A Comprehensive Monograph on Bepotastine (DB04890): From Molecular Structure to Clinical Application

Executive Summary

Bepotastine is a second-generation piperidine antihistamine distinguished by a multi-faceted pharmacological profile that provides comprehensive relief from allergic symptoms. As a small molecule therapeutic, it is identified by DrugBank ID DB04890 and CAS Number 125602-71-3. Its clinical application demonstrates a notable regional divergence: in the United States, it is approved and marketed exclusively as a 1.5% topical ophthalmic solution under the brand name Bepreve™ for the treatment of ocular itching associated with allergic conjunctivitis. In Japan, it has a longer history of use as an oral tablet (Talion®) for systemic allergic conditions, including allergic rhinitis and urticaria.

The high efficacy of Bepotastine stems from a synergistic triple-action mechanism. It functions as a potent and highly selective antagonist of the histamine H1 receptor, a stabilizer of mast cells that inhibits the release of histamine and other inflammatory mediators, and an inhibitor of eosinophil migration into inflamed tissues. This combination effectively targets both the early- and late-phase responses of a type 1 hypersensitivity reaction.

Pharmacokinetically, the ophthalmic formulation is characterized by minimal systemic absorption, which is the cornerstone of its excellent safety and tolerability profile. The most common adverse event is a mild taste in the mouth, a direct result of nasolacrimal drainage, which paradoxically also contributes to a beneficial reduction in associated nasal allergy symptoms. Due to its low systemic exposure and minimal metabolism via the cytochrome P450 system, the ophthalmic solution has a very low potential for clinically significant drug-drug interactions.

Developed initially in Japan, Bepotastine's journey to the U.S. market involved a series of licensing agreements and corporate acquisitions, culminating in its FDA approval in 2009. The patent exclusivity for Bepreve™ has since expired, leading to the availability of multiple generic formulations and reflecting a typical pharmaceutical product lifecycle. Bepotastine represents a modern, rationally designed anti-allergy agent, offering rapid and sustained relief with a favorable safety profile, particularly in its topical ophthalmic formulation.

Chemical Identity and Physicochemical Properties

The precise identification and characterization of a drug substance's chemical and physical properties are fundamental to understanding its formulation, stability, and biological activity. Bepotastine is a well-defined small molecule with a specific stereochemical configuration that is critical to its therapeutic function.

Nomenclature and Identifiers

To ensure unambiguous identification across scientific literature, regulatory databases, and clinical practice, Bepotastine is cataloged under a variety of systematic names and unique identifiers. The most common name is Bepotastine.[1]

Its systematic International Union of Pure and Applied Chemistry (IUPAC) name is 4-piperidin-1-yl]butanoic acid.[4] This name precisely describes its molecular architecture, including the critical (S)-stereochemistry at the chiral center. The Chemical Entities of Biological Interest (ChEBI) database further defines it as an ether derivative of (S)-(4-chlorophenyl)(pyridin-2-yl)methanol.[7]

The most crucial identifiers for the active pharmaceutical ingredient (API) are:

• CAS Number: 125602-71-3 (for the Bepotastine free base).[2]
• DrugBank ID: DB04890.[1]
• PubChem CID: 164522.[8]

The clinically marketed form is a salt, bepotastine besilate (benzenesulfonate), which has its own set of identifiers:

• CAS Number: 190786-44-8.[5]
• PubChem CID: 164521.[5]
• UNII (Unique Ingredient Identifier): 6W18MO1QR3.[5]

Additional database cross-references include KEGG ID D01654 and ChEBI ID CHEBI:31281.[5]

Molecular Structure and Formula

The molecular structure of Bepotastine contains a piperidine ring linked to a butanoic acid chain and an ether group that incorporates a chlorophenyl ring and a pyridine ring. The specific spatial arrangement of these groups is essential for its high-affinity binding to the histamine H1 receptor.

The development of Bepotastine as a single, stereochemically pure isomer is a key feature of its design. The consistent specification of the (S)-enantiomer in its chemical nomenclature and structural representations indicates that the pharmacological activity resides predominantly in this specific isomer.[4] This approach is common in modern drug development to optimize the therapeutic index by eliminating a less active or potentially non-beneficial enantiomer. The existence of "(R)-Bepotastine" as a distinct chemical entity further underscores this stereospecificity.[4]

The molecular formulas and weights for the free base and the clinically relevant besilate salt are distinct, a critical consideration for dosage calculations and formulation. The selection of the besilate salt form for the commercial product, Bepreve™, is a deliberate pharmaceutical strategy. Salt formation is often employed to improve the physicochemical properties of a drug, such as aqueous solubility and stability. The fact that Bepreve™ is a sterile, aqueous 1.5% solution strongly implies that the besilate salt confers the necessary solubility to create a stable and effective ophthalmic product, a significant improvement over the likely properties of the free base.[9]

The key structural and molecular details are summarized in Table 1.

Table 1: Key Chemical and Physicochemical Properties of Bepotastine

Property	Bepotastine (Free Base)	Bepotastine Besilate (Salt)	Source(s)
IUPAC Name	4-piperidin-1-yl]butanoic acid	benzenesulfonic acid;4-piperidin-1-yl]butanoic acid	4
CAS Number	125602-71-3	190786-44-8	2
DrugBank ID	DB04890	DB04890	1
Molecular Formula	C21​H25​ClN2​O3​	C27​H31​ClN2​O6​S (or C21​H25​ClN2​O3​⋅C6​H6​O3​S)	2
Molecular Weight	388.89 g/mol	547.06 g/mol (daltons)	2
Isomeric SMILES	OC(=O)CCCN1CCC(CC1)O[C@H](c1ccccn1)c1ccc(cc1)Cl	C1CN(CCC1O[C@@H](C2=CC=C(C=C2)Cl)C3=CC=CC=N3)CCCC(=O)O.C1=CC=C(C=C1)S(=O)(=O)O	5

Physical and Chemical Characteristics

The macroscopic properties of the Bepotastine API are relevant for its handling, formulation, and storage. As a solid, Bepotastine free base is described as a white to pale beige solid.[7] The besilate salt, used in the final drug product, is a white or pale yellowish crystalline powder.[9]

Key physical properties include:

• Melting Point: 56 - 58°C.[7]
• Boiling Point (Predicted): 546.8±50.0 °C.[7]
• Density (Predicted): 1.26 g/cm³.[7]
• Solubility: The free base is slightly soluble in dimethyl sulfoxide (DMSO) and methanol.[7] The besilate salt is sufficiently soluble in water to produce the 1.5% (15 mg/mL) aqueous ophthalmic solution.[9]
• Storage: The powdered API is recommended to be stored at -20°C in a freezer under an inert atmosphere to ensure long-term stability.[2]

The final formulated product, Bepreve™ ophthalmic solution, is a sterile, aqueous solution with a pH of 6.8 and an osmolality of approximately 290 mOsm/kg, making it physiologically compatible with the eye.[9]

Comprehensive Pharmacological Profile

The therapeutic utility of Bepotastine is derived from its sophisticated and multi-faceted interaction with the biological pathways of allergic inflammation. Its classification as a second-generation antihistamine is based on a combination of high receptor selectivity and a favorable pharmacokinetic profile that minimizes undesirable central nervous system effects.

Mechanism of Action

Bepotastine exerts its anti-allergic effects through a combination of at least three distinct and complementary mechanisms, allowing it to effectively intervene at multiple points in the allergic cascade. This "triple-action" mechanism provides a more comprehensive therapeutic effect than older, single-action antihistamines. It addresses both the immediate symptoms of the early-phase allergic reaction, which are primarily driven by histamine, and the sustained inflammation of the late-phase reaction, which involves the recruitment of immune cells like eosinophils.

1. Histamine H1 Receptor Antagonism: The primary and most direct action of Bepotastine is as a potent, selective, and direct antagonist of the histamine H1 (H1) receptor.[1] During a type 1 hypersensitivity reaction, allergens cross-link IgE antibodies on the surface of mast cells, triggering their degranulation and the release of histamine.[1] Histamine then binds to H1 receptors on vascular endothelial cells and nerve endings, causing the classic symptoms of allergy: vasodilation (redness), increased vascular permeability (swelling, chemosis), and stimulation of sensory nerves (itching, or pruritus).[14] By competitively blocking the H1 receptor, Bepotastine prevents histamine from binding and initiating this cascade, thereby directly alleviating these key symptoms.[15]
2. Mast Cell Stabilization: Beyond simply blocking the effects of histamine, Bepotastine also acts as a mast cell stabilizer.[1] It inhibits the degranulation of mast cells, thereby preventing the release of histamine and other pre-formed and newly synthesized pro-inflammatory mediators, such as leukotrienes and prostaglandins.[9] This mechanism acts upstream of H1 receptor antagonism, helping to suppress the allergic response at its origin and providing a prophylactic effect.
3. Anti-Inflammatory Effects: Bepotastine demonstrates broader anti-inflammatory activity by suppressing the migration and infiltration of eosinophils into inflamed tissues.[1] Eosinophils are key effector cells in the late-phase allergic reaction, typically occurring hours after initial allergen exposure. Their recruitment and activation perpetuate the inflammatory cycle and can lead to chronic tissue damage.[16] By inhibiting eosinophil chemotaxis, Bepotastine helps to quell this late-phase response, preventing the worsening of allergic inflammation in the conjunctiva.[16] Further evidence of its anti-inflammatory properties includes the inhibition of leukotriene B4 and proinflammatory interleukin-5 (IL-5), a key cytokine for eosinophil development and survival.[7]

Pharmacodynamics

The pharmacodynamic profile of Bepotastine is characterized by its high receptor selectivity and a rapid, durable clinical effect.

Receptor Selectivity: A defining feature of Bepotastine as a second-generation antihistamine is its high selectivity for the H1 receptor.[19] It exhibits minimal to no affinity for other physiologically important receptors, including serotonin, muscarinic, benzodiazepine, and beta-adrenergic receptors.[1] This selectivity is the molecular basis for its favorable side-effect profile. Lack of interaction with muscarinic receptors means it does not cause anticholinergic side effects like dry mouth or blurred vision. More importantly, its inability to significantly cross the blood-brain barrier and its lack of affinity for central nervous system receptors prevent the sedation and somnolence commonly associated with first-generation antihistamines.[1]

Onset and Duration of Action: Clinical data demonstrate that Bepotastine has a rapid onset of action, with patients reporting relief from ocular itching within minutes of ophthalmic administration.[15] The therapeutic effect is also durable. Clinical trials using the conjunctival allergen challenge (CAC) model have shown that a single dose of the ophthalmic solution provides significant relief from ocular pruritus for at least 8 hours, with some studies demonstrating efficacy maintained for up to 16 hours.[6] This sustained duration of action supports the convenient twice-daily dosing regimen for the ophthalmic product.[12]

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of Bepotastine is fundamentally dependent on the route of administration. The profound difference in systemic exposure between the topical ophthalmic and systemic oral formulations is the most critical factor governing the drug's safety profile, potential for drug interactions, and distinct clinical applications.

Absorption:

• Ophthalmic Route: When administered as a 1.5% ophthalmic solution, systemic absorption of Bepotastine is minimal.[1] In a study where healthy adults received one drop in both eyes four times daily (a dose higher and more frequent than the recommended regimen), the mean peak plasma concentration ( Cmax​) was only 7.3±1.9 ng/mL.[1] The time to reach this peak concentration ( Tmax​) was approximately 1 to 2 hours post-instillation.[1] Within 24 hours, plasma concentrations in most subjects had fallen below the lower limit of quantification (2 ng/mL), confirming low systemic exposure and rapid clearance.[1]
• Oral Route: In contrast, oral administration leads to high systemic bioavailability.[6] A single 10 mg oral dose of bepotastine besilate resulted in a mean Cmax​ of 99.9±31.4 ng/mL, which is more than 13 times higher than that observed with the ophthalmic route.[21]

Distribution:

Once in the systemic circulation, Bepotastine exhibits moderate binding to plasma proteins, with a bound fraction of approximately 55.4%.1 This binding is independent of the drug's plasma concentration.1 Animal studies in rats have shown that orally administered Bepotastine can be distributed into breast milk and can also cross the placenta to the fetus.22

Metabolism:

Bepotastine undergoes very limited metabolism in the body.1

In vitro studies using human liver microsomes have demonstrated that it is only minimally metabolized by the cytochrome P450 (CYP) family of enzymes.[9] Furthermore, Bepotastine does not significantly inhibit the activity of major CYP isozymes, including CYP3A4, CYP2C9, and CYP2C19, at clinically relevant concentrations.[9] This metabolic profile indicates a very low potential for drug-drug interactions mediated by the CYP system.

Excretion:

The primary route of elimination for Bepotastine is renal excretion.6 Following an oral dose, a substantial majority of the drug—approximately 75% to 90%—is excreted unchanged in the urine within 24 hours.1 The systemic elimination half-life is relatively short, at approximately 2.5 hours, contributing to its rapid clearance from the body.1 This heavy reliance on renal clearance for the systemically absorbed drug means that dose adjustments may be necessary for the oral formulation in patients with moderate-to-severe renal impairment.19 However, due to the minimal systemic exposure from the ophthalmic solution, renal impairment is not a significant clinical concern for patients using the eye drops.

The stark contrast in pharmacokinetic parameters between the two main formulations is summarized in Table 2. This comparison clearly illustrates why the safety and clinical considerations for the topical and systemic forms of Bepotastine are vastly different.

Table 2: Summary of Pharmacokinetic Parameters of Bepotastine

Parameter	Ophthalmic Formulation (1.5% Solution)	Oral Formulation (~10 mg)	Source(s)
Systemic Bioavailability	Minimal (<1.5%)	High	1
Tmax​ (Peak Time)	~1-2 hours	Not Specified (fast onset)	1
Cmax​ (Peak Concentration)	7.3±1.9 ng/mL	99.9±31.4 ng/mL	9
Plasma Protein Binding	~55%	~55%	1
Primary Metabolism	Minimal (non-CYP mediated)	Minimal (non-CYP mediated)	1
Primary Excretion Route	Renal (for absorbed fraction)	Renal	1
% Excreted Unchanged	Not Applicable	75-90%	1
Elimination Half-Life	~2.5 hours	~2.5 hours	1

Clinical Efficacy and Therapeutic Applications

The clinical development and application of Bepotastine have followed distinct paths in different global regions, leading to its establishment as both a specialized topical therapy and a broad-spectrum systemic anti-allergy medication. Its efficacy is supported by a robust program of clinical trials.

Approved Indications and Formulations

United States: In the U.S., Bepotastine is approved by the Food and Drug Administration (FDA) solely for ophthalmic use. The specific indication is for the treatment of ocular itching (pruritus) associated with the signs and symptoms of allergic conjunctivitis (AC).[1]

• Product: Bepreve™ (bepotastine besilate ophthalmic solution) 1.5% w/v.[9]
• Dosage Form: A sterile, topical ophthalmic solution (eye drops).[9]
• Availability: It is available by prescription only and is approved for use in adults and children aged 2 years and older.[26]

Japan: Bepotastine was first commercialized in Japan, where it is approved for systemic use in oral tablet form.

• Product: Talion®.[1]
• Indications: Allergic rhinitis (AR) and urticaria/pruritus associated with various skin diseases (e.g., eczema/dermatitis).[1]

This divergence in regulatory approval and marketing highlights a strategic approach to drug development, where an existing molecule with a proven systemic profile in one market (Japan) was repurposed and reformulated for a high-value, specialized topical application in another (the U.S.).

Summary of Clinical Trials

The efficacy of Bepotastine for its various indications has been validated through a series of Phase 2 and Phase 3 clinical trials. This evidence base confirms its therapeutic benefit in treating key allergic conditions.

Allergic Conjunctivitis (AC): The U.S. approval of Bepreve™ was based on robust data from multiple clinical trials.

• Completed Phase 3 trials, such as NCT00586664 ("Efficacy and Safety Study of Bepotastine Besilate Ophthalmic Solution in Allergic Conjunctivitis"), demonstrated the superiority of Bepotastine over placebo in relieving ocular itching.[29]
• A completed Phase 2 trial (NCT01174823) also confirmed its safety and efficacy in patients with seasonal allergic conjunctivitis.[30]
• A key finding from these studies was that the ophthalmic solution provided a rapid and sustained reduction in ocular itch for at least 8 hours after a single dose.[6]

Perennial Allergic Rhinitis (PAR): The oral formulation's efficacy for allergic rhinitis, supporting its approval in Japan, was investigated in several trials.

• A series of completed Phase 3 trials (NCT01900054, NCT01425632, NCT01861522) evaluated the long-term safety and efficacy of oral Bepotastine (identified as TAU-284) in pediatric patients with perennial allergic rhinitis.[31]

Table 3: Overview of Pivotal Clinical Trials for Bepotastine

Trial Identifier	Phase	Condition	Formulation	Purpose / Key Finding	Source(s)
NCT00586664	3	Allergic Conjunctivitis (AC)	Ophthalmic Solution	To evaluate the efficacy and safety of Bepotastine for treating AC symptoms. Confirmed reduction in ocular itch.	29
NCT01174823	2	Seasonal Allergic Conjunctivitis	Ophthalmic Solution	To evaluate the safety and efficacy of Bepotastine in seasonal AC patients.	30
NCT01900054	3	Perennial Allergic Rhinitis (PAR)	Oral (TAU-284)	To evaluate the long-term safety of Bepotastine in pediatric patients with PAR.	31
NCT01425632	3	Perennial Allergic Rhinitis (PAR)	Oral (TAU-284)	A confirmatory study of Bepotastine's efficacy in pediatric patients with PAR.	31

Efficacy on Nasal Symptoms from Ophthalmic Administration: A particularly noteworthy finding emerged from exploratory analyses of the allergic conjunctivitis trials. Despite being a topical eye drop, Bepreve™ demonstrated a statistically significant ability to alleviate concurrent nasal symptoms associated with allergic rhinitis.[14] Reductions were observed in rhinorrhea (runny nose), nasal pruritus (nasal itching), and nasal congestion.[18] This effect provides a significant clinical advantage, as allergic rhinitis and conjunctivitis are frequently co-morbid conditions. The proposed mechanism for this benefit is the drainage of the instilled medication from the ocular surface through the nasolacrimal duct into the nasal cavity, where it can exert its anti-allergic effects directly on the nasal mucosa.[14] This transforms Bepotastine from a simple eye drop into a potential monotherapy for the broader condition of allergic rhinoconjunctivitis, potentially simplifying treatment regimens for affected patients.

Dosing and Administration

Proper administration of the ophthalmic solution is crucial for achieving optimal efficacy and minimizing potential side effects and contamination.

Ophthalmic Solution (Bepreve™ 1.5%):

• Dosage: The recommended dosage for adults and children 2 years of age and older is one drop instilled into each affected eye twice daily (BID).[9]
• Administration Technique: Patients should be instructed on the correct procedure for instilling eye drops to ensure safety and effectiveness.[27] This includes:

1. Washing hands thoroughly before use.
2. Avoiding contact between the dropper tip and the eye, eyelids, or any other surface to prevent contamination of the solution.[20]
3. Gently pulling down the lower eyelid to create a small pocket and instilling a single drop.
4. After instillation, closing the eye for 1-2 minutes and applying gentle pressure to the tear duct (nasolacrimal occlusion).[26] This technique helps to maximize the drug's residence time on the ocular surface and minimizes its drainage into the systemic circulation, which can reduce the incidence of systemic side effects like the mild taste in the mouth.

• Concurrent Use of Ophthalmic Products: If a patient is using other topical eye medications, it is recommended to wait at least 5 minutes between the administration of each product to prevent washout and ensure proper absorption.[26]

Safety, Tolerability, and Risk Management

The safety profile of Bepotastine, particularly its ophthalmic formulation, is well-established and favorable, characterized by primarily local and mild adverse effects. A comprehensive understanding of its tolerability, contraindications, and potential interactions is essential for safe and effective clinical use.

Adverse Effects Profile

Bepotastine ophthalmic solution is generally well-tolerated. The majority of adverse reactions are mild and transient.

Table 4: Incidence of Reported Adverse Reactions with Bepotastine Ophthalmic Solution 1.5%

System Organ Class	Adverse Reaction	Frequency / Incidence (%)	Source(s)
Nervous System Disorders	Mild taste (Dysgeusia)	~25%	27
Nervous System Disorders	Headache	2-5%	20
Eye Disorders	Eye irritation	2-5%	20
Respiratory, Thoracic and Mediastinal Disorders	Nasopharyngitis	2-5%	17
Immune System Disorders	Hypersensitivity reactions (rash, itching, swelling)	Incidence not known	20

The most common adverse reaction, a mild taste in the mouth, is a direct consequence of the drug's anatomy-driven pathway from the eye. After instillation, a portion of the solution drains through the nasolacrimal duct into the nasopharynx, where it can be tasted. This same physiological route is responsible for the beneficial therapeutic effect on nasal allergy symptoms, creating a unique situation where the primary side effect and a secondary therapeutic benefit share a common mechanism.

Use in Specific Populations

• Pediatric Use: The safety and effectiveness of Bepreve™ have been established in pediatric patients aged 2 years and older.[27] For children between 2 and 10 years of age, efficacy was extrapolated from data in older pediatric patients and adults.[6] Use in children under the age of 2 has not been studied.[27]
• Geriatric Use: Clinical studies have not revealed any overall differences in safety or effectiveness between elderly patients (over 65 years of age) and younger patients. No specific geriatric-related problems that would limit its usefulness have been demonstrated.[27]
• Pregnancy: Bepotastine was previously assigned FDA Pregnancy Category C.[9] There are no adequate and well-controlled studies on the use of Bepotastine in pregnant women.[23] Animal reproduction studies using very high oral doses of Bepotastine did not find evidence of teratogenicity, but did show maternal toxicity and some fetal effects (skeletal anomalies, stillbirths) at exposures thousands of times greater than those achieved with the recommended human ophthalmic dose.[6] Therefore, the ophthalmic solution should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.[35]
• Lactation: It is unknown whether Bepotastine is excreted in human milk following topical ocular administration.[33] Following oral administration in rats, the drug was found to be present in breast milk.[22] However, because systemic absorption from the eye drops is very low, the risk to a breastfed infant is expected to be minimal.[39] As a precaution, nursing mothers may be advised to use nasolacrimal occlusion after instillation to further reduce systemic absorption.[38]

Contraindications and Precautions

• Contraindications: Bepotastine is contraindicated in patients with a known hypersensitivity to the active ingredient or to any other component of the formulation, such as the preservative benzalkonium chloride.[20]
• Precautions for Contact Lens Wearers: Bepreve™ should not be used to treat irritation related to contact lens wear.[26] The preservative in the solution, benzalkonium chloride, can be absorbed by soft contact lenses, potentially causing irritation.[33] Patients should be instructed to remove their contact lenses before instilling the drops and to wait at least 10 minutes before reinserting them.[9] Furthermore, patients should not wear contact lenses if their eyes are red.[9]

Drug Interaction Profile

The potential for drug-drug interactions with Bepotastine is highly dependent on the formulation used. A nuanced analysis is required to reconcile seemingly contradictory information from different sources.

For the ophthalmic formulation (Bepreve™), the potential for clinically significant drug interactions is very low. This conclusion is based on its pharmacokinetic profile:

1. Minimal Systemic Absorption: As established, systemic exposure is negligible.[1]
2. Minimal Metabolism: The drug is not substantially metabolized by the CYP450 enzyme system and does not inhibit major isoforms.[9]

This combination of factors means that the ophthalmic solution is unlikely to affect the systemic levels of other drugs, nor are other drugs likely to significantly affect its minimal systemic concentration. This aligns with clinical resources that state there are "no known interactions" for the ophthalmic product, a pragmatic assessment for prescribers.17

For the oral formulation (Talion®), the risk of drug interactions is theoretically higher. Because the oral form results in high systemic concentrations and relies almost entirely on renal excretion of the unchanged drug, its clearance can be affected by other medications that influence kidney function.[1] Comprehensive databases list numerous potential interactions based on this mechanism.[1] For example:

• Drugs that decrease renal excretion (e.g., NSAIDs like ibuprofen, certain diuretics) could theoretically increase Bepotastine plasma levels.
• Drugs that increase renal excretion could decrease Bepotastine plasma levels and potentially reduce efficacy.

These interactions, while pharmacologically plausible, are primarily a concern for the systemically administered oral product and are not considered clinically relevant for the topically administered ophthalmic solution.

Regulatory and Commercial Landscape

The history of Bepotastine illustrates a common trajectory in the pharmaceutical industry, involving international development, strategic licensing, corporate acquisitions, and the eventual lifecycle transition from a branded product to a generic market.

Regulatory History and Approval

• Discovery and Japanese Approval: Bepotastine was first discovered by the Japanese company Ube Industries, Ltd., and was subsequently co-developed with Tanabe Seiyaku Co., Ltd. (which later became part of Mitsubishi Tanabe Pharma Corporation).[6] It received its first regulatory approvals in Japan as an oral tablet, Talion®, for allergic rhinitis in July 2000 and for urticaria/pruritus in January 2002.[1]
• U.S. Ophthalmic Development and FDA Approval: The path to the U.S. market involved a series of strategic partnerships. Tanabe Seiyaku granted exclusive rights for ophthalmic development to Senju Pharmaceutical Co., Ltd., which in turn licensed the U.S. rights to ISTA Pharmaceuticals.[6] ISTA Pharmaceuticals spearheaded the U.S. clinical development program for the ophthalmic solution. The company filed a New Drug Application (NDA) with the FDA on November 14, 2008.[43] Following a positive recommendation from an advisory committee, Bepreve™ (bepotastine besilate ophthalmic solution) 1.5% was officially approved by the FDA on September 8, 2009, for the treatment of itching associated with allergic conjunctivitis.[1]

Manufacturers and Market Presence

The commercialization of Bepotastine has been managed by several entities due to licensing and corporate consolidation.

• Brand Name Products:
• In the United States, Bepreve™ was initially launched by ISTA Pharmaceuticals. In 2012, ISTA was acquired by Bausch + Lomb, which became the new marketer of the product.[6] Bausch + Lomb was later acquired by Valeant Pharmaceuticals (now Bausch Health Companies), continuing a trend of industry consolidation.[6]
• In Japan, Talion® is marketed by Mitsubishi Tanabe Pharma.[6]
• Generic Formulations: The patent protection for Bepreve™ has expired, opening the market to generic competition. The FDA has approved generic versions of bepotastine besilate 1.5% ophthalmic solution from several manufacturers, including Apotex Inc. (approved March 2019), Mylan (now Viatris, approved March 2019), and Alembic Pharmaceuticals (approved April 2023).[26] The availability of generics has increased patient access and introduced price competition.[26]
• Active Pharmaceutical Ingredient (API) Suppliers: The Bepotastine API is manufactured by various chemical and pharmaceutical companies globally for both research purposes and for the production of finished drug products. These suppliers are located in countries including India, China, Japan, and South Korea.[45]

This entire arc—from discovery and regional launch, through international licensing, specialized reformulation for a new market, brand success followed by corporate acquisition, and finally, patent expiration leading to a multi-source generic market—represents a classic and complete pharmaceutical product lifecycle.

Works cited

1. Bepotastine: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed August 28, 2025, https://go.drugbank.com/drugs/DB04890
2. Bepotastine | 99.32%(HPLC) | In Stock | Histamine Receptor ..., accessed August 28, 2025, https://www.selleckchem.com/products/bepotastine.html
3. CAS No : 125602-71-3| Chemical Name : Bepotastine - Pharmaffiliates, accessed August 28, 2025, https://pharmaffiliates.com/en/125602-71-3-bepotastine-api-pa021800000.html
4. Bepotastine | 125602-71-3 - SynZeal, accessed August 28, 2025, https://www.synzeal.com/en/bepotastine-2
5. Bepotastine Besilate | C27H31ClN2O6S | CID 164521 - PubChem, accessed August 28, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/164521
6. Bepotastine - Wikipedia, accessed August 28, 2025, https://en.wikipedia.org/wiki/Bepotastine
7. BEPOTASTINE | 125602-71-3 - ChemicalBook, accessed August 28, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB3102554.htm
8. Bepotastine | C21H25ClN2O3 | CID 164522 - PubChem, accessed August 28, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Bepotastine
9. Bepreve Label - accessdata.fda.gov, accessed August 28, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022288lbl.pdf
10. Bepotastine besylate - KEGG DRUG, accessed August 28, 2025, https://www.kegg.jp/entry/D01654
11. bepotastine | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY, accessed August 28, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=clinical&ligandId=7466
12. Critical appraisal of bepotastine in the treatment of ocular itching associated with allergic conjunctivitis - PMC, accessed August 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3046989/
13. go.drugbank.com, accessed August 28, 2025, https://go.drugbank.com/drugs/DB04890#:~:text=Drug%20Events%20Today-,Bepotastine%20is%20a%20non%2Dsedating%2C%20selective%20antagonist%20of%20the%20histamine,of%20eosinophils%20into%20inflamed%20tissues.
14. Efficacy and Toxicity Evaluation of Bepotastine Besilate 1.5% Preservative-Free Eye Drops Vs Olopatadine Hydrochloride 0.2% Bak-Preserved Eye Drops in Patients with Allergic Conjunctivitis, accessed August 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10658941/
15. What is the mechanism of Bepotastine salicylate? - Patsnap Synapse, accessed August 28, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-bepotastine-salicylate
16. go.drugbank.com, accessed August 28, 2025, https://go.drugbank.com/drugs/DB04890#:~:text=It%20is%20a%20non%2Dsedating,allergic%20inflammation%20of%20the%20conjunctiva.
17. Bepotastine Besilate (EENT) Monograph for Professionals - Drugs.com, accessed August 28, 2025, https://www.drugs.com/monograph/bepotastine-besilate-eent.html
18. Bepotastine besilate ophthalmic solution 1.5% for alleviating nasal symptoms in patients with allergic conjunctivitis - PMC - PubMed Central, accessed August 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5870655/
19. (PDF) Bepotastine Besilate: A Novel Anti-histamine - ResearchGate, accessed August 28, 2025, https://www.researchgate.net/publication/322660245_Bepotastine_besilate_A_novel_anti-histamine
20. 1. Composition Bepotastine Besilate 1.5% 2. Dosage form and strength Beporest is available in pack of 5ml. 3. Clinical parti, accessed August 28, 2025, https://www.centaurpharma.com/downloads/ophthalmology/anti-allergy/BEPOREST.pdf
21. Pharmacokinetic comparisons of bepotastine besilate and bepotastine salicylate in healthy subjects - PubMed, accessed August 28, 2025, https://pubmed.ncbi.nlm.nih.gov/24105252/
22. Application Type Submission Number Submission Code Letter Date Stamp Date PDUFA Goal Date Reviewer Name Review Completion Date E - FDA, accessed August 28, 2025, https://www.fda.gov/media/77858/download
23. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE BEPREVE® (bepotastine besilate ophthalmic solution) 1.5% is a histamine H1 - Bausch + Lomb, accessed August 28, 2025, https://www.bausch.com/globalassets/pdf/packageinserts/pharma/bepreve-prescribing-info.pdf
24. Pharmacokinetic Modeling of Bepotastine for Determination of Optimal Dosage Regimen in Pediatric Patients with Allergic Rhinitis or Urticaria - PubMed Central, accessed August 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10975960/
25. Bepreve (bepotastine) dosing, indications, interactions, adverse effects, and more, accessed August 28, 2025, https://reference.medscape.com/drug/bepreve-bepotastine-345211
26. Bepreve (Bepotastine): Uses, Side Effects, Dosage & More - GoodRx, accessed August 28, 2025, https://www.goodrx.com/bepotastine/what-is
27. Bepotastine besilate (ophthalmic route) - Side effects & dosage ..., accessed August 28, 2025, https://www.mayoclinic.org/drugs-supplements/bepotastine-besilate-ophthalmic-route/description/drg-20073178
28. FDA Approves Two New Ophthalmic Drugs, accessed August 28, 2025, https://www.reviewofoptometry.com/article/fda-approves-two-new-ophthalmic-drugs
29. Allergic Conjunctivitis (AC) Completed Phase 3 Trials for Bepotastine (DB04890), accessed August 28, 2025, https://go.drugbank.com/indications/DBCOND0076634/clinical_trials/DB04890?phase=3&status=completed
30. Bepotastine Completed Phase 2 Trials for Allergic Conjunctivitis (AC) Treatment - DrugBank, accessed August 28, 2025, https://go.drugbank.com/drugs/DB04890/clinical_trials?conditions=DBCOND0076634&phase=2&purpose=treatment&status=completed
31. Perennial Allergic Rhinitis (PAR) Completed Phase 3 Trials for Bepotastine (DB04890), accessed August 28, 2025, https://go.drugbank.com/indications/DBCOND0058482/clinical_trials/DB04890?phase=3&status=completed
32. Bepotastine Ophthalmic - Saint Luke's Health System, accessed August 28, 2025, https://www.saintlukeskc.org/health-library/bepotastine-ophthalmic
33. Bepotastine besilate ophthalmic solution 1.5% w/v Selective Histamine H1 Receptor Antagonist - [Product Monograph Template - Standard], accessed August 28, 2025, https://pdf.hres.ca/dpd_pm/00035875.PDF
34. Bepotastine (Bepreve): Uses, Side Effects, Interactions, Pictures, Warnings & Dosing, accessed August 28, 2025, https://www.webmd.com/drugs/2/drug-152984/bepotastine-besilate-ophthalmic-eye/details
35. Bepost - ACI Pharmaceuticals, accessed August 28, 2025, http://www.acipharma.net/products/bepost
36. Bepotastine besilate (Ophthalmic route) - SmartEngage - ADAM, accessed August 28, 2025, https://sales-demo.adam.com/content.aspx?productid=47&pid=47&gid=603023
37. PHARMACOLOGY REVIEW(S) - accessdata.fda.gov, accessed August 28, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022288s000_pharmr.pdf
38. Bepotastine ophthalmic (Bepreve) Use During Pregnancy - Drugs.com, accessed August 28, 2025, https://www.drugs.com/pregnancy/bepotastine-ophthalmic.html
39. Bepotastine - Drugs and Lactation Database (LactMed®) - NCBI ..., accessed August 28, 2025, https://www.ncbi.nlm.nih.gov/books/NBK501694/
40. Bepotastine Ophthalmic: MedlinePlus Drug Information, accessed August 28, 2025, https://medlineplus.gov/druginfo/meds/a610012.html
41. www.webmd.com, accessed August 28, 2025, https://www.webmd.com/drugs/2/drug-152984/bepotastine-besilate-ophthalmic-eye/details#:~:text=There%20are%20no%20known%20interactions%20between%20bepotastine%20and%20other%20medicines,other%20drugs%20you%20are%20taking%3F
42. FDA Approves ISTA Pharmaceuticals, Inc.'s Itchy Eye Treatment Bepreve - BioSpace, accessed August 28, 2025, https://www.biospace.com/fda-approves-ista-pharmaceuticals-inc-s-itchy-eye-treatment-bepreve
43. Bepreve (bepotastine) FDA Approval History - Drugs.com, accessed August 28, 2025, https://www.drugs.com/history/bepreve.html
44. Generic Bepreve Availability - Drugs.com, accessed August 28, 2025, https://www.drugs.com/availability/generic-bepreve.html
45. Bepotastine API Suppliers - Find All GMP Manufacturers - Pharmaoffer.com, accessed August 28, 2025, https://pharmaoffer.com/api-excipient-supplier/antihistamines/bepotastine
46. ANDA 206066 ANDA APPROVAL Apotex Corp. US Agent for Apotex Inc. 2400 North Commerce Parkway, Suite 400 Weston - accessdata.fda.gov, accessed August 28, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2019/206066Orig1s000ltr.pdf