INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MÉTIPRED (METHYPRED)

Composition:

Active substance: methylprednisolone;

1 tablet contains methylprednisolone 4 mg or 16 mg;

Excipients: lactose monohydrate, maize starch, gelatin, magnesium stearate, talc.

Pharmaceutical form. Tablets.

Main physicochemical properties:

4 mg tablets: white or almost white, round, flat tablets with bevelled edges and a score line on one side;

16 mg tablets: white or almost white, round, flat tablets with bevelled edges, a score line and the imprint "ORN 346" on one side.

Tablets can be divided into equal doses.

Pharmacotherapeutic group. Systemic corticosteroids.

ATC code: H02AB04.

Pharmacological properties.

Pharmacodynamics. The effect of methylprednisolone, as with other glucocorticoids, is mediated through interaction with steroid receptors in the cytoplasm. The steroid-receptor complex is transported into the cell nucleus, binds to DNA, and alters transcription of genes for most proteins. Glucocorticoids suppress the synthesis of numerous proteins and various enzymes that cause joint destruction (in rheumatoid arthritis), as well as cytokines that play a key role in immune and inflammatory responses. They also induce the synthesis of lipocortin—the key protein in glucocorticoid neuroendocrine interactions—leading to a reduction in inflammatory and immune responses.

Glucocorticoids, including methylprednisolone, suppress or prevent tissue responses to various thermal, mechanical, chemical, infectious, and immunological agents. Thus, glucocorticoids act symptomatically, reducing disease symptoms without affecting the underlying cause. Methylprednisolone is a potent anti-inflammatory steroid. Its anti-inflammatory effect is significantly stronger than that of prednisolone. Methylprednisolone causes less sodium and fluid retention in the body compared to prednisolone. The anti-inflammatory effect of methylprednisolone is at least four times greater than that of hydrocortisone (calculated based on reduction in eosinophil count).

The endocrine effects of methylprednisolone include suppression of adrenocorticotropic hormone (ACTH) secretion and inhibition of endogenous cortisol production; with prolonged use, it may lead to partial atrophy of the adrenal cortex. A single 40 mg dose of methylprednisolone inhibits corticotropin secretion for approximately 36 hours. Methylprednisolone affects calcium and vitamin D metabolism, as well as carbohydrate, protein, and lipid metabolism. Therefore, patients taking methylprednisolone may experience increased blood glucose levels, decreased bone mineral density, muscle atrophy, and dyslipidemia. Glucocorticoids also increase blood pressure and modulate behavior and mood. Methylprednisolone has virtually no mineralocorticoid activity.

Pharmacokinetics.

The pharmacokinetics of methylprednisolone are linear, regardless of the route of administration.

Absorption.

The bioavailability of oral methylprednisolone is typically greater than 80%, but may decrease to 60% when high doses are administered. After oral administration, peak serum concentrations of methylprednisolone are reached within 1–2 hours.

Distribution.

Methylprednisolone is widely distributed into tissues, crosses the blood-brain barrier, and is excreted in breast milk. The plasma protein binding of methylprednisolone in humans is approximately 77%.

Metabolism.

In the human body, methylprednisolone is metabolized in the liver into inactive metabolites. Hepatic metabolism occurs primarily via the CYP3A4 enzyme.

Elimination.

The mean elimination half-life of methylprednisolone ranges from 1.8 to 5.2 hours. The apparent volume of distribution is approximately 1.4 ml/kg. Total clearance is about 5–6 ml/min/kg. The duration of the anti-inflammatory effect lasts 18–36 hours. Approximately 5% of the drug is excreted in the urine.

Clinical characteristics.

Indications.

Endocrine disorders.

Primary and secondary adrenal cortex insufficiency (in this case, hydrocortisone or cortisone are first-line agents; if necessary, synthetic analogs may be used in combination with mineralocorticoids; concomitant use of mineralocorticoids is particularly important in the treatment of children).

Congenital adrenal hyperplasia.

Nonsuppurative thyroiditis.

Hypercalcemia in malignancies.

Nonendocrine disorders.

Rheumatic diseases.

As adjunctive therapy for short-term use (to manage acute conditions or exacerbations) in the following diseases:

psoriatic arthritis;
rheumatoid arthritis, including juvenile rheumatoid arthritis (in some cases, maintenance therapy with low doses may be required);
ankylosing spondylitis;
acute and subacute bursitis;
acute nonspecific tenosynovitis;
acute gouty arthritis;
post-traumatic osteoarthritis;
synovitis of osteoarthritis;
epicondylitis.

Collagenoses.

During periods of exacerbation or, in individual cases, as maintenance therapy in the following diseases:

systemic lupus erythematosus;
systemic dermatomyositis (polymyositis);
acute rheumatic carditis;
polymyalgia rheumatica associated with giant cell arteritis.

Skin diseases.

Pemphigus;
bullous pemphigoid;
severe erythema multiforme (Stevens–Johnson syndrome);
exfoliative dermatitis;
mycosis fungoides;
severe psoriasis;
severe seborrheic dermatitis.

Allergic conditions.

For treatment of the following severe allergic conditions when standard therapy is ineffective:

seasonal or perennial allergic rhinitis;
serum sickness;
bronchial asthma;
drug allergy;
contact dermatitis;
atopic dermatitis.

Eye diseases.

Severe acute and chronic allergic and inflammatory processes involving the eyes, such as:

allergic corneal marginal ulcers;
ocular involvement due to Herpes zoster;
anterior segment inflammation;
diffuse posterior uveitis and choroiditis;
sympathetic ophthalmia;
allergic conjunctivitis;
keratitis;
choriorretinitis;
optic neuritis;
iritis and iridocyclitis.

Respiratory diseases.

Symptomatic sarcoidosis;
Löffler’s syndrome unresponsive to other therapies;
berylliosis;
fulminant or disseminated pulmonary tuberculosis (used in combination with appropriate antituberculosis chemotherapy);
aspiration pneumonitis.

Hematological disorders.

Idiopathic thrombocytopenic purpura in adults;
secondary thrombocytopenia in adults;
acquired (autoimmune) hemolytic anemia;
erythroblastopenia (erythroid anemia);
congenital (erythroid) hypoplastic anemia.

Oncological disorders.

As palliative therapy in the following conditions:

leukemias and lymphomas in adults;
acute leukemia in children.

Edema syndrome.

For induction of diuresis or treatment of proteinuria in nephrotic syndrome without uremia, of idiopathic type or caused by systemic lupus erythematosus.

Gastrointestinal diseases.

For managing critical conditions in the following diseases:

ulcerative colitis;
regional enteritis (Crohn’s disease).

Neurological disorders.

Multiple sclerosis in exacerbation phase;
cerebral edema due to brain tumor.

Diseases of other organs and systems.

Tuberculous meningitis with subarachnoid block or risk of block development, in combination with appropriate antituberculosis chemotherapy;
trichinellosis with nervous system or myocardial involvement.

Organ transplantation.

Contraindications.

Tuberculosis and other acute or chronic bacterial or viral infections with inadequate antibiotic or chemotherapy, systemic fungal infections.

Hypersensitivity to methylprednisolone or to any excipients.

Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids.

Interaction with other medicinal products and other forms of interaction.

Methylprednisolone is a substrate of cytochrome P450 (CYP) enzyme and is predominantly metabolized by the CYP3A4 isoenzyme. CYP3A4 is the dominant enzyme of the most common CYP subtype in the liver of adult humans. It catalyzes 6-β-hydroxylation of steroids, which is a key phase I metabolic step for both endogenous and synthetic corticosteroids. Many other compounds are also substrates of CYP3A4, and some of them (as well as other drugs) alter glucocorticoid metabolism by inducing (enhancing activity) or inhibiting the CYP3A4 isoenzyme.

Inhibitors of CYP3A4 – medicinal products that inhibit CYP3A4 activity generally reduce hepatic clearance and increase plasma concentrations of CYP3A4 substrate drugs, such as methylprednisolone. In the presence of a CYP3A4 inhibitor, dose titration of methylprednisolone may be necessary to avoid steroid toxicity.

Concomitant use with CYP3A inhibitors, including products containing cobicistat, is considered to increase the risk of systemic adverse effects. Such combinations should be avoided unless the benefit outweighs the increased risk of systemic adverse reactions associated with corticosteroid use; in such cases, patients should be monitored for the development of systemic adverse reactions related to corticosteroid therapy.

CYP3A4 inhibitors include: erythromycin, clarithromycin, troleandomycin, ketoconazole, itraconazole, isoniazid, diltiazem, mibefradil, aprepitant, fosaprepitant, HIV protease inhibitors (indinavir and ritonavir), cyclosporine, and ethinylestradiol/norethindrone, grapefruit juice.

Inducers of CYP3A4 – medicinal products that stimulate CYP3A4 activity generally increase hepatic clearance, leading to reduced plasma concentrations of CYP3A4 substrate drugs. When used concomitantly, an increased dose of methylprednisolone may be required to achieve the desired effect. These include: rifampicin, carbamazepine, phenobarbital, primidone, phenytoin.

Substrates of CYP3A4 – the presence of another CYP3A4 substrate may lead to inhibition or induction of methylprednisolone hepatic clearance, requiring appropriate dose adjustment. Adverse reactions associated with the use of one of these medicinal products as monotherapy are more likely when used concomitantly.

Corticosteroids may reduce plasma concentrations of tacrolimus when used concomitantly.

Concomitant use of cyclosporine with methylprednisolone results in mutual inhibition of metabolism, potentially increasing plasma concentrations of one or both drugs. Therefore, adverse effects associated with monotherapy of either drug are more likely when used together. Seizures have been reported during concomitant use of methylprednisolone and cyclosporine.

Corticosteroids may enhance the metabolism of HIV protease inhibitors, resulting in reduced plasma concentrations.

Methylprednisolone potentiates the increased rate of acetylation and clearance of isoniazid.

Interactions with other medicinal products not involving CYP3A4 enzymes:

Fluoroquinolones: concomitant use may lead to tendon damage, especially in elderly patients.

Oral anticoagulants: the effect of methylprednisolone on oral anticoagulants is variable. Reports have been made of both increased and decreased anticoagulant effects when used concomitantly with corticosteroids. Therefore, coagulation parameters should be closely monitored to maintain the desired level of anticoagulant effect.

Anticholinergic agents (neuromuscular blocking agents): corticosteroids may affect the effects of anticholinergic agents:

cases of acute myopathy have been reported with concomitant use of high-dose corticosteroids and neuromuscular blocking anticholinergic agents (see section «Special precautions for use»);
antagonism to the neuromuscular blocking effects of pancuronium and vecuronium has been reported in patients receiving corticosteroids. This interaction may be expected for all competitive neuromuscular blocking agents.

Anticholinesterase agents: steroids may reduce the therapeutic effect of anticholinesterase agents in the treatment of myasthenia gravis.

Antidiabetic agents: since corticosteroids may increase blood glucose concentration, dose adjustment of antidiabetic agents may be required.

Aromatase inhibitor (aminoglutethimide): adrenal cortex suppression caused by aminoglutethimide may worsen endocrine changes induced by prolonged glucocorticoid therapy.

Immunosuppressants: methylprednisolone has additive immunosuppressive effects when used concomitantly with other immunosuppressive medicinal products; this may increase both therapeutic and adverse effects.

Nonsteroidal anti-inflammatory drug (NSAID) aspirin (acetylsalicylic acid) at high doses: concomitant use of corticosteroids with NSAIDs may increase the frequency of gastrointestinal bleeding and ulcers. Methylprednisolone may increase the clearance of high-dose aspirin, potentially reducing serum salicylate levels. Discontinuation of methylprednisolone may lead to increased serum salicylate levels, increasing the risk of salicylate toxicity.

Potassium-depleting agents: when corticosteroids are used concomitantly with potassium-depleting agents (such as diuretics, amphotericin B, laxatives), patients should be closely monitored for possible development of hypokalemia. There is also an increased risk of hypokalemia when corticosteroids are used concomitantly with xanthines or β2-agonists.

Special precautions for use.

Immunosuppressive effects / increased susceptibility to infections

Corticosteroids may increase susceptibility to infections; they may mask some symptoms of infection, and new infections may develop during corticosteroid therapy. The use of corticosteroids may reduce resistance to infections and may impair the body's ability to localize infection. Infections caused by any pathogen—including viruses, bacteria, fungi, protozoa, or helminths—and at any site in the body may be associated with the use of corticosteroids, either as monotherapy or in combination with other immunosuppressive agents affecting cellular immunity, humoral immunity, or neutrophil function. These infections may be mild, but may also be severe or even fatal. The frequency of infectious complications increases with higher corticosteroid doses.

Patients receiving medications that suppress the immune system are more susceptible to infections than healthy individuals. For example, varicella (chickenpox) and measles may have more serious or even fatal outcomes in non-immunized children or adults receiving corticosteroids.

Additionally, corticosteroids should be used with great caution in patients with confirmed or suspected parasitic infections, such as strongyloidiasis (threadworm infection). In such patients, corticosteroid-induced immunosuppression may lead to strongyloidiasis hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

There is no consensus regarding the role of corticosteroids in the treatment of patients with septic shock. Early studies reported both beneficial and adverse outcomes with corticosteroid use in this clinical setting. Later studies indicated that corticosteroids, as adjunctive therapy, had favorable effects in patients with septic shock who had adrenal insufficiency. However, routine use of these agents in patients with septic shock is not recommended. Systematic review of clinical trial data following short courses of high-dose corticosteroids in these patients concluded that there was insufficient evidence to support such use. However, meta-analyses and reviews of trial data suggest that longer courses (5–11 days) of low-dose corticosteroid therapy may reduce mortality, particularly in patients with vasopressor-dependent septic shock.

Administration of live or live-attenuated vaccines to patients receiving corticosteroids in immunosuppressive doses is contraindicated. Patients receiving corticosteroids in immunosuppressive doses may receive inactivated or killed vaccines, although their response to such vaccines may be diminished. These immunization procedures may be performed in patients receiving corticosteroids at non-immunosuppressive doses.

The use of corticosteroids in active tuberculosis should be limited to fulminant or disseminated tuberculosis—where corticosteroids are used in combination with appropriate antituberculosis chemotherapy. If corticosteroids are indicated for patients with latent tuberculosis or a positive tuberculin skin test conversion, treatment should be conducted under close medical supervision due to the risk of disease reactivation. During prolonged corticosteroid therapy, such patients should receive chemoprophylactic agents.

Cases of Kaposi’s sarcoma have been reported in patients receiving corticosteroid therapy. In such cases, discontinuation of corticosteroid therapy may lead to clinical remission.

Blood and lymphatic system

Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) should be used with caution when combined with corticosteroids.

Immune system

Allergic reactions (e.g., angioedema) may occur. Skin reactions and anaphylactic/anaphylactoid reactions have been rarely reported in patients receiving corticosteroid therapy. Appropriate precautions should be taken before administering corticosteroids, especially if the patient has a history of allergy to any medication.

Endocrine system

Corticosteroids administered over prolonged periods at pharmacological doses may suppress the hypothalamic-pituitary-adrenal (HPA) axis (secondary adrenal insufficiency). The degree and duration of adrenal insufficiency vary among patients and depend on the dose, frequency, duration, and timing of glucocorticoid therapy. This effect may be minimized by using alternate-day therapy.

Acute adrenal insufficiency may develop upon abrupt withdrawal of glucocorticoids, potentially leading to fatal outcomes.

Adrenal insufficiency induced by corticosteroid use may be minimized by gradual dose reduction. This relative insufficiency may persist for several months after discontinuation of therapy; therefore, if stressful situations occur during this period, hormone therapy should be reinstated. Since mineralocorticoid secretion may be impaired, electrolytes and/or mineralocorticoids should be administered concomitantly.

Patients undergoing corticosteroid therapy who are exposed to unusual stress situations should receive increased doses of fast-acting corticosteroids before, during, and after the stress.

After abrupt discontinuation of glucocorticoids, a steroid withdrawal syndrome may also occur, which is not immediately related to adrenal insufficiency. Symptoms of this syndrome include: anorexia, nausea, vomiting, lethargy, headache, fever, arthralgia, desquamation, myalgia, weight loss, and/or arterial hypotension. These effects are believed to result from a sudden change in glucocorticoid concentration rather than from low corticosteroid levels.

Since glucocorticoids may cause or exacerbate Cushing's syndrome, patients with Cushing's disease should avoid their use.

Corticosteroids have a more pronounced effect in patients with hypothyroidism.

Metabolism and nutrition

Corticosteroids, including methylprednisolone, may increase blood glucose levels, worsen the condition of patients with existing diabetes mellitus, and predispose patients receiving long-term corticosteroid therapy to develop diabetes mellitus.

Psychiatric disorders

Various psychiatric disorders may occur during corticosteroid therapy, ranging from euphoria, insomnia, mood swings, and personality changes to severe depression with psychotic manifestations. Corticosteroid use may also exacerbate pre-existing emotional instability and predisposition to psychotic reactions.

Potentially severe psychiatric disorders may occur with systemic corticosteroid use (see section "Adverse reactions"). Symptoms typically appear within days or weeks after initiation of therapy. Most reactions resolve upon dose reduction or discontinuation of the drug, although specific treatment may be required. Psychiatric reactions have also been reported upon corticosteroid withdrawal; their frequency is unknown. Patients and caregivers should be advised to consult a physician if any psychiatric disturbances develop, especially if depression or suicidal thoughts are suspected. Patients and caregivers should remain vigilant for psychiatric disorders that may occur during treatment or immediately after gradual dose reduction or discontinuation of systemic steroids.

The patient's psychiatric status should be considered when prescribing corticosteroids, particularly if the patient or their close relatives have a history of serious psychiatric disorders (e.g., depression, bipolar disorder, or previous steroid-induced psychosis).

If a patient receiving steroid therapy is exposed to an unusual stress factor, the dose of fast-acting steroids should be increased before, during, and after the stressful event.

Disorders of the nervous system

Corticosteroids should be used with caution in patients with seizures or myasthenia gravis.

Cases of epidural lipomatosis have been reported in patients receiving corticosteroids, usually after prolonged high-dose therapy.

Disorders of the visual organs

Corticosteroids should be used with caution in ocular conditions caused by herpes simplex virus, as corneal perforation may occur. It is also important to monitor patients with glaucoma or a family history of glaucoma.

Cases of visual disturbances have been reported with systemic or local corticosteroid use.

If a patient develops blurred vision or other visual disturbances, they should consult an ophthalmologist to evaluate possible causes. These may include cataract, glaucoma, or rare conditions such as central serous chorioretinopathy, which has been reported after systemic or local corticosteroid use.

Prolonged corticosteroid use may lead to posterior subcapsular cataract and nuclear cataract (especially in children), exophthalmos, or increased intraocular pressure, which may result in glaucoma with potential optic nerve damage. Patients receiving glucocorticoids have an increased risk of secondary fungal or viral eye infections.

Corticosteroid use has been associated with central serous chorioretinopathy, which may lead to retinal detachment.

Cardiac disorders

Adverse cardiovascular effects associated with glucocorticoid use, such as dyslipidemia and arterial hypertension, may cause additional cardiovascular effects in patients with cardiovascular risk factors when high-dose, long-term glucocorticoid therapy is used. Therefore, corticosteroids should be used judiciously in such patients, with consideration of risk factor modification and, if necessary, additional cardiac monitoring. Use of low doses and alternate-day dosing may reduce the frequency of complications.

Systemic corticosteroids should be used with caution and only if absolutely necessary in patients with congestive heart failure. Caution is also required when prescribing corticosteroids to patients who have recently suffered a myocardial infarction (cases of myocardial rupture have been reported).

Vascular disorders

Corticosteroids should be used with caution in patients with arterial hypertension.

Caution is also required when prescribing the drug to patients taking cardiac medications such as digoxin, as corticosteroids may cause electrolyte disturbances/hypokalemia.

Cases of thrombosis, including venous thromboembolism, have been reported during corticosteroid use. Therefore, caution is advised when prescribing corticosteroids to patients with thromboembolic disorders or those predisposed to them.

Gastrointestinal disorders

There is no consensus on whether corticosteroids cause peptic ulceration during therapy. However, glucocorticoid therapy may mask symptoms of peptic ulceration, so perforation or hemorrhage may occur without significant pain.

The risk of gastrointestinal ulcers increases when corticosteroids are used in combination with NSAIDs.

Corticosteroids should be used with caution in patients with ulcerative colitis if there is a risk of perforation, abscess formation, or other suppurative infection; in diverticulitis; after recent intestinal anastomosis; or in active or latent peptic ulcer disease.

High doses of corticosteroids may cause acute pancreatitis.

Hepatobiliary system

Hepatobiliary disorders with reversible course after discontinuation of the drug have been reported. Therefore, appropriate monitoring is necessary.

The effect of corticosteroids is enhanced in patients with liver cirrhosis.

Disorders of the musculoskeletal system

Cases of acute myopathy have been reported with high-dose corticosteroid use, most commonly in patients with neuromuscular transmission disorders (e.g., myasthenia gravis) or those receiving concomitant therapy with anticholinergic agents, such as neuromuscular blocking agents (e.g., pancuronium). This acute myopathy is generalized, may affect eye and respiratory muscles, and may lead to quadriparesis. Elevated creatine kinase levels may be observed. Clinical improvement or recovery after discontinuation of corticosteroids may take from several weeks to several years.

Osteoporosis is a common (but rarely diagnosed) adverse effect associated with long-term use of high-dose glucocorticoids.

Renal and urinary system

Scleroderma renal crisis.

Caution is required in patients with systemic sclerosis receiving methylprednisolone, due to an observed increased frequency of scleroderma renal crisis (potentially fatal), characterized by arterial hypertension and reduced diuresis. Blood pressure and renal function (plasma creatinine concentration) should be monitored regularly. More intensive blood pressure monitoring is required if renal crisis is suspected.

Corticosteroids should be used with caution in patients with renal insufficiency.

Laboratory findings

With hydrocortisone or cortisone use at medium to high doses, increased blood pressure, sodium and water retention, and increased potassium excretion may occur. These effects are less common with synthetic derivatives, except at high doses. A low-sodium diet and potassium supplementation are recommended. All corticosteroids increase calcium excretion.

Trauma

High-dose systemic corticosteroids should not be used in the treatment of patients with traumatic brain injury.

Other

The product contains lactose (as monohydrate). This medicinal product should not be administered to patients with rare hereditary galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Long-term treatment of elderly patients should be conducted with caution, as older individuals are more susceptible to adverse effects of glucocorticoids, such as increased risk of osteoporosis and fluid retention, which may lead to elevated blood pressure.

Concomitant use of fluoroquinolones and glucocorticoids increases the risk of tendon damage, especially in elderly patients.

Since the occurrence of complications during glucocorticoid therapy depends on the dose and duration of treatment, a careful benefit-risk assessment should be performed in each case when determining both the dose and duration of therapy, as well as the regimen—daily or intermittent.

During corticosteroid therapy, the lowest effective dose should be used. When dose reduction becomes possible, it should be done gradually.

Cases of pheochromocytoma crisis, potentially fatal, have been reported after systemic corticosteroid use. Corticosteroids should be prescribed to patients with suspected or confirmed pheochromocytoma only after appropriate risk-benefit assessment.

Use during pregnancy or breastfeeding.

When prescribing corticosteroids to pregnant women, women who are breastfeeding, or women planning pregnancy, a careful assessment of the benefit to the mother versus the potential risk to the fetus/child is required.

Pregnancy.

Administration of corticosteroids to pregnant animals may cause fetal developmental abnormalities, including cleft palate, intrauterine growth retardation, and effects on brain growth and development.

As there are insufficient data on the safety of corticosteroids in pregnant women, these drugs should be prescribed during pregnancy only if clearly necessary and after careful risk-benefit evaluation.

Some corticosteroids readily cross the placental barrier. In one retrospective study, mothers receiving corticosteroids had an increased incidence of low birth weight infants. Although adrenal insufficiency in neonates exposed to corticosteroids in utero is rare, newborns of mothers who received high doses of corticosteroids during pregnancy should be closely monitored for signs of adrenal insufficiency.

The effect of corticosteroids on the course and outcome of labor is unknown.

Cataracts have been observed in infants whose mothers received long-term corticosteroid therapy during pregnancy.

Period of breastfeeding.

Corticosteroids are excreted in breast milk. Corticosteroids in breast milk may suppress growth and affect endogenous glucocorticoid production in breastfed infants. Since adequate studies on the effects of corticosteroids on human reproductive function have not been conducted, this medicinal product should be used in breastfeeding mothers only when the benefit outweighs the potential risk to the infant.

Fertility.

Animal studies have shown that corticosteroids impair fertility.

Ability to affect reaction speed when driving or operating machinery.

The effect of corticosteroids on reaction speed during driving or operating machinery has not been systematically evaluated. During corticosteroid therapy, adverse reactions such as dizziness, vertigo, visual disturbances, and fatigue may occur. In such cases, patients should not drive or operate machinery.

Dosage and Administration

The initial dose for adults may range from 4 mg to 48 mg of methylprednisolone per day, depending on the nature of the disease. Lower doses are usually sufficient for milder conditions, although some patients may require higher initial doses. High doses may be used in conditions such as multiple sclerosis (200 mg/day), cerebral edema (200–1000 mg/day), and organ transplantation (up to 7 mg/kg/day).

If a satisfactory response to therapy is achieved, the individual maintenance dose should be determined by gradually reducing the initial dose at regular intervals until the lowest dose that maintains the clinical response is identified. Continuous monitoring of the dosing regimen is essential. Situations may arise requiring dose adjustments, including changes in clinical status due to remission or exacerbation of the disease, individual patient response to the drug, and the impact of stress situations unrelated to the primary condition being treated. In the latter case, a temporary increase in dosage may be necessary, depending on the patient's condition. The required dose may vary and must be individually adjusted based on the nature of the disease and the patient's response to therapy.

Dosage must be individualized and based on assessment of disease course and clinical response.

Discontinuation of the drug must not be abrupt; it should be done gradually.

Alternate-day therapy

Alternate-day therapy is a corticosteroid dosing regimen in which a double daily dose of corticosteroid is administered every other morning. The goal of this approach is to achieve maximum clinical benefit in patients requiring long-term therapy while minimizing certain adverse effects, such as suppression of the hypothalamic-pituitary-adrenal (HPA) axis, Cushing's syndrome, corticosteroid withdrawal syndrome, and growth suppression in children.

Children

The medicinal product is used in pediatric practice.

Careful monitoring of growth and development, including in infants, is required when long-term corticosteroid therapy is administered.

Children receiving daily, multiple-dose-per-day glucocorticoid therapy over prolonged periods may exhibit growth retardation. Therefore, such a dosing regimen should be used only when strongly indicated. Alternate-day therapy generally helps avoid or minimize this adverse effect (see section "Dosage and Administration").

Infants and children receiving long-term corticosteroid therapy are at particular risk of increased intracranial pressure.

High doses of corticosteroids may cause pancreatitis in children.

Hypertrophic cardiomyopathy may develop after methylprednisolone administration in premature infants; therefore, appropriate diagnostic evaluation and monitoring of cardiac function and structure are required.

Overdose

There is no recognized clinical syndrome of acute corticosteroid overdose. Reports of acute toxicity and/or death following corticosteroid overdose are rare. There is no specific antidote in case of overdose; supportive and symptomatic treatment should be administered. Methylprednisolone is dialyzable.

Side effects.

The frequency of adverse reactions is defined as follows: very common (≥ 1/10);
common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000);
very rare (< 1/10,000); not known (frequency cannot be estimated from available data).

Benign, malignant and unspecified neoplasms (including cysts and polyps).

Not known: tumor lysis syndrome, Kaposi's sarcoma.

Infections and infestations.

Common: infections.

Not known: opportunistic infections.

Immune system disorders.

Not known: hypersensitivity to the medicinal product (including anaphylactic and anaphylactoid reactions, such as circulatory shock, cardiac arrest, bronchospasm).

Disorders of the blood and lymphatic system.

Not known: leukocytosis.

Endocrine system disorders.

Common: suppression of endogenous ACTH and cortisol secretion (with prolonged use), Cushing's syndrome.

Not known: hypopituitarism, steroid withdrawal syndrome.

Metabolism and nutrition disorders.

Common: sodium retention, fluid retention.

Not known: metabolic acidosis, hypokalemic alkalosis, dyslipidemia, impaired glucose tolerance, increased insulin requirement (or increased need for oral antidiabetic agents in diabetes mellitus), lipomatosis, increased appetite (which may lead to weight gain), epidural lipomatosis, increased blood urea concentration, negative nitrogen balance (due to protein catabolism).

Psychiatric disorders.

Common: mood disturbances, euphoric state.

Not known: mood changes, psychological dependence, suicidal ideation, psychosis (including mania, delusions, hallucinations, schizophrenia or exacerbation of schizophrenia), mental disorder, confusion, anxiety, personality changes, pathological behavior, insomnia, irritability.

Nervous system disorders.

Not known: increased intracranial pressure [with papilledema (benign intracranial hypertension)], seizures, amnesia, cognitive disorder, dizziness, headache.

Ear and labyrinth disorders.

Not known: vertigo.

Eye disorders.

Common: cataract.

Not known: glaucoma, exophthalmos, thinning of sclera and cornea, chorioretinopathy, blurred vision.

Cardiac and vascular disorders.

Common: arterial hypertension.

Not known: arterial hypotension, arterial embolism, thrombotic events. Congestive heart failure (in patients predisposed to its development), cardiac arrhythmia, myocardial rupture after myocardial infarction.

Respiratory, thoracic and mediastinal disorders.

Not known: pulmonary embolism, hiccup.

Gastrointestinal disorders.

Common: peptic ulcer (may be complicated by perforation and hemorrhage).

Not known: gastrointestinal hemorrhage, intestinal perforation, pancreatitis, peritonitis, ulcerative esophagitis, esophagitis, abdominal distension, abdominal pain, diarrhea, dyspepsia, nausea.

Hepatobiliary disorders.

Not known: increased liver enzyme levels.

Skin and subcutaneous tissue disorders.

Common: peripheral edema, bruising, skin atrophy, acne.

Not known: angioneurotic edema, hirsutism, petechiae, telangiectasia, striae, hypo- and hyperpigmentation of the skin, rash, erythema, hyperhidrosis, pruritus, urticaria.

Musculoskeletal and connective tissue disorders.

Common: growth retardation (in children), muscle weakness, osteoporosis.

Not known: osteonecrosis, pathological fractures, muscle atrophy, neuropathic arthropathy, arthralgia, myalgia.

Renal and urinary disorders.

Not known: scleroderma renal crisis*.

Reproductive system and breast disorders.

Not known: irregular menstruation.

General disorders.

Common: impaired wound healing.

Not known: fatigue, malaise.

Investigations.

Common: decreased blood potassium levels.

Not known: increased levels of liver enzymes alanine aminotransferase, aspartate aminotransferase, and increased alkaline phosphatase in blood, increased intraocular pressure, decreased carbohydrate tolerance, increased urinary calcium excretion, suppression of skin test reactions.

Injury.

Not known: tendon rupture (especially Achilles tendon), spinal compression fracture.

* The incidence of scleroderma renal crisis varies among different populations. The highest risk is observed in patients with diffuse scleroderma. The lowest risk has been reported in patients with limited scleroderma (2%) and juvenile scleroderma (1%).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions. Store at a temperature not exceeding 25 °C. Keep out of the reach of children.

Packaging.

30 tablets in a bottle; 1 bottle in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Orion Corporation / Orion Corporation.

Manufacturer's location and address of place of business.

Orionintie 1, 02200 Espoo, Finland / Orionintie 1, 02200 Espoo, Finland.