Metirom

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

Composition:

Active substance: methylprednisolone;

1 vial contains 500 mg of methylprednisolone (as methylprednisolone sodium succinate);

Excipients:

powder: sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, sodium hydroxide;

solvent: benzyl alcohol, water for injections.

Pharmaceutical form. Powder and solvent for solution for injection.

Main physicochemical properties:

powder: white to almost white;

solvent for dosing (bacteriostatic water for injections): clear, colorless liquid, practically free from visible particles.

Pharmacotherapeutic group. Systemic corticosteroids.

ATC code: H02AB04.

Pharmacological Properties

This medicinal product is an injectable form of methylprednisolone (a synthetic glucocorticosteroid) for intramuscular and intravenous administration. This highly concentrated solution is used, in particular, for the treatment of pathological conditions requiring effective and rapid hormonal action. Methylprednisolone exerts a potent anti-inflammatory, immunosuppressive, and antiallergic effect.

Pharmacodynamics

Glucocorticoids penetrate the cell membrane by diffusion and form complexes with specific receptors in the cytoplasm. These complexes then enter the cell nucleus, bind to DNA (chromatin), and stimulate mRNA transcription and subsequent synthesis of various enzyme-dependent proteins, which in turn are responsible for the numerous effects of glucocorticoids after systemic administration. Glucocorticoids not only exert significant effects on inflammatory and immune processes, but also influence carbohydrate, protein, and fat metabolism. They also affect the cardiovascular system, skeletal muscles, and the central nervous system.

Effects on inflammatory and immune processes

The anti-inflammatory, immunosuppressive, and antiallergic properties of glucocorticoids are utilized in most therapeutic indications. These properties lead to the following outcomes:

• reduction in the number of immunocompetent cells around the site of inflammation;
• reduction in vasodilation;
• stabilization of lysosomal membranes;
• suppression of phagocytosis;
• reduction in prostaglandin and related substance formation.

A dose of methylprednisolone of 4 mg produces the same glucocorticosteroid (anti-inflammatory) effect as 20 mg of hydrocortisone. Methylprednisolone exhibits only minimal mineralocorticoid activity (200 mg of methylprednisolone corresponds to 1 mg of desoxycorticosterone).

Effects on carbohydrate and protein metabolism

Glucocorticoids exert a catabolic effect on protein metabolism. The released amino acids are converted in the liver via the process of gluconeogenesis into glucose and glycogen. As a result, glucose uptake by peripheral tissues is reduced, which may lead to hyperglycemia and glucosuria, particularly in patients predisposed to diabetes mellitus.

Effects on fat metabolism

Glucocorticoids exert a lipolytic effect, primarily affecting the extremities. They also exert a lipogenic effect, most pronounced in the chest, neck, and head areas. This leads to redistribution of fat deposits.

The maximum pharmacological effect of corticosteroids lags behind the achievement of their peak plasma concentration, indicating that most of the effects of these drugs are likely due to enzyme activity modulation rather than direct drug action.

Pharmacokinetics

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

Absorption

In vivo, cholinesterases rapidly hydrolyze methylprednisolone sodium succinate into free methylprednisolone. In humans, methylprednisolone forms a weak dissociated bond with albumin and transcortin. Approximately 40–90% of the drug is protein-bound.

Intravenous infusion of the drug at a dose of 30 mg/kg body weight administered over 20 minutes, or 1 g administered over 30–60 minutes, leads to peak plasma methylprednisolone concentrations of approximately 20 mg/mL within about 15 minutes. Approximately 25 minutes after an intravenous bolus injection of 40 mg, peak plasma methylprednisolone concentration reaches 42–47 mg/100 mL. Approximately 120 minutes after intramuscular injection of 40 mg, peak plasma methylprednisolone concentration reaches 34 mg/100 mL. The peak concentration after intramuscular injection is lower than after intravenous injection. However, plasma concentration is maintained over a longer period following intramuscular injection, resulting in equivalent systemic exposure via both routes. The clinical significance of these minor differences is likely minimal, considering the mechanism of action of glucocorticoids. Clinical response is usually observed 4–6 hours after administration. In the treatment of bronchial asthma, favorable effects may be observed as early as 1–2 hours. The plasma elimination half-life of methylprednisolone sodium succinate is 2.3–4 hours and is likely independent of the route of administration.

Methylprednisolone is a glucocorticoid with intermediate duration of action. Its biological half-life is 12–36 hours. The intracellular activity of glucocorticoids is reflected by the clear difference between the plasma elimination half-life and the pharmacological half-life. Pharmacological activity persists after the drug concentration in plasma is no longer detectable. The duration of anti-inflammatory activity of glucocorticoids approximately equals the duration of suppression of the hypothalamic-pituitary-adrenal (HPA) axis. After intravenous administration of C14-labeled methylprednisolone, 75% of total radioactivity is excreted in urine within 96 hours, 9% in feces over 5 days, and 20% in bile.

Distribution

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

Biotransformation

Hepatic metabolism of methylprednisolone is qualitatively similar to that of cortisol. Metabolites are primarily excreted in urine as glucuronides, sulfates, and unconjugated compounds.

In humans, methylprednisolone is metabolized in the liver to inactive metabolites, the main ones being 20α-hydroxymethylprednisolone and 20β-hydroxymethylprednisolone.

Hepatic metabolism occurs predominantly via the CYP3A4 enzyme (for a list of drug interactions mediated by CYP3A4 metabolism, see section "Interaction with other medicinal products and other forms of interaction").

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

Elimination

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

Special patient groups

Sex

After intravenous administration of a single dose, methylprednisolone clearance was higher in healthy women than in healthy men: 0.45 L/h/kg compared to 0.29 L/h/kg. However, no differences in pharmacodynamic parameters were observed.

Elderly patients

After intravenous administration of a single dose, methylprednisolone clearance in healthy elderly men (69–82 years) was lower than in younger men (24–37 years): 0.24 L/h/kg compared to 0.36 L/h/kg.

Children

Methylprednisolone clearance is slightly age-dependent. In younger patients, methylprednisolone metabolism generally occurs more rapidly. In a study of single intravenous dose administration in 14 patients with nephrotic syndrome, younger patients (< 13 years) showed higher clearance than older patients (> 13 years): 0.53 L/h/kg compared to 0.38 L/h/kg.

Renal impairment

In a study of single intravenous dose administration in 6 male patients with chronic renal insufficiency, the pharmacokinetics of methylprednisolone were unchanged compared to healthy control volunteers, with a mean clearance of 0.28 L/h/kg. Furthermore, no differences in pharmacodynamic parameters were observed in these patients with chronic renal insufficiency.

Hepatic impairment

In a study of single intravenous dose administration in 6 male patients with chronic hepatic insufficiency, the pharmacokinetics of methylprednisolone were similar to those in the control group of healthy volunteers, with a mean clearance of 0.29 L/h/kg.

Clinical Characteristics.

Indications.

The use of glucocorticoids should be considered only as symptomatic treatment, except for certain endocrine disorders, when they are used as replacement therapy.

Anti-inflammatory treatment

• Rheumatic diseases

As adjunctive therapy for short-term use (to help the patient through an acute episode or flare-up) in the following conditions:

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

During exacerbations or as supportive therapy in selected cases of the following conditions:

• systemic lupus erythematosus (and lupus nephritis);
• acute rheumatic carditis;
• systemic dermatomyositis (polymyositis);
• polyarteritis nodosa;
• Goodpasture syndrome.
  • Dermatological diseases:
• pemphigus;
• severe multiform erythema (Stevens–Johnson syndrome);
• exfoliative dermatitis;
• bullous dermatitis herpetiformis;
• severe seborrheic dermatitis;
• severe psoriasis;
• mycosis fungoides;
• urticaria.
  • Allergic conditions

Control of severe or disabling allergic conditions unresponsive to adequate conventional therapy in the following diseases:

• bronchial asthma;
• contact dermatitis;
• atopic dermatitis;
• serum sickness;
• hypersensitivity reactions to drugs;
• urticaria;
• acute non-infectious laryngeal edema (epinephrine is the drug of first choice).
  • Ophthalmological diseases

Severe acute and chronic allergic and inflammatory processes in the eye area, including:

• ocular form of Herpes zoster;
• iritis, iridocyclitis;
• chorioretinitis;
• diffuse posterior uveitis and choroiditis;
• optic neuritis;
• sympathetic ophthalmia;
• inflammation of the middle segment of the eye;
• allergic conjunctivitis;
• allergic corneal margin ulcers;
• keratitis.
  • Gastrointestinal tract (GIT) diseases

Critical periods in the following conditions:

• ulcerative colitis (systemic therapy);
• regional enteritis (systemic therapy).
  • Respiratory diseases:
• pulmonary sarcoidosis;
• berylliosis;
• fulminant or disseminated pulmonary tuberculosis when used concomitantly with appropriate antituberculosis chemotherapy;
• Löffler’s syndrome unresponsive to other treatments;
• aspiration pneumonitis;
• moderate to severe Pneumocystis carinii pneumonia in AIDS patients (as adjunctive therapy during the first 72 hours of anti-Pneumocystis treatment);
• exacerbation of chronic obstructive pulmonary disease.
  • Conditions associated with edema

To induce diuresis or remission of proteinuria in nephrotic syndrome, proteinuria without uremia.

Immunosuppressive treatment

• Organ transplantation

Treatment of hematological and oncological diseases

• Hematological diseases:
  • acquired (autoimmune) hemolytic anemia;
  • idiopathic thrombocytopenic purpura in adults (intravenous administration only; intramuscular administration is contraindicated);
  • secondary thrombocytopenia in adults;
  • erythroblastopenia (erythroid anemia);
  • congenital (erythroid) hypoplastic anemia.
• Oncological diseases

Palliative treatment of the following conditions:

• leukemias and lymphomas in adults;
• acute leukemia in children;
• to improve quality of life in patients with terminal-stage cancer.

Others

• Nervous system.
  • Cerebral edema due to primary or metastatic tumor, and/or as adjunctive treatment in surgical procedures or radiation therapy.
  • Exacerbations of multiple sclerosis.
  • Acute spinal cord injury. Treatment should be initiated within the first eight hours after injury.
• Tuberculous meningitis with subarachnoid space blockage or threat of blockage, when used concomitantly with appropriate antituberculosis chemotherapy.
• Trichinellosis with involvement of the nervous system or myocardium.
• Prevention of nausea and vomiting associated with chemotherapy for malignant neoplasms.

Endocrine disorders

• Primary or secondary adrenal insufficiency.
• Acute adrenal insufficiency.

In these indications, hydrocortisone or cortisone are the drugs of choice. Under certain circumstances, synthetic analogs may be used in combination with mineralocorticoids.

• Treatment of shock states: shock due to adrenal insufficiency or shock unresponsive to conventional therapy, in confirmed or suspected adrenal insufficiency (hydrocortisone is generally the drug of choice). If mineralocorticoid effects are undesirable, methylprednisolone may be preferred.
• Prior to surgical procedures and in cases of severe trauma or illness in patients with established adrenal insufficiency, or when there is doubt about adrenal reserve.
• Congenital adrenal hyperplasia.
• Nonsuppurative thyroiditis.
• Hypercalcemia associated with malignant neoplasm.

Contraindications.

Systemic fungal infections.

Hypersensitivity to methylprednisolone or to any of the excipients listed in the section "Composition".

Intrathecal administration.

Epidural administration.

Interaction with other medicinal products and other forms of interactions.

• Methylprednisolone is a substrate of cytochrome P450 (CYP) and is primarily metabolized by the CYP3A4 enzyme. CYP3A4 is the main enzyme of the most abundant CYP subfamily in the liver of adult humans. It catalyzes 6β-hydroxylation of steroids, a key phase I metabolic step for both endogenous and synthetic corticosteroids. Many other compounds, including several drugs, are also substrates of CYP3A4 and some of them have been shown to alter glucocorticoid metabolism by 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 substrates such as methylprednisolone. Therefore, to avoid steroid toxicity, methylprednisolone doses should be titrated.
• CYP3A4 INDUCERS: Medicinal products that induce CYP3A4 activity generally increase hepatic clearance, leading to reduced plasma concentrations of CYP3A4 substrates. When these drugs are used concomitantly, an increase in methylprednisolone dose may be required to achieve the desired effect.
• CYP3A4 SUBSTRATES: The presence of another CYP3A4 substrate may affect the hepatic clearance of methylprednisolone; therefore, appropriate dose adjustments may be necessary. The likelihood of adverse reactions associated with each of these medicinal products may be increased when used concomitantly.
• EFFECTS NOT MEDIATED BY CYP3A4: Other interactions and effects observed with methylprednisolone are described in the table below.

The table below lists and describes the most common and/or clinically significant interactions or interaction outcomes between methylprednisolone and other medicinal products.

Important interactions/effects when methylprednisolone is used with other medicinal products or substances

Class or type of medicinal product MEDICINAL PRODUCT or SUBSTANCE	Interaction/effect
Antibacterial agents ISONIAZID	CYP3A4 INHIBITOR. In addition, methylprednisolone may potentially enhance acetylation and clearance of isoniazid.
Antibiotics, antituberculosis agents RIFAMPICIN	CYP3A4 INDUCER
Oral anticoagulants	The effect of methylprednisolone on oral anticoagulants is variable. Both potentiation and reduction of anticoagulant effects have been reported when corticosteroids are used concomitantly. Therefore, coagulation parameters should be monitored to maintain the desired anticoagulant effect.
Anticonvulsants CARBAMAZEPINE	INDUCER (and SUBSTRATE) of CYP3A4
Anticonvulsants PHENOBARBITAL PHENYTOIN	CYP3A4 INDUCERS
Anticholinergic agents NEUROMUSCULAR BLOCKERS	Corticosteroids may affect the action of anticholinergic agents. Acute myopathy has been reported with concomitant use of high-dose corticosteroids and anticholinergic agents, particularly neuromuscular blockers (see section "Special precautions": Musculoskeletal disorders for more details). In patients receiving corticosteroids, antagonism of the neuromuscular blockade effect of pancuronium and vecuronium has been reported. This type of interaction is possible with all competitive neuromuscular blockers.
Anticholinesterase agents	Steroids may reduce the effect of anticholinesterase agents in patients with myasthenia gravis.
Antidiabetic agents	Since corticosteroids may increase blood glucose concentration, dosage adjustment of antidiabetic agents may be required.
Antiemetics APREPITANT FOSEPRAPIRANT	CYP3A4 INHIBITORS (and SUBSTRATES)
Antifungal agents ITRACONAZOLE KETOCONAZOLE	CYP3A4 INHIBITORS (and SUBSTRATES)
Antiviral agents HIV PROTEASE INHIBITORS	CYP3A4 INHIBITORS (and SUBSTRATES) Protease inhibitors, particularly indinavir and ritonavir, may increase plasma concentrations of corticosteroids. Corticosteroids may induce the metabolism of HIV protease inhibitors, thereby reducing their plasma concentrations.
Pharmacokinetic enhancers COBICISTAT	CYP3A4 INHIBITORS Pharmacokinetic enhancers inhibit CYP3A4 activity, leading to reduced hepatic clearance and increased plasma concentrations of corticosteroids. Dose adjustment of corticosteroids may be required (see section "Special precautions").
Aromatase inhibitors AMINOGlutethimide	Adrenal suppression caused by aminoglutethimide may potentiate endocrine changes induced by prolonged use of glucocorticoids.
Calcium channel blockers DILTIAZEM	CYP3A4 INHIBITOR (and SUBSTRATE)
Oral contraceptives ETHINYLESTRADIOL/NORETHISTERONE	CYP3A4 INHIBITOR (and SUBSTRATE)
GRAPEFRUIT JUICE	CYP3A4 INHIBITOR
Immunosuppressants CYCLOSPORINE	CYP3A4 INHIBITOR (and SUBSTRATE) When cyclosporine and methylprednisolone are used concomitantly, mutual inhibition of metabolism may occur, potentially leading to increased plasma concentrations of one or both drugs. The risk of adverse reactions associated with each individual drug may be increased during concomitant use. Seizures have been reported with concomitant use of methylprednisolone and cyclosporine.
Immunosuppressants CYCLOPHOSPHAMIDE TACROLIMUS	CYP3A4 SUBSTRATES
Macrolide antibiotics CLARITHROMYCIN ERYTHROMYCIN	CYP3A4 INHIBITORS (and SUBSTRATES)
Macrolide antibiotics TROLEANDOMYCIN	CYP3A4 INHIBITOR
NSAIDs (nonsteroidal anti-inflammatory drugs) high-dose acetylsalicylic acid	Concomitant use of corticosteroids and NSAIDs may increase the risk of gastrointestinal bleeding and ulceration. Methylprednisolone may increase the clearance of high-dose acetylsalicylic acid, potentially leading to reduced serum salicylate levels. Discontinuation of methylprednisolone therapy may result in increased serum salicylate concentrations, increasing the risk of salicylate toxicity. Acetylsalicylic acid should be used with caution in combination with corticosteroids in cases of hypoprothrombinemia.
Medicinal products that deplete potassium	Patients receiving corticosteroids together with potassium-depleting medicinal products (i.e., diuretics) should be closely monitored for possible development of hypokalemia. The use of glucocorticoids in combination with thiazide diuretics increases the risk of glucose intolerance. The risk of hypokalemia is also increased when corticosteroids are used concomitantly with amphotericin B, xanthines, or beta2-mimetics.

Incompatibility

To avoid compatibility and stability problems, methylprednisolone sodium succinate should be administered separately from other compounds used intravenously. Medicinal products that are physically incompatible with methylprednisolone sodium succinate in solution include (the list is not exhaustive): sodium allopurinol, doxapram hydrochloride, tigecycline, diltiazem hydrochloride, calcium gluconate, vecuronium bromide, rocuronium bromide, cisatracurium besylate, glycopyrrolate, propofol.

DRUG INTERACTIONS

In the treatment of neoplastic diseases, such as leukemia and lymphoma, methylprednisolone is usually used in combination with alkylating agents, antimetabolites, and vinca alkaloids.

Special precautions for use.

Immunosuppressive effects/increased susceptibility to infections

• Glucocorticoids may increase susceptibility to infections, mask signs of infection, and new infections may occur during their use. The use of corticosteroids may reduce the body's resistance and its ability to localize infection. Corticosteroid therapy, either as monotherapy or in combination with other immunosuppressive agents affecting cellular, humoral immunity or neutrophil function, may be associated with infections caused by any pathogen, including viruses, bacteria, fungi, protozoa, and helminths, in any part of the body. These infections may be mild but can also be severe and sometimes fatal. The frequency of infections increases with higher corticosteroid doses.
• Patients receiving immunosuppressive medicinal products are more susceptible to infections than healthy individuals. For example, varicella and measles may have a more serious course or even fatal outcomes in non-immune children or adults receiving corticosteroids.
• Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Inactivated or killed vaccines and subunit vaccines may be administered to such patients, but the immune response to these vaccines may be reduced or even absent. Immunization procedures may be performed in patients receiving non-immunosuppressive doses of corticosteroids.
• Patients receiving corticosteroid therapy should not be vaccinated against smallpox. Other immunization procedures should be avoided in patients on corticosteroid therapy, especially when high doses are used, due to possible neurological complications and altered immune response.
• In active tuberculosis, corticosteroid use should be limited to cases of fulminant or disseminated tuberculosis and must be initiated simultaneously with appropriate antituberculosis therapy. If corticosteroids are indicated in patients with latent tuberculosis or a positive tuberculin reaction, careful monitoring is required due to the risk of disease reactivation. Patients on long-term corticosteroid therapy should receive chemoprophylaxis.
• Kaposi's sarcoma has been reported in patients receiving corticosteroid therapy. Discontinuation of corticosteroid treatment may lead to clinical remission.
• The role of corticosteroids in septic shock remains controversial. Early studies reported both beneficial and harmful effects. Later, it was hypothesized that adjunctive corticosteroid therapy may benefit patients with confirmed septic shock and adrenal insufficiency. However, routine use of corticosteroids in septic shock is not recommended. One systematic review of short-term, high-dose corticosteroid use did not support their use. However, a meta-analysis and one review of published data suggest that longer courses (5–11 days) of low-dose corticosteroids may reduce mortality, particularly in patients with septic shock requiring vasopressor therapy.

Effects on the immune system

• Allergic reactions may occur. Since skin and anaphylactic/anaphylactoid reactions are rare but possible in patients receiving parenteral corticosteroid therapy, appropriate safety measures should be taken before administration, especially in patients with a history of allergy to any medicinal product.

Effects on the endocrine system

• Patients undergoing unusual stress while on corticosteroid therapy may require increased doses of fast-acting corticosteroids before, during, and after the stressful event.
  • Prolonged use of pharmacological doses of glucocorticoids 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 can be minimized by using an alternate-day dosing regimen.
  • Acute adrenal insufficiency with potentially fatal outcomes may occur following abrupt discontinuation of glucocorticoid therapy.
  • Secondary adrenal insufficiency induced by the drug can be minimized by gradual dose reduction. This relative insufficiency may persist for several months after stopping therapy; therefore, corticosteroid therapy should be reinstated during any stressful event occurring within this period.
  • Abrupt discontinuation of glucocorticoid therapy may also lead to a steroid withdrawal syndrome, which is not directly related to adrenal insufficiency. This syndrome includes symptoms such as anorexia, nausea, vomiting, lethargy, headache, fever, joint pain, skin 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, their use should be avoided in patients with this condition.
  • Corticosteroids have an enhanced effect in patients with hypothyroidism.
  • Periodic thyrotoxic periodic paralysis (PTP) may occur in patients with hyperthyroidism and hypokalemia induced by methylprednisolone. PTP should be suspected in patients receiving methylprednisolone who present with signs or symptoms of muscle weakness, especially those with hyperthyroidism. If PTP is suspected, immediate monitoring of serum potassium levels and appropriate therapy to restore normal potassium levels should be initiated.

Metabolic and nutritional disorders

• Corticosteroids, including methylprednisolone, may increase blood glucose levels, worsen the condition of patients with diabetes mellitus, and increase the risk of developing diabetes in patients on long-term corticosteroid therapy. Such patients should be treated under close medical supervision for the shortest possible duration.

Psychiatric disorders

• Psychiatric disorders may occur during corticosteroid therapy, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to overt psychotic manifestations. Corticosteroids may also exacerbate existing emotional instability or psychotic tendencies.
• Potentially severe psychiatric adverse reactions may occur during systemic steroid therapy. Symptoms typically appear within days or weeks of starting treatment. Most reactions resolve after dose reduction or discontinuation, although specific treatment may be required. Psychological effects have been reported after discontinuation of corticosteroids; frequency is unknown. Patients and caregivers should be encouraged to seek medical help if psychological symptoms develop, especially if depressive symptoms or suicidal thoughts are suspected. Patients and caregivers should be aware of possible psychiatric disorders that may develop during or immediately after dose reduction or discontinuation of systemic steroids.

Nervous system disorders

• Corticosteroids should be used with caution in patients with epilepsy.
• Corticosteroids should be used cautiously in patients with myasthenia gravis.

Although controlled clinical trials have demonstrated the efficacy of corticosteroids in accelerating recovery from acute episodes of multiple sclerosis, they do not show that corticosteroids affect the long-term outcome or natural course of the disease. However, studies indicate that relatively high doses of corticosteroids are required to achieve a significant effect.

• Serious medical events have been reported with intrathecal and epidural administration (see section "Adverse reactions").
• 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 ocular forms of herpes simplex due to the risk of corneal perforation.
• Prolonged use of corticosteroids may lead to the development of posterior subcapsular cataracts and nuclear cataracts (especially in children), exophthalmos, or elevated intraocular pressure, which may result in glaucoma with potential optic nerve damage. Corticosteroids may also lead to secondary fungal or viral eye infections.
• Visual disturbances may occur with topical or systemic corticosteroid use. If symptoms such as blurred vision or other visual disturbances occur, patients should be referred to an ophthalmologist to evaluate possible causes, including cataract, glaucoma, or rare conditions such as central serous chorioretinopathy, which has been reported with systemic or local corticosteroid use.
• Corticosteroid therapy has been associated with central serous chorioretinopathy, which may lead to retinal detachment.

Cardiac disorders

• Adverse cardiovascular effects of glucocorticoids, including dyslipidemia and arterial hypertension, may increase the risk of additional cardiovascular effects in patients receiving the drug who have other cardiovascular risk factors, especially with prolonged high-dose therapy. Therefore, corticosteroids should be used cautiously in such patients. Changes in risk profile should be monitored, and additional cardiac monitoring may be necessary. Use of low doses and alternate-day regimens may reduce the frequency of complications.
• Cardiac arrhythmia, vascular collapse, and/or cardiac arrest have been reported after rapid intravenous administration of high doses of sodium methylprednisolone succinate (more than 0.5 g within less than 10 minutes). Bradycardia has been reported during or after administration of high doses of sodium methylprednisolone succinate, which may not depend on the rate or duration of infusion.

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

Vascular disorders

• Thrombosis, including venous thromboembolism, has been observed during corticosteroid therapy. Therefore, corticosteroids should be used cautiously in patients with thromboembolic disorders or those predisposed to their development.
• Steroids should be used cautiously in patients with arterial hypertension, as this may further increase the risk of elevated blood pressure. Such patients should be treated under close medical supervision for the shortest possible duration.

Gastrointestinal disorders

• High doses of corticosteroids may cause acute pancreatitis.
• Evidence for a direct role of corticosteroids in peptic ulcer development is lacking, but glucocorticoid therapy may mask symptoms of peptic ulcer, and perforation or hemorrhage may occur without significant pain.
• Glucocorticoid therapy may mask peritonitis or other signs and symptoms of gastrointestinal disorders such as perforation, obstruction, or pancreatitis. The risk of gastrointestinal ulceration 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, or other suppurative infections; in diverticulitis, recent intestinal anastomoses, or active or latent gastric or peptic ulcers.

Hepatobiliary disorders

• Drug-induced liver injury, including acute hepatitis or elevated liver enzymes, may occur with cyclic intravenous pulse therapy of methylprednisolone (usually at initial doses ≥1 g/day). Rare cases of hepatotoxicity have been reported. The time to onset of symptoms may be several weeks or longer. In most cases, adverse reactions resolve after discontinuation of treatment. Therefore, appropriate patient monitoring is necessary.
• Enhanced glucocorticoid effects are observed in patients with cirrhosis.

Musculoskeletal and connective tissue disorders

• Acute myopathy has been reported with high-dose corticosteroid therapy, most commonly in patients with neuromuscular transmission disorders (e.g., myasthenia gravis) or those receiving concomitant therapy with anticholinergic agents, including neuromuscular blockers (e.g., pancuronium). This acute myopathy is generalized, may affect ocular 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 often unrecognized adverse reaction associated with long-term, high-dose glucocorticoid therapy.

Renal and urinary disorders

• Corticosteroids should be used with caution in patients with impaired renal function.
• Increased incidence of scleroderma renal crisis has been observed during corticosteroid therapy, including methylprednisolone. Therefore, caution should be exercised when administering the drug to patients with systemic sclerosis.

Laboratory investigations

• Moderate to high doses of hydrocortisone or cortisone may cause elevated blood pressure, salt and water retention, and increased potassium excretion. These effects are less likely with synthetic derivatives, except at high doses. Salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.
• Corticosteroid therapy should be considered when interpreting certain biological tests (e.g., skin tests, thyroid hormone levels).

Injury, poisoning, and procedural complications

• Results from a multicenter study indicate that sodium methylprednisolone succinate should not be routinely used for traumatic brain injury. The study showed increased mortality at 2 weeks and 6 months in patients receiving sodium methylprednisolone succinate compared to placebo (relative risk 1.18). A causal relationship with treatment has not been established.
• Due to the high frequency of subcutaneous atrophy, injections into the deltoid muscle should be avoided.

Others

• Since complications of glucocorticoid therapy depend on dose and duration of treatment, decisions regarding dose, frequency, and duration (daily or alternate-day) should be individualized, considering benefit and risk.
• The lowest possible corticosteroid dose should be used to control the condition, and dose reduction, when possible, should be gradual.
• Treatment duration should be as short as possible. Medical supervision is recommended during prolonged therapy (see also section "Dosage and administration"). Discontinuation of long-term therapy should also occur under medical supervision (gradual tapering, assessment of adrenal function). Key symptoms of adrenal insufficiency include asthenia, orthostatic hypotension, and depression.
• Acetylsalicylic acid and NSAIDs should be used cautiously in combination with corticosteroids.
• Exacerbation of pheochromocytoma, which may be fatal, has been reported after systemic corticosteroid use. Corticosteroids may be used in patients with suspected or confirmed pheochromocytoma only after careful benefit-risk assessment.
• Concomitant therapy with CYP3A inhibitors, including products containing cobicistat, is expected to increase the risk of systemic adverse reactions. Such combinations should be avoided unless the benefit outweighs the increased risk. In such cases, patients should be monitored for systemic corticosteroid adverse reactions (see section "Interaction with other medicinal products and other forms of interaction").

Children

Benzyl alcohol may cause allergic reactions. Intravenous administration of benzyl alcohol has been associated with serious adverse reactions and fatal "gasping syndrome" in neonates (see section "Children"). The minimal dose of benzyl alcohol that may cause toxicity is unknown. Benzyl alcohol should not be used in neonates (under 4 weeks of age) unless otherwise recommended by a physician. Benzyl alcohol should not be used for longer than 1 week due to the increased risk of accumulation in children under 3 years of age, unless otherwise recommended by a physician. Large volumes of the product should be used cautiously and only if absolutely necessary, especially in pregnant women, breastfeeding women, or individuals with hepatic or renal impairment, due to the risk of accumulation and toxicity (metabolic acidosis).

Growth and development of infants and children should be closely monitored during prolonged corticosteroid therapy. Prolonged daily glucocorticoid therapy may cause growth retardation in children; therefore, such regimens should be limited to the most serious indications. Alternate-day glucocorticoid regimens usually prevent or minimize this adverse effect.

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

High doses of corticosteroids may cause pancreatitis in children.

Cases of transient myocardial hypertrophy have been reported in preterm infants receiving corticosteroid therapy for lung disorders.

Children should be treated under close medical supervision for the shortest possible duration.

Important information about certain excipients

This product contains benzyl alcohol.

Not for use in premature infants and neonates. May cause toxic and allergic reactions in infants and children under 3 years of age.

This product contains sodium:

This medicinal product contains more than 1 mmol (23 mg) of sodium per dose. Caution is advised in patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy

Animal studies have shown that corticosteroids administered during pregnancy in high doses may cause fetal developmental abnormalities. However, corticosteroids do not cause congenital anomalies when used in pregnant women. In the absence of adequate human studies on the effect of the drug on reproductive function and fetal development, sodium methylprednisolone succinate should be used during pregnancy only after careful benefit-risk assessment for both mother and fetus. If long-term corticosteroid therapy needs to be discontinued during pregnancy (as with other long-term treatments), it should be done gradually (see also section "Dosage and administration"). However, in some cases (e.g., replacement therapy for adrenal insufficiency), continuation or even dose increase may be necessary.

Some corticosteroids readily cross the placental barrier. A retrospective study observed an increased frequency of low birth weight in infants born to mothers receiving corticosteroids. In humans, the risk of low birth weight depends on the drug dose. This risk can be minimized by using lower corticosteroid doses. Although adrenal insufficiency is rare in newborns exposed to corticosteroids in utero, careful monitoring and assessment of infants exposed to significant corticosteroid doses are recommended to detect signs of adrenal insufficiency.

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

There is no information on the effect of corticosteroids on labor and delivery.

Benzyl alcohol may cross the placental barrier (see section "Special precautions for use"). This warning does not apply to formulations that do not contain benzyl alcohol.

Breastfeeding

Corticosteroids pass into breast milk.

Corticosteroids in breast milk may suppress growth and affect endogenous glucocorticoid production in breastfed infants. This medicinal product should be used during breastfeeding only after careful benefit-risk assessment for both mother and infant.

Fertility

Animal studies have shown that corticosteroids may have an adverse effect on fertility.

Ability to influence reaction speed when driving or operating machinery.

Metirom has a negligible effect on the ability to drive or operate machinery. After corticosteroid administration, adverse effects such as dizziness, vertigo, visual disturbances, and fatigue may occur. Patients experiencing these effects should not drive or operate machinery.

Administration and Dosage

Methylprednisolone sodium succinate solution can be administered via intravenous or intramuscular injection, or by intravenous infusion. Intramuscular administration should not exceed 250 mg at one time or at a single site, as the injection volume increases to 8 ml per 500 mg accordingly. In emergency situations, intravenous injection is preferred (see the table for information on recommended doses). In adult idiopathic thrombocytopenic purpura, the drug should be administered intravenously only (intramuscular administration is contraindicated).

Recommended doses of methylprednisolone sodium succinate

Indications	Administration and Dosage
Adjunctive therapy in life-threatening conditions	The recommended dose is 30 mg/kg administered intravenously over at least 30 minutes. This dose may be repeated in a hospital setting every 4–6 hours for up to 48 hours, depending on clinical necessity (see section "Special Warnings and Precautions for Use").
PULSE THERAPY in cases of severe exacerbation and/or failure of standard therapy, including NSAIDs, gold salts, and penicillamine	Rheumatoid arthritis: 1 g/day intravenously for 1, 2, 3, or 4 days, or 1 g/month intravenously for 6 months. Due to the potential arrhythmogenic effects of high-dose corticosteroids, this therapy should be restricted to inpatient settings equipped with electrocardiographic monitoring and defibrillation capabilities. The dose should be administered intravenously over at least 30 minutes and may be repeated if symptoms do not improve within one week after therapy or if clinically indicated.
Prevention of nausea and vomiting associated with chemotherapy for malignant diseases	Chemotherapy with mild or moderate emetogenic potential: Administer Metirom 250 mg intravenously over at least 5 minutes, one hour before chemotherapy, at the beginning of chemotherapy, and after completion of chemotherapy. To enhance efficacy, chlorinated phenothiazine may be co-administered with the first dose of Metirom. Chemotherapy with high emetogenic potential: Administer Metirom 250 mg intravenously over at least 5 minutes, combined with appropriate doses of metoclopramide or butyrophenone, one hour before chemotherapy, followed by Metirom 250 mg intravenously at the start and after completion of chemotherapy.
Acute spinal cord injury	Treatment must be initiated within the first 8 hours after injury. If treatment is started within 3 hours of injury: Administer methylprednisolone at a dose of 30 mg/kg intravenously as an infusion over 15 minutes under continuous medical supervision. After the bolus injection, wait 45 minutes, then initiate continuous infusion of the drug at 5.4 mg/kg/hour for 23 hours. If treatment is initiated between 3 and 8 hours after injury: Administer methylprednisolone at a dose of 30 mg/kg intravenously as an infusion over 15 minutes under continuous medical supervision. After the bolus injection, wait 45 minutes, then initiate continuous infusion of the drug at 5.4 mg/kg/hour for 47 hours. For the infusion pump, it is preferable to use a different intravenous site than that used for the bolus injection. This rate of bolus administration is permissible only for this indication under ECG monitoring and with defibrillation equipment immediately available. Rapid intravenous bolus administration of high-dose methylprednisolone (doses exceeding 500 mg within less than 10 minutes) may lead to arrhythmias, vascular collapse, and cardiac arrest.
For other indications	The initial dose ranges from 10 to 500 mg depending on the patient's clinical condition and the nature of the disease. Higher doses may be required for short-term management of severe acute conditions such as bronchial asthma, serum sickness, urticarial transfusion reactions, and exacerbations of multiple sclerosis. Initial doses up to and including 250 mg should be administered intravenously over at least 5 minutes; doses exceeding 250 mg should be administered over at least 30 minutes. Subsequent doses may be given intravenously or intramuscularly at intervals determined by the patient's response and clinical status. Corticosteroid therapy is used as adjunctive treatment and does not replace conventional therapy.

The dose should be reduced or discontinued gradually if the drug has been administered for more than several days. If spontaneous remission occurs in a chronic disease, treatment should be discontinued. During prolonged therapy, routine laboratory tests should be performed periodically, including urine analysis, blood glucose measurement two hours after meals, as well as monitoring of blood pressure and body weight, and chest X-ray. In patients with a history of peptic ulcers or marked dyspepsia, X-ray examination of the upper gastrointestinal tract is advisable. In case of abrupt discontinuation of prolonged treatment, medical supervision is also required. For intravenous (or intramuscular) injection, the solution should be prepared according to the instructions.

Instructions for use of the vial supplied with solvent.

Under aseptic conditions, add the solvent to the vial containing the sterile powder. Use only the special solvent provided.

PREPARATION OF INFUSION SOLUTIONS

First, prepare the reconstituted solution according to the instructions. Therapy may be initiated by administering methylprednisolone sodium succinate intravenously over at least 5 minutes (for doses up to and including 250 mg) and over at least 30 minutes (for doses exceeding 250 mg). Subsequent doses may be drawn up and administered similarly. If necessary, the drug may be administered in diluted solutions by mixing the reconstituted preparation with 5% dextrose in water, normal saline, or 5% dext游戏副本

Adverse Reactions

Brief description of the safety profile

The following undesirable adverse reactions are characteristic of methylprednisolone sodium succinate. Hypersensitivity reactions may occur at the beginning of therapy (see section "Special Warnings and Precautions for Use"). Serious infections, including opportunistic infections, may also occur during corticosteroid therapy. Other adverse reactions include: seizures, pathological fractures and vertebral compression fractures, peptic ulcers with perforation or hemorrhage, tendon rupture, psychiatric disorders or symptoms, Cushing's syndrome, steroid withdrawal syndrome, arterial hypertension, myopathy, glaucoma, subcapsular cataract, decreased glucose tolerance, skin rash, fluid retention, abdominal pain, nausea, headache, and dizziness.

When contraindicated routes of administration—namely intrathecal and epidural administration—are used, the following adverse reactions have been reported: arachnoiditis, gastrointestinal/urinary bladder dysfunction, headache, meningitis, paraparesis/paraplegia, seizures, sensory disturbances. The frequency of these adverse reactions is unknown.

Infections and infestations: infections, opportunistic infections, peritonitis. Peritonitis may be the primary sign or symptom of gastrointestinal disorders such as perforation, obstruction, or pancreatitis (see section "Special Warnings and Precautions for Use").

Immune system disorders: hypersensitivity reactions (including anaphylactic and anaphylactoid reactions).

Endocrine disorders: Cushing's syndrome, hypopituitarism, steroid withdrawal syndrome.

Metabolism and nutrition disorders: metabolic acidosis, lipomatosis, sodium retention, fluid retention, hypokalemic alkalosis, dyslipidemia, impaired glucose tolerance, increased insulin or oral hypoglycemic agent requirement in diabetic patients, increased appetite (which may lead to weight gain).

Blood and lymphatic system disorders: leukocytosis.

Psychiatric disorders: affective disorders (including depression, euphoria, affective lability, drug dependence, suicidal thoughts), psychotic disorders (including mania, delusions, hallucinations, and schizophrenia), mental disturbances, confusion, anxiety, mood swings, inappropriate behavior, insomnia, irritability.

Nervous system disorders: epidural lipomatosis, increased intracranial pressure (with optic disc swelling (benign intracran游戏副本ular hypertension)), seizures, amnesia, cognitive impairment, dizziness, headache.

Eye disorders: choroidoretinopathy, cataract, glaucoma (with potential optic nerve damage), exophthalmos, blurred vision (see section "Special Warnings and Precautions for Use").

Ear and labyrinth disorders: vertigo.

Cardiac disorders: congestive heart failure (in predisposed patients), arrhythmia, myocardial rupture following myocardial infarction.

Cases of cardiac arrhythmia, vascular collapse, and/or cardiac arrest have been reported after rapid intravenous administration of high doses of methylprednisolone sodium succinate (more than 0.5 g within less than 10 minutes). Bradycardia has been reported during or after administration of high doses of methylprednisolone sodium succinate, which may be independent of the rate or duration of infusion. Tachycardia has also been reported after administration of high doses of glucocorticoids.

Vascular disorders: thrombotic events, arterial hypertension, arterial hypotension.

Respiratory, thoracic and mediastinal disorders: pulmonary artery thromboembolism, hiccups.

Gastrointestinal disorders: peptic ulcer (with risk of perforation and hemorrhage), intestinal perforation, gastrointestinal hemorrhage, pancreatitis, ulcerative esophagitis, esophagitis, abdominal distension, abdominal pain, diarrhea, dyspepsia, nausea, vomiting.

Hepatobiliary disorders: hepatitis (reported with intravenous administration), elevated liver enzymes in serum (e.g., ALT, AST).

Skin and subcutaneous tissue disorders: angioneurotic edema, hirsutism, petechiae, ecchymosis, skin atrophy, erythema, hyperhidrosis, striae, rash, pruritus, urticaria, acne, hypopigmentation of the skin. Repeated subcutaneous injections may lead to local skin atrophy at the injection site.

Musculoskeletal and connective tissue disorders: muscle weakness, myalgia, myopathy, muscle atrophy, osteoporosis, osteonecrosis, pathological fracture, neuropathic arthropathy, arthralgia, growth retardation.

Reproductive system and breast disorders: menstrual cycle disturbances.

General disorders and administration site conditions: peripheral edema, impaired wound healing, fatigue, malaise, injection site reactions.

Investigations: increased urinary calcium, decreased serum potassium, increased intraocular pressure, decreased carbohydrate tolerance, increased blood urea, increased alanine aminotransferase, increased aspartate aminotransferase, increased alkaline phosphatase in blood, suppression of skin test reactivity.

Injury, poisoning and procedural complications: vertebral compression fractures, tendon rupture.

Children

The frequency, type, and severity of adverse reactions in children are expected to be the same as in adults.

In children receiving long-term glucocorticoid therapy, growth retardation may occur (see section "Special Warnings and Precautions for Use").

Reporting of suspected adverse reactions

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

Shelf life.

2 years.

Reconstituted (ready-to-use) solution: chemical and physical stability has been demonstrated for 48 hours at a temperature not exceeding 25 °C.

From a microbiological standpoint, the solution should be used immediately. If not used immediately, the responsibility for storage conditions and duration lies with the end user.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Incompatibilities.

The compatibility and stability of methylprednisolone sodium succinate solutions for intravenous administration and their mixtures with other intravenous medicinal products depend on the pH of the mixture, concentration, time, temperature, and the solubility characteristics of methylprednisolone itself. Therefore, to avoid compatibility and stability issues, it is recommended, whenever possible, to administer methylprednisolone sodium succinate solutions separately from other medicinal products, either as an intravenous bolus injection, via an intravenous infusion system, or using a "piggy-back" system.

Packaging.

500 mg in a vial of powder, 7.8 ml solvent in an ampoule; 1 vial and 1 ampoule per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

K. T. Rompharm Company S.R.L.

Manufacturer's address and location of operations.

Strada Eroilor No. 1A, Otopeni, 075100, Ilfov County, Romania – Rompharm Building 1 and Rompharm Building 2.