Dexamethasone-4-darnitsa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEXAMETHASONE-4-DARNYTSIA (DEXAMETHASONE-4-DARNYTSIA)

Composition:

Active substance: dexamethasone phosphate;

1 ml of solution contains 4 mg of dexamethasone phosphate in the form of dexamethasone sodium phosphate.

Excipients: disodium phosphate dihydrate, glycerol, disodium edetate, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear liquid, colorless to pale yellow.

Pharmacotherapeutic group. Systemic corticosteroids.

ATC code H02AB02.

Pharmacological Properties.

Pharmacodynamics.

Dexamethasone is a synthetic adrenal cortex 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 trophic hormones.

The mechanism of action of glucocorticoids is not yet fully understood. A substantial amount of evidence supports the cellular-level effects of glucocorticoids. 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, while binding to mineralocorticoid receptors regulates sodium and potassium metabolism and water-electrolyte balance.

Glucocorticoids are lipid-soluble and readily penetrate target cells through the cell membrane. Hormone binding to its 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 GRE or specific genes, regulates mRNA transcription, which may be either increased or decreased. The 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 liver cells) or reduced (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, especially muscle, glucose uptake is reduced, and amino acids (from proteins) are mobilized as substrates for hepatic gluconeogenesis. A direct effect on lipid metabolism is 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 enhances myocardial contractility and peripheral vascular tone.

At high doses, dexamethasone inhibits fibroblast production of collagen types I and III and the formation of glycosaminoglycans. Inhibition of extracellular collagen and matrix formation leads to delayed wound healing. Prolonged administration of high doses causes progressive bone resorption via indirect effects and reduces osteogenesis via direct effects (increased parathyroid hormone secretion and decreased calcitonin secretion), resulting in a negative calcium balance due to reduced intestinal calcium absorption and increased urinary 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 compared to endogenous cortisol. This leads to reduced cortisol secretion and, after prolonged suppression of CRF and ACTH secretion, to adrenal gland atrophy. Adrenal insufficiency may develop as early as days 5–7 of dexamethasone administration at a dose 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 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. Molecular anti-inflammatory effects result from binding to glucocorticoid receptors and subsequent changes in the expression of genes regulating the production of various signaling molecules, proteins, and enzymes involved in the inflammatory response. The biochemical anti-inflammatory action of glucocorticoids results from inhibition of the synthesis and activity of humoral inflammatory mediators: prostaglandins, thromboxanes, cytokines, and leukotrienes. Dexamethasone reduces leukotriene production by inhibiting the release of arachidonic acid from cellular phospholipids, mediated by inhibition of phospholipase A2 activity. This effect on phospholipase A2 is not due to direct action but results from increased concentration of lipocortin (macrocortin), an inhibitor of phospholipase A2. Dexamethasone also inhibits prostaglandin and thromboxane synthesis by reducing the formation of specific mRNA, thereby decreasing cyclooxygenase production. Dexamethasone further 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).

The RECOVERY trial (Randomised Evaluation of COVid-19 thERapY) is a researcher-initiated, individually randomized, open-label, adaptive platform trial designed to evaluate the effects of potential treatments in patients hospitalized with COVID-19.

The trial was conducted across 176 hospitals in the United Kingdom.

A total of 6,425 patients were randomized to receive either dexamethasone (2,104 patients) or usual care alone (4,321 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 (with or without non-invasive ventilation), and 24% were receiving 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 28 days was significantly lower in the dexamethasone group than in the usual care group: 482 of 2,104 patients (22.9%) died in the dexamethasone group versus 1,110 of 4,321 patients (25.7%) in the usual care group (rate ratio 0.83; 95% confidence interval [CI], 0.75 to 0.93; P < 0.001).

The frequency of death was lower in the dexamethasone group compared to the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving supplemental oxygen without invasive ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 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 endpoints

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 likelihood of being discharged alive within 28 days (rate ratio, 1.10; 95% CI, 1.03 to 1.17).

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

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

Subgroup analyses and results are presented in the tables.

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

Table 1

Table 2

Effects of dexamethasone on 28-day mortality, by type of respiratory support at randomization and presence of any chronic comorbidity³

Table 2

1 www.recoverytrial.net

2, 3 (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 after intramuscular administration. After local administration into a joint or soft tissues (inflammatory site), absorption is slower compared to intramuscular injection. Following intravenous administration, onset of action is immediate; after intramuscular administration, clinical effect occurs within 8 hours. The duration of action lasts 17–28 days after intramuscular administration and from 3 days to 3 weeks following local administration.

Distribution

In blood plasma and synovial fluid, dexamethasone phosphate is rapidly converted to dexamethasone. In plasma, approximately 77% of dexamethasone is bound to plasma proteins, primarily to albumin. Only a small amount of dexamethasone binds to other blood proteins. Dexamethasone is lipophilic, therefore it freely penetrates into 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

Degradation of dexamethasone 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.

Excretion

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 for primary or secondary (pituitary) adrenal insufficiency (except in cases of acute adrenal insufficiency, where hydrocortisone or cortisone are more appropriate due to their stronger mineralocorticoid effect);
• Acute adrenal insufficiency (hydrocortisone or cortisone are drugs of choice; concomitant use of mineralocorticoids may be required, especially when using synthetic analogs);
• Congenital adrenal hyperplasia;
• Nonsuppurative thyroiditis and severe forms of radiation thyroiditis.

Rheumatological disorders:

• Rheumatoid arthritis, including juvenile rheumatoid arthritis and extra-articular manifestations of rheumatoid arthritis (rheumatoid lungs, cardiac, ocular, and cutaneous vasculitis).

Skin disorders:

• Pemphigus;
• Severe forms of erythema multiforme (Stevens-Johnson syndrome);
• Exfoliative dermatitis; bullous pemphigoid dermatitis; severe forms of exudative erythema;
• Erythema nodosum;
• Severe forms of seborrheic dermatitis;
• Severe forms of psoriasis;
• Urticaria unresponsive to standard treatment;
• Fungal mycosis;
• Dermatomyositis;
• Scleroderma;
• Angioedema (Quincke's edema).

Allergic disorders:

(when unresponsive to conventional treatment)

• Bronchial asthma;
• Contact dermatitis; atopic dermatitis;
• Serum sickness; chronic or seasonal allergic rhinitis;
• Drug allergy; post-transfusion urticaria.

Ophthalmic disorders:

• Inflammatory eye diseases (acute central choroiditis, optic neuritis);
• Allergic disorders (conjunctivitis, uveitis, scleritis, keratitis, iritis);
• Sympathetic ophthalmia;
• Systemic immune disorders (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 peribulbar injection).

Gastrointestinal disorders:

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

Respiratory disorders:

• Symptomatic sarcoidosis (symptomatic treatment);
• Acute toxic bronchiolitis;
• Chronic bronchitis and asthma (during exacerbations);
• Focal or disseminated pulmonary tuberculosis (in combination with appropriate antituberculosis therapy);
• Berylliosis (granulomatous inflammation);
• Radiation or aspiration pneumonitis.

Hematological disorders:

• 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).

Kidney disorders:

• 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 disorders:

• 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, or traumatic brain injury.

Shock:

• Shock unresponsive to conventional treatment;
• Shock in patients with adrenal insufficiency;
• Anaphylactic shock (intravenous after epinephrine administration);
• Preoperatively, to prevent shock in patients with suspected or confirmed adrenal insufficiency.

Other indications:

• Tuberculous meningitis with subarachnoid block (in combination with appropriate antituberculosis therapy);
• Trichinellosis with neurological symptoms or myocardial involvement;
• Cystic tumor of aponeurosis or tendon (ganglion).
• Dexamethasone-4-Darnitsa 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.

Intra-articular or soft tissue injection indications:

• Rheumatoid arthritis (severe inflammation of a single joint);
• Ankylosing spondylitis (when joint inflammation is unresponsive to conventional treatment);
• 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, annular granuloma, sclerosing folliculitis, discoid lupus, and cutaneous sarcoidosis;
• 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.

Live vaccine administration.

Breastfeeding period (except in emergency cases).

Intramuscular injection is contraindicated in patients with severe coagulation disorders.

Interaction with other medicinal products and other forms of interaction.

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 CYP3A4 enzyme activity (phenytoin, phenobarbital, carbamazepine, primidone, rifabutin, rifampicin) or increase glucocorticoid metabolic clearance (ephedrine and aminoglutethimide). In such cases, the dose of dexamethasone should be increased. Interaction between dexamethasone and all the above-mentioned drugs may distort the results of the dexamethasone suppression test. This should be considered when interpreting test results.

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

By inhibiting CYP3A4 enzyme activity, ketoconazole may increase dexamethasone serum concentrations. Conversely, ketoconazole may suppress adrenal synthesis of glucocorticoids, potentially leading to adrenal insufficiency due to reduced dexamethasone concentrations.

Dexamethasone reduces the therapeutic effect of antidiabetic drugs, antihypertensives, praziquantel, and natriuretic agents (thus, the dose of these drugs should be increased), but enhances the activity of heparin, albendazole, and potassium-wasting diuretics (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 this combination is used.

Concomitant use of high-dose 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 simultaneous intake of the drug with 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 when tapering corticosteroid doses, as salicylate serum concentrations may rise, potentially leading to intoxication.

When used concomitantly with oral contraceptives, 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 fatal pulmonary edema in the mother.

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, or fluorouracil.

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

Special precautions for use.

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

Severe psychiatric reactions may accompany systemic corticosteroid therapy. Symptoms usually appear within several days or weeks after starting 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 cautiously in patients with a history of affective disorders, especially those with a personal or family history of allergic reactions to any other drugs. 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 receiving long-term dexamethasone therapy, abrupt discontinuation may lead to withdrawal syndrome (without apparent signs of adrenal insufficiency), characterized by symptoms such as fever, rhinitis, conjunctival redness, headache, dizziness, somnolence or irritability, muscle and joint pain, vomiting, weight loss, general weakness, and frequently seizures. Therefore, the dose of dexamethasone should be tapered gradually. Sudden cessation of treatment may result in fatal outcomes. 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 treatment, hydrocortisone or cortisone should be administered.

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

Treatment with dexamethasone or natural glucocorticoids may mask symptoms of existing or new infections, as well as signs 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 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. Special care is required during the first weeks after myocardial infarction, and in patients with thromboembolism, myasthenia gravis, glaucoma, hypothyroidism, psychosis or psychoneurosis, as well as 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 vaccination is contraindicated during dexamethasone treatment. Vaccination with inactivated viral or bacterial vaccines may not elicit the expected antibody synthesis and may lack the anticipated protective effect. Dexamethasone should generally not be administered within 8 weeks before vaccination and should not be initiated earlier than 2 weeks after vaccination.

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

Caution is advised 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 from the joint and examined (to rule out 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 has resolved.

The drug should not be injected into unstable joints.

Corticosteroids may distort 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 with systemic and local corticosteroid use. If a patient experiences symptoms such as blurred vision or other visual disturbances, they should be referred to an ophthalmologist for evaluation of possible causes, including cataract, glaucoma, or rare conditions such as central serous chorioretinopathy (CSCR), which have been reported after systemic and local corticosteroid use.

Pheochromocytoma crisis

Pheochromocytoma crisis, potentially leading to fatal outcomes, has been reported after systemic corticosteroid therapy. Corticosteroids should be prescribed to patients with suspected or diagnosed pheochromocytoma only after appropriate benefit-risk assessment.

Preterm newborns: Long-term neurodevelopmental impairment has 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.

Excipients

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy.

Harmful effects on the fetus and newborn infant cannot be excluded. The drug suppresses intrauterine fetal development. Dexamethasone may be administered to pregnant women only in exceptional 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 recommendations for glucocorticoid therapy during pregnancy, the lowest effective dose should be used to control the underlying condition. Infants born to mothers who received glucocorticoids during pregnancy should be carefully monitored for signs of 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. Consequently, high concentrations of dexamethasone may be observed in fetal serum. According to some data, 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 effect of glucocorticosteroids.

Administration of corticosteroids to pregnant animals may cause 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 childbirth 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.

Breastfeeding.

Use during breastfeeding is contraindicated (except in emergency situations).

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

Ability to affect reaction speed when driving or operating machinery.

Dexamethasone does not affect the ability to drive a vehicle or operate mechanical equipment.

Method of Administration and Dosage

Dexamethasone solution for injection may be administered to adults and children from birth.

The injection solution can 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 affected skin area or soft tissue infiltrate). For intravenous infusion, 0.9% sodium chloride solution or 5% glucose solution should be used as diluent.

Diluents intended for intravenous administration or further dilution of the drug must not contain preservatives when used in infants, especially premature infants.

Sterile safety procedures must be followed when mixing the drug with infusion diluent. 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 determined 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 administered until clinical response occurs, 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

Adult patients: 6 mg intravenously once daily for up to 10 days.

Paediatric Population

Adolescents aged 12 years and older: 6 mg intravenously once daily for up to 10 days.

Duration of treatment depends on clinical response and individual patient needs.

Elderly Patients, Patients with Renal or Hepatic Impairment

Dose adjustment is not required.

Local Administration

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

The usual dose of dexamethasone injected into the bursa is 2–3 mg, into the tendon sheath is 0.4–1 mg, and into a ganglion is 1–2 mg.

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

Doses for soft tissue injection (around the joint) range from 2–6 mg.

Dosage in Children

For intramuscular administration in replacement therapy, the recommended 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.

Dexamethasone should be used in children from birth only if absolutely necessary. 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

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Adverse effects during short-term treatment with dexamethasone

Immune system disorders:
Rare: hypersensitivity reactions.

Endocrine disorders:
Common: transient suppression of adrenal function.

Metabolism and nutrition disorders:
Common: decreased carbohydrate tolerance, decreased appetite, and increased body weight; rare: hypertriglyceridemia.

Psychiatric disorders:
Common: psychiatric disorders.

Gastrointestinal disorders:
Rare: peptic ulcer and acute pancreatitis.

Adverse effects during long-term treatment with dexamethasone

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

Endocrine disorders:
Common: persistent suppression of adrenal function, growth retardation in children and adolescents.

Metabolism and nutrition disorders:
Common: obesity.

Eye disorders:
Rare: cataract, glaucoma.

Vascular disorders:
Rare: hypertension.

Skin and subcutaneous tissue disorders:
Thinning of the skin.

Musculoskeletal and connective tissue disorders:
Common: muscle atrophy, osteoporosis; rare: aseptic bone necrosis.

Other adverse effects that may 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); rare: thrombocytopenia and non-thrombocytopenic purpura.

Immune system disorders:
Rare: rash, urticaria, bronchospasm, anaphylactic reactions.

Cardiac disorders:
Multifocal ventricular extrasystoles, transient bradycardia, heart failure; rare: myocardial perforation due to previous myocardial infarction; frequency not known: hypertrophic cardiomyopathy in premature infants.

Vascular disorders:
Hypertensive encephalopathy, arterial hypertension.

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, headache, seizures.

Psychiatric disorders:
Personality and behavioral changes, more commonly manifested as euphoria; insomnia, irritability, hyperkinesia, depression; rare: psychosis.

Endocrine disorders:
Suppression of adrenal function and adrenal atrophy (reduced response to stress), Cushing's syndrome, growth retardation in children and adolescents, menstrual cycle disturbances, hirsutism.

Metabolism and nutrition disorders:
Transition from latent to clinical manifestations of diabetes; increased insulin and oral antidiabetic drug requirements in patients with diabetes mellitus; sodium and water retention; increased potassium excretion; hypokalemic alkalosis; negative nitrogen balance due to protein catabolism; hypocalcemia.

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

Musculoskeletal and connective tissue disorders:
Muscle weakness, steroid-induced myopathy (muscle weakness due to muscle catabolism), osteoporosis (increased calcium ion excretion) and vertebral compression fractures, aseptic necrosis of bones (most commonly affecting femoral and humeral heads), tendon ruptures (especially when used concomitantly with certain quinolone antibiotics), joint cartilage damage and bone necrosis (with frequent intra-articular injections).

Skin and subcutaneous tissue disorders:
Delayed wound healing, skin thinning, striae, petechiae and bruising, hyperemia, increased sweating, acne, suppression of skin tests;
Rare: angioneurotic edema, allergic dermatitis, urticaria.

Eye disorders:
Increased intraocular pressure, glaucoma, cataract, exophthalmos, blurred vision, chorioretinopathy.

Reproductive system and breast disorders:
Rare: impotence.

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

Signs of glucocorticoid withdrawal syndrome.

In patients treated with dexamethasone for prolonged periods, too rapid dose reduction may lead to withdrawal syndrome, resulting in adrenal insufficiency, arterial hypotension, or even fatal outcomes. In some cases, withdrawal symptoms may resemble worsening or relapse of the underlying disease being treated. If severe adverse reactions occur, treatment should be discontinued.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all cases of suspected adverse reactions and/or lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze.

Keep out of reach of children.

Incompatibilities.

The preparation should not be mixed with other medicinal products except 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 is degraded in a 2.5% glucose solution and 0.9% sodium chloride solution containing amikacin.

Some medicinal products, such as lorazepam, should be mixed only 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 medicinal products such as metaraminol, so-called delayed incompatibility develops after 24 hours when mixed with dexamethasone.

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

Packaging.

1 ml in an ampoule; 5 ampoules in a blister pack; 1, 2 or 5 blister packs in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnitsa".

Manufacturer's address and location of its business activities.

13, Boryspilska Street, Kyiv, 02093, Ukraine.