Comprehensive Monograph: Hydrocortisone Acetate (DB14539)

1.0 Executive Summary

Hydrocortisone acetate (DrugBank ID: DB14539; CAS Number: 50-03-3) is a synthetic corticosteroid, specifically the acetate ester of the endogenous glucocorticoid hormone cortisol.[1] First approved for clinical use in 1951, it has remained a cornerstone of therapy for over seven decades due to its potent anti-inflammatory and immunosuppressive properties.[1] As a small molecule drug, its therapeutic action is mediated through a well-defined molecular mechanism. Upon cellular entry, hydrocortisone acetate binds to and activates the cytoplasmic glucocorticoid receptor (GR). The activated drug-receptor complex translocates to the nucleus, where it modulates gene expression through both transactivation of anti-inflammatory genes (e.g., Annexin A1) and transrepression of pro-inflammatory genes (e.g., those encoding cytokines and chemokines).[1] A key downstream effect is the inhibition of phospholipase A2, which blocks the arachidonic acid cascade and prevents the synthesis of inflammatory mediators such as prostaglandins and leukotrienes.[1]

The clinical utility of hydrocortisone acetate is exceptionally broad, a versatility driven largely by formulation science that tailors its pharmacokinetic profile for specific therapeutic goals. It is available in a wide array of formulations, including topical creams and ointments for corticosteroid-responsive dermatoses, systemic oral tablets and injectable suspensions for adrenal insufficiency and severe inflammatory or autoimmune disorders, and rectal foams and suppositories for localized inflammatory bowel diseases like ulcerative colitis.[5]

The safety profile of hydrocortisone acetate is highly dependent on the route of administration and duration of therapy. Localized applications are generally well-tolerated, with adverse effects typically limited to the application site, such as skin irritation or atrophy with long-term use.[2] Systemic administration or significant percutaneous absorption, however, carries the risk of classic corticosteroid-related side effects, including hypothalamic-pituitary-adrenal (HPA) axis suppression, metabolic disturbances, osteoporosis, and increased susceptibility to infection.[9]

Despite its long history, hydrocortisone acetate remains an active area of clinical investigation, demonstrating its continued relevance in modern medicine. Recent pivotal Phase 3 clinical trials have evaluated novel suppository formulations for the treatment of ulcerative colitis, yielding positive results that may lead to new approved indications.[11] This ongoing development highlights a strategic focus on optimizing drug delivery to enhance localized efficacy and minimize systemic exposure, thereby reinventing a legacy molecule to meet contemporary therapeutic needs.

2.0 Chemical Identity and Physicochemical Properties

A precise understanding of the chemical and physical characteristics of hydrocortisone acetate is fundamental to appreciating its formulation, pharmacological activity, and stability.

2.1 Molecular Identity and Nomenclature

Hydrocortisone acetate is a small molecule drug classified as a synthetic adrenocortical steroid.[1] Chemically, it is the 21-acetate ester of hydrocortisone, which is the pharmaceutical name for the endogenous hormone cortisol.[1] This esterification at the C-21 position is a critical structural modification that influences its physicochemical properties and therapeutic applications.

• **Systematic (IUPAC) Name:**phenanthren-17-yl]-2-oxoethyl] acetate.[1]
• Chemical Formula: .[2]
• Molecular Weight: 404.50 g/mol.[1]
• Structural Identifiers:
• SMILES: CC(=O)OCC(=O)[C@]1(CC[C@@H]2[C@@]1(C[C@@H]([C@H]3[C@H]2CCC4=CC(=O)CC[C@]34C)O)C)O.[1]
• InChI: InChI=1S/C23H32O6/c1-13(24)29-12-19(27)23(28)9-7-17-16-5-4-14-10-15(25)6-8-21(14,2)20(16)18(26)11-22(17,23)3/h10,16-18,20,26,28H,4-9,11-12H2,1-3H3/t16-,17-,18-,20+,21-,22-,23-/m0/s1.[1]
• InChIKey: ALEXXDVDDISNDU-JZYPGELDSA-N.[1]
• Synonyms and Trade Names: The compound is known by numerous synonyms, reflecting its long history and widespread use. Common synonyms include Hydrocortisone 21-acetate, Cortisol 21-acetate, Cortisol acetate, and Compound F acetate. It has been marketed under a vast number of trade names, including Cortef, Cortifoam, Cortaid, Carmol HC, Abbocort, Aceto-Cort, Bambicort, and Chemysone.[1]

2.2 Physicochemical Properties

The physical properties of hydrocortisone acetate dictate its behavior in various pharmaceutical dosage forms and its interaction with biological systems.

• Appearance: It is described as a white to practically white or off-white crystalline powder that is odorless.[2]
• Solubility: The molecule is practically insoluble in water, with a reported solubility of 1 mg/100 mL.[2] It is slightly soluble in anhydrous ethanol and methylene chloride and sparingly soluble in chloroform.[2] It is soluble in solvents such as Dimethyl sulfoxide (DMSO).[15] This pronounced lipophilicity and poor aqueous solubility are defining features that heavily influence its formulation strategies.
• Melting Point: It has a melting point of approximately 223 °C, at which it decomposes.[2]
• Stability and Storage: Hydrocortisone acetate is a stable compound but can be sensitive to light and moisture (hygroscopic).[2] It is incompatible with strong oxidizing agents.[2] For laboratory and manufacturing purposes, it is recommended to be stored at room temperature in a cool, dark place (below 15°C), and potentially under an inert gas to ensure stability.[15] As a supplied chemical, it typically has a shelf life of at least two years when stored properly.[15]

A comprehensive list of identifiers is provided in Table 2.1 to facilitate cross-referencing across various chemical, pharmacological, and regulatory databases.

Table 2.1: Key Chemical and Physical Identifiers for Hydrocortisone Acetate

Identifier Type	Value	Source(s)
DrugBank ID	DB14539	1
CAS Number	50-03-3	1
UNII (FDA GSRS)	3X7931PO74	1
European Community (EC) Number	200-004-4	1
ChEBI ID	CHEBI:17609	1
ChEMBL ID	CHEMBL1091	1
PubChem CID	5744	14
KEGG ID	C02821, D00165	1
NCI Thesaurus Code	C61785	1
RTECS Number	GM8960000	17
Beilstein/REAXYS Number	2066841	13
MDL Number	MFCD00037714	2

2.3 The Structure-Function Relationship

The specific chemical structure of hydrocortisone acetate is the result of a deliberate modification designed to optimize its therapeutic performance. The addition of an acetate ester group at the C-21 position of the parent hydrocortisone molecule is a classic pharmaceutical strategy that significantly increases the molecule's lipophilicity (fat solubility).[21] This structural alteration is not merely a minor change but is the primary determinant of the drug's enhanced efficacy in certain applications and its suitability for specific delivery systems.

The increased lipophilicity directly improves the drug's ability to penetrate the lipid-rich stratum corneum, the outermost layer of the skin. This enhanced percutaneous absorption is a key reason why the introduction of the acetate moiety was found to improve the topical activity of hydrocortisone fivefold.[21] The drug's poor water solubility and lipophilic character make it an ideal candidate for formulation in oleaginous or emulsion-based vehicles like ointments and creams, which further facilitate its partitioning into the skin.[2]

Furthermore, this modification is crucial for its use in depot injections. When formulated as a microcrystalline suspension for intra-articular or intramuscular injection, the sparingly soluble hydrocortisone acetate particles dissolve slowly at the injection site. This creates a local reservoir of the drug, leading to a slow onset of action but a prolonged therapeutic effect, which is highly desirable for managing chronic joint inflammation.[24] Thus, the acetate ester functions to transform the rapidly acting hydrocortisone into a molecule optimized for sustained, localized delivery, illustrating a fundamental principle of medicinal chemistry where a simple structural change yields a distinct and clinically valuable pharmacokinetic profile.

3.0 Pharmacology and Mechanism of Action

The therapeutic effects of hydrocortisone acetate are rooted in its ability to mimic and amplify the actions of endogenous glucocorticoids, primarily through the modulation of gene expression to suppress inflammatory and immune responses.

3.1 Molecular Mechanism of Action

Hydrocortisone acetate is a synthetic corticosteroid that functions as an agonist for the glucocorticoid receptor (GR).[1] Its mechanism of action is a multi-step process that ultimately alters cellular protein synthesis.

1. Cellular Entry and Receptor Binding: Owing to its lipophilic steroid structure, hydrocortisone acetate readily diffuses across the cell membrane into the cytoplasm.[3] Inside the cell, it binds to the GR, which resides in the cytoplasm in an inactive complex with heat shock proteins.[1] This binding event displaces the associated proteins and induces a conformational change in the receptor, activating it.[3]
2. Nuclear Translocation and DNA Interaction: The activated hydrocortisone-GR complex then translocates from the cytoplasm into the cell nucleus.[1] Within the nucleus, the complex acts as a ligand-dependent transcription factor, binding to specific DNA sequences known as glucocorticoid response elements (GREs) located in the promoter regions of target genes.[3]
3. Genomic Effects and Transcription Modulation: The interaction with GREs leads to the modulation of gene transcription, a process that underlies the majority of the drug's effects.

• Transactivation: The complex can directly bind to GREs to increase the rate of transcription of specific genes. This leads to the upregulation and synthesis of anti-inflammatory proteins, most notably lipocortin-1 (also known as Annexin A1).[1]
• Transrepression: The complex can also suppress gene expression. This often occurs through protein-protein interactions where the activated GR interferes with other transcription factors, such as nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1), preventing them from binding to their respective DNA response elements. This leads to the downregulation of numerous pro-inflammatory genes, including those that code for cytokines (e.g., interleukins), chemokines, and cellular adhesion molecules.[1]

4. Inhibition of Key Inflammatory Pathways: The genomic effects translate into the suppression of critical inflammatory cascades.

• Inhibition of the Arachidonic Acid Pathway: By increasing the synthesis of lipocortin-1, hydrocortisone acetate indirectly inhibits the enzyme phospholipase A2. This enzyme is responsible for cleaving arachidonic acid from cell membrane phospholipids. By blocking this initial step, the drug prevents the entire downstream synthesis of potent inflammatory mediators, including prostaglandins and leukotrienes.[1]
• Inhibition of the NF-κB Pathway: NF-κB is a master regulator of the inflammatory response. Hydrocortisone acetate interferes with its activation, in part by promoting the production of the inhibitor of NF-κB (IκB). IκB binds to NF-κB in the cytoplasm, preventing its translocation to the nucleus and thereby blocking its ability to activate the transcription of a wide range of inflammatory genes.[3]

3.2 Pharmacodynamics

The molecular actions of hydrocortisone acetate manifest as a triad of powerful pharmacodynamic effects: anti-inflammatory, immunosuppressive, and anti-mitotic.

• Anti-inflammatory Effects: This is the primary and most clinically relevant effect. It results from the coordinated suppression of pro-inflammatory mediators and cells. A key observable effect is the vasoconstriction of small blood vessels in the upper dermis, which reduces erythema (redness) and decreases the delivery of inflammatory cells and mediators to the site of injury or irritation.[2] The drug also reduces capillary permeability, leading to a decrease in inflammatory exudation and edema (swelling).[2]
• Immunosuppressive Effects: Hydrocortisone acetate broadly suppresses the immune system. It inhibits the maturation, differentiation, and proliferation of various immune cells, particularly T-lymphocytes.[1] This leads to reduced antigen presentation, diminished T-cell activation, and decreased antibody production.[3] The drug can also induce apoptosis (programmed cell death) in certain leukocyte populations, further contributing to its immunosuppressive action.[3] These effects are beneficial in treating autoimmune and allergic disorders but also underlie the increased risk of infection associated with systemic corticosteroid use.
• Anti-mitotic Effects: In hyperproliferative conditions like psoriasis, corticosteroids exert an anti-mitotic effect, reducing the rate of epidermal cell division.[23] This is thought to be a secondary effect mediated by the induction of lipocortin.[23] This anti-proliferative action also affects fibroblasts in the dermis, inhibiting collagen synthesis. While therapeutically useful, this effect is also responsible for the common adverse effect of skin atrophy (thinning) seen with prolonged topical use.
• Metabolic and Mineralocorticoid Effects: As the active moiety is hydrocortisone, the drug retains the full spectrum of activities of the natural hormone. This includes effects on carbohydrate, protein, and lipid metabolism, which can lead to hyperglycemia with systemic exposure.[3] It also possesses significant mineralocorticoid activity, promoting sodium and water retention and potassium excretion.[7] While this dual activity is essential for its use as replacement therapy in adrenal insufficiency, the mineralocorticoid effects are often undesirable when the drug is used primarily for its anti-inflammatory properties.[25] In terms of anti-inflammatory potency, hydrocortisone serves as the reference standard (potency = 1) and is less potent than more highly modified synthetic derivatives like prednisone (4 times more potent) and dexamethasone (approximately 40 times more potent).[24]

3.3 Pharmacokinetics (ADME)

The absorption, distribution, metabolism, and excretion (ADME) profile of hydrocortisone acetate is critically dependent on its formulation and route of administration. It is important to distinguish it from cortisone acetate, a related but distinct compound that is an inactive prodrug requiring hepatic conversion to hydrocortisone to become active.[24] Hydrocortisone acetate, being an ester of the already active hydrocortisone, primarily undergoes hydrolysis to release its active moiety, with its overall pharmacokinetic profile being governed by the rate of this process and its absorption from the administration site.

3.3.1 Absorption

• Topical: Percutaneous absorption is highly variable. Key determining factors include the pharmaceutical vehicle (occlusive ointments enhance absorption more than creams, which are more enhancing than lotions), the integrity of the epidermal barrier (absorption is increased through inflamed or damaged skin), and the use of occlusive dressings (which can dramatically increase systemic absorption).[21] The anatomical site of application also plays a major role; absorption can range from as low as 0.2% on the sole of the foot to as high as 36.2% on the scrotum.[30]
• Rectal: Following rectal administration of hydrocortisone acetate foam, the drug is systemically absorbed. A pharmacokinetic study in which endogenous cortisol was suppressed showed that the absolute bioavailability was approximately 30% in healthy volunteers but was reduced to about 16% in patients with colitis, a counterintuitive finding suggesting that inflammation may impair rather than enhance absorption in this context.[35] Peak plasma concentrations ( ) were reached at approximately 2.5 to 2.8 hours ().[35] Regulatory guidance for bioequivalence studies of rectal formulations requires the measurement of plasma hydrocortisone levels.[36]
• Oral: While hydrocortisone acetate is not typically formulated for oral use, its active metabolite, hydrocortisone, is readily absorbed from the gastrointestinal tract. Oral hydrocortisone exhibits high bioavailability, averaging 96%, with peak plasma concentrations achieved in approximately 1.2 hours.[30]
• Intramuscular/Intra-articular Injection: The injectable formulation of hydrocortisone acetate is a suspension of microcrystals. Following injection into a muscle or joint space, these crystals dissolve slowly, leading to a gradual and prolonged absorption over 24 to 48 hours. This results in a slow onset of action but a sustained local and systemic effect.[24]

3.3.2 Distribution

Once hydrocortisone is absorbed into the systemic circulation, it is rapidly distributed throughout the body to tissues including muscle, liver, skin, intestines, and kidneys.[24] It is extensively bound to plasma proteins, with over 90% associated with corticosteroid-binding globulin (also known as transcortin) and, to a lesser extent, albumin.[2] Only the small, unbound fraction of the drug is pharmacologically active and able to diffuse into cells to interact with receptors.[24] The apparent volume of distribution for hydrocortisone is reported to be in the range of 0.4-0.7 L/kg.[2]

3.3.3 Metabolism

The primary metabolic step for hydrocortisone acetate is hydrolysis of the ester bond to release free hydrocortisone. This can occur systemically or locally within tissues. Free hydrocortisone is then primarily metabolized in the liver via several pathways.[23] A key enzyme system is the 11β-hydroxysteroid dehydrogenases (11β-HSDs), which reversibly convert hydrocortisone into its inactive 11-keto metabolite, cortisone.[30] The hydrocortisone and cortisone are further reduced to various inactive tetrahydro-metabolites, which are then conjugated with glucuronic acid or sulfate to form water-soluble compounds for excretion.[24] Additionally, evidence suggests that gut microbiota can contribute to the metabolism of hydrocortisone acetate through deacylation, converting it to hydrocortisone within the gastrointestinal tract.[14]

3.3.4 Elimination

The water-soluble glucuronide and sulfate conjugates of hydrocortisone metabolites are primarily excreted by the kidneys into the urine.[23] A minimal amount of the drug is excreted unchanged in the urine.[2] A portion of the metabolites may also be eliminated through the bile into the feces.[23] The systemic elimination half-life of hydrocortisone is relatively short, averaging around 1.5 hours (range of 1.2 to 2.0 hours).[2] Despite the short half-life, the duration of its biological effects, particularly the genomic effects on protein synthesis, is much longer, with a systemic duration of action listed as 8 to 12 hours.[30]

3.4 Pharmacokinetics as the Driver of Therapeutic Strategy

The significant variation in the pharmacokinetic profiles of hydrocortisone acetate across its different formulations is not an inconsistency but rather the central element of its therapeutic versatility. The selection of a specific dosage form—be it a topical cream, a rectal foam, or an injectable suspension—is a deliberate clinical decision aimed at precisely controlling the drug's absorption, distribution, and duration of action to match the therapeutic objective. This represents a classic example of how pharmaceutical formulation can be used to optimize the clinical performance of a drug molecule.

For the treatment of localized inflammatory dermatoses, the goal is to achieve a high concentration of the drug within the affected skin layers while minimizing systemic absorption to avoid unwanted side effects.[21] The lipophilic nature of hydrocortisone acetate, combined with an occlusive ointment or cream base, facilitates this targeted delivery, allowing for potent local anti-inflammatory action with limited systemic exposure.[2]

Similarly, for ulcerative proctitis, a disease confined to the rectum, the therapeutic strategy is to deliver the drug directly to the site of inflammation. Rectal foams and suppositories are designed for this purpose. Pharmacokinetic studies confirm that while some systemic absorption occurs, it is significantly lower than with oral administration, and resulting plasma levels often remain within the normal physiological range for cortisol, thereby reducing the risk of systemic corticosteroid toxicity.[35]

In stark contrast, the treatment of adrenal insufficiency requires reliable and predictable systemic replacement of cortisol. In this case, oral tablets of hydrocortisone (the active form without the ester) are the formulation of choice, leveraging their high oral bioavailability and rapid absorption to mimic the body's natural diurnal cortisol rhythm.[7] Therefore, the diverse ADME profiles are not accidental but are the result of targeted formulation science that enables a single active moiety to effectively and safely treat a wide spectrum of diseases, from a localized skin rash to a life-threatening systemic hormone deficiency.

4.0 Clinical Indications and Therapeutic Applications

Hydrocortisone acetate is indicated for a vast array of conditions, leveraging its anti-inflammatory and immunosuppressive properties. The specific formulation dictates its primary clinical use, allowing for targeted therapy that is either localized or systemic.

4.1 Topical Formulations (Creams, Ointments, Lotions)

Topical preparations are the most common form of hydrocortisone acetate and are primarily indicated for the relief of the inflammatory and pruritic (itching) manifestations of corticosteroid-responsive dermatoses.[5]

• Specific Conditions: These formulations are widely used to manage a variety of skin conditions, including:
• Eczema and Dermatitis: Atopic dermatitis, contact dermatitis (e.g., from soaps, detergents, cosmetics, or jewelry), and seborrheic dermatitis.[2]
• Psoriasis: For mild to moderate cases.[44]
• Other Inflammatory Rashes: Heat rash (prickly heat), nappy rash (diaper dermatitis), and reactions to insect bites and stings.[44]
• Vehicle Selection: The choice of vehicle is tailored to the type of skin lesion. Creams, which are less greasy, are suitable for moist or weeping skin. Ointments, being more occlusive and moisturizing, are preferred for dry, scaly, or hyperkeratotic lesions. Lotions are best for application over large or hairy areas of the body.[23]

4.2 Systemic Formulations (Oral Tablets, Injections)

Systemic formulations of hydrocortisone (or its salts/esters) are used for conditions requiring broad anti-inflammatory or immunosuppressive effects, or for hormone replacement therapy.

• Primary Indications:
• Endocrine Disorders: As replacement therapy for primary or secondary adrenocortical insufficiency (Addison's disease), congenital adrenal hyperplasia, and non-suppurative thyroiditis.[5]
• Rheumatic and Collagen Diseases: As adjunctive therapy for rheumatoid arthritis, psoriatic arthritis, lupus (systemic lupus erythematosus), and dermatomyositis.[5]
• Allergic States: For control of severe or incapacitating allergic conditions such as severe asthma, allergic rhinitis, and drug hypersensitivity reactions.[7]
• Gastrointestinal Diseases: To manage critical periods of inflammatory bowel disease, including ulcerative colitis and Crohn's disease.[5]
• Other Conditions: A wide range of other conditions including hematologic disorders (e.g., acquired hemolytic anemia), certain neoplastic diseases (e.g., leukemias, lymphomas), and severe respiratory or ophthalmic inflammatory conditions.[7]
• Injectable Hydrocortisone Acetate: The suspension form of hydrocortisone acetate is specifically intended for local injection into inflamed joints (intra-articular), bursae, or soft tissues to provide potent, localized anti-inflammatory relief for conditions like arthritis or epicondylitis.[21] It is important to note that this suspension formulation is not for intravenous use.[53] Other, more soluble salts of hydrocortisone, such as sodium succinate or sodium phosphate, are used for IV or IM administration when rapid, systemic effects are required.[25]

4.3 Rectal Formulations (Foams, Suppositories, Enemas)

Rectal formulations are designed to deliver hydrocortisone acetate directly to the site of inflammation in the lower gastrointestinal tract, thereby maximizing local efficacy and minimizing systemic side effects.

• Primary Indications:
• Inflammatory Bowel Disease: Treatment of ulcerative colitis (particularly ulcerative proctitis), cryptitis, and radiation-induced proctitis.[5] These formulations are often an alternative for patients who have difficulty retaining traditional steroid enemas.[35]
• Anorectal Conditions: Symptomatic relief of inflammation, swelling, and itching associated with hemorrhoids, anal fissures, and pruritus ani.[6]

4.4 Combination Therapies

To enhance efficacy and address multiple symptoms simultaneously, hydrocortisone acetate is frequently formulated in combination with other active pharmaceutical ingredients.

• With Local Anesthetics: Combined with agents like lidocaine, pramoxine, or benzocaine to provide both anti-inflammatory and analgesic (pain-relieving) effects for painful anorectal conditions.[6]
• With Anti-infective Agents:
• Antifungals: Combined with miconazole or iodoquinol for treating inflamed dermatoses where a secondary fungal infection is present or suspected.[6]
• Antibiotics: Combined with neomycin, polymyxin B, or bacitracin for infected dermatoses or for treating inflammatory ophthalmic conditions like conjunctivitis where there is a bacterial component.[6]
• With Antivirals: A combination with acyclovir is available for the topical treatment of recurrent herpes labialis (cold sores).[50]

4.5 Investigational Uses and Clinical Development

Hydrocortisone acetate continues to be evaluated in clinical trials for new formulations and indications, underscoring its ongoing therapeutic relevance.

• Atopic Dermatitis: A Phase 1 clinical trial (NCT04615962) has been conducted to investigate a novel topical cream formulation, SNG100, which contains hydrocortisone acetate, for the treatment of moderate atopic dermatitis.[58]
• Ulcerative Colitis: A pivotal Phase 3 trial, known as the cessa trial (NCT04469686), recently completed evaluation of a novel 90 mg hydrocortisone acetate suppository delivered with a proprietary applicator. The trial demonstrated statistically significant efficacy in achieving clinical remission in patients with ulcerative proctitis.[11]
• Internal Hemorrhoids: A Phase 2 trial (NCT03335774) has been completed, which assessed the safety and efficacy of a 25 mg hydrocortisone acetate suppository for providing symptomatic relief from internal hemorrhoids.[60]

5.0 Dosage and Administration Guidelines

The administration of hydrocortisone acetate must be carefully tailored to the individual patient, the specific condition being treated, and the pharmaceutical formulation being used. A core principle across all uses is to employ the lowest effective dose for the shortest duration necessary to control the disease process. For treatment lasting more than a few weeks, gradual tapering of the dose is essential to prevent adrenal insufficiency upon discontinuation.[24]

5.1 Topical Administration (Creams, Ointments, Lotions)

For dermatological conditions, a thin film of the cream, ointment, or lotion should be applied directly to the affected area of the skin.

• Frequency: The usual frequency of application is two to four times daily, depending on the severity of the condition.[33]
• Application Technique: The preparation should be gently rubbed into the skin. The treated area should not be bandaged or covered with an occlusive dressing unless specifically instructed by a physician, as this can significantly increase systemic absorption.[33]
• Special Populations: For infants being treated in the diaper area, tight-fitting diapers or plastic pants should be avoided as they can act as occlusive dressings.[33]
• Duration: Over-the-counter (OTC) topical hydrocortisone acetate products are typically recommended for use for no longer than seven consecutive days without medical consultation.[45]

5.2 Systemic Administration (Oral - Hydrocortisone)

Oral hydrocortisone is used for systemic conditions and requires careful dose titration.

• Adrenocortical Insufficiency (Adults): The typical replacement dose is 15 to 25 mg per day, administered orally in two or three divided doses. To mimic the natural circadian rhythm of cortisol, the largest dose is given in the morning upon waking.[31]
• Anti-inflammatory (Adults): The initial oral dose for inflammatory conditions can range widely, from 20 mg to 240 mg per day, depending on the severity of the disease.[31]
• Administration: To minimize gastrointestinal irritation, tablets may be taken with food or milk.[28] Oral granules are available for pediatric use and can be sprinkled onto a spoonful of soft food, such as applesauce or yogurt, and consumed immediately.[28]

5.3 Injectable Administration (Hydrocortisone Acetate)

The injectable suspension of hydrocortisone acetate is for local administration into joints or soft tissues and is not for intravenous use.[53]

• Intra-articular/Soft Tissue Injection (Adults): The dose typically ranges from 10 to 75 mg, depending on the size of the joint and the severity of inflammation. Injections are generally repeated at intervals of two to three weeks as needed.[25]

5.4 Rectal Administration (Foam, Suppositories)

Rectal formulations are administered directly into the rectum for localized treatment.

• Ulcerative Proctitis (Foam): The standard dose is one applicatorful, which delivers 90 mg of hydrocortisone acetate, administered once or twice daily for two to three weeks. Once clinical improvement is noted, the frequency may be reduced to every other day as part of a tapering schedule.[39]
• Ulcerative Colitis (Suppository - Investigational): The recent Phase 3 cessa trial evaluated a 90 mg hydrocortisone acetate suppository administered either once daily or twice daily for a 28-day treatment period, followed by a 10-day taper.[11]
• Internal Hemorrhoids (Suppository - Investigational): A Phase 2 clinical trial investigated a 25 mg hydrocortisone acetate suppository administered twice daily for a duration of 14 days.[60]

6.0 Analysis of Recent Clinical Evidence

Recent clinical trials involving hydrocortisone acetate have focused on developing novel formulations and delivery systems to improve targeted therapy for localized inflammatory conditions, particularly in gastroenterology. These studies highlight a strategic effort to enhance the therapeutic index of this well-established drug.

6.1 Pivotal Phase 3 Trial in Ulcerative Colitis (cessa / NCT04469686)

The most significant recent development is the positive outcome of the cessa trial, a pivotal Phase 3 study sponsored by Cristcot LLC. This trial was designed to evaluate the safety and efficacy of a novel 90 mg hydrocortisone acetate suppository administered with the proprietary Sephure® applicator for the treatment of active ulcerative proctitis.[11]

• Study Design: This was a robustly designed randomized, multi-center, double-blind, placebo-controlled study with three parallel arms. A total of 171 eligible patients were randomized to receive either the 90 mg hydrocortisone acetate suppository once daily (QD), twice daily (BID), or a matching placebo for a 28-day treatment period, which was followed by a 10-day dose taper.[11]
• Primary Endpoint: The primary efficacy endpoint was the rate of clinical remission at Day 29. Remission was rigorously defined by a Modified Mayo Score of 0-2, which required a rectal bleeding sub-score of 0, a stool frequency sub-score of 0 or 1, and endoscopic evidence of mucosal healing (endoscopic sub-score of 0 or 1).[11]
• Efficacy Results: The trial successfully met its primary endpoint. A pooled analysis of the active treatment arms showed that 20.2% of patients receiving hydrocortisone acetate achieved clinical remission, compared to only 2.1% of patients in the placebo group, a difference that was statistically significant.[11] When analyzed by dosing regimen, the once-daily arm demonstrated a 23.0% remission rate, while the twice-daily arm had a 17.5% remission rate.[11]
• Secondary Endpoints: The study also demonstrated rapid onset of action. A significant clinical response, defined by a reduction in both rectal bleeding and stool frequency, was observed as early as Day 15 in both active treatment arms.[11]
• Safety and Compliance: The investigational product was well-tolerated. Adverse events were generally mild and consistent with the known safety profile of corticosteroids, with no statistically significant differences observed between the treatment and placebo arms.[11] Notably, patient compliance was exceptionally high, reaching 97% in the once-daily arm, suggesting that the novel applicator and dosing regimen are highly acceptable to patients.[11]
• Regulatory Status: With primary study completion in July 2024, the sponsor has announced plans to submit a New Drug Application (NDA) to the U.S. FDA in the first quarter of 2025, positioning this product as a potential new first-line therapy for ulcerative proctitis.[11]

6.2 Phase 2 Trial in Internal Hemorrhoids (NCT03335774)

Further highlighting the focus on localized anorectal conditions, a Phase 2 trial was conducted to evaluate a lower-strength hydrocortisone acetate suppository for symptomatic internal hemorrhoids.[60]

• Study Design: This was a randomized, double-blind, placebo-controlled, multicenter study involving approximately 103 subjects.[60]
• Treatment Regimen: Patients were randomized to receive either a 25 mg hydrocortisone acetate suppository or a placebo suppository, administered twice daily for a 14-day treatment period.[60]
• Outcome Measures: The primary outcome measures were the reduction in swelling of the internal hemorrhoids, assessed visually via anoscopy, and the reduction in the severity of itching, as reported by patients using a daily questionnaire, both evaluated at Day 15.[60]
• Status: This study was completed in March 2021, providing foundational data for the potential development of this formulation for hemorrhoidal disease.[60]

A summary of the key efficacy results from the pivotal cessa trial is presented in Table 6.1.

Table 6.1: Summary of Key Phase 3 cessa Trial Results (NCT04469686)

Endpoint	Placebo Group	HCA QD Group	HCA BID Group	Pooled Active vs. Placebo
Primary: Clinical Remission at Day 29	2.1%	23.0%	17.5%	20.2% vs. 2.1% (Statistically Significant)
Secondary: Rapid Clinical Response at Day 15	Not Reported	Achieved	Achieved	Not Reported

Data sourced from Cristcot press release.[11] HCA = Hydrocortisone Acetate; QD = Once Daily; BID = Twice Daily.

6.3 The Re-Invention of a Legacy Drug through Pharmaceutical Innovation

The recent clinical development programs for hydrocortisone acetate, especially the cessa trial, exemplify a sophisticated and increasingly prevalent strategy in the pharmaceutical industry: the repositioning and optimization of a legacy drug through innovation in formulation and drug delivery. Rather than pursuing the high-risk, high-cost path of discovering a novel molecular entity, this approach leverages the extensive existing knowledge of a well-characterized drug like hydrocortisone acetate, which has been in clinical use for over 70 years.[1]

The fundamental pharmacology and general safety profile of hydrocortisone are thoroughly understood. Its primary limitation, particularly for chronic use, is the risk of systemic side effects when absorbed into the bloodstream.[7] The cessa trial did not test a new mechanism of action; instead, it tested an improved method of delivering the existing drug directly to the site of localized disease—the rectal mucosa in ulcerative proctitis.[11]

The innovation lies in the combination of a novel suppository formulation with the Sephure® applicator. The sponsor's press release explicitly highlights that this delivery system is designed to enhance patient compliance and that the formulation allows for "rapid metabolism and localized efficacy, reducing systemic exposure".[11] The remarkably high compliance rate of 97% observed in the once-daily arm of the trial provides strong validation for this patient-centric design approach.[11] This strategy effectively mitigates the primary drawback of corticosteroid therapy by maximizing local drug concentration where it is needed and minimizing the amount that enters the systemic circulation. This approach represents a lower-risk development pathway that can yield significant clinical value by addressing unmet needs in patient adherence and safety, thereby demonstrating how foundational molecules can be continuously reinvented to maintain their relevance in modern therapeutics.

7.0 Safety Profile, Contraindications, and Warnings

The safety profile of hydrocortisone acetate is well-characterized and is highly dependent on the dose, duration of treatment, and route of administration. While localized therapy is generally safe, systemic exposure carries a significant risk of adverse effects common to all corticosteroids.

7.1 Adverse Effects

Adverse reactions can be broadly categorized into local effects from topical application and systemic effects resulting from significant absorption or direct systemic administration.

• Local Adverse Effects (Topical/Rectal Application): These are the most common side effects but are typically mild and reversible. They include:
• Application Site Reactions: Burning, itching, irritation, erythema (redness), and dryness are frequently reported upon initial application but often subside with continued use.[2]
• Dermatological Changes: Folliculitis, hypertrichosis (excessive hair growth), acneiform eruptions, hypopigmentation (lightening of the skin), and perioral dermatitis can occur.[2] With prolonged or extensive use, more significant changes such as skin atrophy (thinning), telangiectasia (visible small blood vessels), and striae (stretch marks) can develop. Striae are often permanent.[2]
• Systemic Adverse Effects: These effects are dose- and duration-dependent and arise when the drug is absorbed into the bloodstream in sufficient quantities.
• Endocrine System: The most significant systemic effect is reversible suppression of the hypothalamic-pituitary-adrenal (HPA) axis, which can lead to adrenal insufficiency if the drug is withdrawn abruptly. Chronic systemic exposure can produce manifestations of Cushing's syndrome (e.g., moon face, central obesity, weight gain), hyperglycemia, and glucosuria.[8]
• Fluid and Electrolyte Disturbances: Due to its mineralocorticoid activity, hydrocortisone can cause sodium and water retention, leading to edema and hypertension. It also increases potassium excretion, which can result in hypokalemia.[7]
• Musculoskeletal System: Long-term use can lead to muscle weakness (steroid myopathy), a decrease in muscle mass, and osteoporosis, which increases the risk of vertebral compression fractures. Aseptic necrosis of the femoral and humeral heads is a serious potential complication.[7]
• Gastrointestinal System: Systemic corticosteroids are associated with an increased risk of peptic ulcers, which may perforate or hemorrhage. Pancreatitis and abdominal distention have also been reported.[7]
• Neuro-psychiatric Effects: A range of psychiatric disturbances may occur, from euphoria, insomnia, and mood swings to severe depression and frank psychotic manifestations. Existing emotional instability may be aggravated.[7] Increased intracranial pressure with papilledema (pseudotumor cerebri) has been observed, usually after treatment cessation.[7]
• Ophthalmic Effects: Prolonged use may lead to the development of posterior subcapsular cataracts and glaucoma with possible damage to the optic nerves.[7]
• Effects in Children: Chronic corticosteroid therapy can interfere with normal growth and development in children, necessitating careful monitoring of height and weight.[7]

7.2 Toxicity

Hydrocortisone acetate has specific hazard classifications related to its potential for toxicity with prolonged or high-dose exposure.

• Reproductive Toxicity: The compound is classified under the Globally Harmonized System (GHS) with the hazard statement H360Df: "May damage the unborn child. Suspected of damaging fertility".[20] Therefore, its use during pregnancy is a risk-benefit decision, and it should only be used if the potential benefit to the mother justifies the potential hazard to the fetus.[7]
• Specific Target Organ Toxicity (Repeated Exposure): It is also classified with the hazard statement H373: "May cause damage to organs through prolonged or repeated exposure".[20] This reflects the wide range of systemic adverse effects on the musculoskeletal, endocrine, and other organ systems described above.
• Carcinogenicity: Hydrocortisone acetate is not listed as a carcinogen by the International Agency for Research on Cancer (IARC) or the National Toxicology Program (NTP).[22] However, there have been reports of Kaposi's sarcoma occurring in patients receiving corticosteroid therapy, often for chronic conditions. Discontinuation of the corticosteroid may result in clinical remission of the sarcoma.[7]

7.3 Contraindications and Precautions

There are several absolute contraindications and numerous important warnings and precautions associated with the use of hydrocortisone acetate.

• Absolute Contraindications:
• Patients with a known history of hypersensitivity to hydrocortisone acetate or any other component in the formulation.[2]
• Patients with systemic fungal infections, unless the corticosteroid is required to manage a drug reaction to antifungal therapy.[9]
• Intrathecal (injection into the spinal canal) administration is contraindicated.[70]
• Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids.[70]
• For rectal formulations, contraindications include intestinal obstruction, abscess, perforation, peritonitis, and fresh intestinal anastomoses.[39]
• Warnings and Precautions: While hydrocortisone acetate does not have a formal "black box warning" in the United States, its labeling contains numerous serious warnings.
• Increased Risk of Infection: Corticosteroids suppress the immune system and can mask the signs and symptoms of infection. This increases susceptibility to new infections and can lead to the exacerbation or reactivation of latent infections, such as tuberculosis or amebiasis. Viral illnesses like chickenpox and measles can have a more serious or even fatal course in patients on corticosteroids.[7]
• Cardiovascular Conditions: Use with caution in patients with hypertension, congestive heart failure, or a recent myocardial infarction, as corticosteroids can cause fluid retention and electrolyte imbalances.[9]
• Gastrointestinal Conditions: Use with caution in patients with peptic ulcer disease, diverticulitis, or ulcerative colitis due to an increased risk of gastrointestinal perforation.[9]
• Pheochromocytoma Crisis: There have been reports of fatal pheochromocytoma crisis after the administration of systemic corticosteroids. In patients with a suspected pheochromocytoma, the risk of this complication should be considered before administration.[66]
• Abrupt Discontinuation: Prolonged therapy should not be stopped abruptly. The dose must be tapered gradually to allow for the recovery of HPA axis function and to avoid symptoms of adrenal insufficiency.[9]

7.4 Drug and Food Interactions

Hydrocortisone acetate has a significant potential for interactions with other drugs, as well as some food interactions.

• Drug-Drug Interactions: A comprehensive drug interaction database lists over 600 potential interactions for hydrocortisone.[24] Key interactions include:
• Enzyme Inducers: Drugs that induce hepatic cytochrome P450 enzymes (e.g., phenobarbital, phenytoin, rifampin) can increase the metabolism of corticosteroids, potentially reducing their therapeutic effect and requiring a dose increase.[24]
• Enzyme Inhibitors: Drugs that inhibit these enzymes (e.g., ketoconazole, erythromycin, clarithromycin) can decrease corticosteroid metabolism, leading to increased plasma levels and a higher risk of side effects.[26]
• NSAIDs: Concomitant use with nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk of gastrointestinal ulceration and bleeding.[24]
• Diuretics: Co-administration with potassium-depleting diuretics (e.g., thiazides, furosemide) can enhance hypokalemia.[24]
• Anticoagulants: Corticosteroids may alter the response to oral anticoagulants like warfarin, necessitating close monitoring of prothrombin time (PT) and INR.[24]
• Food-Drug Interactions:
• Grapefruit Juice: Consumption of grapefruit juice may inhibit the metabolism of hydrocortisone, potentially increasing its levels in the body and the risk of side effects.[29]
• Dietary Considerations: During systemic therapy, dietary salt restriction and potassium supplementation may be necessary to manage the mineralocorticoid effects of fluid retention and potassium loss.[9]

8.0 Regulatory Status and Market Landscape

Hydrocortisone acetate has a long-established presence in global pharmaceutical markets, with a regulatory status that varies by strength, formulation, and country. It is available under a multitude of brand names as both a single agent and in combination products.

8.1 Regulatory Approvals and History

First approved for medical use in 1951, hydrocortisone acetate is one of the most well-established corticosteroids in clinical practice.[1]

• United States (U.S. FDA):
• Regulatory Status: The drug is available in both prescription (Rx-only) and over-the-counter (OTC) forms, depending on the strength and indication.[30]
• OTC Formulations: Low-strength topical creams and ointments (e.g., 1%) are commonly marketed under the FDA's OTC drug monograph system. This allows them to be sold without a prescription, provided they comply with the established regulations for ingredients, uses, and labeling. These products are not individually reviewed and approved by the FDA through an NDA.[45]
• Prescription Formulations: Higher-strength topical preparations (e.g., 2.5% cream), rectal foams, and injectable suspensions are available by prescription only. The 2.5% cream is typically approved via an Abbreviated New Drug Application (ANDA), which demonstrates its bioequivalence to a reference listed drug.[34] The rectal foam product Cortifoam® is approved under New Drug Application (NDA) #017351.[73]
• Orphan Drug Designation: On June 27, 2017, hydrocortisone acetate received an Orphan Drug Designation from the FDA for the "Treatment of pediatric ulcerative colitis." This designation provides incentives for the development of drugs for rare diseases. However, it is important to note that the drug is not yet FDA-approved for this specific orphan indication.[74]
• Australia (Therapeutic Goods Administration - TGA):
• Regulatory Status: Similar to the U.S., the availability of hydrocortisone acetate in Australia is tiered based on strength and formulation.
• Pharmacist Only Medicine (Schedule 3): Low-strength (1%) topical creams are registered on the Australian Register of Therapeutic Goods (ARTG) and are classified as Schedule 3 medicines. This means they are available from a pharmacy without a prescription but require consultation with a pharmacist.[46]
• Prescription Only Medicine (Schedule 4): Higher-strength formulations, injectable products, and specialized preparations like ophthalmic (eye) ointments are classified as Schedule 4 medicines and require a doctor's prescription.[79]
• Subsidization: Many hydrocortisone acetate products are subsidized for eligible patients under the Pharmaceutical Benefits Scheme (PBS) and the Repatriation Schedule of Pharmaceutical Benefits (RPBS), which reduces their out-of-pocket cost.[77]

8.2 Brand Names and Formulations

Given its long history and widespread use, hydrocortisone acetate is marketed under a vast number of brand names globally. Table 8.1 provides a selection of prominent brand names available in the United States and Australia.

Table 8.1: Select Brand Names of Hydrocortisone Acetate in the US and Australia

United States (USA)	Australia
Single Agent:	Single Agent:
Cortef	Sigmacort
Cortifoam	Cortic-DS
Anusol-HC	APOHEALTH Hydrocortisone
Cortaid	TRUST Hydrocortic Cream
Cortizone-10	Pharmacy Action Hydrocortisone
Proctocort	Siguent Hycor (eye ointment)
Westcort	TOPIDERM™
Locoid
Combination Products:
Cortisporin (w/ antibiotics)	Not Applicable
Pramosone (w/ pramoxine)	Not Applicable
Epifoam (w/ pramoxine)	Not Applicable
Xerese (w/ acyclovir)	Not Applicable
U-Cort (w/ urea)	Not Applicable

This list is not exhaustive. Brand names sourced from.[1]

The sheer number of available brands and formulations underscores the drug's foundational role in treating inflammatory conditions. The market landscape is characterized by a mix of innovator brands and a large number of generic and store-brand equivalents, particularly for the widely used topical formulations.

9.0 Expert Analysis and Future Directions

Hydrocortisone acetate stands as a testament to the enduring value of foundational molecules in pharmacology. Its seven-decade history is not one of obsolescence but of continuous adaptation, where the principles of pharmaceutical science have been applied to refine and repurpose a well-understood active ingredient to meet diverse clinical needs. The synthesis of the available data reveals that the drug's remarkable versatility is not an inherent property of the molecule alone but is fundamentally driven by formulation science that strategically manipulates its pharmacokinetic profile. By controlling the rate and extent of absorption, clinicians can either harness its potent systemic effects for life-threatening conditions or confine its action to a localized area, thereby maximizing efficacy while minimizing the significant risks associated with systemic corticosteroid exposure.

The implications of recent clinical research, particularly the positive results from the pivotal Phase 3 cessa trial for ulcerative colitis, are profound. This development signals a potential paradigm shift in the management of ulcerative proctitis. If approved, the novel 90 mg hydrocortisone acetate suppository could become a new first-line therapy, offering patients a well-tolerated, localized treatment with a rapid onset of action.[11] The success of this trial is not just about the drug itself but also about the innovative delivery system. The high patient compliance rate of 97% achieved with the Sephure® applicator underscores a critical trend in modern drug development: that the patient experience, ease of use, and adherence are integral components of therapeutic success, on par with the pharmacological activity of the drug.[11] This represents a sophisticated form of drug repositioning, leveraging a known safety profile to create a high-value, low-risk therapeutic solution.

Looking forward, the future of hydrocortisone acetate is likely to follow this trajectory of targeted delivery and patient-centric design. Further innovation can be anticipated in the development of advanced formulations that offer even greater control over drug release and tissue penetration. This could include novel topical vehicles for dermatological conditions that enhance efficacy with even lower systemic absorption, or new long-acting injectable suspensions for intra-articular use that reduce the frequency of administration. The Orphan Drug Designation for pediatric ulcerative colitis also points toward a focus on addressing unmet medical needs in specific, vulnerable populations where a favorable risk-benefit profile is paramount.[74] Ultimately, hydrocortisone acetate serves as a powerful case study, demonstrating that the therapeutic lifecycle of a drug is not finite. Through continuous innovation in formulation and delivery, the clinical utility of even the most established molecules can be expanded, ensuring their relevance and value to patients for decades to come.

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