Vuity Pi
Vuity Pi
These highlights do not include all the information needed to use VUITY Blurred Vision: Patients should be advised not to drive or operate
safely and effectively. See full prescribing information for VUITY. machinery if vision is not clear (e.g., blurred vision). Exercise caution in
night driving and other hazardous activities in poor illumination. (5.1)
VUITY® (pilocarpine hydrochloride ophthalmic solution) 1.25%, for
topical ophthalmic use Risk of Retinal Detachment: Rare cases of retinal detachment and retinal
Initial U.S. Approval: 1974 tear have been reported with miotics, including VUITY. Individuals with
pre-existing retinal disease are at increased risk. Therefore, examination
----------------------------RECENT MAJOR CHANGES------------------------- of the retina is advised in all patients prior to initiation of therapy.
Warnings and Precautions, Blurred Vision (5.1) 8/2022 Patients should be advised to seek immediate medical care with sudden
Warnings and Precautions, Risk of Retinal Detachment (5.2) 8/2022 onset of flashing lights, floaters, or vision loss. (5.2)
Dosage and Administration (2) 3/2023
Iritis: Caution is advised in patients with iritis. (5.3)
-----------------------------INDICATIONS AND USAGE--------------------------
VUITY is a cholinergic muscarinic receptor agonist indicated for the -------------------------------ADVERSE REACTIONS------------------------------
treatment of presbyopia in adults. (1) Most common adverse reactions (>5%) are headache, conjunctival hyperemia,
and eye irritation. (6.1)
------------------------DOSAGE AND ADMINISTRATION----------------------
To report SUSPECTED ADVERSE REACTIONS, contact Allergan at
Instill one drop of VUITY in each eye once daily. A second dose (one
1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
additional drop in each eye) may be administered 3-6 hours after the first
dose. (2)
See 17 for PATIENT COUNSELING INFORMATION.
-------------------------------CONTRAINDICATIONS------------------------------
Hypersensitivity (4)
If more than one topical ophthalmic product is being used, the products should be administered at least 5 minutes apart.
4 CONTRAINDICATIONS
VUITY is contraindicated in patients with known hypersensitivity to the active ingredient or to any of the excipients.
In addition, patients may experience temporary dim or dark vision with miotics, including VUITY. Patients should be
advised to exercise caution in night driving and other hazardous activities in poor illumination.
Individuals with pre-existing retinal disease are at increased risk. Therefore, examination of the retina is advised in all
patients prior to the initiation of therapy.
Patients should be advised to seek immediate medical care with sudden onset of flashing lights, floaters, or vision loss.
5.3 Iritis
VUITY is not recommended to be used when iritis is present because adhesions (synechiae) may form between the iris
and the lens.
VUITY dosed once daily was evaluated in 375 participants with presbyopia in two randomized, double-masked,
vehicle-controlled studies (GEMINI 1 and GEMINI 2) of 30 days duration. The most common adverse reactions reported
in >5% of participants were headache and conjunctival hyperemia. Ocular adverse reactions reported in 1-5% of
participants were blurred vision, eye pain, visual impairment, eye irritation, and increased lacrimation.
VUITY was also evaluated in 114 participants with presbyopia in a randomized, double-masked, vehicle-controlled
14-day study (VIRGO) in which participants received two doses of VUITY in each eye, 6 hours apart daily. The most
common adverse reactions reported in >5 % of participants were headache and eye irritation. Ocular adverse reactions
reported in 1-5% of participants were visual impairment, eye pain, blurred vision, and vitreous floaters.
The following adverse reactions have been identified during postapproval use of VUITY. Because these reactions are
reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to VUITY exposure.
Eye disorders: vitreous detachment, vitreomacular traction, retinal tear, retinal detachment.
Data
Human Data
No adequate and well-controlled trials of VUITY have been conducted in pregnant women. In a retrospective case series
of 15 women with glaucoma, 4 patients used ophthalmic pilocarpine either pre-pregnancy, during pregnancy or
postpartum. There were no adverse effects observed in patients or in their infants.
Animal Data
In embryofetal development studies, oral administration of pilocarpine to pregnant rats throughout organogenesis
produced maternal toxicity, skeletal anomalies and reduction in fetal body weight at 90 mg/kg/day (approximately
485-fold higher than the maximum human ophthalmic dose [MHOD] of 0.03 mg/kg/day assuming administration of 2
drops/eye/day, on a mg/m2 basis).
In a peri-/postnatal study in rats, oral administration of pilocarpine during late gestation through lactation increased
stillbirths at a dose of 36 mg/kg/day (approximately 195-fold higher than the MHOD). Decreased neonatal survival and
reduced mean body weight of pups were observed at ≥18 mg/kg/day (approximately 100 times the maximum human
ophthalmic dose of VUITY).
8.2 Lactation
Risk Summary
There is no information regarding the presence of pilocarpine in human milk, the effects on the breastfed infants, or the
effects on milk production to inform risk of VUITY to an infant during lactation.
Pilocarpine and/or its metabolites are excreted in the milk of lactating rats. Systemic levels of pilocarpine following
topical ocular administration are low [see Clinical Pharmacology (12.3)], and it is not known whether measurable levels
of pilocarpine would be present in maternal milk following topical ocular administration.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for
VUITY and any potential adverse effects on the breastfed child from VUITY.
Data
Animal Data
Following a single oral administration of 14C-pilocarpine to lactating rats, the radioactivity concentrations in milk were
similar to those in plasma.
10 OVERDOSAGE
Systemic toxicity following topical ocular administration of pilocarpine is rare, but occasionally patients who are sensitive
may develop sweating and gastrointestinal overactivity. Accidental ingestion can produce sweating, salivation, nausea,
tremors and slowing of the pulse and a decrease in blood pressure. In moderate overdosage, spontaneous recovery is to be
expected and is aided by intravenous fluids to compensate for dehydration. For patients demonstrating severe poisoning,
atropine, the pharmacologic antagonist to pilocarpine, should be used.
11 DESCRIPTION
VUITY (pilocarpine hydrochloride ophthalmic solution) 1.25% is a cholinergic muscarinic receptor agonist prepared as
an isotonic, clear, colorless, sterile ophthalmic solution containing 1.25% of pilocarpine hydrochloride. The chemical
name for pilocarpine hydrochloride is (3S,4R)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl]oxolan-2-one
hydrochloride. Its molecular weight is 244.72 and its molecular formula is C11H16N2O2 · HCl. Its structural formula is:
Each mL of VUITY contains pilocarpine hydrochloride 1.25% (12.5 mg) as the active ingredient, equivalent to 1.06%
(10.6 mg) pilocarpine free-base. Preservative is: benzalkonium chloride 0.0075%. Inactive ingredients in the ophthalmic
solution are: boric acid, sodium citrate dihydrate, sodium chloride, purified water, and may also include hydrochloric acid
and/or sodium hydroxide for pH adjustment to between 3.5 and 5.5, if necessary.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Pilocarpine hydrochloride is a cholinergic muscarinic agonist which activates muscarinic receptors located at smooth
muscles such as the iris sphincter muscle and ciliary muscle. VUITY contracts the iris sphincter muscle, constricting the
pupil to improve near and intermediate visual acuity while maintaining some pupillary response to light. VUITY also
contracts the ciliary muscle and may shift the eye to a more myopic state.
12.3 Pharmacokinetics
Systemic exposure to pilocarpine was evaluated in 22 participants with presbyopia who were administered 1 drop of
VUITY in each eye once daily for 30 days (GEMINI 1). The mean (SD) Cmax and AUC values from time 0 to last
measurable concentration over 10-hour period post-last dose on Day 30 were 1.95 (0.98) ng/mL and 4.14
(2.16) ng·hr/mL, respectively. The median Tmax value on Day 30 was 0.3 hours postdose with a range from 0.2 to 0.5
hours postdose.
Systemic exposure to pilocarpine was also evaluated in 8 participants with presbyopia who were administered 1 drop of
VUITY in each eye twice daily for 14 days (VIRGO). The Day 14 mean (SD) Cmax following first daily dosing was 1.81
(0.51) ng/mL and following second daily dosing was 2.12 (1.75) ng/mL. The Day 14 mean (SD) AUC over 6-hour post-
dose following first daily dose was 4.35 (1.50) ng·hr/mL and following second daily dose was 4.22 (3.14) ng·hr/mL.
There was no significant systemic drug accumulation over time, with accumulation index ratios between Day 1 and Day
14 based on AUC as 1.42 and 1.03 for the first and second daily dose, respectively.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Pilocarpine did not induce tumors in mice at any dosage level studied (up to 30 mg/kg/day; approximately 80-times the
MHOD). In rats, an oral dose of 18 mg/kg/day (approximately 100 times the MHOD), resulted in a statistically significant
increase in the incidence of benign pheochromocytomas in both male and female rats, and a statistically significant
increase in the incidence of hepatocellular adenomas in female rats.
Mutagenesis
Pilocarpine did not show any potential to cause genetic toxicity in a series of studies that included: 1) bacterial assays
(Salmonella and E. coli) for reverse gene mutations; 2) an in vitro chromosome aberration assay in a Chinese hamster
ovary cell line; 3) an in vivo chromosome aberration assay (micronucleus test) in mice; and 4) a primary DNA damage
assay (unscheduled DNA synthesis) in rat hepatocyte primary cultures.
Impairment of Fertility
Pilocarpine oral administration to male and female rats at a dosage of 18 mg/kg/day (100 times the MHOD) resulted in
impaired reproductive function, including reduced fertility, decreased sperm motility, and morphologic evidence of
abnormal sperm. It is unclear whether the reduction in fertility was due to effects on males, females, or both. In dogs,
exposure to pilocarpine at a dosage of 3 mg/kg/day for 6 months resulted in evidence of impaired spermatogenesis
(approximately 55 times the MHOD).
14 CLINICAL STUDIES
The efficacy of VUITY dosed once daily for the treatment of presbyopia was demonstrated in two 30-Day Phase 3,
randomized, double-masked, vehicle-controlled studies, namely GEMINI 1 (NCT03804268) and GEMINI 2
(NCT03857542). A total of 750 participants aged 40 to 55 years old with presbyopia were randomized (375 to VUITY
group) in two studies and participants were instructed to administer one drop of VUITY or vehicle once daily in each eye.
In both studies, the proportion of participants gaining 3 lines or more in mesopic, high contrast, binocular distance
corrected near visual acuity (DCNVA), without losing more than 1 line (5 letters) of corrected distance visual acuity
(CDVA) with the same refractive correction was statistically significantly greater in the VUITY group compared to the
vehicle group at Day 30, Hour 3 (see Table 1).
Table 1: Primary Efficacy Results from GEMINI 1 and GEMINI 2 Studies (Intent-to-Treat Population)
GEMINI 1 GEMINI 2
VUITY Vehicle p-value VUITY Vehicle p-value
N=163 N=160 N=212 N=215
Proportion of participants gaining 31% 8% p<0.01 26% 11% p<0.01
3-lines or more in mesopic
DCNVA, without losing more
than 1 line (5 letters) of CDVA at
Day 30, Hour 3
Figures 1 and 2 present the proportion of participants who gained 3-lines or more in mesopic DCNVA at Day 30.
Figure 1: Proportion of Participants Achieving 3-Lines or More Improvement in Mesopic, High Contrast, Binocular DCNVA
at Day 30 in GEMINI 1 (Intent-to-Treat Population)
50
VUITY
Vehicle
40
30
20
10
0
0 1 3 6 8 10
0.
0.
25
5
Hour
Timepoint Hour 0 Hour 0.25 Hour 0.5 Hour 1 Hour 3 Hour 6 Hour 8 Hour 10
VUITY (%) 4.3 17.7 34.8 41.6 30.7 18.4 10.6 7.5
Vehicle (%) 5.9 9.8 9.8 15.7 8.1 8.8 8.5 8.6
Difference (95% CI) -1.5 (-6.4, 3.3) 7.9 (0.3, 15.5) 25.0 (16.2, 33.8) 25.9 (16.4, 35.5) 22.5 (14.3, 30.8) 9.7 (2.3, 17.0) 2.1 (-4.4, 8.5) -1.1 (-7.1, 5.0)
Figure 2: Proportion of Participants Achieving 3-lines or More Improvement in Mesopic, High Contrast, Binocular DCNVA
at Day 30 in GEMINI 2 (Intent-to-Treat Population)
50
VUITY
Vehicle
40
30
20
10
0
0 1 3 6 8 10
0.
0.
25
5
Hour
Timepoint Hour 0 Hour 0.25 Hour 0.5 Hour 1 Hour 3 Hour 6 Hour 8 Hour 10
VUITY (%) 7.8 16.1 32.1 37.3 27.6 16.3 14.5 12.6
Vehicle (%) 4.0 6.6 9.6 12.1 10.8 9.9 8.6 8.7
Difference (95% CI) 3.8 (-0.9, 8.4) 9.4 (3.2, 15.7) 22.5 (14.7, 30.3) 25.2 (17.0, 33.4) 16.7 (9.1, 24.3) 6.5 (-0.1, 13.1) 5.9 (-0.5, 12.2) 3.8 (-2.3, 10.0)
The efficacy of VUITY dosed twice daily for the treatment of presbyopia was also demonstrated in a 14-Day,
randomized, double-masked, vehicle-controlled study, namely VIRGO (NCT04983589). A total of 230 participants aged
40 to 55 years old with presbyopia were randomized (114 to VUITY group) and participants were instructed to administer
one drop of VUITY or vehicle twice daily in each eye, with each dose administered 6 hours apart.
In this study, the proportion of participants gaining 3 lines or more in mesopic, high contrast, binocular distance corrected
near visual acuity (DCNVA), without losing more than 1 line (5 letters) of corrected distance visual acuity (CDVA) with
the same refractive correction was statistically significantly greater in the VUITY group compared to the vehicle group at
Day 14, Hour 9 (3 hours after the second dose) (see Table 2).
VIRGO
VUITY BID Vehicle BID p-value
N=114 N=116
Proportion of participants gaining 35% 8% p< 0.01
3-lines or more in mesopic
DCNVA, without losing more
than 1 line (5 letters) of CDVA at
Day 14, Hour 9 (3 hours after the
second dose)
Figure 3 presents the proportion of participants who gained 3-lines or more in mesopic DCNVA at Day 14.
Figure 3: Proportion of Participants Achieving 3-lines or More Improvement in Mesopic, High Contrast, Binocular DCNVA
at Day 14 in VIRGO (Intent-to-Treat Population)
60
VUITY BID
Vehicle BID
40
30
20
10
0
0 1 3 6 7 9
Dose 1 Dose 2
Hour
Difference (95% CI) 8.8 (2.0, 15.7) 44.9 (34.4, 55.4) 30.0 (19.8, 40.1) 22.9 (13.9, 31.8) 48.4 (38.2, 58.5) 28.2 (18.0, 38.4)
Storage
Store at 15°C to 25°C (59°F to 77°F). After opening, VUITY can be used until the expiration date on the bottle.
17 PATIENT COUNSELING INFORMATION
Night Driving
VUITY may cause temporary dim or dark vision. Advise patients to exercise caution with night driving and when
hazardous activities are undertaken in poor illumination [see Warnings and Precautions (5.1)].
Accommodative Spasm
Temporary problems when changing focus between near and distant objects may occur. Advise patients not to drive or use
machinery if vision is not clear (e.g., blurred vision) [see Warnings and Precautions (5.1)].
v5.0USPI7098