Solu-Cortef^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Pfizer, Inc. (USA)

Manufactured By

Pfizer Manufacturing Belgium, NV (Belgium)

ATC Code

H02AB09 (Hydrocortisone)

Active Substance

Hydrocortisone (Rec.INN registered by WHO)

Dosage Forms

	Solu-Cortef®	Lyophilisate for preparation of solution for intravenous and intramuscular administration 100 mg: two-chamber vial 1 pc. (with solvent)
		Lyophilisate for preparation of solution for intravenous and intramuscular administration 100 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for intravenous and intramuscular administration as a powder or porous mass of white or almost white color.

Excipients: sodium dihydrogen phosphate monohydrate – 0.9 mg, sodium hydrogen phosphate – 8.8 mg.

Colorless glass vials (1) – cardboard packs^×.

Lyophilisate for preparation of solution for intravenous and intramuscular administration as a powder or porous mass of white or almost white color; attached solvent is clear, colorless; reconstituted solution is clear, slightly opalescent, colorless or slightly yellowish.

Excipients: sodium dihydrogen phosphate monohydrate – 0.9 mg, sodium hydrogen phosphate – 8.8 mg.

Solvent composition benzyl alcohol – 18 mg, water for injection – q.s. to 2 ml.

Two-chamber Act-o-Vial vials made of colorless glass with solvent (1) – cardboard packs^×.

^× perforation may be applied for control of first opening.

Clinical-Pharmacological Group

Injectable corticosteroids

Pharmacotherapeutic Group

Glucocorticosteroid

Pharmacological Action

Glucocorticosteroids (GCS), penetrating cell membranes, form complexes with specific cytoplasmic receptors. The formed complexes penetrate the cell nucleus where they bind to DNA (chromatin). Subsequently, these complexes stimulate mRNA transcription followed by the synthesis of various enzymes, which explains the effect of GCS with systemic use. GCS not only have a significant impact on the inflammatory process and immune response, but also affect carbohydrate, protein and fat metabolism.

The maximum pharmacological activity of GCS is manifested not at the peak concentration in plasma, but after it. Thus, the action of GCS is primarily due to their influence on enzyme activity.

It has anti-inflammatory, anti-shock, desensitizing, antitoxic, antiallergic, immunosuppressive and antimetabolic effects. Unlike cytostatics, the immunosuppressive properties are not associated with a mitostatic effect, but are the cumulative result of suppressing different stages of immunogenesis: migration of stem cells (bone marrow), migration of B-cells and interaction of T- and B-lymphocytes. It inhibits the release of cytokines (interleukins and interferon) from lymphocytes and macrophages, suppresses the release of inflammatory mediators from eosinophils, reduces the metabolism of arachidonic acid and the synthesis of prostaglandins. By stimulating steroid receptors, it induces the formation of lipocortin. It promotes the deposition of glycogen in the liver, increases the glucose content in the blood, inhibits the excretion of sodium ions and water, enhances the excretion of potassium ions from the body, and reduces the synthesis of histamine. It reduces inflammatory cellular infiltrates, reduces the migration of leukocytes and lymphocytes to the area of inflammation. In large doses, it inhibits the development of lymphoid and connective tissue, including the reticuloendothelial system (RES), reduces the number of mast cells, which are the site of hyaluronic acid formation; suppresses hyaluronidase and helps reduce capillary permeability. It delays protein synthesis and accelerates protein breakdown. By affecting the pituitary gland, it suppresses the production of corticotropin. Long-term administration into the body can lead to suppression and atrophy of the adrenal cortex, suppression of the formation of pituitary gonadotropic and thyrotropic hormones.

Pharmacokinetics

After intramuscular administration, the C_max of hydrocortisone in blood plasma is reached in approximately 30-60 minutes.

Approximately 40-90% of hydrocortisone is bound to blood plasma proteins. Most of hydrocortisone is bound to one of the globulins (transcortin), and only a small amount is bound to albumin. The free unbound fraction of the hormone determines its biological activity, and the bound fraction serves as a reserve.

Metabolism of hydrocortisone occurs mainly in the liver. Within 24 hours, 22-30% of the intramuscularly or intravenously administered hydrocortisone is excreted in the urine. The drug is almost completely eliminated from the body within 12 hours, so to maintain high concentrations of hydrocortisone in the blood, it must be administered intramuscularly or intravenously every 4-6 hours.

Indications

Endocrine diseases

• Primary or secondary adrenal insufficiency (drugs of choice are Hydrocortisone or cortisone; if necessary, their synthetic analogues can be used in combination with mineralocorticoids, especially in pediatric practice);
• Acute adrenal insufficiency (drugs of choice are Hydrocortisone or cortisone; there may be a need for simultaneous use of mineralocorticoids).

As symptomatic therapy

• In the preoperative period, in case of severe trauma or severe illness, in patients with established or suspected adrenal insufficiency;
• Shock that does not respond to conventional therapy when adrenal insufficiency may be present;
• Congenital adrenal hyperplasia;
• Subacute thyroiditis;
• Hypercalcemia due to cancer.

Rheumatic diseases (as adjunctive therapy for short-term use to relieve acute conditions or exacerbations)

• Acute and subacute bursitis;
• Acute gouty arthritis;
• Acute nonspecific tenosynovitis;
• Ankylosing spondylitis;
• Epicondylitis;
• Post-traumatic osteoarthritis;
• Psoriatic arthritis;
• Rheumatoid arthritis, including juvenile rheumatoid arthritis (in some cases, maintenance therapy with low doses may be required);
• Synovitis in osteoarthritis.

Systemic connective tissue diseases (during exacerbation or in some cases as maintenance therapy)

• Acute rheumatic carditis;
• Systemic dermatomyositis (polymyositis);
• Systemic lupus erythematosus.

Skin diseases

• Dermatitis herpetiformis;
• Exfoliative dermatitis;
• Mycosis fungoides;
• Pemphigus;
• Malignant exudative erythema (Stevens-Johnson syndrome);
• Severe psoriasis;
• Severe seborrheic dermatitis.

Allergic conditions (in cases of severe or disabling conditions where conventional therapy is ineffective)

• Acute non-infectious laryngeal edema;
• Atopic dermatitis;
• Status asthmaticus;
• Contact dermatitis;
• Drug hypersensitivity reactions;
• Seasonal or perennial allergic rhinitis;
• Serum sickness;
• Urticarial-type post-transfusion reactions.

Eye diseases (severe acute and chronic allergic and inflammatory processes involving the eyes)

• Allergic conjunctivitis;
• Allergic marginal corneal ulcers;
• Inflammation of the anterior segment;
• Chorioretinitis;
• Diffuse posterior uveitis and choroiditis;
• Ophthalmic form of Herpes zoster;
• Iritis and iridocyclitis;
• Keratitis;
• Optic neuritis;
• Sympathetic ophthalmia.

Gastrointestinal diseases (to bring the patient out of a critical condition)

• Ulcerative colitis (systemic therapy);
• Regional enteritis (systemic therapy).

Respiratory tract diseases

• Aspiration pneumonitis;
• Berylliosis;
• Fulminant and disseminated pulmonary tuberculosis in combination with appropriate anti-tuberculosis chemotherapy;
• Loeffler’s syndrome not amenable to therapy with other agents;
• Clinically significant sarcoidosis.

Hematological diseases

• Acquired (autoimmune) hemolytic anemia;
• Congenital (erythroid) hypoplastic anemia;
• Erythroblastopenia (erythrocyte anemia);
• Idiopathic thrombocytopenic purpura in adults (intravenous administration only; intramuscular administration is contraindicated);
• Secondary thrombocytopenia in adults.

Oncological diseases (as palliative therapy)

• Acute leukemias in children;
• Leukemias and lymphomas in adults.

Edematous syndrome

• To stimulate diuresis and achieve remission of proteinuria in patients with nephrotic syndrome without uremia; in nephrotic syndrome of idiopathic type or in lupus erythematosus.

Emergency conditions

• Shock resulting from adrenal insufficiency, or resistant to standard therapy, with possible presence of adrenal insufficiency;
• Acute allergic manifestations after administration of epinephrine (status asthmaticus, anaphylactic reactions, insect bites, etc.);
• In the therapy of hemorrhagic traumatic and surgical shock, where standard therapy is ineffective.

Other indications for use

• Trichinosis with nervous system or myocardial involvement;
• Tuberculous meningitis with subarachnoid block or threat of block (in combination with appropriate anti-tuberculosis chemotherapy).

ICD codes

Dosage Regimen

The drug can be administered as an IV or IM injection or as an IV infusion, but in emergency conditions, it is preferable to start treatment with an IV injection. After the acute period, either parenteral dosage forms of the drug with a longer duration of action or oral forms of the drug are prescribed. Treatment with the drug begins with IV administration over 30 seconds (e.g., 100 mg) and up to 10 minutes (e.g., 500 mg or more). High doses of corticosteroids should be prescribed only until the patient’s condition stabilizes, but for no longer than 48-72 hours. The initial dose of the drug is 100-500 mg or more, depending on the severity of the patient’s condition. The drug dose is repeated every 2, 4, or 6 hours depending on the patient’s response and the clinical picture of the disease. Children should be given lower doses (but not less than 25 mg/day), however, when choosing a dose, the severity of the condition and the patient’s response to therapy are primarily taken into account, not age and body weight.

Preparation of solutions

Parenteral drug products should be inspected visually for color change or the presence of particles. Only a clear solution should be used.

Vial

For IV or IM injection, prepare a solution by adding no more than 2 ml of Water for Injection or bacteriostatic Water for Injection with a bacteriostatic agent to the vial (observing aseptic technique). For IV infusion, first prepare a solution by adding no more than 2 ml of Water for Injection to the vial, then this solution can be added to 100-1000 ml of 5% aqueous dextrose solution (or 0.9% sodium chloride solution, or 5% dextrose in 0.9% sodium chloride solution if the patient does not require sodium restriction).

ACT-O-VIAL dual-chamber vial

1. Press on the plastic activator to allow the diluent to flow into the lower chamber.
2. Gently agitate the vial until the lyophilized powder is dissolved.
3. Remove the plastic disc covering the center of the stopper.
4. Wipe the surface of the stopper with an antiseptic.
5. Insert the needle through the center of the stopper until the needle tip is visible. Invert the vial and withdraw the required amount of solution with a syringe.

For IV or IM injections, no further dilution is required. For IV infusion, first prepare the solution as described above, then add the resulting solution to 100-1000 ml of 5% aqueous dextrose solution (or 0.9% sodium chloride solution, or 5% dextrose in 0.9% sodium chloride solution if the patient does not require sodium restriction). If it is desirable to administer a small volume of fluid, 100-3000 mg of hydrocortisone (as hydrocortisone sodium succinate) can be added to 50 ml of the above solutions. The resulting solutions are stable for 4 hours and can be administered IV directly or through a secondary drip set.

If the drug solutions are prepared as indicated above, then the pH = 7-8, and the osmolarity = 0.36 osmol (the osmolarity of 0.9% sodium chloride solution is 0.28 osmol).

Adverse Reactions

Note: The adverse effects listed below are typical for all corticosteroids with parenteral use, not just for this specific drug.

Fluid and electrolyte balance sodium retention in the body; chronic heart failure in predisposed patients; arterial hypertension; fluid retention in the body; potassium loss; hypokalemic alkalosis; increased calcium excretion.

Musculoskeletal system “steroid” myopathy; muscle weakness; osteoporosis; pathological fractures; compression fractures of the vertebrae; aseptic necrosis of the epiphyses of long bones; tendon ruptures, especially of the Achilles tendon.

Digestive system peptic ulcer with possible perforation and bleeding (prophylactic antacid therapy may be indicated); gastric bleeding; pancreatitis; esophagitis; intestinal perforation; increased activity of ALT, AST and alkaline phosphatase in the blood serum (usually these changes are minor, not associated with any clinical syndromes, and are reversible after discontinuation of treatment).

Skin slow wound healing; petechiae and ecchymoses; thinning and reduced skin strength; Kaposi’s sarcoma. It has been reported that patients receiving corticosteroid therapy have developed Kaposi’s sarcoma. Clinical remission may occur upon discontinuation of corticosteroids.

Metabolism negative nitrogen balance due to protein catabolism.

Nervous system increased intracranial pressure with papilledema; pseudotumor cerebri; seizures; mental disorders, including euphoria, insomnia, mood swings, personality changes, depression; acute psychotic manifestations; exacerbation of pre-existing emotional instability or tendency to psychotic reactions.

Endocrine system menstrual cycle disorders; development of Cushing’s syndrome; suppression of the hypothalamic-pituitary-adrenal system; decreased glucose tolerance; manifestation of latent diabetes mellitus; increased requirement for insulin or oral hypoglycemic agents in patients with diabetes mellitus; growth retardation in children.

Sensory organs posterior subcapsular cataract; increased intraocular pressure; exophthalmos.

Immune system masked clinical picture of infectious diseases; activation of latent infections, including reactivation of tuberculosis; occurrence of infections caused by opportunistic pathogens, of any localization, ranging from mild to potentially fatal; hypersensitivity reactions, including anaphylaxis and anaphylactic reactions (e.g., bronchospasm, laryngeal edema, urticaria); suppression of reactions during skin tests.

Other the diluent contains benzyl alcohol, which can cause “Gasping Syndrome” (respiratory disorders manifested as gasping) with a fatal outcome in premature newborns.

Contraindications

• Systemic fungal infections;
• History of hypersensitivity to any components of the drug.

It is not recommended to use the drug in patients with acute and subacute myocardial infarction, as the use of corticosteroids in them may lead to the spread of the necrosis focus, slowing of scar tissue formation and, as a result, to rupture of the heart muscle;

The drug supplied in ACT-O-VIAL dual-chamber vials is not recommended for use in newborns, as the diluent contains benzyl alcohol.

Use with caution in the following cases

• In eye lesions caused by the herpes simplex virus, as this may lead to corneal perforation;
• In ulcerative colitis, if there is a threat of perforation, abscess or other pyogenic infection, as well as in diverticulitis, in the presence of fresh intestinal anastomoses, in active or latent peptic ulcer, renal failure, arterial hypertension, osteoporosis, myasthenia gravis.

Use in Pregnancy and Lactation

A number of animal studies have shown that administration of high doses of corticosteroids to pregnant females can lead to fetal malformations. Appropriate studies on the effect of corticosteroids on human reproductive function have not been conducted, so the use of these drugs during pregnancy, in nursing mothers, or in women of childbearing age requires an assessment of the probable positive effect of the drug compared to the potential risk to the mother, embryo, or fetus. Corticosteroids should be prescribed during pregnancy only for absolute indications.

Corticosteroids easily cross the placenta. Children born to mothers who received significant doses of corticosteroids during pregnancy should be carefully examined to identify signs of adrenal insufficiency. The effect of corticosteroids on the course and outcome of labor is unknown.

Corticosteroids are excreted in breast milk, so if it is necessary to prescribe the drug Solu-Cortef^® during breastfeeding, breastfeeding should be discontinued.

Use in Renal Impairment

Use with caution in renal impairment.

Pediatric Use

Contraindicated in newborns

Special Precautions

When prescribing high doses of hydrocortisone for a period longer than 48-72 hours, hypernatremia may develop. In this case, it is recommended to replace Solu-Cortef^® with another corticosteroid, for example, methylprednisolone sodium succinate, which causes little or no sodium retention in the body.

Patients who may be exposed to stress during corticosteroid therapy are shown an increase in the dose of the drug before, during, and after the stressful situation. Such patients should be under strict medical supervision due to the possible development of adrenal insufficiency.

During corticosteroid therapy, some infections may have a masked clinical picture, and new infections may develop. When using corticosteroids, resistance to infections may decrease, and the body’s ability to localize the infectious process may also decrease. The development of infections caused by various pathogens, such as viruses, bacteria, fungi, protozoa, or helminths, which are localized in various systems of the human body, may be associated with the use of corticosteroids, both as monotherapy and in combination with other immunosuppressants that affect cellular immunity, humoral immunity, or neutrophil function. These infections may be mild, however, in some cases, severe course and even death are possible. The higher the doses of corticosteroids used, the higher the likelihood of infectious complications.

The use of hydrocortisone in active tuberculosis should be limited to cases of fulminant and disseminated tuberculosis, when corticosteroids are used to treat the disease in combination with appropriate anti-tuberculosis chemotherapy. If corticosteroids are prescribed to patients with latent tuberculosis or with positive tuberculin tests, then treatment should be carried out under strict medical supervision, since reactivation of the disease is possible. During long-term therapy with the drug, such patients should receive appropriate prophylactic treatment.

Patients receiving treatment with corticosteroids in doses that have an immunosuppressive effect are contraindicated to receive live or live attenuated vaccines, but killed or inactivated vaccines can be administered, however, the response to the administration of such vaccines may be reduced. Patients receiving treatment with corticosteroids in doses that do not have an immunosuppressive effect can be immunized according to the appropriate indications.

Administration of hydrocortisone may lead to increased blood pressure, retention of water and salts in the body, and increased potassium excretion. It may be necessary to restrict dietary salt intake and additionally prescribe potassium supplements. All corticosteroids increase calcium excretion from the body. Since in rare cases, anaphylactoid reactions (e.g., bronchospasm) may develop in patients receiving parenteral corticosteroid therapy, appropriate preventive measures should be taken before administering the drug, especially if the patient has a history of allergic reactions to any drugs.

With long-term daily corticosteroid therapy, growth retardation may be observed in children, so such a dosing regimen should be prescribed to children only if there are serious indications. Acute myopathy most often develops with the use of high doses of corticosteroids in patients with impaired neuromuscular transmission (e.g., myasthenia gravis), or in patients simultaneously receiving treatment with peripheral muscle relaxants (e.g., pancuronium). Such acute myopathy is generalized, can affect the eye and respiratory muscles, and lead to the development of tetraparesis. An increase in creatine phosphokinase levels is possible. In this case, improvement or recovery after discontinuation of corticosteroids may occur only after many weeks or even several years.

Effect on ability to drive vehicles and operate machinery

Due to the possibility of developing adverse reactions from the nervous system (e.g., seizures), as well as from the organs of vision, persons taking the drug Solu-Cortef^® should exercise caution when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

A clinical syndrome of acute overdose of the drug has not been described. Hydrocortisone is removed by dialysis.

Drug Interactions

Inducers of hepatic microsomal enzymes, such as phenobarbital, phenytoin, and rifampicin, may increase the clearance of corticosteroids, which may require an increase in the dose of the drug to achieve the desired effect.

Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and reduce their clearance. In this case, the dose of corticosteroids should be reduced to avoid overdose phenomena.

Corticosteroids may increase the clearance of acetylsalicylic acid taken in high doses over a long period, which may lead to a decrease in serum salicylate concentrations or increase the risk of salicylate toxicity upon discontinuation of corticosteroids. In patients with hypoprothrombinemia, acetylsalicylic acid should be prescribed with caution in combination with corticosteroids.

Corticosteroids have varied effects on the action of indirect anticoagulants. Both enhancement and reduction of the effect of anticoagulants taken simultaneously with hydrocortisone have been reported. To maintain the required anticoagulant effect, constant monitoring of blood coagulation parameters is necessary.

Storage Conditions

Store at a temperature from 15°C (59°F) to 25°C (77°F) in a place inaccessible to children. The prepared solution should be stored at room temperature for no more than 72 hours in a light-protected place.

Shelf Life

The shelf life is 5 years.

Dispensing Status

By prescription.

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.