Cortef^® (Tablets) Instructions for Use

Marketing Authorization Holder

Pfizer, Inc. (USA)

Manufactured By

Patheon Inc. (Canada)

Labeled By

PACKAGING COORDINATORS, LLC (USA)

Quality Control Release

PATHEON Inc. (Canada)

ATC Code

H02AB09 (Hydrocortisone)

Active Substance

Hydrocortisone (Rec.INN registered by WHO)

Dosage Form

Cortef®

Tablets 10 mg: 100 pcs.

Dosage Form, Packaging, and Composition

Tablets are white, round, biconvex, with a score on one side and an imprint of “CORTEF” and the number “10” on the other side.

Excipients: lactose monohydrate – 231 mg, corn starch – 10.94 mg, sucrose – 4.44 mg, calcium stearate – 1.3 mg, mineral oil – 0.95 mg, sorbic acid – 0.01 mg.

100 pcs. – HDPE bottles (1) – cardboard packs (a first-opening control feature may be applied).

Clinical-Pharmacological Group

Corticosteroids for oral administration

Pharmacotherapeutic Group

Glucocorticosteroid

Pharmacological Action

Glucocorticosteroid. Suppresses the functions of leukocytes and tissue macrophages. Limits the migration of leukocytes to the area of inflammation. Impairs the ability of macrophages for phagocytosis, as well as for the formation of interleukin-1. Promotes stabilization of lysosomal membranes, thereby reducing the concentration of proteolytic enzymes in the area of inflammation. Reduces capillary permeability caused by the release of histamine. Suppresses fibroblast activity and collagen formation.

Inhibits the activity of phospholipase A₂, which leads to suppression of the synthesis of prostaglandins and leukotrienes. Suppresses the release of COX (mainly COX-2), which also contributes to the reduction of prostaglandin production.

Reduces the number of circulating lymphocytes (T- and B-cells), monocytes, eosinophils, and basophils due to their movement from the vascular bed into the lymphoid tissue; suppresses antibody formation.

Hydrocortisone suppresses the release of ACTH and β-lipotropin by the pituitary gland but does not reduce the level of circulating β-endorphin. Inhibits the secretion of TSH and FSH.

When applied directly to blood vessels, it has a vasoconstrictor effect.

Hydrocortisone has a pronounced dose-dependent effect on the metabolism of carbohydrates, proteins, and fats. Stimulates gluconeogenesis, promotes the uptake of amino acids by the liver and kidneys, and increases the activity of gluconeogenesis enzymes. In the liver, Hydrocortisone enhances glycogen storage by stimulating the activity of glycogen synthase and the synthesis of glucose from protein metabolism products. The increase in blood glucose levels activates insulin secretion.

Hydrocortisone suppresses glucose uptake by fat cells, which leads to the activation of lipolysis. However, due to increased insulin secretion, lipogenesis is stimulated, leading to fat accumulation.

It has a catabolic effect in lymphoid and connective tissue, muscles, adipose tissue, skin, and bone tissue. To a lesser extent than mineralocorticoids, it affects water-electrolyte metabolism processes: promotes the excretion of potassium and calcium ions, and the retention of sodium ions and water in the body. Osteoporosis and Cushing’s syndrome are the main factors limiting long-term glucocorticosteroid therapy. As a result of the catabolic effect, growth suppression in children is possible.

In high doses, Hydrocortisone can increase the excitability of brain tissue and contribute to a lowering of the seizure threshold. Stimulates excessive production of hydrochloric acid and pepsin in the stomach, which contributes to the development of peptic ulcer.

When used systemically, the therapeutic activity of hydrocortisone is due to its anti-inflammatory, anti-allergic, immunosuppressive, and antiproliferative effects.

When used externally and locally, the therapeutic activity of hydrocortisone is due to its anti-inflammatory, anti-allergic, and anti-exudative (due to the vasoconstrictor effect) effects.

It is 4 times less potent than prednisolone in anti-inflammatory activity and exceeds other glucocorticosteroids in mineralocorticoid activity.

Pharmacokinetics

Plasma protein binding – 40-90%. Metabolized primarily in the liver. T_1/2 – 80-120 min. Excreted by the kidneys mainly in the form of metabolites.

Indications

For parenteral administration: acute adrenal insufficiency, immediate-type allergic reactions, status asthmaticus, prevention and treatment of shock, myocardial infarction complicated by cardiogenic shock, thyrotoxic crisis, thyroiditis, congenital adrenal hyperplasia, hypercalcemia due to neoplastic disease, short-term or supplementary therapy in the acute period of rheumatic diseases, collagen diseases, pemphigus, bullous herpetiform dermatitis (Duhring’s disease), polymorphic bullous erythema, exfoliative dermatitis, mycosis fungoides, severe forms of psoriasis and seborrheic dermatitis, severe acute and chronic allergic and inflammatory processes involving the eyes, symptomatic sarcoidosis, Loeffler’s syndrome not amenable to other types of therapy, berylliosis, focal or disseminated form of tuberculosis with simultaneous anti-tuberculosis chemotherapy, aspiration pneumonitis, idiopathic thrombocytopenic purpura in adults (only IV!), secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, erythroblastopenia, congenital (erythroid) hypoplastic anemia, palliative therapy for leukemias and lymphomas in adults, for acute leukemias in children, to enhance diuresis or to reduce proteinuria in nephrotic syndrome without uremia, in nephrotic syndrome of idiopathic type or in lupus erythematosus, in the critical stage of ulcerative colitis and regional enteritis (as systemic treatment), tuberculous meningitis with the development of subarachnoid block or its threat (in combination with anti-tuberculosis chemotherapy), trichinellosis with nervous system or myocardial involvement, bronchial asthma, joint diseases.

For local administration: inflammation of the anterior segment of the eyeball with intact corneal epithelium and after injuries and surgical interventions on the eyeball.

For external use: allergic dermatitis, seborrhea, various forms of eczema, neurodermatitis, psoriasis, prurigo, lichen planus verrucosus.

ICD codes

Dosage Regimen

For parenteral administration. The dosage regimen is individual. It is administered IV bolus, IV drip, rarely – IM. For emergency therapy, IV administration is recommended. The initial dose is 100 mg (administered over 30 sec) – 500 mg (administered over 10 min), then repeated every 2-6 hours, depending on the clinical situation. High doses should be used only until the patient’s condition stabilizes, but usually not more than 48-72 hours, as hypernatremia may develop. For children – at least 25 mg/kg/day. As a depot form, it is administered intra- or periarticularly at a dose of 5-50 mg once with an interval of 1-3 weeks. IM – 125-250 mg/day.

In ophthalmology, it is used 2-3 times/day.

Externally – 1-3 times/day.

Adverse Reactions

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

From the metabolism: increased excretion of calcium ions, hypocalcemia, weight gain, negative nitrogen balance (increased protein breakdown), increased sweating, fluid and sodium ion retention (peripheral edema), hypernatremia, hypokalemic syndrome (including hypokalemia, arrhythmia, myalgia or muscle spasm, unusual weakness and fatigue).

From the Central Nervous System delirium, disorientation, euphoria, hallucinations, manic-depressive psychosis, depression, paranoia, increased intracranial pressure, nervousness or anxiety, insomnia, dizziness, vertigo, pseudotumor cerebelli, headache, seizures.

From the Cardiovascular System arrhythmias, bradycardia (up to cardiac arrest); development (in predisposed patients) or worsening of chronic heart failure, ECG changes characteristic of hypokalemia, increased blood pressure, hypercoagulation, thromboses. In patients with acute and subacute myocardial infarction – spread of the necrosis focus, slowed formation of scar tissue, which can lead to rupture of the heart muscle; with intracranial administration – nosebleed.

From the Digestive System nausea, vomiting, pancreatitis, steroid ulcer of the stomach and duodenum, erosive esophagitis, gastrointestinal bleeding and perforation, increased or decreased appetite, flatulence, hiccups; rarely – increased activity of hepatic transaminases and alkaline phosphatase.

From the Sensory Organs sudden loss of vision (with parenteral administration in the head, neck, nasal turbinates, scalp, deposition of drug crystals in the eye vessels is possible), 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.

From the Musculoskeletal System slowed 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, decreased muscle mass (atrophy); with intra-articular injection – increased joint pain.

Dermatological Reactions delayed wound healing, petechiae, ecchymoses, skin thinning, hyper- or hypopigmentation, steroid acne, striae, tendency to develop pyoderma and candidiasis.

Allergic Reactions generalized (including skin rash, skin itching, anaphylactic shock), local allergic reactions.

Effects due to Immunosuppressive Action: development or exacerbation of infections (concomitant use of immunosuppressants and vaccination contribute to the appearance of this side effect).

Local Reactions with parenteral administration – burning, numbness, pain, paresthesia and infections at the injection site; rarely – necrosis of surrounding tissues, scar formation at the injection site; with intramuscular injection (especially into the deltoid muscle) – atrophy of the skin and subcutaneous tissue.

Other leukocyturia, withdrawal syndrome.

With intravenous administration – arrhythmias, facial flushing, seizures.

With Topical Application rarely – itching, hyperemia, burning, dryness, folliculitis, acne, hypopigmentation, perioral dermatitis, allergic dermatitis, skin maceration, secondary infection, skin atrophy, striae, miliaria. With prolonged use or application to large skin areas, the development of systemic side effects characteristic of corticosteroids is possible.

Contraindications

For short-term use for vital indications – hypersensitivity to hydrocortisone.

For intra-articular injection and injection directly into the lesion site previous arthroplasty, pathological bleeding (endogenous or caused by anticoagulant use), intra-articular bone fracture, infectious (septic) inflammatory process in the joint and periarticular infections (including in the anamnesis), as well as general infectious disease, severe periarticular osteoporosis, absence of signs of inflammation in the joint (“dry” joint, e.g., in osteoarthritis without synovitis), severe bone destruction and joint deformity (sharp narrowing of the joint space, ankylosis), joint instability as an outcome of arthritis, aseptic necrosis of the epiphyses forming the joint.

For Topical Application bacterial, viral, fungal skin diseases, skin tuberculosis, skin manifestations of syphilis, skin tumors, post-vaccination period, impaired skin integrity (ulcers, wounds), childhood (under 2 years, for anal itching – under 12 years), rosacea, acne vulgaris, perioral dermatitis.

For Use in Ophthalmology bacterial, viral, fungal eye diseases, tuberculous eye lesions, trachoma, violation of the integrity of the ocular epithelium.

Use in Pregnancy and Lactation

Use during pregnancy is possible only if the intended benefit to the mother outweighs the potential risk to the fetus; it is recommended to use minimal doses and short-term therapy. Children whose mothers received Hydrocortisone during pregnancy should be carefully monitored for signs of adrenal cortex insufficiency.

If use during lactation is necessary, the issue of discontinuing breastfeeding should be decided.

In experimental studies, it has been shown that corticosteroids can cause fetal development disorders. There is currently no clear confirmation of this data in humans.

Use in Hepatic Impairment

Use with caution in severe hepatic insufficiency.

Use in Renal Impairment

Use with caution in severe chronic renal insufficiency.

Pediatric Use

Contraindications for topical application childhood under 2 years, for anal itching – under 12 years.

Special Precautions

Use with caution in parasitic and infectious diseases of viral, fungal or bacterial nature (current or recently suffered, including recent contact with a patient) – herpes simplex, herpes zoster (viremic phase), chickenpox, measles, amebiasis, strongyloidiasis (established or suspected), systemic mycosis; active and latent tuberculosis. Use in severe infectious diseases is permissible only against the background of specific therapy.

Use with caution within 8 weeks before and 2 weeks after vaccination, with lymphadenitis after BCG vaccination, with immunodeficiency states (including AIDS or HIV infection).

Use with caution in gastrointestinal diseases: gastric and duodenal ulcer, esophagitis, gastritis, acute or latent peptic ulcer, recently created intestinal anastomosis, nonspecific ulcerative colitis with threat of perforation or abscess formation, diverticulitis.

Use with caution in diseases of the cardiovascular system, including after recent myocardial infarction (in patients with acute and subacute myocardial infarction, spread of the necrosis focus, slowed formation of scar tissue and, as a result, rupture of the heart muscle is possible), with decompensated chronic heart failure, arterial hypertension, hyperlipidemia), in endocrine diseases – diabetes mellitus (including impaired carbohydrate tolerance), thyrotoxicosis, hypothyroidism, Cushing’s disease, with severe chronic renal and/or hepatic insufficiency, nephrourolithiasis, with hypoalbuminemia and conditions predisposing to its occurrence, with systemic osteoporosis, myasthenia gravis, acute psychosis, obesity (III-IV degree), with poliomyelitis (except for the form of bulbar encephalitis), open-angle and closed-angle glaucoma, pregnancy, lactation.

If intra-articular injection is necessary, use with caution in patients with a generally severe condition, with ineffectiveness (or short duration) of the action of 2 previous injections (taking into account the individual properties of the corticosteroids used).

If hydrocortisone is insufficiently effective within 48-72 hours and longer therapy is necessary, it is advisable to replace Hydrocortisone with another glucocorticoid drug that does not cause sodium retention in the body. During treatment with hydrocortisone, it is recommended to prescribe a diet with restricted sodium and increased potassium content.

Hydrocortisone-induced relative adrenal insufficiency may persist for several months after its discontinuation. Considering this, during stressful situations occurring in this period, hormone therapy is resumed with the simultaneous administration of salts and/or mineralocorticoids.

In patients with active tuberculosis, Hydrocortisone should be used in combination with appropriate anti-tuberculosis therapy. In the latent form of tuberculosis or during the turn of tuberculin tests, the patient’s condition should be carefully monitored, and if necessary, chemoprophylaxis should be carried out.

Drug Interactions

With simultaneous use, Hydrocortisone increases the toxicity of cardiac glycosides (due to resulting hypokalemia, the risk of arrhythmias increases); with acetylsalicylic acid – accelerates its excretion and reduces its concentration in blood plasma (upon discontinuation of hydrocortisone, the concentration of salicylates in the blood increases and the risk of side effects increases); with paracetamol – increased risk of hepatotoxic action of paracetamol (induction of liver enzymes and formation of a toxic metabolite of paracetamol); with cyclosporine – increased side effects of hydrocortisone due to inhibition of its metabolism; with ketoconazole – increased side effects of hydrocortisone due to a decrease in its clearance.

Hydrocortisone reduces the effectiveness of hypoglycemic agents; enhances the effect of indirect anticoagulants of coumarin derivatives.

Hydrocortisone reduces the effect of vitamin D on the absorption of calcium ions in the intestinal lumen. Ergocalciferol and parathyroid hormone prevent the development of osteopathy caused by corticosteroids.

Hydrocortisone enhances the metabolism of isoniazid, mexiletine (especially in “fast acetylators”), leading to a decrease in their plasma concentrations; increases (with long-term therapy) the content of folic acid; reduces the concentration of praziquantel in the blood.

Hydrocortisone in high doses reduces the effect of somatropin.

Hypokalemia caused by corticosteroids may increase the severity and duration of muscle blockade against the background of muscle relaxants.

Antacids reduce the absorption of corticosteroids.

With simultaneous use with corticosteroids, thiazide diuretics, carbonic anhydrase inhibitors, other corticosteroids, amphotericin B increase the risk of hypokalemia; drugs containing sodium ions – edema and increased blood pressure.

NSAIDs and ethanol increase the risk of ulceration of the gastrointestinal mucosa and bleeding; in combination with NSAIDs for the treatment of arthritis, a reduction in the dose of corticosteroids is possible due to summation of the therapeutic effect. Indomethacin, displacing corticosteroids from binding with albumins, increases the risk of their side effects.

Amphotericin B and carbonic anhydrase inhibitors increase the risk of osteoporosis.

The therapeutic effect of corticosteroids is reduced under the influence of inducers of microsomal liver enzymes (including phenytoin, barbiturates, ephedrine, theophylline, rifampicin) due to an increase in the rate of metabolism of these substances.

Inhibitors of adrenal cortex function (including mitotane) may necessitate an increase in the dose of corticosteroids.

The clearance of corticosteroids increases against the background of thyroid hormone preparations.

Immunosuppressants increase the risk of infections and lymphoma or other lymphoproliferative disorders associated with the Epstein-Barr virus.

Estrogens (including oral estrogen-containing contraceptives) reduce the clearance of corticosteroids, prolong their T_1/2 and their therapeutic and toxic effects. The appearance of hirsutism and acne is facilitated by the simultaneous use of other steroid hormonal agents – androgens, estrogens, anabolics, oral contraceptives.

Tricyclic antidepressants may enhance the severity of depression caused by corticosteroid use (not indicated for the therapy of these side effects).

The risk of cataract development increases when used against the background of other corticosteroids, antipsychotic agents (neuroleptics), carbobutamide and azathioprine. Simultaneous administration with m-cholinolytics, as well as with agents possessing m-cholinolytic action (including antihistamines, tricyclic antidepressants), with nitrates contributes to increased intraocular pressure.

With simultaneous use of corticosteroids with live antiviral vaccines and against the background of other types of immunization, the risk of virus activation and development of infections increases.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

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.