Netarsudil, a Rho kinase inhibitor, is combined with latanoprost, a prostaglandin F2alpha analog, in an ophthalmic solution for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. The drug is administered topically once daily in the evening to each affected eye. The most common adverse reaction reported in clinical studies with netarsudil; latanoprost was conjunctival hyperemia; which resulted in 5% of drug recipients discontinuing therapy. Latanoprost treatment has been associated with increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes. Changes in pigmentation of the iris may be irreversible.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Ophthalmic Administration
-Wash hands before and after use.
-Remove contact lenses before instilling ophthalmic drops. Lenses may be reinserted 15 minutes after drug administration.
-Tilt the head back slightly and pull the lower eyelid down with the index finger to form a pouch. Squeeze the prescribed number of drops into the pouch and gently close eyes for 1 to 2 minutes. Do not blink.
-Care should be taken to avoid contamination. Do not touch the tip of the dropper to the eye, fingertips, or other surfaces.
-May be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than 1 topical ophthalmic drug is being used, the drugs should be administered at least 5 minutes apart.
Prostaglandin analogs, such as latanoprost, have been associated with increased pigmentation of the iris, periorbital tissues (eyelids), and eyelashes. Iridal discoloration happens slowly and may not be noticeable for several months to several years. This change is caused by an increase in the amount of brown pigment in the iris due to an increased melanin content in the melanocytes. The increase in brown pigment has not been shown to progress further upon discontinuation of treatment; however, the resultant color change may be permanent. The drug may also gradually change eyelashes and vellus hair; these changes include increased length, thickness, and number of lashes or hairs (hypertrichosis). Eyelid skin darkening (eyelid skin hyperpigmentation) has also been reported.
Ocular adverse reactions were experienced by recipients of netarsudil; latanoprost during clinical trials. The most frequently reported reactions included conjunctival hyperemia (59%; 5% discontinued therapy due to conjunctival hyperemia), instillation site ocular pain (20%), corneal verticillata (vortex keratopathy, 15%), and conjunctival hemorrhage (11%). Ocular pruritus, visual impairment (i.e., decreased visual acuity, blurred vision), increased lacrimation, and instillation site discomfort or ocular irritation were reported in 5% to 8% of patients. Other adverse reactions that have been reported with netarsudil as an individual drug component and not listed above include instillation site erythema, corneal staining, and eyelid erythema. Other adverse reactions that have been reported with latanoprost as an individual drug component and not listed above include foreign body sensation, punctate keratitis, eyelid discomfort, eyelid margin crusting, eyelid erythema, eyelid edema, photophobia, and xerophthalmia.
Systemic adverse reactions that have been reported with latanoprost as an individual drug component include myalgia, arthralgia, back pain, allergic reactions, rash, upper respiratory tract infection, naso-pharyngitis, and influenza.
Netarsudil; latanoprost should, in general, not be used in patients with active ocular inflammation, as the drug may exacerbate this condition. In addition, caution is advised when considering use in patients with a history of iritis or uveitis.
Netarsudil; latanoprost should be used with caution in patients with aphakia, pseudophakic patients with a torn posterior lens capsule, and patients with known risk factors for macular edema. Macular edema, including cystoid macular edema, has been reported during treatment with prostaglandin analogs.
Netarsudil; latanoprost ophthalmic solution is formulated with the preservative benzalkonium chloride, which may be absorbed by soft contact lenses. Remove contact lenses before instilling the ophthalmic drops; contact lenses may be reinserted 15 minutes after drug administration.
Use of ophthalmic multiple-dose containers, such as netarsudil; latanoprost ophthalmic solution, has been associated with bacterial keratitis. In most cases, these containers had been inadvertently contaminated by patients with a corneal disease or a disruption in ocular epithelial surface. If there is any damage to the ocular epithelial surface (e.g., ocular surgery, ocular trauma, ocular infection, corneal abrasion), the drug should be used with caution.
Reactivation of herpes simplex virus epithelial keratitis has been reported during latanoprost therapy. Administer netarsudil; latanoprost cautiously to patients with a history of herpetic keratitis; avoid use of the drug in patients with active herpes simplex keratitis due to the potential for exacerbation of inflammation.
Use of netarsudil; latanoprost in pediatric patients younger than 18 years of age (i.e., neonates, infants, children, adolescents) has not been evaluated; however, due to safety concerns related to increased pigmentation following prolonged treatment, use ophthalmic prostaglandin analogs in this population is not recommended.
Administer netarsudil; latanoprost during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. No adequate or well-controlled studies have been conducted regarding the use of netarsudil; latanoprost during human pregnancy, and it is unknown if the drug produces an adverse effect on human reproduction or the fetus. In animal studies, exposing pregnant rabbits to latanoprost doses 80-times the recommended human ocular dose (RHOD) caused embryofetal lethality; however, this effect was not observed when the doses were decreased to 15-times the RHOD. Intravenous injections of netarsudil (plasma exposure 126-times the RHOD, based on Cmax) administered to rats during organogenesis resulted in abortions and embryofetal lethality. The no-observed-adverse-effect-level (NOAEL) for embryofetal development toxicity in pregnant rats was a netarsudil plasma exposure 40-times the RHOD, based on Cmax.
According to the manufacturer, it is not known whether netarsudil or latanoprost are excreted in breast milk. In addition, it is unknown if the netarsudil; latanoprost produces an adverse effect on milk product or the breast-fed infant. Systemic exposure to netarsudil following ophthalmic administration is low, and it is unknown whether measurable concentrations of netarsudil would be present in maternal milk following topical ocular administration. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension:
Ophthalmic dosage:
Adults: 1 drop instilled in each affected eye once daily in the evening. Do not exceed the recommended dose or frequency.
Maximum Dosage Limits:
-Adults
1 drop per day per affected eye.
-Geriatric
1 drop per day per affected eye.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Netarsudil; Latanoprost products.
Netarsudil and latanoprost both act to reduce intraocular pressure (IOP); when given in combination, the IOP lowering effects are additive. Data from 2 clinical trials involving patients with open-angle glaucoma and ocular hypertension found the average IOP lowering effect of the combination product (netarsudil; latanoprost) to be 1 to 3 mmHg greater than the lowering effect of either drug component given as monotherapy.
-Netarsudil: Netarsudil is a Rho kinase inhibitor, which is believed to reduce intraocular pressure by increasing the outflow of aqueous humor through the trabecular meshwork route. The exact mechanism is unknown.
-Latanoprost: Latanoprost, an analog of prostaglandin F2alpha, is a prodrug which lowers IOP by increasing aqueous humor outflow. Latanoprost is a selective agonist at a subtype of prostaglandin receptors, known as the FP receptor. By acting on the FP receptor, latanoprost increases the outflow of aqueous humor thereby reducing intraocular pressure. According to the manufacturer, studies in both animals and man suggest that increased uveoscleral outflow is the primary mechanism of action.
Netarsudil; latanoprost ophthalmic solution is administered topically to the eye.
-Latanoprost: Latanoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to form a biologically active acid. Once absorbed into systemic circulation, latanoprost acid has a volume of distribution of 0.16 +/- 0.02 L/kg, and drug concentrations in the plasma are measurable only during the first-hour post-dose (plasma elimination half-life of 17 minutes). Latanoprost acid is primarily metabolized by the liver to the 1,2-dinor and 1,2,3,4-tetranor metabolites via fatty acid beta-oxidation. These metabolites are mainly eliminated by the kidneys with 88% of the ophthalmic dose being recovered in the urine.
-Netarsudil: After topical ocular administration, netarsudil is metabolized by esterases in the eye to form the active metabolite, AR-13503. Systemic exposures of netarsudil and AR-13403 are low. In a study in 18 healthy subjects who received topical administration of netarsudil 0.02% once daily (1 drop bilaterally in the morning) for 8 days, there were no quantifiable plasma concentrations of netarsudil (lower limit of quantitation (LLOQ) 0.1 ng/mL) post-dose on day 1 and day 8. Only 1 plasma concentration of 0.11 ng/mL for the active metabolite was noted for 1 subject on day 8, at 8 hours post-dose.
Affected cytochrome P450 isoenzymes: none
-Route-Specific Pharmacokinetics
Other Route(s)
Ophthalmic Route
-Latanoprost: Following ocular administration, latanoprost is absorbed through the cornea where the isopropyl ester prodrug is hydrolyzed to the acid form to become biologically active. Latanoprost acid can be measured in the aqueous humor during the first 4 hours, with peak aqueous humor concentrations being reached about 2 hours after drug administration. Reduction of intraocular pressure starts approximately 3 to 4 hours after drug administration and peaks after 8 to 12 hours; IOP reductions are present for at least 24 hours.