Continuing Education Activity

Netarsudil is a medication used in the treatment and management of glaucoma and ocular hypertension. Netarsudil is classified as a rho-kinase inhibitor. Primary open-angle glaucoma is characterized by progressive and irreversible optic neuropathy with a loss of optic nerve fibers. In patients with glaucoma, visual field loss can be minimized with accurate treatment regimens, regular follow-up, and enhanced patient compliance. This activity reviews the indications, contraindications, adverse events, and other key elements of netarsudil therapy for clinical management of glaucoma and ocular hypertension pertinent to interprofessional team members.

Objectives:

• Identify the indications for netarsudil therapy.
• Review the mechanism of action of netarsudil.
• Review the appropriate monitoring for adverse events for patients on netarsudil therapy.
• Summarize the interprofessional team approach for improving the patient outcomes on netarsudil therapy.

Indications

Glaucoma is a leading cause of irreversible blindness, affecting over 60 million people worldwide.[1] Medical therapy to lower the intraocular pressure (IOP) is currently the initial therapy to prevent progression and optic nerve damage. Current medications used in glaucoma patients may increase uveoscleral outflow or decrease aqueous humor production. 

Medications to increase uveoscleral outflow:

• Prostaglandin analogs
• Alpha agonists

Medications to decrease aqueous humor production:

• Beta-blockers
• Carbonic anhydrase inhibitors
• Alpha agonists

The FDA approved netarsudil ophthalmic solution (0.02%) in December 2017. It is indicated to reduce elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Netarsudil does not yet have any non-FDA-approved indications. The European Medicines Agency approved netarsudil in 2019. Netarsudil is available as a 0.02% ophthalmic solution for once-daily topical application.[2]

Mechanism of Action

Netarsudil is approved for primary open-angle glaucoma (POAG) and ocular hypertension. Glaucoma is irreversible, progressive optic neuropathy with progressive visual field loss, for which the primary proven treatment is to decrease the intraocular pressure (IOP).[3] Ocular hypertension is defined as abnormally high intraocular pressure (IOP) with no evidence of visual field loss or damage to the optic nerve (normal IOP=9-21 mm Hg). Intraocular pressure is regulated by a fine balance between aqueous humor production and the rate of aqueous outflow through the trabecular meshwork (TM) outflow and the uveoscleral outflow pathway. The majority of the aqueous humor is filtered through the TM pathway.

Currently available therapeutic options mainly increase uveoscleral outflow or decrease aqueous humor production to lower IOP instead of directly targeting the trabecular meshwork pathway. Interestingly, netarsudil lowers IOP directly through the relaxation of the trabecular meshwork, leading to an increase in aqueous outflow through the trabecular meshwork pathway. Netarsudil is a novel drug that is a potent Rho-associated kinase (ROCK) inhibitor and the norepinephrine transporter (NET) inhibitor. In preclinical studies, after ocular instillation of netarsudil, the highest concentrations were found in the cornea and conjunctiva. In human corneal tissue, the half-life of netarsudil was 175 minutes.[4] 

Studies have also shown that netarsudil is metabolized to active metabolite netarsudil-M1, demonstrating a fivefold higher activity than netarsudil against Rho-associated kinases. Rho-associated kinase (ROCK) is a naturally occurring kinase that enhances the assembly of actin fibers and focal adhesions within the trabecular meshwork. Inhibition of the norepinephrine transporter increases adrenergic transmission, leading to decreased aqueous humor production.[5] 

Netarsudil inhibits rho kinase and norepinephrine transporters found in the trabecular pathway, increasing trabecular outflow, reducing aqueous humor production, and lowering intraocular pressure.[6] In a nutshell, netarsudil lowered intraocular pressure by affecting aqueous humor dynamics (AHD) in three different ways: Increasing trabecular outflow, decreasing episcleral venous pressure (EVP), and reducing aqueous humor production. It appears to be a distinctive combination of mechanisms that lowers the intraocular pressure.[7] 

For the patients who require more rigorous IOP control, a fixed-dose combination of netarsudil with latanoprost is also available. A once-daily netarsudil/latanoprost fixed-dose combination provided better efficacy with statically significant IOP reduction with acceptable ocular safety in clinical trials.[8] 

A recent study showed the benefit of netarsudil in steroid-induced glaucoma. Steroid-induced glaucoma is an iatrogenic disease process. The mechanism behind steroid-induced glaucoma is through the Wnt pathway. The Wnt signaling pathways are signal transduction pathways. This Wnt pathway is related to the rho-associated protein kinase. It has been demonstrated that by administering dexamethasone produced, the Wnt/β-catenin  pathway gets activated, which promotes cross-linkage of actin fibers resulting in conformational changes in the trabecular meshwork, ultimately leading to obstruction in the outflow of aqueous humor and elevation of IOP, which is a specific factor in the pathogenesis of glaucoma. Given netarsudil’s key role in ROCK inhibition, netarsudil is a promising treatment option for steroid-induced glaucoma.[9][10] 

Interestingly, the preclinical studies showed potential advantages of netarsudil therapy for normal-tension glaucoma (aka normal pressure glaucoma). The preclinical study on normotensive monkeys decreased IOP significantly with netarsudil administration compared with contralateral placebo-treated eyes. The studies suggest that IOP reduction by netarsudil does not depend on the baseline IOP compared to other glaucoma drugs. Consequently, in patients who require an IOP below normal levels to prevent glaucoma progression, netarsudil may be an efficient treatment option.[11]

Administration

Netarsudil ophthalmic solution (0.02%) is instilled in one drop into the affected eye(s) once daily in the evening. Netarsudil may be used with other eye drops to lower intraocular pressure. If the patient is using more than one ophthalmic medication, they should be instructed to wait at least five minutes between the application of each medication. Clinicians should direct the patient to remove contact lenses before instilling netarsudil solution and wait for fifteen minutes post-administration before reinserting the contact lenses. Strict aseptic precautions are necessary to minimize contamination of the dropper tip to avoid the risk of bacterial keratitis.

Nasolacrimal punctual occlusion is a beneficial technique to reduce side effects by decreasing systemic absorption of the netarsudil drops. The patient should lie down for 3 minutes or longer to ensure efficacy. This technique would reduce the amount of netarsudil solution entering the nose. The punctual occlusion also increases the contact time of netarsudil with the eyes to ensure maximum efficacy with a single dose.[12]

Adverse Effects

The most common ocular adverse reaction following netarsudil ophthalmic solution is conjunctival hyperemia. Conjunctival hyperemia is due to rho kinase-mediated inhibition of calcium sensitization, resulting in blood vessel smooth muscle relaxation on the conjunctiva. Administering netarsudil at night can mitigate this adverse drug reaction. The severity of conjunctival hyperemia may reduce with time.[10] 

Other common adverse drug reactions include corneal verticillata. Corneal verticillata occurred in about 20% of the patients in controlled clinical studies. Cornea verticillata, also called vortex keratopathy, is a condition characterized by corneal deposits at the level of the basal epithelium forming a faint golden-brown whorl pattern. Vortex keratopathy usually resolves after cessation of netarsudil treatment.[13] 

A subconjunctival hemorrhage is the second most common adverse drug reaction of netarsudil therapy. A subconjunctival hemorrhage is usually a tiny, unilateral petechial micro hemorrhage around the limbus. Subconjunctival hemorrhage was self-limiting in most patients and typically resolved with continued use of netarsudil. Additional adverse drug reactions to netarsudil therapy are mild. These adverse drug reactions include corneal staining, headaches, blurry vision, instillation site pain, and erythema.[10]

Contraindications

As per the manufacturer package insert, there are no known contraindications to the use of netarsudil. Caution is necessary to prevent bacterial keratitis associated with the multiple-dose vial. The risk of bacterial keratitis is higher with the use of contact lenses.[14]

Monitoring

For patients receiving netarsudil therapy, normal intraocular pressure (IOP) checkups should be done by applanation tonometry, which is superior to pneumotonometry or non-contact air-puff tonometry.[15] Normal IOP ranges between 11 and 21 mm Hg. Fundus examination: an examination of the optic disc at the slit lamp or with indirect ophthalmoscopy is helpful for patients with glaucoma to examine the optic nerve, which may show a large cup to disc ratio, notching of the neuroretinal rim, and disc hemorrhage. Conjunctival hyperemia should be assessed during each visit, which is the most common adverse drug reaction. Netarsudil should be discontinued if the patient develops corneal verticillata.[15]

Toxicity

Esterases extensively metabolize Netarsudil in the eye, and thus, the systemic concentration of the drug is very low. Although systemic absorption of netarsudil upon ocular installation is relatively low, no clinical trials have been conducted on the effects of netarsudil on pregnant women. Given that netarsudil is highly protein-bound in human plasma, this leads to low plasma concentrations; hence netarsudil is unlikely to cause any systemic pharmacological effects following topical application. Only preclinical studies have been done to determine the in-utero effects of netarsudil. In preclinical studies, researchers found embryofoetal lethality and abortions at doses greater than 126 times recommended human ophthalmic dose.

In another preclinical study performed on rabbits, lethal embryopathy resulted from daily intravenous doses of netarsudil at 5 mg/kg/day, which is 1480 times greater than the recommended human ophthalmic dose. Other anomalies include gastroschisis, absent lung lobe, and umbilical herniation at 1330 times the recommended human dose. Thus netarsudil has a very high therapeutic index. In patients below the age of 18, safety and efficacy have yet to be established. Given the low systemic absorption of netarsudil after ocular installation, it is assumed to have no side effects on the breastfeeding infant. However, it is suggested to exercise caution during breastfeeding, given that this subject warrants further investigation.[16]

Enhancing Healthcare Team Outcomes

Netarsudil is a unique drug in that it increases aqueous outflow via the trabecular meshwork, decreases episcleral venous pressure, and reduces aqueous humor production. Netarsudil is the rho kinase inhibitor used for patients with primary open-angle glaucoma and ocular hypertension. Although netarsudil is not the first-line therapy for primary open-angle glaucoma or ocular hypertension, it is a novel drug indicated for IOP control without significant toxicity concerns. Netarsudil may be particularly indicated for patients with normotensive or steroid-induced glaucoma. In two large, randomized, double-masked trials, researchers found once-daily dosing of netarsudil 0.02% effective and well-tolerated for treating patients with ocular hypertension and open-angle glaucoma.[17] [Level 1]

Patient compliance is also better with once-daily dosing of netarsudil; thus, it would benefit all interprofessional healthcare team members to understand the mechanism of action, indication, and adverse drug reactions and their management thoroughly. An interprofessional team approach is necessary to impart comprehensive and patient-centered care. There needs to be excellent communication between ophthalmologists, primary care physicians, mid-level practitioners (PAs and NPs), pharmacists, residents, medical students, and nurses.

For patients receiving netarsudil therapy, intraocular pressure should be checked by an ophthalmic specialist. Common adverse drug reactions need to be assessed. The ophthalmologists play a pivotal role in managing the patients on netarsudil therapy.[18] The pharmacist plays a significant role in educating the patient about the adverse effects of the drug mentioned above. The pharmacist can also help with medication reconciliation to avoid errors such as omissions, duplications, dosing errors, or drug interactions.[19] 

Trained ophthalmic nurses can perform initial screening, monitor disease progression, and assist with early treatment of glaucoma with netarsudil therapy.[20] The ophthalmology residents are directly involved in patient care. Residents are also responsible for preoperative assessment and postoperative management.[21] Medical students can contribute significantly to patient education regarding the proper use of netarsudil.[22]

Collaboration and communication across these various disciplines in a healthcare team can achieve the best patient outcomes. In summary, the interprofessional team approach using evidence-based medicine and patient-centered care correlates with reduced healthcare service utilization and helps achieve better clinical outcomes.[23] [Level 5]