Latanoprostene bunod

• Solution, Ophthalmic; 0.024%: Vyzulta (2.5 mL, 5 mL)

• Adults: One drop in the affected eye(s) once daily in the evening.
• Adolescents older than 16 years: One drop in the affected eye(s) once daily in the evening.

• Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Latanoprostene bunod should be used with caution in patients with hepatic impairment; data are lacking in these patients.

• Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Latanoprostene bunod should be used with caution in patients with renal impairment; data are lacking in these patients. For intermittent hemodialysis, no dosage adjustment is needed.

Pediatric

• Use in pediatric patients aged 16 years and younger is not recommended because of potential safety concerns related to increased pigmentation following long-term chronic use.

Pregnancy

• There are no available human data for the use of VYZULTA during pregnancy to inform any drug associated risks. Latanoprostene bunod has caused miscarriages, abortion, and fetal harm in rabbits. Latanoprostene bunod was shown to be abortifacient and teratogenic when administered intravenously (IV) to pregnant rabbits at exposures ≥ 0.28 times the clinical dose. Doses ≥ 20 mcg/kg/day (23 times the clinical dose) produced 100% embryofetal lethality. Structural abnormalities observed in rabbit fetuses included anomalies of the great vessels and aortic arch vessels, domed head, sternebral and vertebral skeletal anomalies, limb hyperextension and malrotation, abdominal distension and edema. Latanoprostene bunod was not teratogenic in the rat when administered IV at 150 mcg/kg/day (87 times the clinical dose). 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.
• Animal Data: Embryofetal studies were conducted in pregnant rabbits administered latanoprostene bunod daily by intravenous injection on gestation days 7 through 19, to target the period of organogenesis. The doses administered ranged from 0.24 to 80 mcg/kg/day. Abortion occurred at doses ≥ 0.24 mcg/kg/day latanoprostene bunod (0.28 times the clinical dose, on a body surface area basis, assuming 100% absorption). Embryofetal lethality (resorption) was increased in latanoprostene bunod treatment groups, as evidenced by increases in early resorptions at doses ≥ 0.24 mcg/kg/day and late resorptions at doses ≥ 6 mcg/kg/day (approximately 7 times the clinical dose). No fetuses survived in any rabbit pregnancy at doses of 20 mcg/kg/day (23 times the clinical dose) or greater. Latanoprostene bunod produced structural abnormalities at doses ≥ 0.24 mcg/kg/day (0.28 times the clinical dose). Malformations included anomalies of sternum, coarctation of the aorta with pulmonary trunk dilation, retroesophageal subclavian artery with absent brachiocephalic artery, domed head, forepaw hyperextension and hindlimb malrotation, abdominal distention/edema, andmissing/fused caudal vertebrae.
  An embryofetal study was conducted in pregnant rats administered latanoprostene bunod daily by intravenous injection on gestation days 7 through 17, to target the period of organogenesis. The doses administered ranged from 150 to 1500 mcg/kg/day. Maternal toxicity was produced at 1500 mcg/kg/day (870 times the clinical dose, on a body surface area basis, assuming 100% absorption), as evidenced by reduced maternal weight gain. Embryofetal lethality (resorption and fetal death) and structural anomalies were produced at doses ≥ 300 mcg/kg/day (174 times the clinical dose). Malformations included anomalies of the sternum, domed head, forepaw hyperextensionand hindlimb malrotation, vertebral anomalies and delayed ossification of distal limb bones. A no observed adverse effect level (NOAEL) was established at 150 mcg/kg/day (87 times the clinical dose) in this study.

Breast Feeding

• There are no data on the presence of VYZULTA in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered, along with the mother’s clinical need for VYZULTA, and any potential adverse effects on the breastfed infant from VYZULTA.

Geriatric

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

• Intraocular pressure
• Ocular pigmentation changes

• None

• Increased pigmentation of the iris and periorbital tissue (eyelid) can occur. Iris pigmentation is likely to be permanent.

• Gradual changes to eyelashes including increased length, increased thickness and number of eyelashes. Usually reversible upon discontinuation of treatment.

• Most common ocular adverse reactions with incidence ≥ 2% are conjunctival hyperemia (6%), eye irritation (4%), eye pain (3%), and instillation site pain (2%)

• Absorption

• The systemic exposure of latanoprostene bunod and its metabolites latanoprost acid and butanediol mononitrate were evaluated in one study with 22 healthy subjects after topical ocular administration of VYZULTA 0.024% once daily (one drop bilaterally in the morning) for 28 days. There were no quantifiable plasma concentrations of latanoprostene bunod (lower limit of quantitation, LLOQ, of 10.0 pg/mL) or butanediol mononitrate (LLOQ of 200 pg/mL) post-dose on Day 1 and Day 28. The mean maximal plasma concentrations (Cmax) of latanoprost acid (LLOQ of 30 pg/mL) were 59.1 pg/mL and 51.1 pg/mL on Day 1 and Day 28, respectively. The mean time of maximal plasma concentration (Tmax) for latanoprost acid was approximately 5 minutes post-administration on both Day 1 and Day 28.

• Distribution

• There were no ocular distribution studies performed in humans

• Metabolism

• After topical ocular administration, latanoprostene bunod is rapidly metabolized in the eye to latanoprost acid (active moiety), an F2α prostaglandin analog, and butanediol mononitrate. After latanoprost acid reaches the systemic circulation, it is primarily metabolized by the liver to the 1,2-dinor and 1,2,3,4-tetranor metabolites via fatty acid β-oxidation. Butanediol mononitrate is metabolized to 1,4-butanediol and nitric oxide. The metabolite 1,4-butanediol is further oxidized to succinic acid and enters the tricarboxylic acid (TCA) cycle.

• Elimination

• The elimination of latanoprost acid from human plasma is rapid as latanoprost acid plasma concentration dropped below the LLOQ (30 pg/mL) in the majority of subjects by 15 minutes following ocular administration of VYZULTA 0.024% in humans.

• Reduction of intraocular pressure

• Reduction of the intraocular pressure starts approximately 1 to 3 hours after the first administration with the maximum effect reached after 11-13 hours in eyes with elevated intraocular pressure.

• A 9-month toxicology study administered topical ocular doses of latanoprostene bunod to one eye of cynomolgus monkeys: control (vehicle only), one drop of 0.024% bid, one drop of 0.04% bid and two drops of 0.04% per dose, bid. The systemic exposures are equivalent to 4.2-fold, 7.9-fold, and 13.5-fold the clinical dose, respectively, on a body surface area basis (assuming 100% absorption). Microscopic evaluation of the lungs after 9 months observed pleural/subpleural chronic fibrosis/inflammation in the 0.04% dose male groups, with increasing incidence and severity compared to controls. Lung toxicity was not observed at the 0.024% dose.

• Carcinogenesis

• Latanoprostene bunod has not been tested for carcinogenic activity in long-term animal studies. Latanoprost acid is a main metabolite of latanoprostene bunod. Exposure of rats and mice to latanoprost acid, resulting from oral dosing with latanoprost in lifetime rodent bioassays, was not carcinogenic.

• Mutagenesis

• Latanoprostene bunod was not mutagenic in bacteria and did not induce micronuclei formation in the in vivorat bone marrow micronucleus assay. Chromosomal aberrations were observed in vitrowith human lymphocytes in the absence of metabolic activation.

• Impairment of Fertility

• Fertility studies have not been conducted with latanoprostene bunod. The potential to impact fertility can be partially characterized by exposure to latanoprost acid, a common metabolite of both latanoprostene bunod and latanoprost. Latanoprost acid has not been found to have any effect on male or female fertility in animal studies.

Potential for Pigmentation

• Patients should be advised about the potential for increased brown pigmentation of the iris, which may be permanent. Patients should also be informed about the possibility of eyelid skin darkening, which is usually reversible after discontinuation of VYZULTA.

Potential for Eyelash Changes

• Patients should also be informed of the possibility of eyelash and vellus hair changes in the treated eye during treatment with VYZULTA. These changes may result in a disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment.

Handling the Container

• Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye, surrounding structures, fingers, or any other surface in order to avoid contamination of the solution by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

When to Seek Physician Advice

• Advise patients that if they develop a new ocular condition (e.g., trauma or infection), experience a sudden decrease in visual acuity, have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician’s advice concerning the continued use of VYZULTA.

Use with Contact Lenses

• Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following administration of VYZULTA.

Use with Other Ophthalmic Drugs

• If more than one topical ophthalmic drug is being used, the drugs should be administered with at least five (5) minutes between applications.

• Latanoprostene bunod ophthalmic solution 0.024%

American Academy of Ophthalmology 2020

• Gedde SJ, Vinod K, Wright MM, et al. Primary Open-Angle Glaucoma Preferred Practice Pattern®. Ophthalmology. 2021;128(1):P71-P150. doi:10.1016/j.ophtha.2020.10.022