Dexamethasone-KRKA (Tablets) Instructions for Use

Marketing Authorization Holder

Krka d.d., Novo mesto (Slovenia)

ATC Code

H02AB02 (Dexamethasone)

Active Substance

Dexamethasone (Rec.INN registered by WHO)

Dosage Form

Dexamethasone-KRKA

Tablets 0.5 mg: 10, 20, 30, 50, 60, 90, or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets are white or almost white, round, flat, with a beveled edge.

Excipients: lactose monohydrate, pregelatinized starch, colloidal silicon dioxide, magnesium stearate.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Corticosteroids for oral administration

Pharmacotherapeutic Group

Glucocorticosteroid

Pharmacological Action

Glucocorticosteroid (GCS) is a methylated derivative of fluprednisolone; it inhibits the release of interleukin-1 and interleukin-2, and interferon gamma from lymphocytes and macrophages. It has anti-inflammatory, anti-allergic, desensitizing, anti-shock, antitoxic, and immunosuppressive effects.

It suppresses the release of adrenocorticotropic hormone (ACTH) and beta-lipotropin by the pituitary gland but does not reduce the content of circulating beta-endorphin. It inhibits the secretion of thyroid-stimulating hormone (TSH) and follicle-stimulating hormone (FSH).

It increases the excitability of the central nervous system (CNS), reduces the number of lymphocytes and eosinophils, and increases the number of erythrocytes (stimulates the production of erythropoietins).

It interacts with specific cytoplasmic receptors, forms a complex that penetrates the cell nucleus, stimulates the synthesis of mRNA, which induces the formation of proteins, including lipocortin, which mediate cellular effects. Lipocortin inhibits phospholipase A2, suppresses the release of arachidonic acid, and inhibits the synthesis of endoperoxides, Pg, leukotrienes, which contribute to inflammation, allergy, etc.

Protein metabolism: it reduces the amount of protein in plasma (due to globulins) with an increase in the albumin/globulin ratio; increases the synthesis of albumins in the liver and kidneys; enhances protein catabolism in muscle tissue.

Lipid metabolism: it increases the synthesis of higher fatty acids and triglycerides (TG), redistributes fat (accumulation of fat mainly in the shoulder girdle, face, abdomen), and leads to the development of hypercholesterolemia.

Carbohydrate metabolism: it increases the absorption of carbohydrates from the gastrointestinal tract (GIT); increases the activity of glucose-6-phosphatase, leading to an increase in the release of glucose from the liver into the blood; increases the activity of phosphoenolpyruvate carboxykinase and the synthesis of aminotransferases, leading to the activation of gluconeogenesis.

Water-electrolyte metabolism: it retains Na+ and water in the body, stimulates the excretion of K+ (mineralocorticoid activity), reduces the absorption of Ca2+ from the GIT, “leaches” Ca2+ from the bones, and increases the excretion of Ca2+ by the kidneys.

The anti-inflammatory effect is associated with the inhibition of the release of inflammatory mediators by eosinophils; induction of lipocortin formation and a decrease in the number of mast cells producing hyaluronic acid; with a decrease in capillary permeability; stabilization of cell membranes and organelle membranes (especially lysosomal).

The anti-allergic effect develops as a result of suppression of the synthesis and secretion of allergy mediators, inhibition of the release of histamine and other biologically active substances from sensitized mast cells and basophils, a decrease in the number of circulating basophils, suppression of the development of lymphoid and connective tissue, a decrease in the number of T- and B-lymphocytes, mast cells, a decrease in the sensitivity of effector cells to allergy mediators, inhibition of antibody formation, and a change in the body’s immune response.

In chronic obstructive pulmonary disease (COPD), the action is based mainly on the inhibition of inflammatory processes, suppression of the development or prevention of edema of the mucous membranes, inhibition of eosinophilic infiltration of the submucosal layer of the bronchial epithelium, deposition of circulating immune complexes in the bronchial mucosa, as well as inhibition of erosion and desquamation of the mucous membrane. It increases the sensitivity of beta-adrenergic receptors of small and medium-caliber bronchi to endogenous catecholamines and exogenous sympathomimetics, and reduces the viscosity of mucus by inhibiting or reducing its production.

The anti-shock and antitoxic action is associated with an increase in blood pressure (due to an increase in the concentration of circulating catecholamines and restoration of sensitivity to them of adrenergic receptors, as well as vasoconstriction), a decrease in vascular wall permeability, membrane-stabilizing properties, and activation of liver enzymes involved in the metabolism of endo- and xenobiotics.

The immunosuppressive effect is due to the inhibition of the release of cytokines (interleukin-1, interleukin-2; interferon gamma) from lymphocytes and macrophages.

It suppresses the synthesis and secretion of ACTH, and secondarily – the synthesis of endogenous GCS. It inhibits connective tissue reactions during the inflammatory process and reduces the possibility of scar tissue formation.

A feature of the action is significant inhibition of pituitary function and an almost complete absence of mineralocorticoid activity. Doses of 1-1.5 mg/day suppress the adrenal cortex; biological T_1/2 is 32-72 hours (duration of suppression of the hypothalamus-pituitary-adrenal cortex system).

In terms of glucocorticoid activity, 0.5 mg of dexamethasone corresponds to approximately 3.5 mg of prednisone (or prednisolone), 15 mg of hydrocortisone, or 17.5 mg of cortisone.

Pharmacokinetics

Dexamethasone is rapidly and almost completely absorbed after oral administration. The bioavailability of dexamethasone tablets is approximately 80%. C_max in plasma and the maximum effect after oral administration are achieved after 1-2 hours; after a single dose, the effect lasts for approximately 2.75 days.

In plasma, approximately 77% of dexamethasone is bound to proteins, mainly albumin. A small amount of dexamethasone is bound to non-albumin proteins. Dexamethasone is a fat-soluble substance that can penetrate into extra- and intracellular spaces. In the CNS (hypothalamus, pituitary gland), its effects are due to binding to membrane receptors. In peripheral tissues, it binds to cytoplasmic receptors. Its breakdown occurs at its site of action, i.e., in the cell. It is metabolized mainly in the liver to form inactive metabolites. It is excreted by the kidneys.

Indications

From the endocrine system: replacement therapy for primary and secondary (pituitary) adrenal insufficiency, congenital adrenal hyperplasia, subacute thyroiditis and severe forms of post-radiation thyroiditis.

Rheumatic diseases: rheumatoid arthritis (including juvenile chronic arthritis) and extra-articular lesions in rheumatoid arthritis (lungs, heart, eyes, cutaneous vasculitis).

Systemic connective tissue diseases, vasculitis and amyloidosis (as part of combination therapy): systemic lupus erythematosus (treatment of polyserositis and internal organ damage), Sjögren’s syndrome (treatment of lung, kidney and brain damage), systemic sclerosis (treatment of myositis, pericarditis and alveolitis), polymyositis, dermatomyositis, systemic vasculitis, amyloidosis (replacement therapy for adrenal insufficiency), scleroderma.

Skin diseases: pemphigoid, bullous dermatitis, dermatitis herpetiformis, exfoliative dermatitis, exudative erythema (severe forms), erythema nodosum, seborrheic dermatitis (severe forms), psoriasis (severe forms), lichen, fungoid mycosis, angioedema, bronchial asthma, contact dermatitis, atopic dermatitis, serum sickness, allergic rhinitis, drug disease (hypersensitivity to drugs), urticaria after blood transfusion, systemic immune diseases (sarcoidosis, temporal arteritis).

Eye diseases: proliferative changes in the orbit (endocrine ophthalmopathy, pseudotumors), sympathetic ophthalmia, immunosuppressive therapy for corneal transplantation.

Gastrointestinal diseases: ulcerative colitis (severe exacerbations), Crohn’s disease (severe exacerbations), chronic autoimmune hepatitis, rejection reaction after liver transplantation.

Blood diseases: congenital or acquired acute pure aplastic anemia, autoimmune hemolytic anemia, secondary thrombocytopenia in adults, erythroblastopenia, acute lymphoblastic leukemia (induction therapy), myelodysplastic syndrome, angioimmunoblastic malignant T-cell lymphoma (in combination with cytostatics), plasmacytoma (in combination with cytostatics), anemia after myelofibrosis with myeloid metaplasia or lymphoplasmacytic immunocytoma, systemic histiocytosis (systemic process).

Kidney diseases: primary and secondary glomerulonephritis (Goodpasture’s syndrome), kidney damage in systemic connective tissue diseases (systemic lupus erythematosus, Sjögren’s syndrome), systemic vasculitis (usually in combination with cyclophosphamide), glomerulonephritis in polyarteritis nodosa, Churg-Strauss syndrome, Wegener’s granulomatosis, Henoch-Schönlein purpura, mixed cryoglobulinemia, kidney damage in Takayasu’s arteritis, interstitial nephritis, immunosuppressive therapy after kidney transplantation, induction of diuresis or reduction of proteinemia in idiopathic nephrotic syndrome (without uremia) and in kidney damage against the background of systemic lupus erythematosus.

Malignant diseases: palliative therapy for leukemia and lymphoma in adults, acute leukemia in children, hypercalcemia in malignant neoplasms.

Other indications: tuberculous meningitis with subarachnoid block (in combination with adequate anti-tuberculosis therapy), trichinosis with neurological or myocardial manifestations.

ICD codes

Dosage Regimen

Doses are set individually for each patient, depending on the nature of the disease, expected duration of treatment, drug tolerance, and the patient’s response to the therapy.

The recommended initial dose for adults is from 0.5 mg to 9 mg/day.

The usual maintenance dose is from 0.5 mg to 3 mg/day.

The minimum effective daily dose is 0.5-1 mg.

The maximum daily dose is 10-15 mg.

The daily dose can be divided into 2-4 doses.

After achieving the therapeutic effect, the dose is gradually reduced (usually by 0.5 mg every 3 days until the maintenance dose is reached).

When using high doses orally for a long time, the drug is recommended to be taken with meals, and antacids should be taken between meals. The duration of dexamethasone use depends on the nature of the pathological process and the effectiveness of treatment and ranges from several days to several months or more. Treatment is discontinued gradually (at the end, several injections of corticotropin are prescribed).

• For bronchial asthma, rheumatoid arthritis, ulcerative colitis – 1.5-3 mg/day;
• For systemic lupus erythematosus – 2-4.5 mg/day;
• For oncohematological diseases – 7.5-10 mg.

For the treatment of acute allergic diseases, it is advisable to combine parenteral and oral administration: Day 1 – 4-8 mg parenterally; Day 2 – orally, 4 mg 3 times a day; Days 3, 4 – orally, 4 mg 2 times a day; Days 5, 6 – 4 mg/day, orally; Day 7 – drug discontinuation.

Dosing in children

Children (depending on age) are prescribed 2.5-10 mg/m² of body surface area/day, divided into 3-4 doses.

Diagnostic tests for adrenal cortex hyperfunction

Short 1-mg dexamethasone test 1 mg dexamethasone orally at 11:00; blood sampling for serum cortisol determination at 8:00 the next day.

Special 2-day 2 mg dexamethasone test 2 mg dexamethasone orally every 6 hours for 2 days; 24-hour urine is collected to determine the concentration of 17-hydroxycorticosteroids.

Adverse Reactions

Classification of the frequency of adverse effects (WHO): very common >1/10, common from > 1/100 to < 1/10, uncommon from > 1/1000 to < 1/100, rare from >1/10000 to < 1/1000, very rare from < 1/10000, including isolated reports.

From the immune system uncommon – hypersensitivity reactions, decreased immune response and increased susceptibility to infections.

From the endocrine system common – transient adrenal insufficiency, growth retardation in children and adolescents, adrenal insufficiency and atrophy (decreased response to stress), Cushing’s syndrome, menstrual cycle disorders, hirsutism, conversion of latent diabetes mellitus to clinically manifest, increased need for insulin or oral hypoglycemic drugs in patients with diabetes mellitus, sodium and water retention, increased potassium loss; very rare – hypokalemic alkalosis, negative nitrogen balance due to protein catabolism.

Metabolism and nutrition disorders common – decreased carbohydrate tolerance, increased appetite and weight gain, obesity; uncommon – hypertriglyceridemia.

From the nervous system common – mental disorders; uncommon – optic disc edema and increased intracranial pressure (pseudotumor cerebri) after therapy discontinuation, dizziness, headache; very rare – seizures, euphoria, insomnia, irritability, hyperkinesia, depression; rare – psychoses.

From the digestive system uncommon – peptic ulcers, acute pancreatitis, nausea, hiccups, gastric or duodenal ulcers; very rare – esophagitis, ulcer perforation and gastrointestinal bleeding (hematemesis, melena), pancreatitis, gallbladder and intestinal perforations (especially in patients with chronic inflammatory bowel diseases).

From the sensory organs uncommon – posterior subcapsular cataract, increased intraocular pressure, tendency to develop secondary bacterial, fungal or viral eye infections, trophic changes of the cornea, exophthalmos.

From the cardiovascular system uncommon – arterial hypertension, hypertensive encephalopathy; very rare – multifocal ventricular extrasystoles, transient bradycardia, heart failure, myocardial rupture after a recent acute myocardial infarction.

From the skin common – erythema, thinning and fragility of the skin, delayed wound healing, striae, petechiae and ecchymoses, increased sweating, steroid acne, suppression of skin reaction during allergy tests; very rare – angioedema, allergic dermatitis, urticaria.

From the musculoskeletal system common – muscle atrophy, osteoporosis, muscle weakness, steroid myopathy (muscle weakness due to muscle tissue catabolism); uncommon – aseptic bone necrosis; very rare – compression fractures of vertebrae, tendon ruptures (especially with concomitant use of some quinolones), damage to articular cartilage and bone necrosis (associated with frequent intra-articular injections).

From the hematopoietic system rare – thromboembolic complications, decreased monocyte and/or lymphocyte count, leukocytosis, eosinophilia (as with other glucocorticosteroids), thrombocytopenia and non-thrombocytopenic purpura.

Allergic reactions rare – skin rash, itching, angioedema, bronchospasm, anaphylactic shock.

From the genitourinary system rare – impotence.

Signs and symptoms of glucocorticosteroid withdrawal syndrome

If the dose of the drug is rapidly reduced in a patient who has been taking glucocorticosteroids for a long time, signs of adrenal insufficiency, arterial hypotension, and death may develop.

In some cases, withdrawal symptoms may be similar to the symptoms and signs of exacerbation or relapse of the disease for which the patient is being treated. If severe adverse events occur, treatment with Dexamethasone-KRKA should be discontinued.

Contraindications

For short-term use for “vital” indications, the only contraindication is hypersensitivity to the active substance or auxiliary components of the drug.

The drug Dexamethasone-KRKA is contraindicated in patients with galactosemia, lactase deficiency and glucose-galactose malabsorption syndrome, because the drug contains lactose.

With caution. Parasitic and infectious diseases of viral, fungal or bacterial nature (current or recently suffered, including recent contact with a patient) – herpes simplex, herpes zoster (viremic phase), chickenpox, measles; amebiasis, strongyloidiasis (established or suspected); systemic mycosis; active and latent tuberculosis, pre- and post-vaccination period (8 weeks before and 2 weeks after vaccination), lymphadenitis after BCG vaccination, immunodeficiency states (including AIDS or HIV infection).

Gastrointestinal diseases gastric and duodenal ulcer, esophagitis, gastritis, acute or latent peptic ulcer, recently created intestinal anastomosis, ulcerative colitis with threat of perforation or abscess formation, diverticulitis.

Cardiovascular diseases, including recent myocardial infarction (in patients with acute and subacute myocardial infarction, spread of the necrosis focus, slowing of scar tissue formation and, as a result, rupture of the heart muscle is possible), decompensated chronic heart failure, arterial hypertension, hyperlipidemia.

Endocrine diseases diabetes mellitus (including impaired carbohydrate tolerance), thyrotoxicosis, hypothyroidism, Cushing’s disease.

Severe chronic renal and/or hepatic failure, nephrourolithiasis; hypoalbuminemia and conditions predisposing to its occurrence; systemic osteoporosis, myasthenia gravis, acute psychosis, obesity (III-IV degree), poliomyelitis (except for the form of bulbar encephalitis), open-angle and closed-angle glaucoma, lactation period.

Use in Pregnancy and Lactation

During pregnancy (especially in the first trimester), the drug Dexamethasone-KRKA can be used only when the expected therapeutic effect outweighs the potential risk to the fetus. With long-term therapy with dexamethasone during pregnancy, the possibility of impaired fetal growth cannot be excluded. If the drug Dexamethasone-KRKA is used in the last trimester of pregnancy, there is a risk of adrenal cortex atrophy in the fetus, which may require replacement therapy in the newborn.

If a woman received glucocorticosteroids during pregnancy, additional use of glucocorticosteroids during childbirth is recommended. If labor is prolonged or a caesarean section is planned, it is recommended to administer 100 mg of hydrocortisone intravenously every 8 hours in the peripartum period.

If therapy with Dexamethasone-KRKA is necessary, breastfeeding should be discontinued.

Use in Hepatic Impairment

Contraindicated in severe chronic hepatic failure.

Use in Renal Impairment

Contraindicated in severe chronic renal failure, nephrourolithiasis.

Pediatric Use

Dexamethasone is used in children and adolescents only for strict indications. During treatment, strict monitoring of the child’s or adolescent’s growth and development is necessary.

Special Precautions

In patients requiring long-term dexamethasone therapy, “withdrawal” syndrome may develop after discontinuation of therapy (even without clear signs of adrenal insufficiency): fever, nasal discharge, conjunctival hyperemia, headache, dizziness, drowsiness and irritability, muscle and joint pain, vomiting, weight loss, weakness, convulsions. Therefore, Dexamethasone must be discontinued by gradually reducing the dose. Rapid withdrawal of the drug can be fatal.

In patients who have received long-term dexamethasone therapy and have been subjected to stress after its discontinuation, it is necessary to resume the use of dexamethasone, because induced adrenal insufficiency may persist for several months after discontinuation of the drug.

Dexamethasone therapy may mask signs of existing or new infections and signs of intestinal perforation in patients with ulcerative colitis. Dexamethasone may worsen the course of systemic fungal infections, latent amebiasis or pulmonary tuberculosis.

In patients with acute pulmonary tuberculosis, Dexamethasone can be prescribed (together with antituberculosis drugs) only in the case of a fulminant or severe disseminated process. Patients with inactive pulmonary tuberculosis receiving dexamethasone therapy, or patients with positive tuberculin tests should receive concurrent antituberculosis chemoprophylaxis.

Special attention and careful medical supervision are necessary for patients with osteoporosis, arterial hypertension, heart failure, tuberculosis, glaucoma, hepatic or renal failure, diabetes mellitus, active peptic ulcers, fresh intestinal anastomoses, ulcerative colitis and epilepsy. With caution the drug is prescribed in the first weeks after acute myocardial infarction, to patients with thromboembolism, with myasthenia gravis, glaucoma, hypothyroidism, psychosis or psychoneuroses, as well as to patients over 65 years of age.

During dexamethasone therapy, decompensation of diabetes mellitus or conversion of latent to clinically manifest diabetes mellitus is possible.

With long-term treatment, monitoring of serum potassium levels is necessary.

During dexamethasone therapy, vaccination with live vaccines is contraindicated.

Immunization with killed viral or bacterial vaccines does not produce the expected increase in the titer of specific antibodies and therefore does not provide the necessary protective effect. Dexamethasone-KRKA is usually not prescribed 8 weeks before vaccination and for 2 weeks after vaccination.

Patients taking high doses of dexamethasone for a long time should avoid contact with patients with measles; in case of accidental contact, prophylactic treatment with immunoglobulin is recommended.

Caution should be exercised when treating patients who have recently undergone surgery or bone fractures, since Dexamethasone may slow down wound and fracture healing.

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

Dexamethasone-KRKA is used in children and adolescents only for strict indications. During treatment, strict monitoring of the child’s or adolescent’s growth and development is necessary.

Special information about some components of the drug

The drug Dexamethasone-KRKA contains lactose, therefore its use in patients with galactosemia, lactase deficiency and glucose-galactose malabsorption syndrome is contraindicated.

Effect on the ability to drive vehicles and operate complex machinery

Dexamethasone-KRKA does not affect the ability to drive vehicles and work with technical devices requiring concentration and speed of psychomotor reactions.

Overdose

A single intake of a large number of tablets does not lead to clinically significant intoxication.

Symptoms possible intensification of dose-dependent side effects. In this case, the dose of the drug should be reduced.

Treatment supportive and symptomatic.

There is no specific antidote.

Hemodialysis is ineffective.

Drug Interactions

Concomitant use of dexamethasone and non-steroidal anti-inflammatory drugs (NSAIDs) increases the risk of development and formation of gastrointestinal ulcers.

The effect of dexamethasone is reduced with simultaneous use of inducers of the CYP3A4 isoenzyme (e.g., phenytoin, phenobarbital, carbamazepine, primidone, rifabutin, rifampicin) or drugs that increase the metabolic clearance of glucocorticoids (ephedrine and aminoglutethimide); in such cases, it is necessary to increase the dose of dexamethasone.

Interaction between dexamethasone and the above drugs may distort the results of dexamethasone suppression tests. If dexamethasone tests are to be performed during therapy with one of the listed drugs, this interaction must be taken into account when interpreting the test results.

Concomitant use of dexamethasone and inhibitors of the CYP3A4 isoenzyme (e.g., ketoconazole, macrolide antibiotics) may lead to an increase in the concentration of dexamethasone in the blood.

Concomitant use of drugs that are metabolized by CYP3A4 (e.g., indinavir, erythromycin) may increase their clearance, which may be accompanied by a decrease in their serum concentrations.

Dexamethasone reduces the effectiveness of hypoglycemic drugs, antihypertensive drugs, praziquantel and natriuretics (it is necessary to increase the dose of these drugs); increases the activity of heparin, albendazole and potassium-sparing diuretics (if necessary, the dose of these drugs is reduced).

Dexamethasone may alter the effect of coumarin anticoagulants, so more frequent monitoring of prothrombin time is recommended during therapy. Antacids reduce the absorption of dexamethasone in the stomach. Smoking does not affect the pharmacokinetics of dexamethasone.

With simultaneous use of oral contraceptives, the T_1/2 of glucocorticosteroids may increase, with a corresponding enhancement of their biological effects and an increase in the frequency of adverse side effects.

Concomitant use of ritodrine and dexamethasone during labor is contraindicated, as it may lead to maternal death due to pulmonary edema. Concomitant use of dexamethasone and thalidomide may cause toxic epidermal necrolysis.

Potential, therapeutically beneficial interactions: simultaneous use of dexamethasone and 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 caused by chemotherapy (cisplatin, cyclophosphamide, methotrexate, fluorouracil).

Storage Conditions

Store the drug at a temperature not exceeding 25°C (77°F), in the original packaging. Keep out of reach of children.

Shelf Life

Shelf life – 5 years. Do not use the drug after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.