Dexamethasone-darnitsa
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEXAMETHASONE-DARNITSA (DEXAMETHASONE-DARNITSA)
Composition:
Active substance: dexamethasone;
1 tablet contains dexamethasone 0.5 mg;
Excipients: lactose monohydrate, microcrystalline cellulose, colloidal anhydrous silicon dioxide, sodium croscarmellose, magnesium stearate.
Pharmaceutical form. Tablets.
Main physicochemical properties: white or almost white tablets, flat cylindrical in shape, with beveled edges.
Pharmacotherapeutic group. Systemic corticosteroids. Glucocorticoids. Dexamethasone. ATC code H02AB02.
Pharmacological Properties.
Pharmacodynamics.
Dexamethasone-Darnytsia is a synthetic adrenal cortex hormone (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 activation factor and adenohypophyseal trophic hormones.
The mechanism of action of glucocorticosteroids is not yet fully understood. Currently, there is sufficient evidence supporting the mechanism of glucocorticosteroid action at the cellular level. Two well-characterized receptor systems are present in the cell cytoplasm. Glucocorticosteroids exert anti-inflammatory and immunosuppressive effects and regulate glucose metabolism through binding to glucocorticoid receptors, while binding to mineralocorticoid receptors enables them to regulate sodium and potassium metabolism and water-electrolyte balance.
Glucocorticosteroids 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 the regulatory site of the DNA molecule, also 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 the ribosome, leading to the synthesis of new proteins. Depending on the target cells and cellular processes, protein synthesis may be enhanced (e.g., tyrosine transaminase formation in liver cells) or reduced (e.g., IL-2 production in lymphocytes). Since glucocorticosteroid receptors are present in all tissue types, it can be assumed that glucocorticosteroids affect most cells in the body.
Clinical Efficacy and Safety – COVID-19
Clinical Efficacy
An investigator-initiated, individually randomized, controlled, open-label, adaptive platform trial RECOVERY (Randomised Evaluation of Covid-19 Therapy)1, designed to evaluate outcomes of potential treatments in patients hospitalized 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 standard care (4321 patients). Laboratory-confirmed SARS-CoV-2 infection was present in 89% of patients.
At randomization, 16% of patients were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% received oxygen alone (with or without non-invasive ventilation), and 24% received neither.
The mean age of patients was 66.1 ± 15.7 years. Women comprised 36% of the study population. A history of diabetes was reported in 24% of patients, heart disease in 27%, and chronic lung disease in 21%.
Primary Endpoint
Mortality at day 28 was significantly lower in the dexamethasone group compared to the standard 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, the dexamethasone group had lower mortality compared to the standard 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 did not require respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91–1.55).
Secondary Endpoint
Patients in the dexamethasone group had a shorter hospitalization duration compared to the standard care group (median, 12 days vs. 13 days) and a higher probability of hospital discharge within 28 days (rate ratio, 1.10; 95% CI, 1.03–1.17).
Consistent with the primary endpoint, the greatest effect in reducing hospitalization duration by day 28 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 observed in patients not receiving oxygen (rate ratio, 0.96; 95% CI, 0.85–1.08).
| Result |
Dexamethasone |
Usual care |
Rate ratio* |
| (N = 2104) |
(N = 4321) |
(95% CI) |
|
| Number/total patients (%) |
|||
| Primary endpoint |
482/2104 (22.9) |
1110/4321 (25.7) |
0.83 (0.75–0.93) |
| 28-day mortality |
|||
| Secondary endpoint |
|||
| Discharged from hospital within 28 days |
1413/2104 (67.2) |
2745/4321 (63.5) |
1.10 (1.03–1.17) |
| Invasive mechanical ventilation or death†: |
456/1780 (25.6) |
994/3638 (27.3) |
0.92 (0.84–1.01) |
|
102/1780 (5.7) |
285/3638 (7.8) |
0.77 (0.62–0.95) |
|
387/1780 (21.7) |
827/3638 (22.7) |
0.93 (0.84–1.03) |
* The ratio of outcomes was adjusted for age based on 28-day mortality and hospital discharge data. The risk ratio was 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, 1 case of steroid-induced psychosis, and 1 case of upper gastrointestinal bleeding. All cases were resolved.
Subgroup Analysis
Effects of dexamethasone on 28-day mortality, according to age and respiratory support received at randomization*2
| Dexamethasone |
Usual Care |
RR (95% CI) |
||||||||
| No oxygen (x |
2 |
= 0.70; p=0.40) |
||||||||
| 1 |
||||||||||
| < 70 |
10/197 (5.1%) |
18/462 (3.9%) |
|
|
||||||
| ≥ 70 < 80 |
25/114 (21.9%) |
35/224 (15.6%) |
|
|||||||
| ≥ 80 |
54/190 (28.4%) |
92/348 (26.4%) |
|
|||||||
| Subtotal |
89/501 (17.8%) |
145/1034 (14.0%) |
|
|||||||
| Oxygen only (x |
2 |
= 2.54; p=0.11) |
||||||||
| 1 |
||||||||||
| < 70 |
53/675 (7.9%) |
193/1473 (13.1%) |
|
|||||||
| ≥ 70 < 80 |
104/306 (34.0%) |
178/531 (33.5%) |
|
|||||||
| ≥ 80 |
141/298 (47.3%) |
311/600 (51.8%) |
|
|||||||
| Subtotal |
298/1279 (23.3%) |
682/2604 (26.2%) |
|
|||||||
| Mechanical ventilation (x |
2 |
= 0.28; p=0.60) |
||||||||
| 1 |
||||||||||
| < 70 |
66/269 (24.5%) |
217/569 (38.1%) |
|
|||||||
| ≥ 70 < 80 |
26/49 (53.1%) |
58/104 (55.8%) |
|
|||||||
| ≥ 80 |
3/6 (50.0%) |
8/10 (80.0%) |
|
|||||||
| Subtotal |
95/324 (29.3%) |
283/683 (41.4%) |
|
|||||||
| All participants |
482/2104 (22.9%) |
1110/4321 (25.7%) |
p < 0.001 |
|||||||
| Dexamethasone better |
Usual Care better |
|||||||||
Effects of dexamethasone on 28-day mortality, according to respiratory support method at randomization and presence of any chronic comorbidity3
| Dexamethasone |
Usual Care |
RR (95% Cl) |
|||||||||
| No oxygen (x |
2 |
= 0.08; p=0.78) |
|
||||||||
| 1 |
|||||||||||
| Pre-existing comorbidity |
65/313 (20.8%) |
100/598 (16.7%) |
|
||||||||
| Without pre-existing comorbidity |
24/188 (12.8%) |
45/436 (10.3%) |
|
||||||||
| Intermediate total |
89/501 (17.8%) |
145/1034 (14.0%) |
|
||||||||
| Oxygen only (x |
2 |
= 2.05; p=0.15 |
|||||||||
| 1 |
|||||||||||
| Pre-existing comorbidity |
221/702 (31.5%) |
481/1473 (32.7%) |
|
||||||||
| Without pre-existing comorbidity |
77/577 (13.3%) |
201/1131 (17.8%) |
|
||||||||
| Intermediate total |
298/1279 (23.3%) |
682/2604 (26.2%) |
|
||||||||
| Mechanical ventilation (x |
2 |
= 1.52; p=0.22 |
|||||||||
| 1 |
|||||||||||
| Pre-existing comorbidity |
51/159 (32.1%) |
150/346 (43.4%) |
|
||||||||
| Without pre-existing comorbidity |
44/165 (26.7%) |
133/337 (39.5%) |
|
||||||||
| Intermediate total |
95/324 (29.3%) |
283/683 (41.4%) |
|
||||||||
| All participants |
482/2104(22.9%) |
1110/4321 (25.7%) |
p < 0.001 |
||||||||
| Dexamethasone better |
Usual Care better |
||||||||||
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.
After oral administration, dexamethasone is almost completely absorbed. The bioavailability of dexamethasone tablets approaches 80%. Maximum plasma concentrations and peak effects are observed within 1–2 hours. After a single dose, the effect lasts for 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 plasma proteins. Dexamethasone is a lipophilic substance and therefore distributes into extracellular and intracellular spaces. It exerts its action in the central nervous system (hypothalamus, pituitary) by binding to membrane receptors. In peripheral tissues, it binds and acts via cytoplasmic receptors. Dexamethasone is metabolized at the site of its action, i.e., within the cell. The drug is predominantly metabolized in the liver. A small amount of dexamethasone is metabolized in the kidneys and other tissues. The primary route of elimination is renal.
Clinical characteristics.
Indications.
Allergic diseases: control of severe or disabling allergic conditions unresponsive to conventional therapy: bronchial asthma; atopic dermatitis; contact dermatitis; drug allergy; chronic or seasonal allergic rhinitis; serum sickness.
Skin diseases: dermatitis herpetiformis; exfoliative erythroderma; mycosis fungoides; pemphigus; severe multiform erythema (Stevens-Johnson syndrome).
Endocrine disorders: replacement therapy for primary or secondary (pituitary) adrenal insufficiency (hydrocortisone or cortisone are drugs of choice; synthetic analogs may be used in combination with mineralocorticoids if necessary; concomitant use with mineralocorticoids is extremely important in pediatric practice); congenital adrenal hyperplasia; hypercalcemia due to malignancy; nonsuppurative thyroiditis.
Gastrointestinal diseases: to carry the patient through the critical period in: Crohn's disease; ulcerative colitis.
Hematologic diseases: acquired (autoimmune) hemolytic anemia; congenital (erythroid) hypoplastic anemia; idiopathic thrombocytopenic purpura in adults; pure red cell aplasia; some cases of secondary thrombocytopenia.
Oncologic diseases: palliative treatment of leukemia and lymphoma.
Neurologic diseases: acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor, craniotomy, or head trauma.
Ocular diseases: sympathetic ophthalmia; temporal arteritis; uveitis; inflammatory ocular conditions unresponsive to topical glucocorticosteroids.
Renal diseases: stimulation of diuresis or reduction of proteinuria in idiopathic nephrotic syndrome and impaired renal function in systemic lupus erythematosus.
Respiratory tract diseases: berylliosis; focal or disseminated pulmonary tuberculosis (to be used in conjunction with appropriate antituberculosis chemotherapy); idiopathic eosinophilic pneumonia; symptomatic sarcoidosis.
Rheumatic diseases: as adjunctive therapy for short-term administration (to carry the patient through an acute episode or exacerbation) in: acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (some cases may require low-dose maintenance therapy); treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus.
Other indications: diagnostic test for adrenal hyperfunction; trichinosis with neurologic symptoms or myocardial trichinosis; tuberculous meningitis with subarachnoid block or threat of block (together with appropriate antituberculosis therapy); 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.
Contraindications.
Individual hypersensitivity to dexamethasone or to any other components of the medicinal product.
Parasitic, viral, bacterial, or systemic fungal infections (current or recent, including recent exposure to infected individuals), unless appropriate therapy is administered.
Live vaccination, Cushing's syndrome, and breastfeeding (except in emergency situations).
Interaction with other medicinal products and other forms of interaction.
Concomitant use of dexamethasone with nonsteroidal anti-inflammatory drugs and ethanol increases the risk of gastrointestinal bleeding and ulcer formation.
The efficacy of dexamethasone is reduced when coadministered with rifampicin, carbamazepine, phenobarbital, phenytoin, primidone, ephedrine, or aminoglutethimide; therefore, the dose of dexamethasone should be increased in such combinations. The interaction between dexamethasone and all the aforementioned medicinal products may distort the results of the dexamethasone suppression test. This should be taken into account when evaluating test results.
Concomitant use of dexamethasone and medicinal products that inhibit CYP3A4 enzyme activity, such as ketoconazole and macrolide antibiotics, may lead to increased serum and plasma concentrations of dexamethasone. Dexamethasone is a moderate inducer of CYP3A4. Concurrent use with medicinal products 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 serum concentrations of dexamethasone. Conversely, ketoconazole may suppress adrenal synthesis of glucocorticoids, thus adrenal insufficiency may develop due to decreased dexamethasone concentrations.
Dexamethasone reduces the therapeutic effect of: antidiabetic agents and antihypertensive agents, coumarin anticoagulants, praziquantel, and natriuretic agents (therefore, the dose of these medicinal products should be increased); it enhances the activity of heparin, albendazole, and potassium-wasting agents (the dose of these medicinal products should be reduced if necessary).
Dexamethasone may alter the effect of coumarin anticoagulants; therefore, prothrombin time should be monitored more frequently when this combination of medicinal products is used.
Concomitant use of dexamethasone and high doses of other glucocorticoids or β2-adrenergic agonists increases the risk of hypokalemia.
In patients with hypokalemia, cardiac glycosides are more likely to cause arrhythmias and have greater toxicity.
Antacids reduce the absorption of dexamethasone in the stomach. It has not been established whether concomitant intake of food or alcohol affects the pharmacokinetics of dexamethasone; however, concurrent administration of medicinal products with high-sodium food is not recommended.
Glucocorticosteroids enhance renal clearance of salicylates, thus achieving therapeutic salicylate concentrations in serum may sometimes be difficult. Caution should be exercised in patients gradually reducing the dose of glucocorticosteroids, as increased serum salicylate concentrations and intoxication may occur.
When oral contraceptives are used concomitantly, the elimination half-life of glucocorticosteroids may be prolonged, enhancing their biological effect and potentially increasing the risk of adverse effects.
Concomitant use of ritodrine and dexamethasone is contraindicated during labor, as it may lead to pulmonary edema. Fatal outcomes in parturients due to this condition have been reported.
Concomitant use with live antiviral vaccines and during other types of immunization increases the risk of viral activation and development of infections.
Enhances metabolism of isoniazid and mexiletine (especially in "rapid acetylators"), leading to decreased plasma concentrations.
Increases the risk of hepatotoxic effects of paracetamol (induction of "hepatic" enzymes and formation of a toxic paracetamol metabolite).
Increases (with prolonged therapy) serum folate levels.
Hypokalemia caused by glucocorticosteroids may enhance the intensity and duration of muscle blockade induced by muscle relaxants.
In high doses, reduces the effect of somatropin.
Reduces the effect of vitamin D on Ca2+ absorption in the intestinal lumen.
Ergocalciferol and parathyroid hormone prevent the development of glucocorticoid-induced osteopathy.
Indomethacin, by displacing dexamethasone from albumin binding, increases the risk of its adverse effects.
Amphotericin B and carbonic anhydrase inhibitors increase the risk of osteoporosis.
Use of mitotane and other inhibitors of adrenal cortex function may necessitate an increase in glucocorticosteroid dosage.
Clearance of glucocorticosteroids is increased when used concomitantly with thyroid hormones.
Immunosuppressants increase the risk of infections and lymphoma or other Epstein-Barr virus-related lymphoproliferative disorders.
Estrogen (including estrogen-containing oral contraceptives) reduces glucocorticosteroid clearance, prolongs elimination half-life, and enhances their therapeutic and toxic effects.
Development of hirsutism and acne is promoted by concomitant use of other steroidal hormonal medicinal products— androgens, estrogens, anabolics, oral contraceptives.
Tricyclic antidepressants may enhance the severity of depression caused by glucocorticosteroid administration.
The risk of cataract development is increased when used concomitantly with other glucocorticosteroids, antipsychotic medicinal products (neuroleptics), carbutoxamide, and azathioprine.
Concomitant use with anticholinergic agents, antihistamines, tricyclic antidepressants, and nitrates promotes an increase in intraocular pressure.
Concomitant use of cyclosporine and glucocorticosteroids leads to increased activity; seizures may occur with their concomitant use.
Concomitant use of dexamethasone and thalidomide may cause toxic epidermal necrolysis.
Concomitant use of dexamethasone with anticholinesterase medicinal products may cause marked weakness in patients with myasthenia gravis.
Hypokalemia, which may lead to cardiac failure, has been observed with concomitant use of dexamethasone, amphotericin B, and medicinal products that promote potassium excretion (diuretics).
Therapeutically beneficial interactions: 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 for the prevention of nausea and vomiting induced by chemotherapy with cisplatin, cyclophosphamide, methotrexate, or fluorouracil.
Special precautions for use.
Prior to and during glucocorticoid therapy, it is necessary to monitor complete blood count, blood glucose levels, and plasma electrolyte concentrations.
During treatment with dexamethasone (especially prolonged therapy), ophthalmologist supervision is required, along with monitoring of arterial pressure and water-electrolyte balance, particularly serum potassium levels, as well as peripheral blood picture and blood glucose levels. To reduce adverse effects, steroid-sparing agents, antacids, and increased potassium (K⁺) intake (via diet or K⁺ supplements) may be prescribed. The diet should be rich in K⁺, proteins, and vitamins, and contain low amounts of fats, carbohydrates, and salt.
Prolonged treatment with the medicinal product may lead to suppression of the hypothalamic-pituitary-adrenal (HPA) axis and adrenal cortex atrophy, which may persist for years after discontinuation of dexamethasone.
Patients who have received more than physiological doses of systemic glucocorticoids (approximately 1 mg of dexamethasone) for longer than 3 weeks should discontinue dexamethasone therapy gradually, depending on the dose, duration of treatment, and disease characteristics, particularly its relapse potential. Sudden withdrawal of the drug, especially after prior use of high doses, may cause withdrawal syndrome (without apparent signs of adrenal insufficiency), presenting with symptoms such as fever, rhinitis, conjunctival hyperemia, headache, dizziness, somnolence or irritability, lethargy, muscle and joint pain, nausea, vomiting, weight loss, general weakness, and convulsions. Therefore, the dose of dexamethasone should be tapered gradually. Abrupt discontinuation may result in a fatal outcome.
Rapid withdrawal of systemic glucocorticoids after treatment courses lasting less than 3 weeks at doses up to 6 mg per day is unlikely to cause clinically significant suppression of the HPA axis. However, gradual discontinuation is recommended in the following patient groups, even if treatment lasted less than 3 weeks:
- Patients undergoing repeated dexamethasone therapy, particularly if previous treatment courses lasted more than 3 weeks;
- Patients receiving a repeated course of treatment within one year after prolonged therapy (months, years);
- Patients with adrenal insufficiency not caused by exogenous corticosteroid use;
- Patients receiving more than 6 mg/day of dexamethasone.
Adrenal cortex atrophy develops by the fifth month of daily treatment.
If a patient experiences severe stress (due to trauma, surgery, or serious illness) during or after discontinuation of dexamethasone therapy, the dose should be increased or hydrocortisone or cortisone should be administered.
Patients who have undergone prolonged dexamethasone therapy and experience severe stress after stopping treatment should resume dexamethasone, as adrenal insufficiency 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. During treatment, contact with individuals suffering from colds or other infections should be avoided.
Dexamethasone may cause exacerbation of systemic fungal infections, latent amoebiasis, and pulmonary tuberculosis.
Patients with active pulmonary tuberculosis should receive dexamethasone (together with anti-tuberculosis agents) only in cases of fulminant or disseminated pulmonary tuberculosis. Patients with inactive pulmonary tuberculosis receiving dexamethasone, or those with positive tuberculin reactions, should receive chemoprophylaxis.
Live vaccination is contraindicated during dexamethasone therapy. Inactivated viral or bacterial vaccines do not elicit the expected antibody response and do not provide protective immunity. Dexamethasone should not be administered within 8 weeks before vaccination or earlier than 2 weeks after vaccination.
The medicinal product should be prescribed with caution to patients with infections, especially chickenpox and measles, as these diseases may have a more severe course when dexamethasone is used. Individuals who have not had these diseases should take precautions to avoid exposure. In case of contact with infected persons, immediate medical consultation is required. Prophylactic treatment with immunoglobulin is recommended.
In active forms of tuberculosis, dexamethasone use should be limited to fulminant or disseminated cases, where glucocorticoids are used concurrently with specific anti-tuberculosis therapy. Patients with latent tuberculosis or positive tuberculin reactions requiring corticosteroids should be under continuous medical supervision to prevent relapse.
Glucocorticoids should be used with caution in patients with ocular herpes simplex, as their use may lead to corneal perforation.
Caution and medical monitoring are recommended for patients with osteoporosis, arterial hypertension, heart failure, tuberculosis, glaucoma, hepatic or renal insufficiency, diabetes mellitus, gastritis, esophagitis, diverticulitis, active peptic ulcer, recent intestinal anastomosis, colitis, epilepsy, thyrotoxicosis, Cushing's syndrome, obesity (grade III–IV), nephrolithiasis, hyperlipidemia, poliomyelitis (except bulbar encephalitis form), hypoalbuminemia, or conditions predisposing to hypoalbuminemia, as well as patients with immunodeficiency states (including AIDS or HIV infection), and BCG vaccination-related lymphadenitis.
Particular care is required for patients during the first weeks after myocardial infarction, patients with thromboembolism, severe myasthenia gravis, glaucoma, hypothyroidism, psychosis or psychoneurosis, and elderly patients.
During dexamethasone therapy, exacerbation of diabetes mellitus or progression from latent to clinical diabetes may occur.
The effect of glucocorticoids is enhanced in patients with liver cirrhosis or hypothyroidism.
Patients with impaired water-electrolyte balance should use dexamethasone cautiously, as moderate to high doses of glucocorticoids may cause salt and fluid retention and increased potassium excretion. In such cases, salt restriction and additional potassium supplementation are indicated. All corticosteroids increase calcium excretion, potentially disrupting mineralocorticoid secretion. Therefore, additional salt and/or mineralocorticoid administration may be necessary.
Prolonged use of glucocorticoids may lead to the development of posterior subcapsular cataracts, glaucoma (with possible optic nerve damage), and increased risk of secondary viral or fungal ocular infections.
Caution is advised for 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 already receiving systemic (oral) corticosteroids for other reasons (e.g., patients with chronic obstructive pulmonary disease) who do not require supplemental oxygen.
Particular attention should be paid to the use of systemic glucocorticoids in patients with active or a history of severe affective disorders, including depression, manic-depressive psychosis, or previous steroid-induced psychosis. Patients and/or caregivers should be warned about the potential for serious psychiatric side effects. Symptoms typically appear within days or weeks after starting treatment. The risk of these adverse effects is higher with high-dose regimens. Most reactions resolve after dose reduction or discontinuation of the drug, although specific treatment may sometimes be required. If such symptoms occur, medical advice should be sought. Psychiatric disorders may also occur during glucocorticoid withdrawal.
Glucocorticoids may interfere with the results of skin allergy tests.
Dexamethasone should be used in children only when clearly indicated. Careful monitoring of growth and development is required during dexamethasone therapy in children.
The medicinal product contains lactose and therefore should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.
This medicinal product contains 1.0 mg of sodium cross-linked carboxymethylcellulose. Caution is advised when administering to patients on a sodium-restricted diet.
Use during pregnancy or breastfeeding.
The medicinal product should not be used during pregnancy or breastfeeding.
Ability to affect reaction speed when driving or operating machinery.
No data are available. The possibility of adverse reactions affecting the nervous system and visual organs should be considered.
Method of Administration and Dosage.
The dose should be individually determined according to the patient's specific condition, the intended duration of treatment, tolerance to glucocorticoids, and the body's response.
Adults.
The recommended initial dose is 0.75–9 mg per day, depending on the diagnosis. Initial doses of dexamethasone should be administered until a clinical response is achieved, after which the dose should be gradually reduced to the lowest clinically effective dose. If oral treatment with high doses lasts longer than several days, the dose should be tapered gradually over several consecutive days or even over a longer period (usually by 0.5 mg every 3 days). The maintenance dose is generally 2–4.5 mg per day. The daily dose may be divided into 2–4 doses. The maximum daily dose is usually 15 mg, and the minimum effective dose is 0.5–1 mg per day. In the treatment of exacerbations of multiple sclerosis, the daily dose may be 30 mg of dexamethasone during the first week of treatment, followed by alternate-day doses ranging from 4 mg to 12 mg for 1 month.
During prolonged high-dose oral therapy, it is recommended to take dexamethasone with food and to use antacids between meals.
Children.
The initial dose of dexamethasone is determined by the physician according to the characteristics of the specific disease.
The recommended oral dose for replacement therapy is 0.02 mg/kg body weight or 0.67 mg/m² body surface area per day, administered in 3 divided doses.
For all other indications, the initial dose range is 0.02–0.3 mg/kg per day in 3–4 divided doses (0.6–9 mg/m² body surface area per day).
For the treatment of COVID-19
Adults and children (adolescents aged 12 years and older with body weight of at least 40 kg): 6 mg* of dexamethasone intravenously or orally once daily for up to 10 days.
The duration of treatment is determined individually based on the patient's clinical condition.
* It is recommended to use dexamethasone at the appropriate dosage.
Elderly patients and patients with renal or hepatic impairment.
Dose adjustment is not required.
Diagnostic testing for adrenal hyperfunction.
The dexamethasone suppression test (Liddle's test) is performed as a low-dose and high-dose test. During the low-dose test, dexamethasone is administered at 0.5 mg every 6 hours for 48 hours (i.e., at 8 a.m., 2 p.m., 8 p.m., and 2 a.m.). Urinary 17-hydroxycorticosteroids or free cortisol levels in 24-hour urine should be measured before and after dexamethasone administration. These dexamethasone doses suppress glucocorticoid production in nearly all healthy volunteers. Six hours after the last dose, plasma cortisol levels are below 135–138 nmol/L (4.5–5 µg/100 mL). A reduction in urinary excretion of 17-hydroxycorticosteroids below 3 mg/day or free cortisol below 54–55 nmol/day (19–20 µg/day) excludes adrenal hyperfunction. In patients with Cushing's disease or syndrome, urinary excretion of glucocorticoids remains unchanged during the low-dose test.
During the high-dose test, dexamethasone is administered at 2 mg every 6 hours for 48 hours (i.e., 8 mg of dexamethasone per day). Urine collection for 17-hydroxycorticosteroids or free cortisol measurement should also be performed (free cortisol in plasma may be measured if necessary). In Cushing's disease, urinary excretion of 17-hydroxycorticosteroids or free cortisol decreases by 50% or more, whereas in adrenal tumors or ectopic ACTH (or corticoliberin) syndrome, glucocorticoid excretion remains unchanged. In some patients with ectopic ACTH syndrome, suppression of glucocorticoid excretion is not observed even after administration of dexamethasone at a dose of 32 mg per day.
For comparison, the following equivalent doses in milligrams for various glucocorticosteroids are provided below.
A dose of 0.75 mg of dexamethasone is equivalent to 2 mg of paramethasone, or 4 mg of methylprednisolone and triamcinolone, or 5 mg of prednisone and prednisolone, or 20 mg of hydrocortisone, or 25 mg of cortisone, or 0.75 mg of betamethasone.
These dosage ratios apply only to oral or intravenous administration of these medicinal products. If these agents or their derivatives are administered intramuscularly or intra-articularly, their relative properties may vary significantly.
Children.
Experience regarding the efficacy and safety of glucocorticosteroids in children is based on well-established studies demonstrating similar therapeutic effects of glucocorticosteroids in pediatric and adult populations. There are reports confirming the efficacy and safety of the medicinal product in children for the treatment of nephrotic syndrome (in children aged 2 years and older) and aggressive lymphomas and leukemia (in children from 1 month of age). The use of glucocorticosteroids in children for other indications, such as severe bronchial asthma and wheezing, is based on adequate and well-controlled studies conducted in adults, under the assumption that the course of the disease and its pathophysiology are essentially similar in both age groups.
Careful monitoring of growth and development is necessary in children and adolescents during dexamethasone treatment.
Overdose.
There are rare reports of acute overdose or fatal outcomes due to acute overdose.
A single ingestion of an excessive amount of tablets usually does not lead to clinically significant intoxication.
Overdose, typically only after several weeks of excessive dosing, manifests as an exacerbation of the described adverse effects, particularly: Cushing's syndrome, acne, ecchymoses, hirsutism, nausea, anorexia, peptic ulcer of the gastrointestinal tract, arthralgia, myopathy, myalgia, dyspnea, dizziness, loss of consciousness, fever, increased blood pressure, hyperlipidemia, osteoporosis, orthostatic hypotension, increased susceptibility to infections, steroid-induced diabetes, "moon face," and sexual dysfunction.
Treatment. The dose of the medicinal product should be reduced or discontinued; further treatment is symptomatic. There is no specific antidote. Hemodialysis is not an effective method for accelerating the elimination of dexamethasone from the body.
Side effects.
The frequency of adverse reactions depends on the dose and duration of treatment. The most common side effects of short-term treatment are temporary adrenal insufficiency, glucose intolerance, increased appetite and weight gain, and psychiatric disturbances; less common adverse effects include allergic reactions, hypertriglyceridemia, peptic ulcer of the stomach and duodenum, and acute pancreatitis.
Long-term treatment most frequently leads to prolonged impairment of adrenal function, growth retardation in children, central obesity, skin fragility, muscle atrophy, and osteoporosis; less frequently – decreased immune defense and increased susceptibility to infectious diseases, cataract, glaucoma, arterial hypertension, and avascular bone necrosis.
Eye disorders: increased intraocular pressure, glaucoma, cataract, exophthalmos, exacerbation of viral or fungal ophthalmic infections.
Respiratory, thoracic and mediastinal disorders: pulmonary edema.
Gastrointestinal disorders: nausea, vomiting, dyspepsia, hiccups, flatulence, esophagitis, esophageal candidiasis, increased or decreased appetite; rarely – peptic ulcers of the stomach and duodenum, possible ulcer perforation and gastrointestinal bleeding (hematemesis, melena), pancreatitis, and perforation of the gallbladder and intestine (especially in patients with chronic bowel inflammation), gastrointestinal atony; in individual cases – increased activity of liver transaminases and alkaline phosphatase.
Endocrine disorders: suppression of adrenal function and adrenal atrophy (reduced response to stress), Cushing's syndrome, delayed sexual development in children, disturbances in sex hormone secretion (menstrual cycle disturbances, amenorrhea, hirsutism, impotence), hyperglycemia, "steroid" diabetes mellitus, transition of latent diabetes to clinically active form, reduced carbohydrate tolerance, increased insulin requirement or need for oral antidiabetic drugs in diabetic patients.
Metabolism and nutritional disorders: increased excretion of calcium ions, hypocalcemia, weight gain, negative nitrogen balance (increased protein catabolism), fluid and sodium ion retention (peripheral edema), hypernatremia, increased potassium excretion, hypokalemic syndrome: hypokalemia, hypokalemic alkalosis, arrhythmia, myalgia or muscle cramps, unusual weakness, and increased fatigue.
Nervous system disorders: after treatment, optic disc edema and increased intracranial pressure (pseudotumor cerebri) may occur, epilepsy exacerbation, dizziness, syncope, convulsions, headache, hyperkinesia, neuritis, neuropathy, paresthesia; in children, the drug may cause cerebral cortex paralysis.
Psychiatric disorders: changes in personality and behavior, most commonly manifesting as affective disturbances (irritability, euphoria, delirium, paranoia, nervousness, restlessness, disorientation, depression, mood lability, suicidal thoughts), sleep disturbances, cognitive dysfunction (including confusion and amnesia), psychotic reactions (including mania, hallucinations, psychoses, and exacerbation of schizophrenia).
Cardiac and vascular disorders: paroxysmal bradycardia, cardiac arrest, cardiac arrhythmias, angina attack, cardiomegaly, vascular insufficiency, chronic heart failure, fat embolism, arterial hypertension, hypertrophic cardiomyopathy in premature infants; very rarely – cardiac rupture in patients who recently suffered myocardial infarction; also possible: polymorphic ventricular extrasystoles, hypertensive encephalopathy, tachycardia, thromboembolism, thrombophlebitis, vasculitis.
Blood and lymphatic system disorders: cases of thromboembolism, decreased number of monocytes and/or lymphocytes, leukocytosis, eosinophilia (as with other glucocorticoids); rarely – thrombocytopenia and non-thrombocytopenic purpura.
Immune system disorders: suppressed response to skin tests and vaccinations, immunosuppression, hypersensitivity reactions, including rash, pruritus, hyperemia, allergic dermatitis, urticaria, angioedema (Quincke's edema), bronchospasm, anaphylactic shock.
Skin and subcutaneous tissue disorders: delayed wound healing, thin and sensitive skin, dry skin, hyper- or hypopigmentation, petechiae, bruising, acne, striae, telangiectasia.
Musculoskeletal and connective tissue disorders: muscle weakness, muscle atrophy, steroid myopathy (muscle weakness causing muscle catabolism), osteoporosis (increased calcium excretion), fractures of long bones or compression fractures of the spine, avascular osteonecrosis (most commonly avascular necrosis of femoral and humeral heads), tendon ruptures (especially with concomitant use of certain quinolones), growth retardation and impaired bone mineralization in children, premature closure of epiphyseal growth zones.
Other: increased risk of developing or exacerbating fungal, viral, or bacterial infections, development of opportunistic infections, suppression of regenerative and reparative processes, edema, increased sweating, leukocyturia, withdrawal syndrome. The drug may cause physical dependence.
Symptoms of glucocorticosteroid withdrawal syndrome: in patients treated with dexamethasone for a prolonged period, rapid dose reduction may lead to withdrawal syndrome and cases of adrenal insufficiency, arterial hypotension, or even fatal outcome. In some cases, withdrawal symptoms may resemble signs of worsening or relapse of the disease for which the patient was being treated.
Shelf life. 2 years.
Do not use the medicinal product after the expiry date stated on the packaging.
Storage conditions.
Store in the original packaging, in a place inaccessible to children, at a temperature not exceeding 25 °C.
Packaging.
10 tablets in a blister pack; 5 blisters per carton.
Prescription status. Prescription only.
Manufacturer. JSC "Pharmaceutical Company "Darnitsya".
Manufacturer's address and location of its business activities.
13, Borispilska St., Kyiv, 02093, Ukraine.