Hydrocortisone rompharm

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT HYDROCORTISONE ROMPHARM (HYDROCORTISONE ROMPHARM)

Composition:

Active substance: hydrocortisone;

1 vial contains 100 mg of hydrocortisone (as hydrocortisone sodium succinate);

Excipients: sodium dihydrogen phosphate, disodium hydrogen phosphate anhydrous, 10% solution of sodium hydroxide.

Pharmaceutical form. Powder for solution for injection/infusion.

Main physico-chemical properties: white or almost white powder.

Pharmacotherapeutic group. Simple corticosteroid preparations for systemic use. Glucocorticoids. Hydrocortisone. ATC code H02AB09.

Pharmacological properties.

Pharmacodynamics.

Glucocorticoids of natural and synthetic origin are steroid hormones of the adrenal cortex.

Natural glucocorticoids (hydrocortisone and cortisone), which also possess salt-retaining properties, are used as replacement therapy in adrenal insufficiency. Their synthetic analogs are used in disorders of many organ systems, primarily due to their anti-inflammatory effect.

Hydrocortisone sodium succinate has the same metabolic and anti-inflammatory activity as hydrocortisone. After parenteral administration of equimolar amounts, both compounds demonstrate identical biological activity. The hydrocortisone sodium succinate ester has high water solubility, allowing high doses of hydrocortisone to be administered immediately intravenously in a small volume of solvent. This is particularly important when a rapid achievement of high blood levels of hydrocortisone is required. After intravenous administration of hydrocortisone sodium succinate, a noticeable effect appears within 1 hour and persists for a variable period.

Glucocorticoids produce significant and diverse metabolic effects. In addition, these agents modify the body's immune response to various stimuli.

After intravenous administration, the relative activity index of methylprednisolone sodium succinate versus hydrocortisone sodium succinate, as measured by reduction in eosinophil count, is five to one. This ratio corresponds to the relative activity index of oral methylprednisolone versus hydrocortisone.

Hydrocortisone Rompharm has the same qualitative therapeutic effects as hydrocortisone.

Mechanism of action

After penetrating the cell membrane, glucocorticoids form complexes with specific receptors in the cytoplasm. These complexes enter the nucleus, bind to DNA (chromatin), and stimulate transcription of mRNA, followed by subsequent synthesis of proteins by various enzymes. This mechanism is believed to be responsible for the systemic effects of glucocorticoids. Maximum pharmacological effects of the drug are observed before reaching peak plasma concentration, indicating that its efficacy is more related to enzyme modulation than to direct action of the drug.

Pharmacokinetics.

After intravenous administration of a single dose of hydrocortisone sodium succinate exceeding 20 mg to healthy males, nonlinear pharmacokinetics of hydrocortisone were observed. The corresponding pharmacokinetic parameters of hydrocortisone are presented in Table 1 below.

Mean pharmacokinetic parameters of hydrocortisone after intravenous administration of single doses

Table 1.

AUC0-∞ ‒ area under the curve from zero to infinity.

Absorption

At the 10th minute after intravenous administration to healthy males of single doses of hydrocortisone sodium succinate 5, 10, 20 and 40 mg, maximum drug concentrations were 312, 573, 1095 and 1854 ng/mL, respectively. Hydrocortisone sodium succinate is rapidly absorbed after intramuscular administration.

Distribution

Hydrocortisone is widely distributed in body tissues, crosses the blood-brain barrier, and penetrates into breast milk. The volume of distribution of hydrocortisone at steady state is approximately 20 to 40 L (see Table 1). Hydrocortisone binds to the glycoprotein transcortin (corticosteroid-binding globulin) and to albumin. In humans, protein binding of hydrocortisone is approximately 92%.

Biotransformation

Hydrocortisone (i.e., cortisol) is metabolized by 11β-HSD2 to cortisone and further to dihydrocortisone and tetrahydrocortisone. Other metabolites include dihydrocortisol, 5α-dihydrocortisol, tetrahydrocortisol, and 5α-tetrahydrocortisol. Cortisone can be converted back to cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1).

Hydrocortisone is also metabolized by CYP3A4 to 6β-hydroxycortisol (6β-OHF), and 6β-OHF accounts for 2.8–31.7% of all formed metabolites. This parameter demonstrates high inter-individual variability in biotransformation.

Elimination

The administered dose is almost completely eliminated within 12 hours. When hydrocortisone sodium succinate is administered via intramuscular injection, elimination is similar to that following intravenous injection.

Clinical characteristics.

Indications.

Conditions in which a rapid and intense corticosteroid effect is desired.

Endocrine disorders:

• primary or secondary adrenocortical insufficiency;
• acute adrenocortical insufficiency;
• use in the preoperative period, in case of severe trauma or illness, in patients with adrenal insufficiency or when there is doubt regarding adrenal reserve function;
• shock unresponsive to conventional therapy when adrenal insufficiency is present or suspected;
• congenital adrenal hyperplasia;
• nonpurulent thyroiditis;
• hypercalcemia associated with malignant neoplasm.

Nonendocrine disorders

Rheumatic diseases, as adjunctive therapy for short-term use (to help the patient through an acute episode or exacerbation) in the following conditions:

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

Collagenoses, during exacerbations or as supportive therapy in selected cases of the following diseases:

• acute rheumatic carditis;
• systemic dermatomyositis (polymyositis);
• systemic lupus erythematosus.

Dermatological diseases:

• bullous dermatitis herpetiformis;
• exfoliative dermatitis;
• mycosis fungoides;
• pemphigus;
• severe multiform erythema (Stevens–Johnson syndrome);
• severe forms of psoriasis;
• severe seborrheic dermatitis.

Allergic conditions: control of severe allergic conditions or allergic conditions causing loss of work capacity and unresponsive to conventional treatment, in the following:

• acute noninfectious laryngeal edema;
• atopic dermatitis;
• bronchial asthma;
• contact dermatitis;
• hypersensitivity reactions to drugs;
• seasonal or perennial allergic rhinitis;
• serum sickness;
• urticarial transfusion reactions.

Ophthalmological diseases: severe acute and chronic allergic and inflammatory processes involving the eye, such as:

• allergic conjunctivitis;
• allergic marginal corneal ulcers;
• anterior segment inflammation;
• chorioretinitis;
• diffuse posterior uveitis and choroiditis;
• ocular form of herpes zoster;
• iritis and iridocyclitis;
• keratitis;
• optic neuritis;
• sympathetic ophthalmia.

Gastrointestinal diseases: to help the patient through a critical period in the following conditions:

• ulcerative colitis (systemic therapy);
• regional enteritis (systemic therapy).

Respiratory diseases:

• aspiration pneumonitis;
• berylliosis;
• fulminant or disseminated pulmonary tuberculosis, when used concomitantly with appropriate antituberculous chemotherapy;
• Löffler’s syndrome unresponsive to other treatments;
• sarcoidosis.

Hematological diseases:

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

Neoplastic diseases, palliative treatment of the following conditions:

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

Conditions associated with edema: to induce diuresis or remission of proteinuria in nephrotic syndrome, without uremia, of idiopathic type or due to lupus.

Emergency conditions:

• shock due to adrenal insufficiency, or shock unresponsive to conventional therapy when adrenal insufficiency is possible;
• acute allergic conditions (status asthmaticus, anaphylactic reactions, insect stings, etc.) that do not resolve after epinephrine administration.

Others:

• trichinosis involving nerves or myocardium;
• tuberculous meningitis with subarachnoid block or threat of block, when used concomitantly with appropriate antituberculous chemotherapy.

Contraindications.

Sodium succinate hydrocortisone is contraindicated:

• in patients with hypersensitivity to the active substance or to any of the excipients listed in the section "Excipients";
• in patients with systemic fungal infections, acute viral and bacterial infections (see section "Special precautions for use");
• in patients with gastric or duodenal ulcer;
• in patients with tropical helminthic infections;
• for intrathecal administration, unless the drug is part of certain chemotherapy regimens (in such cases, solvents containing benzyl alcohol must not be used);
• for epidural administration;
• in patients receiving immunosuppressive doses of corticosteroids, live or attenuated vaccines are contraindicated (see section "Special precautions for use").

In idiopathic thrombocytopenic purpura in adults, intramuscular administration is contraindicated. For this indication, only intravenous administration is permitted.

Interaction with other medicinal products and other forms of interactions.

Hydrocortisone is metabolized by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) and cytochrome P450 3A4 (CYP3A4) (see section "Pharmacokinetics"). The CYP3A4 enzyme catalyzes 6β-hydroxylation of steroids, which is an important phase I metabolic step for endogenous and synthetic corticosteroids. Many other compounds are also substrates of CYP3A4. Some of them have shown effects on glucocorticoid metabolism by inducing (activating) or inhibiting the CYP3A4 enzyme.

CYP3A4 INHIBITORS. Drugs that may reduce hepatic clearance and increase plasma concentration of hydrocortisone. When using a CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, or grapefruit juice), including HIV protease inhibitors (e.g., ritonavir) and drugs enhancing hydrocortisone pharmacokinetics (e.g., drugs containing cobicistat used in HIV treatment), the dose of hydrocortisone may need to be reduced to avoid steroid toxicity.

CYP3A4 INDUCERS. Drugs that may increase hepatic clearance and reduce plasma concentration of hydrocortisone. When using a CYP3A4 inducer (e.g., rifampicin, carbamazepine, phenobarbital, or phenytoin), the dose of hydrocortisone may need to be increased to achieve the desired therapeutic response.

CYP3A4 SUBSTRATES. In the presence of another CYP3A4 substrate, hepatic clearance of hydrocortisone may change, requiring appropriate dose adjustment. Adverse effects occurring with individual use of each drug may occur more frequently when used concomitantly.

EFFECTS NOT MEDIATED BY CYP3A4. Other interactions between medicinal products and effects occurring during hydrocortisone use are described below, listing and describing the most common and/or clinically significant drug interactions or effects observed during hydrocortisone use.

Antibacterial agents: isoniazid – CYP3A4 INHIBITOR.

Antibiotics, antituberculosis agents: rifampicin – CYP3A4 INDUCER.

Oral anticoagulants: the effect of corticosteroids on oral anticoagulants may vary. Reports exist of both potentiation and reduction of anticoagulant effects when used concomitantly with corticosteroids. Coagulation parameters must be monitored to maintain the desired anticoagulant effect.

Anticonvulsants: carbamazepine – CYP3A4 INDUCER (and SUBSTRATE); phenobarbital, phenytoin – CYP3A4 INDUCERS.

Anticholinergic agents: neuromuscular blocking agents – corticosteroids may affect the action of anticholinergic drugs.

1. Cases of acute myopathy have been observed during concomitant use of high-dose corticosteroids and anticholinergic agents, such as neuromuscular blocking agents (see section "Special precautions for use. Effect on the musculoskeletal system").
2. In patients receiving corticosteroids, antagonism of neuromuscular blockade effects of pancuronium and vecuronium has been documented. This interaction may occur with all competitive neuromuscular blocking agents.

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

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

Antiemetics: aprepitant, fosaprepitant – CYP3A4 INHIBITORS (and SUBSTRATES).

Antifungal agents: itraconazole, ketoconazole – CYP3A4 INHIBITORS (and SUBSTRATES).

Antiviral agents: HIV protease inhibitors – CYP3A4 INHIBITORS (and SUBSTRATES).

1. Protease inhibitors, such as indinavir and ritonavir, may increase plasma concentrations of corticosteroids.
2. Corticosteroids may induce metabolism of HIV protease inhibitors, leading to reduced plasma concentrations of the inhibitors.

Aromatase inhibitors: aminoglutethimide – adrenal suppression caused by aminoglutethimide may exacerbate endocrine disturbances arising from prolonged glucocorticoid therapy.

Calcium channel blockers: diltiazem – CYP3A4 INHIBITOR (and SUBSTRATE).

Cardiac glycosides: digoxin – concomitant use of corticosteroids and cardiac glycosides may increase the risk of arrhythmias or toxicity of digitalis glycosides due to hypokalemia. Serum electrolyte levels, especially potassium, should be carefully monitored in all patients receiving any form of this drug combination.

Estrogens (including estrogen-containing oral contraceptives) – CYP3A4 INHIBITOR (and SUBSTRATE). Estrogens may potentiate the effects of hydrocortisone by increasing transcortin concentration, thereby reducing the amount of hydrocortisone available for metabolism. Dose adjustment of hydrocortisone may be required when estrogens are added to or withdrawn from a stable dosing regimen.

Grapefruit juice – CYP3A4 INHIBITOR.

Immunosuppressants: cyclosporine – CYP3A4 INHIBITOR (and SUBSTRATE). Concomitant use of cyclosporine and corticosteroids may increase the activity of both drugs. Seizures have been observed in patients receiving this drug combination.

Immunosuppressants: cyclophosphamide, tacrolimus – CYP3A4 SUBSTRATES.

Macrolide antibiotics: clarithromycin, erythromycin – CYP3A4 INHIBITORS (and SUBSTRATES).

Macrolide antibiotics: troleandomycin – CYP3A4 INHIBITOR.

Nonsteroidal anti-inflammatory drugs (NSAIDs): high-dose acetylsalicylic acid.

1. Concomitant use of NSAIDs and corticosteroids may increase the frequency of gastrointestinal bleeding and ulcers.
2. Corticosteroids may increase the clearance of high-dose aspirin, potentially leading to low serum salicylate levels.

Discontinuation of corticosteroids may lead to increased serum salicylate levels, increasing the risk of salicylate intoxication.

Potassium-sparing diuretics: in patients receiving corticosteroids concomitantly with potassium-wasting diuretics, careful monitoring for possible development of hypokalemia is required. An increased risk of hypokalemia also exists with combined use of corticosteroids and amphotericin B, xanthines, or β₂-adrenergic agonists. Cases of myocardial enlargement and congestive heart failure have been reported with concomitant use of amphotericin B and hydrocortisone.

Special precautions for use.

Immunosuppressive effect/Increased susceptibility to infections

Corticosteroids may increase susceptibility to infections, mask some signs of infection, and new infections may occur during corticosteroid therapy. The use of corticosteroids may also reduce the body's resistance to infections and its ability to localize infection.

Development of infections in any body site caused by various pathogens (including viral, bacterial, fungal, protozoal infections, and infections caused by helminths) may occur both with corticosteroid monotherapy and with corticosteroids used in combination with other immunosuppressive agents affecting cellular immunity, humoral immunity, or neutrophil function. Such infections may be mild but can also be severe and sometimes fatal. The frequency of infectious complications increases with higher corticosteroid doses.

Patients receiving immunosuppressants are more susceptible to infectious diseases than healthy individuals. For example, varicella (chickenpox) or measles may have a more severe course or even a fatal outcome in children or adults who have not previously had these diseases and who are receiving corticosteroids.

Live or attenuated vaccines must not be administered to patients receiving immunosuppressive doses of corticosteroids (see section "Contraindications"). Inactivated or killed vaccines may be administered to such patients, although the response to these vaccines may be reduced. Immunization procedures are indicated for patients receiving corticosteroids at non-immunosuppressive doses.

Hydrocortisone may be used in the treatment of active disseminated or fulminant tuberculosis only in combination with appropriate antituberculosis therapy. If corticosteroids are indicated for patients with latent tuberculosis or tuberculin reactivity, careful monitoring is required, as the disease may reactivate. During prolonged corticosteroid therapy, such patients should receive chemoprophylaxis.

Kaposi's sarcoma has been reported in patients receiving corticosteroids. Discontinuation of therapy may lead to clinical remission.

The role of corticosteroids in the treatment of septic shock remains controversial, as early studies showed both positive and negative outcomes. Later, adjunctive corticosteroid therapy was shown to have beneficial effects in patients with septic shock and adrenal insufficiency. However, corticosteroids are not recommended as standard therapy for septic shock. Systematic reviews of short-term, high-dose corticosteroid therapy have not provided evidence to support its benefit. However, meta-analyses and data reviews indicate that longer treatment courses (5–11 days) with low-dose corticosteroids may reduce mortality, particularly in patients with septic shock requiring vasopressor support.

Concomitant use of CYP3A inhibitors, including drugs containing cobicistat, is expected to increase the risk of systemic adverse effects. Such combinations should be avoided unless the benefit of treatment outweighs the increased risk of systemic corticosteroid side effects. Patients receiving such therapy should be monitored for signs of systemic corticosteroid adverse effects (see section "Interaction with other medicinal products and other forms of interaction").

Effect on the immune system

There is a risk of allergic reactions. Rarely, skin reactions and anaphylactic/anaphylactoid reactions (e.g., bronchospasm) have been reported in patients receiving parenteral corticosteroid therapy. Therefore, appropriate precautionary measures should be taken before administration, especially in patients with a history of allergic reactions to any medicinal products.

Effect on the endocrine system

Patients receiving corticosteroid therapy who experience unusual stress (due to surgery, trauma, or infection) should receive fast-acting corticosteroids in increased doses before, during, and after such stressful events.

Patients who have experienced significant stress after glucocorticoid therapy should be carefully monitored for symptoms of adrenal insufficiency.

Prolonged use of pharmacological doses of corticosteroids may suppress the hypothalamic-pituitary-adrenal system (secondary adrenal insufficiency). The severity and duration of induced adrenal insufficiency vary among patients and depend on the dose, frequency, timing, and duration of glucocorticoid therapy.

Additionally, abrupt discontinuation of glucocorticoids may cause acute adrenal insufficiency with potentially fatal outcomes.

Symptoms of secondary drug-induced adrenal insufficiency can be minimized by gradual dose reduction. This type of relative insufficiency may persist for several months after therapy cessation. If any stressful situation occurs during this period, hormonal therapy should be reinstated.

Abrupt withdrawal of glucocorticoids may also lead to steroid withdrawal syndrome, which is likely unrelated to adrenal insufficiency. This syndrome presents with 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 and are not related to low corticosteroid levels.

Glucocorticoids should not be used in patients with Cushing's disease, as these drugs may induce or exacerbate Cushing's syndrome.

The effect of corticosteroids is enhanced in patients with hypothyroidism. Initiation of hormone replacement therapy in patients with hyper- or hypothyroidism should be monitored during corticosteroid treatment.

Effect on metabolism and nutrition

Corticosteroids, including hydrocortisone, may increase blood glucose levels, promote the development of diabetes mellitus, or worsen pre-existing diabetes in patients receiving long-term corticosteroid therapy.

Effect on the psyche

Psychiatric disorders ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to overt psychosis may occur during corticosteroid therapy. Existing emotional instability or predisposition to psychosis may also be exacerbated.

Potentially severe psychiatric adverse reactions may occur with systemic steroid use. Symptoms typically appear within days or weeks after starting treatment. Most reactions resolve after dose reduction or drug discontinuation, although specific therapy may be required. Psychiatric disorders of unknown frequency have been reported after discontinuation of corticosteroids. Patients and caregivers should be advised to seek medical help if they notice the development of concerning psychiatric symptoms, especially mood depression or suicidal thoughts. Patients and caregivers should be warned about psychiatric disturbances that may occur during or immediately after tapering or discontinuation of systemic steroids.

Effect on the nervous system

Corticosteroids should be used with caution in patients with epileptic disorders.

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

Severe adverse events have been observed with intrathecal/epidural administration of the drug (see section "Adverse reactions").

When administered via contraindicated routes (intrathecal/epidural), adverse reactions such as arachnoiditis, gastrointestinal or bladder dysfunction, headache, meningitis, paraparesis/paraplegia, seizures, and sensory disturbances have been reported. The frequency of these events is unknown.

Epidural lipomatosis has been reported in patients receiving corticosteroids, usually after prolonged high-dose therapy.

Effect on the organs of vision

Corticosteroids should be used cautiously in patients with ocular herpes simplex due to the risk of corneal perforation. Regular ophthalmological examinations are recommended.

Prolonged corticosteroid use may lead to posterior subcapsular cataracts and nuclear cataracts (particularly in children), exophthalmos, or increased intraocular pressure, which may result in glaucoma with potential optic nerve damage. In patients receiving glucocorticoids, secondary fungal and viral eye infections may also develop more rapidly.

Visual disturbances may be reported during systemic or local corticosteroid use. If a patient experiences symptoms such as blurred vision or other visual disturbances, they should be referred for ophthalmological examination to determine possible causes, including cataract, glaucoma, or rare conditions such as central serous chorioretinopathy (CSCR), which has been reported after systemic or local corticosteroid use. CSCR may lead to retinal detachment (see section "Adverse reactions").

Effect on the heart

Undesirable effects of glucocorticoids on the cardiovascular system, such as dyslipidemia and arterial hypertension, may increase the risk of additional cardiovascular events in patients with pre-existing cardiovascular risk factors when high-dose, long-term glucocorticoid therapy is used. Therefore, corticosteroids should be used judiciously in such patients, with attention to risk modification and, if necessary, additional cardiac monitoring. Use of lower doses may reduce the frequency of corticosteroid-related complications.

Systemic corticosteroids should be used cautiously in congestive heart failure and only if absolutely necessary.

Effect on the blood vessels

Thrombosis, including venous thromboembolism, has been reported during corticosteroid therapy (see section "Adverse reactions"). Corticosteroids should be used cautiously in patients with thromboembolic disorders or predisposition to them.

Corticosteroids should be used cautiously in patients with arterial hypertension.

Effect on the gastrointestinal tract

High-dose corticosteroids may cause acute pancreatitis.

There is no direct evidence linking corticosteroid use to peptic ulcers during treatment. However, glucocorticoid therapy may mask symptoms of peptic ulcers, leading to perforation or hemorrhage without significant pain. Glucocorticoid treatment may also mask peritonitis or other gastrointestinal symptoms such as perforation, obstruction, or pancreatitis. The risk of gastrointestinal ulcers increases when corticosteroids are used concomitantly with NSAIDs.

Corticosteroids should be used cautiously in patients with nonspecific ulcerative colitis if there is a risk of perforation, abscess, or other pyogenic infection, as well as in diverticulitis, recent intestinal anastomoses, or active or latent peptic ulcers.

Effect on the hepatobiliary system

Hepatobiliary disorders, which may be reversible upon discontinuation of therapy, have been reported. Therefore, appropriate monitoring of patients is necessary.

Enhanced hydrocortisone effects may occur in patients with liver disease due to significantly impaired metabolism and elimination of the drug. Therefore, hydrocortisone dose reduction may be required to avoid steroid toxicity.

Effect on the musculoskeletal system

Acute myopathy has been reported with high-dose corticosteroid use, most commonly in patients with neuromuscular transmission disorders (e.g., myasthenia gravis) or those receiving concomitant anticholinergic agents, such as neuromuscular blockers (e.g., pancuronium). This acute myopathy is generalized, may affect ocular and respiratory muscles, and may lead to quadriparesis. Creatine kinase levels may be elevated. Clinical improvement or full recovery after discontinuation of corticosteroids may occur within weeks to years.

Osteoporosis typically occurs with prolonged use of high-dose glucocorticoids. Corticosteroids should be used cautiously in patients with osteoporosis.

Disorders of the kidneys and urinary tract

Corticosteroids should be used cautiously in patients with renal insufficiency.

Laboratory findings

Corticosteroids should be used cautiously in heart failure due to the mineralocorticoid effect of hydrocortisone.

Hydrocortisone may cause increased blood pressure, salt and water retention, and increased potassium excretion. Patients may require dietary salt restriction and potassium supplementation. All corticosteroids increase calcium excretion.

Injuries, poisoning, and procedure-related complications

Systemic corticosteroids are not indicated and should not be used in the treatment of traumatic brain injury or stroke, as they are likely to provide no benefit or may even cause harm. A multicenter study found increased mortality at 2 weeks and 6 months after traumatic brain injury in patients receiving sodium methylprednisolone succinate compared to those receiving placebo. A causal link to sodium methylprednisolone succinate treatment has not been established.

Other

Since complications of glucocorticoid therapy depend on dose and duration of treatment, the benefit-risk ratio should be assessed in each individual case, determining the drug dose, treatment duration, and whether daily or intermittent therapy should be used.

The lowest effective corticosteroid dose that controls the patient's condition should be used. If dose reduction is possible, it should be done gradually.

Acetylsalicylic acid and nonsteroidal anti-inflammatory drugs should be used cautiously in combination with corticosteroids (see section "Interaction with other medicinal products and other forms of interaction").

Tumor lysis crisis has been reported during systemic corticosteroid use, which may be fatal. Corticosteroids should be prescribed to patients with diagnosed or suspected pheochromocytoma only after careful assessment of treatment benefits and risks.

Tumor lysis syndrome

Tumor lysis syndrome (TLS) has been reported in the post-marketing period in patients with malignant tumors, particularly hematological 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 high tumor proliferation rate, high tumor burden, or high sensitivity to cytotoxic agents, should be closely monitored and appropriate preventive measures taken.

This medicinal product contains less than 1 mmol sodium (23 mg per injection vial), i.e., it is essentially "sodium-free." This medicinal product contains 0.4 mmol (9.46 mg) sodium per injection vial. This should be taken into account when administering doses exceeding 200 mg to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Use during pregnancy

There are insufficient data on the use of hydrocortisone in pregnant women.

Animal studies have shown that administration of high doses of corticosteroids, including hydrocortisone, to pregnant animals may cause fetal developmental abnormalities. However, corticosteroids do not cause congenital fetal anomalies when used in pregnant women. Since adequate studies on the effects of corticosteroids on human reproductive function have not been conducted, Hydrocortisone Rompharm may be used during pregnancy only after careful assessment of the benefit-risk ratio for mother and fetus.

Some corticosteroids readily cross the placenta. Some retrospective studies have observed an increased frequency of low birth weight in infants born to mothers who received corticosteroids. In humans, the risk of low birth weight depends on the drug dose. This risk can be minimized by using low-dose corticosteroids. Infants born to mothers who received high-dose corticosteroids should be carefully monitored for signs of adrenal insufficiency.

Cataracts have been observed in infants whose mothers received prolonged corticosteroid therapy during pregnancy.

Use during breastfeeding

Corticosteroids pass into breast milk. Hydrocortisone Rompharm should be used during breastfeeding only after careful assessment of the benefit-risk ratio for mother and child.

Reproductive function

Animal studies have shown a negative effect of corticosteroids on reproductive function.

Ability to influence reaction speed when driving or operating machinery.

The effect of corticosteroids on the ability to drive or operate machinery has not been evaluated. After corticosteroid treatment, potential adverse effects such as visual disturbances, muscle weakness, syncope, vertigo, mood changes (euphoria and depression), and seizures should be considered, as they may affect the ability to drive or operate machinery. Patients experiencing these effects should not drive or operate machinery.

Administration and Dosage

Route of administration: for intravenous or intramuscular injection, or for intravenous infusion.

For intravenous or intramuscular injection, prepare a solution by adding 2 mL of bacteriostatic water for injection to the vial containing the sterile powder (following aseptic technique). Further dilution is not required for intravenous or intramuscular injection. The solution should be shaken before use.

For intravenous infusion, prepare the solution as described above (following aseptic technique) by adding 2 mL of bacteriostatic water for injection to the vial. This solution, containing 100 mg of hydrocortisone, may be further diluted to 100–1000 mL (but not less than 100 mL) with one of the following diluents:

• 5% glucose solution;
• 0.9% sodium chloride solution for injection.

For patients on a sodium-restricted diet, 5% glucose solution should be used.

The pH of the prepared solution ranges from 7 to 8.

From a microbiological standpoint, the prepared infusion solution should be used immediately.

Parenteral preparations should be visually inspected for discoloration or particulate matter in the prepared solution. If discoloration or particulate matter is observed in the prepared solution, the product should be discarded.

For initial emergency treatment, intravenous injection is preferred. After initial emergency management, longer-acting injectable or oral corticosteroids should be considered. Treatment should begin with intravenous administration over a period of 30 seconds to 10 minutes (e.g., initial dose of hydrocortisone sodium succinate equivalent to 100 mg of hydrocortisone, or up to 500 mg or more). High-dose corticosteroid therapy should be continued until the patient's condition stabilizes—usually no longer than 48–72 hours. Although adverse effects are highly associated with high-dose use, peptic ulceration may also occur during short-term corticosteroid therapy. Therefore, prophylactic therapy with antacids may be recommended.

If high-dose hydrocortisone therapy is required for longer than 48–72 hours, hypernatremia may develop. Under such conditions, it is advisable to replace Hydrocortisone Rompharm with a corticosteroid containing methylprednisolone sodium succinate, which causes minimal or no sodium retention.

The initial dose of Hydrocortisone Rompharm, equivalent to hydrocortisone sodium succinate, ranges from 100 mg to 500 mg (or more), depending on the severity of the condition.

This dose may be repeated at intervals of 2, 4, or 6 hours, depending on the patient's response to treatment and clinical status. Patients who have undergone significant stress following corticosteroid therapy should be closely monitored for signs and symptoms of adrenal insufficiency.

Corticosteroid therapy is used as an adjunct and does not replace conventional therapy.

In patients with liver disease, the effect may be enhanced (see section "Special Warnings and Precautions for Use"), and dose reduction may be considered for such patients.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Children.

The dose of the medicinal product may be reduced in children, including infants; however, dosing should be based primarily on the severity of the condition and the patient's response to therapy, rather than age or body weight. The daily dose should not be less than 25 mg (see section "Special Warnings and Precautions for Use").

When corticosteroids are used long-term, careful monitoring of a child's growth and development is essential.

In children receiving prolonged glucocorticoid therapy several times daily, growth retardation may occur. Such treatment regimens should be limited to the most serious indications.

Children receiving long-term corticosteroid therapy are at particular risk of increased intracranial pressure.

High-dose corticosteroids may induce pancreatitis in children.

Cases of hypertrophic cardiomyopathy have been reported following hydrocortisone administration in premature infants; therefore, appropriate diagnostic evaluation and monitoring of cardiac function and structure are recommended.

Overdose.

There is no specific clinical syndrome of hydrocortisone sodium succinate overdose. Repeated, frequent administration (daily or several times per week) over a prolonged period may lead to the development of Cushing's syndrome.

In case of overdose, symptomatic and supportive treatment should be administered.

There is no specific antidote.

Hydrocortisone is dialyzable.

Adverse Reactions

The adverse reactions listed below are typical for all systemic corticosteroids. Their inclusion in this list does not necessarily mean that the specific event was observed with this particular medicinal product.

Information on the frequency of adverse reactions is lacking.

Glucocorticoid therapy may even at low doses cause the following adverse effects:

Infections and infestations: Opportunistic infections, latent infections, infectious diseases (exacerbation of infection, including reactivation of tuberculosis).

Benign, malignant and unspecified neoplasms (including cysts and polyps): Kaposi's sarcoma, pheochromocytoma crisis.

Blood and lymphatic system disorders: Leukocytosis.

Immune system disorders: Hypersensitivity reactions, anaphylactic reactions, anaphylactoid reactions.

Endocrine disorders: Cushing's syndrome, hypopituitarism, steroid withdrawal syndrome, suppression of the hypothalamic-pituitary-adrenal axis.

Metabolism and nutrition disorders: Metabolic acidosis, sodium retention, fluid retention, hypokalemic alkalosis; dyslipidemia, impaired glucose tolerance; increased insulin requirement (or requirement for oral hypoglycemic agents in diabetes mellitus), worsening of pre-existing diabetes mellitus, lipomatosis, increased appetite (which may lead to weight gain).

Psychiatric disorders: Affective disorders (including depression, euphoria, affective lability, drug dependence, suicidal ideation), psychotic disorders (including mania, delusions, hallucinations, and schizophrenia), mental disorders, personality changes, anxiety, confusion, mood swings; pathological behavior, insomnia, irritability, exacerbation of pre-existing psychotic behavior.

Nervous system disorders: Epidural lipomatosis, increased intracranial pressure, benign intracranial hypertension, seizures, amnesia, cognitive disorders, dizziness, headache.

Eye disorders: Central serous chorioretinopathy; cataract, glaucoma, exophthalmos, blurred vision (see section "Special precautions for use").

Ear and labyrinth disorders: Vertigo.

Cardiac disorders: Congestive heart failure (in predisposed patients), hypertrophic cardiomyopathy in premature newborns.

Vascular disorders: Thrombosis, arterial hypertension and hypotension.

Respiratory, thoracic and mediastinal disorders: Pulmonary embolism, gasping syndrome, hiccups.

Gastrointestinal disorders: Peptic ulcer (with possible perforation and hemorrhage), intestinal perforation, gastric bleeding, pancreatitis, esophagitis, abdominal distension, abdominal pain, diarrhea, dyspepsia, nausea.

Skin and subcutaneous tissue disorders: Angioneurotic edema, hirsutism, petechiae, ecchymosis, skin atrophy, erythema, hyperhidrosis, striae, rash, pruritus, urticaria, acne, hypopigmentation of the skin.

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

Reproductive system and breast disorders: Irregular menstrual cycle.

General disorders and administration site conditions: Impaired healing, peripheral edema, fatigue, weakness, injection site reactions.

Investigations: Increased intraocular pressure, decreased carbohydrate tolerance, elevated blood glucose, decreased serum potassium, increased urinary calcium, increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, increased blood urea; suppression of skin test reactions*, weight gain.

Injury, poisoning and procedural complications: Spinal compression fracture, tendon rupture.

* Not included in the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions in accordance with local requirements.

Shelf life.

30 months.

Storage conditions.

Store in the original packaging to protect from light at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Incompatibilities.

This medicinal product should not be mixed with other medical products except those mentioned in the section "Dosage and administration".

Packaging.

Powder in a vial, 1 vial in a cardboard pack; 5 vials in a blister, 2 blisters in a cardboard pack.

Prescription status. Prescription only.

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

Manufacturer's address and place of business.

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