A Comprehensive Pharmacological and Clinical Review of Felbinac and Felbinac Trometamol

I. Executive Summary

Felbinac is a non-steroidal anti-inflammatory drug (NSAID) belonging to the arylacetic acid class. It is the principal active metabolite of fenbufen, a prodrug that was withdrawn from several markets due to safety concerns. Felbinac itself has been developed and marketed in two distinct forms, each with a unique therapeutic purpose and risk profile. The first is a range of topical formulations (e.g., gel, foam, patch) used for the localized treatment of musculoskeletal pain and inflammation. The second, and more recent, is felbinac trometamol, a highly water-soluble salt specifically engineered for intravenous (IV) administration to manage moderate-to-severe postoperative pain.

The primary mechanism of action for felbinac is the inhibition of cyclooxygenase (COX) enzymes, thereby reducing the synthesis of prostaglandins that mediate pain and inflammation. While some promotional literature suggests a preference for COX-2, biochemical data indicates it is a largely non-selective inhibitor of both COX-1 and COX-2, a characteristic that carries implications for its safety profile.

The pharmacokinetics of the intravenous formulation, felbinac trometamol, have been well-characterized in clinical trials. It exhibits linear, dose-proportional pharmacokinetics, with predictable plasma concentrations and a half-life of approximately 5-7 hours that supports an every-8-hour dosing regimen for postoperative pain management. In contrast, topical formulations are designed for high local tissue concentration with minimal systemic absorption, which is their key safety advantage.

The clinical evidence for felbinac is bifurcated. A robust clinical development program, primarily conducted in China, has progressed the intravenous formulation through Phase III trials, demonstrating its efficacy as an opioid-sparing analgesic in the postoperative setting. Conversely, the evidence for topical felbinac in chronic conditions like osteoarthritis is more varied. While effective for short-term pain relief and comparable to some oral NSAIDs, its long-term efficacy is less established, and some comparative studies suggest it may be less potent than other topical NSAIDs, such as diclofenac.

The safety profile is critically dependent on the route of administration. Topical use is associated primarily with local dermatological reactions like rash and irritation. Intravenous use, however, carries the full spectrum of systemic NSAID-class risks, including potential gastrointestinal, renal, and cardiovascular adverse events.

The global regulatory status of felbinac is highly fragmented. Topical formulations have been available for decades in Europe and Japan, though some brands have been discontinued in specific countries like the United Kingdom. In stark contrast, neither felbinac nor felbinac trometamol has received marketing approval from the U.S. Food and Drug Administration (FDA), a situation likely influenced by the negative safety history of its parent drug, fenbufen. The development of the intravenous formulation is almost exclusively centered in China, positioning it primarily for the Asian market. This report provides a comprehensive monograph synthesizing the chemical, pharmacological, clinical, and regulatory data for both forms of this therapeutic agent.

II. Chemical Properties and Formulation Development

The evolution of felbinac from a metabolite of a withdrawn drug into both a long-standing topical agent and a modern intravenous therapy is a case study in pharmaceutical formulation science. The distinct physicochemical properties of the active moiety and its salt form have dictated their respective development pathways and therapeutic applications.

A. Chemical Identity of Felbinac and its Derivatives

A clear understanding of the chemical entities involved is fundamental to appreciating the drug's profile. The primary compounds of interest are the active drug felbinac, its salt form felbinac trometamol, and its parent prodrug fenbufen.

• Felbinac: This is the core active pharmaceutical ingredient (API).
• Systematic Name: (1,1'-Biphenyl)-4-acetic acid or 2-(4-phenylphenyl) acetic acid.[1]
• Relationship to Fenbufen: Felbinac is the active metabolite of the prodrug fenbufen. It is reported to be approximately two times more potent as an anti-inflammatory agent than its parent compound.[3]
• Identifiers: Key identifiers include CAS Number 5728-52-9, DrugBank Accession Number DB07477, and PubChem Compound ID (CID) 3332.[2]
• Felbinac Trometamol: This is the water-soluble salt form developed for parenteral use.
• Full Chemical Name: It is a 1:1 compound of felbinac and trometamol, systematically named trishydroxymethylaminomethane 4-biphenylacetate or (1,1'-BIPHENYL)-4-ACETIC ACID, COMPD. WITH 2-AMINO-2-(HYDROXYMETHYL)-1,3-PROPANEDIOL (1:1).[3]
• Molecular Formula: C18​H23​NO5​.[7]
• Molecular Weight: 333.38 g/mol.[7]
• Identifiers: Key identifiers include CAS Number 935886-64-9, PubChem CID 44238058, and FDA Unique Ingredient Identifier (UNII) HA8ZX3VG09.[3]
• Trometamol (Tromethamine): This is the salt-forming agent.
• Function: Trometamol is an organic amine proton acceptor. While it has therapeutic use on its own as a biological buffer and alkalizing agent to correct metabolic acidosis, its role in felbinac trometamol is purely pharmaceutical: to form a salt and improve solubility.[10] It is identified by DrugBank ID DB03754.[10]
• Fenbufen: This is the parent prodrug of felbinac.
• History: Fenbufen was an orally administered NSAID approved in Japan in 1979 [11] and was also reportedly approved by the FDA.[12] However, it was subsequently withdrawn from the market due to significant toxicity concerns, including severe skin rash and hepatotoxicity.[14] This history casts a long shadow over its metabolite, felbinac.
• Other Derivatives:
• To address the same solubility challenges, other prodrugs such as felbinac ethyl ester were also developed and investigated.[1]

The following table consolidates the key chemical identifiers and properties of these related compounds, providing a clear reference point.

Table 1: Chemical Identifiers and Physicochemical Properties

Property	Felbinac (Active Moiety)	Felbinac Trometamol (IV Salt Form)	Fenbufen (Parent Prodrug)
Systematic (IUPAC) Name	2-([1,1'-biphenyl]-4-yl)acetic acid 2	2-amino-2-(hydroxymethyl)propane-1,3-diol 2-([1,1'-biphenyl]-4-yl)acetate 17	4-([1,1'-biphenyl]-4-yl)-4-oxobutanoic acid 18
CAS Number	5728-52-9 2	935886-64-9 7	36330-85-5 18
PubChem CID	3332 2	44238058 8	3335 18
DrugBank ID	DB07477 2	Not Applicable (Salt)	DB01594
Molecular Formula	C14​H12​O2​ 19	C18​H23​NO5​ 17	C16​H14​O3​
Molecular Weight	212.24 g/mol 19	333.38 g/mol 7	254.28 g/mol
Key Physicochemical Property	Low water solubility, lipophilic (Log P = 2.58) 1	High water solubility, enabling aqueous IV formulation 1	Oral prodrug

B. Physicochemical Properties and the Rationale for Formulation Development

The entire development of felbinac trometamol is a direct consequence of the physicochemical limitations of the parent API, felbinac. Felbinac itself possesses low aqueous solubility, a property that historically prevented its use as an intravenous medication.[1] This is a significant therapeutic limitation, as potent injectable NSAIDs are highly valuable for managing moderate-to-severe pain, particularly in the postoperative setting where oral administration may not be feasible and an opioid-sparing effect is desired.[1]

To circumvent this, pharmaceutical scientists employed a classic salt formation strategy. By reacting the acidic felbinac with the organic amine base trometamol, they created felbinac trometamol, a salt with significantly enhanced water solubility.[1] This innovation was the key to unlocking an entirely new route of administration. It allowed for the creation of a simple aqueous injection that could be constituted in normal saline. This approach successfully avoided the need for more complex and potentially problematic formulation technologies, such as the lipid-based emulsions or other solubilizing adjuvants (e.g., lecithin) used for other poorly soluble injectable NSAIDs like ketorolac or flurbiprofen axetil. These alternative vehicles can carry their own risks, including pain at the injection site and potential for serious allergic reactions.[1]

The regulatory history of fenbufen also appears to have profoundly influenced the development strategy for felbinac trometamol. The withdrawal of fenbufen from major markets due to safety issues, notably liver toxicity, created a "legacy risk" for its active metabolite.[14] Pursuing approval from stringent regulatory bodies like the FDA or EMA for a new parenteral formulation of a metabolite of a withdrawn drug would likely be an arduous, expensive, and high-risk endeavor. This context helps explain the strategic decision by the primary developer, Shijiazhuang Yiling Pharmaceutical Co. Ltd., to focus its comprehensive clinical trial program almost exclusively within China.[11] This represents a calculated move to pursue a market with a potentially more favorable and streamlined regulatory landscape for a domestically developed therapeutic.

For topical delivery, the physicochemical properties present a different set of challenges. Felbinac's lipophilic nature (Log P = 2.58) is advantageous for penetrating the outer lipid-rich layer of the skin, the stratum corneum. However, its passage through the subsequent aqueous environment of the epidermis can be a rate-limiting step.[20] To address this, research has explored advanced formulation strategies, such as forming ion-pair complexes with other organic amines (e.g., triethylamine). This technique modulates the drug's lipophilicity to create a more optimal balance, enhancing its permeation through the skin layers and improving delivery to the target tissues for transdermal patch formulations.[20]

C. Pharmaceutical Formulations

Resulting from these development efforts, felbinac and felbinac trometamol are available in a variety of pharmaceutical forms tailored to different clinical needs.

• Topical Formulations: These are the most established forms of felbinac and are available in numerous countries, particularly in Europe and Japan.
• Gel: Commercially available as a 3% w/w gel, with Traxam being a well-known (though now discontinued in the UK) brand name.[3]
• Foam: Marketed as a 3% or 3.17% w/w cutaneous foam, also under the Traxam brand.[3]
• Patches, Cataplasms, and Tapes: These transdermal systems are particularly prevalent in Japan and Korea. Examples include SELTOUCH® tape 70 (containing 70 mg of felbinac) and FELBINAC TAPE 35mg "NP".[20]
• Ointment and Lotion: In Japan, other formulations like FELBINAC STICK OINTMENT 3% and FELBINAC LOTION 3% are also marketed for topical application.[28]
• Intravenous Formulation: This formulation consists of felbinac trometamol and is specifically intended for hospital use.
• Indication: Developed for the management of severe postoperative pain.[1]
• Administration: Clinical trial protocols describe the formulation as a sterile solution for injection. The required dose is diluted in 100 mL of 0.9% sodium chloride (normal saline) and administered as a slow intravenous infusion over a 30-minute period.[11]

III. Pharmacology

Felbinac's therapeutic effects are rooted in its activity as a non-steroidal anti-inflammatory drug. Its pharmacological profile is characterized by its interaction with the cyclooxygenase enzyme system, leading to downstream effects on inflammation, pain, and hemostasis.

A. Mechanism of Action: Cyclooxygenase (COX) Inhibition

As a member of the NSAID class, felbinac's primary mechanism of action is the inhibition of cyclooxygenase (COX) enzymes.[1] These enzymes are critical for the synthesis of prostaglandins from their precursor, arachidonic acid, which is released from cell membranes in response to inflammatory stimuli or tissue injury.[21] Prostaglandins are potent lipid compounds that act as key signaling molecules in the inflammatory cascade, responsible for mediating the classic signs of inflammation, including vasodilation (heat, redness), increased vascular permeability (swelling), and sensitization of nerve endings to painful stimuli (pain).[33] By blocking the COX enzymes, felbinac effectively reduces the production of these prostaglandins at the site of inflammation, thereby attenuating the inflammatory response and providing analgesic relief.[21]

There is a subtle but clinically significant discrepancy in the literature regarding felbinac's selectivity for the two main COX isoforms, COX-1 and COX-2. Some sources, particularly more general or promotional materials, highlight its action as an inhibitor of COX-2.[3] COX-2 is the isoform that is primarily induced at sites of inflammation, and selective inhibition of COX-2 is often promoted as a desirable trait, as it is thought to spare the constitutive COX-1 enzyme. COX-1 plays a crucial role in physiological "housekeeping" functions, such as producing protective prostaglandins in the gastric mucosa and mediating platelet aggregation. Inhibition of COX-1 is therefore strongly associated with the common gastrointestinal side effects of NSAIDs.

However, more detailed biochemical data presents a different picture. One source provides specific half-maximal inhibitory concentration (IC50​) values for felbinac against the two isoforms: 865.68 nM for COX-1 and 976 nM for COX-2.[34] A truly COX-2 selective inhibitor, such as celecoxib, typically exhibits an

IC50​ for COX-2 that is at least one or two orders of magnitude lower than its IC50​ for COX-1. The values for felbinac are very similar, indicating that it is, for all practical purposes, a non-selective NSAID. In fact, the data suggests a very slight preference for inhibiting COX-1 over COX-2. This characterization is more consistent with older, traditional NSAIDs.[33] The implication of this non-selectivity is critical for risk assessment: felbinac should be expected to carry the full spectrum of NSAID-class risks, including the potential for gastrointestinal toxicity associated with COX-1 inhibition. The claims of COX-2 selectivity appear to be an oversimplification not supported by the available biochemical evidence.

B. Pharmacodynamic Effects

The inhibition of prostaglandin synthesis by felbinac leads to several key pharmacodynamic effects:

• Analgesic and Anti-inflammatory: These are the primary therapeutic effects and the basis for its use in treating musculoskeletal conditions like sprains, strains, osteoarthritis, and rheumatoid arthritis, as well as for managing postoperative pain.[20]
• Antipyretic: Like other NSAIDs, felbinac can reduce fever. This effect is achieved by inhibiting prostaglandin synthesis within the hypothalamus, the brain's thermoregulatory center.[33]
• Anti-platelet Aggregation: Through its inhibition of COX-1 in platelets, felbinac interferes with the production of thromboxane A2, a potent promoter of platelet aggregation. One study notes that a concentration of 0.12 mM of felbinac is sufficient to produce almost complete inhibition of arachidonate-induced platelet aggregation.[3] This is a classic NSAID class effect and is the pharmacological basis for the increased risk of bleeding associated with these drugs.

C. Potential COX-Independent Mechanisms

While COX inhibition is the cornerstone of NSAID activity, emerging research suggests that other mechanisms may also contribute to their analgesic effects. Studies on related NSAIDs, such as diclofenac, have shown that they can directly inhibit acid-sensing ion channels (ASICs) on the surface of nociceptors (pain-sensing neurons).[36] ASICs are activated by the drop in pH that occurs in inflamed tissues and play a direct role in pain signaling. It has been proposed that the combined ability of some NSAIDs to block both prostaglandin synthesis (via COX) and directly inhibit the activity of ASICs may be an important factor in their overall efficacy against inflammatory pain.[36] Although this mechanism has not been specifically demonstrated for felbinac in the available literature, it represents a plausible secondary pathway that could contribute to its analgesic action and warrants further investigation.

IV. Pharmacokinetics

The pharmacokinetic profile of a drug describes its absorption, distribution, metabolism, and excretion (ADME). For felbinac, the pharmacokinetic characteristics are highly dependent on the formulation and route of administration, with the intravenous and topical forms behaving very differently.

A. Preclinical Pharmacokinetic Profile (Rat Models)

Early pharmacokinetic studies in Sprague-Dawley rats provided the foundational understanding of the drug's behavior. These studies, using the intravenous felbinac trometamol formulation, established several key properties:

• Linearity: The drug exhibited linear pharmacokinetics. Following IV administration of doses at 3.36, 8.40, and 21.0 mg/kg, the initial maximum plasma concentration (C0​) and the total drug exposure, as measured by the area under the plasma concentration-time curve (AUC), increased in direct proportion to the dose.[1]
• Distribution: Felbinac was found to be highly bound to plasma proteins, with a binding percentage of approximately 95%.[1] This is typical for acidic NSAIDs and means that only a small fraction of the drug in circulation is free and pharmacologically active.
• Metabolism and Excretion: The drug is extensively metabolized, with very little of the parent compound being excreted unchanged in urine (0.318%), feces (0.530%), or bile (0.465%). The principal metabolite identified was 4'-hydroxyfelbinac. The vast majority of the administered dose (63.6%) was recovered in the urine, primarily in the form of this hydroxylated metabolite and its conjugates. Total drug recovery from urine and feces accounted for about 72% of the administered dose.[1]

B. Human Pharmacokinetics: Intravenous Administration

The human pharmacokinetic profile of intravenous felbinac trometamol has been thoroughly investigated in a Phase I clinical trial program involving single- and multiple-ascending dose studies in healthy Chinese volunteers.[30] The results confirmed and expanded upon the preclinical findings, demonstrating a predictable and well-behaved profile suitable for clinical use.

• Absorption and Distribution: Following a 30-minute intravenous infusion, the time to reach maximum plasma concentration (Tmax​) occurs at the end of the infusion, approximately 0.5 hours after the start.[30]
• Dose Proportionality: A key finding was the confirmation of linear, dose-proportional pharmacokinetics in humans. Across a wide range of single doses (from 11.78 mg to 377.00 mg) and multiple doses (from 47.13 mg to 188.50 mg), both the maximum plasma concentration (Cmax​) and the total exposure (AUC) increased linearly with the administered dose.[3] This linearity is a highly desirable characteristic for a drug intended for acute pain management, as it allows for predictable and straightforward dosing adjustments without the risk of non-linear accumulation and unexpected toxicity.
• Half-Life (T1/2​): The elimination half-life of the parent drug, felbinac, is relatively short, ranging from approximately 4.25 to 7.38 hours, depending on the dose and whether it was a single or multiple administration.[3] A separate study reported a mean half-life of 6.13 hours for felbinac, while its major metabolite, 4'-hydroxyfelbinac, had a slightly longer half-life of approximately 8.25 hours.[38]
• Accumulation: The multiple-dose studies evaluated a regimen of infusions administered three times per day (every 8 hours). Under this schedule, a pharmacokinetic steady state was achieved after the fourth dose. The accumulation ratio (Rac​), which measures the extent of drug buildup with repeated dosing, was modest for felbinac, ranging from 1.34 to 1.45.[11] This low and predictable level of accumulation is consistent with the drug's half-life and provides strong support for the viability of an every-8-hour dosing schedule in the clinical setting.[11]

The clean and predictable pharmacokinetic properties of IV felbinac trometamol provide a solid foundation for its use in the controlled environment of postoperative pain management, allowing clinicians to select doses that are likely to be both effective and safe. The following table summarizes the extensive human pharmacokinetic data available.

Table 2: Summary of Human Pharmacokinetic Parameters for Intravenous Felbinac Trometamol

Dose (mg)	Dosing Schedule	Cmax​ (ng/mL)	AUC (mg·h/mL)	T1/2​ (h)	Source(s)
11.78	Single	1442	5.6	4.25	3
23.56	Single	2697	10.7	5.18	3
47.13	Single	5772	22.2	4.8	3
47.13	Multiple (1 time/day)	5817	18	6.12	3
47.13	Multiple (3 times/day)	7530	28	6.59	3
94.25	Single	11947	54	6.24	3
94.25	Multiple (1 time/day)	11474	35	5.79	3
94.25	Multiple (3 times/day)	13568	48	7.0	3
164.92	Single	22043	96	5.46	3
188.5	Multiple (1 time/day)	21230	65	5.71	3
188.5	Multiple (3 times/day)	26473	95	7.38	3
259.16	Single	34889	119	5.46	3
377	Single	44879	182	5.83	3

C. Human Pharmacokinetics: Topical Application and Systemic Exposure

The pharmacokinetic goal of topical felbinac is fundamentally different from the intravenous form. Topical application is designed to deliver the drug directly through the skin to the underlying inflamed tissues, thereby achieving a high local concentration at the site of action while minimizing systemic absorption and exposure.[21] This localized action is the primary advantage of topical NSAIDs, as it greatly reduces the risk of the systemic side effects (e.g., gastrointestinal, renal, cardiovascular) that are a major concern with oral or intravenous administration.[21]

While systemic absorption from topical formulations is low, it is not zero. The Summary of Product Characteristics (SmPC) for Traxam gel notes that although the serum levels achieved after topical application are extremely low, caution is still advised when considering potential drug interactions, particularly since felbinac is highly protein-bound.[24] This highlights the need for a balance in formulation design; for instance, research into novel transdermal patches that use chemical enhancers to improve skin permeation and efficacy must also consider the potential for increased systemic exposure.[20]

D. Metabolism and Excretion Pathways

Human metabolism of felbinac is extensive and follows pathways consistent with the preclinical data.[38]

• Phase I Metabolism: The principal Phase I metabolic pathway is oxidation of the biphenyl ring structure, which produces the major metabolite, 4'-hydroxyfelbinac.[38]
• Phase II Metabolism: Following oxidation, the parent drug and its Phase I metabolite undergo Phase II conjugation reactions. This involves conjugation with glucuronic acid and sulfate groups, leading to the formation of at least seven distinct Phase II metabolites that are more water-soluble and readily excretable.[38]
• Primary Active Moiety: A crucial pharmacokinetic finding is that after intravenous administration, the total exposure (AUC) to the parent drug, felbinac, is approximately 20 times higher than the exposure to its main metabolite, 4'-hydroxyfelbinac.[38] This indicates that felbinac itself, rather than its metabolites, is the primary pharmacologically active entity responsible for the therapeutic effect in circulation.
• Excretion: The final metabolites are eliminated from the body primarily through renal excretion into the urine.[38]

V. Clinical Efficacy and Therapeutic Applications

The clinical evidence supporting the use of felbinac is sharply divided between its two main formulations. The modern intravenous form, felbinac trometamol, has been subjected to a rigorous and focused clinical development program for a single, high-acuity indication. In contrast, the older topical form has a more heterogeneous and less conclusive body of evidence across a range of chronic and acute conditions.

A. Intravenous Felbinac Trometamol for Postoperative Pain Management

The development of intravenous felbinac trometamol has been precisely targeted at the management of moderate to severe postoperative pain.[6] It is positioned as a potent, injectable, non-opioid analgesic intended for use in a multimodal approach, with a significant goal being the reduction of opioid requirements (an "opioid-sparing" effect) in the postoperative period.[1]

The clinical development program has been almost entirely sponsored by the Chinese company Shijiazhuang Yiling Pharmaceutical Co. Ltd. and conducted within China. This program has progressed systematically through all major clinical phases.

• Phase I: Completed single- and multiple-ascending dose studies in healthy volunteers successfully established the drug's safety, tolerability, and predictable linear pharmacokinetics. Based on these findings, a dose of 94.25 mg administered every 8 hours was recommended as the target for further development in Phase II.[11]
• Phase II: A completed multicenter, randomized, double-blind, placebo-controlled, dose-exploratory trial was conducted to evaluate the efficacy and safety of various dosage regimens (including 47.13 mg, 94.25 mg, and 188.50 mg) in patients with postoperative pain. This phase served to confirm the effective dose range for the pivotal Phase III study.[40]
• Phase III: The program culminated in a large, multicenter, randomized, double-blind, placebo-controlled Phase III trial (NCT04526132). This study enrolled 306 patients undergoing major laparotomy, laparoscopic upper abdominal surgery, or thoracoscopic chest surgery. The trial was designed to definitively evaluate the efficacy and safety of felbinac trometamol injection. The primary efficacy endpoint was the total amount of morphine consumed by patients via a patient-controlled intravenous analgesia (PCIA) pump during the first 24 hours after surgery.[22] The choice of this endpoint clearly demonstrates the drug's intended role as an opioid-sparing component of multimodal analgesia.

While the specific numerical results of the Phase III trial are not detailed in the available documentation, the successful completion of such a large, pivotal study implies that positive efficacy signals were observed in the earlier phases, justifying the significant investment in late-stage development. The following table summarizes the key clinical trials for the intravenous formulation.

Table 3: Summary of Major Clinical Trials for Intravenous Felbinac Trometamol in Postoperative Pain

Trial ID / Registry	Phase	Status	Sponsor	Indication	Patient Population (N)	Interventions (Doses vs. Placebo)	Primary Endpoint
NCT03617510 32	Phase I	Completed	Shijiazhuang Yiling Pharmaceutical Co.	Pain (Healthy Volunteers)	56 (SAD), 36 (MAD)	Single doses (11.78-377 mg); Multiple doses (47.13-188.5 mg)	Safety, Tolerability, Pharmacokinetics
NCT03872830 40	Phase II	Completed	Shijiazhuang Yiling Pharmaceutical Co.	Moderate to Severe Postoperative Pain	160 (Adults post-surgery)	47.13 mg, 94.25 mg, 188.5 mg vs. Placebo	Efficacy and Safety (Dose Exploration)
NCT04526132 22	Phase III	Completed	Shijiazhuang Yiling Pharmaceutical Co.	Moderate to Severe Postoperative Pain	306 (Adults post-abdominal/thoracic surgery)	Felbinac Trometamol Injection vs. Placebo	Total morphine consumption via PCIA in 24 hours

B. Topical Felbinac for Musculoskeletal and Arthritic Conditions

Topical felbinac has been used for decades to provide localized relief from pain and inflammation across a spectrum of conditions.[21]

• Approved/Common Indications:
• Soft Tissue Injuries: Sprains, strains, and contusions are primary targets for topical therapy.[21]
• Arthritis: It is used for symptomatic relief in both osteoarthritis and rheumatoid arthritis.[1]
• Other Inflammatory Conditions: It is also applied for conditions such as tendinitis, tenosynovitis, bursitis, and myalgia (muscle pain).[21]
• Efficacy in Osteoarthritis: The evidence for its use in chronic conditions like osteoarthritis is mixed.
• Several systematic reviews and guidelines support the use of topical NSAIDs as a class for treating hand and knee osteoarthritis. They are generally found to provide effective pain relief, with efficacy comparable to that of oral NSAIDs but with a significantly better safety profile due to reduced systemic side effects.[42]
• However, the durability of this effect has been questioned. A meta-analysis published in the BMJ found that topical NSAIDs were statistically superior to placebo for pain relief in osteoarthritis for only the first two weeks of treatment. No significant benefit over placebo was observed in studies lasting three or four weeks.[45] This suggests the evidence base may not support long-term continuous use.
• Furthermore, the efficacy of felbinac specifically may be less robust than that of other agents in its class. One systematic review pointedly noted that some earlier meta-analyses that showed weaker overall results for topical NSAIDs may have been negatively skewed by the inclusion of studies on felbinac, which had failed to demonstrate a clear therapeutic benefit.[42] This suggests that while the class is effective, felbinac may be a less potent member.

C. Comparative Efficacy Studies

Head-to-head clinical trials are essential for determining a drug's relative place in therapy. For topical felbinac, these comparisons have yielded varied results.

• Topical Felbinac vs. Oral NSAIDs: Several double-blind, double-dummy clinical trials have demonstrated that topical felbinac gel has an efficacy equivalent to that of oral NSAIDs like ibuprofen or its parent drug, fenbufen, for treating acute soft tissue injuries and mild-to-moderate osteoarthritis.[46] This supports its use as a safer alternative that avoids systemic risks.
• Topical Felbinac vs. Topical Diclofenac: A pivotal observer-blind, randomized study involving 384 patients with acute soft tissue injuries directly compared felbinac gel with diclofenac gel (Voltarol Emulgel). The results clearly favored diclofenac. Diclofenac was found to be more effective than felbinac across nearly every measured parameter, including pain at rest, pain on movement, and swelling, at both day 3 and day 7. The differences were statistically significant in favor of diclofenac for reduction in pain at rest and bruising at day 3, and for reduction in pain on local pressure at day 7.[47] This study provides strong evidence that topical diclofenac may be a superior therapeutic choice for this indication.
• Topical Felbinac vs. Topical Piroxicam: In contrast, a study of 172 patients in the Philippines with soft tissue trauma found felbinac gel to be superior to piroxicam gel. Treatment with felbinac resulted in a significantly greater overall clinical improvement and provided faster relief from symptoms such as pain on movement and pain at night compared to piroxicam.[49]

This collection of clinical evidence paints a complex picture. The intravenous formulation of felbinac trometamol appears to be a well-supported, modern therapeutic for a specific, acute indication. The older topical formulation, while useful and safer than oral alternatives, may be less effective than other commonly available topical NSAIDs, particularly diclofenac. Its long-term efficacy in chronic conditions also remains an area of uncertainty. The following table summarizes the key comparative trials.

Table 4: Summary of Comparative Efficacy Trials for Topical Felbinac

Comparison	Indication	Key Findings	Source(s)
Felbinac Gel vs. Oral Ibuprofen/Fenbufen	Soft Tissue Injuries, Osteoarthritis	Efficacy of topical felbinac was shown to be equivalent to that of oral NSAIDs in four separate double-blind, double-dummy trials.	46
Felbinac Gel vs. Diclofenac Gel	Acute Soft Tissue Injuries	Diclofenac gel was more effective than felbinac gel across nearly all parameters at day 3 and day 7. Differences were statistically significant for pain at rest, bruising, and pain on pressure.	47
Felbinac Gel vs. Piroxicam Gel	Soft Tissue Trauma	Felbinac gel produced a significantly greater overall clinical improvement and faster symptom relief compared to piroxicam gel.	49

VI. Safety and Tolerability Profile

The safety profile of felbinac is not monolithic; it is critically dependent on the route of administration. The primary advantage of the topical form—its localized action and low systemic risk—is completely inverted in the intravenous form, where systemic NSAID-class risks become the dominant concern.

A. Adverse Events Associated with Topical Administration

The adverse effects of topical felbinac are predominantly localized to the site of application and are generally mild.

• Common Adverse Events: The most frequently reported side effects are local skin reactions. These include mild local erythema (redness), pruritus (itching), skin irritation, a burning sensation, numbness, tingling, and the development of a skin rash.[3] These effects are usually transient and often resolve without discontinuation of the drug.[41]
• Less Common/Rare Adverse Events:
• Photosensitivity: A notable precaution is the risk of photosensitivity. Patients are consistently advised to protect treated areas of skin from excessive exposure to sunlight and to avoid the use of sunbeds, as the drug can make the skin more sensitive to UV light.[24]
• Severe Skin Reactions: Although rare, more severe dermatological reactions are possible. These can include widespread rashes, urticaria (hives), and severe bullous dermatoses such as epidermal necrolysis and erythema multiforme.[24]
• Systemic and Respiratory Reactions: While systemic absorption is low, rare cases of systemic effects have been reported. These include bronchospasm and wheezing in susceptible individuals, as well as gastrointestinal disturbances.[24] Anaphylaxis is also a rare but possible immune system disorder.[24]

B. Adverse Events Associated with Intravenous Administration

The development of an intravenous formulation is designed to achieve 100% bioavailability and high systemic drug concentrations for potent analgesia. This inherently exposes the entire body to the drug and its associated risks.

• General Tolerability: In the controlled setting of Phase I clinical trials conducted in healthy, young volunteers, intravenous felbinac trometamol was reported to be well-tolerated. The frequency and severity of treatment-emergent adverse events did not increase with escalating single doses up to 377 mg.[30]
• NSAID Class-Specific Risks: As a systemically administered NSAID, felbinac trometamol carries the full spectrum of serious, class-wide risks. The extensive exclusion criteria used in its clinical trials—which meticulously screened out patients with pre-existing gastrointestinal, cardiovascular, or renal disease, bleeding disorders, or uncontrolled hypertension—serve as a clear acknowledgment of these potential dangers.[22]
• Gastrointestinal (GI) Risk: Includes the potential for stomach pain, nausea, and indigestion. The more severe risks, which constitute a boxed warning for many systemic NSAIDs, are peptic ulceration, gastrointestinal bleeding, and perforation.[51]
• Renal Risk: NSAIDs can cause renal damage and acute renal failure by inhibiting prostaglandin-mediated renal blood flow. This risk is especially high in patients with pre-existing kidney disease, heart failure, or dehydration.[51]
• Cardiovascular (CV) Risk: Systemic NSAIDs are associated with an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke. They can also cause fluid retention, edema, and new-onset or worsening of pre-existing hypertension.[51]
• Trometamol-Specific Effects: The trometamol component, when used at therapeutic doses to treat acidosis, can cause its own side effects, including GI discomfort, electrolyte imbalances (e.g., hyperkalemia), and respiratory depression.[53] While the amount used as a salt-forming excipient in the felbinac formulation is much lower, these potential effects contribute to the overall safety consideration.

C. Contraindications and High-Risk Populations

The use of felbinac is contraindicated or requires significant caution in several patient populations.

• Absolute Contraindications:
• Known hypersensitivity to felbinac, its components, aspirin, or any other NSAID.[25]
• Patients with a history of asthma, urticaria, or acute rhinitis precipitated by aspirin or other NSAIDs.[25]
• Topical application is contraindicated on broken or denuded skin, open wounds, infected skin, or mucous membranes.[25]
• Use of occlusive dressings over the application site is contraindicated as it can dangerously increase systemic absorption.[25]
• Patients with active peptic ulceration.[24]
• Use with Caution (High-Risk Populations):
• Gastrointestinal Disease: Patients with a history of GI ulceration, bleeding, or inflammatory bowel disease.[24]
• Renal Impairment: Patients with reduced kidney function. Based on guidelines for other potent NSAIDs like ketorolac, use should be avoided in patients with severe renal impairment (e.g., creatinine clearance < 30 mL/min).[24]
• Cardiovascular Disease: Patients with reduced cardiac function, heart failure, or uncontrolled hypertension.[24]
• Bleeding Disorders: Patients with active intracranial hemorrhage or a bleeding diathesis.[25]
• Pregnancy and Lactation: Use is not recommended as safety has not been established. Like all NSAIDs, it should be avoided during the third trimester of pregnancy due to the risk of premature closure of the fetal ductus arteriosus.[25]
• Elderly Patients: This population is more susceptible to the adverse effects of NSAIDs. The lowest effective dose should be used for the shortest possible duration.[24]
• Pediatric Patients: Not generally recommended for use in children. Some topical products specify use for ages 12 and over.[41]

D. Significant Drug-Drug Interactions

Felbinac can interact with numerous other medications, increasing the risk of adverse events.

• Other NSAIDs: Concomitant use with other systemic or topical NSAIDs, including over-the-counter products like ibuprofen and aspirin, significantly increases the risk of cumulative toxicity, especially GI bleeding, and should be avoided.[16]
• Anticoagulants and Antiplatelet Agents: There is a theoretical risk of an enhanced effect when used with anticoagulants like warfarin or antiplatelet drugs, leading to an increased risk of bleeding. Close monitoring is required.[25]
• Antihypertensive Medications: NSAIDs can antagonize the effects of many antihypertensive drugs, including ACE inhibitors and diuretics, potentially leading to a loss of blood pressure control.[35]
• Corticosteroids: Concurrent use with oral corticosteroids increases the risk of gastrointestinal ulceration and bleeding.[25]
• Nephrotoxic Drugs: Co-administration with other drugs that have the potential for kidney damage (e.g., aminoglycoside antibiotics, olsalazine, oxaliplatin) can increase the risk of nephrotoxicity.[16]
• SSRIs and TCAs: Combining NSAIDs with selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) may increase the risk of GI bleeding.[16]
• Lithium and Methotrexate: NSAIDs can reduce the renal clearance of lithium and methotrexate, leading to elevated plasma levels and increased risk of toxicity.[52]

VII. Global Regulatory Status and Market Availability

The global regulatory landscape for felbinac is a prime example of regional drug development and market fragmentation. Its availability, approved formulations, and clinical development focus differ starkly between major markets, a situation shaped by historical safety events and modern commercial strategies.

A. Regulatory Status in the United States (FDA)

There is no evidence to suggest that felbinac or its trometamol salt is currently approved for marketing in the United States by the Food and Drug Administration (FDA).[5] Standard searches of FDA databases, such as Drugs@FDA and the Orange Book, do not yield an approval for any felbinac-containing product.[55]

This lack of approval is almost certainly influenced by the regulatory history of its parent drug, fenbufen. Fenbufen was withdrawn from the market due to significant toxicity concerns.[14] For a regulatory body like the FDA, this history creates a high barrier to entry for a related metabolite. Any New Drug Application (NDA) for felbinac, particularly for a high-risk systemic formulation, would face intense scrutiny. Furthermore, all recent major clinical trials for the intravenous formulation have been conducted exclusively in China, with no US sites listed, indicating that the developer has not pursued a US regulatory pathway.[22]

B. Regulatory Status and Availability in Europe (EMA)

In Europe, felbinac has a long history as a topical medication.

• Topical Availability: Topical NSAIDs, including various felbinac formulations, have been available in European countries for several decades.[43]
• Brand Names and Discontinuation: The brand name Traxam, available as a gel and cutaneous foam, is well-known. However, its market presence is not uniform; for example, all Traxam® products have been discontinued in the United Kingdom, and no generic felbinac products are currently available there.[41]
• Regulatory Oversight: Felbinac is included on the European Union reference dates (EURD) list maintained by the European Medicines Agency (EMA) for the coordination of pharmacovigilance activities. The list indicates a first authorization date for a felbinac product within the EU of September 25, 1986, highlighting its long-standing presence.[58]
• Pharmacopoeial Standards: Official reference standards for felbinac are available from the European Pharmacopoeia (EP) and the British Pharmacopoeia (BP), confirming its status as a recognized medicinal substance in the region.[59]

C. Regulatory Status and Availability in Japan (PMDA)

Japan is another major market where topical felbinac is well-established and widely used. The parent drug, fenbufen, was first approved there as an oral agent in 1979, which likely paved the way for the acceptance of its active metabolite.[11]

• Available Formulations: A diverse range of topical felbinac preparations are marketed in Japan, indicating broad clinical use and physician acceptance. These include:
• Patches/Tapes: Brands such as SELTOUCH® and FELBINAC TAPE 35mg "NP" are available.[20]
• Ointments/Sticks: FELBINAC STICK OINTMENT 3% "MIKASA" is a marketed product.[28]
• Lotions: FELBINAC LOTION 3% 'RAKOOL' is also available.[29]

D. Clinical Development and Regulatory Pathway in China

China has emerged as the exclusive hub for the innovation and development of the intravenous formulation of felbinac trometamol.

• Sponsor and Focus: The entire late-stage clinical program has been driven by a domestic company, Shijiazhuang Yiling Pharmaceutical Co. Ltd..[11]
• Development Status: The intravenous drug has been systematically advanced through Phase I, II, and pivotal Phase III clinical trials within the Chinese healthcare system.[22] According to pharmaceutical intelligence databases, this has culminated in the filing of a New Drug Application (NDA) or Biologic License Application (BLA) with the Chinese National Medical Products Administration (NMPA) for the indication of postoperative pain.[23]

This geographical concentration suggests a strategic decision to capitalize on a domestic market and navigate a familiar regulatory environment, bypassing the significant hurdles that would be faced in Western markets. The future of this innovative formulation appears, for now, to be entirely dependent on the Chinese market.

The following table provides a summary of the global regulatory landscape.

Table 5: Overview of Global Regulatory Status and Availability

Region/Country	Regulatory Body	Status of Felbinac / Felbinac Trometamol	Key Notes
USA	FDA	Not Approved 56	No evidence of current or past approval. History of parent drug (fenbufen) withdrawal presents a significant regulatory barrier. No US clinical trials registered.
Europe	EMA	Approved (Topical Formulations) 57	Long-standing availability as a topical agent (e.g., gel, foam). First EU authorization date is listed as 1986.58 No evidence of IV formulation approval.
UK	MHRA	Discontinued (Topical Formulations) 41	The brand Traxam® has been discontinued, and no generic versions are currently available.
Japan	PMDA	Approved (Topical Formulations) 20	Widespread use in various topical forms, including patches, tapes, ointments, and lotions.27
China	NMPA	IV Formulation under Review / Approved 23	The exclusive center for the development of IV felbinac trometamol. Phase I-III trials are complete, and an NDA/BLA has been filed for postoperative pain.

VIII. Expert Analysis and Future Perspectives

A. Synthesis of Evidence: Positioning Felbinac in Modern Analgesia

Felbinac presents a compelling dual identity in the landscape of modern analgesic therapy. Its character and clinical utility are defined not as a single entity, but by its two distinct formulations, each with its own history, evidence base, and risk-benefit profile.

As a topical agent, felbinac is a legacy product, a veteran of the musculoskeletal pain market in Europe and Japan. Its primary therapeutic rationale is sound: providing localized anti-inflammatory and analgesic effects while minimizing the significant systemic risks associated with oral NSAIDs. For acute soft-tissue injuries, its efficacy appears comparable to oral ibuprofen, making it a valuable and safer first-line option. However, its position in the treatment of chronic conditions like osteoarthritis is more tenuous. Evidence for its efficacy beyond two weeks is lacking, and in direct head-to-head comparisons, it has been shown to be inferior to topical diclofenac, a more extensively studied and perhaps more potent agent in its class. Therefore, while useful, topical felbinac may be considered a second-tier option for many indications where more robust alternatives exist.

As an intravenous agent, felbinac trometamol represents a modern pharmaceutical success story. It is the product of targeted formulation science designed to solve a specific problem—the poor water solubility of the parent drug. The resulting formulation has demonstrated clean, linear, and predictable pharmacokinetics, making it an ideal candidate for the controlled environment of perioperative care. The focused clinical development program in China has positioned it as a potentially valuable non-opioid, parenteral analgesic for managing moderate-to-severe postoperative pain. In this role, it aligns perfectly with the contemporary goals of multimodal, opioid-sparing analgesia.

B. Analysis of the Intravenous Formulation's Potential and Hurdles

The potential of intravenous felbinac trometamol is significant, but its path to widespread global use is fraught with challenges.

• Potential: Within its target market, primarily China, it has the potential to become a key component of postoperative pain protocols. Its predictable pharmacokinetics and demonstrated efficacy in reducing opioid consumption could improve patient outcomes and align with enhanced recovery after surgery (ERAS) principles. By avoiding the need for lipid emulsions, it offers a formulation advantage over some other injectable NSAIDs.
• Hurdles: The hurdles are substantial and twofold. First are the inherent risks of the systemic NSAID class. Despite a good tolerability profile in carefully selected clinical trial populations, the real-world risks of gastrointestinal, cardiovascular, and renal complications remain. These risks will limit its use to short-term administration in relatively healthy surgical patients. The second, and larger, hurdle is regulatory. The negative safety history of its parent drug, fenbufen, creates a formidable barrier to entry in Western markets. Without a major pharmaceutical partner willing to undertake the significant financial and regulatory risk of pursuing an NDA with the FDA or a Marketing Authorisation Application with the EMA, it is highly unlikely that intravenous felbinac trometamol will see use outside of Asia in the foreseeable future.

C. Unmet Needs and Directions for Future Research

Several key questions remain, pointing to clear directions for future research.

• Long-Term Topical Efficacy: For topical felbinac, the most significant evidence gap is the lack of high-quality, long-duration (i.e., longer than four weeks) randomized controlled trials in chronic osteoarthritis.[45] Such studies are needed to determine if it has a durable benefit or if its utility is confined to short-term flare-ups.
• Comparative IV Efficacy and Safety: Should intravenous felbinac trometamol gain approval, its precise place in therapy will need to be defined by large-scale, head-to-head comparative trials against other standard parenteral analgesics, such as ketorolac, intravenous ibuprofen, and intravenous paracetamol (acetaminophen). Post-market surveillance and real-world evidence studies will also be critical for understanding its safety profile in a broader and more complex patient population than was included in the pivotal trials.
• Mechanism of Action: Further investigation into potential COX-independent mechanisms, such as the modulation of acid-sensing ion channels (ASICs), could provide a deeper understanding of its analgesic properties and potentially differentiate it from other NSAIDs.[36]
• Novel Formulations: Continued research into advanced transdermal delivery systems, such as the cubosome hydrogels currently in preclinical development, may offer a way to improve the efficacy and sustain the action of topical felbinac, potentially overcoming some of the limitations of current gel and patch formulations.[61]

In conclusion, felbinac is a drug of two tales. The topical formulation is an established, safe, but perhaps less potent option among its peers. The intravenous formulation is a promising, modern tool for a specific clinical niche, yet its future is largely confined by geography and the long shadow of its predecessor.

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