with an incidence of ≥1.0%, less than 2.0%,
and more common than with placebo included the following: hypertension, dizziness,
oropharyngeal pain, and bronchitis.
52-Week Trial
YUPELRI was studied in one 52-week, open-label, active-control (tiotropium 18 mcg
once daily) trial in 1,055 patients with COPD. In this trial, 335 patients were treated
with YUPELRI 175 mcg once daily and 356 patients with tiotropium. The demographic
and baseline characteristics of the long-term safety trial were similar to those of the
placebo-controlled 12-week studies described, with the exception that concurrent
LABA or LABA/ICS therapy was used in 50% of patients. The adverse reactions
reported in the long-term safety trial for YUPELRI were consistent with those observed
in the placebo-controlled studies of 12-weeks.

To report side effect(s):
The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662,
Call NPC at +966-11-2038222, Ext 2317-2356-2340
SFDA Call Center: 19999
E-mail: npc.drug@sfda.gov.sa
Website: https://ade.sfda.gov.sa/
Other GCC States:
Please contact the relevant competent authority.
4.9 Overdose:
An overdose of YUPELRI may lead to anticholinergic signs and symptoms such as
nausea, vomiting, dizziness, lightheadedness, blurred vision, increased intraocular
pressure (causing pain, vision disturbances, or reddening of the eye), obstipation or
difficulties in voiding. In COPD patients, orally inhaled administration of YUPELRI at
a once daily dose of up to 700 mcg (4 times the maximum recommended daily dose)
for 7 days was well tolerated.
Treatment of over dosage consists of discontinuation of YUPELRI along with
institution of appropriate symptomatic and/or supportive therapy.

An overdose of YUPELRI may lead to anticholinergic signs and symptoms such as
nausea, vomiting, dizziness, lightheadedness, blurred vision, increased intraocular
pressure (causing pain, vision disturbances, or reddening of the eye), obstipation or
difficulties in voiding. In COPD patients, orally inhaled administration of YUPELRI at
a once daily dose of up to 700 mcg (4 times the maximum recommended daily dose)
for 7 days was well tolerated.
Treatment of over dosage consists of discontinuation of YUPELRI along with
institution of appropriate symptomatic and/or supportive therapy.

Pharmacotherapeutic group: Drugs for obstructive airway diseases. Other drugs for
obstructive airway diseases, inhalants. Anticholinergics.
ATC code: R03BB08

Mechanism of Action
Revefenacin is a long-acting muscarinic antagonist, which is often referred to as an
anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to
M5. In the airways, it exhibits pharmacological effects through inhibition of M3
receptor at the smooth muscle leading to bronchodilation. The competitive and
reversible nature of antagonism was shown with human and animal origin receptors
and isolated organ preparations. In preclinical in vitro as well as in vivo models,
prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects
was dose-dependent and lasted longer than 24 hours. The clinical relevance of these
findings is unknown. The bronchodilation following inhalation of revefenacin is
predominantly a site-specific effect.

Cardiac Electrophysiology
QTc interval prolongation was studied in a randomized, double-blind, placebo- and
positive-controlled, single dose, crossover trial in 48 healthy subjects. Following a
single dose of revefenacin 700 mcg (4 times the recommended dosage), no effects on
prolongation of QTc interval were observed.

Revefenacin pharmacokinetic parameters are presented as the mean [standard deviation
(SD)] unless otherwise specified. Following repeat dosing of inhaled YUPELRI, steady
state was achieved within 7 days with <1.6-fold accumulation. Revefenacin exposure
(Cmax and AUC) in COPD patients is approximately 60% lower as compared to healthy
subjects. Exposure (Cmax and AUC) of the active metabolite in COPD patients is
approximately 2-fold higher as compared to healthy subjects. Revefenacin Cmax was
0.16 ng/mL (0.11) and AUC was 0.22 nghr/mL (0.20) at steady-state after inhaled
YUPELRI 175 mcg dose in COPD patients. Cmax of the active metabolite was 0.20
ng/mL (0.13) and AUC was 0.69 nghr/mL (0.53) at steady-state after inhaled
YUPELRI 175 mcg dose in COPD patients.
Revefenacin and its active metabolite exposure increased in a slightly greater than dose
proportional manner with increasing revefenacin dose. After single or multiple oncedaily
dosing of YUPELRI, both AUC and Cmax of revefenacin and its active metabolite
increased by approximately 11-fold over the 88 to 700 mcg (8-fold) dose range.
Absorption
Following inhaled administration of YUPELRI in healthy subjects or COPD patients,
Cmax of revefenacin and its active metabolite occurred at the first postdose sampling
time which ranged from 14 to 41 minutes after start of nebulization. The absolute
bioavailability following an oral dose of revefenacin is low (<3%).
Distribution
Following intravenous administration to healthy subjects, the mean steady-state volume
of distribution of revefenacin was 218 L suggesting extensive distribution to tissues. In
vitro protein binding of revefenacin and its active metabolite in human plasma was on
average 71% and 42%, respectively.
Elimination
The terminal half-life of revefenacin and its active metabolite after once-daily dosing
of YUPELRI in COPD patients is 22 to 70 hours.

Metabolism
In vitro and in vivo data showed that revefenacin is primarily metabolized via
hydrolysis of the primary amide to a carboxylic acid forming its major active
metabolite. Following inhaled administration of YUPELRI in COPD patients,
conversion to its active metabolite occurred rapidly, and plasma exposures of the active
metabolite exceeded those of revefenacin by approximately 4- to 6-fold (based on
AUC). The active metabolite is formed by hepatic metabolism and possesses activity
at target muscarinic receptors that is lower (approximately one-third to one-tenth) than
that of revefenacin. It could potentially contribute to systemic antimuscarinic effects at
therapeutic doses.

Excretion
Following administration of a single intravenous dose of radiolabeled revefenacin to
healthy male subjects, approximately 54% of total radioactivity was recovered in the
feces and 27% was excreted in the urine. Approximately 19% of the administered
radioactive dose was recovered in the feces as the active metabolite. Following
administration of a single radiolabeled oral dose of revefenacin, 88% of total
radioactivity was recovered in the feces and < 5% was present in urine, suggesting low
oral absorption. There was minimal renal excretion (<1%) of revefenacin and its active
metabolite following inhaled administration of YUPELRI in COPD patients.
Specific Populations: Population pharmacokinetic analysis showed no evidence of a
clinically significant effect of age (44 to 79 years), gender (59% male), smoking status
(42% current smoker) or weight (46 to 155 kg) on systemic exposure of revefenacin
and its active metabolite.
Patients with Hepatic Impairment: The pharmacokinetics of YUPELRI was evaluated
in subjects with moderate hepatic impairment (Child-Pugh score of 7-9). There was no
increase in C max of revefenacin and 1.5-fold increase in C max of the active metabolite.
There was 1.2-fold increase in AUC of revefenacin and up to 4.7-fold increase in AUC
of the active metabolite. YUPELRI has not been evaluated in subjects with severe
hepatic impairment.
Patients with Renal Impairment: The pharmacokinetics of YUPELRI was evaluated in
subjects with severe renal impairment (CrCl <30 mL/min). There was 1.5-fold increase
in C max of revefenacin and up to 2-fold increase in Cmax of the active metabolite. There
was up to 2.3-fold increase in AUCinf of revefenacin; the active metabolite exposure
(AUCinf) was increased by up to 2.5-fold. YUPELRI has not been evaluated in subjects
with end stage renal disease.

Drug Interactions
Revefenacin and Cytochrome P450: Neither revefenacin nor its active metabolite
inhibits the following cytochrome P450 isoforms: CYP1A2, CYP2B6, CYP2C8,
CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. Neither revefenacin nor its active
metabolite induces CYP1A2, CYP2B6, and CYP3A4/5.
Revefenacin and Efflux Transporters: Revefenacin is a substrate of P-gp and BCRP.
Neither revefenacin nor its active metabolite is an inhibitor of these efflux transporters.
Revefenacin and Uptake Transporters: The active metabolite of revefenacin is a
substrate of OATP1B1 and OATP1B3. Neither revefenacin nor its active metabolite is
an inhibitor of the uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.

Carcinogenesis, Mutagenesis, Impairment of Fertility
Two-year inhalation studies in Sprague-Dawley rats and CD1 mice were conducted to
assess the carcinogenic potential of revefenacin. No evidence of tumorigenicity was
observed in male and female rats at inhaled doses up to 338 mcg/kg/day (approximately
35 times the MRHD based upon summed AUCs for revefenacin and its active
metabolite). No evidence of tumorigenicity was observed in male and female mice at
inhaled doses up to 326 mcg/kg/day (approximately 40 times the MRHD based on
summed AUCs for revefenacin and its active metabolite).
Revefenacin and its active metabolite were negative for mutagenicity in the Ames test
for bacterial gene mutation. Revefenacin was negative for genotoxicity in the in vitro
mouse lymphoma assay and in vivo rat bone marrow micronucleus assay.
There were no effects on male or female fertility and reproductive performance in rats
at subcutaneous revefenacin doses up to 500 mcg/kg/day (approximately 30 times the
MRHD on an mg/m2 basis for revefenacin)

6.1 List of Excipients:
• Sodium Chloride
• Citric Acid Monohydrate
• Sodium Citrate Dihydrate
• Hydrochloric acid
• Sodium Hydroxide
• Water for Injection.

Not Applicable

o Store YUPELRI in the protective foil pouch.
o Store below 30°C. Protect from direct sunlight and excessive heat.
o The YUPELRI solution unit-dose vial should only be removed from the foil pouch
and opened IMMEDIATELY BEFORE USE. The vial and any residual content
should be discarded after use.

o Discard any solution that is not clear and colorless.
o Keep out of reach of children. Not a child-resistant package.
o YUPELRI should only be administered via a standard jet nebulizer connected to
an air compressor with an adequate airflow and equipped with a mouthpiece.
o Do not swallow or inject YUPELRI.

YUPELRI inhalation solution is supplied as a 175 mcg/3 mL sterile, clear, colorless,
aqueous solution in unit-dose low-density polyethylene vials. Each vial is overwrapped
in a foil pouch and supplied in cartons containing either 30 individually pouched unitdose
vials or 7 individually pouched unit-dose vials.

Patients should throw the plastic dispensing vials away immediately after use. Due to
their small size, the vials pose a danger of choking to young children.