Dexamethasone

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEXAMETHASONE (DEXAMETHASONE)

Composition:

Active substance: dexamethasone sodium phosphate;

1 ml of solution contains 4 mg of dexamethasone sodium phosphate calculated as dry substance;

Excipients: propylene glycol, glycerin, disodium edetate, phosphate buffer solution pH 7.5, methylparaben (E 218), propylparaben (E 216), water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Systemic corticosteroids.

ATC code H02AB02.

Pharmacological properties.

Pharmacodynamics.

Dexamethasone is a synthetic adrenocortical hormone (a corticosteroid) with glucocorticoid activity. It exerts anti-inflammatory and immunosuppressive effects and also influences energy metabolism, glucose metabolism, and (via negative feedback) the secretion of hypothalamic corticotropin-releasing factor and adenohypophyseal tropic hormones.

The mechanism of action of glucocorticoids is not yet fully understood. However, 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. Corticosteroids exert their anti-inflammatory and immunosuppressive effects and regulate glucose metabolism through binding to glucocorticoid receptors. 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 induces a conformational change in the receptor, increasing its affinity for DNA. The hormone-receptor complex enters the cell nucleus and binds to a regulatory site on the DNA molecule, known as the glucocorticoid response element (GRE). The activated receptor, bound to the GRE or specific genes, regulates mRNA transcription, which may be either increased or decreased. The newly formed mRNA is transported to the 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 liver cells) or reduced (e.g., interleukin-2 (IL-2) production in lymphocytes). Since glucocorticoid receptors are present in all tissue types, glucocorticoids can be considered to 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 formation from pyruvate or amino acids and promotes glycogen synthesis. In peripheral tissues, particularly in muscles, glucose uptake is reduced, and amino acids are mobilized (from proteins) as substrates for hepatic gluconeogenesis. A direct effect on lipid metabolism is the 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 synthesis and secretion, and improves the kidney's ability to excrete acids.

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

When administered in high doses, dexamethasone inhibits fibroblastic production of type I and type III collagen and the formation of glycosaminoglycans. Thus, by suppressing extracellular collagen and matrix formation, wound healing is delayed. Prolonged administration of high doses leads to progressive bone resorption via indirect effects and reduced osteogenesis via direct effects (increased parathyroid hormone secretion and decreased calcitonin secretion), as well as a negative calcium balance due to reduced intestinal calcium absorption and increased urinary calcium excretion. This typically results in secondary hyperparathyroidism and phosphaturia.

Effects on the pituitary and hypothalamus. Dexamethasone is approximately 30 times more potent than cortisol. Thus, it is a more powerful inhibitor of corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH) secretion compared to endogenous cortisol. This leads to reduced cortisol secretion, and after prolonged suppression of CRF and ACTH secretion, to adrenal atrophy. Adrenal insufficiency may develop as early as day 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) with high doses, adrenal cortex function should recover within 1 week; after long-term therapy, normalization occurs later, usually within 1 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 altered expression of several genes regulating the formation of various signaling molecules, proteins, and enzymes involved in the inflammatory response. The biochemical anti-inflammatory effect of glucocorticoids arises from blocking the production and function of humoral mediators of inflammation: prostaglandins, thromboxanes, cytokines, and leukotrienes. Dexamethasone reduces leukotriene formation by decreasing the release of arachidonic acid from cellular phospholipids, due to inhibition of phospholipase A2 activity. The effect on phospholipases is not due to direct action but results from increased lipocortin (macrocortin) concentration, an inhibitor of phospholipase A2. Dexamethasone also inhibits prostaglandin and thromboxane formation by reducing the synthesis of specific DNA, thereby decreasing cyclooxygenase production. Dexamethasone reduces platelet-activating factor production by increasing lipocortin concentration. Other biochemical anti-inflammatory effects include reduced tumor necrosis factor and interleukin (IL-1) production.

In animal studies, cleft palate was observed in rats, mice, hamsters, rabbits, dogs, and primates, but not in horses or sheep. In some cases, cleft palate was associated with central nervous system and cardiac malformations. In primates, brain abnormalities were observed after irradiation. In addition, intrauterine growth retardation may occur. All these effects were noted when dexamethasone was administered in high doses.

An individually randomized, controlled, open-label trial of the adaptive platform RECOVERY (Randomised Evaluation of Covid-19 Therapy)\textsuperscript{1}, initiated by researchers to evaluate outcomes of potential treatments in patients hospitalized with COVID-19, was conducted.

The trial was carried out in 176 hospitals across 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% received oxygen only (with or without non-invasive ventilation), and 24% received no respiratory support.

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

Primary endpoint. Mortality at day 28 was significantly lower in the dexamethasone group than in the usual care group: death occurred in 482 of 2104 patients (22.9%) versus 1110 of 4321 patients (25.7%), respectively (risk 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%; risk ratio 0.64; 95% CI 0.51–0.81). A similar reduction was observed among patients receiving supplemental oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; risk 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%; risk ratio 1.19; 95% CI 0.91–1.55).

Secondary endpoint. Patients in the dexamethasone group had shorter hospital stays than those in the usual care group (median 12 days vs. 13 days) and a higher probability of discharge within 28 days (risk ratio 1.10; 95% CI 1.03–1.17).

Consistent with the primary endpoint, the greatest effect on discharge within 28 days was observed in patients receiving invasive mechanical ventilation at randomization (risk ratio 1.48; 95% CI 1.16–1.90), a smaller effect in patients receiving oxygen only (risk ratio 1.15; 95% CI 1.06–1.24), and no favorable effect in patients not receiving oxygen (risk ratio 0.96; 95% CI 0.85–1.08).

* The ratio of outcomes was adjusted for age, taking into account results for 28-day mortality and hospital discharge. Risk ratios were adjusted for age regarding receipt of 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, 4 serious adverse events related to investigational treatment were recorded: 2 cases of hyperglycemia development, 1 case of steroid-induced psychosis, and 1 case of upper gastrointestinal tract bleeding. All events were resolved.

Subgroup analysis

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

Effects of dexamethasone on 28-day mortality according to respiratory support and presence of any chronic comorbidity 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.

Absorption. Dexamethasone reaches peak plasma concentration within the first 5 minutes following intravenous administration and within 1 hour following intramuscular administration. After local injection into a joint or soft tissues (inflammatory site), absorption occurs more slowly than after intramuscular administration. Following intravenous administration, onset of action is immediate; after intramuscular administration, clinical effect begins within 8 hours. The duration of action lasts 17–28 days after intramuscular administration and from 3 days to 3 weeks after local administration.

Distribution. In plasma and synovial fluid, dexamethasone phosphate is rapidly converted into dexamethasone. In plasma, approximately 77% of dexamethasone is protein-bound, primarily to albumin. Only a small amount binds to other proteins. Dexamethasone is lipophilic, thus freely penetrating 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 via cytoplasmic receptors.

Biotransformation. Dexamethasone 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.

Elimination. The biological half-life of dexamethasone is 24–72 hours. It is primarily excreted in the urine.

Clinical characteristics.

Indications.

Dexamethasone is administered intravenously or intramuscularly in emergency situations and when oral administration is not feasible.

Endocrine disorders:

• Replacement therapy in primary or secondary (pituitary) adrenal insufficiency (except for acute adrenal insufficiency, where hydrocortisone or cortisone are more suitable due to their stronger hormonal effect);

• Acute adrenal insufficiency (hydrocortisone or cortisone are drugs of choice; concomitant use with mineralocorticoids may be necessary, especially when synthetic analogs are used);

• Prior to surgery and in cases of severe trauma or illness in patients with established adrenal insufficiency or uncertain adrenocortical reserve;

• Shock unresponsive to conventional therapy, with known or suspected adrenal insufficiency;

• Congenital adrenal hyperplasia;

• Non-purulent thyroiditis and severe forms of radiation-induced thyroiditis.

Rheumatological diseases

(as adjunctive therapy during periods when baseline therapy has failed, i.e., in patients in whom analgesic and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (NSAIDs) were unsatisfactory):

• Rheumatoid arthritis, including juvenile rheumatoid arthritis and extra-articular manifestations of rheumatoid arthritis (rheumatic lungs, cardiac, ocular, and skin vasculitis);

• Synovitis in osteoarthritis; post-traumatic osteoarthritis; epicondylitis; acute nonspecific tenosynovitis; acute gouty arthritis; psoriatic arthritis; ankylosing spondylitis; systemic connective tissue diseases; vasculitis.

Skin diseases:

• Pemphigus; severe erythema multiforme (Stevens-Johnson syndrome); exfoliative dermatitis; bullous dermatitis herpetiformis; severe forms of exudative erythema; nodular erythema; severe forms of seborrheic dermatitis; severe forms of psoriasis; urticaria unresponsive to standard treatment; mycosis fungoides; dermatomyositis.

Allergic diseases:

(those unresponsive to conventional treatment):

• Bronchial asthma; contact dermatitis; atopic dermatitis; serum sickness; chronic or seasonal allergic rhinitis; drug allergy; transfusion-related urticaria.

Ocular diseases:

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

The solution may be administered systemically or locally (subconjunctival, retrobulbar, or parabulbar injection).

Gastrointestinal diseases:

For managing critical conditions such as:

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

Respiratory tract diseases:

• Symptomatic sarcoidosis (symptomatic); acute toxic bronchiolitis; chronic bronchitis and asthma (during exacerbation); focal or disseminated pulmonary tuberculosis (in combination with appropriate antituberculosis therapy); berylliosis (granulomatous inflammation); 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); idiopathic thrombocytopenic purpura in adults (intravenous administration only – intramuscular administration is contraindicated).

Renal diseases:

• Immunosuppressive therapy in kidney transplantation; stimulation of diuresis or reduction of proteinuria in idiopathic nephrotic syndrome (without uremia) and renal dysfunction in systemic lupus erythematosus.

Malignant neoplastic diseases:

• Palliative treatment of leukemia and lymphoma in adults; acute leukemia in children; hypercalcemia associated with malignancies.

Cerebral edema:

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

Shock:

• Shock unresponsive to standard therapy; shock in patients with adrenal cortex insufficiency; anaphylactic shock (intravenous after epinephrine administration); preoperative use to prevent shock in suspected or confirmed adrenal cortex insufficiency.

Other indications:

• Tuberculous meningitis with subarachnoid block (in combination with appropriate antituberculosis therapy); trichinellosis with neurological symptoms or myocardial trichinellosis; cystic tumor of aponeurosis or tendon (ganglion);

• Dexamethasone is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults and adolescents (aged 12 years and older with body weight ≥40 kg) who require supplemental oxygen therapy.

Indications for intra-articular or soft tissue injection:

• Rheumatoid arthritis (severe inflammation of a single joint); ankylosing spondylitis (when inflamed joints are unresponsive to conventional therapy); psoriatic arthritis (oligoarticular form and tenosynovitis); monoarthritis (after evacuation of synovial fluid); osteoarthritis of joints (only in cases of synovitis and effusion); periarticular rheumatism (epicondylitis, tenosynovitis, bursitis); acute and gouty arthritis.

Local injection (injection at the site of lesion):

• Keloid lesions; hypertrophic, inflammatory, and infiltrated lesions in lichen, psoriasis, granuloma annulare, sclerosing folliculitis, discoid lupus, and cutaneous sarcoidosis; discoid lupus erythematosus; Urbach-Wiethe disease; localized alopecia.

Contraindications.

Hypersensitivity to the active substance or to any other component of the medicinal product.

Acute viral, bacterial, or systemic fungal infections (unless appropriate therapy is administered).

Cushing's syndrome.

Vaccination with live vaccines.

Breastfeeding period (except in emergency cases).

Intramuscular injection is contraindicated in patients with severe coagulation disorders.

Local injection is contraindicated in bacteremia, systemic fungal infections, patients with unstable joints, and infections at the site of administration, including septic arthritis due to gonorrhea or tuberculosis.

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 simultaneously with drugs that induce the CYP 3A4 enzyme (phenytoin, phenobarbital, carbamazepine, primidone, rifabutin, rifampicin) or increase glucocorticoid metabolic clearance (ephedrine and aminoglutethimide). In such cases, the dose of dexamethasone should be increased. Interactions between dexamethasone and all the above-mentioned drugs may affect the results of the dexamethasone suppression test. This should be considered when evaluating test results.

Concomitant use of dexamethasone and drugs that inhibit CYP 3A4 enzyme activity (ketoconazole, macrolides) may lead to increased dexamethasone serum concentrations. Dexamethasone is a moderate inducer of CYP 3A4. Concomitant use with drugs metabolized by CYP 3A4 (indinavir, erythromycin) may increase their clearance, resulting in decreased serum concentrations.

By inhibiting CYP 3A4 enzyme activity, ketoconazole may increase dexamethasone serum concentration. Conversely, ketoconazole may suppress adrenal synthesis of glucocorticoids, thus adrenal insufficiency may develop due to decreased dexamethasone concentration.

Dexamethasone reduces the therapeutic effect of antidiabetic drugs, antihypertensives, praziquantel, and natriuretic agents (therefore, the dose of these drugs should be increased), but enhances the activity of heparin, albendazole, and kaliuretic agents (the dose of these drugs should be reduced if necessary).

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

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 dexamethasone absorption in the stomach. The effect of dexamethasone when taken simultaneously 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 serum concentrations. Caution is required in patients gradually tapering corticosteroid doses, as serum salicylate concentrations may rise, leading to intoxication.

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

Concomitant use of ritodrine and dexamethasone is contraindicated during labor, as it may lead to a fatal outcome for the mother due to pulmonary edema. Fatal outcomes in mothers due to this condition have been reported.

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 therapy with CYP3A inhibitors, particularly drugs containing cobicistat, is expected to increase the risk of systemic adverse effects. This combination should be avoided unless benefit outweighs risk; in such cases, patients should be monitored for systemic corticosteroid effects.

Special precautions for use.

Hypersensitivity reactions are rarely observed during parenteral corticosteroid therapy; therefore, appropriate precautions should be taken before initiating dexamethasone treatment due to the possibility of allergic reactions (especially in patients with a history of allergic reactions to any other drugs).

Systemic use of corticosteroids may be accompanied by severe psychiatric reactions. Symptoms usually appear within several days or weeks after the start of treatment. The risk of developing these symptoms increases with high-dose regimens. Most reactions resolve upon dose reduction or discontinuation of the drug. Close monitoring and timely detection of psychiatric changes—particularly depressive mood, suicidal thoughts, and intentions—are essential. Corticosteroids should be used with special caution in patients with a history of affective disorders, especially those with a history of allergic reactions to any other drugs or in their close relatives. Adverse effects may be prevented by using the lowest effective dose for the shortest possible duration or by administering the required daily dose once in the morning.

In patients receiving prolonged dexamethasone therapy, withdrawal syndrome (without apparent signs of adrenal insufficiency) may occur upon discontinuation, with symptoms including fever, rhinitis, conjunctival redness, headache, dizziness, somnolence or irritability, muscle and joint pain, vomiting, weight loss, general weakness, and often seizures. Therefore, the dexamethasone dose should be tapered gradually. Abrupt discontinuation may result in fatal outcomes. If a patient experiences severe stress (due to trauma, surgery, or serious illness) during therapy, the dexamethasone dose should be increased. If this occurs during treatment discontinuation, hydrocortisone or cortisone should be administered.

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

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 amoebiasis, and pulmonary tuberculosis.

Patients with active pulmonary tuberculosis should receive dexamethasone (in combination with anti-tuberculosis agents) only in cases of rapidly progressive or widely disseminated pulmonary tuberculosis. Patients with inactive pulmonary tuberculosis receiving dexamethasone, or those 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, or epilepsy. Special care is required during the first weeks after myocardial infarction, and for patients with thromboembolism, myasthenia gravis, glaucoma, hypothyroidism, psychosis or psychoneurosis, and elderly patients.

During treatment, diabetes may worsen or latent diabetes may progress to clinical manifestation.

During prolonged therapy, serum potassium levels should be monitored.

Live vaccination is contraindicated during dexamethasone treatment. Inactivated viral or bacterial vaccines may not elicit the expected antibody synthesis and may lack protective efficacy. Dexamethasone should generally not be administered within 8 weeks before vaccination, nor should treatment be initiated earlier than 2 weeks after vaccination.

Patients who have received 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 required in patients recovering from surgery or bone fractures, as dexamethasone may delay wound healing and bone tissue formation.

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

Intra-articular administration of corticosteroids may lead to local and systemic effects. Frequent use may cause cartilage damage or bone necrosis.

Before intra-articular injection, synovial fluid should be aspirated and examined (to check for infection). Corticosteroids should not be injected into infected joints. If joint infection develops after injection, appropriate antibiotic therapy should be initiated.

Patients should be advised to avoid physical stress on affected joints until inflammation resolves.

Avoid injecting the drug into unstable joints.

Corticosteroids may alter the results of skin allergy tests.

In the treatment of coronavirus disease 2019 (COVID-19), systemic corticosteroids should not be discontinued in patients already receiving systemic (oral) corticosteroids for other reasons (e.g., patients with chronic obstructive pulmonary disease) who do not require supplemental oxygen.

Visual disturbances may occur during systemic and local use of corticosteroids. If a patient develops blurred vision or other visual disturbances, they should be referred to an ophthalmologist to evaluate possible causes, including cataract, glaucoma, or rare conditions such as central serous chorioretinopathy (CSC), which has been reported after systemic and local corticosteroid use.

Pheochromocytoma crisis. Cases of pheochromocytoma crisis, potentially leading 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.

Hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy has been reported after systemic administration of corticosteroids, including dexamethasone, in preterm infants. In most reported cases, this was reversible after discontinuation of treatment. Preterm neonates receiving systemic dexamethasone therapy should undergo diagnostic evaluation and monitoring of cardiac function and structure (see "Adverse reactions").

Preterm neonates: Long-term neurodevelopmental impairments have been reported after early treatment (< 96 hours) of preterm infants with chronic lung disease using dexamethasone at initial doses of 0.25 mg/kg twice daily.

Special warnings regarding excipients.

The medicinal product contains less than 1 mmol (23 mg) of sodium per dose, which is considered a negligible amount.

Propylene glycol may cause symptoms similar to those caused by alcohol consumption.

Methylparaben and propylparaben may cause allergic reactions (possibly delayed).

Use during pregnancy or breastfeeding.

Pregnancy. A harmful effect on the fetus and newborn infant cannot be excluded. The drug suppresses fetal development. Dexamethasone may be administered to pregnant women only in exceptional emergency cases when the expected benefit to the mother outweighs the potential risk to the fetus. Particular caution is advised in cases of preeclampsia. According to general recommendations, the lowest effective dose should be used during pregnancy to control the underlying condition. 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. Therefore, 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 death, elevated leukocyte (neutrophil) counts in the fetus, and adrenal insufficiency. There is no evidence confirming the teratogenic effects of glucocorticosteroids.

Administration of corticosteroids to pregnant animals has caused fetal developmental abnormalities, including cleft palate, intrauterine growth retardation, and effects on brain growth and development. There is no evidence that corticosteroids increase the frequency of congenital malformations such as cleft palate/lip in humans (see section "Pharmacological properties").

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

Studies have shown an increased risk of neonatal hypoglycemia after prenatal short-term use of corticosteroids, including dexamethasone, in women at risk of late preterm delivery.

Breastfeeding. Use during breastfeeding is contraindicated (except in emergency cases).

A small amount of glucocorticoids passes into breast milk; therefore, mothers receiving dexamethasone should not breastfeed, especially when doses exceed physiological levels (approximately 1 mg). This may lead to impaired infant growth and reduced secretion of endogenous corticosteroids.

Ability to affect reaction speed when driving or operating machinery.

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

Administration and Dosage

Dexamethasone, injection solution, is intended for use in adults and children from birth.

The injection solution may be administered intravenously (by injection or infusion with glucose solution or sodium chloride solution), intramuscularly, or locally (by intra-articular injection or injection into the site of skin lesions or soft tissue infiltrates). For intravenous infusion, 0.9% sodium chloride solution or 5% glucose solution should be used as the diluent.

Solutions intended for intravenous administration or further dilution of the drug must not contain preservatives when used in neonates, particularly preterm infants.

The drug should be mixed with the infusion solution under sterile conditions. The mixture should be used within 24 hours, as infusion solutions generally do not contain preservatives. Parenteral preparations should be visually inspected for particulate matter and discoloration prior to each administration.

Dosage should be individually adjusted according to the patient's specific condition, anticipated duration of treatment, corticosteroid tolerance, and individual response.

Parenteral Administration

Dexamethasone should be administered parenterally in emergency situations, when oral therapy is not feasible, and in conditions specified in the section "Indications".

The injection solution is intended for intravenous, intramuscular, or infusion administration (with glucose solution or sodium chloride solution).

The recommended average initial daily dose for intravenous or intramuscular administration is 0.5–9 mg per day; the dose may be increased if necessary. Initial doses should be maintained until clinical response is achieved, after which the dose should be gradually reduced to the lowest clinically effective dose.

When high doses are administered for several days, the dose should be gradually tapered over the following days or for a longer period.

Treatment of COVID-19. In adult patients, administer 6 mg intravenously once daily for up to 10 days.

Paediatric Population. In adolescents aged 12 years and older, it is recommended to administer 6 mg intravenously once daily for up to 10 days. The duration of treatment depends on the clinical response and individual patient needs.

Elderly Patients, Patients with Renal Impairment, Patients with Hepatic Impairment. Dose adjustment is not required.

Local Administration

For intra-articular injection, the recommended doses range from 0.4 mg to 4 mg, depending on the size of the affected joint. Typically, 2–4 mg is administered into large joints and 0.8–1 mg into small joints. Repeated intra-articular injections may be performed after 3–4 months. Injections into a single joint may be repeated up to three or four times during a patient’s lifetime, and no more than two joints should be treated simultaneously. More frequent intra-articular injections may damage joint cartilage and lead to bone necrosis.

The usual dose of dexamethasone injected into the synovial sac is 2–3 mg, into tendon sheaths is 0.4–1 mg, and into ganglia is 1–2 mg.

The dose administered at the site of injury is equivalent to the intra-articular dose. Dexamethasone may be simultaneously administered at no more than two sites of injury.

Dosages for soft tissue injection (around the joint) range from 2 to 6 mg.

Paediatric Dosage

For intramuscular administration, the recommended replacement therapy dose is 0.02 mg/kg body weight or 0.67 mg/m² body surface area, divided into three doses administered every third day, or 0.008–0.01 mg/kg body weight or 0.2–0.3 mg/m² body surface area per day.

For all other indications, the recommended dose is 0.02–0.1 mg/kg body weight or 0.8–5 mg/m² body surface area every 12–24 hours.

Equivalent doses of corticosteroids:

Children. Should be used in children from birth only in cases of extreme necessity. Careful monitoring of growth and development in children and adolescents is required during treatment with dexamethasone.

Overdose.

There have been isolated reports of acute overdose or fatal outcomes due to acute overdose.

Overdose usually occurs only after several weeks of administration. Overdose may cause most of the adverse effects listed in the section "Side Effects," particularly Cushing's syndrome. There is no specific antidote. Management of overdose should be supportive and symptomatic. Hemodialysis is not an effective method for accelerating the elimination of dexamethasone from the body.

Adverse reactions.

Adverse effects during short-term treatment with dexamethasone

Immune system: hypersensitivity reactions.

Endocrine system: transient suppression of adrenal gland function.

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

Psychiatric disorders: psychiatric disorders.

Gastrointestinal disorders: peptic ulcer, acute pancreatitis.

Adverse effects during long-term treatment with dexamethasone

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

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

Metabolism and nutrition: obesity.

Eye disorders: cataract, glaucoma.

Vascular disorders: hypertension, telangiectasia.

Skin and subcutaneous tissue disorders: thinning of the skin.

Musculoskeletal and connective tissue disorders: muscle atrophy, osteoporosis, avascular bone necrosis, fractures of tubular 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 due to previous myocardial infarction. Hypertrophic cardiomyopathy in preterm infants (see section "Special precautions").

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, headache, convulsions.

Psychiatric disorders: personality and behavioral changes, more commonly manifesting as euphoria; insomnia, irritability, hyperkinesia, depression, nervousness, restlessness, manic-depressive psychosis, delirium, disorientation, hallucinations, paranoia, mood lability, suicidal thoughts, psychosis, sleep disturbances, confusion, amnesia, worsening of schizophrenia, worsening 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 diabetes; increased insulin and oral antidiabetic drug requirements in diabetic patients; sodium and water retention; increased potassium loss; hypokalemic alkalosis; negative nitrogen balance due to protein catabolism; hypocalcemia.

Gastrointestinal disorders: dyspepsia, vomiting, nausea, hiccup, gastric or duodenal peptic ulcer, esophagitis, gastrointestinal perforations and hemorrhages (hematemesis, melena), pancreatitis, gallbladder perforation, 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, tendon ruptures (especially when used concomitantly with certain quinolones), joint cartilage damage and bone necrosis (with frequent intra-articular injections).

Skin and subcutaneous tissue disorders: delayed wound healing, striae, petechiae and bruising, increased sweating, acne, suppressed response to skin tests, angioedema (Quincke's edema), allergic dermatitis, urticaria, pruritus.

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

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 injection; swelling, hyper- or hypopigmentation of the skin, atrophy of the skin and subcutaneous tissue, sterile abscess, skin redness.

Symptoms of glucocorticoid withdrawal syndrome

In patients who have been treated with dexamethasone for a prolonged period, withdrawal syndrome may occur if the dose is reduced too rapidly, leading to adrenal insufficiency, arterial hypotension, and potentially fatal outcomes. In some cases, symptoms of withdrawal may resemble those of exacerbation or recurrence of the disease for which the patient was being treated. If severe adverse reactions occur, treatment should be discontinued.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Storage conditions. Store in the original packaging, out of reach of children, at a temperature not exceeding 25 °C.

Incompatibilities. The medicinal product should not be mixed with other drugs except the following: 0.9% sodium chloride solution or 5% glucose solution.

Precipitation occurs when dexamethasone is mixed with chlorpromazine, diphenhydramine, doxapram, doxorubicin, daunorubicin, idarubicin, hydromorphone, ondansetron, prochlorperazine, potassium nitrate, and vancomycin.

Approximately 16% of dexamethasone degrades in 2.5% glucose solution and 0.9% sodium chloride solution containing amikacin.

Some medicinal products, such as lorazepam, should be mixed with dexamethasone in glass vials, not in plastic bags (lorazepam concentration decreases to below 90% within 3–4 hours when stored in polyvinyl chloride bags at room temperature).

With certain drugs, such as metaraminol, a so-called delayed incompatibility develops after 24 hours when mixed with dexamethasone.

Dexamethasone and glycopyrrolate: the pH of the final solution is 6.4, which is outside the stability range.

Packaging. 1 ml in a vial; 100 vials per carton, or 5 vials per blister, 1 blister per carton or 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Lekhim-Kharkiv".

Manufacturer's location and address of business activity.

Ukraine, 61115, Kharkiv region, city of Kharkiv, 36 Severina Pototskogo Street.