Depersolon (Solution) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Ltd. (Hungary)

ATC Code

H02AB (Glucocorticoids)

Active Substance

Mazipredone (Rec.INN registered by WHO)

Dosage Form

Depersolon

Injection solution 30 mg/1 ml: amp. 3 pcs.

Dosage Form, Packaging, and Composition

Solution for intravenous and intramuscular administration colorless or slightly greenish, transparent.

Excipients: benzyl alcohol, ethanol 96%, propylene glycol, water for injections.

1 ml – dark glass ampoules (3) – cardboard packs.

Clinical-Pharmacological Group

Injectable corticosteroids

Pharmacotherapeutic Group

Glucocorticosteroid

Pharmacological Action

Mazipredone is a synthetic glucocorticosteroid, a soluble derivative of prednisolone.

It exerts anti-inflammatory, immunosuppressive, and anti-allergic effects.

After easily penetrating into target cells, it binds to glucocorticoid receptors in the cytoplasm. Free receptors are usually bound to the so-called heat shock protein (HSP90). After binding to glucocorticoid receptors, the structure of HSP90 changes and it leaves the receptor. The latter moves into the cell nucleus. The multifaceted action of glucocorticosteroids is due to the presence of glucocorticoid response elements (GRE) in the promoter regions of several genes, some of which are “switched off” as a result of receptor binding to their GRE, while others are activated. The ubiquitous intracellular transcription factor NF-kB plays a key role in this complex process. Various inflammatory mediators activate NF-kB to trigger cytokine production. Glucocorticosteroids, however, induce the transcription of the IkB protein, which captures activated NF-kB and forms an inactive cytoplasmic complex with it. In addition, glucocorticosteroids activate lipocortins, which are representatives of another protein family, and enhance the transcription of β₂-receptor genes. The essence of lipocortin action is the inhibition of the chain of reactions leading to the formation of prostaglandins, leukotrienes, and platelet-activating factor. These mediators usually increase vascular permeability, leading to tissue edema, cause leukocyte migration, and fibrin deposition.

Depersolon acts on all stages of the inflammatory process, among which it is particularly important to note the inhibition of phospholipase A2 and the blockade of arachidonic acid formation through stimulation of the synthesis of an inhibitory polypeptide, the so-called lipocortin-1, with subsequent suppression of the biosynthesis of inflammatory mediators, the so-called pleiotropic cytokines of the acute phase inflammatory response: interleukin-1, TNF-α, as well as interleukins 4 and 5. Furthermore, it blocks the transcription of genes for such inflammatory enzymes as NO synthase and cyclooxygenase. It suppresses the functions of neutrophils and macrophages, including the release of chemical mediators and their effects on capillaries. It stabilizes cellular and organelle membranes (especially lysosomal) and increases their resistance to various damaging factors. By blocking inflammatory reactions in connective tissue, it prevents the formation of scar tissue.

It suppresses the inflammatory process regardless of its etiology; in cases of excessive or “useless” inflammatory reaction it has a beneficial effect, however, it poses a danger in infections due to the suppression of the protective inflammatory process.

The immunosuppressive effect is achieved through the action of mazipredone on numerous targets, among which the suppression of cytokine secretion is particularly important. It suppresses lymphocyte proliferation, including leukemia lymphocytes, the expression of MHC II on macrophages and adhesion molecules of endothelial cells, causes eosinopenia and prevents eosinophil degranulation and neutrophil adhesion, prevents the release of cytokines (mainly interleukin-2 and γ-interferon) by cells and the secretion and release of prostaglandin E2, and also blocks collagen synthesis in fibroblasts. Large doses of glucocorticosteroids suppress antibody production.

Prevents the development of allergic reactions. Reduces the number of circulating eosinophils, basophils and the release of immediate allergy mediators. The interaction of allergens with antibodies remains unchanged, but the damaging effects of inflammation are absent.

Affects various types of metabolism in the human body.

Carbohydrate metabolism: activates gluconeogenesis (increased absorption of carbohydrates from the gastrointestinal tract, increased activity of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase with increased release of glucose from the liver into the blood), while peripheral glucose utilization (glucose transport across the cell membrane) may decrease, leading to hyperglycemia and sometimes glucosuria, manifestation of latent diabetes mellitus.

Protein metabolism: anabolism decreases (decrease in the amount of globulins, increase in albumin synthesis in the liver and kidneys, increase in the albumin/globulin ratio) with unchanged or even increased intensity of catabolic processes, which leads to a negative nitrogen balance with atrophy of muscle tissue. Osteoporosis is possible due to a decrease in the protein matrix of bone tissue, growth retardation in children, skin atrophy, which, with increased capillary fragility, leads to increased skin vulnerability and striae formation. Wound and peptic ulcer healing is slowed and occurs with the formation of fibrous tissue.

Fat metabolism: the synthesis of higher fatty acids and triglycerides is enhanced with fat deposition in the shoulder girdle, face and abdomen and its mobilization from the subcutaneous fat of the extremities with subsequent hypercholesterolemia.

Water-electrolyte metabolism (mineralocorticoid effects): sodium retention in the renal tubules increases, potassium excretion in the urine increases. Reduces hypercalcemia in cases of excessive calcium absorption from the gastrointestinal tract (sarcoidosis, vitamin D intoxication), increases calcium excretion in the urine with possible stone formation.

Suppresses the feedback of the hypothalamic-pituitary-adrenal system with long-term use (with subsequent slow recovery), which, upon abrupt discontinuation of treatment, leads to the development of adrenal insufficiency in the patient: suppresses the synthesis and secretion of ACTH by the pituitary gland, thereby suppressing the synthesis of endogenous glucocorticosteroids and androgens by the adrenal glands.

The anti-inflammatory effect of the drug is 4 times stronger than that of hydrocortisone.

Depersolon has insignificant mineralocorticoid activity.

When administered intravenously, it has a pronounced effect of prednisolone; when administered intramuscularly, the action occurs later.

Pharmacokinetics

Rapidly distributed in the body upon intravenous administration. When administered intramuscularly, the plasma T_1/2 is approximately 3.3 hours. 35-40% of Depersolon is excreted by the kidneys unchanged.

Indications

Conditions requiring parenteral administration of glucocorticosteroids

• Shock states (burn, traumatic, surgical, toxic, cardiogenic) – when vasoconstrictors, plasma substitutes and other symptomatic therapy are ineffective;
• Allergic reactions (acute severe forms), blood transfusion shock, anaphylactic shock, anaphylactoid reactions;
• Bronchial asthma (severe form), status asthmaticus;
• Intoxication in infectious diseases (with long-term use of glucocorticosteroids, antibiotics are prescribed simultaneously);
• Acute and chronic adrenal cortex insufficiency (in combination with mineralocorticoids);
• Hepatic coma.

ICD codes

Dosage Regimen

Adults: in shock resistant to standard therapy, a single dose is 30-90 mg intravenously by slow bolus (about 3 min) or by drip. The maximum daily dose is 150-300 mg.

If intravenous administration is not possible, it can be administered deep into the gluteal muscle, but the action occurs later.

If necessary, an additional 30-60 mg of the drug is administered intravenously or intramuscularly.

For other indications, a single dose is 30-45 mg intravenously slowly or intramuscularly (into the gluteal muscle). Upon improvement of the condition, treatment should be continued with decreasing doses of prednisolone tablets.

Children aged 2 to 12 months a single dose of 2-3 mg/kg body weight intravenously or deep into the gluteal muscle, children aged 1 to 14 years – 1-2 mg/kg intravenously slowly (about 3 min) or deep into the gluteal muscle. If necessary, the dose can be repeated after 20-30 minutes.

Adverse Reactions

The frequency and severity of side effects depend on the duration of use, the dose used, and the possibility of observing the circadian rhythm of Depersolon administration.

The following side effects may be noted when using Depersolon

From the endocrine system: decreased glucose tolerance, steroid diabetes mellitus or manifestation of latent diabetes mellitus, suppression of adrenal function, Itsenko-Cushing syndrome (moon face, pituitary-type obesity, hirsutism, increased blood pressure, dysmenorrhea, amenorrhea, muscle weakness, striae), delayed sexual development in children.

From the digestive system: nausea, vomiting, pancreatitis, steroid ulcer of the stomach and duodenum, erosive esophagitis, gastrointestinal bleeding and perforation of the gastrointestinal tract wall, increased or decreased appetite, indigestion, flatulence, hiccups. In rare cases – increased activity of liver transaminases and alkaline phosphatase.

From the cardiovascular system: arrhythmias, bradycardia (up to cardiac arrest); development (in predisposed patients) or increased severity of heart failure, ECG changes characteristic of hypokalemia, increased blood pressure, hypercoagulation, thrombosis. In patients with acute and subacute myocardial infarction – spread of the necrosis focus, slowing of scar tissue formation, which can lead to rupture of the heart muscle.

From the nervous system: delirium, disorientation, euphoria, hallucinations, manic-depressive psychosis, depression, paranoia, increased intracranial pressure, nervousness or anxiety, insomnia, dizziness, vertigo, pseudotumor cerebri, headache, convulsions.

From the organ of vision: posterior subcapsular cataract, increased intraocular pressure with possible damage to the optic nerve, tendency to develop secondary bacterial, fungal or viral eye infections, trophic changes of the cornea, exophthalmos, sudden loss of vision (with parenteral administration in the head, neck, nasal conchae, scalp areas, deposition of drug crystals in the eye vessels is possible).

From metabolism: increased calcium excretion, hypocalcemia, weight gain, negative nitrogen balance (increased protein breakdown), increased sweating.

Side effects due to mineralocorticoid activity: fluid and sodium retention (peripheral edema), hypernatremia, hypokalemic syndrome (hypokalemia, arrhythmia, myalgia or muscle spasm, unusual weakness and fatigue).

From the musculoskeletal system: slowing of growth and ossification processes in children (premature closure of epiphyseal growth zones), osteoporosis (very rarely – pathological bone fractures, aseptic necrosis of the humeral and femoral head), muscle tendon rupture, steroid myopathy, decrease in muscle mass (atrophy).

Dermatological reactions: slowed wound healing, petechiae, ecchymoses, thinning of the skin, hyper- or hypopigmentation, steroid acne, striae, tendency to develop pyoderma and candidiasis.

Allergic reactions: skin rash, itching, anaphylactic shock, local allergic reactions.

Local reactions: burning, numbness, pain, tingling at the injection site, infections at the injection site, rarely – necrosis of surrounding tissues, scar formation at the injection site, atrophy of the skin and subcutaneous tissue upon intramuscular injection (especially dangerous when injected into the deltoid muscle).

Other: development or exacerbation of infections (concomitant use of immunosuppressants and vaccination contribute to the appearance of this side effect), leukocyturia, “withdrawal” syndrome.

Contraindications

For short-term use for vital indications, the only contraindication is hypersensitivity to the components of the drug.

In children during the growth period, glucocorticosteroids should be used only for absolute indications under the especially careful supervision of the attending physician.

The drug should be prescribed with caution in the following diseases and conditions

• Gastrointestinal diseases: gastric and duodenal ulcer, esophagitis, gastritis, acute or latent peptic ulcer, recently created intestinal anastomosis, ulcerative colitis with threat of perforation or abscess formation, diverticulitis;
• Parasitic and infectious diseases of viral, fungal or bacterial nature (at the time of treatment and recently suffered, including recent contact with a patient): herpes simplex, herpes zoster (viremic phase), varicella, measles; amoebiasis, strongyloidosis; systemic mycosis; active and latent tuberculosis. Use in severe infectious diseases is permissible only against the background of specific therapy.
• Pre- and post-vaccination period (8 weeks before and 2 weeks after vaccination), lymphadenitis after BCG vaccination;
• Immunodeficiency states (including AIDS or HIV infection);
• Cardiovascular system diseases (including recently suffered myocardial infarction – in patients with acute and subacute myocardial infarction, spread of the necrosis focus, slowing of scar tissue formation and, consequently, rupture of the heart muscle is possible), severe chronic heart failure, arterial hypertension, hyperlipidemia.
• Endocrine diseases: diabetes mellitus (including impaired glucose tolerance), thyrotoxicosis, hypothyroidism, Itsenko-Cushing’s disease, obesity (grade III-IV);
• Severe chronic renal and/or hepatic insufficiency, nephrourolithiasis;
• Hypoalbuminemia and conditions predisposing to its occurrence;
• Systemic osteoporosis, myasthenia gravis, acute psychosis, poliomyelitis (except for the form of bulbar encephalitis), open-angle and closed-angle glaucoma;
• Pregnancy.

Use in Pregnancy and Lactation

During pregnancy (especially in the first trimester), the drug is used only for vital indications. With long-term therapy during pregnancy, the possibility of impaired fetal growth cannot be excluded. If used in the third trimester of pregnancy, there is a risk of adrenal cortex atrophy in the fetus, which may require replacement therapy in the newborn.

Since glucocorticosteroids pass into breast milk, if it is necessary to use the drug, the issue of discontinuing breastfeeding should be considered.

Use in Hepatic Impairment

The drug should be used with caution in severe chronic hepatic insufficiency.

The effect of the drug is enhanced in patients with liver cirrhosis.

Use in Renal Impairment

The drug should be used with caution in severe chronic renal insufficiency.

Pediatric Use

When using Depersolon, slowing of growth and ossification processes in children (premature closure of epiphyseal growth zones), as well as delayed sexual development in children, is possible.

During long-term treatment with Depersolon in children, careful monitoring of growth and development dynamics is necessary. Children who have been in contact with patients with measles or varicella during the treatment period are prophylactically prescribed specific immunoglobulins.

In children with bronchial asthma, the use of Depersolon simultaneously with sympathomimetic aerosols is contraindicated.

Special Precautions

During treatment with Depersolon (especially long-term), observation by an ophthalmologist, monitoring of blood pressure, water-electrolyte balance, as well as peripheral blood picture and blood glucose level is necessary.

To reduce side effects, antacids can be prescribed, and potassium intake can be increased (diet, potassium preparations). Food should be rich in proteins, vitamins with limited content of fats, carbohydrates and table salt.

The effect of the drug is enhanced in patients with hypothyroidism and liver cirrhosis.

The drug may enhance pre-existing emotional instability or psychotic disorders. If there is a history of psychosis, Depersolon in high doses is prescribed under strict medical supervision.

It should be used with caution in acute and subacute myocardial infarction – it is possible for the focus of necrosis to spread, the formation of scar tissue to slow down, and the heart muscle to rupture.

In stressful situations during maintenance therapy (e.g., surgery, trauma, or infectious diseases), the dose of the drug should be adjusted due to the increased need for glucocorticoids.

Abrupt withdrawal, especially after prior use of high doses, may lead to the development of withdrawal syndrome (anorexia, nausea, lethargy, generalized musculoskeletal pain, general weakness), as well as exacerbation of the disease for which Depersolon was prescribed.

Vaccination should not be carried out during treatment with Depersolon due to reduced effectiveness (immune response).

When prescribing Depersolon for intercurrent infections, septic conditions, and tuberculosis, it is necessary to simultaneously administer treatment with bactericidal antibiotics.

During long-term treatment of children with Depersolon, careful monitoring of growth and development dynamics is necessary. Children who have been in contact with patients with measles or chickenpox during treatment should be prophylactically prescribed specific immunoglobulins.

Due to its weak mineralocorticoid effect, for replacement therapy in adrenal insufficiency, Depersolon is used in combination with mineralocorticoids.

In patients with diabetes mellitus, blood glucose levels should be monitored and therapy adjusted if necessary.

X-ray monitoring of the osteoarticular system (images of the spine, hand) is indicated.

Depersolon in patients with latent infectious diseases of the kidneys and urinary tract can cause leukocyturia, which may have diagnostic significance.

Depersolon increases the content of 11- and 17-oxyketocorticosteroid metabolites.

Overdose

In case of overdose, the described side effects may be intensified. It is necessary to reduce the dose of Depersolon. Symptomatic therapy is carried out.

Drug Interactions

The use of Depersolon simultaneously with sympathomimetic aerosols is contraindicated in children with bronchial asthma.

With the simultaneous administration of Depersolon and indirect anticoagulants, the anticoagulant effect of the latter may be weakened, less often – enhanced; dose adjustment is necessary.

The combination of Depersolon with anticoagulants and thrombolytics increases the risk of ulcerative bleeding from the gastrointestinal tract.

Concomitant use with salicylates is accompanied by accelerated excretion and decreased concentration, and upon withdrawal of Depersolon – by an increase in the concentration of salicylates in the blood with a probability of side effects, including the occurrence of gastrointestinal bleeding.

The combination of Depersolon with diuretics, especially thiazide derivatives and carbonic anhydrase inhibitors, amphotericin B, can lead to increased potassium excretion from the body and an increased risk of heart failure; with sodium-containing drugs – leads to edema and increased blood pressure.

Simultaneous use of Depersolon with antihypertensive agents, oral hypoglycemic drugs, and insulin reduces their effectiveness.

Combination with cardiac glycosides increases the risk of glycoside intoxication with the development of ventricular extrasystole due to hypokalemia.

Hormonal contraceptives enhance the effect of Depersolon.

Simultaneous use of Depersolon and ethanol or NSAIDs increases the risk of erosive and ulcerative lesions and bleeding from the gastrointestinal tract (a dose reduction of the drug may be required).

The appearance of hirsutism, acne, and edema is facilitated by the simultaneous use of Depersolon with other steroid hormonal drugs (androgens, estrogens, oral contraceptives, and steroid anabolic agents).

Furthermore, simultaneous use with hormonal contraceptives is accompanied by an enhancement of the effect of Depersolon due to a decrease in its clearance.

The risk of cataract development increases with the simultaneous use of Depersolon with antipsychotic agents, carbutamide, and azathioprine.

Simultaneous use with inducers of liver microsomal enzymes (phenytoin and barbiturates, ephedrine, rifampicin, theophylline) leads to a decrease in the concentration and a weakening of the effect of Depersolon.

Simultaneous use of Depersolon with M-cholinoblockers, including antihistamines, tricyclic antidepressants, and nitrates, contributes to an increase in intraocular pressure.

Taking Depersolon during treatment with pasikvatel leads to a decrease in the concentration of the latter.

Concomitant use with paracetamol increases the hepatotoxic effect due to the induction of liver enzymes and the formation of a toxic metabolite of paracetamol.

Concomitant use with vitamin D reduces its effect on calcium absorption in the intestine.

With simultaneous use with somatotropin, the effectiveness of the latter is reduced.

With the simultaneous use of isoniazid and mexiletine with Depersolon, the metabolism of isoniazid and mexiletine is enhanced and their blood concentrations are reduced, especially in slow acetylators.

Carbonic anhydrase inhibitors and loop diuretics may contribute to the development of osteoporosis.

Ergocalciferol and parathyroid hormone prevent the development of glucocorticosteroid osteopathy.

ACTH enhances the effect of Depersolon.

Cyclosporine and ketoconazole, by slowing down the metabolism of Depersolon, in some cases increase its toxicity.

With simultaneous use with mitotane and other inhibitors of adrenal cortex function, an increase in the dose of Depersolon may be required.

Simultaneous use with live antiviral vaccines and other types of immunization contributes to the activation of viruses with the development of infectious diseases.

Antithyroid drugs reduce, and thyroid hormones increase the clearance of Depersolon.

Storage Conditions

Storage conditions

Store at a temperature of 8-15°C (46-59°F) in a place inaccessible to children.

Shelf Life

Shelf life

2 years.

Do not use after the expiration date printed on the packaging.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.