A Comprehensive Pharmacological and Clinical Monograph of Fluorometholone (DB00324)

I. Executive Summary

Fluorometholone is a potent, synthetic, fluorinated corticosteroid primarily utilized in ophthalmology for its robust anti-inflammatory properties. Classified as a small molecule drug, it functions as a high-affinity agonist for the glucocorticoid receptor (GR). Its mechanism of action involves the modulation of gene expression, leading to the synthesis of anti-inflammatory proteins that inhibit the upstream release of arachidonic acid, thereby blocking the production of key inflammatory mediators such as prostaglandins and leukotrienes. This broad-spectrum activity makes it highly effective for treating a wide array of corticosteroid-responsive inflammatory conditions of the anterior segment of the eye, including allergic conjunctivitis, uveitis, keratitis, and post-operative inflammation.

Fluorometholone is available in various topical ophthalmic formulations, including suspensions (0.1% and 0.25%) and an ointment (0.1%), marketed under brand names such as FML®, FML Forte®, and Flarex®. The acetate ester form, fluorometholone acetate, is a more lipophilic prodrug designed for enhanced corneal penetration. Clinically, Fluorometholone is often favored over more potent corticosteroids like dexamethasone due to a comparatively lower propensity to cause a significant elevation in intraocular pressure (IOP). However, its therapeutic efficacy must be carefully balanced against a significant safety profile inherent to all corticosteroids. Prolonged use (10 days or longer) carries a well-documented risk of inducing or exacerbating glaucoma, posterior subcapsular cataract formation, delayed wound healing, and an increased susceptibility to secondary ocular infections. Consequently, its use requires strict medical supervision, including routine monitoring of IOP, and is contraindicated in patients with most viral, fungal, or mycobacterial infections of the eye. The dosing regimen is tailored to the severity of inflammation, typically involving an intensive initial frequency followed by a gradual tapering to prevent rebound inflammation.

II. Identification and Physicochemical Properties

1.1. Nomenclature and Identifiers

Fluorometholone is a well-characterized synthetic steroid with a comprehensive set of identifiers across chemical, pharmacological, and regulatory databases, ensuring its unambiguous identification for research, clinical, and commercial purposes.

Its primary non-proprietary name is Fluorometholone.[1] The Chemical Abstracts Service (CAS) has assigned it the registry number 426-13-1, which is a universally recognized unique identifier.[1] The systematic name, according to the International Union of Pure and Applied Chemistry (IUPAC), is (6S,8S,9R,10S,11S,13S,14S,17R)-17-acetyl-9-fluoro-11,17-dihydroxy-6,10,13-trimethyl-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-3-one.[1]

The drug is known by numerous synonyms and historical research codes, reflecting its development and commercial history. These include 9α-Fluoro-11β,17α-dihydroxy-6α-methylpregna-1,4-diene-3,20-dione, 6α-Methyl-9α-fluoro-21-desoxyprednisolone, U-8614, and NSC 33001.[4] Commercial synonyms and brand names include Oxylone, Cortilet, Delmeson, Efflumidex, Fluaton, and Flumetholon.[1]

Its profile is cataloged in major biomedical databases under specific accession numbers: DrugBank ID DB00324, PubChem Compound ID (CID) 9878, ChEBI ID CHEBI:31625, ChEMBL ID CHEMBL1200600, FDA Unique Ingredient Identifier (UNII) SV0CSG527L, and KEGG Drug ID D01367.[1] Under the Anatomical Therapeutic Chemical (ATC) classification system, it is categorized under multiple codes reflecting its diverse applications, with S01BA07 (Ophthalmologicals; Anti-inflammatory agents; Corticosteroids, plain) being its primary designation for ophthalmic use.[3] Other codes include D07AB06 for dermatological preparations and C05AA06 for agents used in treating hemorrhoids.[3]

1.2. Chemical Structure and Properties

The pharmacological activity and formulation characteristics of Fluorometholone are direct consequences of its distinct molecular structure and resulting physicochemical properties.

The empirical chemical formula for Fluorometholone is C22​H29​FO4​.[1] It has an average molecular weight of approximately 376.47 g/mol and a precise monoisotopic mass of 376.20498756 Da.[1] Structurally, it is a synthetic, fluorinated glucocorticoid derived from Δ¹-progesterone.[3] Its structure is distinguished by several key substitutions on the steroid nucleus that are critical to its activity profile:

• A fluoro group at the 9α position, which significantly potentiates glucocorticoid activity and enhances anti-inflammatory effects.
• A methyl group at the 6α position, which further increases anti-inflammatory potency and reduces the mineralocorticoid (salt-retaining) effects common to other steroids.
• Hydroxy groups at the 11β and 17α positions, which are important for receptor binding and glucocorticoid activity.
• A lack of a hydroxyl group at the C21 position, classifying it as a "21-desoxy" steroid.[6]

This specific combination of molecular features represents a deliberate effort in medicinal chemistry. The 9α-fluoro and 6α-methyl groups are classic modifications to amplify the desired anti-inflammatory effects. The absence of the C21-hydroxyl group, however, is a particularly noteworthy feature. This structural deviation from highly potent corticosteroids like dexamethasone is believed to be a primary contributor to Fluorometholone's reduced tendency to elevate intraocular pressure. It is hypothesized that this modification alters its metabolism within the trabecular meshwork—the primary site of aqueous humor outflow and IOP regulation—leading to a more favorable safety profile in this specific regard. Thus, the molecule is engineered to be a potent topical anti-inflammatory agent while attempting to mitigate one of the most significant risks associated with this drug class.

Physicochemically, Fluorometholone presents as an odorless, white to slightly yellow-white crystalline powder.[7] It exhibits a high melting point, ranging from 280°C to 303°C, at which it undergoes some decomposition.[3] Its solubility profile is a defining characteristic for its formulation. It is practically insoluble in water, with a reported solubility of approximately 30 mg/L at 25°C, and is only slightly soluble in alcohol.[3] It is, however, soluble in solvents like dimethyl sulfoxide (DMSO).[4] This poor aqueous solubility makes it impossible to formulate as a simple solution for ophthalmic use and necessitates its preparation as a microfine sterile suspension to ensure adequate drug delivery to the ocular surface.[13] Its octanol-water partition coefficient (LogP) is 2.0, indicating a moderate lipophilicity that is essential for enabling its penetration across the lipid-rich layers of the cornea to reach target tissues in the anterior chamber.[3]

Table 1: Drug Identification and Physicochemical Properties of Fluorometholone
Category	Identifier / Property
Drug Identification
Primary Name	Fluorometholone
DrugBank ID	DB00324 2
CAS Registry Number	426-13-1 3
IUPAC Name	(6S,8S,9R,10S,11S,13S,14S,17R)-17-acetyl-9-fluoro-11,17-dihydroxy-6,10,13-trimethyl-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-3-one 1
UNII (FDA)	SV0CSG527L 3
PubChem CID	9878 1
ChEBI ID	CHEBI:31625 3
Primary ATC Code	S01BA07 (Corticosteroids, plain - Ophthalmological) 3
Physicochemical Properties
Molecular Formula	C22​H29​FO4​ 1
Molecular Weight	376.47 g/mol 11
Monoisotopic Mass	376.20498756 Da 2
Appearance	White to slightly yellow-white, odorless crystalline powder 11
Melting Point	280-303 °C (with decomposition) 3
Water Solubility	~30 mg/L (at 25 °C); practically insoluble 3
LogP	2.0 3

III. Pharmacology

3.1. Mechanism of Action

Fluorometholone exerts its therapeutic effects through a well-defined pathway characteristic of glucocorticoid hormones, acting as a potent agonist at the cytosolic glucocorticoid receptor (GR).[2] Its high affinity for this receptor is demonstrated by a half-maximal inhibitory concentration (

IC50​) of 1.5 nM and a dissociation constant (Kd​) of 2.8 nM in radioligand binding assays, underscoring its potency at the molecular level.[4]

The mechanism of action follows the classical model for steroid hormone signaling [2]:

1. Cellular Entry: Due to its lipophilic nature, Fluorometholone readily diffuses across the cell membrane of target cells in ocular tissues (e.g., conjunctiva, cornea, iris).
2. Receptor Binding and Activation: Inside the cell, it binds to the GR, which resides in the cytoplasm as part of a multi-protein complex that includes heat shock proteins (HSPs). This binding event induces a conformational change in the receptor, causing the dissociation of the HSPs and exposing the receptor's nuclear localization signals.
3. Nuclear Translocation: The activated Fluorometholone-GR complex then translocates from the cytoplasm into the cell nucleus.
4. Gene Regulation: Within the nucleus, the complex functions as a ligand-dependent transcription factor. It binds to specific DNA sequences known as Glucocorticoid Response Elements (GREs) located in the promoter regions of steroid-responsive genes.[2]

This interaction with GREs initiates the primary downstream anti-inflammatory effects through two main genomic mechanisms: transactivation and transrepression. The most critical of these is the transactivation of genes encoding anti-inflammatory proteins. A key target is the family of phospholipase A2 (PLA2) inhibitory proteins, collectively referred to as lipocortins (such as annexin A1).[2]

By upregulating the production of lipocortins, Fluorometholone establishes a powerful blockade at a critical upstream juncture of the inflammatory cascade. Lipocortins inhibit the activity of PLA2, the enzyme responsible for cleaving arachidonic acid from membrane phospholipids. Arachidonic acid is the essential precursor for the synthesis of a wide range of potent pro-inflammatory eicosanoids. By preventing its release, Fluorometholone effectively shuts down the cyclooxygenase (COX) and lipoxygenase (LOX) pathways, thereby inhibiting the production of both prostaglandins and leukotrienes.[2]

The consequence of this upstream intervention is a profound and broad-spectrum suppression of the inflammatory response. It addresses all cardinal signs of inflammation by inhibiting edema, fibrin deposition, capillary dilation, and leukocyte migration to the site of inflammation. Furthermore, it suppresses the chronic aspects of inflammation and tissue remodeling by inhibiting capillary and fibroblast proliferation, collagen deposition, and subsequent scar formation.[2] This comprehensive mechanism explains its efficacy in treating the diverse manifestations of ocular inflammation, from acute allergic reactions to chronic uveitis.

3.2. Pharmacokinetics (Ocular)

The clinical efficacy and safety of Fluorometholone are heavily influenced by its pharmacokinetic profile following topical ophthalmic administration. The primary goal is to achieve high, therapeutic concentrations in the anterior segment of the eye while minimizing systemic absorption and associated risks.

Absorption and Distribution:

Upon topical instillation, Fluorometholone is absorbed into ocular tissues, primarily through the cornea and conjunctiva, and distributes into the aqueous humor.16 Its moderate lipophilicity (LogP = 2.0) facilitates passage through the lipid-rich corneal epithelium. The acetate ester form, fluorometholone acetate, is even more lipophilic and is designed to act as a prodrug, enhancing corneal penetration.19 Studies in rabbits have shown that after administration of a 0.1% fluorometholone acetate suspension, the drug is rapidly absorbed, with peak concentrations appearing in the cornea at the earliest sampling time of 0.5 hours.15

Once inside ocular tissues, esterases rapidly hydrolyze fluorometholone acetate to release the active parent compound, Fluorometholone.[15] This bioconversion ensures that the active moiety is delivered to the target sites within the anterior chamber. Physiologically based pharmacokinetic (PBPK) modeling suggests that the route of absorption may differ by formulation; solutions may be absorbed primarily through the cornea, whereas suspensions, which have a longer residence time, may be absorbed significantly through the conjunctiva.[20]

Metabolism:

Metabolism of Fluorometholone occurs predominantly within local ocular tissues.16 The eye possesses metabolic enzymes capable of biotransforming corticosteroids. The formulation significantly impacts clearance; ophthalmic ointments, which remain on the ocular surface longer than suspensions, exhibit a lower metabolic clearance rate, leading to prolonged drug exposure at the site of action.16 Active transport systems within the cornea, lens, and ciliary epithelium may also play a role in the disposition of the drug within the eye.21

Systemic Exposure and Elimination:

A key feature of ophthalmic Fluorometholone is its minimal systemic absorption.16 It has demonstrated lower systemic penetration activity compared to more potent ocular steroids like dexamethasone.16 The low total dose administered with each application typically prevents systemic drug levels from reaching a clinically significant threshold.16 This pharmacokinetic property is fundamental to the drug's safety profile, as it largely circumvents the widespread adverse effects associated with systemic corticosteroid therapy. However, the barrier is not absolute. In cases of very frequent, long-term use, or compromised ocular surface integrity, enough drug may be absorbed to cause rare systemic effects like Cushing's syndrome or adrenal suppression.22 To further minimize this risk, patients are often advised to perform nasolacrimal occlusion (applying pressure to the tear duct for 1-2 minutes after instillation), which reduces drainage through the nasolacrimal duct and subsequent absorption from the highly vascular nasal mucosa.15

Any drug that does enter systemic circulation is expected to be metabolized by the liver and its metabolites excreted via urine and bile, consistent with the elimination pathways for other corticosteroids.[15] Comprehensive systemic pharmacokinetic parameters such as volume of distribution, systemic half-life, and clearance have not been well-characterized for the ophthalmic route.[2]

IV. Clinical Use and Therapeutic Indications

4.1. Approved Indications

Fluorometholone is a cornerstone therapy for a broad spectrum of inflammatory ocular conditions that are responsive to corticosteroid treatment. Its primary, FDA-approved indication is for the management of inflammation affecting the palpebral and bulbar conjunctiva, the cornea, and the anterior segment of the globe.[3]

This overarching indication encompasses a variety of specific clinical scenarios where suppression of the inflammatory response is the therapeutic goal. These include:

• Allergic Conditions: Symptomatic relief of allergic conjunctivitis, characterized by itching, redness, and swelling.[8]
• Anterior Segment Inflammation: Treatment of non-infectious inflammatory conditions such as chronic anterior uveitis, iritis, and cyclitis.[8]
• Corneal Conditions: Management of superficial punctate keratitis and other forms of non-infectious keratitis.[8]
• Post-Operative and Post-Traumatic Inflammation: Control of inflammation following ocular surgery (e.g., cataract extraction) or physical/chemical injury to the eye.[26]
• Other Responsive Conditions: It is also used for conditions like blepharitis and keratoconjunctivitis, often in combination with an anti-infective agent.[8]

Beyond ophthalmology, Fluorometholone has been employed topically in dermatology as a moderately potent (Group II) corticosteroid for various skin disorders and has been included in preparations for treating hemorrhoids and acne.[2]

4.2. Formulations, Strengths, and Brand Names

To meet diverse clinical needs, Fluorometholone is available in several ophthalmic formulations and strengths, as both single-agent and combination products. The choice of formulation depends on the severity of the condition, the desired duration of action, and patient preference.

Dosage Forms and Strengths:

• Ophthalmic Suspension (Eye Drops): This is the most common formulation. It is available in two main strengths:
• 0.1%: Available as both Fluorometholone base and Fluorometholone acetate.[13]
• 0.25%: Available as Fluorometholone base for more severe inflammation.[22]
• Ophthalmic Ointment: A 0.1% formulation is available, which provides prolonged contact time with the ocular surface and is often used for overnight application or in cases of severe inflammation.[18]

Brand Names and Products:

Fluorometholone is marketed globally under several brand names. In the United States, common brands include:

• FML® (Fluorometholone Ophthalmic Suspension, USP) 0.1% [8]
• FML Forte® (Fluorometholone Ophthalmic Suspension, USP) 0.25% [8]
• FML® S.O.P.® (Fluorometholone Ophthalmic Ointment, USP) 0.1% [26]
• Flarex® (Fluorometholone Acetate Ophthalmic Suspension) 0.1% [8]
• Other brand names include Fluor-Op® and Eflone®.[8]

Combination Products:

For inflammatory conditions where a concurrent superficial bacterial infection is present or suspected, Fluorometholone is available in fixed-dose combinations with an anti-infective agent:

• With Sulfacetamide Sodium: Marketed as FML-S® Liquifilm.[8]
• With Tobramycin: Available in combination with the aminoglycoside antibiotic tobramycin.[18]

Key Excipients:

Most ophthalmic suspensions of Fluorometholone contain benzalkonium chloride as a preservative.13 This is a critical consideration for patients who wear soft contact lenses, as the preservative can be absorbed by the lens material, potentially causing ocular irritation.36

Table 2: Commercial Formulations and Strengths of Fluorometholone
Brand Name	Active Ingredient	Dosage Form	Strength(s)	Key Preservative
FML® Liquifilm®	Fluorometholone	Ophthalmic Suspension	0.1% 17	Benzalkonium chloride 13
FML Forte®	Fluorometholone	Ophthalmic Suspension	0.25% 22	Benzalkonium chloride
FML® S.O.P.®	Fluorometholone	Ophthalmic Ointment	0.1% 26	N/A (often preservative-free)
Flarex®	Fluorometholone Acetate	Ophthalmic Suspension	0.1% 35	Benzalkonium chloride 35
FML-S® Liquifilm®	Fluorometholone, Sulfacetamide Sodium	Ophthalmic Suspension	0.1%, 10% 18	Benzalkonium chloride

4.3. Dosage and Administration

The proper dosage and administration of Fluorometholone are critical for maximizing therapeutic efficacy while minimizing the risk of adverse effects. The regimen must be individualized based on the specific formulation, the severity of the inflammation, and the patient's response to treatment.

General Administration Instructions:

• Hygiene: Patients should wash their hands thoroughly before and after use.[24]
• Contamination Avoidance: The tip of the dropper bottle or ointment tube must not touch the eye, eyelids, or any other surface to prevent contamination of the sterile product.[17]
• Suspension Preparation: All suspension formulations must be shaken well immediately before each use to ensure uniform distribution of the drug particles.[24]

Administration Technique:

• Eye Drops (Suspension): The patient should tilt their head back, look upward, and gently pull down the lower eyelid to create a small pocket (the conjunctival sac). The prescribed number of drops is then instilled into this pocket. The eye should be gently closed for 1 to 2 minutes. Applying gentle pressure to the inner corner of the eye (nasolacrimal occlusion) for this period is recommended to minimize systemic absorption.[24]
• Eye Ointment: A thin ribbon of ointment (approximately 1/2 inch or 1.3 cm) is squeezed into the conjunctival sac. The patient should blink gently and then close the eye for 1 to 2 minutes to allow the ointment to spread over the ocular surface.[24]

Treatment Duration and Discontinuation:

A crucial aspect of Fluorometholone therapy is that it should not be stopped abruptly, especially in chronic conditions. Abrupt cessation can lead to a rebound of inflammation. Therefore, once a favorable response is achieved, the dosage should be gradually tapered by decreasing the frequency of application.17 The patient should be re-evaluated by their physician if signs and symptoms fail to improve after two days of therapy.17

The dosing strategy for Fluorometholone is a clear reflection of the principles of acute inflammation management. The initial high-frequency dosing acts as a "loading" phase, designed to quickly achieve therapeutic drug concentrations in ocular tissues to overwhelm the inflammatory cascade and bring it under control. Once this is achieved, typically within 24 to 48 hours, maintaining such a high dose is unnecessary and increases the risk of side effects. The regimen then transitions to a lower-frequency maintenance phase. The final, gradual taper is essential to allow the body's natural inflammatory control mechanisms to resume function without a sudden withdrawal of the potent external anti-inflammatory agent. This carefully orchestrated protocol is vital for successful clinical outcomes.

Table 3: Dosage and Administration Guidelines
Formulation	Patient Population	Initial Dosing (First 24-48h)	Maintenance Dosing
Fluorometholone Suspension 0.1% / 0.25%	Adults & Children ≥2 years	1 drop every 4 hours 17	1 drop 2 to 4 times daily 17
Fluorometholone Acetate Suspension 0.1%	Adults	2 drops every 2 hours 35	1 to 2 drops 4 times daily 35
Fluorometholone Ointment 0.1%	Adults & Children ≥2 years	Apply 1/2 inch ribbon every 4 hours 18	Apply 1/2 inch ribbon 1 to 3 times daily 18
Note: Pediatric dosage must be determined by a physician. Therapy should be tapered gradually upon discontinuation. Re-evaluation is necessary if no improvement is seen after 2 days.

V. Safety and Tolerability Profile

5.1. Adverse Drug Reactions

While Fluorometholone is an effective anti-inflammatory agent, its use is associated with a range of potential adverse effects, from minor local irritation to serious, vision-threatening complications. The most significant risks are linked to prolonged use (defined as 10 days or longer).

Significant Risks Associated with Long-Term Use:

• Elevated Intraocular Pressure (IOP) and Glaucoma: This is the most common and clinically significant serious adverse effect.[23] Prolonged use can induce ocular hypertension in susceptible individuals ("steroid responders"), which, if untreated, can lead to glaucomatous optic nerve damage, progressive visual field loss, and ultimately, blindness.[17] While Fluorometholone is recognized as having a lower propensity to raise IOP compared to dexamethasone, the risk remains substantial and mandates routine IOP monitoring during therapy.[13]
• Posterior Subcapsular Cataract Formation: Chronic use of ophthalmic corticosteroids is a well-established cause of cataracts, leading to clouding of the lens and progressive vision impairment.[17]
• Immunosuppression and Secondary Infections: By suppressing the local immune response, Fluorometholone can increase the risk of secondary ocular infections. It may mask, activate, or exacerbate existing bacterial, viral (especially herpes simplex), or fungal infections.[22] Fungal infections of the cornea are particularly prone to develop with long-term steroid application and should be suspected in any case of persistent corneal ulceration.[17]
• Delayed Wound Healing: Corticosteroids inhibit fibroblast proliferation and collagen deposition, which can delay corneal and scleral wound healing after surgery or trauma.[17]
• Corneal and Scleral Thinning: In patients with pre-existing conditions that cause thinning of the cornea or sclera, the use of topical corticosteroids can exacerbate this process and may lead to globe perforation.[17]

Common and Local Adverse Effects:

• Application Site Reactions: Transient burning or stinging upon instillation is commonly reported.[24]
• Visual Disturbances: Temporary blurred vision immediately following application is common, particularly with the ointment formulation.[24]
• Ocular Irritation: Other symptoms include a foreign body sensation, eye pain, itching, redness (hyperemia), increased tearing (lacrimation), and eye discharge.[17]

Less Common and Rare Adverse Effects:

• Ocular: Mydriasis (pupil dilation), ptosis (drooping of the upper eyelid), loss of accommodation, and acute anterior uveitis have been reported.[2]
• Systemic: Although extremely uncommon due to minimal systemic absorption, rare cases of systemic hypercorticoidism (Cushing's syndrome) and adrenal suppression have been documented following intensive, long-term topical use.[17]
• Other: Dysgeusia (taste perversion) and skin rash have also been reported.[23]

The safety profile of Fluorometholone presents a clinical challenge. Its primary advantage over other potent steroids is its reduced impact on IOP, which can create a perception of it being a "safer" drug. However, this relative benefit must not lead to clinical complacency. The fundamental risks inherent to the corticosteroid class—including cataractogenesis, immunosuppression, and delayed healing—remain fully present. The risk of IOP elevation, while reduced, is not eliminated and still demands the same level of clinical vigilance, including regular slit-lamp examinations and IOP measurements, as would be required for any other ophthalmic corticosteroid.

Table 4: Summary of Adverse Drug Reactions Associated with Fluorometholone
System Organ Class	Frequency	Adverse Reaction
Eye Disorders	Common (1% to 10%)	Increased intraocular pressure 23
	Very Rare (<0.01%)	Corneal calcification (with phosphate-containing drops in patients with corneal damage) 23
	Incidence Not Known	Posterior subcapsular cataract formation, delayed wound healing, secondary ocular infection (bacterial, viral, fungal), corneal/scleral thinning and perforation, blurred vision, eye irritation/pain, stinging/burning on instillation, foreign body sensation, conjunctival/ocular hyperemia, eye pruritus, increased lacrimation, eye/eyelid edema, eye discharge, mydriasis, ptosis, visual field defects, acute anterior uveitis, keratitis, corneal ulcers 2
Endocrine Disorders	Rare (<0.1%)	Systemic hypercorticoidism, adrenal suppression (with intensive long-term use) 22
Gastrointestinal Disorders	Incidence Not Known	Dysgeusia (taste perversion) 17
Immune System Disorders	Incidence Not Known	Hypersensitivity, allergic reactions 17
Skin and Subcutaneous Tissue Disorders	Incidence Not Known	Rash 17

5.2. Contraindications

The use of Fluorometholone is absolutely contraindicated in certain conditions where its immunosuppressive effects could lead to severe and uncontrolled infections or other harm. These include [13]:

• Viral Infections: Most viral diseases of the cornea and conjunctiva, particularly acute epithelial herpes simplex keratitis (dendritic keratitis), as steroids can cause geographic ulceration and worsen the infection. Other viral contraindications include vaccinia and varicella.
• Mycobacterial Infections: Ocular tuberculosis and other mycobacterial infections of the eye.
• Fungal Infections: Fungal diseases of any ocular structures (keratomycosis).
• Hypersensitivity: Known or suspected hypersensitivity to Fluorometholone, other corticosteroids, or any of the inactive ingredients in the formulation.

5.3. Warnings and Precautions

To ensure safe use, several critical warnings and precautions must be observed:

• IOP Monitoring: Intraocular pressure must be routinely monitored in all patients receiving therapy for 10 days or longer.[17]
• Use in Glaucoma: The drug should be used with caution in patients with a history of glaucoma, as it may further increase IOP.[17]
• History of Herpes Simplex: Use requires great caution in patients with a history of ocular herpes simplex, as steroids can reactivate the latent virus. Frequent slit-lamp microscopy is essential for monitoring.[17]
• Contact Lens Wear: Formulations containing the preservative benzalkonium chloride can be absorbed by soft contact lenses. Patients should be instructed to remove lenses prior to instillation and wait at least 15 minutes before reinserting them.[22]
• Pregnancy: Fluorometholone is classified as FDA Pregnancy Category C. Animal studies in rabbits have demonstrated that it is embryocidal and teratogenic, causing fetal loss and abnormalities such as cleft palate and spina bifida at low multiples of the human dose. There are no adequate and well-controlled studies in pregnant women. Therefore, it should be used during pregnancy only if the potential benefit to the mother clearly justifies the potential risk to the fetus.[17]
• Lactation: It is unknown whether topical ophthalmic administration of Fluorometholone results in sufficient systemic absorption to produce detectable quantities in human milk. Systemically administered corticosteroids are known to be excreted in breast milk. Caution should be exercised when administering to a nursing woman.[16]

5.4. Drug and Disease Interactions

Drug-Drug Interactions:

Due to the minimal systemic absorption of ophthalmic Fluorometholone, clinically significant systemic drug-drug interactions are not expected and are generally considered a low risk.14 While some databases list numerous potential moderate interactions based on the systemic corticosteroid drug class, these are largely theoretical for the ophthalmic route of administration.46 No specific interactions with other ophthalmic products have been formally established, but it is standard practice to wait at least 5 to 10 minutes between the administration of different eye medications.14

Disease Interactions:

The most significant interactions are with pre-existing diseases of the eye:

• Ocular Infections: As detailed in the contraindications, Fluorometholone can mask the signs of an acute purulent infection or exacerbate existing viral, fungal, or mycobacterial infections.[46]
• Ocular Toxicities: The drug can worsen conditions such as glaucoma by increasing IOP and can lead to perforation in diseases that cause corneal or scleral thinning.[46]

VI. Regulatory and Manufacturing Information

6.1. Regulatory History and Status

Fluorometholone has a long history of clinical use and regulatory approval in major markets worldwide.

• United States: It was first approved for use in the United States by the Food and Drug Administration (FDA) on January 11, 1972.[5] Subsequent formulations, such as FML Forte® (0.25% suspension) and Flarex® (0.1% acetate suspension), received approval on April 23, 1986, and in 1986, respectively.[51] It is regulated as a prescription-only (Rx) medication.[26]
• International Status: The drug is also approved in numerous other countries. For example, its first authorization in the United Kingdom was in April 1980, and in New Zealand, it was first approved in April 1972.[14]
• Generic Availability: Following the expiration of key patents, generic versions of Fluorometholone ophthalmic suspension 0.1% have become available. In a notable development, on January 10, 2024, Amneal Pharmaceuticals announced the FDA approval and launch of a generic version, which was granted 180 days of competitive generic therapy (CGT) exclusivity, a status intended to encourage the marketing of generics for drugs with inadequate competition.[50]

6.2. Patents and Synthesis

The development and manufacturing of Fluorometholone have evolved significantly since its inception, reflecting broader trends in pharmaceutical chemistry and process optimization.

• Historical Context: The compound was first described in U.S. Patent 2,867,637, filed in the 1950s.[54] The initial synthesis routes described in this and other early patents were often lengthy and complex, involving numerous chemical steps and sometimes relying on microbial fermentation for specific transformations (e.g., 1,2-dehydrogenation or 11β-hydroxylation). These processes, while innovative for their time, were not always ideal for efficient, large-scale industrial production.[54] For instance, some routes required 8 to 12 steps starting from commercially available precursors like 17-α-hydroxyprogesterone.[54]
• Evolution of Synthesis: The complexity of these early manufacturing methods likely contributed to the drug's long-standing status as a branded product. Over time, advancements in synthetic organic chemistry led to the development of more efficient, purely chemical synthesis pathways. Newer patent literature, such as EP2246359A1, describes streamlined processes that avoid fermentation, reduce the number of steps, and improve yields and purity, making the synthesis more amenable to industrial scale-up.[54]
• Impact on Market: This evolution in manufacturing science is a key enabler of generic competition. The development of more cost-effective production methods, combined with the expiration of the original composition of matter and use patents, created the economic and legal conditions necessary for generic manufacturers to enter the market. The recent launch of a generic Fluorometholone product is the direct outcome of this long-term scientific and industrial progression, ultimately increasing patient access to this important medication.[50]

VII. Conclusion

Fluorometholone (DB00324) is a well-established synthetic corticosteroid that holds a significant place in the ophthalmic therapeutic armamentarium. Its efficacy is rooted in a potent, receptor-mediated mechanism that provides broad-spectrum suppression of the ocular inflammatory cascade. The deliberate molecular design of the drug, particularly the absence of a C21-hydroxyl group, confers a clinical advantage by reducing its propensity to elevate intraocular pressure compared to other potent corticosteroids, making it a preferred agent for many inflammatory conditions.

However, its clinical utility is intrinsically linked to a comprehensive understanding of its significant risk profile. The potential for serious adverse effects, including glaucoma, cataract formation, and secondary infections with prolonged use, cannot be overstated. The clinical management of patients on Fluorometholone must therefore be guided by a principle of vigilant monitoring and cautious application: using the lowest effective dose for the shortest possible duration, adhering to strict administration and tapering protocols, and respecting its absolute contraindications.

The evolution of its synthesis from complex early methods to efficient modern processes, culminating in recent generic availability, illustrates the complete lifecycle of a successful pharmaceutical agent. For clinicians, Fluorometholone remains an invaluable tool for managing ocular inflammation, provided its use is governed by a thorough appreciation of the delicate balance between its potent therapeutic benefits and its inherent risks.

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