Hydrocortisone acetate

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HYDROCORTISONE ACETATE (HYDROCORTISONI ACETAS)

Composition:

Active ingredient: hydrocortisone;

1 ml of suspension contains hydrocortisone acetate equivalent to 100% dry substance 25 mg;

Excipients: propylene glycol, sorbitol (E 420), povidone, sodium chloride, benzyl alcohol, water for injections.

Pharmaceutical form. Injectable suspension.

Main physicochemical properties: after shaking for 2 minutes, the preparation is a white or white with yellowish tint suspension, which settles on standing, with a specific odor.

Pharmacotherapeutic group. Corticosteroids for systemic use, plain preparations. Hydrocortisone. ATC code H02AB09.

Pharmacological Properties

Pharmacodynamics

Hydrocortisone acetate belongs to the group of naturally occurring glucocorticosteroids. It exerts anti-shock, antitoxic, immunosuppressive, antiexudative, antipruritic, anti-inflammatory, desensitizing, and anti-allergic effects. It suppresses hypersensitivity reactions, as well as proliferative and exudative processes at the site of inflammation. The action of hydrocortisone acetate is mediated through specific intracellular receptors. Its anti-inflammatory effect involves inhibition of all phases of inflammation: stabilization of cellular and subcellular membranes, reduction in the release of proteolytic enzymes from lysosomes, and inhibition of superoxide anion and other free radical formation. Hydrocortisone inhibits the release of inflammatory mediators, including interleukin-1 (IL-1), histamine, serotonin, and bradykinin; reduces the release of arachidonic acid from phospholipids and suppresses the synthesis of prostaglandins, leukotrienes, and thromboxanes. It decreases inflammatory cellular infiltrates and reduces migration of leukocytes and lymphocytes into the inflammatory site. It suppresses connective tissue reactions during the inflammatory process and reduces the intensity of scar tissue formation. It decreases the number of mast cells producing hyaluronic acid, inhibits hyaluronidase activity, and promotes reduced capillary permeability. It inhibits collagenase production and enhances synthesis of protease inhibitors. It reduces protein synthesis and enhances protein catabolism in muscle tissue. By stimulating steroid receptors, it induces the formation of a specific class of proteins—lipocortins—which possess anti-edematous activity. It exerts anti-insulin effects, increasing glycogen levels in the liver and leading to hyperglycemia. It promotes sodium and water retention in the body, thereby increasing blood volume and elevating arterial pressure (anti-shock effect). It stimulates potassium excretion, reduces calcium absorption from the gastrointestinal tract, and decreases bone tissue mineralization.

Like other glucocorticoids, hydrocortisone reduces the number of T-lymphocytes in the blood, thereby diminishing the influence of T-helper cells on B-lymphocytes, inhibits immune complex formation, and reduces manifestations of allergic reactions.

Pharmacokinetics

Hydrocortisone administered topically may be absorbed and produce systemic effects. It is absorbed relatively slowly from the site of administration. Up to 90% of the drug is bound to plasma proteins (80% to transcortin and 10% to albumins), with approximately 10% remaining as free fraction. Metabolism occurs in the liver. In contrast to synthetic derivatives, only a small amount of the drug crosses the placenta (up to 67% is inactivated within the placenta itself to inactive metabolites). Hydrocortisone metabolites are primarily excreted by the kidneys.

Clinical characteristics.

Indications.

Osteoarthritis, various monoarthritides (of the knee, elbow, and hip joints), rheumatoid arthritis and arthritis of other origins (except tuberculosis and gonococcal arthritis). Periarthritis of the shoulder and scapula, bursitis, epicondylitis, tenosynovitis.

Prior to surgery on ankylosed joints.

As a local adjunct to systemic corticosteroid therapy.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Systemic infections (unless specific anti-infective therapy is administered).

Patients who have been vaccinated with live vaccines.

Intra-articular and periarticular injections of this medicinal product are contraindicated if the joint or surrounding tissues are infected. The presence of infection is also a contraindication for injections into tendon sheaths and bursae. The drug must not be injected directly into tendons, or into the spine or other non-arthrodial joints.

Interaction with other medicinal products and other forms of interaction.

Metabolism of corticosteroids may be increased, and therapeutic effects reduced, by some barbiturates (e.g., phenobarbital) and phenytoin, rifampicin, rifabutin, primidone, carbamazepine, and aminoglutethimide.

Mifepristone may reduce the effect of corticosteroids for 3–4 days.

Erythromycin and ketoconazole may inhibit corticosteroid metabolism.

Ritonavir may increase plasma concentrations of hydrocortisone acetate.

Estrogens and other oral contraceptives increase plasma concentrations of corticosteroids, and dose adjustment may be required when oral contraceptives are added or discontinued during a stable dosing regimen.

Concomitant treatment with CYP3A inhibitors, including drugs containing cobicistat, is expected to increase the risk of systemic adverse effects. This combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side effects; in such cases, patients should be monitored for the development of systemic corticosteroid effects.

Concomitant use with corticosteroids may suppress the growth-promoting effect of somatropin.

Corticosteroids may counteract the expected effects of hypoglycemic agents (including insulin), antihypertensives, and diuretics.

The effectiveness of coumarin anticoagulants may depend on concomitant corticosteroid therapy; careful monitoring of INR or prothrombin time is required to prevent spontaneous bleeding.

Serum levels of salicylates (acetylsalicylic acid and benorilate) may rise significantly upon discontinuation of corticosteroid therapy, potentially leading to intoxication. Concurrent use of salicylates or nonsteroidal anti-inflammatory drugs (NSAIDs) with corticosteroids increases the risk of gastrointestinal bleeding and ulcers.

Hypokalemic effects of acetazolamide, loop diuretics, thiazide diuretics, and carbenoxolone are potentiated by corticosteroids; signs of hypokalemia should be monitored during concomitant use. The risk of hypokalemia increases with concomitant use of theophylline and amphotericin. Corticosteroids should not be administered concomitantly with amphotericin unless required for reaction control.

The risk of hypokalemia also increases when high doses of corticosteroids are administered with high doses of sympathomimetics, such as bambuterol, fenoterol, formoterol, ritodrine, salbutamol, salmeterol, and terbutaline. The toxicity of cardiac glycosides, such as digoxin, increases in the presence of hypokalemia.

Concomitant use of methotrexate may increase the risk of hematological toxicity.

High doses of corticosteroids impair immune response; therefore, administration of live vaccines should be avoided (see section "Special precautions").

Special precautions for use.

Since joints and tissues are more susceptible to infection following corticosteroid injections, local injections of this medicinal product must be administered under aseptic conditions.

Adrenal suppression

Adrenal cortical atrophy develops during prolonged therapy and may persist for years after discontinuation of treatment. Therefore, withdrawal of corticosteroids after long-term therapy should always be gradual to avoid acute adrenal insufficiency, with dosage tapered gradually over weeks or months depending on the dose and duration of treatment. During prolonged therapy, any intercurrent illness, trauma, or surgical intervention requires temporary dose increase. If corticosteroid therapy has been discontinued after prolonged treatment, temporary reinitiation may be necessary.

Patients should be given clear instructions regarding preventive measures to minimize risk, including detailed information about the prescribing physician, the medicinal product, dosage, and duration of treatment.

Anti-inflammatory/immunosuppressive effects and infection

Suppression of inflammatory response and immune function increases susceptibility to infections and their severity. Clinical presentation is often atypical, and serious infections such as septicemia and tuberculosis may be masked and reach an advanced stage before recognition. New infections may occur during corticosteroid use.

Varicella (chickenpox) is of particular concern, as this usually mild disease may lead to fatal outcomes in immunocompromised patients. Patients (or parents of children) with uncertain history of varicella should be advised to avoid close personal contact with individuals with varicella or herpes zoster, and to seek urgent medical attention if exposed. Passive immunization with varicella/zoster immune globulin is required for patients who have been in contact with infected individuals, are immunocompromised, and are receiving systemic corticosteroids or have received them within the previous 3 months; if exposure is confirmed, the disease requires specialized care and urgent treatment. Corticosteroid therapy should not be discontinued, and dose increase may be necessary.

Patients should be advised to exercise special caution to avoid contact with measles and to seek immediate medical attention if exposure occurs. Prophylaxis with normal intramuscular immunoglobulin may be required.

Live vaccines should not be administered to individuals with immunosuppression caused by high-dose corticosteroids. Inactivated vaccines or toxoids may be administered, although their efficacy may be reduced.

Special caution and frequent monitoring are required when prescribing systemic corticosteroids to patients with the following conditions:

• History of tuberculosis or characteristic radiographic findings in chest X-ray. However, development of active tuberculosis may be prevented by prophylactic antituberculosis therapy;
• Diabetes mellitus (or family history of diabetes);
• Osteoporosis (postmenopausal women are particularly at risk);
• Hypertension or congestive heart failure;
• Presence or history of severe affective disorders (especially steroid-induced psychosis);
• Glaucoma (or family history of glaucoma);
• Previous corticosteroid-induced myopathy;
• Peptic ulcer disease;
• Epilepsy;
• Hepatic insufficiency;
• Renal insufficiency.

Large volumes should be used cautiously and only when necessary, especially in patients with impaired liver or kidney function due to the risk of accumulation and toxicity (metabolic acidosis).

Recent myocardial infarction

Patients should be monitored for psychotic reactions, muscle weakness, electrocardiographic changes, hypertension, and adverse hormonal effects during treatment.

Corticosteroids should be used with caution in patients with hypothyroidism.

Children

Corticosteroids may cause growth retardation in early childhood, childhood, and adolescence; this may be irreversible. Treatment should be limited to the minimum effective dose for the shortest possible duration to minimize suppression of the hypothalamic-pituitary-adrenal (HPA) axis and growth retardation (see section "Dosage and administration").

Increased risk of accumulation in young children.

Geriatric patients

General adverse effects of systemic corticosteroids may have more serious consequences in the elderly, particularly osteoporosis, hypertension, hypokalemia, diabetes, susceptibility to infections, and skin thinning. Careful clinical monitoring is required to avoid life-threatening reactions (see section "Dosage and administration").

Withdrawal symptoms

In patients who have received systemic corticosteroid doses above physiological levels (approximately 40 mg of cortisone or equivalent) for more than 3 weeks, discontinuation should not be abrupt. The method of dose reduction depends largely on the likelihood of disease relapse upon tapering systemic corticosteroids. Clinical assessment of disease activity may be required during withdrawal. If disease recurrence is unlikely upon discontinuation of systemic corticosteroids, but there is uncertainty regarding HPA axis suppression, the systemic corticosteroid dose may be rapidly reduced to physiological levels. Once a daily dose equivalent to 40 mg of cortisone is reached, the dose should be reduced more slowly to allow HPA axis recovery.

Abrupt discontinuation of systemic corticosteroid therapy lasting up to 3 weeks may be appropriate if disease recurrence is unlikely. Abrupt cessation of cortisone at doses up to 200 mg daily or equivalent for up to 3 weeks is unlikely to cause clinically significant HPA axis suppression in most patients. Gradual withdrawal of systemic corticosteroid therapy should be considered even after treatment courses of 3 weeks or less in the following patient groups:

• Patients who have had repeated courses of systemic corticosteroids, especially if lasting more than 3 weeks;
• Short courses within 1 year after discontinuation of long-term therapy (months or years);
• Patients who may have causes of adrenal insufficiency unrelated to exogenous corticosteroid therapy;
• Patients receiving systemic corticosteroid doses exceeding 200 mg of cortisone per day (or equivalent);
• Patients receiving repeated evening doses.

Patients and/or caregivers should be warned that potentially serious psychiatric adverse reactions may occur with systemic corticosteroid use (see section "Adverse reactions"). Symptoms typically appear within days or weeks of starting treatment. Risk may be higher with high doses/systemic exposure (see section "Interaction with other medicinal products and other forms of interaction"), although dose levels do not reliably predict onset, type, severity, or duration of reactions. Most adverse reactions resolve after dose reduction or discontinuation, although specific treatment may be required. Patients and caregivers should be advised to consult a physician if concerning psychological symptoms occur, especially if depression or suicidal thoughts are suspected. Patients and caregivers should also be aware of possible psychiatric disorders that may occur during or immediately after dose reduction/discontinuation of systemic corticosteroids, although such reactions are infrequently reported.

Special caution is required when considering systemic corticosteroid use in patients with current or past severe affective disorders, either in themselves or in first-degree relatives. These include depressive or bipolar disorders and previous steroid psychosis.

Visual disturbances

Visual disturbances may occur with both systemic and local corticosteroid use. If a patient develops symptoms such as blurred vision or other visual disturbances, the patient should be referred to an ophthalmologist for evaluation of possible causes, which may include cataract, glaucoma, or rare conditions such as central serous chorioretinopathy, which has been reported after use of systemic and local corticosteroids.

This medicinal product contains sorbitol. If the patient has been diagnosed with intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

This medicinal product contains benzyl alcohol and therefore must not be used in preterm infants and newborns. It may cause toxic and allergic reactions in infants and children under 3 years of age.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

The ability of corticosteroids to cross the placenta varies among individual agents, but cortisone readily crosses the placenta.

Administration of corticosteroids to pregnant animals may cause fetal developmental abnormalities, including cleft palate, intrauterine growth retardation, and effects on brain growth and development. There is no evidence that corticosteroids increase the frequency of congenital anomalies such as cleft palate/lip in humans, but prolonged or repeated use during pregnancy may increase the risk of intrauterine growth retardation. Neonates exposed to corticosteroids in utero may theoretically experience adrenal hypofunction, but this usually resolves spontaneously after birth and is not clinically significant. Corticosteroids should be prescribed only when benefit to mother and child outweighs risks. However, when corticosteroid use is critically important, pregnant women with normal pregnancy course should be treated the same as non-pregnant patients.

Breastfeeding

Corticosteroids pass into breast milk, although there are no data for cortisone. Doses up to 200 mg of cortisone daily are unlikely to cause systemic effects in the infant. Infants exposed to higher doses may experience adrenal suppression, but the benefits of breastfeeding may outweigh the theoretical risk.

Ability to influence reaction speed when driving or operating machinery.

Negligible.

Method of Administration and Dosage

Before use, shake the contents of the ampoule until a homogeneous suspension is formed.

Adults and children aged 14 years and older: The single dose depends on the size of the joint and the severity of the disease – 5–50 mg of hydrocortisone administered intra-articularly and periarticularly.

Within 24 hours, adults may receive injections in no more than 3 joints.

Children: The single dose of hydrocortisone depends on the size of the joint and the severity of the disease – 5–30 mg administered intra-articularly and periarticularly.

Elderly patients: Steroids should be used with caution due to increased risk of adverse effects.

The therapeutic effect after intra-articular administration of the drug develops within 6–24 hours and lasts from several days to several weeks. Re-administration of the drug may be performed no sooner than 3 weeks after the previous injection.

The drug must not be injected directly into tendons; in cases of tendinitis, it should be administered into the tendon sheath.

The drug must not be used for systemic corticosteroid therapy.

Children.

Corticosteroids may cause growth retardation in early childhood, childhood, and adolescence, which may be irreversible. Treatment should be limited to the minimum effective dose for the shortest possible duration to minimize suppression of the hypothalamic-pituitary-adrenal axis and growth retardation (see section "Method of Administration and Dosage").

There is an increased risk of drug accumulation in young children.

This medicinal product contains benzyl alcohol and therefore must not be used in premature infants and newborns. It may cause toxic and allergic reactions in infants and children under 3 years of age.

Overdose.

Symptoms

Overdose is unlikely with this medicinal product, and there is no specific antidote. Overdose may cause nausea and vomiting, sodium and water retention, hyperglycemia, and occasionally gastrointestinal bleeding.

Treatment

Treatment should be symptomatic. However, to prevent gastrointestinal bleeding, cimetidine (200–400 mg given by slow intravenous injection every 6 hours) or ranitidine (50 mg given by slow intravenous injection every 6 hours) may be administered.

Adverse reactions.

With intra-articular or other local injections, the main adverse effect is temporary local exacerbation with increased pain and swelling, which usually subsides within a few hours.

Under certain circumstances, especially following high or prolonged local doses, corticosteroids may be absorbed in quantities sufficient to produce systemic effects.

The frequency of predicted adverse effects, including hypothalamic-pituitary-adrenal suppression, correlates with the relative potency of the drug, dosage, frequency of administration, and duration of treatment (see section "Special precautions").

Adverse effects are particularly likely at the beginning of treatment or when the dose is increased.

All adverse reactions are listed by system organ classes and frequency of occurrence: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), and not known – frequency cannot be estimated from the available data.

(a) Reactions occur frequently and may occur in both adults and children. The frequency of severe reactions in adults is estimated at 5–6%. Psychological effects were reported upon discontinuation of corticosteroids; psychological dependence occurred; frequency unknown.

Withdrawal symptoms

Rapid reduction of corticosteroid dosage after prolonged use may lead to acute adrenal insufficiency, arterial hypotension, and fatal outcome (see section "Special precautions"). Withdrawal syndrome may also manifest as fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful pruritic skin nodules, and weight loss.

Shelf life. 3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Freezing is not permitted. Keep out of reach of children.

Incompatibility. The medicinal product must not be mixed with other medicinal products in the same container.

Packaging. 2 ml in a vial; 10 vials in a pack. 2 ml in a vial; 5 vials in a blister pack; 2 blisters in a pack.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.