DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Instill one drop in each eye, wait minutes and instill second drop in each eye once daily 2). 2.1 Recommended Dosage. Instill one drop in each eye, wait minutes and instill second drop in each eye once daily from the same single-dose vial.. 2.2 Administration Instructions. Contact lenses should be removed prior to the instillation of VIZZ and may be reinserted 10 minutes after instillation.If more than one topical ophthalmic product is being used, the products should be administered at least minutes apart.To open vial, twist off top [see How Supplied/Storage and Handling (16.1)] Discard the opened single-dose vial after use.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reactions were instillation site irritation (20%), dim vision (16%), and headache (13%) 6.1). To report SUSPECTED ADVERSE REACTIONS, contact LENZ Therapeutics, Inc. at 1-888-711-LENZ or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.VIZZ dosed once daily was evaluated for safety and efficacy in 466 participants with presbyopia in randomized, double-masked, controlled phase studies for 42 days (CLARITY-1, NCT05656027 and CLARITY-2, NCT05728944). VIZZ dosed once daily was also evaluated for long term safety in 217 participants with presbyopia in separate randomized, double-masked, controlled phase study (CLARITY-3, NCT05753189) for 6-month duration.The most common reported adverse reactions of participants were instillation site irritation (20%), dim vision (16%), and headache (13%). Adverse reactions reported in 5% of participants were conjunctival hyperemia (8%) and ocular hyperemia (7%). The majority of adverse reactions were mild, transient, and self-resolving.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong term studies in animals have not been performed to evaluate carcinogenic potential.. MutagenesisAceclidine did not show any potential to cause genetic toxicity in series of studies that included: 1) bacterial assays (Salmonella and E. coli) for reverse gene mutations; 2) an in vitro chromosome aberration assay in cultured human peripheral blood lymphocytes; and 3) an in vivo chromosome aberration assay (micronucleus test) in mice.. Impairment of FertilityOral administration of aceclidine produced no adverse effect on fertility in rats at doses up to 1.5 mg/kg/day (approximately 25 times the MRHOD based on body surface area).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Aceclidine is cholinergic muscarinic agonist that stimulates muscarinic receptors located on smooth muscles. VIZZ is predominantly pupil selective miotic that interacts with the iris with minimal ciliary muscle stimulation. VIZZ causes contraction of the iris sphincter muscle, resulting in pinhole effect that extends depth of focus to improve vision.. 12.3 Pharmacokinetics. Aceclidine undergoes hydrolysis in the eye to acetate and 3-quinuclidinol (3-Q) with one mole of aceclidine hydrolyzed to one mole of 3-Q. Pharmacokinetic studies are performed on the analysis of 3-Q, which is metabolite formed from the hydrolysis of aceclidine.Systemic exposure of aceclidine hydrochloride was evaluated in 16 subjects with presbyopia following once daily VIZZ administration (one drop of VIZZ in each eye followed by second drop in each eye two minutes later) for days. The mean maxand AUC 0-tvalues for 3-Q after Day dosing were 2.114 ng/mL and 4.899 hrng/mL, respectively. There was little to no accumulation of 3-Q after repeat once daily dosing of VIZZ. After days, the mean (SD) RAUC 0-tand RC maxvalues were 1.189 (0.770) and 0.996 (0.314), respectively. 1/2could not be estimated at any timepoint due to the limited amount of quantifiable 3-Q concentrations after ocular dosing.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of VIZZ for the treatment of presbyopia was demonstrated in two, randomized, double-masked, controlled studies, CLARITY-1 and CLARITY-2. total of 466 participants aged 45 to 75 years old with presbyopia were randomized. Participants had refractive range from -4.00 to +1.00 sphere, with astigmatism up to 2.00 D, and spherical equivalent no more myopic than -4.00 D. Both studies included participants who were post-refractive surgery and/or pseudophakic.Participants were instructed to instill drops of VIZZ (or control) in each eye once daily, one drop in each eye followed by second drop in each eye two minutes later. Participants were treated for 42 days. Ophthalmic efficacy assessments were conducted on Day 1, Day 15, and Day 28 of the study at various timepoints through 10 hours post dose.In each study, the proportion of participants gaining lines or more in high contrast, distance corrected, near visual acuity (DCNVA) at 40 cm, without loss of line or more (>=5 letters) of distance corrected, distance visual acuity (DCDVA) at meters was statistically significantly greater in the VIZZ group compared to the control group at Day 1, Hour 3.Table 1. Primary Efficacy Endpoint from CLARITY-1 and CLARITY-2 Studies Day 1, at Hours Post Dose (FAS Population)CLARITY-1CLARITY-2VIZZ N=157 Brimonidine N=156 p-valueVIZZ N=77 Vehicle N=76 p-valueProportion of participants gaining 3-lines or more in DCNVA at 40cm, without losing line or more (>=5 letters) of DCDVA at 4m at Day 1, at hours65%12%p<0.0171%8%p<0.01Figure and Figure demonstrate the onset of the VIZZ effect on presbyopia, from 30 minutes post dose and lasting 10 hours.Figure Percentage of Participants Achieving Lines or More Improvement in High Contrast, Monocular Near Vision (DCNVA at 40 cm) and No Loss of or More Lines (DCDVA at m) on Day at All Measured Time Points (CLARITY-2, FAS population with Observed data)Figure Percentage of Participants Achieving Lines or More Improvement in High Contrast, Monocular Near Vision (DCNVA at 40 cm) and No Loss of or More Lines (DCDVA at m) on Day at All Measured Time Points (CLARITY-1, FAS population with Observed data). Figure 1. Figure 2.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.VIZZ dosed once daily was evaluated for safety and efficacy in 466 participants with presbyopia in randomized, double-masked, controlled phase studies for 42 days (CLARITY-1, NCT05656027 and CLARITY-2, NCT05728944). VIZZ dosed once daily was also evaluated for long term safety in 217 participants with presbyopia in separate randomized, double-masked, controlled phase study (CLARITY-3, NCT05753189) for 6-month duration.The most common reported adverse reactions of participants were instillation site irritation (20%), dim vision (16%), and headache (13%). Adverse reactions reported in 5% of participants were conjunctival hyperemia (8%) and ocular hyperemia (7%). The majority of adverse reactions were mild, transient, and self-resolving.

DESCRIPTION SECTION.

11 DESCRIPTION. VIZZ (aceclidine ophthalmic solution) 1.44% is cholinergic muscarinic receptor agonist supplied as sterile, clear to opalescent, colorless to slightly yellow, and viscous ophthalmic solution containing 1.75% of aceclidine hydrochloride (equivalent to 1.44% aceclidine).The chemical names for aceclidine hydrochloride are: 1) 3-Acetoxyquinuclidine Hydrochloride; 2) 3-Quinuclidinyl Acetate Hydrochloride. Its molecular weight is 205.68 g/mol and its molecular formula is 9H 15NO HCl. Each mL of VIZZ contains aceclidine hydrochloride 1.75% (17.82 mg) as the active ingredient. Inactive ingredients in the ophthalmic solution are: polysorbate 80, mannitol, hypromellose, edetate disodium dihydrate, sodium citrate dihydrate, water for injection, and may also include hydrochloric acid and/or sodium hydroxide for pH adjustment to between 4.5 and 5.5, if necessary. VIZZ does not contain antimicrobial preservatives.. Chemical Structure.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. VIZZ (aceclidine ophthalmic solution) 1.44% is supplied as sterile, clear to opalescent, colorless to slightly yellow, and viscous ophthalmic solution in configurations of single-dose vials. VIZZ does not include antimicrobial preservatives.Each single-dose vial is comprised of transparent low-density polyethylene (LDPE).5 single-dose vials are packaged in foil pouch.. VIZZ is supplied in:NDC NumberDescriptionVial Configuration84226-100-11carton box of 25 single-dose vials (5 pouches five vials of 0.4 mL each)84226-100-21carton box of 25 single-dose vials (5 pouches five vials of 0.25 mL each). Figure. Figure. 16.2 Storage and Handling. Store refrigerated at 36F to 46F (2C to 8C). Do not freeze.When stored in refrigerated conditions, VIZZ can be used until the expiration date.Once pouch or vial(s) are removed from refrigeration, VIZZ may be stored at room temperature [up to 77F (25C)] but must be used within 30 days.Discard the opened single-dose vial after use.During shipment, VIZZ may be maintained at temperatures up to 104F (40C) for period not exceeding days.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Night DrivingAdvise patients that they may experience 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)]. Blurred VisionTemporary 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)] . When to Seek Physician AdviceAdvise patients to seek immediate medical care with sudden onset of flashing lights, floaters, or vision loss [see Warnings and Precautions (5.2)]. Contact Lens WearAdvise patients to remove contact lenses prior to the instillation of VIZZ. Wait 10 minutes after instillation before reinserting their contact lenses [see Warnings and Precautions (5.5)]. Potential for Eye Injury or ContaminationAdvise patients to avoid touching the tip of the single-dose vial to the eye or to any other surface in order to prevent eye injury or contamination [see Warnings and Precautions (5.6)]. Advise patients to discard the opened single-dose vial and any remaining contents after use. Concomitant Topical Ocular TherapyAdvise patients if more than one topical ophthalmic medication is being used, the medicines should be administered at least minutes apart [see Dosage and Administration (2)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no information regarding the presence of VIZZ or its metabolite in human or animal milk, the effects on breastfed infants or the effects on milk production to inform the risk of VIZZ to an infant during lactation.Systemic levels of aceclidine and its metabolites following topical ocular administration are low [see Clinical Pharmacology (12.3)] and it is not known whether measurable levels of aceclidine or its metabolites would be present in human milk following topical ocular administration. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for VIZZ and any potential adverse effects on the breastfed child from VIZZ or from the underlying maternal condition.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong term studies in animals have not been performed to evaluate carcinogenic potential.. MutagenesisAceclidine did not show any potential to cause genetic toxicity in series of studies that included: 1) bacterial assays (Salmonella and E. coli) for reverse gene mutations; 2) an in vitro chromosome aberration assay in cultured human peripheral blood lymphocytes; and 3) an in vivo chromosome aberration assay (micronucleus test) in mice.. Impairment of FertilityOral administration of aceclidine produced no adverse effect on fertility in rats at doses up to 1.5 mg/kg/day (approximately 25 times the MRHOD based on body surface area).

OVERDOSAGE SECTION.

10 OVERDOSAGE. Systemic toxicity following topical ocular administration of miotics is rare, but occasionally patients who are sensitive may develop increased salivation, sweating, gastrointestinal overactivity, and slowing of the pulse. Accidental ingestion can produce sweating, salivation, nausea, tremors, slowing of the pulse, and decrease in blood pressure. In moderate overdosage, spontaneous recovery is to be expected and is aided by intravenous fluids to compensate for dehydration.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Aceclidine undergoes hydrolysis in the eye to acetate and 3-quinuclidinol (3-Q) with one mole of aceclidine hydrolyzed to one mole of 3-Q. Pharmacokinetic studies are performed on the analysis of 3-Q, which is metabolite formed from the hydrolysis of aceclidine.Systemic exposure of aceclidine hydrochloride was evaluated in 16 subjects with presbyopia following once daily VIZZ administration (one drop of VIZZ in each eye followed by second drop in each eye two minutes later) for days. The mean maxand AUC 0-tvalues for 3-Q after Day dosing were 2.114 ng/mL and 4.899 hrng/mL, respectively. There was little to no accumulation of 3-Q after repeat once daily dosing of VIZZ. After days, the mean (SD) RAUC 0-tand RC maxvalues were 1.189 (0.770) and 0.996 (0.314), respectively. 1/2could not be estimated at any timepoint due to the limited amount of quantifiable 3-Q concentrations after ocular dosing.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no adequate and well controlled studies of VIZZ administration in pregnant women to inform drug associated risk. In animal reproduction studies, oral administration of aceclidine to pregnant rats and rabbits throughout organogenesis and lactation did not produce adverse maternal, fetal or neonatal effects at clinically relevant doses.. Data. Animal DataIn embryofetal development studies, oral administration of aceclidine to pregnant rats and rabbits throughout organogenesis produced no maternal toxicity, skeletal anomalies, nor reduction in fetal body weight at 1.5 mg/kg/day (approximately 110-fold and 70-fold the human plasma exposure to the metabolite, 3-quinuclidinol, in rats and rabbits, respectively, at the MRHOD, assuming administration of drops/eye/day).In pre-/postnatal development study in rats, oral administration of aceclidine during organogenesis through lactation produced no adverse maternal, fetal, or neonatal effects at doses up to 1.5 mg/kg/day (approximately 110-fold higher than the MHOD based on body surface area, assuming administration of drops/eye/day).

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. Store refrigerated at 36F to 46F (2C to 8C). Do not freeze.When stored in refrigerated conditions, VIZZ can be used until the expiration date.Once pouch or vial(s) are removed from refrigeration, VIZZ may be stored at room temperature [up to 77F (25C)] but must be used within 30 days.Discard the opened single-dose vial after use.During shipment, VIZZ may be maintained at temperatures up to 104F (40C) for period not exceeding days.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no adequate and well controlled studies of VIZZ administration in pregnant women to inform drug associated risk. In animal reproduction studies, oral administration of aceclidine to pregnant rats and rabbits throughout organogenesis and lactation did not produce adverse maternal, fetal or neonatal effects at clinically relevant doses.. Data. Animal DataIn embryofetal development studies, oral administration of aceclidine to pregnant rats and rabbits throughout organogenesis produced no maternal toxicity, skeletal anomalies, nor reduction in fetal body weight at 1.5 mg/kg/day (approximately 110-fold and 70-fold the human plasma exposure to the metabolite, 3-quinuclidinol, in rats and rabbits, respectively, at the MRHOD, assuming administration of drops/eye/day).In pre-/postnatal development study in rats, oral administration of aceclidine during organogenesis through lactation produced no adverse maternal, fetal, or neonatal effects at doses up to 1.5 mg/kg/day (approximately 110-fold higher than the MHOD based on body surface area, assuming administration of drops/eye/day).. 8.2 Lactation. Risk SummaryThere is no information regarding the presence of VIZZ or its metabolite in human or animal milk, the effects on breastfed infants or the effects on milk production to inform the risk of VIZZ to an infant during lactation.Systemic levels of aceclidine and its metabolites following topical ocular administration are low [see Clinical Pharmacology (12.3)] and it is not known whether measurable levels of aceclidine or its metabolites would be present in human milk following topical ocular administration. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for VIZZ and any potential adverse effects on the breastfed child from VIZZ or from the underlying maternal condition.. 8.4 Pediatric Use. Presbyopia does not occur in the pediatric population.. 8.5 Geriatric Use. No overall differences in safety or effectiveness of VIZZ have been observed between patients 65 years of age and older and younger adult patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Blurred Vision:Patients may experience temporary dim or dark vision after instillation. Do not drive or operate machinery if vision is not clear (e.g., blurred vision). Exercise caution in night driving and other hazardous activities in poor illumination 5.1). Risk of Retinal Tear/Detachment:Rare cases of retinal tears and detachments have been reported with miotics. Examination of the retina is advised in all patients prior to initiation of therapy. Patients should be advised to seek immediate medical care with sudden onset of flashing lights, floaters, or vision loss 5.2). Iritis: Caution is advised in patients with history of iritis 5.3). Blurred Vision:Patients may experience temporary dim or dark vision after instillation. Do not drive or operate machinery if vision is not clear (e.g., blurred vision). Exercise caution in night driving and other hazardous activities in poor illumination 5.1). Risk of Retinal Tear/Detachment:Rare cases of retinal tears and detachments have been reported with miotics. Examination of the retina is advised in all patients prior to initiation of therapy. Patients should be advised to seek immediate medical care with sudden onset of flashing lights, floaters, or vision loss 5.2). Iritis: Caution is advised in patients with history of iritis 5.3). 5.1 Blurred Vision. Miotics may cause accommodative spasm. Do not drive or operate machinery if vision is not clear (e.g., blurred vision).Patients may experience temporary dim or dark vision. Exercise caution in night driving and other hazardous activities in poor illumination.. 5.2 Risk of Retinal Tear/Detachment. Rare cases of retinal tear and detachment have been reported with miotics when used in susceptible individuals and those with pre-existing retinal disease. Examination of the retina is advised in all patients prior to the initiation of treatment with VIZZ. Patients should be advised to seek immediate care with sudden onset of flashing lights, floaters, or vision loss.. 5.3 Iritis. Sequelae of ocular inflammation, i.e., adhesions (synechiae) between the iris and the lens, may be exacerbated with miotic use in patients with known history of iritis.. 5.4 Hypersensitivity. VIZZ is not recommended for use in patients with known hypersensitivity to aceclidine or any other ingredient in VIZZ.. 5.5 Use with Contact Lenses. Contact lenses should be removed prior to the instillation of VIZZ and may be reinserted 10 minutes after instillation.. 5.6 Potential for Eye Injury or Contamination. To prevent eye injury or contamination, care should be taken to avoid touching the single-dose vial to the eye or to any other surface.