Dexamethasone

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Dexamethasone (DEXAMETHASONE)

Composition:

Active substance: dexamethasone;

1 tablet contains 0.5 mg of dexamethasone;

Excipients: potato starch, calcium stearate, lactose monohydrate, sodium croscarmellose.

Pharmaceutical form. Tablets.

Main physicochemical properties: white tablets.

Pharmacotherapeutic group. Systemic corticosteroids. Glucocorticoids. ATC code H02AB02.

Pharmacological properties.

Pharmacodynamics.

Dexamethasone is a synthetic corticosteroid hormone of the adrenal cortex that exerts glucocorticoid effects. It produces anti-inflammatory and immunosuppressive actions, and also affects energy metabolism, glucose metabolism, and (via negative feedback) the secretion of hypothalamic corticotropin-releasing factor and adenohypophyseal trophic hormones.

The mechanism of action of glucocorticoids is not yet fully understood. There is substantial evidence supporting the concept that glucocorticoids act at the cellular level. Two well-defined receptor systems exist in the cytoplasm of cells. By binding to glucocorticoid receptors, corticosteroids exert anti-inflammatory and immunosuppressive effects and regulate glucose metabolism. Through binding to mineralocorticoid receptors, they regulate sodium and potassium metabolism and water-electrolyte balance.

Glucocorticoids are lipid-soluble and readily penetrate target cells through the cell membrane. Hormone binding to the receptor alters the receptor's conformation, increasing its affinity for DNA. The hormone-receptor complex enters the cell nucleus and binds to regulatory sites on the DNA molecule, known as glucocorticoid response elements (GREs). The activated receptor, bound to GREs or specific genes, modulates mRNA transcription, either increasing or decreasing it. Newly formed mRNA is transported to ribosomes, leading to the synthesis of new proteins. Depending on the target cells and cellular processes, protein synthesis may be enhanced (e.g., tyrosine transaminase production in hepatocytes) or suppressed (e.g., IL-2 production in lymphocytes). Since glucocorticoid receptors are present in all tissue types, it can be assumed that glucocorticoids affect most cells in the body.

Effects on energy metabolism and glucose homeostasis

Dexamethasone, together with insulin, glucagon, and catecholamines, regulates energy storage and utilization. In the liver, it increases glucose production from pyruvate or amino acids and promotes glycogen formation. In peripheral tissues, particularly muscles, glucose uptake is reduced, and amino acids are mobilized (from proteins), serving as substrates for hepatic gluconeogenesis. A direct effect on lipid metabolism includes central redistribution of adipose tissue and enhanced lipolytic response to catecholamines.

Via receptors in the renal proximal tubules, dexamethasone increases renal blood flow and glomerular filtration, inhibits vasopressin production and secretion, and improves the kidney's ability to excrete acids.

By increasing the number and affinity of β-adrenergic receptors, which mediate the positive inotropic effects of catecholamines, dexamethasone directly enhances myocardial contractility and peripheral vascular tone.

At high doses, dexamethasone inhibits fibroblast production of type I and type III collagen and glycosaminoglycans. Thus, by suppressing extracellular collagen and matrix formation, wound healing is delayed. Prolonged administration of high doses leads to progressive bone resorption and reduced osteogenesis, both directly (by increasing parathyroid hormone secretion and decreasing calcitonin secretion) and indirectly, resulting in a negative calcium balance due to reduced intestinal calcium absorption and increased urinary calcium excretion. This commonly leads to secondary hyperparathyroidism and phosphaturia.

Effects on the pituitary and hypothalamus

Dexamethasone is approximately 30 times more potent than cortisol. Therefore, it is a more powerful inhibitor of corticotropin-releasing factor (CRF) and ACTH secretion than endogenous cortisol. This leads to reduced cortisol secretion, and after prolonged suppression of CRF and ACTH secretion, adrenal gland atrophy may occur. Adrenal insufficiency can develop as early as days 5 to 7 of dexamethasone administration at doses equivalent to 20–30 mg of prednisone per day, or after 30 days of low-dose therapy. After discontinuation of short-term therapy (up to 5 days), adrenal function typically recovers within one week; after long-term therapy, recovery may take longer, usually up to one year. In some patients, irreversible adrenal atrophy may develop.

Anti-inflammatory and immunosuppressive effects of glucocorticoids are based on their molecular and biochemical actions. The molecular anti-inflammatory effect results from binding to glucocorticoid receptors and subsequent changes in the expression of genes regulating various inflammatory mediators, proteins, and enzymes. The biochemical anti-inflammatory effect of glucocorticoids arises from inhibition of the synthesis and activity of humoral mediators of inflammation: prostaglandins, thromboxanes, cytokines, and leukotrienes. Dexamethasone reduces leukotriene production by inhibiting phospholipase A2 activity, thereby decreasing the release of arachidonic acid from cellular phospholipids. This effect on phospholipase A2 is not direct but results from increased concentrations of lipocortin (macrocortin), an inhibitor of phospholipase A2. Dexamethasone also reduces prostaglandin and thromboxane synthesis by decreasing the formation of specific mRNA, and consequently, the amount of cyclooxygenase produced. Dexamethasone reduces platelet-activating factor (PAF) production by increasing lipocortin concentration. Other biochemical anti-inflammatory effects include reduced production of tumor necrosis factor (TNF) and interleukin (IL-1).

Clinical efficacy and safety in the treatment of COVID-19

Clinical efficacy

A randomized, controlled, open-label, adaptive platform trial, RECOVERY (Randomised Evaluation of Covid-19 Therapy)1, initiated by investigators, was conducted to evaluate outcomes of potential treatments in hospitalized patients with COVID-19.

The trial was conducted across 176 hospitals in the United Kingdom. A total of 6425 patients were randomized to receive either dexamethasone (2104 patients) or usual care (4321 patients). 89% of patients had laboratory-confirmed SARS-CoV-2 infection.

At randomization, 16% of patients were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were receiving oxygen therapy (with or without non-invasive ventilation), and 24% were receiving neither.

The mean age of patients was 66.1 ± 15.7 years. 36% of patients were women. 24% had a history of diabetes, 27% had heart disease, and 21% had chronic lung disease.

Primary endpoint

Mortality at day 28 was significantly lower in the dexamethasone group compared to the usual care group: 482 of 2104 patients (22.9%) versus 1110 of 4321 patients (25.7%), respectively (rate ratio 0.83; 95% confidence interval (CI) 0.75–0.93; P < 0.001).

Among patients receiving invasive mechanical ventilation, mortality was lower in the dexamethasone group than in the usual care group (29.3% vs. 41.4%; rate ratio 0.64; 95% CI 0.51–0.81). Similarly, among patients receiving supplemental oxygen without invasive ventilation, mortality was lower in the dexamethasone group (23.3% vs. 26.2%; rate ratio 0.82; 95% CI 0.72–0.94).

There was no clear benefit of dexamethasone among patients who were not receiving any respiratory support at randomization (17.8% vs. 14.0%; rate ratio 1.19; 95% CI 0.91–1.55).

Secondary endpoint

Hospital length of stay was shorter in the dexamethasone group than in the usual care group (median 12 days vs. 13 days), and the probability of hospital discharge within 28 days was higher (rate ratio 1.10; 95% CI 1.03–1.17).

Consistent with the primary endpoint, the greatest reduction in hospitalization duration by day 28 was observed among patients receiving invasive mechanical ventilation at randomization (rate ratio 1.48; 95% CI 1.16–1.90). A smaller benefit was seen in patients receiving oxygen only (rate ratio 1.15; 95% CI 1.06–1.24), and no favorable effect was observed in patients not receiving oxygen (rate ratio 0.96; 95% CI 0.85–1.08).

* The ratio of outcomes was adjusted for age based on 28-day mortality and hospital discharge results. The risk ratios were adjusted for age regarding the outcome of receiving invasive mechanical ventilation or death, and its components.

† Patients who received invasive mechanical ventilation at randomization were excluded from this category.

Safety

During the study, four serious adverse events related to the investigational treatment were recorded: two cases of hyperglycemia, one case of steroid-induced psychosis, and one case of upper gastrointestinal tract bleeding. All events were resolved.

Subgroup Analysis

Effects of dexamethasone administration on 28-day mortality, according to age and respiratory support method at randomization²

Effects of dexamethasone on 28-day mortality, according to respiratory support method and presence of any chronic comorbidity, obtained at randomization3

1 www.recoverytrial.net

2, 3 (source: Horby P. et al., 2020; https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1;

doi: https://doi.org/10.1101/2020.06.22.20137273).

Pharmacokinetics.

Dexamethasone is rapidly and almost completely absorbed after oral administration. The bioavailability of dexamethasone in tablet form approaches 80% (various sources report bioavailability ranging from 53% to 112%). Peak plasma concentration is reached within 1–2 hours after oral administration, and the duration of effect after a single dose is approximately 2.75 days.

Approximately 77% of dexamethasone in plasma is protein-bound, primarily to albumin. Only a small amount of dexamethasone binds to other proteins. Dexamethasone is lipophilic, therefore it freely penetrates cells and interstitial spaces. In the central nervous system (hypothalamus, pituitary gland), it binds and acts via membrane receptors. In peripheral tissues, it binds and acts through cytoplasmic receptors. Its degradation occurs at the site of action, i.e., within the cell itself. Dexamethasone is primarily metabolized in the liver, and possibly also in the kidneys and other tissues. It is predominantly excreted in urine.

Clinical characteristics.

Indications.

Endocrine disorders:

• Replacement therapy for primary or secondary (pituitary) adrenal insufficiency (except acute adrenal insufficiency, where hydrocortisone or cortisone are drugs of choice due to their more pronounced hormonal effect); congenital adrenal hyperplasia; subacute thyroiditis (de Quervain's) and severe forms of radiation thyroiditis.

Rheumatic diseases:

• Rheumatoid arthritis, including juvenile rheumatoid arthritis and extra-articular manifestations of rheumatoid arthritis (rheumatoid lungs, cardiac and ocular involvement, cutaneous vasculitis), as adjunctive therapy during periods when basic therapy has not yet taken effect and when analgesic and anti-inflammatory effects of NSAIDs have been unsatisfactory.

Systemic connective tissue diseases, vasculitis syndromes, and amyloidosis (supportive and symptomatic treatment in certain cases during the course of the underlying disease):

• Systemic lupus erythematosus (treatment of polyserositis and internal organ involvement); Sjögren's syndrome (treatment of pulmonary, renal, and cerebral involvement); systemic sclerosis (treatment of myositis, pericarditis, and alveolitis); polymyositis, dermatomyositis;
• systemic vasculitides; amyloidosis (replacement therapy in adrenal insufficiency).

Skin diseases:

• Pemphigus; bullous pemphigoid dermatitis; exfoliative dermatitis; erythema exudativum (severe forms); nodular erythema; seborrheic dermatitis (severe forms); psoriasis (severe forms); lichen; urticaria unresponsive to standard treatment; mycosis fungoides; scleroderma; angioedema (Quincke's edema).

Allergic diseases (unresponsive to standard treatment):

• Asthma, contact dermatitis, atopic dermatitis, serum sickness, allergic rhinitis, drug allergy, post-transfusion urticaria.

Ocular diseases:

• Inflammatory eye diseases (acute central choroiditis, optic neuritis); allergic diseases (conjunctivitis, uveitis, scleritis, keratitis, iritis); systemic immune diseases (sarcoidosis, temporal arteritis); proliferative changes in the orbit (endocrine ophthalmopathy, pseudotumor); sympathetic ophthalmia; immunosuppressive therapy in corneal transplantation.

Gastrointestinal diseases:

• Ulcerative colitis (severe exacerbation), Crohn's disease (severe exacerbation), chronic autoimmune hepatitis, rejection reaction following liver transplantation.

Respiratory tract diseases:

• Acute toxic bronchiolitis, chronic bronchitis;
• allergic bronchopulmonary aspergillosis; extrinsic allergic alveolitis; idiopathic fibrosing alveolitis; sarcoidosis; eosinophilic infiltration, focal or disseminated pulmonary tuberculosis (in combination with appropriate antituberculosis therapy); tuberculous pleurisy (in combination with appropriate antituberculosis therapy); pleurisy associated with systemic connective tissue diseases; pulmonary vasculitis; berylliosis (granulomatous inflammation); obliterative bronchitis caused by toxic gas poisoning, radiation or aspiration pneumonitis.

Hematological diseases:

• Acquired or congenital chronic aplastic anemia; autoimmune hemolytic anemia; secondary thrombocytopenia in adults; erythroblastopenia; acute lymphoblastic leukemia (induction therapy); myelodysplastic syndrome; angioimmunoblastic malignant T-cell lymphoma (in combination with cytostatics); plasmacytoma (in combination with cytostatics); severe anemia following myelofibrosis with myeloid metaplasia or lymphoplasmacytoid immunocytoma; systemic histiocytosis (systemic dependence).

Renal diseases:

• Primary and secondary glomerulonephritis (Goodpasture's syndrome); renal failure in systemic connective tissue diseases (systemic lupus erythematosus, Sjögren's syndrome); systemic vasculitis (usually in combination with cyclophosphamide); glomerulonephritis in polyarteritis nodosa; Churg-Strauss syndrome; Wegener's granulomatosis; Schönlein-Henoch purpura; mixed cryoglobulinemia; renal failure in Takayasu arteritis; interstitial nephritis; immunosuppressive therapy in kidney transplantation; induction of diuresis and reduction of proteinuria in idiopathic nephrotic syndrome (without uremia) and renal failure in systemic lupus erythematosus.

Oncological diseases:

• Palliative treatment of leukemia and lymphoma in adults, acute leukemia in children, hypercalcemia in malignant diseases.

Neurological diseases:

• Cerebral edema due to primary or metastatic brain tumors, craniotomy, and traumatic brain injury.

Coronavirus disease 2019 (COVID-19):

• Treatment of coronavirus disease 2019 (COVID-19) in adults and adolescent patients (aged 12 years and older with body weight of at least 40 kg) who require supplemental oxygen therapy.

Other indications:

• Tuberculous meningitis with subarachnoid block (in combination with appropriate antituberculosis therapy), trichinosis with neurological symptoms or myocardial trichinosis; diagnostic testing for adrenal hyperfunction.

Contraindications.

Hypersensitivity to dexamethasone or to any other component of the medicinal product. Acute viral, bacterial, or systemic fungal infections (unless appropriate therapy is administered), Cushing's syndrome, live vaccine vaccination, and breastfeeding (except in emergency situations).

Interaction with other medicinal products and other types of interactions.

Concomitant use of dexamethasone and nonsteroidal anti-inflammatory drugs increases the risk of gastrointestinal bleeding and ulcer formation.

The effect of dexamethasone is reduced when used concomitantly with drugs that activate the CYP3A4 enzyme (phenytoin, phenobarbital, carbamazepine, primidone, rifabutin, rifampicin) or increase the metabolic clearance of glucocorticoids (ephedrine and aminoglutethimide); in such cases, the dose of dexamethasone should be increased. Interaction between dexamethasone and all the above-mentioned medicinal products may distort the results of the dexamethasone suppression test. This should be considered when evaluating test results.

Concomitant use of dexamethasone and drugs that inhibit CYP3A4 enzyme activity, such as ketoconazole and macrolides, may lead to increased serum concentrations of dexamethasone. Dexamethasone is a moderate inducer of CYP3A4. Concomitant use with drugs metabolized by CYP3A4, such as indinavir and erythromycin, may increase their clearance, resulting in decreased serum concentrations.

By inhibiting CYP3A4 enzyme activity, ketoconazole may increase the serum concentration of dexamethasone. On the other hand, ketoconazole may suppress adrenal synthesis of glucocorticoids, thus adrenal insufficiency may develop due to decreased dexamethasone concentration.

Dexamethasone reduces the therapeutic effect of antidiabetic agents and antihypertensive drugs, praziquantel, and natriuretics (therefore, the dose of these agents should be increased); it enhances the activity of heparin, albendazole, and potassium-wasting diuretics (the dose of these agents should be reduced if necessary).

Dexamethasone may alter the effect of coumarin anticoagulants; therefore, prothrombin time should be monitored more frequently when this combination is used.

Concomitant use of high doses of glucocorticoids and β2-adrenergic agonists increases the risk of hypokalemia. In patients with hypokalemia, cardiac glycosides are more likely to cause arrhythmias and have higher toxicity.

Dexamethasone reduces the therapeutic effect of anticholinesterase agents used in myasthenia gravis.

Antacids reduce the absorption of dexamethasone in the stomach. The effect of dexamethasone when taken concomitantly with food and alcohol has not been studied, but concomitant intake of drugs and food high in sodium is not recommended. Smoking does not affect the pharmacokinetics of dexamethasone.

Glucocorticoids enhance renal clearance of salicylates, making it sometimes difficult to achieve therapeutic salicylate concentrations in serum. Caution should be exercised in patients being gradually tapered off corticosteroids, as salicylate serum concentrations and intoxication may occur.

When oral contraceptives are used concomitantly, the half-life of glucocorticoids may be prolonged, enhancing their biological effect and potentially increasing the risk of adverse effects.

Concomitant use of ritodrine and dexamethasone is contraindicated during childbirth, as it may lead to a fatal outcome in the mother due to pulmonary edema. There have been reports of fatal cases resulting from this condition in postpartum women.

Concomitant use of dexamethasone and thalidomide may cause toxic epidermal necrolysis.

Interactions with therapeutic benefits: concomitant administration of dexamethasone with metoclopramide, diphenhydramine, prochlorperazine, or 5-HT3 receptor antagonists (serotonin or 5-hydroxytryptamine type 3 receptors, such as ondansetron or granisetron) is effective in preventing nausea and vomiting induced by chemotherapy with cisplatin, cyclophosphamide, methotrexate, and fluorouracil.

Concomitant use with CYP3A inhibitors, including drugs containing cobicistat, is expected to increase the risk of systemic adverse effects. Such combinations should be avoided unless the benefit outweighs the risk of systemic corticosteroid side effects. In such cases, patients should be monitored for systemic corticosteroid effects.

Special precautions for use.

Severe psychiatric reactions may occur during systemic administration of corticosteroids. Symptoms typically appear within several days or weeks after initiation of therapy. The risk of developing these symptoms increases with high-dose regimens. Most reactions resolve upon dose reduction or discontinuation of the drug. Patients should be monitored closely and changes in mental status, especially depressive mood, suicidal thoughts, and intentions, should be promptly identified. Corticosteroids should be used with particular caution in patients with a history of affective disorders, particularly those with a personal history of allergic reactions to any other medications, as well as in patients with such a family history. Adverse effects may be prevented by using the lowest effective doses for the shortest possible duration or by administering the required daily dose once in the morning.

In patients undergoing prolonged treatment with dexamethasone, withdrawal syndrome (without apparent signs of adrenal insufficiency) may occur upon discontinuation of therapy, with symptoms such as fever, rhinitis, conjunctival redness, headache, dizziness, drowsiness or irritability, muscle and joint pain, vomiting, weight loss, general weakness, and frequent occurrence of seizures. Therefore, the dose of dexamethasone should be tapered gradually. Abrupt discontinuation may be fatal.

If a patient experiences severe stress (due to trauma, surgery, or serious illness) during therapy, the dose of dexamethasone should be increased. If such stress occurs during discontinuation of therapy, hydrocortisone or cortisone should be administered.

Patients who have received prolonged dexamethasone therapy and experience significant stress after stopping treatment should resume dexamethasone, as adrenal insufficiency induced by the drug may persist for several months after therapy cessation.

Treatment with dexamethasone or natural glucocorticoids may mask symptoms of existing or new infections, as well as symptoms of intestinal perforation. Dexamethasone may exacerbate systemic fungal infections, latent amebiasis, and pulmonary tuberculosis.

Patients with active pulmonary tuberculosis should receive dexamethasone (in combination with anti-tuberculosis agents) only in cases of rapidly progressive or severe disseminated pulmonary tuberculosis. Patients with inactive pulmonary tuberculosis receiving dexamethasone, or patients with a positive tuberculin reaction, should receive chemoprophylaxis.

Caution and medical supervision are recommended for patients with osteoporosis, arterial hypertension, heart failure, tuberculosis, glaucoma, hepatic or renal insufficiency, diabetes, active peptic ulcer, recent intestinal anastomosis, ulcerative colitis, and epilepsy. Particular care is required during the first weeks after myocardial infarction, in patients with thromboembolism, myasthenia gravis, glaucoma, hypothyroidism, psychosis or psychoneurosis, and in elderly patients.

During treatment, worsening of diabetes or transition from latent to clinical diabetes may occur.

During prolonged therapy, serum potassium levels should be monitored.

Live vaccine vaccination is contraindicated during dexamethasone treatment. Vaccination with inactivated viral or bacterial vaccines may not lead to the expected antibody synthesis and may lack the anticipated protective effect. Dexamethasone should generally not be used within 8 weeks before vaccination and should not be initiated earlier than 2 weeks after vaccination.

Patients who have undergone prolonged high-dose dexamethasone therapy and have never had measles should avoid contact with infected individuals; in case of accidental exposure, prophylactic immunoglobulin treatment is recommended.

Caution is advised in patients recovering from surgery or bone fractures, as dexamethasone may delay wound healing and bone tissue formation.

Systemic corticosteroids should not be discontinued in patients who are already receiving (oral) corticosteroids for other reasons (e.g., patients with chronic obstructive pulmonary disease) and do not require supplemental oxygen.

The effect of glucocorticoids is enhanced in patients with liver cirrhosis or hypothyroidism.

Corticosteroids may distort the results of skin allergy tests.

During post-marketing surveillance, tumor lysis syndrome (TLS) has been observed in patients with hematological malignancies after administration of dexamethasone alone or in combination with other chemotherapeutic agents. Close monitoring of patients at high risk of TLS—such as those with high proliferation rates, large tumor mass, and high sensitivity to cytotoxic agents—is required, along with appropriate preventive measures.

Systemic and local glucocorticoid therapy may lead to visual disturbances. In case of blurred vision or other visual disturbances, patients should be referred for ophthalmological examination to determine the cause. This may include cataract, glaucoma, or the rare condition choroidopathy, which has been reported during systemic and local corticosteroid use.

Cases of pheochromocytoma crisis, which may lead to fatal outcomes, have been reported after systemic corticosteroid therapy. Corticosteroids should be administered to patients with suspected or diagnosed pheochromocytoma only after appropriate benefit-risk assessment.

The medicinal product contains lactose. If a patient has been diagnosed with intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

Use during pregnancy or breastfeeding.

Harmful effects on the fetus and newborn infant cannot be excluded. The drug suppresses fetal development in utero. Dexamethasone may be prescribed to pregnant women only in rare emergency situations when the expected benefit to the mother outweighs the potential risk to the fetus. Particular caution is recommended in cases of preeclampsia. According to general guidelines for glucocorticoid therapy during pregnancy, the lowest effective dose required to control the underlying condition should be used. Infants born to mothers who received glucocorticoids during pregnancy should be carefully monitored for adrenal insufficiency.

Glucocorticoids cross the placenta and reach high concentrations in the fetus. Dexamethasone is less actively metabolized in the placenta than, for example, prednisone, so high concentrations of dexamethasone may be observed in fetal serum. Some data suggest that even pharmacological doses of glucocorticoids may increase the risk of placental insufficiency, oligohydramnios, delayed fetal development, or intrauterine fetal death, elevated white blood cell (neutrophil) counts in the fetus, and adrenal insufficiency. There is no evidence confirming teratogenic effects of glucocorticosteroids.

Additional doses of glucocorticoids are recommended during childbirth for women who received glucocorticosteroids during pregnancy. In cases of prolonged labor or planned cesarean section, intravenous administration of 100 mg hydrocortisone every 8 hours is recommended.

A small amount of glucocorticoids passes into breast milk; therefore, breastfeeding is not recommended for mothers receiving dexamethasone, especially when doses exceed physiological levels (approximately 1 mg). This may lead to growth retardation in the infant and reduced secretion of endogenous corticosteroids.

Ability to affect reaction speed when driving or operating machinery.

Dexamethasone does not affect the ability to drive vehicles or operate other machinery.

Administration and Dosage

The dosage should be individually determined according to the patient's specific condition, the intended duration of treatment, corticoid tolerance, and individual response.

Therapy

The recommended initial dose for adults is 0.5–9 mg daily. The maintenance dose is usually 0.5–3 mg daily. The daily dose may be divided into 2–4 doses.

Initial doses of dexamethasone should be administered until a clinical response is observed, after which the dose should be gradually reduced to the lowest clinically effective dose. If oral treatment with high doses continues for more than several days, the dose should be tapered gradually over several consecutive days or even longer (typically by 0.5 mg every 3 days). The maximum daily dose is usually 15 mg; the minimum effective dose is 0.5–1 mg daily.

During prolonged high-dose therapy, dexamethasone should be taken with food, and antacids may be used between meals.

Treatment of COVID-19

Adults and children aged 12 years and older with body weight of at least 40 kg: 6 mg of dexamethasone orally once daily for up to 10 days.

The duration of treatment is determined individually based on the patient's clinical condition.

Elderly patients, patients with renal or hepatic impairment: dose adjustment is not required.

Dosage for children

The recommended dose for oral administration in replacement therapy is 0.02 mg/kg body weight or 0.67 mg/m² body surface area daily, given in 3 divided doses.

For all other indications, the initial dose range is 0.08–0.3 mg/kg daily or 2.5–10 mg/m² body surface area daily, administered in 3–4 divided doses.

Diagnostic testing for adrenal hyperfunction

Dexamethasone suppression test (Liddle’s test). This test is performed as both a low-dose and a high-dose test.

In the low-dose test, administer dexamethasone 0.5 mg every 6 hours for 48 hours (specifically at 8 a.m., 2 p.m., 8 p.m., and 2 a.m.). Measure urinary 17-hydroxycorticosteroids or free cortisol in 24-hour urine samples before and after dexamethasone administration. These dexamethasone doses suppress corticosteroid production in nearly all healthy individuals. Six hours after the last dose, plasma cortisol levels should be below 135–138 nmol/L (4.5–5 µg/100 mL). A reduction in urinary excretion of 17-hydroxycorticosteroids to less than 3 mg daily or free cortisol to less than 54–55 nmol daily (19–20 µg daily) excludes adrenal hyperfunction. In patients with Cushing's disease or Cushing's syndrome, urinary corticosteroid excretion remains unchanged during the low-dose test.

In the high-dose test, administer dexamethasone 2 mg every 6 hours for 48 hours (i.e., 8 mg dexamethasone daily). Urine should also be collected for measurement of 17-hydroxycorticosteroids or free cortisol (and plasma free cortisol may be measured if necessary). In Cushing's disease, urinary excretion of 17-hydroxycorticosteroids or free cortisol decreases by 50% or more. In contrast, in adrenal tumors or ectopic ACTH (or ectopic corticoliberin) syndrome, corticosteroid excretion remains unchanged. In some patients with ectopic ACTH syndrome, suppression of corticosteroid excretion does not occur even after administration of dexamethasone at a dose of 32 mg daily.

Equivalent corticosteroid doses:

These dosage ratios apply only to oral or intravenous administration of these drugs. When these drugs or their derivatives are administered intramuscularly or intra-articularly, their relative properties may change significantly.

Children.

Dexamethasone should be used in children and adolescents only when clearly necessary. Careful monitoring of children's growth and development is required during dexamethasone treatment.

Overdose.

There have been isolated reports of acute overdose, including cases with fatal outcome.

Overdose following several weeks of excessive dosing may cause most of the adverse effects, primarily iatrogenic Cushing's syndrome.

A single ingestion of an excessive amount of tablets does not lead to clinically significant intoxication. There is no specific antidote. Treatment of overdose should be supportive and symptomatic. Hemodialysis is not an effective method for accelerating dexamethasone elimination from the body.

Adverse Reactions

Adverse effects during short-term treatment with dexamethasone

Immune system disorders: hypersensitivity reactions.

Endocrine system disorders: transient suppression of adrenal gland function.

Metabolism and nutrition disorders: decreased carbohydrate tolerance, increased appetite and weight gain, hypertriglyceridemia.

Psychiatric disorders: psychiatric disturbances.

Gastrointestinal disorders: peptic ulcer, acute pancreatitis.

Adverse effects during long-term treatment with dexamethasone

Immune system disorders: reduced immune response and increased susceptibility to infections.

Endocrine system disorders: persistent suppression of adrenal gland function; growth retardation in children and adolescents, premature closure of epiphyseal growth plates.

Metabolism and nutrition disorders: obesity.

Eye disorders: cataract, glaucoma, chorioretinopathy.

Vascular disorders: hypertension; telangiectasia.

Skin and subcutaneous tissue disorders: skin thinning.

Musculoskeletal and connective tissue disorders: muscle atrophy, osteoporosis (increased calcium excretion from the body), aseptic bone necrosis; fractures of long bones.

Adverse effects that may also occur in individual organs and systems during treatment with dexamethasone

Blood and lymphatic system disorders: thromboembolic complications, decreased number of monocytes and/or lymphocytes, leukocytosis, eosinophilia (as with other glucocorticoids); thrombocytopenia and non-thrombocytopenic purpura.

Immune system disorders: rash, bronchospasm, anaphylactic reactions; development of opportunistic infections.

Cardiac disorders: multifocal ventricular extrasystoles, transient bradycardia, heart failure, cardiac arrest; myocardial perforation following previous myocardial infarction.

Vascular disorders: hypertensive encephalopathy.

Respiratory, thoracic and mediastinal disorders: reactivation of latent tuberculosis.

Nervous system disorders: optic nerve edema and increased intracranial pressure (benign intracranial hypertension) after discontinuation of treatment; dizziness, vertigo; seizures; headache.

Psychiatric disorders: personality and behavioral changes, more commonly manifested as euphoria; insomnia, irritability, hyperkinesis, depression, nervousness, restlessness; manic-depressive psychosis, delirium, disorientation, hallucinations, paranoia, mood lability, suicidal ideation; psychoses; sleep disturbances, confusion, amnesia; worsening of schizophrenia, exacerbation of epilepsy.

Endocrine system disorders: suppression of adrenal gland function and adrenal atrophy (reduced response to stress), Cushing's syndrome, menstrual cycle disturbances, hirsutism.

Metabolism and nutrition disorders: transition from latent to clinical manifestations of diabetes, increased requirement for insulin and oral antidiabetic drugs in diabetic patients, sodium and water retention, increased potassium loss; hypokalemic alkalosis, negative nitrogen balance due to protein catabolism; hypocalcemia.

Gastrointestinal disorders: esophagitis, nausea, hiccup, dyspepsia, vomiting; peptic ulcer of stomach or duodenum, gastrointestinal perforations and hemorrhages (hematemesis, melena), pancreatitis, gallbladder perforation and intestinal perforation (especially in patients with inflammatory bowel diseases).

Musculoskeletal and connective tissue disorders: muscle weakness, steroid myopathy (muscle weakness due to muscle catabolism), vertebral compression fractures, damage to joint cartilage and bone necrosis (with frequent intra-articular injections), tendon ruptures (especially when used concomitantly with certain quinolones).

Skin and subcutaneous tissue disorders: delayed wound healing, striae, petechiae and ecchymoses, increased sweating, acne, suppression of skin tests; angioedema, allergic dermatitis, urticaria; skin itching.

Eye disorders: increased intraocular pressure, exophthalmos; exacerbation of bacterial, fungal or viral eye infections; corneal thinning, blurred vision.

Reproductive system and breast disorders: impotence; amenorrhea.

General disorders and administration site conditions: transient burning and tingling sensation in the perineum following intravenous administration or high-dose administration; edema; hyper- or hypopigmentation of the skin, atrophy of skin and subcutaneous tissue, sterile abscess, skin redness.

Signs of glucocorticoid withdrawal syndrome.

In patients treated with dexamethasone for a prolonged period, too rapid dose reduction may lead to withdrawal syndrome and, as a result, adrenal insufficiency, arterial hypotension, and potentially fatal outcomes. In some cases, withdrawal symptoms may resemble those of worsening or relapse of the underlying disease. If severe adverse reactions occur, treatment must be discontinued.

Shelf life. 5 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25°C.

Keep out of reach of children.

Packaging.

Tablets No. 10, No. 10×5 in blisters in a carton.

Prescription category. Prescription only.

Manufacturer.

Limited Liability Company "Experimental Plant 'GNCLS'".

Limited Liability Company "Pharmaceutical Company 'Zdorov'ya'".

Manufacturer's address and place of business.

8 Vorobiova Street, Kharkiv, Kharkiv Region, Ukraine.

(Limited Liability Company "Experimental Plant 'GNCLS')

22 Shevchenka Street, Kharkiv, Kharkiv Region, 61013, Ukraine.

(Limited Liability Company "Pharmaceutical Company 'Zdorov'ya')