Prednisolone-darnitsa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PREDNISOLONE-DARNITSA (PREDNISOLONE-DARNITSA)

Composition:

Active substance: prednisolone;

1 tablet contains 5 mg of prednisolone;

Excipients: lactose monohydrate, potato starch, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white, flat cylindrical tablets with beveled edges.

Pharmacotherapeutic group. Hormonal drugs for systemic use. Simple corticosteroids for systemic use. Glucocorticoids.

ATC code: H02AB06.

Pharmacological properties.

Pharmacodynamics.

Prednisolone is a dehydrogenated analogue of hydrocortisone. It exerts anti-inflammatory, anti-allergic, desensitizing, anti-shock, and immunosuppressive effects. When prednisolone is administered, the drug's effects are realized through stabilization of cell membranes, inhibition of macrophage accumulation, reduction of leukocyte migration, and decreased capillary permeability, thereby preventing edema formation. Prednisolone suppresses phagocytosis, affects arachidonic acid metabolism, and also influences the synthesis and release of inflammatory mediators. The immunosuppressive effect of prednisolone is due to suppression of T- and B-lymphocyte activity, reduction of complement levels in blood, and inhibition of interleukin-2 production and effects. It exerts a catabolic effect and increases blood glucose levels. Prednisolone exhibits some mineralocorticoid activity, enhancing renal tubular reabsorption of Na+ and water, while increasing excretion of K+ and Ca2+ from the body, especially when their plasma levels are elevated. Prednisolone suppresses the synthesis and secretion of adrenocorticotropic hormones by the pituitary gland and, secondarily, glucocorticosteroids by the adrenal glands.

Pharmacokinetics.

Rapidly absorbed from the gastrointestinal tract. Has high bioavailability. Time to reach maximum plasma concentration – 1–1.5 hours. A significant portion of the drug (90%) binds to corticosteroid-binding globulin (transcortin) and albumin. Metabolized in the liver, kidneys, small intestine, and bronchi. Oxidized forms of prednisolone are glucuronidated or sulfated. Elimination half-life (T_1/2) – 2–4 hours. Excreted primarily by the kidneys as metabolites, with up to 20% excreted unchanged.

Clinical characteristics.

Indications.

Rheumatic fever, rheumatic carditis, chorea minor.

Connective tissue diseases (systemic lupus erythematosus, scleroderma, polyarteritis nodosa, dermatomyositis).

Multiple sclerosis.

Acute and chronic inflammatory joint diseases (rheumatoid arthritis, juvenile arthritis, ankylosing spondylitis, gouty and psoriatic arthritis, polyarthritis, periarthritis of shoulder and scapula, osteoarthritis (including post-traumatic), adult-onset Still's syndrome, bursitis, nonspecific tenosynovitis, synovitis, epicondylitis).

Bronchial asthma, status asthmaticus.

Interstitial lung diseases (acute alveolitis, pulmonary fibrosis, sarcoidosis stage II–III), lung cancer (in combination with cytostatics), berylliosis, aspiration pneumonia (in combination with specific therapy), Löffler's eosinophilic pneumonia, tuberculosis (pulmonary tuberculosis, tuberculous meningitis) – in combination with specific therapy.

Primary and secondary adrenal insufficiency (including post-adrenalectomy states), congenital adrenal hyperplasia, adrenogenital syndrome, subacute thyroiditis.

Acute and chronic allergic disorders (drug and food allergies, serum sickness, pollinosis, atopic dermatitis, contact dermatitis involving large body surface area, urticaria, allergic rhinitis, Quincke's edema, Stevens-Johnson syndrome, toxicoderma).

Hepatitis.

Hypoglycemic conditions.

Autoimmune diseases (including acute glomerulonephritis).

Nephrotic syndrome.

Inflammatory gastrointestinal disorders (ulcerative colitis, Crohn's disease, localized enteritis).

Blood and hematopoietic organ disorders (agranulocytosis, pancytopenia, multiple myeloma, acute lymphoid and myeloid leukemia, lymphogranulomatosis, thrombocytopenic purpura, secondary thrombocytopenia in adults, autoimmune hemolytic anemia, erythroblastopenia, congenital erythroid hypoplastic anemia).

Autoimmune and other skin disorders (eczema, seborrheic dermatitis, psoriasis, Lyell's syndrome, bullous dermatitis herpetiformis, pemphigus, exfoliative dermatitis).

Cerebral edema postoperative, post-radiation, post-traumatic, associated with brain tumor (to be used after parenteral glucocorticosteroids).

Eye diseases, including allergic and autoimmune conditions (sympathetic ophthalmia, allergic forms of conjunctivitis, allergic corneal ulcer, non-infectious keratitis, iridocyclitis, iritis, severe chronic anterior and posterior uveitis, choroiditis, optic neuritis).

Prevention of transplant rejection.

Hypercalcemia associated with malignancies.

For prevention and relief of nausea and vomiting during cytostatic therapy.

Contraindications.

Hypersensitivity to components of the drug.

Parasitic and infectious diseases of viral, fungal, or bacterial etiology currently present or recently resolved: herpes simplex, herpes zoster (viremic phase), varicella, measles; amebiasis, strongyloidiasis (confirmed or suspected); systemic mycosis; active or latent tuberculosis.

Post-vaccination period (duration of 10 weeks: 8 weeks before and 2 weeks after vaccination), lymphadenitis following BCG vaccination.

Immunodeficiency states caused by HIV infection.

Gastrointestinal disorders: gastric and duodenal ulcer, esophagitis, gastritis, acute or latent peptic ulcer, recently created intestinal anastomosis, ulcerative colitis with risk of perforation or abscess formation, diverticulitis.

Cardiovascular disorders: recent myocardial infarction, decompensated chronic heart failure, arterial hypertension, predisposition to thromboembolic disease.

Endocrine disorders: diabetes mellitus and impaired glucose tolerance, thyrotoxicosis, hypothyroidism, Cushing's disease.

Severe chronic renal and/or hepatic insufficiency, nephrolithiasis.

Hypoalbuminemia. Systemic osteoporosis. Myasthenia gravis. Acute psychosis. Obesity (grade III–IV). Poliomyelitis (except bulbar encephalitis form). Open-angle and closed-angle glaucoma.

Interaction with other medicinal products and other types of interactions.

Concomitant use of prednisolone with other medicinal products may result in:

With thyroid hormones, hepatic enzyme inducers, including barbiturates, phenytoin, pyrimethamine, carbamazepine, rifampicin – reduced effects of prednisolone due to increased systemic clearance.

With estrogens (including oral contraceptives containing estrogen), cyclosporine, CYP3A4 inhibitors such as erythromycin, clarithromycin, ketoconazole, diltiazem, aprepitant, itraconazole, oleandomycin – enhanced therapeutic and toxic effects of prednisolone.

With antacids – reduced absorption of prednisolone.

With salicylate derivatives and other nonsteroidal anti-inflammatory drugs – increased risk of gastric mucosal ulceration; prednisolone decreases serum levels of salicylate derivatives, increasing their renal clearance; the drug increases the risk of hepatotoxic reactions of paracetamol due to induction of hepatic enzymes and formation of its toxic metabolite.

With cardiac glycosides – enhanced toxicity of the latter, and due to induced hypokalemia – increased risk of arrhythmias.

With hypoglycemic agents – suppression of hypoglycemic effect of oral antidiabetic agents and insulin.

With antihypertensive drugs – reduced effectiveness of the latter.

With tricyclic antidepressants – enhanced depressive symptoms caused by prednisolone and increased intraocular pressure.

With immunosuppressants – increased risk of infections and development of lymphoma or other lymphoproliferative disorders associated with Epstein-Barr virus.

With diuretics, laxatives, amphotericin B – increased risk of hypokalemia; prednisolone enhances the risk of osteoporosis when used concomitantly with amphotericin B and carbonic anhydrase inhibitors.

With M-cholinoblockers, antihistamines, nitrates – increased intraocular pressure and reduced effectiveness of antihistamines.

With neuroleptics, carbamazepine, azathioprine – increased risk of cataract development.

With estrogens, anabolic agents, oral contraceptives – manifestations of hirsutism and acne.

With live antiviral vaccines and other types of immunization – increased risk of viral activation and infection development.

With muscle relaxants in the context of hypokalemia – increased intensity and duration of muscle blockade with muscle relaxants.

With anticholinesterase agents – development of muscle weakness in patients with myasthenia (especially in patients with myasthenia gravis).

With mitotane and other inhibitors of adrenal cortex function – may necessitate increased dosage of the drug.

With antiemetics – enhanced antiemetic effect.

With isoniazid, mexiletine, praziquantel – reduced plasma concentrations.

With somatotropin (at high doses) – reduced effect of the latter.

With fluoroquinolones – tendon damage.

With cyclosporine – seizures have been reported. Since simultaneous administration of these drugs causes mutual inhibition of metabolism, it is likely that seizures and other adverse effects associated with the use of each drug as monotherapy or in combination may occur more frequently. Concomitant use may lead to increased plasma concentrations of other drugs.

With prolonged therapy, prednisolone increases the levels of folic acid.

The drug reduces the effect of vitamin D on intestinal Ca²⁺ absorption.

Special precautions for use.

Before initiating treatment, the patient should be examined to identify possible contraindications. Clinical examination should include evaluation of the cardiovascular system, chest X-ray, examination of the stomach and duodenum, urinary system, and visual organs. Laboratory tests should include: complete blood count, blood and urine glucose concentrations, and plasma electrolyte levels.

During prolonged glucocorticoid therapy, regular monitoring is recommended including blood pressure measurement, blood and urine glucose testing, fecal occult blood testing, coagulation profile, spinal X-ray, and ophthalmologic examination (once every 3 months).

Treatment with glucocorticoids, even at low doses, may mask signs and symptoms of pre-existing or newly developed infections (including opportunistic infections) and complicate their diagnosis. During treatment, contact with individuals suffering from colds or other infections should be avoided.

Children who have been in contact with patients with measles or chickenpox during treatment should be given specific immunoglobulins as prophylaxis (within 10 days after contact).

Vaccination should not be performed during treatment.

If unusual stressful situations occur during glucocorticoid therapy, the dose of fast-acting corticosteroids should be increased before, during, and after the stressful event.

Alcohol consumption should be avoided during prednisolone therapy.

Depending on the duration of treatment and dosage, the drug may negatively affect calcium metabolism. Osteoporosis prophylaxis is recommended, especially important in patients with risk factors (including family history, advanced age, postmenopausal status, inadequate protein and calcium intake, excessive smoking, excessive alcohol consumption, and reduced physical activity). Prophylaxis should be based on adequate calcium and vitamin D intake, as well as physical activity.

To minimize adverse effects of prednisolone therapy, appropriate dietary measures are justified.

Reversible impairment of spermatogenesis may occur with prolonged use of high doses of prednisolone (30 mg daily for at least 4 weeks), which may persist for several months after discontinuation of the drug.

Patients who have received supraphysiological doses of prednisolone (approximately 7.5 mg prednisolone or equivalent) for more than 3 weeks should discontinue treatment gradually. Gradual withdrawal is required even if treatment lasted less than 3 weeks in the following patient groups:

• patients undergoing repeated courses of prednisolone therapy;
• patients receiving repeated treatment within one year after prolonged therapy (months, years);
• patients receiving more than 40 mg daily of prednisolone or equivalent;
• patients with adrenal insufficiency not caused by exogenous corticosteroid use.

After discontinuation of treatment, withdrawal syndrome, adrenal insufficiency, and exacerbation of the condition for which prednisolone was prescribed may occur. If adrenal insufficiency is observed after completion of prednisolone therapy, the drug should be immediately reinstated, and dose reduction should proceed very slowly and cautiously (e.g., reducing the daily dose by 2–3 mg every 7–10 days).

Adrenal cortex atrophy may develop during prolonged therapy and may persist for many years after treatment discontinuation.

Steroid-induced secondary adrenal insufficiency can be minimized by gradual dose reduction. This type of insufficiency may persist for several months after therapy ends; therefore, corticosteroid therapy should be reinstated during any stressful situation occurring during this period.

Sudden discontinuation, especially after prior use of high doses, may lead to withdrawal syndrome characterized by fever, decreased appetite, nausea, vomiting, diarrhea, lethargy, dizziness, generalized musculoskeletal pain, and asthenia.

Due to the risk of hypercortisolism, a new course of cortisone therapy after prior prolonged prednisolone treatment within several months should always begin with low initial doses (except in life-threatening acute conditions).

In children during growth periods, glucocorticosteroids should be used only for absolute indications and under particularly careful medical supervision.

Concomitant antibiotic therapy is required during intercurrent infections, septic conditions, and tuberculosis.

If prednisolone is necessary while taking oral hypoglycemic agents or anticoagulants, the dosing regimen of these drugs should be adjusted accordingly.

Electrolyte balance should be carefully monitored when prednisolone is used concomitantly with diuretics. During prolonged prednisolone therapy, potassium supplements and an appropriate diet should be prescribed to prevent hypokalemia, and intraocular pressure should be monitored due to the risk of increased intraocular pressure and development of subcapsular cataract.

Use in severe infectious diseases is possible only in conjunction with specific antimicrobial therapy.

Postmenopausal women should undergo evaluation for possible development of osteoporosis.

In Addison’s disease, concomitant use of barbiturates should be avoided due to the risk of acute adrenal insufficiency (Addisonian crisis).

If psoriasis or seizures are present in the medical history, prednisolone should be used only at the lowest effective doses.

The drug should be used with particular caution in patients with hepatic or renal insufficiency and migraine.

Special attention should be paid to the use of systemic corticosteroids in patients with current or past history of severe affective disorders, including depression, manic-depressive psychosis, or previous steroid-induced psychosis. Patients and/or caregivers should be warned about the possibility of serious psychiatric adverse effects. Symptoms typically appear within days or weeks after starting treatment. The risk of such adverse effects is higher with high-dose therapy. Most reactions resolve after dose reduction or discontinuation of the drug, although specific treatment may sometimes be required. If such symptoms develop, medical advice should be sought. Psychiatric disorders may also occur during glucocorticoid withdrawal.

Use during pregnancy or breastfeeding.

Controlled studies in pregnant women have not been conducted. Use during pregnancy (especially in the first trimester) is possible only if the benefit to the mother outweighs the potential risk to the fetus. When using the drug during breastfeeding, it should be remembered that prednisolone passes into breast milk.

Ability to affect reaction speed when driving or operating machinery.

During treatment, caution is required when driving vehicles or engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions.

Dosage and Administration.

The dosage is determined individually. When prescribing, the circadian rhythm of glucocorticoid secretion should be taken into account: the larger part of the daily dose (2/3) or the entire dose should be taken in the morning hours, around 8 a.m., and 1/3 in the evening.

Adults.

For acute conditions and as replacement therapy, the drug should be administered at a dose of 20–30 mg per day, with gradual transition to a maintenance daily dose of 5–10 mg. If necessary, the initial dose may range from 15 to 100 mg per day, and the maintenance dose may be 5–15 mg per day.

Children.

The initial dose of the drug for children is 1–2 mg/kg per day, divided into 4–6 doses, and the maintenance dose is 300–600 mcg/kg per day.

The drug should be taken orally, without chewing, and swallowed with a small amount of liquid.

Treatment should be discontinued gradually by slowly reducing the dose.

Children.

The drug may be used in pediatric practice.

Overdose.

The risk of overdose increases with prolonged use of the drug, especially at high doses.

Symptoms: elevated arterial blood pressure, peripheral edema, increased adverse effects.

Treatment of acute overdose: immediate gastric lavage or induction of vomiting. There is no specific antidote.

Treatment of chronic overdose: reduction of the drug dose.

Adverse Reactions.

The frequency and severity of adverse effects depend on the duration of use, the dose administered, and the ability to maintain a circadian rhythm of administration.

Eye disorders: glaucoma, optic nerve disc edema, cataract, posterior subcapsular cataract, increased intraocular pressure with potential optic nerve damage, predisposition to secondary bacterial, fungal, or viral eye infections, corneal trophic changes, exophthalmos.

Gastrointestinal disorders: unpleasant taste in the mouth, dyspepsia, esophageal candidiasis, nausea, vomiting, epigastric pain, diarrhea, pancreatitis, "steroid" gastric and duodenal ulcers, erosive esophagitis, gastrointestinal bleeding and perforation, increased or decreased appetite, flatulence, hiccup. In isolated cases – increased activity of "liver" transaminases and alkaline phosphatase.

Renal and urinary system disorders: increased risk of urates and uroliths formation, increased number of leukocytes and erythrocytes in urine without evidence of kidney damage, leukocyturia.

Endocrine system disorders: increased need for insulin and oral hypoglycemic agents, hyperlipidemia, postmenopausal bleeding, reduced glucose tolerance, "steroid" diabetes mellitus or manifestation of latent diabetes mellitus, suppression of the hypothalamic-pituitary-adrenal system, menstrual cycle disturbances, growth retardation in children and adolescents, delayed sexual development in children, Cushing's syndrome (moon face, centripetal obesity, hirsutism, elevated blood pressure, dysmenorrhea, amenorrhea, myasthenia, striae).

Metabolism and nutritional disorders: disturbances in mineral and electrolyte balance, hypocalcemia, negative nitrogen balance (increased protein breakdown), weight gain. Adverse effects due to glucocorticoid activity of prednisolone: fluid and sodium retention (peripheral edema), hypernatremia, hypokalemic syndrome – arrhythmia, myalgia or muscle cramps, unusual weakness and fatigue.

Nervous system disorders: peripheral neuropathies, paresthesia, autonomic disorders, headache, dizziness, pseudotumor cerebri, increased intracranial pressure, convulsions.

Psychiatric disorders: irritability, sleep disturbances, euphoria, suicidal tendencies, increased concentration, psychological dependence, mania, exacerbation of schizophrenia, dementia, psychosis, epileptic seizures, cognitive dysfunction (including amnesia and disturbances of consciousness), delirium, disorientation, euphoria, hallucinations, manic-depressive psychosis, depression, paranoia, nervousness, restlessness, insomnia.

Cardiovascular disorders: arterial hypotension, atherosclerosis, thrombosis, vasculitis, peripheral edema, arrhythmia, bradycardia, arterial hypertension, development or worsening of chronic heart failure, ECG changes typical of hypokalemia. In patients with acute and subacute myocardial infarction – extension of the necrotic area, delayed scar formation, which may lead to myocardial rupture.

Blood and lymphatic system disorders: increased total leukocyte count with decreased eosinophils, monocytes, and lymphocytes. Lymphoid tissue mass decreases. Leukocyturia, hypercoagulability leading to thrombosis and thromboembolism.

Immune system disorders: hypersensitivity reactions, including rash, pruritus, hyperemia, urticaria, Quincke's edema, anaphylactic shock.

Skin and subcutaneous tissue disorders: skin atrophy, telangiectasia, acne, hirsutism, purpura, post-steroid panniculitis characterized by appearance of erythema and hot subcutaneous nodules within 2 weeks after discontinuation of the drug, Kaposi's sarcoma, delayed regeneration process, petechiae, bruising, hematomas, ecchymoses, striae, thinning of the skin, hyper- or hypopigmentation, acne, predisposition to pyoderma.

Musculoskeletal and connective tissue disorders: delayed growth and ossification processes in children (premature closure of epiphyseal growth zones), osteoporosis, very rarely – pathological fractures, avascular necrosis of the head of the humerus or femur, muscle tendon rupture, "steroid" myopathy, decreased muscle mass (atrophy).

Infections and infestations: masking of symptoms of bacterial, viral, fungal infections, opportunistic infections, decreased resistance to infections.

General disorders and administration site conditions: withdrawal syndrome, edema, aphthous ulcers, malaise, persistent hiccup when the drug is used in high doses; adrenal insufficiency leading to arterial hypotension; hypoglycemia and fatal outcomes under stress conditions such as surgery, trauma, or infection if the prednisolone dose is not increased.

Sudden discontinuation of the drug may result in withdrawal syndrome; severity of symptoms depends on the degree of adrenal atrophy and may include headache, nausea, abdominal pain, dizziness, anorexia, weakness, mood changes, lethargy, fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful pruritus of the skin, weight loss. In more severe cases – severe psychiatric disturbances, increased intracranial pressure, steroid pseudorheumatism in patients with rheumatism, and fatal outcomes.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

10 tablets in a blister pack; 4 blisters per carton.

Prescription category. Prescription only.

Manufacturer.

JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and place of business.

13 Boryspylska Street, Kyiv, 02093, Ukraine.