YUVEZZI - Visus Therapeutics, Inc.

The recommended dosage of YUVEZZI is one drop in each eye once daily.

Remove contact lenses prior to instillation of YUVEZZI. Wait 10 minutes after dosing before reinserting contact lenses.

If more than one topical ophthalmic medication is being used, the medicines must be administered at least 5 minutes apart.

One single-dose vial can be used to dose both eyes. Discard the open single-dose vial and any remaining contents immediately after use.

Miotics may cause accommodative spasm. Advise patients to not drive or operate machinery if vision is not clear (e.g., blurred vision).

In addition, patients may experience temporary dim or dark vision with miotics. Advise patients to exercise caution in night driving and other hazardous activities in poor illumination.

Rare cases of retinal tear and detachment have been reported with miotics. Individuals with pre-existing retinal disease are at increased risk. Examination of the retina is advised in all patients prior to the initiation of therapy.

Advise patients to seek immediate medical care with sudden onset of flashes of lights, floaters, or vision loss.

Sequelae of ocular inflammation, i.e., adhesions (synechiae) between the iris and the lens, may be exacerbated with miotic use, therefore, YUVEZZI is not recommended to be used when iritis is present.

YUVEZZI may potentiate syndromes associated with vascular insufficiency. YUVEZZI should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypotension, or thromboangiitis obliterans.

To prevent eye injury or contamination, avoid touching the single-dose vial to the eye, eyelids, or to any other surface.

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.

YUVEZZI was evaluated in 536 patients with presbyopia in two randomized, double-masked, controlled studies. BRIO™ I (NCT05270863) was a single-dose crossover study in which 178 patients received YUVEZZI. BRIO II (NCT05135286) included 358 patients who received YUVEZZI in the long-term safety portion of the study (up to 12 months duration, including a 6-month open-label extension). Adverse reactions reported in > 5% to 7% of participants were eye pain upon instillation and visual impairment. Adverse reactions reported in > 10% to 16% of participants were eye irritation upon instillation and headache. The majority of adverse events were mild, transient, and self-resolving.

Because brimonidine tartrate, a component of YUVEZZI, may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with YUVEZZI is advised.

Although specific drug interaction studies have not been conducted with YUVEZZI, the possibility of an additive or potentiating effect with central nervous system (CNS) depressants (alcohol, opiates, barbiturates, sedatives, or anesthetics) should be considered.

Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not known whether the concurrent use of these agents with YUVEZZI in humans can lead to resulting interference with pupil constriction effects. Caution is advised in patients taking tricyclic antidepressants, which can affect the metabolism and uptake of circulating amines.

Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine tartrate and potentially result in an increased systemic side effect such as hypotension. Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines.

Risk Summary

There are no adequate and well-controlled studies of YUVEZZI administration in pregnant women to inform a drug-associated risk. Topical ocular administration of YUVEZZI to pregnant rats throughout organogenesis did not produce adverse effects up to 3 times the maximum recommended human ocular dose (MRHOD). Topical ocular administration of YUVEZZI to pregnant rabbits throughout organogenesis at approximately 3 times the MRHOD resulted in maternal toxicity with no effect on the fetus, including reduced maternal food consumption, body weight change, and related moribundity in 2/25 animals during the dosing period. Body weight and food consumption effects recovered after the dosing stopped ( see Data ).

Because animal reproductive studies are not always predictive of human response, YUVEZZI should be administered during pregnancy only if the potential benefit justifies the potential risk to the pregnant mother and fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies.

Data

Human Data

No adequate and well-controlled trials of YUVEZZI have been conducted in pregnant women.

Animal Data

YUVEZZI was not teratogenic in embryofetal development studies when given by topical ocular administration to pregnant rats or rabbits throughout organogenesis at dose levels up to approximately 3 times the MRHOD of 1.815 mg/day carbachol and 0.066 mg/day brimonidine tartrate based on body surface area scaling. Topical ocular administration of YUVEZZI to pregnant rats on gestation days (GD) 6 to 17 at dose levels of up to 0.224 mg/day carbachol and 0.008 mg/day brimonidine tartrate (approximately 3 times the MRHOD, based on body surface area) produced no maternal toxicity or embryofetal effects. Topical ocular administration of YUVEZZI to pregnant rabbits on GD 7 to 19 at the dose level of 1.12 mg/day carbachol and 0.04 mg/day brimonidine tartrate (approximately 3 times the MRHOD, based on body surface area scaling) led to maternal toxicity with no embryofetal effects. Maternal findings included significantly reduced food consumption (41%) and body weight change (-87%), with related moribundity in 2/25 animals during the dosing period, compared with the vehicle control group. Body weight and food consumption effects resolved after a 10-day recovery period.

Risk Summary

There is no information regarding the presence of carbachol and brimonidine tartrate in human milk, the effects on the breastfed infants, or the effects on milk production to inform risk of YUVEZZI to an infant during lactation.

Systemic levels of carbachol and brimonidine tartrate following topical ocular administration of YUVEZZI are low [see Clinical Pharmacology (12.3)] , and it is not known whether measurable levels of carbachol and brimonidine tartrate 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 YUVEZZI and any potential adverse effects on the breastfed child from YUVEZZI.

Presbyopia does not occur in the pediatric population.

No overall differences in safety or effectiveness have been observed between elderly and adult patients.

The proposed mechanism of action of this fixed-dose combination of carbachol and brimonidine in presbyopia is pupillary constriction and the creation of a pinhole effect that improves near visual acuity and depth of focus. Carbachol is a cholinergic agent which produces constriction of the iris sphincter and ciliary body. Brimonidine tartrate, an alpha-adrenergic agonist, blocks contraction of the iris dilator muscle and relaxes tonic contraction of the ciliary muscle, enhancing selectivity for the pupil and increasing bioavailability of carbachol in the aqueous humor.

Pupil size was assessed using automated digital pupillometry under mesopic conditions. Average pupil diameter reduction following YUVEZZI was significantly superior to both active monotherapies from pre-dose baseline to Hour 0.5 through Hour 10 in the BRIO I study, and to vehicle from pre-dose baseline to Hour 0.5 through Hour 8 in the BRIO II study.

Absorption

Systemic exposures to brimonidine tartrate and carbachol were evaluated in participants with presbyopia who were administered 1 drop of YUVEZZI to each eye. Brimonidine tartrate plasma concentrations were quantifiable in 5 of 14 subjects, with C _maxand T _maxup to 0.066 ng/mL and 0.52 hours respectively. Carbachol plasma concentrations were quantifiable in 6 of 14 subjects, with C _maxand T _maxup to 1.02 ng/mL and 4.42 hours respectively.

Distribution

Brimonidine is approximately 29% bound to plasma proteins in healthy subjects. The protein binding of carbachol has not been studied.

Elimination

Metabolism

In humans, brimonidine is extensively metabolized by the liver. Metabolism of carbachol has not been studied.

Excretion

Urinary excretion is the major route of elimination of brimonidine and its metabolites. Approximately 87% of an orally administered radioactive dose of brimonidine was eliminated within 120 hours, with 74% found in the urine. Excretion of carbachol has not been studied.

Carcinogenesis

Long term studies in animals have not been performed to evaluate carcinogenic potential of YUVEZZI or carbachol.

No brimonidine tartrate–related carcinogenic effects were observed with dietary administration at dose levels up to 2.5 mg/kg/day in mice for 21 months or 1 mg/kg/day in rats for 24 months.

Mutagenesis

Carbachol was not mutagenic or clastogenic in a battery of in vitro and in vivo studies including the Ames bacterial reverse mutation test, an in vitro micronucleus assay in TK6 cells, and an in vivo rat bone marrow micronucleus assay.

Brimonidine tartrate was not mutagenic or clastogenic in a series of in vitro and in vivo studies, including the Ames bacterial reverse mutation test, a chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, and 3 in vivo studies in CD-1 mice: a host-mediated assay, cytogenic study, and dominant lethal assay.

Impairment of Fertility

Fertility studies of YUVEZZI or carbachol have not been conducted.

A reproduction and fertility study in rats with brimonidine tartrate demonstrated no adverse effect on male or female fertility at oral doses up to 1 mg/kg.

Storage

Store at 36°F to 77°F (2°C to 25°C). Once a pouch is opened, store the single-dose vials in the foil pouch away from light until ready for use. Discard opened single-dose vials and any remaining contents immediately after use.