VYZULTA™ is a prostaglandin analog indicated for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.

Posology, frequency and duration of use:

The recommended dosage is one drop in the conjunctival sac of the affected eye(s) once daily in the evening. Do not administer VYZULTA (latanoprostene bunod ophthalmic solution, 0.024%) more than once daily since it has been shown that more frequent administration of prostaglandin analogs may decrease the intraocular pressure lowering effect.

Method of administration:

If VYZULTA™ is to be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure, administer each drug product at least five (5) minutes apart.

Additional information on special populations

Renal/liver failure:

VYZULTA™ is not studied in these special populations.

Pediatric population:

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.

Geriatric population:

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

Pigmentation:

VYZULTA™ (latanoprostene bunod ophthalmic solution, 0.024%) may cause changes to pigmented tissues. The most frequently reported changes with prostaglandin analogs have been increased pigmentation of the iris and periorbital tissue (eyelid).

Pigmentation is expected to increase as long as latanoprostene bunod ophthalmic solution is

administered. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of VYZULTA™, pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes are likely to be reversible in most patients. Patients who receive prostaglandin analogs, including VYZULTA™, should be informed of the possibility of increased pigmentation, including permanent changes. The long-term effects of increased pigmentation are not known.

Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with VYZULTA™ (latanoprostene bunod ophthalmic solution), 0.024% can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly.

Eyelash Changes:

VYZULTA™ may gradually change eyelashes and vellus hair in the treated eye. These changes include increased length, thickness, and the number of lashes or hairs. Eyelash changes are usually reversible upon discontinuation of treatment.

Intraocular Inflammation:

VYZULTA™ should be used with caution in patients with a history of intraocular inflammation (iritis/uveitis) and should generally not be used in patients with active intraocular inflammation as it may exacerbate this condition.

Macular Edema:

Macular edema, including cystoid macular edema, has been reported during treatment with prostaglandin analogs. VYZULTA™ should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.

Bacterial Keratitis:

There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.

Use with Contact Lenses:

Contact lenses should be removed prior to the administration of VYZULTA™ because this product contains benzalkonium chloride. Lenses may be reinserted 15 minutes after admistration. It is known that it causes damaged colors of soft contact lenses.

No specific interaction studies have been performed with VYZULTA™. If more than one topical ophthalmic medicinal product is being used, the medicinal products must be administered at least five (5) minutes apart.

Additional information for special populations

No clinical interaction study implemented for special populations.

Pediatric population

No clinical interaction study implemented for pediatric population.

Geriatric use

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

General advice

Pregnancy category: C

Women of child bearing potential/Birth control (Contraception):

There is no information on VYZULTA™ administration in women with child bearing potential or on the requirement of contraception in women using VYZULTA™. It should be careful when the product administered to women of child bearing potential.

Pregnancy:

There are no sufficient data with respect to effects on pregnancy of VYZULTA™.  Investigations on animals showed that there is reproductive toxicity (see part 5.3).

The potential risk for humans is unknown.

VYZULTA™ should not be used in pregnancy unless needed.

Risk Summary

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 μg/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)[see Data].

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

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, and missing/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 hyperextension and 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.

Lactation:

Risk Summary

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™.

Reproduction/Fertility:

Fertility studies have not been conducted with latanoprostene bunod.

As with any eye drops, patients may experience temporary blurred vision or redness, pain, or itching of the treated eye (s). If blurred vision occurs at instillation, the patients should wait until their vision clears before driving or using machinery.

Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon  (≥ 1/1.000 to < 1/100); rare (≥ 1/10.000 to < 1/1.000); very rare (< 1/10.000), not known (cannot be estimated from the available data). 

Eye disorders

Common: Conjunctival hyperemia, eye irritation, eye pain, instillation site pain

Unknown: Pigmentation, eyelash changes, intraocular inflammation, macular edema, bacterial keratitis, usage with contact lenses (see Part 4.4 Special warnings and precautions for use), ocular hyperemia, conjunctival irritation, conjunctival edema, vision blurred, punctuate keratisis and foreign body sensation.

To report any side effects:

· Saudi Arabia:

· Other GCC States:

No overdose has been reported for ophthalmic use.

Pharmacotherapeutic group: Ophthalmological prostaglandin analogs

ATC code: S01EE06

Mechanism of action:

VYZULTA™ is thought to lower intraocular pressure by increasing outflow of aqueous humor through both the trabecular meshwork and uveoscleral routes. Intraocular pressure is a major modifiable risk factor for glaucoma progression. Reduction of intraocular pressure reduces risk of glaucomatous visual field loss.

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.

In clinical studies up to 12 months duration, patients with open-angle glaucoma or ocular hypertension with average baseline intraocular pressures (IOPs) of 26.7 mmHg, the IOP-lowering effect of VYZULTA™ once daily (in the evening) was up to 7 to 9 mmHg.

General properties

Absorption:

Given the relative metabolic stability of latanoprost acid compared to butandiol mononitrate ocular absorption of latanoprosten bunod was characterized by the pharmakokinetic profile of latanoprosten bunod. 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 min post administration on both Day 1 and Day 28.

Distribution:

There were no ocular distribution studies performed in humans. In the monkey, after topical ocular application of 4.8 μg/eye [3H]latanoprost, concentrations of radioactivity peaked in ocular tissues examined by 1 h. Maximum concentrations of radioactivity were for cornea, conjunctiva, anterior sclera, iris, anterior chamber, and ciliary body, respectively. Radioactivity in the ciliary body was most concentrated in the circular, radial, and longitudinal muscles, the pharmacological target, while the ciliary body stroma contained very low levels of radioactivity. The elimination half-life from these tissues was estimated at 3-4 h, similar to what was seen for LA disappearance after LBN topical ocular dosing.

Specific studies on the distribution of butanediol mononitrate, the other principal metabolite of latanoprostene bunod, were not conducted due to the metabolic instability of butanediol mononitrate, its negligible systemic exposure in animals and humans, and its well described metabolism to endogenously produced compounds in the literature. Tissue distribution studies of [¹⁴C]1,4-butanediol in rats showed that only 2.28% of the radioactivity remained in the carcass after 72 h, with most excreted as ¹⁴CO2 (94%), consistent with its known oxidation to γ-hydroxybutyric acid (successive steps catalyzed by alcohol dehydrogenase and aldehyde dehydrogenase). Of the residual radioactivity (3,72%) in carcass, most was present in skin, liver and muscle.

Due to the metabolic instability and reactivity of nitric oxide and complexity of distribution once it reaches the general circulation, its tissue distribution was not studied. Exogenously administered nitric oxide has been shown in blood to rapidly (0.05-1.8 msec) in literature.

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 (BDMN) is metabolized to 1,4-butanediol and nitric oxide. Butanediol mononitrate (BDMN), rapidly forms nitric oxide (NO) and 1,4-butanediol; although butanediol mononitrate metabolism was not evaluated in ocular tissues, studies have shown that ocular topical administration of LBN resulted in elevation of the downstream signaling messenger of nitric oxide, cyclique GMP in both the aqueous humor and iris/ciliary body providing indirect evidence that metabolism of BDMN occurs and that nitric oxide is available in the eye at the target tissue.

Systemically, the de-nitration of BDMN to form NO and 1,4-butanediol was shown to be catalyzed by glutathione-S-transferases in liver cytosol. The subsequent oxidative metabolic steps of 1,4-butanediol to succinate acid and to carbon dioxide in the tricarboxylic acid (TCA) cycle have been described in the literature and will be summarized in this section.

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 min following ocular administration of VYZULTA™ in humans. Specific excretion studies for butandiol mononitrate were not done; however, the disposition of its two principal metabolites, nitric oxide and 1,4-butanediol, have been studied after inhalation and oral administration, respectively. In human subjects inhaling 20, 40, and 80 ppm nitric oxide, nitric oxide was shown to be excreted by a renal mechanism in the form of nitrate, with renal clearance estimated at 20 mL/min. The other metabolite, 1,4-butanediol, was shown to be metabolized to succinate acid and enter the TCA cycle and almost quantitatively excreted in expired air as carbon dioxide.

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

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.

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.

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.

None.

Store between 2-8 ºC. Protect from light. Do not freeze.

VYZULTA™ is supplied as a 5-ml sterile ophthalmic solution in a 7.5-ml clear low density polyethylene (LDPE) bottle with a controlled dropper tip and turquoise polypropylene cap. Tamper evidence is provided with a shrink band around the cap and neck area of the package.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.