Metipred: detailed information

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

Composition:

Active ingredient: methylprednisolone;

1 tablet contains 4 mg or 16 mg of methylprednisolone;

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

Pharmaceutical form. Tablets.

Main physico-chemical 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 and a score line with the imprint "ORN 346" on one side.

The tablets can be divided into equal doses.

Pharmacotherapeutic group. Corticosteroids for systemic use.

ATC code H02AB04.

Pharmacological properties.

Pharmacodynamics. The effect of methylprednisolone, as well as 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 – a key protein in the neuroendocrine interaction of glucocorticoids, 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).

Endocrine effects of methylprednisolone include suppression of adrenocorticotropic hormone secretion, inhibition of endogenous cortisol production, and, with prolonged use, 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.

Oral bioavailability of 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 into breast milk. The plasma protein binding of methylprednisolone in humans is approximately 77%.

Metabolism.

In the human body, methylprednisolone is metabolized in the liver to 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 of methylprednisolone is approximately 1.4 ml/kg. Total clearance is about 5–6 ml/min/kg. The duration of anti-inflammatory effect lasts 18–36 hours. Approximately 5% of the drug is excreted from the body in urine.

Clinical characteristics.

Indications.

Endocrine disorders.

Primary and secondary adrenocortical insufficiency (in these cases, hydrocortisone or cortisone are the drugs of first choice; 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 associated with malignancies.

Nonendocrine disorders.

Rheumatic diseases.

As adjunctive therapy for short-term administration (to control acute episodes or exacerbations) in the following conditions:

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 selected cases, as maintenance therapy in the following conditions:

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

Skin disorders.

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 allergies;
contact dermatitis;
atopic dermatitis.

Ocular diseases.

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

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

Respiratory diseases.

Symptomatic sarcoidosis;
Löffler’s syndrome refractory to other treatments;
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 (erythrocytic 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, either idiopathic or due to systemic lupus erythematosus.

Gastrointestinal disorders.

For management of critical conditions in the following diseases:

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

Neurological disorders.

Acute exacerbations of multiple sclerosis;
cerebral edema associated with brain tumors.

Disorders of other organs and systems.

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

Organ transplantation.

Contraindications.

Tuberculosis and other acute or chronic bacterial or viral infections when adequate antibiotic or chemotherapy is insufficient, 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) enzymes and is metabolized predominantly 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, 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) can alter glucocorticoid metabolism by inducing (increasing 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 drugs 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, close monitoring for systemic corticosteroid-related adverse reactions is required.

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 these drugs are used concomitantly, an increased dose of methylprednisolone may be required to achieve the desired therapeutic effect. Such drugs 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 adjustments. Adverse reactions associated with monotherapy of either agent 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. Consequently, 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 enhances the rate of acetylation and clearance of isoniazid.

Interactions with other medicinal products not related to CYP3A4 enzymes:

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

Anticoagulants (oral): the effect of methylprednisolone on oral anticoagulants is variable. Reports have described both potentiation and reduction of anticoagulant effects when used concomitantly with corticosteroids. Therefore, coagulation parameters must 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 blockade effects of pancuronium and vecuronium has been reported in patients receiving corticosteroids. This interaction may be expected with all competitive neuromuscular blocking agents.

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

Antidiabetic agents: since corticosteroids may increase blood glucose levels, dosage adjustment of antidiabetic agents may be necessary.

Aromatase inhibitor (aminoglutethimide): adrenal suppression caused by aminoglutethimide may exacerbate 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 drugs (NSAIDs), aspirin (acetylsalicylic acid) at high doses: concomitant use of corticosteroids with NSAIDs may increase the risk of gastrointestinal bleeding and ulceration. 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 can mask some symptoms of infection; in addition, 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 corticosteroid use, 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 and, in some cases, fatal. The frequency of infectious complications increases with higher corticosteroid doses.

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

Furthermore, corticosteroids should be used with great caution in patients with confirmed or suspected parasitic infections, such as strongyloidiasis (roundworm 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 positive and negative outcomes with corticosteroid use in this clinical setting. Later studies indicated that corticosteroids, as adjunctive therapy, had beneficial 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 study data following short-term, high-dose corticosteroid regimens concluded that there was insufficient evidence to support such use. However, meta-analyses and study reviews have shown that longer (5–11 days) courses 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 at immunosuppressive doses is contraindicated. Patients receiving corticosteroids at immunosuppressive doses may be vaccinated with 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—corticosteroids are used in such cases 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, as reactivation of disease is possible. 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., angioneurotic edema) 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 medicinal product.

Endocrine system

Corticosteroids administered over a prolonged period 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, timing, and duration of glucocorticoid therapy. This effect may be minimized by using alternate-day therapy.

Acute adrenal insufficiency may develop upon abrupt discontinuation of glucocorticoids, which may lead to a fatal outcome.

Adrenal insufficiency caused by drug use may be minimized by gradual dose reduction. This type of relative insufficiency may persist for several months after discontinuation of therapy; therefore, if stressful situations occur during this period, hormonal 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 rapidly acting corticosteroids before, during, and after the stressful event.

After abrupt discontinuation of glucocorticoids, a steroid withdrawal syndrome may also develop, which at first glance appears unrelated to adrenal insufficiency. Symptoms of this syndrome include: anorexia, nausea, vomiting, lethargy, headache, fever, joint pain, 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 pre-existing diabetes mellitus, and predispose patients receiving long-term corticosteroid therapy to develop diabetes mellitus.

Mental disorders

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

Potentially severe psychiatric disorders may develop during systemic corticosteroid therapy (see section "Adverse reactions"). Symptoms typically appear within several days or weeks after starting therapy. Most reactions resolve after dose reduction or discontinuation of the drug, although specific treatment may be required. Psychiatric reactions have been reported upon discontinuation of corticosteroids; 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.

When using corticosteroids, the patient’s condition should be carefully considered, especially 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 rapidly 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.

With prolonged corticosteroid use, posterior subcapsular cataract and nuclear cataract (especially in children), exophthalmos, or increased intraocular pressure may develop, potentially leading to glaucoma with possible optic nerve damage. Patients receiving glucocorticoids have an increased risk of secondary fungal and viral eye infections.

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

Cardiac disorders

Adverse reactions related to glucocorticoid use affecting the cardiovascular system, such as dyslipidemia and arterial hypertension, may cause additional cardiovascular effects in patients with risk factors for cardiovascular complications when glucocorticoids are used at high doses and for prolonged periods. Therefore, corticosteroids should be used judiciously in such patients, and risk factor modification should be considered, with additional cardiac monitoring if necessary. Use of low doses and alternate-day dosing may reduce the frequency of complications.

Systemic corticosteroids should be used with caution and only when absolutely necessary in patients with congestive heart failure. Caution is also required when prescribing the drug to patients who have recently had a myocardial infarction (cases of myocardial perforation 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 should be exercised when prescribing corticosteroids to patients with thromboembolic disorders or those predisposed to them.

Gastrointestinal disorders

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

Musculoskeletal system disorders

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 occur. 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.

Kidney and urinary system

Scleroderma renal crisis.

Caution is required in patients with systemic scleroderma receiving methylprednisolone, due to 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. In suspected renal crisis, blood pressure should be monitored more closely.

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

Laboratory findings

With hydrocortisone or cortisone use at moderate 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 associated with glucocorticoid use, 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 drug dose and duration of treatment, a careful benefit-risk assessment should be performed in each case when determining both dose and duration of therapy, as well as the regimen—daily or intermittent.

During corticosteroid therapy, the lowest effective dose should be prescribed, and when dose reduction becomes possible, it should be done gradually.

After systemic corticosteroid use, cases of phaeochromocytoma crisis, which may lead to fatal outcomes, have been reported. Corticosteroids should be prescribed to patients with suspected or confirmed phaeochromocytoma only after appropriate risk-benefit assessment.

Use during pregnancy or breastfeeding.

When prescribing corticosteroids to pregnant women, women who are breastfeeding, or women planning to become pregnant, a careful assessment of the benefit to the mother versus the potential risk to the fetus/child should be performed.

Pregnancy.

Administration of corticosteroids to pregnant animals may cause fetal abnormalities, including cleft palate, intrauterine growth retardation, and affect 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, after careful risk-benefit evaluation.

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

Breastfeeding period.

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. In milder conditions, lower doses are usually sufficient, 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).

Once a satisfactory response to therapy has been achieved, the individual maintenance dose should be determined by gradually reducing the initial dose at regular intervals until the lowest dose that maintains the desired clinical effect is established. Continuous monitoring of the dosing regimen is essential. Dose adjustments may be necessary in certain situations, including changes in clinical status due to remission or exacerbation of the disease, individual patient response to the drug, and the impact of stressful conditions unrelated to the primary disease being treated. In the latter case, a temporary increase in dosage may be required, 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 the corticosteroid is administered every other day in the 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 axis, Cushing's syndrome, corticosteroid withdrawal syndrome, and growth suppression in children.

Children

The medicinal product is used in pediatric practice.

Close monitoring of growth and development, including in infants, is required during prolonged corticosteroid therapy.

Children receiving daily, multiple-dose glucocorticoid therapy over prolonged periods may exhibit growth suppression. Therefore, such a dosing regimen should be used only when strongly indicated. Alternate-day therapy generally allows avoidance or minimization of 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-dose 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 recommended.

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 removed by dialysis.

Adverse Reactions

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).

Blood and lymphatic system disorders.

Not known: Leukocytosis.

Endocrine 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 requirement for oral antidiabetic agents in patients with 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 feelings.

Not known: Mood changes, psychological dependence, suicidal ideation, psychosis (including mania, delusions, hallucinations, schizophrenia or exacerbation of schizophrenia), psychiatric 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 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 following 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, vomiting.

Hepatobiliary disorders.

Not known: Increased liver enzymes.

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

Shelf life. 5 years.

Storage conditions. Store at temperatures not exceeding 25°C. Keep out of reach of children.

Packaging.

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

Prescription status. 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.

Manufacturer.

Orion Corporation / Orion Corporation.

Manufacturer's location and address of place of business.

Joensuunkatu 7, 24100 Salo, Finland / Joensuunkatu 7, 24100 Salo, Finland.

INSTRUCTION

for medical use of the medicinal product

METHYPRED

(METHYPRED)

Composition:

Active ingredient: methylprednisolone;

1 tablet contains methylprednisolone 4 mg.

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

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, round, flat tablets with bevelled edges and a score line on one side.

Pharmacotherapeutic group. Systemic corticosteroids.

ATC code H02AB04.

Pharmacological properties.

Pharmacodynamics. The effect of methylprednisolone, as with other glucocorticoids, is mediated through interaction with cytoplasmic steroid receptors. 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, a pivotal protein in the neuroendocrine interaction of glucocorticoids, 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 than 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 secretion, inhibition of endogenous cortisol production, and, with prolonged use, 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 receiving 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 over 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. Plasma protein binding of methylprednisolone in humans is approximately 77%.

Metabolism.

In humans, methylprednisolone is metabolized in the liver to inactive metabolites. Hepatic metabolism occurs primarily via the CYP3A4 enzyme.

Excretion.

The mean elimination half-life of methylprednisolone ranges from 1.8 to 5.2 hours. The apparent volume of distribution is approximately 1.4 L/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 urine unchanged.

Clinical characteristics.

Indications.

Endocrine disorders.

Primary and secondary adrenal insufficiency (in these conditions, hydrocortisone or cortisone are drugs of first choice; 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 associated with malignancies.

Non-endocrine 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 in osteoarthritis;
epicondylitis.

Collagenoses.

During exacerbations or, in selected cases, as maintenance therapy in the following conditions:

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

Skin disorders.

Pemphigus;
bullous pemphigoid;
severe multiform erythema (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 allergies;
contact dermatitis;
atopic dermatitis.

Ocular diseases.

Severe acute and chronic allergic and inflammatory processes involving the eye, 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;
chorioretinitis;
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.

Hematologic disorders.

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

Oncologic 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 disorders.

For managing critical conditions in the following diseases:

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

Neurological disorders.

Multiple sclerosis during exacerbation phase;
cerebral edema associated with brain tumors.

Diseases of other organs and systems.

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

Organ transplantation.

Contraindications.

Tuberculosis and other acute or chronic bacterial or viral infections when adequate antibiotic or chemotherapy is lacking, 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) enzymes and is metabolized primarily by the CYP3A4 isoenzyme. CYP3A4 is the predominant 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 (as well as other drugs) alter glucocorticoid metabolism by either inducing (increasing 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 substrates 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 corticosteroid-related adverse reactions.

Inducers of CYP3A4 – medicinal products that enhance CYP3A4 activity generally increase hepatic clearance, resulting in reduced plasma concentrations of CYP3A4 substrates. 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 adjustments. Adverse reactions associated with the use of either agent as monotherapy are more likely when used concomitantly.

Corticosteroids may reduce plasma concentrations of tacrolimus when used concurrently.

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

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

Methylprednisolone enhances the acetylation rate 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 described 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 actions 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 of neuromuscular blockade effects of pancuronium and vecuronium has been reported in patients receiving corticosteroids. This interaction may be expected with all competitive neuromuscular blocking agents.

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

Antidiabetic agents: since corticosteroids may increase blood glucose levels, dosage adjustment of antidiabetic agents may be necessary.

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

Nonsteroidal anti-inflammatory drugs (NSAIDs), high-dose aspirin (acetylsalicylic acid): concomitant use of corticosteroids with NSAIDs may increase the risk 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 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; in addition, 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, at any site in the body, may be associated with the use of corticosteroids 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 and, in some cases, 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.

Furthermore, 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 positive and negative outcomes with corticosteroid use in this clinical setting. Later studies indicated that corticosteroids, as adjunctive therapy, had a beneficial effect in patients with septic shock who had adrenal insufficiency. However, routine use of these agents in patients with septic shock is not recommended. According to a systematic review of clinical trial data, short courses of high-dose corticosteroids showed no evidence supporting their use in such patients. However, meta-analysis and review 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 be vaccinated with inactivated or killed vaccines, although their response to such vaccines may be diminished. Immunization procedures may be performed in patients receiving corticosteroids at non-immunosuppressive doses.

The use of corticosteroids in active tuberculosis should be limited to cases of fulminant or disseminated tuberculosis; in such cases, corticosteroids are used in combination with appropriate antituberculosis chemotherapy. If corticosteroids are indicated in patients with latent tuberculosis or with a recent conversion of tuberculin skin tests, treatment should be conducted under close medical supervision due to the risk of disease reactivation. Chemoprophylactic agents should be administered to such patients during prolonged corticosteroid therapy.

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., angioneurotic edema) may occur. Skin reactions and anaphylactic/anaphylactoid reactions have been rarely reported in patients receiving corticosteroid therapy. Appropriate precautions should be taken before corticosteroid administration, 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, timing, and duration of glucocorticoid therapy. This effect may be minimized by using alternate-day therapy.

Acute adrenal insufficiency may develop upon abrupt discontinuation of glucocorticoids, which may lead to fatal outcomes.

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

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

Abrupt discontinuation of glucocorticoids may also lead to a steroid withdrawal syndrome, apparently unrelated to adrenal insufficiency. Symptoms of this syndrome include: anorexia, nausea, vomiting, lethargy, headache, fever, joint pain, desquamation, myalgia, weight loss, and/or hypotension. These effects are believed to result from a sudden change in glucocorticoid concentration rather than from low corticosteroid levels.

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

The effects of corticosteroids are more pronounced 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 use: from euphoria, insomnia, mood changes, and personality changes to severe depression with psychotic manifestations. In addition, pre-existing emotional instability and predisposition to psychotic reactions may be exacerbated during corticosteroid therapy.

Potentially severe psychiatric disorders may develop during systemic corticosteroid therapy (see section "Adverse reactions"). Symptoms typically appear within several days or weeks after starting therapy. Most reactions resolve after 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 disorders develop, particularly if depression or suicidal thoughts are suspected. Patients and caregivers should remain vigilant for psychiatric disorders that may occur during therapy or immediately after gradual dose reduction or discontinuation of systemic steroids.

When prescribing corticosteroids, the patient's condition should be considered, especially 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.

Nervous system disorders

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.

Eye disorders

Corticosteroids should be used with caution in patients with eyes affected by herpes simplex virus, as corneal perforation may occur. Close monitoring is also important in patients with glaucoma or a family history of glaucoma.

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

With prolonged corticosteroid use, posterior subcapsular cataract and nuclear cataract (especially in children), exophthalmos, or increased intraocular pressure may develop, potentially leading to glaucoma with possible optic nerve damage. Patients using glucocorticoids have an increased risk of secondary eye infections caused by fungi or viruses.

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

Cardiac disorders

Adverse reactions related to glucocorticoid use affecting the cardiovascular system, such as dyslipidemia and arterial hypertension, may cause additional cardiovascular effects in patients with cardiovascular risk factors when glucocorticoids are used at high doses and for prolonged durations. Therefore, corticosteroids should be used judiciously in such patients, risk factors should be modified, and cardiac function should be monitored as needed. Use of low doses and alternate-day corticosteroid regimens 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 the drug to patients who have recently experienced 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 with corticosteroid use. Therefore, caution is required when prescribing corticosteroids to patients with thromboembolic disorders or those predisposed to them.

Gastrointestinal disorders

There is no consensus that corticosteroids cause peptic ulcer development during therapy. However, glucocorticoid therapy may mask symptoms of peptic ulcer, so perforation or hemorrhage may occur without prominent pain.

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

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

High doses of corticosteroids may cause acute pancreatitis.

Hepatobiliary system

Reversible hepatobiliary disorders have been reported after discontinuation of the drug. Therefore, appropriate monitoring is necessary.

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

Musculoskeletal system disorders

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 anticholinergic therapy, 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 scleroderma receiving methylprednisolone, due to an observed increased incidence of scleroderma renal crisis (potentially fatal), characterized by arterial hypertension and reduced urine output. Blood pressure and renal function (plasma creatinine concentration) should be monitored regularly. If renal crisis is suspected, blood pressure should be monitored more closely.

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

Laboratory findings

With hydrocortisone or cortisone use at moderate to high doses, increased blood pressure, sodium and water retention, and increased potassium excretion may occur. These effects are less commonly observed 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

Long-term treatment of elderly patients should be conducted with caution, as elderly individuals are more susceptible to adverse effects associated with glucocorticoid use, 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.

When treating with corticosteroids, the lowest effective dose should be prescribed, and 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 benefit-risk assessment for both mother and fetus/infant should be performed.

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 needed, after careful risk-benefit evaluation.

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

The effect of corticosteroids on labor and delivery outcomes is unknown.

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

Breastfeeding period.

Fertility.

Animal studies have shown that corticosteroids impair fertility.

Ability to affect reaction speed when driving or operating 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 an adequate response is achieved during therapy, the patient should be transitioned to an individual maintenance dose by gradually reducing the initial dose at regular intervals until the lowest dose that maintains the desired clinical effect is determined. 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 stressful 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 should be individualized and based on assessment of disease course and clinical response.

The drug must not be discontinued abruptly; tapering should be performed gradually.

Alternate-day therapy

Alternate-day therapy is a corticosteroid dosing regimen in which a double daily dose of corticosteroid is administered every other day in the morning. The goal of this regimen 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 axis, Cushing's syndrome, corticosteroid withdrawal syndrome, and growth suppression in children.

Children

The medicinal product is used in pediatric practice.

Close monitoring of growth and development, including in infants, is required during prolonged corticosteroid therapy.

Growth retardation may occur in children receiving daily, multiple daily doses of glucocorticoids over prolonged periods. Therefore, such a dosing regimen should be used only when absolutely necessary. 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.

Overdose

Adverse Reactions

The frequency of adverse reactions is classified as follows: very common (≥ 1/10);
common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000);
very rare (< 1/10000); not known (frequency cannot be determined 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).

Blood and lymphatic system disorders.

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 need for oral antidiabetic agents in patients with 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, euphoria.

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.

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 enzymes.

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 blood levels of liver enzymes alanine aminotransferase, aspartate aminotransferase, and increased alkaline phosphatase, increased intraocular pressure, decreased carbohydrate tolerance, increased urinary calcium excretion, suppression of skin test reactivity.

Injury.

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

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing 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 all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions. Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging.

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

Prescription status. 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.

Manufacturer.

Limited liability company «Kusum Pharm» / Товариство з обмеженою відповідальністю «Кусум Фарм».

Manufacturer’s location and address of place of business.

Ukraine, 40020, Sumy region, Sumy, Skryabina str., 54 / Україна, 40020, Сумська область, м. Суми, вул. Скрябіна, 54.