[Betamethasone (DB00443): A Comprehensive Pharmacological and Clinical Monograph]

Section 1: Introduction and Drug Identification

1.1 Overview and Historical Context

Betamethasone is a potent, long-acting synthetic corticosteroid belonging to the glucocorticoid class of steroid hormones.[1] It is a fluorinated derivative of prednisolone, engineered to possess high glucocorticoid (anti-inflammatory) activity while exhibiting negligible mineralocorticoid (salt-retaining) effects.[2] This selective pharmacological profile makes it a cornerstone therapeutic agent for managing a vast spectrum of inflammatory, allergic, and autoimmune disorders.

The development of betamethasone represents a significant milestone in medicinal chemistry. Patented in 1958 and subsequently approved for medical use in the United States in 1961, it provided clinicians with a powerful new tool for controlling inflammation.[1] Its enduring clinical importance is underscored by its inclusion on the World Health Organization's (WHO) List of Essential Medicines, specifically for its cream and ointment formulations, which are considered fundamental for a basic health system.[1] Its widespread use continues to this day; in 2022, it was the 263rd most commonly prescribed medication in the United States, accounting for over 1 million prescriptions.[1]

Chemically, betamethasone is a stereoisomer of dexamethasone, another widely used synthetic corticosteroid. The two molecules share the same chemical formula and atomic connectivity but differ in the three-dimensional arrangement of the methyl group at the C-16 position of the steroid nucleus.[1] In betamethasone, this group is in the beta (

β) configuration, whereas in dexamethasone, it is in the alpha (α) configuration. This subtle structural distinction, while seemingly minor, has implications for their biological activity, receptor interactions, and even their respective impurity profiles in pharmaceutical manufacturing, where each can be an impurity of the other.[6] This isomeric relationship necessitates a careful comparative evaluation, which will be explored in subsequent sections of this report.

1.2 Physicochemical Properties and Nomenclature

A complete understanding of betamethasone begins with its fundamental chemical and physical identity. The molecule has been deliberately modified from the natural hydrocortisone structure to optimize its therapeutic properties. The addition of a fluorine atom at the 9α position dramatically enhances glucocorticoid activity, while the introduction of a 16β-methyl group nearly abolishes the undesirable mineralocorticoid activity.[1] This is a classic example of medicinal chemistry design to create a more potent and selective therapeutic agent. The key identifiers and physicochemical properties of the parent compound, betamethasone alcohol, are consolidated in Table 1.1.

Table 1.1: Key Identifiers and Physicochemical Properties of Betamethasone

Property Category	Detail	Source(s)
Identifiers
Common Name	Betamethasone	2
DrugBank ID	DB00443	2
CAS Number	378-44-9	2
FDA UNII	9842X06Q6M	5
Nomenclature
IUPAC Name	(8S,9R,10S,11S,13S,14S,16S,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-3-one	6
Synonyms	Bétaméthasone, Betametasona, 9-Fluoro-16β-methylprednisolone, Celestone, Flubenisolone, Becort, SCH 4831, NSC-39470	2
Chemical Formulae
Molecular Formula	C22​H29​FO5​	2
InChI	InChI=1S/C22H29FO5/c1-12-8-16-15-5-4-13-9-14(25)6-7-19(13,2)21(15,23)17(26)10-20(16,3)22(12,28)18(27)11-24/h6-7,9,12,15-17,24,26,28H,4-5,8,10-11H2,1-3H3/t12-,15-,16-,17-,19-,20-,21-,22-/m0/s1	1
InChIKey	UREBDLICKHMUKA-DVTGEIKXSA-N	1
SMILES	C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@@]4([C@]3([C@H](C[C@@]2([C@]1(C(=O)CO)O)C)O)F)C	6
Molecular Weights
Average Mass	392.46 g/mol	6
Monoisotopic Mass	392.199902243 Da	2
Physical Properties
Appearance	White to practically white, odorless, crystalline powder	5
Melting Point	~231-237 °C (with decomposition)	5
Solubility	Practically insoluble in water; sparingly soluble in alcohol; very slightly soluble in methylene chloride	5
pKa (Predicted)	12.13±0.70	5
LogP	1.9 - 2.01	5

Section 2: Comprehensive Pharmacology

2.1 Pharmacodynamics: Mechanism of Action

The diverse therapeutic effects of betamethasone stem from its potent interaction with the glucocorticoid receptor (GR), leading to profound changes in gene expression and cellular function. The mechanism is primarily genomic, involving a multi-step process that ultimately results in powerful anti-inflammatory, immunosuppressive, and antiproliferative actions.[13]

Receptor Binding and Nuclear Translocation

As a lipophilic steroid molecule, betamethasone readily diffuses across the cell membrane into the cytoplasm. There, it binds with high affinity to the inactive glucocorticoid receptor, which is part of a multiprotein complex that includes heat shock proteins (HSPs).[13] This binding event triggers a conformational change in the GR, causing the dissociation of the HSPs and other chaperone proteins. This unmasking of the GR's nuclear localization signal allows the activated betamethasone-GR complex to translocate from the cytoplasm into the cell nucleus.[13]

Modulation of Gene Transcription

Once inside the nucleus, the betamethasone-GR complex functions as a ligand-activated transcription factor. It primarily exerts its effects through two major pathways:

1. Transactivation: The complex binds directly to specific DNA sequences known as Glucocorticoid Response Elements (GREs) located in the promoter regions of target genes. This binding event recruits coactivator proteins and initiates the transcription of genes with anti-inflammatory properties. A key example of this is the upregulation of annexin-1 (also known as lipocortin-1), a protein that plays a crucial role in suppressing inflammation.[13]
2. Transrepression: The complex can also suppress gene expression, particularly of pro-inflammatory genes. This is often achieved indirectly by interfering with the activity of other key transcription factors, such as nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). By tethering to these factors, the GR complex prevents them from binding to their own response elements on DNA, thereby inhibiting the transcription of a wide array of pro-inflammatory molecules.[13]

Physiological Consequences

The net result of this genomic modulation is a powerful and multifaceted dampening of the inflammatory and immune responses.

• Anti-inflammatory Effect: Betamethasone's primary anti-inflammatory action is mediated by the inhibition of phospholipase A2 (PLA2), an effect driven by the increased synthesis of annexin-1. By inhibiting PLA2, betamethasone blocks the release of arachidonic acid from cell membranes, thereby halting the entire arachidonic acid cascade. This prevents the synthesis of potent inflammatory mediators, including prostaglandins and leukotrienes.[13] Concurrently, the transrepression of genes for cytokines (e.g., interleukins like IL-17 and IL-23, and tumor necrosis factor-alpha or TNF-α) and enzymes like cyclooxygenase-2 (COX-2) further reduces inflammation, capillary permeability, and the recruitment of leukocytes to the site of injury.[13]
• Immunosuppressive Effect: Betamethasone broadly suppresses the immune system by affecting the function and proliferation of nearly all immune cells. It particularly inhibits the function of T-lymphocytes and macrophages, reduces antigen presentation by dendritic cells, and stabilizes lysosomal membranes, preventing the release of tissue-damaging enzymes.[13] This widespread immunosuppression is the basis for its utility in treating autoimmune diseases and severe allergic reactions.
• Antiproliferative Effect: In certain diseases characterized by excessive cell growth, such as psoriasis, betamethasone exerts an antiproliferative effect. It inhibits the abnormal proliferation of keratinocytes, which is a key pathological feature of psoriatic plaques, contributing to the normalization of the epidermis.[14]

While the genomic pathway accounts for the majority of betamethasone's sustained effects, which can begin within hours and last for days, some rapid actions of corticosteroids are thought to be mediated by non-genomic mechanisms involving membrane-bound receptors and direct modulation of intracellular signaling pathways. This duality helps explain the full temporal spectrum of its clinical activity.

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

The pharmacokinetic profile of betamethasone is highly dependent on its route of administration and formulation. The processes of absorption, distribution, metabolism, and excretion dictate both its therapeutic efficacy and its potential for systemic toxicity. Understanding these parameters is fundamental to its safe and effective clinical use.

Absorption

• Systemic Administration: When administered orally or via injection, betamethasone is readily absorbed into the systemic circulation. Injectable formulations, such as those containing betamethasone sodium phosphate and betamethasone acetate, are designed to provide both a rapid onset of action (within approximately two hours) and a prolonged duration of effect, which can last for seven days or more.[1]
• Topical Administration: The percutaneous absorption of topical betamethasone is a critical variable that governs the balance between local efficacy and systemic risk. It is not a fixed value but is influenced by a combination of factors:
• Vehicle and Formulation: The vehicle in which the steroid is formulated plays a major role. Ointments, being more occlusive and lipophilic, generally provide greater skin penetration and are more potent than creams or lotions.[16] Furthermore, "augmented" formulations (e.g., Diprolene®) contain vehicles with penetration enhancers like propylene glycol, which significantly increase absorption and elevate the effective potency of the drug.[12]
• Epidermal Barrier Integrity: Absorption is minimal through normal, intact skin. However, it is substantially increased when the epidermal barrier is compromised, such as in inflammatory conditions like eczema or psoriasis, or in areas of broken skin.[19]
• Occlusion: The use of occlusive dressings (e.g., plastic wrap) over the application site dramatically increases hydration of the stratum corneum and can increase percutaneous absorption by a factor of 10 or more.[18]
• Application Site and Area: Absorption varies across different anatomical regions, being higher in areas with thinner skin (e.g., face, scrotum, axilla) compared to areas with thicker skin (e.g., palms, soles). Applying the product over a large body surface area also increases the total amount of drug absorbed systemically.[19]

This variability in topical absorption is the primary reason why a treatment intended for local effect can lead to significant systemic side effects, such as HPA axis suppression. The clinician's ability to use topical betamethasone safely is therefore directly dependent on the careful management of these pharmacokinetic variables.

Distribution

Once in the systemic circulation, regardless of the route of entry, betamethasone is bound to plasma proteins to a moderate extent, approximately 65%.[5] It has a volume of distribution of about 1.4 L/kg.[5] Betamethasone readily crosses the placenta, a key property that allows for its use in promoting fetal lung maturation in cases of threatened preterm labor.[1]

Metabolism

Betamethasone is primarily metabolized in the liver. For esterified forms like betamethasone dipropionate, the initial step involves hydrolysis to the active betamethasone alcohol and its primary metabolite, B17P. These compounds are then further metabolized, typically through hydroxylation (e.g., to 6β-hydroxy derivatives).[19]

Excretion

The metabolites of betamethasone are predominantly excreted by the kidneys into the urine.[19] A small portion of the drug, around 5%, is excreted unchanged in the urine.[5] Some metabolites may also be eliminated via the bile.[20] The systemic biological half-life of betamethasone is approximately 5.6 hours, classifying it as a long-acting corticosteroid.[5]

Section 3: Formulations and Clinical Applications

3.1 Pharmaceutical Preparations: Esters, Formulations, and Potency

The clinical versatility of betamethasone is largely due to the wide array of pharmaceutical preparations available. Medicinal chemists and pharmaceutical scientists have utilized esterification and sophisticated formulation science to create products tailored for specific diseases, administration routes, and body locations. This highlights a core principle of modern pharmacotherapy: the formulation is often as critical as the active pharmaceutical ingredient itself.

Ester Derivatives

Betamethasone is rarely used as the parent alcohol; instead, it is formulated as various esters to optimize its physicochemical properties for specific applications.[1]

• Betamethasone Dipropionate and Betamethasone Valerate: These are the most common esters for topical use. The addition of the dipropionate or valerate side chains increases the molecule's lipophilicity, which enhances its ability to penetrate the stratum corneum of the skin.[19] This targeted delivery to the epidermis and dermis maximizes local anti-inflammatory effects while aiming to minimize systemic absorption. In terms of potency, betamethasone dipropionate is generally considered stronger than betamethasone valerate.[16]
• Betamethasone Sodium Phosphate: This ester is highly water-soluble (hydrophilic). This property makes it ideal for creating aqueous solutions for parenteral (injectable) and oral administration, allowing for rapid systemic distribution.[1]

Dosage Forms and Combination Products

The choice between an ointment, cream, lotion, or foam is a critical therapeutic decision based on the characteristics of the skin condition being treated.

• Topical Formulations: A diverse range of vehicles is used to deliver topical betamethasone, including ointments (highly occlusive, best for dry, lichenified, or hyperkeratotic skin), creams (less greasy, cosmetically elegant, suitable for many conditions), lotions (thin, easy to spread on large or hairy areas), gels, foams (particularly useful for the scalp), and sprays.[1]
• Systemic Formulations: For systemic therapy, betamethasone is available as an oral solution or tablet and as an injectable suspension, often combining the fast-acting sodium phosphate salt with the longer-acting acetate or dipropionate ester (e.g., Celestone Soluspan®) to provide both immediate and sustained effects.[1]
• Combination Products: To address multiple pathological factors simultaneously, betamethasone is often co-formulated with other active agents:
• With an Antifungal: The combination with clotrimazole (e.g., Lotrisone®) is used to treat fungal infections (tinea) that have a significant inflammatory component.[1]
• With a Keratolytic Agent: The combination with salicylic acid (e.g., Diprosalic®) is effective for thick, scaly psoriatic plaques, as the salicylic acid helps to remove the excess scale, allowing for better penetration of the steroid.[1]
• With a Vitamin D Analog: The combination with calcipotriene (also known as calcipotriol) (e.g., Taclonex®, Enstilar®) is a first-line treatment for plaque psoriasis. This dual-action therapy targets both the inflammation (with betamethasone) and the abnormal keratinocyte proliferation and differentiation (with calcipotriene).[1]

The following table provides a summary of common commercial formulations, illustrating the relationship between the chemical ester, the dosage form, and its primary clinical use.

Table 3.1: Commercial Formulations of Betamethasone

Ester / Combination Product	Dosage Form	Strength(s)	Common Brand Name(s)	Primary Clinical Application
Betamethasone Dipropionate (Augmented)	Ointment, Gel	0.05%	Diprolene®	Severe, corticosteroid-responsive dermatoses
Betamethasone Dipropionate	Cream, Ointment, Lotion	0.05%	Diprosone®, Maxivate®, Sernivo®	Moderate to severe dermatoses, plaque psoriasis
Betamethasone Valerate	Cream, Ointment, Lotion, Foam	0.1%, 0.12%	Betnovate®, Luxiq®, Valisone®	Mild to moderate dermatoses, scalp psoriasis
Betamethasone Dipropionate + Clotrimazole	Cream, Lotion	0.05% / 1%	Lotrisone®, Lotriderm®	Inflamed tinea infections (e.g., tinea cruris, tinea corporis)
Betamethasone Dipropionate + Calcipotriene	Ointment, Suspension, Foam	0.05% / 0.005%	Taclonex®, Dovobet®, Enstilar®	Plaque psoriasis
Betamethasone Sodium Phosphate / Acetate	Injectable Suspension, Oral Solution	Varies (e.g., 6 mg/mL)	Celestone®, Celestone Soluspan®	Systemic inflammatory, allergic, and autoimmune conditions

3.2 Therapeutic Indications

Betamethasone exhibits a fundamental therapeutic duality. It is used "outside-in" via topical application to treat localized skin diseases, and "inside-out" via systemic administration to suppress widespread internal inflammatory and autoimmune processes. The list of indications is vast, reflecting its potent and pleiotropic effects.

A. Topical Applications

Topical betamethasone is indicated for the relief of the inflammatory and pruritic (itching) manifestations of a wide range of corticosteroid-responsive dermatoses.[2]

• Common Dermatoses: These include eczema (atopic, contact, and seborrheic dermatitis), psoriasis (particularly plaque-type), neurodermatitis, and discoid lupus erythematosus.[1]
• Other Dermatologic Uses: It is also used for conditions such as lichen planus and lichen sclerosus.[32]
• Specialized Application: A 0.05% betamethasone cream has been shown to be an effective treatment for phimosis (an inability to retract the foreskin) in boys, often serving as a non-surgical alternative to circumcision.[1]

B. Systemic Applications (Oral and Injectable)

Systemic betamethasone is reserved for moderate to severe conditions where potent, widespread anti-inflammatory or immunosuppressive therapy is required.[1]

• Rheumatic Disorders: Used to manage acute exacerbations of rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis, bursitis, and acute gouty arthritis. Intra-articular injections are used for osteoarthritis.[1]
• Allergic States: For control of severe or incapacitating allergic conditions that are intractable to conventional treatment, such as severe bronchial asthma, angioedema, allergic rhinitis, and severe drug hypersensitivity reactions.[1]
• Dermatologic Diseases: For severe dermatoses such as pemphigus, bullous dermatitis herpetiformis, severe erythema multiforme (Stevens-Johnson syndrome), exfoliative dermatitis, and severe psoriasis.[1]
• Endocrine Disorders: Used as replacement therapy in primary or secondary adrenocortical insufficiency (usually in conjunction with a mineralocorticoid), congenital adrenal hyperplasia, and nonsuppurative thyroiditis.[27]
• Gastrointestinal Diseases: To manage critical periods of ulcerative colitis and regional enteritis (Crohn's disease).[1]
• Hematologic Disorders: For the treatment of acquired (autoimmune) hemolytic anemia, idiopathic thrombocytopenic purpura (ITP) in adults, and pure red cell aplasia.[2]
• Neoplastic Diseases: For the palliative management of leukemias and lymphomas in adults and acute leukemia in children.[1]
• Neurologic Disorders: To manage acute exacerbations of multiple sclerosis and to treat cerebral edema associated with brain tumors or trauma.[2]
• Ophthalmic Diseases: For severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa.[33]
• Renal Diseases: To induce diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus.[28]
• Obstetrics (Antenatal Use): A critical indication is the administration to pregnant women in preterm labor (typically between 24 and 34 weeks of gestation) to accelerate fetal lung maturation. This significantly reduces the risk and severity of neonatal respiratory distress syndrome (NRDS) and associated mortality.[1]
• Miscellaneous and Off-Label Uses: Includes treatment for berylliosis, symptomatic sarcoidosis, and off-label uses such as prophylaxis for acute mountain sickness and as an adjunct in bacterial meningitis.[2]

Section 4: Safety Profile: Adverse Effects, Contraindications, and Warnings

The profound efficacy of betamethasone is inextricably linked to a significant and predictable profile of potential adverse effects. The entire safety profile can be understood as a logical extension of its potent glucocorticoid pharmacology. The risks are highly dependent on the potency of the formulation, the dose, the duration of therapy, the extent of systemic absorption, and the route of administration. A critical paradigm in its use is that "topical is not always local"; significant systemic absorption of potent topical formulations can lead to the same adverse effects seen with oral or injectable therapy.

4.1 Adverse Drug Reactions (ADRs)

Adverse effects can be broadly categorized into those that occur locally at the site of application and those that are systemic.

A. Local/Topical Adverse Drug Reactions

These are primarily associated with the use of topical formulations and are more common with higher potency agents, prolonged use, application to thin skin (face, intertriginous areas), and the use of occlusive dressings.

• Common Reactions: The most frequent side effects are application site reactions, including a sensation of burning, itching (pruritus), stinging, irritation, erythema (redness), and dryness.[1]
• Reactions with Prolonged or Inappropriate Use: Long-term or high-potency topical use can lead to significant cutaneous changes:
• Skin Atrophy: A thinning of the epidermis and dermis, leading to fragile, transparent, or shiny skin.[30]
• Striae Distensae: Permanent stretch marks, often reddish-purple in color.[29]
• Telangiectasia and Purpura: The formation of fine, prominent blood vessels (spider veins) and easy bruising or bleeding under the skin (ecchymoses).[1]
• Other Effects: Folliculitis (inflammation of hair follicles), acneiform eruptions, perioral dermatitis (a rash around the mouth), hypertrichosis (excessive localized hair growth), and alterations in skin pigmentation (either lightening or darkening).[1]

B. Systemic Adverse Drug Reactions

Systemic ADRs are the primary concern with oral and injectable betamethasone but can also occur with topical use if there is significant percutaneous absorption. These effects span multiple organ systems.

• Endocrine and Metabolic:
• Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression: Exogenous corticosteroids suppress the body's natural production of cortisol. Prolonged use can lead to adrenal atrophy and secondary adrenal insufficiency, which can become a life-threatening crisis if the steroid is withdrawn abruptly or if the patient experiences major stress (e.g., surgery, trauma).[1]
• Iatrogenic Cushing's Syndrome: Chronic overdose leads to a cushingoid state, characterized by weight gain, central obesity, a "moon face," a "buffalo hump" (fat deposition on the upper back), and thin skin.[27]
• Hyperglycemia: Corticosteroids antagonize the action of insulin, leading to increased blood sugar levels. This can worsen glycemic control in patients with known diabetes or unmask latent diabetes.[13]
• Immunologic:
• Increased Susceptibility to Infection: By suppressing the immune system, betamethasone increases the risk of new bacterial, viral, fungal, or parasitic infections and can mask their symptoms, delaying diagnosis and treatment. It may also reactivate latent infections, such as tuberculosis.[1]
• Musculoskeletal:
• Osteoporosis: Long-term use inhibits osteoblast function and enhances osteoclast activity, leading to bone loss and an increased risk of vertebral and other fractures.[27]
• Myopathy: A steroid-induced muscle disease can cause weakness and wasting, primarily affecting the proximal muscles.[1]
• Growth Retardation: In children, prolonged corticosteroid use can suppress growth.[30]
• Neuropsychiatric:
• A wide range of psychiatric effects can occur, from mild mood swings, euphoria, insomnia, and irritability to severe depression, anxiety, personality changes, and, in rare cases, psychosis and hallucinations.[1]
• Ophthalmic:
• Prolonged use is associated with the development of posterior subcapsular cataracts and an increase in intraocular pressure, which can lead to glaucoma and optic nerve damage.[22]
• Cardiovascular:
• Due to mineralocorticoid-like effects (though minimal with betamethasone at standard doses), it can cause sodium and fluid retention, leading to edema and hypertension. Hypokalemia (low potassium) can also occur, predisposing to cardiac arrhythmias.[1]
• Gastrointestinal:
• Increased risk of peptic ulceration and gastrointestinal bleeding, particularly when used with NSAIDs. Pancreatitis has also been reported.[33]

The following table organizes these extensive adverse reactions for clinical reference.

Table 4.1: Summary of Adverse Drug Reactions by System Organ Class and Administration Route

System Organ Class	Common/Serious Topical ADRs	Common/Serious Systemic ADRs
Dermatologic	Burning, itching, dryness, erythema, folliculitis. Severe: Skin atrophy, striae, telangiectasia, purpura, acneiform eruptions, hypertrichosis, pigmentation changes.	Thin fragile skin, impaired wound healing, acne, petechiae, ecchymoses.
Endocrine/Metabolic	Severe: HPA axis suppression and Cushing's syndrome with significant absorption.	Common/Severe: HPA axis suppression, Cushing's syndrome, hyperglycemia, weight gain, growth suppression in children, negative nitrogen balance.
Immunologic	Increased risk of local skin infections (e.g., tinea incognito).	Severe: Increased susceptibility to systemic infections, masking of infection, reactivation of latent infections (e.g., tuberculosis).
Musculoskeletal	N/A	Severe: Osteoporosis, vertebral compression fractures, myopathy, tendon rupture.
Psychiatric	N/A	Common: Insomnia, mood swings, euphoria, irritability. Severe: Depression, anxiety, psychosis.
Ophthalmic	Severe: Cataracts and glaucoma with periocular application.	Severe: Posterior subcapsular cataracts, glaucoma, increased intraocular pressure, exophthalmos.
Cardiovascular	N/A	Common/Severe: Hypertension, sodium/fluid retention (edema), congestive heart failure, hypokalemia, arrhythmias.
Gastrointestinal	N/A	Common: Increased appetite, indigestion. Severe: Peptic ulcer with perforation/hemorrhage, pancreatitis.

4.2 Contraindications, Warnings, and Precautions

The use of betamethasone requires careful consideration of patient-specific factors and contraindications.

Absolute Contraindications

Betamethasone is strictly contraindicated in the following situations:

• Patients with a known hypersensitivity to betamethasone, other corticosteroids, or any component in the specific formulation.[21]
• Patients with active systemic fungal infections, as corticosteroids can exacerbate these conditions.[33]
• For intramuscular administration in patients with Idiopathic Thrombocytopenic Purpura (ITP).[34]
• Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids due to the risk of vaccine-induced illness.[33]
• Topical use is contraindicated for ophthalmic (eye) use.[20]

Warnings and Precautions

• Epidural Injection Warning: The epidural administration of corticosteroids, including betamethasone, is not an approved use. This route has been associated with rare but serious adverse neurological events, including spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke.[1]
• HPA Axis Suppression and Withdrawal: As noted, all corticosteroids can suppress the HPA axis. Patients receiving high doses of potent topical steroids over large surface areas, under occlusion, or for prolonged periods should be periodically evaluated for adrenal suppression (e.g., via ACTH stimulation test or urinary free cortisol test). Abrupt discontinuation of long-term therapy can precipitate an adrenal crisis and must be avoided; a gradual taper is required.[1]
• Infections: Corticosteroids can mask the signs of an infection and decrease the body's resistance. If a dermatological infection develops during topical therapy, an appropriate antimicrobial agent must be used. If the infection does not resolve, the corticosteroid should be discontinued until the infection is controlled.[21]
• Pediatric Use: Children have a higher body surface area to mass ratio, making them more susceptible to systemic absorption and toxicity from topical corticosteroids. This includes HPA axis suppression, Cushing's syndrome, and linear growth retardation. Use in children should be limited to the least potent formulation for the shortest possible duration. Many potent formulations are not recommended for use in children under 12 or 13 years of age.[16]
• Pregnancy and Lactation: Betamethasone is classified as Pregnancy Category C. Teratogenic effects have been demonstrated in animal studies. It should be used during pregnancy only if the potential benefit to the mother clearly justifies the potential risk to the fetus. Systemically administered corticosteroids are known to be excreted in breast milk and could potentially suppress growth or cause other adverse effects in a nursing infant; therefore, caution should be exercised.[22]
• Pre-existing Medical Conditions: Caution is required in patients with conditions that can be exacerbated by corticosteroids, including diabetes mellitus, osteoporosis, peptic ulcer disease, hypertension, congestive heart failure, liver disease (cirrhosis), myasthenia gravis, and a history of psychiatric illness.[27]

Section 5: Clinically Significant Interactions

The potential for drug interactions with betamethasone is significant, particularly when it is administered systemically. The stark difference in the number of documented interactions for systemic betamethasone (over 600) versus topical betamethasone (around 48) serves as a powerful quantitative indicator of the importance of systemic exposure.[32] As topical absorption increases due to factors like high potency or occlusion, so does the risk of these systemic interactions.

5.1 Drug-Drug Interactions

Interactions can alter the efficacy of betamethasone or the co-administered drug, or increase the risk of toxicity.

• Hepatic Enzyme Modulators:
• CYP3A4 Inducers: Drugs that induce the cytochrome P450 3A4 enzyme, such as phenobarbital, phenytoin, and rifampin, can increase the hepatic metabolism of betamethasone. This may lead to decreased plasma concentrations and reduced therapeutic effect, potentially requiring an increase in the corticosteroid dose.[36]
• CYP3A4 Inhibitors: Conversely, strong inhibitors of CYP3A4, such as ketoconazole and macrolide antibiotics (e.g., erythromycin), can decrease the metabolism of betamethasone. This can lead to elevated plasma levels and an increased risk of systemic corticosteroid side effects.[36]
• Nonsteroidal Anti-inflammatory Drugs (NSAIDs): The concurrent use of betamethasone with NSAIDs (e.g., aspirin, ibuprofen) should be done with caution, as it significantly increases the risk of gastrointestinal side effects, including peptic ulceration and bleeding.[36]
• Anticoagulants: Corticosteroids can either increase or decrease the anticoagulant effect of coumarin-type anticoagulants like warfarin. Therefore, coagulation parameters (e.g., INR) must be monitored closely to maintain the desired level of anticoagulation.[36]
• Potassium-Depleting Agents: When betamethasone is used with drugs that deplete potassium, such as thiazide or loop diuretics and amphotericin B, there is an increased risk of severe hypokalemia. Serum potassium levels should be monitored carefully.[36]
• Antidiabetic Agents: Because corticosteroids can raise blood glucose levels, patients with diabetes taking insulin or oral hypoglycemic agents may require an upward adjustment of their antidiabetic medication dosage to maintain glycemic control.[36]
• Vaccines: Immunosuppressive doses of betamethasone can diminish the immune response to vaccines. Administration of live or live, attenuated vaccines is contraindicated, as it may lead to a disseminated infection. Killed or inactivated vaccines may be administered, but the response cannot be guaranteed.[28]
• Digitalis Glycosides: In patients taking digoxin, steroid-induced hypokalemia can increase the risk of digitalis toxicity and associated arrhythmias.[36]

5.2 Drug-Disease Interactions

Betamethasone can significantly impact the course of various underlying diseases, necessitating careful patient selection and monitoring.

• Infections: The immunosuppressive effects can mask the signs of an infection, allowing it to progress. It can also activate latent infections or worsen existing ones. It should not be used in untreated serious infections.[27]
• Diabetes Mellitus: The hyperglycemic effect of betamethasone can lead to a loss of glycemic control in patients with diabetes, requiring more intensive management of their condition.[27]
• Hyperadrenocorticism (Cushing's Syndrome): As an exogenous glucocorticoid, betamethasone mimics the effects of excess cortisol and will exacerbate the signs and symptoms of endogenous Cushing's syndrome.[27]
• Ocular Diseases: Betamethasone can increase intraocular pressure, potentially worsening glaucoma, and can accelerate cataract formation. Its use is contraindicated in patients with active ocular herpes simplex due to the risk of corneal perforation.[27]
• Gastrointestinal Disorders: Caution is warranted in patients with active or latent peptic ulcers, diverticulitis, or ulcerative colitis, as there is an increased risk of gastrointestinal perforation.[27]
• Cardiovascular Disease: The potential for sodium and fluid retention can exacerbate hypertension and congestive heart failure.[27]
• Osteoporosis: Corticosteroid use is a major risk factor for osteoporosis, and it will accelerate bone density loss in patients with pre-existing disease.[27]

5.3 Drug-Food Interactions

The provided research materials indicate the existence of two alcohol/food interactions but do not specify their nature.[46] In general clinical practice, patients on systemic corticosteroids are advised to be cautious with alcohol consumption, as it may further increase the risk of gastric irritation and peptic ulcer disease. A diet low in sodium and rich in potassium and calcium may be recommended during long-term therapy to counteract the metabolic effects of the steroid.

Section 6: Comparative Analysis with Other Corticosteroids

To fully appreciate the clinical role of betamethasone, it is essential to compare it with other key corticosteroids, particularly its stereoisomer, dexamethasone, and the super-potent topical agent, clobetasol. The existence of a wide spectrum of corticosteroid potencies is not a redundancy but a crucial therapeutic feature, allowing clinicians to tailor therapy to the specific severity and location of a disease, thereby balancing efficacy with risk.

6.1 Topical Potency Classification

The potency of topical corticosteroids is the primary determinant of their appropriate clinical use and is conventionally ranked using a seven-class system, where Class I is the most potent ("super-potent") and Class VII is the least potent. This classification is based on the vasoconstrictor assay, which measures the drug's ability to blanch the skin by constricting dermal capillaries—an effect that correlates well with anti-inflammatory activity.[47] It is critical to note that the percentage of the drug in a product does not directly equate to its potency; the specific ester and the vehicle are equally important determinants.

Table 6.1: Comparative Topical Corticosteroid Potency Chart

Potency Class	Class Name	Representative Agent(s)
Class I	Super-potent	Clobetasol propionate 0.05% (e.g., Temovate®, Clobex®) Augmented betamethasone dipropionate 0.05% (e.g., Diprolene® Ointment/Gel)
Class II	High-potency	Betamethasone dipropionate 0.05% Ointment (e.g., Diprosone®) Fluocinonide 0.05% Ointment
Class III	Medium- to High-potency	Betamethasone dipropionate 0.05% Cream Triamcinolone acetonide 0.5% Cream
Class IV	Medium-potency	Betamethasone valerate 0.1% Ointment (e.g., Betnovate®) Triamcinolone acetonide 0.1% Cream
Class V	Medium-potency	Betamethasone valerate 0.1% Cream, Lotion, Foam (e.g., Luxiq®) Hydrocortisone valerate 0.2% Cream
Class VI	Mild-potency	Desonide 0.05% Cream
Class VII	Least-potent	Hydrocortisone 1% Cream

Note: Dexamethasone is not typically formulated for topical use and is therefore not included in standard topical potency charts.

(Sources: 12)

6.2 Betamethasone vs. Dexamethasone

The comparison between betamethasone and dexamethasone is unique because they are stereoisomers, differing only in the spatial orientation of the C-16 methyl group.[1]

• Potency and Activity: For systemic use, both are considered highly potent, long-acting glucocorticoids with minimal mineralocorticoid activity, and they are often used interchangeably. Their anti-inflammatory potency is roughly equivalent, with some sources suggesting 0.6 mg of betamethasone is comparable to 0.75 mg of dexamethasone.[5]
• Clinical Efficacy: The assumption of their interchangeability appears to be context-dependent.
• In the setting of preterm labor, a large systematic review and network meta-analysis found no clinically or statistically significant difference between the two drugs for critical neonatal outcomes, such as neonatal death or long-term neurodevelopmental disability. Both effectively cross the placenta to promote fetal lung maturation.[49]
• However, in the context of local infiltration analgesia for total knee arthroplasty (TKA), a recent prospective randomized controlled trial demonstrated that betamethasone provided superior and more sustained postoperative pain relief compared to dexamethasone. The analgesic effect of betamethasone extended to 48 hours and even 2 weeks postoperatively, whereas the effect of dexamethasone was significant only up to 24 hours.[51] This suggests that for localized applications, subtle differences in tissue binding, solubility, or local metabolism might lead to clinically meaningful differences in performance.
• Interaction Profile: While their systemic side effect profiles are broadly similar, data suggests dexamethasone interacts with a substantially larger number of drugs (829) than systemic betamethasone (621).[46] This could reflect true differences in metabolic pathways or simply a more extensive history of study for dexamethasone.

6.3 Betamethasone vs. Clobetasol (Topical)

This comparison highlights the upper end of the potency spectrum and the clinical rationale for choosing between a potent and a super-potent agent.

• Potency: This is the defining difference. Clobetasol propionate 0.05% is unequivocally a Class I, super-potent corticosteroid, making it one of the most powerful topical agents available.[18] While augmented betamethasone dipropionate 0.05% also achieves Class I status, the standard formulations of betamethasone dipropionate and betamethasone valerate are less potent, falling into Classes II through V. Therefore, clobetasol is significantly stronger than all non-augmented betamethasone products.[25]
• Clinical Applications: The choice of agent is dictated by this potency gap. Clobetasol is reserved for the most severe and recalcitrant inflammatory dermatoses, such as severe plaque psoriasis or discoid lupus, and is particularly useful for short-term "pulse" therapy on thick-skinned areas like the palms and soles.[18] The various betamethasone formulations, in contrast, offer a broader therapeutic range. Betamethasone dipropionate is suitable for moderate-to-severe conditions, while the less potent betamethasone valerate is appropriate for mild-to-moderate dermatoses or for use on more sensitive skin areas where clobetasol would carry an unacceptably high risk of side effects.[17]
• Side Effect Profile: As a direct consequence of its higher potency, clobetasol carries a markedly greater risk of both local side effects (e.g., skin atrophy, striae) and systemic absorption leading to HPA axis suppression. Its use must be strictly limited in duration (e.g., to 2-4 consecutive weeks) and total weekly dose (e.g., not to exceed 50 grams per week) to mitigate these risks.

Section 7: Expert Synthesis and Clinical Recommendations

7.1 Synthesis of Betamethasone's Clinical Profile

Betamethasone is a highly effective and pleiotropic synthetic glucocorticoid that remains a cornerstone of therapy for a vast array of inflammatory, autoimmune, and allergic diseases. Its clinical profile is defined by a profound "double-edged sword" nature: its remarkable efficacy is the direct result of its potent pharmacological actions, and these same actions are responsible for its significant and predictable risk profile. The ability to modulate gene expression to suppress inflammation and the immune response provides relief for debilitating conditions, from severe eczema and psoriasis to life-threatening asthma and autoimmune disorders. Its role in accelerating fetal lung maturation has saved countless neonatal lives.

However, this therapeutic power demands respect and a deep understanding of its potential for harm. The risks of HPA axis suppression, iatrogenic Cushing's syndrome, osteoporosis, hyperglycemia, and increased susceptibility to infection are not random occurrences but are the logical consequences of its mechanism of action. The key to navigating this duality lies in a nuanced understanding of its pharmaceutical preparations and pharmacokinetic principles. The choice of ester, the design of the vehicle, and the route of administration are not minor details; they are the primary tools a clinician has to control the drug's delivery, thereby harnessing its benefits while mitigating its inherent risks. The critical lesson from decades of use is that topical therapy is not always strictly local, and systemic exposure from skin application is a real and clinically important phenomenon that must be managed through rational prescribing.

7.2 Recommendations for Rational Prescribing and Risk Management

To optimize therapeutic outcomes and ensure patient safety, the use of betamethasone should be guided by the following principles:

• Patient and Indication Selection: Systemic and super-potent topical corticosteroids should be reserved for severe or recalcitrant conditions that have failed to respond to safer, less potent alternatives. Before initiating therapy, a thorough patient history should be taken to identify comorbidities—such as diabetes, hypertension, osteoporosis, peptic ulcer disease, or a history of serious infections—that could be exacerbated by corticosteroid treatment.
• Formulation Choice and Potency Matching: The guiding principle should be to use the least potent formulation that will effectively control the condition. The choice of vehicle (ointment, cream, lotion, foam) should be tailored to the type of skin lesion and the anatomical location. High-potency (Class I-II) agents should be avoided on thin-skinned areas like the face, groin, axilla, and scrotum whenever possible.
• Dose and Duration Minimization: Therapy should be administered for the shortest duration necessary to achieve the desired clinical outcome. For chronic dermatoses requiring long-term management, clinicians should consider intermittent application strategies (e.g., "weekend therapy" where the steroid is applied only two days a week) to reduce cumulative dose and minimize the risk of local side effects like skin atrophy. Systemic therapy, if used for more than a few weeks, must be tapered gradually upon discontinuation to allow for the recovery of the HPA axis and prevent an adrenal crisis.
• Comprehensive Patient Education: Effective patient counseling is paramount to safe use. Patients must be educated on the correct application technique (e.g., applying a thin film), the prescribed frequency, and the specific duration of treatment. They should be explicitly warned against using the medication on non-prescribed areas, on other individuals, or for longer than directed. The risks associated with occlusive dressings (e.g., plastic wrap, tight-fitting diapers) should be clearly explained and discouraged unless specifically instructed by the physician. Patients should also be taught to recognize the early signs of both local (e.g., skin thinning) and systemic side effects.
• Vigilant Monitoring: Patients on long-term systemic therapy or high-risk topical therapy (e.g., high-potency agents over a large surface area) require regular monitoring. This should include periodic checks of blood pressure, body weight, and blood glucose. For patients on prolonged therapy, periodic ophthalmic examinations to screen for cataracts and glaucoma are recommended. In select high-risk cases, laboratory evaluation for HPA axis suppression may be warranted. In pediatric patients, monitoring for normal growth and development is essential.

Works cited

1. Betamethasone - Wikipedia, accessed July 28, 2025, https://en.wikipedia.org/wiki/Betamethasone
2. Betamethasone: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 28, 2025, https://go.drugbank.com/drugs/DB00443
3. go.drugbank.com, accessed July 28, 2025, https://go.drugbank.com/drugs/DB00443#:~:text=Betamethasone%20is%20a%20long%2Dacting%20corticosteroid%20with%20immunosuppressive%20and%20antiinflammatory%20properties.&text=It%20can%20be%20used%20topically,disease%20states%20including%20autoimmune%20disorders.
4. Betamethasone valerate | DrugBank Online, accessed July 28, 2025, https://go.drugbank.com/salts/DBSALT000849
5. Betamethasone | 378-44-9 - ChemicalBook, accessed July 28, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7392335.htm
6. Betamethasone | CAS 378-44-9 - LGC Standards, accessed July 28, 2025, https://www.lgcstandards.com/US/en/Betamethasone/p/MM0200.00
7. Betamethasone | C22H29FO5 | CID 9782 - PubChem, accessed July 28, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Betamethasone
8. CAS Number 378-44-9 | Betamethasone - Spectrum Chemical, accessed July 28, 2025, https://www.spectrumchemical.com/cas/378-44-9
9. Betamethasone | C22H29FO5 | CID 9782 - PubChem, accessed July 28, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/16-beta-Methyl-1%2C4-pregnadiene-9-alpha-fluoro-11-beta%2C17-alpha%2C21-triol-3%2C20-dione
10. Betamethasone | CAS 378-44-9 | SCBT - Santa Cruz Biotechnology, accessed July 28, 2025, https://www.scbt.com/p/betamethasone-378-44-9
11. Betamethasone (CAS 378-44-9) - Cayman Chemical, accessed July 28, 2025, https://www.caymanchem.com/product/20363/betamethasone
12. Betamethasone (topical): uses, dosing, warnings, adverse events, interactions - MedCentral, accessed July 28, 2025, https://www.medcentral.com/drugs/monograph/978-382270/betamethasone-dipropionate-topical
13. What is the mechanism of Betamethasone? - Patsnap Synapse, accessed July 28, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-betamethasone
14. What is the mechanism of Betamethasone Valerate? - Patsnap Synapse, accessed July 28, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-betamethasone-valerate
15. Calcipotriol/Betamethasone Dipropionate for the Treatment of Psoriasis: Mechanism of Action and Evidence of Efficacy and Safety versus Topical Corticosteroids - MDPI, accessed July 28, 2025, https://www.mdpi.com/2077-0383/13/15/4484
16. Betamethasone: Uses, Side Effects, Dosage & Reviews - GoodRx, accessed July 28, 2025, https://www.goodrx.com/betamethasone-dipropionate/what-is
17. What Does Topical Steroid (Corticosteroid) Potency Mean? - GoodRx, accessed July 28, 2025, https://www.goodrx.com/classes/corticosteroids/topical-steroid-potency-chart
18. Topical Corticosteroids - StatPearls - NCBI Bookshelf, accessed July 28, 2025, https://www.ncbi.nlm.nih.gov/books/NBK532940/
19. Betamethasone dipropionate - Wikipedia, accessed July 28, 2025, https://en.wikipedia.org/wiki/Betamethasone_dipropionate
20. Betamethasone Cream: Package Insert / Prescribing Info - Drugs.com, accessed July 28, 2025, https://www.drugs.com/pro/betamethasone-cream.html
21. Label: BETAMETHASONE DIPROPIONATE cream - DailyMed, accessed July 28, 2025, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cadb8d68-5fe6-471d-9d14-5bda6034b802
22. Betamethasone - WikEM, accessed July 28, 2025, https://wikem.org/wiki/Betamethasone
23. 94315-BETAMETHASONE VALERATE - Guinama, accessed July 28, 2025, https://www.guinama.com/documentacion-tecnica/94315_FT-Betamethasone-valerate-EN-Laboratorios-GUINAMA.pdf
24. Betamethasone valerate - Wikipedia, accessed July 28, 2025, https://en.wikipedia.org/wiki/Betamethasone_valerate
25. Topical Steroid Ladder Potency Strength Chart - TSW Assist, accessed July 28, 2025, https://tswassist.com/topical-steroid-ladder-potency-strength-chart/
26. Betamethasone: Friend (Soluble), Foe (Particulate), or Either?, accessed July 28, 2025, https://academic.oup.com/painmedicine/article-pdf/10/2/420/5190068/10-2-420.pdf
27. Betamethasone oral solution - Cleveland Clinic, accessed July 28, 2025, https://my.clevelandclinic.org/health/drugs/19617-betamethasone-oral-solution
28. Betamethasone sodium phosphate and betamethasone acetate ..., accessed July 28, 2025, https://www.mayoclinic.org/drugs-supplements/betamethasone-sodium-phosphate-and-betamethasone-acetate-injection-route/description/drg-20425905
29. betamethasone dipropionate 0.05 % topical cream - Kaiser Permanente, accessed July 28, 2025, https://healthy.kaiserpermanente.org/health-wellness/drug-encyclopedia/drug.betamethasone-dipropionate-0-05-topical-cream.257860
30. Betamethasone Topical: MedlinePlus Drug Information, accessed July 28, 2025, https://medlineplus.gov/druginfo/meds/a682799.html
31. Betamethasone dipropionate (topical application route) - Side ..., accessed July 28, 2025, https://www.mayoclinic.org/drugs-supplements/betamethasone-dipropionate-topical-application-route/description/drg-20073667
32. Betamethasone topical Interactions - Drugs.com, accessed July 28, 2025, https://www.drugs.com/drug-interactions/betamethasone-topical.html
33. Betamethasone: Side Effects, Uses, Dosage, Interactions, Warnings, accessed July 28, 2025, https://www.rxlist.com/betamethasone/generic-drug.htm
34. Betamethasone (Celestone Soluspan): Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD, accessed July 28, 2025, https://www.webmd.com/drugs/2/drug-5720/celestone-soluspan-injection/details
35. Betamethasone: Side Effects, Dosage, Uses and More - Healthline, accessed July 28, 2025, https://www.healthline.com/health/drugs/betamethasone-injectable-suspension
36. Betamethasone: Generic, Allergy & Arthritis Uses, Warnings, Side Effects - MedicineNet, accessed July 28, 2025, https://www.medicinenet.com/betamethasone/article.htm
37. Betamethasone Topical: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed July 28, 2025, https://www.rxlist.com/betamethasone_topical/generic-drug.htm
38. Betamethasone Side Effects: Common, Severe, Long Term - Drugs.com, accessed July 28, 2025, https://www.drugs.com/sfx/betamethasone-side-effects.html
39. Side-effects of topical steroids: A long overdue revisit - PMC, accessed July 28, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4228634/
40. What are the side effects of long-term use of topical betamethasone (Beta-Methasone)? - Dr.Oracle AI, accessed July 28, 2025, https://www.droracle.ai/articles/93380/side-effect-of-long-term-use-of-topical-betamathasone
41. Betamethasone Topical Side Effects: Common, Severe, Long Term - Drugs.com, accessed July 28, 2025, https://www.drugs.com/sfx/betamethasone-topical-side-effects.html
42. www.nhs.uk, accessed July 28, 2025, https://www.nhs.uk/medicines/betamethasone-tablets/side-effects-of-betamethasone-tablets/
43. Betamethasone (Celestone Soluspan): Uses, Side Effects, Dosage & More - GoodRx, accessed July 28, 2025, https://www.goodrx.com/betamethasone-sodium-phosphate-betamethasone-acetate/what-is
44. Betamethasone topical: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing, accessed July 28, 2025, https://www.webmd.com/drugs/2/drug-978-724/betamethasone-dipropionate-topical/betamethasone-dipropionate-topical/details
45. Betamethasone: Package Insert / Prescribing Information - Drugs.com, accessed July 28, 2025, https://www.drugs.com/pro/betamethasone.html
46. Betamethasone Interactions Checker - Drugs.com, accessed July 28, 2025, https://www.drugs.com/drug-interactions/betamethasone.html
47. Topical steroids factsheet - National Eczema Society, accessed July 28, 2025, https://eczema.org/wp-content/uploads/Topical-steroids-Mar-23.pdf
48. Topical Steroid Potency Chart - The National Psoriasis Foundation, accessed July 28, 2025, https://www.psoriasis.org/potency-chart/
49. Dexamethasone versus betamethasone for preterm birth: a systematic review and network meta-analysis - PubMed, accessed July 28, 2025, https://pubmed.ncbi.nlm.nih.gov/33482400/
50. Dexamethasone vs. betamethasone for preterm birth: a systematic review and network meta-analysis | Request PDF - ResearchGate, accessed July 28, 2025, https://www.researchgate.net/publication/348626910_Dexamethasone_vs_betamethasone_for_preterm_birth_a_systematic_review_and_network_meta-analysis
51. Comparison of analgesic effects between betamethasone and dexamethasone in total knee arthroplasty: a prospective randomized controlled trial - Frontiers, accessed July 28, 2025, https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2025.1575417/epub
52. Comparison of analgesic effects between betamethasone and dexamethasone in total knee arthroplasty: a prospective randomized controlled trial - Frontiers, accessed July 28, 2025, https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2025.1575417/full
53. Betamethasone Topical vs Dexamethasone Comparison - Drugs.com, accessed July 28, 2025, https://www.drugs.com/compare/betamethasone-topical-vs-dexamethasone
54. Betamethasone vs Dexamethasone Comparison - Drugs.com, accessed July 28, 2025, https://www.drugs.com/compare/betamethasone-vs-dexamethasone