Medrol

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

Composition:

Active substance: methylprednisolone;

1 tablet contains 4 mg, 16 mg, or 32 mg of methylprednisolone;

Excipients: tablets containing 4 mg of methylprednisolone – lactose monohydrate; corn starch; sucrose; calcium stearate;

tablets containing 16 mg of methylprednisolone – lactose monohydrate; corn starch; sucrose; calcium stearate; mineral oil;

tablets containing 32 mg of methylprednisolone – lactose monohydrate; corn starch; sucrose; calcium stearate; mineral oil.

Pharmaceutical form. Tablets.

Main physicochemical properties:

4 mg tablets – white, semi-oval elliptical tablets with an embossing «MEDROL 4» on one side and a cross-shaped score on the other;

16 mg tablets – white, convex elliptical tablets with an embossing «MEDROL 16» on one side and a cross-shaped score on the other;

32 mg tablets – white, convex elliptical tablets with a cross-shaped score on one side and marking «UPJOHN 176» on the other.

The cross-shaped score on the tablets is not functional and is not intended for dividing the tablet.

Pharmacotherapeutic group. Systemic corticosteroids. Glucocorticoids. ATC code H02AB04.

Pharmacological properties.

Methylprednisolone is a potent anti-inflammatory steroid. It has greater anti-inflammatory activity and less tendency to sodium and water retention than prednisolone. The relative activity of methylprednisolone compared to hydrocortisone is at least four to one.

Pharmacodynamics.

Methylprednisolone belongs to the group of synthetic glucocorticoids. Glucocorticoids penetrate cell membranes and form complexes with specific cytoplasmic receptors. These complexes then enter the cell nucleus, bind to DNA (chromatin), stimulate mRNA transcription, and subsequent synthesis of proteins of various enzymes, which explains the systemic effects of glucocorticoids. Glucocorticoids not only exert a significant influence on the inflammatory process and immune response, but also affect carbohydrate, protein, and fat metabolism, the cardiovascular system, skeletal muscles, and the central nervous system.

Effect on inflammation and immune response.

Most indications for the use of glucocorticoids are due to their anti-inflammatory, immunosuppressive, and antiallergic properties. These properties lead to the following therapeutic effects:

• reduction in the number of immune-active cells near the inflammatory site;
• reduction in vasodilation;
• stabilization of lysosomal membranes;
• inhibition of phagocytosis;
• reduction in the production of prostaglandins and related compounds.

A dose of 4.4 mg of methylprednisolone acetate (4 mg of methylprednisolone) exerts the same glucocorticosteroid (anti-inflammatory) effect as 20 mg of hydrocortisone. Methylprednisolone exerts only minimal mineralocorticoid activity (200 mg of methylprednisolone is equivalent to 1 mg of desoxycorticosterone).

Effect on carbohydrate and protein metabolism.

Glucocorticoids have a catabolic effect on proteins. The released amino acids are converted via gluconeogenesis in the liver into glucose and glycogen. Glucose uptake in peripheral tissues is reduced, which may lead to hyperglycemia and glucosuria, particularly in patients predisposed to diabetes mellitus.

Effect on fat metabolism.

Glucocorticoids have a lipolytic effect, primarily affecting tissues of the extremities. Glucocorticoids also exhibit a lipogenic effect, most pronounced in the chest, neck, and head areas. This leads to redistribution of fat deposits. The maximum pharmacological activity of corticosteroids occurs after the peak plasma concentration has already passed; therefore, it is believed that the majority of therapeutic effects are primarily due to modification of enzyme activity rather than the direct action of the drug.

Pharmacokinetics.

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

Absorption.

Methylprednisolone is rapidly absorbed, and peak plasma concentrations of methylprednisolone in healthy volunteers are reached approximately within 1.5–2.3 hours (depending on the dose) after oral administration of the drug. The absolute bioavailability of methylprednisolone in healthy volunteers after oral administration is generally high (82–89%).

Distribution.

Methylprednisolone is widely distributed into tissues, crosses the blood-brain barrier, and is excreted in breast milk. The apparent volume of distribution of methylprednisolone is approximately 1.4 L/kg. Plasma protein binding of methylprednisolone in humans is approximately 77%.

Metabolism.

In the human body, methylprednisolone is metabolized in the liver to inactive metabolites. The main metabolites are 20-α-hydroxymethylprednisolone and 20-β-hydroxymethylprednisolone. Its metabolism in the liver occurs predominantly via the CYP3A4 enzyme (for a list of drug interactions based on CYP3A-mediated metabolism, see section "Interaction with other medicinal products and other forms of interaction").

Methylprednisolone, like many CYP3A4 substrates, may also be a substrate for the P-glycoprotein transporter of the ATP-binding cassette (ABC) family, which affects its tissue distribution and interactions with other medicinal products.

Elimination.

The mean elimination half-life of methylprednisolone ranges from 1.8 to 5.2 hours. Total clearance is approximately 5–6 mL/min/kg.

Dose adjustment is not required in patients with renal insufficiency. Methylprednisolone is removed by hemodialysis.

Clinical characteristics.

Indications.

Endocrine disorders.

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

Congenital adrenal hyperplasia.

Non-suppurative thyroiditis.

Hypercalcemia associated with malignant tumors.

Non-endocrine disorders.

1. Rheumatic diseases.

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

• 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.

2. Collagenoses.

During periods of exacerbation or, in selected cases, as maintenance therapy in the following disorders:

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

3. Skin disorders.

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

4. Allergic conditions.

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

• seasonal or perennial allergic rhinitis;
• serum sickness;
• bronchial asthma;
• hypersensitivity reactions to drugs;
• contact dermatitis;
• atopic dermatitis.

5. Eye disorders.

Severe acute and chronic allergic and inflammatory processes affecting the eye and its adnexa, 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;
• choroidoretinitis;
• optic neuritis;
• iritis and iridocyclitis.

6. Respiratory tract disorders.

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

7. Hematological disorders.

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

8. Oncological disorders.

As palliative therapy in the following conditions:

• leukemias and lymphomas in adults;
• acute leukemia in children.

9. Edema syndrome.

For induction of diuresis or reduction of proteinuria in nephrotic syndrome without uremia, either idiopathic or associated with systemic lupus erythematosus.

10. Gastrointestinal disorders.

For management of critical conditions in the following diseases:

• ulcerative colitis;
• Crohn’s disease.

11. Nervous system disorders.

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

12. 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.

13. Organ transplantation.

Contraindications.

• Systemic fungal infections.
• Systemic infections when specific antimicrobial therapy has not been initiated.
• Hypersensitivity to methylprednisolone or to any of the excipients listed in the section "Composition."

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 the cytochrome P450 (CYP) enzyme system and is metabolized primarily by CYP3A4. CYP3A4 is the predominant enzyme of the most common CYP subfamily 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) alter glucocorticoid metabolism by either inducing (increasing activity) or inhibiting the CYP3A4 enzyme.

CYP3A4 inhibitors – 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. CYP3A4 inhibitors include grapefruit juice; the macrolide antibiotic troleandomycin; and the pharmacokinetic booster cobicistat.

CYP3A4 inducers – medicinal products that enhance 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 therapeutic effect. Such medicinal products include the antibacterial and antituberculosis agent rifampicin; and the anticonvulsants phenobarbital and phenytoin.

CYP3A4 substrates – the presence of another CYP3A4 substrate may affect the hepatic clearance of methylprednisolone, necessitating appropriate dose adjustment. Adverse reactions associated with the use of either drug as monotherapy may be more likely when they are used concomitantly. These include immunosuppressants: cyclophosphamide, tacrolimus.

Interactions with other medicinal products (not involving CYP3A4 enzymes) – other interactions and their outcomes are described in the table below.

List and description of the most common and/or clinically significant interactions or interaction outcomes between methylprednisolone and other medicinal products.

Special precautions for use.

Immunosuppressive effects/increased susceptibility to infections.

Corticosteroids may increase susceptibility to infections; they may mask some signs 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, in any part of 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 can 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. Varicella and measles, for example, may have more serious or even fatal outcomes in non-immunized children or adults receiving corticosteroids.

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; however, 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 and should be combined with appropriate antituberculosis therapy. If corticosteroids are indicated in patients with latent tuberculosis or with a positive tuberculin skin test conversion, treatment should be conducted under close supervision, as reactivation of the disease is possible. 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.

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 of corticosteroid use in this clinical setting. Later studies indicated that corticosteroids as adjunctive therapy had a beneficial effect in patients with established 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 data following short courses of high-dose corticosteroids in such patients, there was no evidence supporting this use. However, data from a meta-analysis and one review showed that longer courses (5–11 days) of low-dose corticosteroid therapy may reduce mortality, particularly in patients with septic shock requiring vasopressor therapy.

Effects on the 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 administration, especially if the patient has a history of allergy to any drug.

The medicinal product contains lactose derived from bovine milk. Patients with known or suspected hypersensitivity to bovine milk protein, its components, or other dairy products should be cautious, as the product may contain trace elements of milk components.

Effects on the endocrine system.

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.

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 (see section "Dosage and administration").

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

Adrenal insufficiency caused by the drug can be minimized by gradual dose reduction. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, if any stress situation occurs during this period, hormonal therapy should be reinstated. Due to possible negative effects on mineralocorticoid secretion, mineralocorticoids should be co-administered and/or salt intake increased.

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 low corticosteroid levels.

Since glucocorticoids 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.

Periodic thyrotoxic periodic paralysis (PTP) may occur in patients with hyperthyroidism and hypokalemia induced by methylprednisolone administration.

PTP should be suspected in patients receiving methylprednisolone who present with signs or symptoms of muscle weakness, particularly in patients with hyperthyroidism.

In suspected PTP, immediate monitoring of serum potassium levels and appropriate therapy to restore normal potassium levels are required.

Metabolic and nutritional disorders.

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.

Psychiatric disorders.

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

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

Increased doses of rapidly acting corticosteroids before, during, and after a stress situation are recommended for patients receiving corticosteroids who are exposed to an unusual stress situation.

Disorders of the nervous system.

Corticosteroids should be used with caution in patients with seizures and in patients with myasthenia gravis (see information on myopathy in the subsection "Musculoskeletal disorders" of this section).

Although controlled clinical trials have demonstrated the efficacy of corticosteroids in accelerating the resolution of multiple sclerosis exacerbations, they have not shown an effect on the final outcome or natural course of the disease. According to these studies, relatively high doses of corticosteroids are required to achieve a significant effect (see section "Dosage and administration").

Cases of epidural lipomatosis have been reported in patients receiving corticosteroids, usually after prolonged use at high doses.

Disorders of the visual organs.

Visual disturbances have been reported with systemic and local use of corticosteroids. If symptoms such as blurred vision or other visual disturbances occur, patients should be referred to an ophthalmologist to identify possible causes, including cataract, glaucoma, or rare conditions such as central serous chorioretinopathy, which has been reported after systemic and local corticosteroid use. Central serous chorioretinopathy may lead to retinal detachment.

Corticosteroids should be used with caution in ocular infections caused by herpes simplex virus, as corneal perforation may occur. 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 possible optic nerve damage. The risk of secondary fungal and viral eye infections is increased in patients receiving glucocorticoids.

Corticosteroid use has been associated with the development of 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 predispose patients with pre-existing cardiovascular risk factors to additional cardiovascular effects when high doses are used 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. Low doses and alternate-day therapy may reduce the frequency of complications during corticosteroid therapy.

Systemic corticosteroids should be used with caution and only when absolutely necessary in patients with congestive heart failure.

Vascular disorders.

Cases of thrombosis, including venous thromboembolism, have been reported with corticosteroid use. Therefore, caution should be exercised when prescribing corticosteroids to patients with thromboembolic disorders or those at risk of developing them.

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

Gastrointestinal disorders.

High doses of corticosteroids may cause acute pancreatitis.

There is no consensus on whether corticosteroids directly cause peptic ulceration during therapy. However, glucocorticoid therapy may mask symptoms of peptic ulcer, potentially leading to perforation or hemorrhage without significant pain. Glucocorticoid therapy may mask peritonitis or other signs or symptoms associated with gastrointestinal disturbances such as perforation, obstruction, or pancreatitis. The risk of gastrointestinal ulcers is increased when corticosteroids are combined with NSAIDs.

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

Hepatobiliary disorders.

Hepatobiliary disorders have been reported, which were reversible upon discontinuation of the drug. Therefore, appropriate monitoring is necessary.

Disorders of the musculoskeletal system.

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

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

Disorders of the kidneys and urinary system.

Use with caution in patients with systemic sclerosis, as an increased incidence of scleroderma renal crisis has been observed with corticosteroid use, including methylprednisolone. Corticosteroids should be used with caution in patients with renal insufficiency.

Investigations.

Administration of hydrocortisone or cortisone in moderate to high doses may cause elevated blood pressure, salt and water retention, and increased potassium excretion. The likelihood of such effects is lower with synthetic derivatives, except when high doses are used. A low-salt diet and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.

Injuries, poisonings, and procedural complications.

Systemic corticosteroids are not indicated and should not be used for the treatment of traumatic brain injury. A multicenter study found increased mortality at 2 weeks and 6 months after injury in patients receiving methylprednisolone compared to those receiving placebo. A causal relationship with methylprednisolone treatment has not been established.

Other.

Since complications of glucocorticoid therapy depend on the dose and duration of treatment, careful assessment of the benefit-risk ratio is required in each case when determining both the dose and duration of therapy, as well as the choice of administration regimen—daily or intermittent.

During corticosteroid therapy, the lowest possible dose that provides adequate therapeutic effect should be prescribed, and when dose reduction becomes feasible, it should be done gradually.

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, patients should be monitored for systemic adverse reactions related to corticosteroid use.

Aspirin and nonsteroidal anti-inflammatory drugs should be used with caution in combination with corticosteroids.

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

During post-marketing surveillance, tumor lysis syndrome (TLS) has been reported in patients with malignant neoplasms, including hematologic malignancies and solid tumors, after administration of systemic corticosteroids alone or in combination with other chemotherapeutic agents. Patients at high risk of TLS, such as those with tumors exhibiting high proliferation rates, high tumor burden, and high sensitivity to cytotoxic agents, should be closely monitored, and appropriate preventive measures should be taken.

The product contains monohydrate lactose and therefore should not be used in patients with rare hereditary forms of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

The product contains sucrose; therefore, patients with diagnosed intolerance to certain sugars should consult their physician before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy.

Results of some animal studies have demonstrated that administration of corticosteroids to pregnant females at high doses may lead to fetal malformations. Although there is no evidence that corticosteroids cause congenital malformations when used in pregnant women, study results from treatment during pregnancy do not fully exclude fetal damage.

Since adequate studies on the effects of methylprednisolone on human reproductive function have not been conducted, this medicinal product should be prescribed during pregnancy only after careful evaluation of the risk-benefit ratio for mother and fetus.

Some corticosteroids readily cross the placental barrier. In one retrospective study, an increased frequency of low birth weight in newborns whose mothers received corticosteroids was observed. In humans, the risk of low birth weight has been shown to be dose-dependent and may be minimized by using lower corticosteroid doses. Neonates whose mothers received sufficiently high doses of corticosteroids during pregnancy should be closely monitored for signs of adrenal insufficiency, although such insufficiency in neonates exposed to corticosteroids in utero is rare.

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 pass into breast milk and may suppress growth and affect endogenous glucocorticoid production in breastfed infants. This medicinal product should be used in breastfeeding women only after careful evaluation of the risk-benefit ratio for mother and infant.

Fertility.

Corticosteroids have been shown to reduce fertility in rats; however, these data are insufficient.

Ability to affect reaction speed when driving or operating machinery.

The effect of corticosteroids on reaction speed during driving and/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 cross-shaped score on the tablet is not functional and is not intended for splitting the tablet.

The initial dose of the medicinal product may vary depending on the indication. Lower doses are usually sufficient for milder conditions, although some patients may require higher initial doses. High-dose therapy may be used in certain clinical situations such as cerebral edema (200–1000 mg/day), organ transplantation (up to 7 mg/kg/day), and multiple sclerosis. In the treatment of multiple sclerosis during an acute relapse, oral administration of methylprednisolone at 500 mg/day for 5 days or 1000 mg/day for 3 days is effective. If satisfactory clinical response is not achieved within an appropriate period, therapy with methylprednisolone tablets should be discontinued and alternative therapy initiated. If the drug has been administered for a prolonged period, discontinuation should be done gradually rather than abruptly.

After achieving a satisfactory response, the individual maintenance dose should be determined by gradually reducing the initial dose in defined intervals to the lowest dose that maintains the desired clinical effect. It should be remembered that continuous monitoring of dosing is required. Situations that may necessitate dose adjustment include 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, it may be necessary to increase the dose of methylprednisolone temporarily, depending on the patient's condition.

It should be emphasized that the required dose may vary and must be individually adjusted depending on the nature of the disease and the patient's response to therapy.

ALTERNATE-DAY THERAPY (ADT)

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 type of therapy is to achieve maximum benefits of corticosteroid use in patients requiring long-term therapy while minimizing certain adverse effects, including suppression of the hypothalamic-pituitary-adrenal (HPA) axis, Cushingoid state, corticosteroid withdrawal syndrome, and growth suppression in children.

Children

The drug is used in pediatric practice.

Close monitoring of growth and development in infants and children is essential during prolonged corticosteroid therapy.

Growth retardation may occur in children receiving glucocorticoids daily in divided doses multiple times per day for prolonged periods. Such a dosing regimen should be used only when absolutely necessary. Alternate-day therapy generally allows avoidance or minimization of this adverse effect (see section "Dosage and Administration. Alternate-day Therapy").

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

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 following adverse reactions associated with treatment are listed below by MedDRA system organ classes and frequency. The frequency of adverse reactions is defined as: common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); not known (frequency cannot be estimated from the available data).

Infections and infestations: common: infections (including increased susceptibility to infections and increased severity of infections with suppression of clinical symptoms); not known: opportunistic infections, reactivation of latent tuberculosis, peritonitis†.

Blood and lymphatic system disorders: not known: leukocytosis.

Immune system disorders: not known: hypersensitivity to the medicinal product, anaphylactic reaction, anaphylactoid reaction.

Endocrine disorders: common: Cushingoid syndrome; not known: suppression of the hypothalamic-pituitary-adrenal axis.

Benign, malignant and unspecified neoplasms (including cysts and polyps): not known: Kaposi's sarcoma.

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 patients with diabetes mellitus), lipomatosis, increased appetite (which may lead to weight gain), epidural lipomatosis.

Psychiatric disorders: common: affective disorders (including depressed mood and euphoric mood); not known: psychosis (including mania, delusions, hallucinations and schizophrenia), psychotic behavior, affective disorders (including affective lability, psychological dependence, suicidal ideation), mental disorder, personality changes, confusion, anxiety, mood swings, pathological behavior, insomnia, irritability.

Nervous system disorders: not known: increased intracranial pressure (with optic disc swelling (benign intracranial hypertension)), seizures, amnesia, cognitive disorder, dizziness, headache.

Eye disorders: rare: blurred vision (see section "Special instructions"); common: cataract; not known: glaucoma, exophthalmos, thinning of sclera and cornea, chorioretinopathy.

Ear and labyrinth disorders: not known: vertigo.

Cardiac disorders: not known: congestive heart failure (in patients predisposed to this condition), myocardial rupture at the site of previous myocardial infarction.

Vascular disorders: common: arterial hypertension; not known: arterial hypotension, arterial embolism, thrombotic events, flushing.

Respiratory, thoracic and mediastinal disorders: not known: pulmonary embolism, hiccup.

Gastrointestinal disorders: common: peptic ulcer (with possible perforation and hemorrhage); not known: intestinal perforation, gastrointestinal hemorrhage, pancreatitis, ulcerative esophagitis, esophagitis, abdominal distension, abdominal pain, diarrhea, dyspepsia, nausea.

Hepatobiliary disorders: not known: increased levels of liver enzymes (e.g., alanine aminotransferase, aspartate aminotransferase).

Skin and subcutaneous tissue disorders: common: skin atrophy, acne; not known: angioneurotic edema, hirsutism, petechiae, ecchymosis, erythema, hyperhidrosis, striae cutis, rash, pruritus, urticaria, telangiectasia.

Musculoskeletal and connective tissue disorders: common: muscle weakness, growth retardation; not known: myalgia, myopathy, muscle atrophy, osteoporosis, osteonecrosis, pathological fractures, neurogenic arthropathy, arthralgia.

Reproductive system and breast disorders: not known: irregular menstruation.

General disorders and administration site conditions: common: impaired wound healing; not known: peripheral edema, fatigue, malaise, withdrawal symptoms (too rapid dose reduction of corticosteroids after prolonged use may lead to acute adrenal insufficiency, arterial hypotension, and fatal outcome) (see section "Special instructions").

Investigations: common: decreased blood potassium levels; not known: increased intraocular pressure, decreased carbohydrate tolerance, increased urinary calcium levels, increased blood alkaline phosphatase levels, increased blood urea levels, suppression of reactions in skin tests*.

Injury, poisoning and procedural complications: not known: tendon rupture (including Achilles tendon), spinal compression fracture.

† Peritonitis may be the primary presenting sign or symptom of gastrointestinal disorders such as perforation, obstruction, or pancreatitis (see section "Special instructions").

* The term name does not belong to the MedDRA classification.

The frequency of expected adverse reactions associated with corticosteroid use, including hypothalamic-pituitary-adrenal suppression, correlates with the relative potency of the drug, dosage, duration of treatment, and route of administration (see section "Special instructions").

Reporting of suspected adverse reactions.

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

Shelf life.

For tablets containing 4 mg of methylprednisolone – 3 years; for tablets containing 16 mg of methylprednisolone – 5 years; for tablets containing 32 mg of methylprednisolone – 3 years.

Storage conditions.

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

Packaging.

Tablets 4 mg: 30 tablets in a bottle, 1 bottle in a cardboard box;

Tablets 16 mg: 10 tablets in a blister, 5 blisters in a cardboard box;

Tablets 32 mg: 10 tablets in a blister, 2 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Pfizer Italia S.r.l./
Pfizer Italia S.r.l.

Manufacturer's address and place of business.
Località Marino del Tronto – 63100 Ascoli Piceno (AP), Italy /
Località Marino del Tronto – 63100 Ascoli Piceno (AP), Italy.