Netarsudil: A Comprehensive Pharmacological and Clinical Monograph

1.0 Abstract and Overview

Netarsudil is a first-in-class ophthalmic medication approved for the reduction of elevated intraocular pressure (IOP) in adult patients with open-angle glaucoma (OAG) or ocular hypertension (OHT).[1] As a small molecule amino-isoquinoline amide, its primary distinction lies in a novel, multi-faceted mechanism of action that directly targets the conventional aqueous humor outflow pathway, the principal site of pathological resistance in glaucoma.[1] Netarsudil functions as a dual inhibitor of Rho-associated protein kinase (ROCK) and the norepinephrine transporter (NET).[1] This dual inhibition produces a triple-action effect on aqueous humor dynamics: (1) it enhances trabecular outflow by inducing relaxation of the trabecular meshwork cells; (2) it is believed to decrease aqueous humor production by reducing blood flow to the ciliary body; and (3) it lowers episcleral venous pressure (EVP).[2]

Pivotal Phase 3 clinical trials, including the ROCKET-1 and ROCKET-2 studies, established the efficacy of a 0.02% ophthalmic solution of netarsudil administered once daily. These trials demonstrated that netarsudil was non-inferior to the beta-blocker timolol 0.5% in reducing IOP in the key patient population with baseline pressures below 25 mmHg.[3] A notable characteristic of netarsudil is its ability to lower IOP consistently across a range of baseline pressures, suggesting potential utility in conditions such as normal-tension glaucoma.[3]

The safety profile of netarsudil is characterized by a high incidence of localized, ocular adverse events, the most common of which is conjunctival hyperemia, occurring in over half of treated patients.[6] Other common ocular effects include cornea verticillata, instillation site pain, and conjunctival hemorrhage.[10] These effects are generally mild to moderate in severity and lead to treatment discontinuation in a minority of patients.[6] In stark contrast, netarsudil exhibits an excellent systemic safety profile. Due to rapid metabolism within the cornea and negligible systemic absorption, it is associated with minimal to no systemic adverse effects, a significant advantage over systemically active agents like beta-blockers.[3]

Marketed under brand names such as Rhopressa® and Rhokiinsa®, netarsudil represents a significant advancement in the pharmacological management of glaucoma. Its unique, pathophysiology-targeted mechanism has also led to the development and approval of a fixed-dose combination with the prostaglandin analog latanoprost (Rocklatan®/Roclanda®), which provides a potent, dual-outflow treatment option for patients requiring more substantial IOP reduction.[12]

2.0 Chemical Identity, Formulation, and Physicochemical Properties

2.1 Chemical Identification and Nomenclature

Netarsudil is a synthetic organic, small molecule compound classified chemically as an amino-isoquinoline amide.[1] As a distinct chemical entity, it is identified by a comprehensive set of internationally recognized nomenclature and registry numbers that ensure its unambiguous characterization for scientific, regulatory, and clinical purposes.

The primary identifier assigned by the Chemical Abstracts Service is CAS Number 1254032-66-0, which corresponds to the netarsudil free base.[1] The drug is also formulated as various salts, each with its own specific CAS number, including netarsudil dimesilate (CAS: 1422144-42-0) and netarsudil dihydrochloride (CAS: 1253952-02-1).[16] During its development phase, netarsudil was known by the codes AR-13324 and AR-11324.[4] The International Union of Pure and Applied Chemistry (IUPAC) name for the molecule isphenyl]methyl 2,4-dimethylbenzoate.[1] Its molecular formula is

C28​H27​N3​O3​, with a corresponding molecular weight of approximately 453.54 g/mol.[9] The table below provides a consolidated summary of its key chemical identifiers.

Table 1: Key Chemical and Physical Identifiers for Netarsudil

Identifier Type	Value	Source(s)
DrugBank ID	DB13931	1
Type	Small Molecule	15
CAS Number (free base)	1254032-66-0	1
IUPAC Name	phenyl]methyl 2,4-dimethylbenzoate	1
Molecular Formula	C28​H27​N3​O3​	1
Molecular Weight	453.542 g·mol⁻¹	9
InChI	InChI=1S/C28H27N3O3/c1-18-3-10-25(19(2)13-18)28(33)34-17-20-4-6-21(7-5-20)26(15-29)27(32)31-24-9-8-23-16-30-12-11-22(23)14-24/h3-14,16,26H,15,17,29H2,1-2H3,(H,31,32)/t26-/m1/s1	1
InChIKey	OURRXQUGYQRVML-AREMUKBSSA-N	1
SMILES	CC1=CC(=C(C=C1)C(=O)OCC2=CC=C(C=C2)C@@HC(=O)NC3=CC4=C(C=C3)C=NC=C4)C
Brand Names (US/EU)	Rhopressa® / Rhokiinsa®
ATC Code	S01EX05

2.2 Physicochemical Properties and Formulation

The active pharmaceutical ingredient is typically used as netarsudil dimesilate, a salt form that enhances its physicochemical properties for formulation. This salt is a white to light-yellow crystalline powder characterized as a weak acid. It is moderately hygroscopic, freely soluble in water, and soluble in methanol, properties that facilitate its formulation as an aqueous ophthalmic solution.

Netarsudil is commercially available as a sterile, buffered, isotonic ophthalmic solution at a concentration of 0.02%, which is equivalent to 0.2 mg of netarsudil per mL. The formulation is designed for topical ocular administration. A critical component of the formulation is the inclusion of the preservative benzalkonium chloride (BAK) at a concentration of 0.015%. The presence of BAK has direct and significant clinical implications. BAK is a well-known quaternary ammonium compound used widely in ophthalmic preparations for its antimicrobial properties, which are essential for maintaining the sterility of multiple-dose containers. However, its use necessitates specific precautions for patients. It is known to be absorbed by soft contact lenses, which can lead to discoloration of the lenses and prolonged exposure of the ocular surface to the preservative. Consequently, patients must be instructed to remove their contact lenses before instilling the eye drops and to wait at least 15 minutes before reinsertion.

Furthermore, the choice of BAK as a preservative impacts the drug's tolerability profile, particularly in vulnerable patient populations. BAK can disrupt the tear film, cause ocular surface irritation, and exacerbate symptoms of dry eye disease. In patients with pre-existing conditions that compromise the cornea, such as corneal endothelial disease, the use of BAK-containing solutions requires additional caution and monitoring. This connection between a formulation excipient and specific clinical practice guidelines underscores the importance of considering the entire product, not just the active ingredient, when evaluating a medication's suitability for a patient.

The storage requirements for the product also reflect its chemical stability. Unopened bottles of the netarsudil ophthalmic solution must be stored under refrigeration at a temperature between 2°C and 8°C (36°F and 46°F). Once a bottle is opened, it may be stored either in the refrigerator or at room temperature (between 2°C and 25°C or 36°F and 77°F) for a period of up to six weeks.

3.0 Nonclinical and Clinical Pharmacology

3.1 Overview of Drug Class and Novelty

Netarsudil is the first approved therapeutic agent in the class of Rho kinase (ROCK) inhibitors for ophthalmic use, representing a significant innovation in the medical management of glaucoma. Glaucoma is a progressive optic neuropathy where elevated IOP is the primary modifiable risk factor. The pathophysiology of primary open-angle glaucoma (POAG), the most common form of the disease, is fundamentally linked to increased resistance to the outflow of aqueous humor through the trabecular meshwork (TM), also known as the conventional outflow pathway.

The novelty of netarsudil lies in its ability to directly target this diseased tissue. For decades, the mainstay of glaucoma therapy has involved medications that either decrease the production of aqueous humor (e.g., beta-blockers, carbonic anhydrase inhibitors, alpha-adrenergic agonists) or increase its drainage through the secondary, or uveoscleral, outflow pathway (e.g., prostaglandin analogs). While effective, these approaches do not address the primary cellular and structural dysfunction within the TM that causes elevated IOP. Netarsudil marks a paradigm shift by being the first medication designed to specifically restore function to the conventional outflow pathway, thereby addressing the root cause of elevated IOP in many patients. This targeted approach suggests a potential for not only symptomatic IOP control but also for modifying the disease process at a cellular level.

3.2 Mechanism 1: Rho Kinase (ROCK) Inhibition

The principal mechanism of action of netarsudil is the competitive inhibition of two isoforms of Rho-associated protein kinase, ROCK I and ROCK II. Rho kinases are crucial serine/threonine kinases that act as downstream effectors in the Rho GTPase signaling pathway, a fundamental regulator of the actin cytoskeleton, cell adhesion, and smooth muscle contraction. In the eye, the TM and Schlemm's canal (SC) cells exhibit smooth muscle-like properties, and their contractile tone is a key determinant of resistance to aqueous humor outflow.

In glaucomatous eyes, the TM is often characterized by increased cellular stiffness, excessive deposition of extracellular matrix proteins (fibrosis), and heightened contractile activity, all of which are mediated by the Rho/ROCK pathway. By inhibiting ROCK, netarsudil directly counteracts these pathological changes. Nonclinical studies have shown that netarsudil disrupts the formation of actin stress fibers and focal adhesions in TM cells and decreases the phosphorylation of myosin light chain, a key downstream marker of ROCK-mediated contractility. This leads to a profound relaxation of the TM and SC cells, reducing cellular stiffness and expanding the juxtacanalicular tissue spaces. This structural change increases the effective filtration area and significantly enhances the facility of aqueous humor outflow through the conventional pathway. Clinical studies in patients with POAG or OHT have confirmed this mechanism, demonstrating that treatment with netarsudil increases trabecular outflow facility by approximately 35% from baseline, an effect that accounts for the majority of its IOP-lowering activity. Additionally, by inhibiting ROCK, netarsudil has been shown to block the pro-fibrotic effects of transforming growth factor-beta 2 (TGF-β2) in TM cells, suggesting a potential to mitigate the chronic, fibrotic remodeling of the outflow pathway that characterizes glaucoma progression.

3.3 Mechanism 2: Norepinephrine Transporter (NET) Inhibition

In addition to its primary activity as a ROCK inhibitor, netarsudil also functions as a reversible inhibitor of the norepinephrine transporter (NET). The NET is a plasma membrane protein responsible for the reuptake of norepinephrine from the synaptic cleft into presynaptic neurons, thereby terminating its signaling activity.

By inhibiting NET in the ciliary body, netarsudil prevents this reuptake process. This leads to an increased local concentration and prolonged duration of action of endogenous norepinephrine at noradrenergic synapses. Norepinephrine acts on alpha-adrenergic receptors on the blood vessels supplying the ciliary processes, the site of aqueous humor production. The resulting enhanced signaling is thought to induce vasoconstriction, which in turn reduces blood flow to the ciliary body. This reduction in perfusion is believed to decrease the rate of aqueous humor formation, contributing a secondary, "inflow-reducing" component to netarsudil's overall IOP-lowering effect.

3.4 Mechanism 3: Reduction of Episcleral Venous Pressure (EVP)

A third, distinct mechanism contributing to netarsudil's efficacy is its ability to lower episcleral venous pressure (EVP). EVP is the pressure within the venous plexus that collects aqueous humor after it has passed through Schlemm's canal, and it represents the "floor" below which IOP cannot be lowered by improving outflow facility alone. Most glaucoma medications have little to no effect on EVP.

Netarsudil has been shown in both nonclinical and clinical studies to significantly reduce EVP. This effect is likely mediated by the same ROCK inhibition that acts on the TM. By causing vasodilation of the episcleral veins, netarsudil reduces the back-pressure against which aqueous humor must drain. A clinical study in patients with POAG or OHT measured a mean diurnal reduction in EVP of 0.79 mmHg following seven days of treatment with netarsudil. This unique ability to lower EVP provides an additional avenue for IOP reduction that is not accessible to most other drug classes. This triple-action synergy—enhancing conventional outflow, reducing aqueous production, and lowering EVP—makes netarsudil a uniquely comprehensive agent for IOP management. This is particularly relevant for patients in whom elevated EVP may be a significant contributor to their overall IOP, such as in cases of normal-tension glaucoma or certain secondary glaucomas.

4.0 Pharmacokinetics: Ocular and Systemic Disposition

The pharmacokinetic profile of netarsudil is ideally suited for a topical ophthalmic agent, engineered to maximize local drug delivery and activity at the target tissues within the eye while minimizing systemic exposure and its associated risks. This profile is a direct determinant of its clinical efficacy, safety, and dosing regimen.

4.1 Absorption and Distribution

Following topical administration as an eye drop, netarsudil is readily absorbed into the anterior segment of the eye, achieving high concentrations in the cornea and conjunctiva, the initial sites of contact and metabolism. The esterification of the parent molecule into the 2,4-dimethyl benzoate ester was a deliberate design choice to improve its lipophilicity and enhance its ability to penetrate the cornea.

In stark contrast to its high local concentration, the systemic absorption of netarsudil is negligible. This is a cornerstone of its favorable safety profile. A clinical pharmacology study involving healthy volunteers who received netarsudil 0.02% once daily in both eyes for eight days demonstrated this conclusively. Across all time points and all subjects, plasma concentrations of the parent drug, netarsudil, were not found to be above the lower limit of quantitation (LLOQ) of 0.100 ng/mL. Furthermore, out of 251 plasma samples analyzed for the active metabolite, only a single sample from one subject had a concentration above the LLOQ. This extremely low systemic exposure means that the drug is highly unlikely to exert any systemic pharmacological effects or participate in systemic drug-drug interactions. This provides a significant safety advantage over other classes of glaucoma medications, such as topical beta-blockers (e.g., timolol), which can be absorbed systemically and cause clinically significant cardiovascular and respiratory side effects like bradycardia and bronchospasm.

Both netarsudil and its active metabolite, AR-13503, exhibit a high degree of protein binding in plasma. The active metabolite is approximately 60% bound, and it is believed that the parent drug binds even more extensively. This high protein binding would further restrict the activity of any small amount of drug that does reach the systemic circulation, effectively sequestering it and preventing it from interacting with off-target receptors.

4.2 Metabolism

Netarsudil functions as a prodrug, meaning it is administered in an inactive form and is converted to its pharmacologically active form within the body. This conversion occurs locally within the eye. Upon penetrating the cornea, netarsudil is rapidly and efficiently hydrolyzed by esterase enzymes present in high concentrations in corneal tissue. This metabolic process cleaves the ester bond, releasing the active metabolite, AR-13503 (also referred to as netarsudil-M1), which is responsible for the drug's therapeutic effects as a ROCK and NET inhibitor.

This local bioactivation is a key pharmacokinetic feature. It ensures that the highest concentration of the active drug is generated directly at the intended site of action in the anterior segment of the eye. In vitro metabolism studies using human corneal tissue, human plasma, and human liver microsomes have confirmed that this esterase-mediated conversion is the primary metabolic pathway. These studies also showed that the active metabolite, AR-13503, does not undergo further detectable metabolism, and that esterase activity in human plasma was not detected over a three-hour incubation, reinforcing that the activation process is largely confined to the eye.

4.3 Elimination

The elimination kinetics of netarsudil have been characterized primarily through in vitro and animal studies due to the unquantifiable plasma levels in humans. In studies using in vitro human corneal tissue, the elimination half-life of the parent drug was determined to be approximately 175 minutes. Animal models provide further insight into the duration of action. In rabbits, the elimination half-life of the active metabolite is reported to be 16 to 17 hours. This prolonged half-life at the site of action supports a duration of effect lasting at least 24 hours, which provides the pharmacological rationale for the convenient once-daily dosing regimen recommended for patients. The combination of local activation, negligible systemic escape, and a prolonged local duration of action represents a highly optimized pharmacokinetic profile for a topical glaucoma medication.

5.0 Clinical Development Program and Efficacy Analysis

The clinical development of netarsudil was a comprehensive program involving multiple studies across all phases of clinical research, designed to establish the optimal dose, efficacy, and safety of the drug for reducing elevated IOP. The program culminated in the pivotal Phase 3 ROCKET trials, which provided the primary evidence for its regulatory approval.

5.1 Overview of Clinical Trials

The development program for netarsudil included ten completed clinical studies prior to its initial approval, comprising five Phase 1 or Phase 2 studies, four Phase 3 studies, and one observational study. Early phase studies were crucial for dose selection. A Phase 2 dose-ranging study (CS202) compared netarsudil 0.01% and 0.02% against latanoprost 0.005%. This study, along with another that also evaluated a 0.04% concentration, found that netarsudil 0.02% offered a similar efficacy profile to the 0.04% concentration but with superior tolerability. Based on this optimal balance of efficacy and safety, the 0.02% concentration administered once daily in the evening was selected to advance into the Phase 3 program. The clinical trial program has investigated netarsudil as both a monotherapy and as an adjunctive therapy in patients with OAG or OHT.

5.2 Pivotal Phase 3 Trials: ROCKET-1 and ROCKET-2

The cornerstone of the netarsudil efficacy data comes from two large, randomized, double-masked, multicenter, parallel-group, non-inferiority trials known as ROCKET-1 (NCT02246764) and ROCKET-2. These studies were designed to compare the IOP-lowering efficacy and safety of netarsudil 0.02% once daily (QD) with the well-established standard of care, timolol 0.5% twice daily (BID), over a three-month period. ROCKET-2 included an additional treatment arm of netarsudil 0.02% dosed BID. In total, 1167 patients with OAG or OHT were enrolled across the two studies after a washout of their prior ocular hypotensive medications.

The primary efficacy endpoint in these trials was the mean IOP measured at three specific time points (8:00 AM, 10:00 AM, and 4:00 PM) at Week 2, Week 6, and Month 3. The primary analysis was conducted on a specific per-protocol population of patients whose maximum baseline IOP after washout was less than 25 mmHg.

The results from these trials demonstrated that once-daily netarsudil produced clinically and statistically significant reductions in IOP from baseline (p<0.001). In the crucial primary efficacy population (baseline IOP <25 mmHg), netarsudil 0.02% QD was proven to be non-inferior to timolol 0.5% BID at all nine time points assessed through Month 3. In this population, the mean treated IOP across the nine time points ranged from 16.4 to 18.1 mmHg in the netarsudil group and from 16.8 to 17.6 mmHg in the timolol group.

A critical nuance emerged from the ROCKET-1 trial. In the overall intent-to-treat population, which included patients with baseline IOPs up to 27 mmHg, netarsudil did not meet the pre-specified criteria for non-inferiority to timolol. However, a post-hoc analysis of the subgroup with baseline IOPs below 25 mmHg did demonstrate non-inferiority, aligning with the primary findings of ROCKET-2. This finding suggests that the relative efficacy of netarsudil compared to timolol is most pronounced in patients with mild to moderate levels of IOP elevation. This is a key differentiator from other drug classes, such as prostaglandin analogs, which often exhibit their greatest absolute IOP reduction in patients with very high baseline pressures. This characteristic has important implications for the therapeutic positioning of netarsudil, highlighting its potential value in patient populations that have historically been more challenging to treat, such as those with normal-tension glaucoma or those who require additional IOP lowering from an already-treated, moderate baseline.

Table 2: Summary of Pivotal Phase 3 Clinical Trials (ROCKET-1 & ROCKET-2)

Trial Name	NCT ID	Design	Patient Population (N)	Treatment Arms	Primary Endpoint	Key Efficacy Result	Key Safety Finding	Source(s)
ROCKET-1	NCT02246764	Double-masked, randomized, non-inferiority	~411	1. Netarsudil 0.02% QD 2. Timolol 0.5% BID	Mean IOP at 9 time points through 3 months	Non-inferior to timolol in post-hoc analysis of patients with baseline IOP <25 mmHg.	Conjunctival hyperemia in 53% of netarsudil patients vs. 8% of timolol patients.
ROCKET-2	Not specified	Double-masked, randomized, non-inferiority	~756	1. Netarsudil 0.02% QD 2. Netarsudil 0.02% BID 3. Timolol 0.5% BID	Mean IOP at 9 time points through 3 months in patients with baseline IOP <25 mmHg	Netarsudil QD was non-inferior to timolol in the primary efficacy population (baseline IOP <25 mmHg).	Conjunctival hyperemia in 50% of netarsudil QD patients vs. 11% of timolol patients.

5.3 Efficacy in Specific Contexts

Beyond the pivotal trials, other studies have elucidated the efficacy of netarsudil in various clinical scenarios, further defining its role in glaucoma management.

Consistency Across Baseline IOPs: A unique and clinically important feature of netarsudil is its consistent IOP-lowering effect, irrespective of the patient's starting pressure. A Phase 1 study in healthy, normotensive volunteers (baseline IOP 14 to 20 mmHg) showed that netarsudil produced substantial and statistically significant IOP reductions, with a maximum reduction of 6 mmHg. This contrasts with many other glaucoma medications whose absolute effect diminishes as baseline IOP decreases. This property supports the potential utility of netarsudil in treating normal-tension glaucoma, a condition where optic nerve damage occurs despite IOPs being within the statistically "normal" range, and for which further lowering of pressure is the only proven treatment.

Adjunctive Therapy and Real-World Evidence: While the ROCKET trials established its efficacy as a monotherapy, in clinical practice, netarsudil is frequently prescribed as an adjunctive agent for patients who are not at their target IOP despite being on multiple other medications. A retrospective study evaluated the effectiveness of adding netarsudil to patients on maximally tolerated medical therapy (mean of 3.5 medications at baseline). In this challenging-to-treat population, the addition of netarsudil resulted in a mean IOP reduction of 3.53 mmHg, a 17% decrease from the treated baseline. Treatment success was achieved in 58% of eyes, allowing these patients to defer or avoid the need for laser or incisional surgery.

These findings were corroborated by a prospective, open-label, Phase 4 real-world study (NCT03808688). In this study, when netarsudil was added to an existing regimen of one or more IOP-lowering agents, it provided a mean additional IOP reduction of approximately 4.3 to 4.5 mmHg, representing a further 20-21% decrease in pressure. These studies confirm that netarsudil's unique mechanism of action provides an additive effect when combined with other classes of glaucoma drugs, making it a valuable tool for achieving lower IOP targets in complex cases.

6.0 Comprehensive Safety and Tolerability Profile

The safety and tolerability profile of netarsudil is distinctly characterized by a high frequency of local, ocular adverse reactions, which are generally mild and manageable, coupled with an exceptionally favorable systemic safety profile owing to its minimal systemic absorption. This dichotomy is central to understanding its clinical use and patient counseling.

6.1 Ocular Adverse Reactions

The vast majority of adverse events associated with netarsudil are confined to the eye. Data pooled from the pivotal ROCKET clinical trials provide a clear picture of the type and incidence of these events.

Conjunctival Hyperemia: This is the most frequently reported adverse reaction, occurring in 51% to 53% of patients receiving once-daily netarsudil. This rate is substantially higher than that observed with comparators like timolol (~8-11%). The hyperemia is a direct pharmacological effect attributed to the vasodilation of conjunctival blood vessels caused by ROCK inhibition. While cosmetically apparent, the redness was graded as mild in the majority of cases (77.6%) and was often sporadic. Despite its high incidence, it was the reason for treatment discontinuation in only 6% of patients, indicating that most patients found it tolerable.

Cornea Verticillata: Also known as vortex keratopathy, this condition was observed in approximately 17% to 20% of patients treated with netarsudil. It manifests as faint, golden-brown, whorl-like patterns of deposits in the basal layer of the corneal epithelium. These deposits were first noted after about four weeks of daily dosing. Importantly, this finding did not result in any apparent changes to visual function, such as reduced visual acuity, and was found to be reversible, with most cases resolving upon discontinuation of the medication.

Instillation Site Pain and Conjunctival Hemorrhage: Instillation site pain, described as burning or stinging upon application, was reported by approximately 17% to 20% of patients. Conjunctival hemorrhage, typically presenting as small, unilateral, petechial micro-hemorrhages near the limbus, was also a common finding, reported in 8% to 20% of patients.

Other Common Reactions: A number of other ocular side effects were reported in 5% to 10% of patients. These include instillation site erythema (redness), corneal staining, blurred vision, increased lacrimation (watery eyes), erythema of the eyelid, and a reduction in visual acuity.

Table 3: Incidence of Common Ocular Adverse Reactions (≥5%) from Controlled Clinical Studies

Adverse Reaction	Netarsudil 0.02% QD (%)	Timolol 0.5% BID (%)	Source(s)
Conjunctival Hyperemia	53	8-11
Cornea Verticillata	20	<1
Instillation Site Pain	20	Not specified
Conjunctival Hemorrhage	20	<1
Instillation Site Erythema	5-10	Not specified
Corneal Staining	5-10	Not specified
Blurred Vision	5-10	Not specified
Increased Lacrimation	5-10	Not specified
Erythema of Eyelid	5-10	Not specified
Reduced Visual Acuity	5-10	Not specified

6.2 Systemic Adverse Reactions

The systemic safety profile of netarsudil is excellent. As established by pharmacokinetic studies showing negligible systemic absorption, there are no known systemic safety issues associated with its topical ocular use. In pooled analyses of the Phase 3 trials, the frequency of treatment-related serious adverse events was extremely low and similar between the netarsudil (0.1%) and timolol (0%) groups. This lack of systemic side effects presents a clear clinical advantage, particularly when selecting therapy for patients with contraindications to other glaucoma medications, such as elderly patients or those with comorbid respiratory or cardiovascular conditions like asthma, COPD, or bradycardia, for whom beta-blockers are inappropriate. The clinical choice often involves a trade-off: accepting the high likelihood of cosmetic or minor comfort issues locally with netarsudil in exchange for the near-certainty of avoiding potentially serious systemic complications.

6.3 Warnings and Precautions

The prescribing information for netarsudil includes several warnings and precautions related to its use:

Epithelial Corneal Edema: Postmarketing surveillance has identified reports of epithelial corneal edema, sometimes described as having a honeycomb or bullous appearance. These events have occurred primarily in patients with pre-existing corneal conditions that could affect endothelial function, such as a history of corneal surgery or corneal stromal edema. The edema has been observed to resolve upon discontinuation of the drug. Patients should be advised to report any eye pain or decreased vision to their physician.

Bacterial Keratitis: As with all multiple-dose topical ophthalmic products, there is a risk of bacterial keratitis if the container is inadvertently contaminated by the patient. Patients must be counseled on proper administration techniques, including avoiding contact between the dropper tip and the eye or any other surface, to prevent contamination.

6.4 Contraindications

Netarsudil has a very favorable profile with regard to contraindications. The official prescribing information from the manufacturer lists "None" under the contraindications section. The only implicit contraindication is a known hypersensitivity to netarsudil or any of the excipients in the formulation, such as benzalkonium chloride.

6.5 Drug Interactions

Given the negligible systemic exposure following topical ocular administration, the potential for pharmacokinetic or pharmacodynamic drug-drug interactions with systemically administered medications is considered extremely low. Multiple drug interaction databases note no known severe, serious, moderate, or minor interactions for netarsudil ophthalmic solution. When used concomitantly with other topical ophthalmic drugs, they should be administered at least five minutes apart to avoid washout effects. It is important to note that the fixed-dose combination product containing netarsudil and latanoprost (Rocklatan) does carry potential moderate interactions associated with the latanoprost component, particularly with other prostaglandin analogs.

7.0 Dosage, Administration, and Special Populations

7.1 Recommended Dosing Regimen

The recommended dosage of netarsudil ophthalmic solution 0.02% is one drop instilled into the affected eye(s) once daily in the evening. The evening administration schedule is common for IOP-lowering medications and is intended to provide optimal pressure control throughout the night and into the following day.

Clinical trials investigated both once-daily and twice-daily dosing regimens. While twice-daily dosing provided a slightly greater reduction in IOP, it was associated with a substantially less favorable safety profile, including higher rates and increased severity of ocular adverse reactions. In a 12-month study, the discontinuation rate due to adverse reactions in the twice-daily group was 53.8%. Consequently, twice-daily dosing is not well tolerated and is not recommended.

If a patient misses a dose, they should be instructed to skip the missed dose and continue with their regular schedule by instilling the next dose the following evening. Patients should be explicitly counseled not to instill extra drops to make up for a missed dose, as this may increase the risk of side effects.

7.2 Administration Instructions

Proper administration technique is crucial for ensuring the efficacy and safety of any topical ophthalmic medication. Patients should be counseled on the following steps:

1. Wash hands thoroughly before use.
2. To prevent contamination, the tip of the dropper bottle should not touch the eye, eyelids, surrounding areas, or any other surface. Contamination of the solution can lead to bacterial keratitis, a serious eye infection that may result in vision loss.
3. Tilt the head back, look up, and gently pull down the lower eyelid to create a small pocket.
4. Squeeze the bottle to instill one drop into the pocket.
5. After instilling the drop, gently close the eye. Do not blink or rub the eye. Apply gentle pressure with a finger to the inner corner of the eye (over the tear duct) for one to two minutes. This technique, known as punctal occlusion, helps to maximize the drug's contact time with the eye and minimizes its drainage into the nasolacrimal system, thereby reducing the potential for systemic absorption.

Use with Contact Lenses: As the formulation contains benzalkonium chloride, which can be absorbed by soft contact lenses, patients must remove their lenses before administering the eye drops. They should wait at least 15 minutes after instillation before reinserting their lenses.

Concomitant Use with Other Ophthalmic Medications: If the patient is using more than one type of eye drop, the medications should be administered at least five minutes apart. This interval prevents the second drop from washing out the first, ensuring that each medication can be properly absorbed.

7.3 Use in Specific Populations

Pediatric Population: The safety and effectiveness of netarsudil have not been established in pediatric patients under the age of 18 years. Its use in this population is not recommended.

Geriatric Population: Glaucoma is most prevalent in the elderly. Clinical studies of netarsudil included a substantial number of older adults, and the results have not demonstrated any geriatric-specific problems that would limit its usefulness or require dosage adjustments in this population.

Pregnancy: There is a lack of adequate and well-controlled studies on the use of netarsudil in pregnant women. Given that systemic exposure to netarsudil following topical ocular administration is negligible, the risk to the fetus is anticipated to be low. Animal reproduction studies involving intravenous administration of netarsudil did not show adverse embryofetal effects at clinically relevant systemic exposures. However, at much higher doses (126-fold the plasma exposure at the recommended human dose), embryofetal lethality and other toxicities were observed in rats and rabbits. Therefore, netarsudil should be used during pregnancy only if the potential clinical benefit to the mother justifies the potential, albeit likely low, risk to the fetus.

Lactation: It is not known whether netarsudil or its metabolites are excreted in human milk. However, because maternal systemic exposure is negligible, it is unlikely that clinically significant amounts of the drug would be present in breast milk to affect a nursing infant. Until more data are available, caution should be exercised when administering netarsudil to a nursing woman, especially if the infant is a newborn or preterm. To further minimize potential exposure, the lactating mother can be advised to use punctal occlusion after instillation.

8.0 Comparative Assessment and Therapeutic Positioning

Netarsudil's entry into the glaucoma treatment landscape provided a novel mechanism of action, necessitating a careful assessment of its efficacy and safety relative to established therapies. Its unique profile defines its specific roles as a monotherapy, an adjunctive agent, and a component of a powerful fixed-dose combination.

8.1 Comparison with Timolol

Timolol, a non-selective beta-adrenergic antagonist, has long been a gold standard comparator in glaucoma clinical trials due to its consistent efficacy in reducing aqueous humor production. The pivotal ROCKET trials were designed to establish netarsudil's non-inferiority to timolol.

Efficacy: As detailed previously, netarsudil 0.02% QD was demonstrated to be non-inferior to timolol 0.5% BID in the specific population of patients with a baseline IOP below 25 mmHg. In longer-term (12-month) follow-up, the mean IOP reduction with once-daily netarsudil was slightly less than that with twice-daily timolol (final IOP of 18.8 mmHg for netarsudil vs. 17.6 mmHg for timolol from a baseline of ~22.5 mmHg).

Safety and Tolerability: The comparison reveals a starkly inverted safety profile. Netarsudil is associated with a very high rate of local ocular side effects, most notably conjunctival hyperemia (53% vs. ~10% for timolol), cornea verticillata (20% vs. <1%), and conjunctival hemorrhage (20% vs. <1%). In contrast, timolol is generally well-tolerated locally. However, timolol carries the risk of potentially serious systemic side effects due to systemic absorption, including bradycardia, hypotension, bronchospasm, fatigue, and depression. Netarsudil has no known systemic adverse effects. User-reported satisfaction ratings reflect this trade-off, with timolol generally receiving higher ratings than netarsudil (Rhopressa), likely due to the visible and symptomatic nature of netarsudil's ocular side effects.

8.2 Comparison with Latanoprost

Latanoprost, a prostaglandin analog (PGA), is the most widely prescribed first-line therapy for OAG. PGAs work by increasing aqueous humor outflow through the secondary, or uveoscleral, pathway.

Efficacy: Direct comparative data from a Phase 2 trial indicated that netarsudil 0.02% was approximately 1 mmHg less effective in mean diurnal IOP reduction compared to latanoprost 0.005% in a patient population with baseline IOPs ranging from 22 to 36 mmHg. This positions latanoprost and other PGAs as generally more potent monotherapy agents, particularly in patients with higher baseline pressures.

Mechanism: The mechanisms of netarsudil and latanoprost are highly complementary. Netarsudil primarily targets the conventional (trabecular) outflow pathway, while latanoprost targets the uveoscleral pathway. This creates a strong rationale for using the two agents in combination, as they address both major aqueous humor drainage routes simultaneously.

8.3 The Role of Rocklatan (Netarsudil/Latanoprost FDC)

The complementary nature of netarsudil and latanoprost led to the development of Rocklatan, a fixed-dose combination (FDC) product containing netarsudil 0.02% and latanoprost 0.005% in a single, once-daily evening drop. Approved by the FDA in March 2019, Rocklatan was developed to provide a more potent IOP-lowering option for patients who do not reach their target pressure with monotherapy.

Clinical trials (the MERCURY series) demonstrated that Rocklatan provides a statistically significant and clinically meaningful greater IOP reduction than either netarsudil or latanoprost administered alone. The combination product lowered IOP by an additional 2.0 to 2.3 mmHg compared to latanoprost monotherapy. This superior efficacy establishes a clear role for the combination product. While netarsudil as a monotherapy may be considered a second-line option for some patients, its greatest clinical utility may be realized when combined with a PGA. This strategy leverages its unique mechanism to augment the effect of the most potent first-line agents, creating a powerful dual-outflow therapy that can help more patients achieve their target IOPs and potentially delay the need for more invasive procedures.

8.4 Therapeutic Positioning

Based on its complete clinical profile, netarsudil can be positioned in several key roles within the glaucoma treatment algorithm:

First-Line Monotherapy: While PGAs remain the dominant first-line choice, netarsudil is a viable alternative for specific patients. This includes individuals with contraindications or intolerance to PGAs, or those with contraindications to beta-blockers (e.g., patients with asthma, COPD, or bradycardia) for whom netarsudil's systemic safety is a paramount advantage. It may also be a particularly suitable first-line option for patients with normal-tension glaucoma, given its efficacy at lower baseline pressures and its unique effect on EVP.

Adjunctive Therapy: This is a very common role for netarsudil in clinical practice. For patients already on a PGA or other medications who require additional IOP lowering, adding netarsudil provides a mechanistically distinct and additive effect. Its demonstrated efficacy in patients on maximally tolerated medical therapy makes it a crucial tool to intensify treatment before escalating to laser trabeculoplasty or incisional surgery.

Component of FDC Therapy: For patients requiring a substantial IOP reduction from the outset, or for those who fail to reach target on PGA monotherapy, the Rocklatan FDC offers a convenient and highly effective option that combines two complementary mechanisms in a single drop, which can also improve patient adherence.

9.0 Regulatory and Commercialization Landscape

9.1 Regulatory Approval History

Netarsudil's journey to market was marked by key regulatory milestones in major global markets.

United States (FDA): The New Drug Application (NDA) for Rhopressa® (netarsudil ophthalmic solution) 0.02% was submitted by Aerie Pharmaceuticals, Inc.. Following a positive 9-1 vote in its favor from an FDA advisory committee, the drug received early approval from the U.S. Food and Drug Administration on December 18, 2017. It was approved for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. This marked the approval of the first new class of glaucoma drug in the U.S. in approximately two decades. Subsequently, the fixed-dose combination product, Rocklatan® (netarsudil/latanoprost), was approved by the FDA on March 12, 2019.

Europe (EMA): The European Medicines Agency (EMA) approved netarsudil in 2019 for the same indications. In the European Union, the drug is marketed under the brand name Rhokiinsa®. The fixed-dose combination is marketed as Roclanda®.

9.2 Manufacturer and Commercial Partners

Originator and Manufacturer: Netarsudil was discovered and developed by Aerie Pharmaceuticals, Inc., an ophthalmic pharmaceutical company. The foundational basic science research that identified Rho kinase as a promising therapeutic target for lowering IOP was conducted at Duke Ophthalmology. Aerie Pharmaceuticals established its own sterile fill production facility in Athlone, Ireland, which received FDA approval to manufacture both Rhopressa® and Rocklatan® for commercial distribution in the United States and for global supply.

Commercialization Partners: Aerie Pharmaceuticals has pursued a strategy of global expansion through strategic partnerships. In October 2020, Aerie entered into a collaboration with Santen Pharmaceutical Co., Ltd., a leading global ophthalmology company, for the development and commercialization of netarsudil products in Japan and East Asia. This partnership was expanded in December 2021 to grant Santen exclusive commercialization rights for Rhopressa®/Rhokiinsa® and Rocklatan®/Roclanda® in Europe, China, and several other regions. Under this agreement, Aerie is responsible for manufacturing and supplying the products to Santen from its facility in Ireland. In the United States, recent product information indicates a commercial relationship with Alcon Inc., as evidenced by the copyright notice (©2024 Alcon Inc.) on the official Rhopressa® patient website.

9.3 Brand Names and Global Availability

To accommodate different regulatory and marketing environments, netarsudil and its combination product are sold under distinct brand names in the United States and Europe:

• United States: The monotherapy product is named Rhopressa®, and the fixed-dose combination with latanoprost is Rocklatan®.
• European Union: The monotherapy product is named Rhokiinsa®, and the fixed-dose combination is Roclanda®.

10.0 Conclusion and Future Perspectives

Netarsudil represents a landmark therapeutic advance in the field of ophthalmology and the management of glaucoma. As the first-in-class Rho kinase (ROCK) inhibitor approved for this indication, it introduced a fundamentally new mechanism of action that directly targets the pathophysiology of the diseased trabecular meshwork, the primary site of outflow resistance in open-angle glaucoma. Its unique, triple-action mechanism—enhancing conventional outflow, reducing aqueous humor production, and lowering episcleral venous pressure—provides a comprehensive approach to intraocular pressure reduction within a single molecule.

The clinical value of netarsudil is defined by a distinct risk-benefit profile. Its efficacy, particularly as an additive therapy and in its fixed-dose combination with latanoprost, is well-established, providing clinicians with a powerful tool to help more patients achieve their target IOPs. This is complemented by an exceptional systemic safety profile, a direct result of its negligible systemic absorption, which makes it a valuable option for patients with systemic comorbidities that preclude the use of other drug classes, such as beta-blockers. However, this systemic safety is balanced against a high incidence of local, ocular adverse events, most notably conjunctival hyperemia. While these effects are typically mild and manageable for most patients, they require careful counseling and monitoring to ensure patient comfort and adherence.

The development of netarsudil has successfully shifted the therapeutic paradigm toward targeting the conventional outflow pathway. Its greatest impact may ultimately lie in its role in combination therapy, where its complementary mechanism synergizes with prostaglandin analogs to create a potent dual-outflow treatment.

Looking forward, the success of targeting the ROCK pathway in glaucoma opens avenues for further research. The anti-fibrotic properties of ROCK inhibitors suggest a potential for disease-modifying effects that could slow the long-term structural degradation of the trabecular meshwork, a possibility that warrants investigation in long-term clinical studies. Furthermore, the unique pharmacology of netarsudil suggests potential applications in other ocular conditions, such as steroid-induced glaucoma, where trabecular meshwork dysfunction is prominent , and potentially in corneal endothelial disorders. The long-term impact of netarsudil will be measured not only by its ability to lower IOP but also by whether its unique, pathophysiology-targeted approach translates into superior, long-term preservation of the optic nerve and visual field for millions of patients worldwide.

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