Epinastine: A Comprehensive Pharmacological and Clinical Monograph

1.0 Abstract

Epinastine is a second-generation, topically active antihistamine and mast cell stabilizer classified as a small molecule drug. It is distinguished by a multi-faceted mechanism of action that includes potent, direct antagonism of the histamine H1-receptor and inhibition of histamine release from mast cells. This dual activity provides both immediate and sustained relief from allergic symptoms. While it possesses affinity for other receptors, including H2, adrenergic, and serotonergic sites, its physicochemical properties prevent it from crossing the blood-brain barrier, resulting in a non-sedating profile that is a hallmark of its class. The primary approved therapeutic indication for its ophthalmic formulation is the prevention of ocular itching associated with allergic conjunctivitis. Clinical studies have demonstrated a rapid onset of action and a duration of effect that supports a convenient twice-daily dosing regimen. Pharmacokinetically, topical administration leads to high local concentrations in the tear film with minimal systemic absorption, which, combined with its limited metabolism, results in a favorable safety profile with a very low risk of systemic side effects or drug-drug interactions. Epinastine is generally well-tolerated, with the most common adverse events being localized ocular effects. It is available globally under various brand names, and in the United States, generic formulations are marketed following the discontinuation of the original brand, Elestat®.

2.0 Chemical Identity and Physicochemical Properties

Epinastine is a synthetic small molecule drug belonging to the chemical classes of tetracyclic guanidines and benzazepines.[1] It was first synthesized in 1975 and subsequently developed as a potent agent with significant H1-antihistaminic properties.[1] The active pharmaceutical ingredient used in clinical formulations is the hydrochloride salt, Epinastine HCl, which enhances its stability and solubility for administration.[5]

Its chemical structure is formally described as a benzazepine, specifically 6,11-dihydro-5H-dibenzo[b,e]azepine, in which the azepine ring is fused with a 4,5-dihydro-1H-imidazole-2-amine moiety.[2] This complex, multi-ring structure is fundamental to its pharmacological activity and pharmacokinetic profile.

For unambiguous identification across scientific and regulatory databases, Epinastine is cataloged under numerous identifiers. The Chemical Abstracts Service (CAS) has assigned the number 80012-43-7 to the parent compound and 108929-04-0 to the hydrochloride salt.[1] Its IUPAC name is (RS)-3-amino-9,13b-dihydro-1H-dibenz(c,f)imidazo(1,5-a)azepine, reflecting its stereochemistry as a racemic mixture.[1] The molecular formula for the parent base is

C16​H15​N3​, with a corresponding molecular weight of 249.31 g/mol.[9] The hydrochloride salt has the formula

C16​H15​N3​⋅HCl (or C16​H16​ClN3​) and a molecular weight of 285.78 g/mol.[6]

The Anatomical Therapeutic Chemical (ATC) Classification System assigns Epinastine the codes R06AX24 for systemic use as an antihistamine and S01GX10 for ophthalmic use.[9] A comprehensive list of these and other key identifiers is provided in Table 2.1.

Table 2.1: Epinastine Chemical and Database Identifiers

Identifier Type	Value	Source(s)
Common Name	Epinastine	9
Drug Type	Small Molecule
IUPAC Name	(RS)-3-amino-9,13b-dihydro-1H-dibenz(c,f)imidazo(1,5-a)azepine	1
CAS Number (Parent)	80012-43-7	1
CAS Number (HCl Salt)	108929-04-0	6
DrugBank ID	DB00751	1
PubChem CID	3241	1
ChEMBL ID	CHEMBL1106	1
UNII (Parent)	Q13WX941EF	1
Molecular Formula (Parent)	C16​H15​N3​	9
Molecular Weight (HCl Salt)	285.78 g/mol	7
ATC Codes	R06AX24, S01GX10	1

3.0 Pharmacology and Mechanism of Action

3.1 Overview of Pharmacological Class

Epinastine is pharmacologically classified as a second-generation antihistamine.[1] This classification is pivotal, as it distinguishes Epinastine from older, first-generation agents (e.g., diphenhydramine) primarily by its inability to readily cross the blood-brain barrier, thereby avoiding sedative side effects.[12] Beyond this defining characteristic, Epinastine possesses a multi-faceted anti-allergic profile that includes mast cell stabilizing properties and activity against several other inflammatory mediators, rendering it a highly effective agent for managing allergic conditions.[3]

3.2 Multi-Modal Mechanism of Action

The therapeutic efficacy of Epinastine stems from a synergistic combination of at least three distinct, yet complementary, mechanisms that target different stages of the allergic cascade.

Direct H1-Receptor Antagonism: The primary mechanism is its function as a potent, topically active, and direct histamine H1-receptor antagonist.[5] Histamine, released from mast cells upon allergen exposure, binds to H1 receptors on nerve endings and blood vessels, triggering the classic symptoms of itching (pruritus) and vasodilation (leading to redness and swelling). Epinastine competitively binds to these H1 receptors, physically blocking histamine and thereby preventing or alleviating these symptoms.[6] This action provides rapid symptomatic relief.

Mast Cell Stabilization: Epinastine is also a potent inhibitor of histamine release from mast cells; it is a mast cell stabilizer.[1] This prophylactic mechanism prevents the degranulation of mast cells in response to an allergen-IgE trigger.[3] The stabilization is thought to occur via the modulation of delayed chloride channels in the mast cell membrane, which are critical for the degranulation process.[15] By preventing the release of histamine and other pre-formed inflammatory mediators (e.g., proteases) in the first place, this action helps to suppress the initiation and progression of the allergic response.[12]

Additional Anti-inflammatory Activities: Epinastine’s anti-allergic activity is broader than that of a simple antihistamine. It has been shown to possess anti-leukotriene, anti-Platelet-Activating Factor (anti-PAF), and anti-bradykinin activities.[3] These mediators are involved in the later phases of the allergic reaction, contributing to sustained inflammation, vascular permeability, and recruitment of other immune cells. Furthermore, Epinastine has been shown to suppress the immune responses of Th-2 cells through the functional modulation of dendritic cells, which are key players in the development of allergic immune responses.[12] This comprehensive suppression of multiple inflammatory pathways contributes to its robust clinical efficacy.

3.3 Receptor Binding Profile and Selectivity

A detailed analysis of Epinastine's receptor binding profile reveals a high degree of selectivity for its primary target, which is crucial for its efficacy and favorable side effect profile.

Primary Target (H1 Receptor): Epinastine demonstrates a very high binding affinity for the histamine H1-receptor.[1] In vitro binding assays have determined its half-maximal inhibitory concentration (

IC50​) to be 9.8 nM. This affinity is notably higher than that of other potent second-generation antihistamines, such as terfenadine (IC50​ = 77 nM) and astemizole (IC50​ = 15 nM), indicating greater potency at its target site.[17]

Secondary and Low-Affinity Targets: While highly selective for the H1-receptor, Epinastine does interact with other receptors, though with significantly lower affinity. Its affinity for the histamine H2-receptor is approximately 400 times lower than for the H1-receptor.[4] It also possesses a marked affinity for adrenergic

α1​- and α2​-receptors, as well as serotonergic 5-HT2​ receptors.[5] Conversely, it has a low affinity for muscarinic (cholinergic), dopaminergic, and

β-adrenergic receptors, which accounts for the absence of common anticholinergic side effects (e.g., dry mouth, blurred vision) and other off-target effects associated with less selective antihistamines.[13]

3.4 Pharmacodynamic Properties and Clinical Significance

The pharmacodynamic properties of Epinastine are a direct result of its mechanism of action and receptor binding profile, translated into clinically relevant outcomes.

Non-Sedating Profile: The most significant pharmacodynamic advantage of Epinastine is its non-sedating profile.[6] While its affinity for adrenergic and serotonergic receptors could theoretically cause CNS effects like drowsiness, this is prevented by its molecular structure.[17] Epinastine is a polar molecule that exists in a cationic (positively charged) state at physiological pH.[3] These physicochemical properties prevent it from effectively penetrating the blood-brain barrier.[1] Positron emission tomography (PET) studies have confirmed that Epinastine hardly penetrates the human brain, making it one of the most CNS-impermeable antihistamines.[4] This represents a "safety by design" feature, where the drug's pharmacokinetic distribution physically excludes it from the central compartment, thereby preventing potential CNS side effects that might otherwise arise from its pharmacodynamic receptor profile. Its pharmacological actions are thus almost exclusively confined to peripheral tissues where they are needed.

Cardiovascular Safety: A critical safety concern with some early second-generation antihistamines (terfenadine, astemizole) was their potential to cause life-threatening cardiac arrhythmias by blocking the delayed rectifier potassium current (IKr​), which is conducted by the HERG channel. Electrophysiological studies have clearly demonstrated that Epinastine does not inhibit this cardiac potassium channel, even at concentrations 1000 times higher than those at which terfenadine and astemizole show marked inhibition.[4] This lack of effect on cardiac repolarization means Epinastine does not carry the risk of cardiotoxicity or QT interval prolongation, a crucial safety advantage.[3]

4.0 Pharmacokinetics and Metabolism (ADME)

The pharmacokinetic profile of Epinastine is characterized by its route of administration, with topical ophthalmic application resulting in a distinct absorption, distribution, metabolism, and excretion (ADME) pattern that is central to its efficacy and safety.

4.1 Absorption and Bioavailability

Ophthalmic Administration: When administered as a 0.05% ophthalmic solution, Epinastine is designed for local action with minimal systemic absorption.[17] Following instillation, the drug rapidly reaches high concentrations in the tear film, the target site for treating allergic conjunctivitis. A study in patients with allergic conjunctivitis found that tear concentrations peaked rapidly, with a mean maximum concentration (

Cmax​) of 27.1 µg/mL.[17] In stark contrast, systemic exposure is extremely low. The mean plasma

Cmax​ following twice-daily dosing was only 0.042 ± 0.014 ng/mL, reached at a Tmax​ of approximately 1.8 hours.[17] This pharmacokinetic profile—high local concentration and negligible systemic load—is ideal for a topical therapy, maximizing efficacy at the site of action while minimizing the risk of systemic adverse effects.

Oral Administration: For comparison, oral formulations of Epinastine (10-20 mg tablets), which are available in some international markets, are readily absorbed and result in much higher systemic exposure. The maximum plasma concentration following oral administration is approximately 10 ng/mL, which is over 200 times higher than that observed with ophthalmic dosing.[4]

4.2 Distribution

Plasma Protein Binding: Once in the systemic circulation, Epinastine is moderately bound to plasma proteins, with a binding fraction of 64%.[1]

CNS Penetration and Tissue Distribution: As established pharmacodynamically, Epinastine's polarity and charge prevent it from crossing the blood-brain barrier, a key element of its second-generation classification and non-sedating profile.[1] Preclinical studies in animals have also shown that Epinastine binds to melanin and can accumulate in pigmented ocular tissues, such as the iris and choroid.[18] This binding is moderate and reversible and may act as a depot, potentially contributing to its sustained duration of action in the eye.[18]

4.3 Metabolism

Epinastine undergoes very limited metabolic biotransformation in humans.[12] Less than 10% of an administered dose is metabolized, with the vast majority of the drug being eliminated in its unchanged, active form.[5] In vitro incubation studies using recombinant cytochrome P450 (CYP) isoforms have identified that the minor metabolism that does occur is primarily mediated by CYP3A4 and CYP2D6, with a minor contribution from CYP2B6.[17] The minimal reliance on metabolic clearance is a significant advantage, as it reduces the potential for variability in drug levels due to genetic polymorphisms in CYP enzymes or drug-drug interactions involving these pathways.

4.4 Excretion

The primary route of elimination for Epinastine is excretion of the unchanged drug.[5] Following an intravenous dose in healthy subjects, approximately 55-57.5% of the dose is recovered unchanged in the urine, and about 30-33.5% is recovered in the feces.[5] The total systemic clearance is approximately 56 L/hr, and the terminal plasma elimination half-life is about 12 hours.[1]

The pharmacokinetic characteristics of the ophthalmic formulation form the basis of its exceptional safety profile. The extremely low systemic absorption ensures that plasma concentrations remain far below the threshold required to cause systemic side effects or to saturate metabolic pathways. This, combined with the fact that the drug is minimally metabolized and primarily excreted unchanged, virtually eliminates the risk of clinically significant systemic drug-drug interactions. For patients, particularly the elderly or those on multiple medications (polypharmacy), this predictable and clean pharmacokinetic profile makes Epinastine ophthalmic solution a very safe therapeutic choice.

5.0 Clinical Efficacy and Therapeutic Applications

5.1 Approved Indication: Prevention of Itching in Allergic Conjunctivitis

In the United States and many other jurisdictions, the sole approved indication for Epinastine 0.05% ophthalmic solution is the prevention of itching associated with allergic conjunctivitis.[5] Allergic conjunctivitis is an inflammatory condition of the eye's surface triggered by airborne allergens, leading to symptoms of itching, redness, tearing, and swelling.[14]

The clinical efficacy of Epinastine for this indication has been robustly established in well-controlled clinical trials. A key model used to evaluate efficacy is the conjunctival antigen challenge (CAC), where a known allergen is instilled into the eyes of allergic subjects to provoke a reaction. In these studies, Epinastine HCl 0.05% was shown to be significantly superior to the vehicle (placebo eye drops) in improving ocular itching.[5]

A critical aspect of its clinical performance is its rapid onset of action. The CAC studies demonstrated that Epinastine begins to relieve itching within 3 to 5 minutes after administration, providing fast relief for patients.[3] The duration of its therapeutic effect has been shown to be at least 8 hours, which provides sustained protection and makes a twice-daily dosing regimen clinically appropriate and convenient.[3] Furthermore, its efficacy is maintained over extended periods of use; clinical trials have shown it to be safe and effective for up to 8 weeks of continuous treatment without any evidence of tachyphylaxis (a diminishing response to the drug over time).[7]

The prescribing information consistently emphasizes that Epinastine is intended for prophylactic use. Patients are advised to continue treatment throughout the period of allergen exposure (e.g., for the entire pollen season), even on days when symptoms are absent.[8] This recommendation is directly linked to its dual mechanism of action. While the H1-receptor antagonism provides immediate relief from existing symptoms, the mast cell stabilizing effect is preventative.[15] By continuously stabilizing mast cells, the drug prevents the release of histamine and other mediators upon subsequent allergen exposure. Therefore, using the drops only "as-needed" when symptoms arise would fail to leverage this crucial prophylactic component of its mechanism, leading to suboptimal therapeutic outcomes. Effective patient counseling on the importance of adherence to the continuous, twice-daily regimen is essential for maximizing the clinical benefits of Epinastine.

5.2 International and Alternative Formulations/Uses

While the United States has only approved the ophthalmic formulation, Epinastine is available in other dosage forms in over 15 Asian and European countries.[17] Oral tablets, typically in 10 mg and 20 mg strengths, and oral syrups are used for the systemic treatment of various allergic diseases.[4] These indications include chronic urticaria, psoriasis vulgaris, other pruritic dermatoses, and allergic rhinitis, where its systemic antihistaminic properties are leveraged.[4] In addition, an intranasal formulation of Epinastine was under consideration for development in the United States and Canada for the treatment of rhinitis, aiming to build on the success of the ocular form.[25]

5.3 Emerging Research

Innovation in drug delivery for Epinastine continues. A novel 0.5% topical eyelid cream (development code STN1011402) has been developed as an alternative to traditional eye drops.[26] This formulation is designed to be applied to the skin of the upper and lower eyelids. The drug is then absorbed transdermally through the thin eyelid skin to reach the conjunctiva, where it exerts its therapeutic effect.[26] This novel route of administration could offer an improved user experience for patients who find instilling eye drops difficult or uncomfortable.

6.0 Safety, Tolerability, and Risk Profile

Epinastine ophthalmic solution is generally well-tolerated, with a safety profile characterized by predominantly mild, localized adverse effects and a low risk of systemic complications.

6.1 Adverse Drug Reactions

The adverse reactions associated with Epinastine are categorized as ocular (local) and non-ocular (systemic), with ocular effects being the most common.

Table 6.1: Reported Adverse Reactions and Frequencies

System Organ Class	Frequency	Adverse Reaction	Source(s)
Ocular	Common (1-10%)	Burning sensation in the eye	5
		Folliculosis (conjunctival follicles)	5
		Hyperemia (eye redness)	5
		Pruritus (itching)	5
	Postmarketing	Increased lacrimation (watery eyes)	8
Non-Ocular	Common (~10%)	Infection (cold symptoms, upper respiratory infections)	5
	Uncommon (1-3%)	Headache	5
		Rhinitis (runny nose)	5
		Sinusitis	5
		Increased cough	5
		Pharyngitis (sore throat)	5

The most frequently reported ocular adverse events, occurring in approximately 1% to 10% of patients, are local reactions at the site of administration. These include a transient burning or stinging sensation upon instillation, folliculosis, hyperemia, and pruritus.[5] It can be difficult to distinguish some of these symptoms, such as itching and redness, from the underlying allergic conjunctivitis being treated.[14]

The most common non-ocular adverse event is infection, reported in approximately 10% of patients and described as cold symptoms or upper respiratory tract infections.[5] It is noted that these events were often similar to the underlying disease being studied.[8] Less frequent systemic effects, seen in 1% to 3% of patients, include headache, rhinitis, sinusitis, increased cough, and pharyngitis.[5] Postmarketing experience has also identified increased lacrimation as a reported side effect.[8]

6.2 Contraindications, Warnings, and Precautions

Contraindications: The primary contraindication for Epinastine ophthalmic solution is a history of hypersensitivity to Epinastine hydrochloride or any of the other ingredients in the formulation.[7]

Warnings and Precautions:

• Contact Lens Use: A significant precaution relates to the use of the product by contact lens wearers. The ophthalmic solution contains benzalkonium chloride (BAK) as a preservative, which can be absorbed by soft contact lenses and may cause discoloration.[5] Patients must be instructed to remove their contact lenses prior to instilling the drops and to wait at least 10 to 15 minutes before reinserting them.[20] Importantly, Epinastine ophthalmic solution should not be used to treat contact lens-related irritation, and patients should not wear contact lenses if their eyes are red.[14]
• Contamination of Solution: To prevent microbial contamination of the solution, patients must be counseled to avoid allowing the tip of the dropper bottle to touch the eye, eyelids, surrounding structures, or any other surface.[20] Using a contaminated solution can lead to serious ocular infections, such as bacterial keratitis, and subsequent vision loss.[5]
• Topical Use Only: The solution is for topical ophthalmic use only and must not be injected or ingested.[19]

6.3 Use in Specific Populations

• Pregnancy: The U.S. Food and Drug Administration (FDA) has assigned Epinastine to Pregnancy Category C.[1] This designation is based on animal reproduction studies where adverse effects were observed at very high oral doses (e.g., reduced pup body weight gain in rats and fetal resorptions in rabbits at doses thousands of times higher than the maximum recommended ocular human dose).[5] There are no adequate and well-controlled studies in pregnant women. Therefore, Epinastine ophthalmic solution should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.[5]
• Lactation: It is not known whether Epinastine is excreted in human breast milk following ophthalmic administration. However, studies in lactating rats have shown that the drug is excreted in their milk.[7] Because many drugs are excreted in human milk, caution should be exercised when administering Epinastine to a nursing woman.[7]
• Pediatric Use: The safety and efficacy of Epinastine ophthalmic solution have been established in pediatric patients aged 2 years and older in the United States.[21] Some product labeling specifies an age limit of 3 years and older.[5] European labeling may be more restrictive, with some indications for adolescents 12 years of age and older.[23] Safety and effectiveness in children below the age of 2 have not been established.[21]
• Geriatric Use: Clinical studies have not revealed any overall differences in safety or effectiveness between elderly and younger adult patients.[7] No dosage adjustment is necessary for this population.
• Renal and Hepatic Impairment: Given the minimal systemic absorption and metabolism of the topically administered drug, no dosage adjustments are considered necessary for patients with renal or hepatic impairment.[19]

6.4 Drug Interaction Profile

Due to the extremely low systemic concentrations of Epinastine achieved following topical ophthalmic dosing, clinically significant systemic drug-drug interactions are not anticipated.[13] No formal drug interaction studies have been conducted with the ophthalmic formulation.[18] The low potential for interaction is a significant safety advantage, particularly in patients taking multiple systemic medications.

6.5 Nonclinical Toxicology

A comprehensive battery of nonclinical toxicology studies has been conducted to assess the long-term safety of Epinastine.

• Carcinogenicity: In 18-month and 2-year dietary carcinogenicity studies in mice and rats, respectively, Epinastine was not found to be carcinogenic at doses up to 40 mg/kg. This dose is approximately 30,000 times higher than the maximum recommended ocular human dose (MROHD) on a mg/kg basis, assuming 100% absorption.[5]
• Mutagenicity and Clastogenicity: Epinastine was found to be negative for mutagenicity in the Ames/Salmonella assay and in an in vitro chromosome aberration assay using human lymphocytes. It was also negative in in vivo clastogenicity studies, including the mouse micronucleus assay and a chromosome aberration assay in Chinese hamsters.[5] These results indicate that Epinastine does not have the potential to cause genetic mutations or damage chromosomes.
• Impairment of Fertility: Epinastine had no effect on the fertility of male rats. A decrease in fertility was observed in female rats, but only at an oral dose approximately 90,000 times the MROHD.[7]

7.0 Formulations, Dosage, and Administration

7.1 Ophthalmic Formulation Analysis

Epinastine is commercially available for ophthalmic use as a sterile, isotonic solution of Epinastine Hydrochloride at a concentration of 0.05%.[5] This corresponds to 0.5 mg of Epinastine HCl per mL of solution, which is equivalent to 0.44 mg/mL of the Epinastine free base.[5]

The formulation is a clear, colorless liquid with a pH of approximately 7 and an osmolality range of 250 to 310 mOsm/kg, making it physiologically compatible with the tear film.[5] In addition to the active ingredient, the solution contains several excipients that ensure its stability, sterility, and tolerability. These inactive ingredients include [5]:

• Preservative: Benzalkonium chloride (0.01% or 0.1 mg/mL)
• Chelating Agent: Edetate disodium
• Tonicity Agent: Sodium chloride
• Buffering Agents: Sodium phosphate (monobasic or dihydrogen phosphate dihydrate)
• pH Adjusters: Sodium hydroxide and/or hydrochloric acid
• Vehicle: Purified water (or water for injection)

The product is supplied sterile in opaque white low-density polyethylene (LDPE) plastic bottles with integrated dropper tips and sealed with high-impact polystyrene (HIPS) or polypropylene (PP) caps.[5] Common fill volumes are 5 mL or 10 mL.[5] The product should be stored at controlled room temperature, typically between 15°C and 25°C (59°F to 77°F), and the bottle should be kept tightly closed when not in use and protected from light.[5] Once opened, the contents should typically be used within 4 weeks to ensure sterility.[23]

7.2 Dosage, Administration, and Patient Counseling

Recommended Dosage: The standard recommended dosage for both adults and pediatric patients (aged 2 years and older in the US) is one drop instilled into each affected eye twice daily, typically in the morning and evening.[8] As a preventative therapy, treatment should be continued throughout the period of allergen exposure, even on days when symptoms are absent, to maintain control of the allergic response.[8]

Method of Administration: The product is for topical ophthalmic use only.[20] Proper administration technique is crucial for safety and efficacy. Patients should be instructed to:

1. Wash their hands thoroughly before use.[35]
2. Tilt their head back and gently pull down the lower eyelid to form a small pouch.[35]
3. Instill one drop into the pouch without allowing the dropper tip to touch the eye, eyelid, fingers, or any other surface to avoid contamination.[20]
4. Close the eye and apply gentle pressure to the inner corner (near the nose) for about one minute to minimize systemic absorption by blocking the nasolacrimal duct.

Patient Counseling: Key counseling points for patients include:

• The importance of consistent, twice-daily use for prevention, rather than only using the drops when symptoms are present.[8]
• Detailed instructions on contact lens wear: remove lenses before use and wait at least 10-15 minutes before reinserting them.[20]
• A reminder not to use the product to treat irritation caused by contact lenses and not to wear lenses if the eye is red.[14]
• The importance of not contaminating the dropper tip.[20]
• To report any new or worsening eye pain, redness, or irritation to their healthcare provider.[35]

8.0 Regulatory Status and Market Landscape

8.1 United States Approval and Market History

In the United States, Epinastine HCl 0.05% ophthalmic solution was first approved by the Food and Drug Administration (FDA) on October 16, 2003, under the brand name Elestat®.[33] The New Drug Application (NDA 21-565) was submitted by Allergan, and the drug was approved for the prevention of itching associated with allergic conjunctivitis.[37]

The commercial lifecycle of Epinastine in the US illustrates a common trajectory for successful pharmaceutical products. After a period of market exclusivity, the FDA approved several generic versions of Epinastine HCl 0.05% ophthalmic solution under Abbreviated New Drug Applications (ANDAs).[33] For example, ANDAs have been approved for manufacturers such as Sun Pharmaceutical Industries and Somerset Therapeutics.[33] Elestat® served as the Reference Listed Drug (RLD), the standard to which these generic products had to demonstrate bioequivalence.[37] Following the entry of lower-cost generics into the market, the brand-name Elestat® formulation was eventually discontinued by Allergan.[37] This discontinuation appears to be a commercial decision driven by market dynamics rather than any safety or efficacy concerns, as the drug remains a validated and prescribed therapy in its generic forms.

8.2 European Union National Authorizations

Epinastine is widely available across the European Union, where it has been authorized in numerous member states through the Mutual Recognition Procedure (MRP) or Decentralised Procedure (DCP), under the reference number SE/H/0315/001.[39] The marketing authorization holder for most of these products is AbbVie or one of its national subsidiaries.[39] Unlike in the US, branded versions of the drug remain prominent in the European market.

Table 8.1: International Brand Names and Authorization Status

Region/Country	Brand Name(s)	Regulatory Status & Notes	Source(s)
United States	Elestat® (discontinued), Epinastine HCl (generic)	FDA approved (Initial: Oct 16, 2003). Brand discontinued; multiple generics available.	33
European Union		Nationally authorised via MRP/DCP.	39
- Germany, Spain, Sweden, Ireland	Relestat	MAH: AbbVie	39
- France, Czech Republic	Purivist	MAH: AbbVie	39
- Greece	Optallerg	MAH: Verisfield (UK) Ltd	39
Other	Alesion®, Flurinol®, Epinas®, Talerc®	Available as oral tablets/syrup in over 15 Asian and European countries.	1

8.3 Regulatory Status in Other Jurisdictions

Australia: The provided documentation, which describes the function of Australia's Therapeutic Goods Administration (TGA) and its public database, the Australian Register of Therapeutic Goods (ARTG), does not contain any specific records indicating that Epinastine has been approved for supply in Australia.[41] Searches of the ARTG within the context of the available materials did not yield any results for Epinastine, suggesting it may not be a registered therapeutic good in that country.

9.0 Expert Analysis and Concluding Remarks

Epinastine stands as a well-established and clinically valuable agent in the therapeutic armamentarium for allergic conjunctivitis. Its enduring relevance is anchored in a compelling combination of potent efficacy, a multi-modal mechanism of action, and an exceptional safety profile that has been validated over two decades of clinical use.

The primary strength of Epinastine lies in its dual mechanism. By acting as both a direct H1-receptor antagonist and a mast cell stabilizer, it addresses the allergic response at two critical junctures. The H1-blockade provides rapid relief from acute symptoms like itching, with an onset of action within minutes, while the mast cell stabilization offers a prophylactic effect, preventing the release of inflammatory mediators upon subsequent allergen exposure. This comprehensive approach, further augmented by its activity against other mediators like leukotrienes and PAF, provides robust and sustained control of the allergic cascade.

From a safety perspective, Epinastine exemplifies the advantages of a second-generation antihistamine. Its molecular design—specifically its polarity and charge at physiological pH—prevents CNS penetration, a "safety by design" feature that ensures a non-sedating profile. This is a crucial advantage for patient quality of life, allowing for effective symptom control without cognitive impairment. Furthermore, its lack of interaction with cardiac potassium (IKr​) channels distinguishes it from older agents and confirms its excellent cardiovascular safety profile. The pharmacokinetic profile of the ophthalmic formulation is nearly ideal for a topical agent: it achieves high, therapeutically effective concentrations at the ocular surface while resulting in negligible systemic absorption. This, combined with its minimal metabolism, renders the risk of systemic side effects or drug-drug interactions exceptionally low, making it a safe choice for a broad range of patients, including those on complex medication regimens.

The limitations associated with Epinastine are not intrinsic to the molecule itself but are related to the formulation. The most common adverse events are mild and transient local ocular effects, such as a burning sensation upon instillation. The inclusion of the preservative benzalkonium chloride (BAK) necessitates specific precautions for contact lens wearers, which requires careful patient education. The development of alternative delivery systems, such as the investigational topical eyelid cream, represents a potential avenue to mitigate these formulation-related challenges and improve the patient experience.

In conclusion, Epinastine is a potent, rapid-acting, and highly safe topical therapy for allergic conjunctivitis. Its well-understood pharmacology, predictable pharmacokinetics, and extensive clinical validation underscore its position as a first-line therapeutic option. The transition to a generic market in the United States has ensured its continued accessibility, solidifying its role as a cornerstone of treatment for ocular allergic disease.

Works cited

1. Epinastine - Wikipedia, accessed September 23, 2025, https://en.wikipedia.org/wiki/Epinastine
2. www.ncbi.nlm.nih.gov, accessed September 23, 2025, https://www.ncbi.nlm.nih.gov/books/NBK557538/#:~:text=The%20chemical%20structure%20of%20epinastine,%2Dimidazole%2D2%2Damine.
3. Epinastine - StatPearls - NCBI Bookshelf, accessed September 23, 2025, https://www.ncbi.nlm.nih.gov/sites/books/n/statpearls/article-21247/
4. EPINASTINE: AN UPDATE OF ITS PHARMACOLOGY, METABOLISM, CLINICAL EFFICACY AND TOLERABILITY IN THE TREATMENT OF ALLERGIC DISEASES, accessed September 23, 2025, https://access.portico.org/Portico/show?viewFile=pdf&auId=pjbf7dd63zp
5. Page 3 ELESTAT™ (epinastine HCl ophthalmic solution) 0.05 ..., accessed September 23, 2025, https://s3-us-west-2.amazonaws.com/drugbank/fda_labels/DB00751.pdf?1265922794
6. Epinastine Hydrochloride | C16H16ClN3 | CID 157313 - PubChem, accessed September 23, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Epinastine-Hydrochloride
7. NDA 21-565/S-005 Page 2 ELESTAT™ (epinastine HCl ophthalmic solution) 0.05% Sterile DESCRIPTION ELESTAT™ (epinastine HCl op - accessdata.fda.gov, accessed September 23, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021565s005lbl.pdf
8. Epinastine Hydrochloride Ophthalmic Solution (Epinastine Hydrochloride): Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed September 23, 2025, https://www.rxlist.com/epinastine-hydrochloride-drug.htm
9. Epinastine - brand name list from Drugs.com, accessed September 23, 2025, https://www.drugs.com/ingredient/epinastine.html
10. Epinastine | CAS 80012-43-7 | SCBT - Santa Cruz Biotechnology, accessed September 23, 2025, https://www.scbt.com/p/epinastine-80012-43-7
11. Epinastine | CAS#80012-43-7 | antihistamine | MedKoo, accessed September 23, 2025, https://www.medkoo.com/products/43941
12. Pharmacokinetic Comparison of Epinastine Using Developed Human Plasma Assays, accessed September 23, 2025, https://www.mdpi.com/1420-3049/25/1/209
13. Epinastine hydrochloride for atopic disease - PubMed, accessed September 23, 2025, https://pubmed.ncbi.nlm.nih.gov/15510239/
14. Epinastine Ophthalmic: MedlinePlus Drug Information, accessed September 23, 2025, https://medlineplus.gov/druginfo/meds/a604011.html
15. Epinastine - StatPearls - NCBI Bookshelf, accessed September 23, 2025, https://www.ncbi.nlm.nih.gov/books/NBK557538/
16. www.ncbi.nlm.nih.gov, accessed September 23, 2025, https://www.ncbi.nlm.nih.gov/books/NBK557538/#:~:text=Epinastine%20causes%20the%20cessation%20of,the%20degranulation%20of%20mast%20cells.
17. 21-565 Elestat Clinical Pharmacology Biopharmaceutics Review - accessdata.fda.gov, accessed September 23, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-565_Elestat_BioPharmr.pdf
18. Summary of Product Characteristics - HPRA, accessed September 23, 2025, https://assets.hpra.ie/products/Human/15489/Licence_PA1824-018-001_19062025124143.pdf
19. Summary of Product Characteristics - HPRA, accessed September 23, 2025, https://assets.hpra.ie/products/Human/33046/LicenseSPC_PPA1328-196-001_05022014170039.pdf
20. Epinastine | Drug Lookup | Pediatric Care Online, accessed September 23, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/5666/Epinastine
21. Epinastine (ophthalmic route) - Side effects & dosage - Mayo Clinic, accessed September 23, 2025, https://www.mayoclinic.org/drugs-supplements/epinastine-ophthalmic-route/description/drg-20063663
22. EPINASTINE HYDROCHLORIDE solution - DailyMed, accessed September 23, 2025, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cafe4650-6aa4-4466-9beb-064ee5a0e401
23. Relestat, 0.5 mg/ml, eye drops, solution. - Summary of Product Characteristics (SmPC), accessed September 23, 2025, https://www.medicines.org.uk/emc/product/29/smpc
24. Epinastine Ophthalmic Dosage Guide + Max Dose, Adjustments ..., accessed September 23, 2025, https://www.drugs.com/dosage/epinastine-ophthalmic.html
25. Arls 12/31/05 Inspire Pharmaceuticals Inc - SEC.gov, accessed September 23, 2025, https://www.sec.gov/Archives/edgar/vprr/0603/06033497.pdf
26. Safety and efficacy of a novel 0.5% epinastine topical eyelid cream in allergic conjunctivitis: a phase 3 trial - PMC, accessed September 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11607043/
27. Elestat vs. Azelastine for Allergic Conjunctivitis: Important Differences and Potential Risks., accessed September 23, 2025, https://www.goodrx.com/compare/elestat-vs-azelastine
28. Epinastine: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed September 23, 2025, https://www.rxlist.com/epinastine/generic-drug.htm
29. Epinastine Hydrochloride 0.05% Eye Drops - Aristopharma Ltd, accessed September 23, 2025, https://aristopharma.com/upload/product_pdf/1649742243.pdf
30. Epinastine ophthalmic Uses, Side Effects & Warnings - Drugs.com, accessed September 23, 2025, https://www.drugs.com/mtm/epinastine-ophthalmic.html
31. Ophthalmics for Allergic Conjunctivitis Review - Medicaid.nv.gov, accessed September 23, 2025, https://www.medicaid.nv.gov/Downloads/provider/NVRx_DCR_20110623_Ophthalmic_Antihistamines.pdf
32. Therapeutic Class Overview - Ophthalmic Antihistamines - Medicaid.nv.gov, accessed September 23, 2025, https://www.medicaid.nv.gov/Downloads/provider/Ophthalmic_Antihistamines_2017-06.pdf
33. EPINASTINE HYDROCHLORIDE - FDA Drug Approval Details - MedPath, accessed September 23, 2025, https://trial.medpath.com/drug/approvals/fda/11b9c53fb7ce6f29
34. EPINASTINE HYDROCHLORIDE - FDA Approval - MedPath, accessed September 23, 2025, https://trial.medpath.com/drug/approvals/fda/0269866a73c8a32d
35. Epinastine eye solution - Cleveland Clinic, accessed September 23, 2025, https://my.clevelandclinic.org/health/drugs/19446-epinastine-eye-solution
36. Epinastine (Into the eye) - Allina Health account, accessed September 23, 2025, https://account.allinahealth.org/library/content/45/4790
37. Generic Elestat Availability - Drugs.com, accessed September 23, 2025, https://www.drugs.com/availability/generic-elestat.html
38. 21-565 Elestat Medical Review - accessdata.fda.gov, accessed September 23, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-565_Elestat_Medr.pdf
39. epinastine: List of nationally authorised medicinal products - PSUSA ..., accessed September 23, 2025, https://www.ema.europa.eu/en/documents/psusa/epinastine-list-nationally-authorised-medicinal-products-psusa00001231202210_en.pdf
40. en.wikipedia.org, accessed September 23, 2025, [https://en.wikipedia.org/wiki/Epinastine#:~:text=Epinastine%20(brand%20names%20Alesion%2C%20Elestat,drops%20to%20treat%20allergic%20conjunctivitis.](https://www.google.com/url?q=https://en.wikipedia.org/wiki/Epinastine%23:~:text%3DEpinastine%2520(brand%2520names%2520Alesion%252C%2520Elestat,drops%2520to%2520treat%2520allergic%2520conjunctivitis.&sa=D&source=editors&ust=1758629900922319&usg=AOvVaw1sFYbWM_3kofB2rht-fRwx)
41. Therapeutic Goods Administration (TGA) | Australian Government Department of Health, Disability and Ageing, accessed September 23, 2025, https://www.tga.gov.au/
42. TGA – Therapeutic Goods Administration - Healthdirect, accessed September 23, 2025, https://www.healthdirect.gov.au/partners/tga-therapeutic-goods-administration
43. Australian Register of Therapeutic Goods (ARTG) | Therapeutic ..., accessed September 23, 2025, https://www.tga.gov.au/products/australian-register-therapeutic-goods-artg