Cortef (Hydrocortisone)

CORTEF®

Pharmacia & Upjohn

Hydrocortisone

Corticosteroid

Action And Clinical Pharmacology: Hydrocortisone (cortisol) is a corticosteroid secreted by the adrenal cortex. In physiologic doses, it is administered to replace deficient endogenous hormones. In larger (pharmacologic) doses, hydrocortisone decreases inflammation and suppresses the immune response. It stimulates erythroid cells of the bone marrow, prolongs survival time of erythrocytes and platelets, and produces neutrophilia and eosinopenia. Hydrocortisone promotes protein catabolism, gluconeogenesis, and redistribution of fat from peripheral to central areas of the body. It reduces intestinal absorption and increases renal excretion of calcium.

In pharmacologic doses, systemically administered glucocorticoids suppress release of corticotropin from the pituitary. The degree and duration of hypothalamic-pituitary-adrenal (HPA) axis suppression produced is highly variable among patients and depends on the dose, frequency and time of administration, and duration of therapy. If suppressive doses are administered for prolonged periods, the adrenal cortex atrophies and patients develop cushingoid features and respond to stress like patients with primary adrenocortical insufficiency. The duration of anti-inflammatory activity approximately equals the duration of HPA-axis suppression. In one study, the duration of HPA-axis suppression after a single oral dose of hydrocortisone 250 mg was 1.25 to 1.5 days.

Hydrocortisone is extensively bound to the plasma proteins, corticosteroid binding globulin (transcortin) and albumin. With physiologic concentrations, it is bound primarily to transcortin and only 5 to 10% of cortisol in plasma is unbound.

Hydrocortisone is metabolized in most tissues, but primarily in the liver to biologically inactive compounds. The half-life of hydrocortisone may be prolonged in patients with hypothyroidism. Inactive metabolites are excreted by the kidneys, primarily as glucuronides and sulfates, but also as unconjugated products. Negligible amounts are excreted in bile.

Indications And Clinical Uses: Endocrine Disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance); congenital adrenal hyperplasia; nonsuppurative thyroiditis; hypercalcemia associated with cancer.

Nonendocrine Disorders: Rheumatic Disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: psoriatic arthritis, rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low dose maintenance therapy), ankylosing spondylitis, acute and subacute bursitis, acute non-specific tenosynovitis, acute gouty arthritis, post-traumatic osteoarthritis, synovitis of osteoarthritis, epicondylitis.

Collagen Diseases: During an exacerbation or as maintenance therapy in selected cases of systemic lupus erythematosus, acute rheumatic carditis, systemic dermatomyositis (polymyositis).

Dermatologic Diseases: pemphigus, bullous dermatitis herpeti-formis, severe erythema multiforme (Stevens-Johnson syndrome), exfoliative dermatitis, mycosis fungoides, severe psoriasis and severe seborrheic dermatitis.

Allergic States: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment: seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, serum sickness and drug hypersensitivity reactions.

Ophthalmic Diseases: Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: allergic conjunctivitis, keratitis, allergic corneal marginal ulcers, herpes zoster ophthalmicus, iritis and iridocyclitis, chorioretinitis, anterior segment inflammation, diffuse posterior uveitis and choroiditis, optic neuritis, sympathetic ophthalmia.

Respiratory Diseases: Symptomatic sarcoidosis, Leffler’s syndrome not manageable by other means, berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, aspiration pneumonitis.

Hematologic Disorders: Idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, erythroblastopenia (RBC anemia), congenital (erythroid) hypoplastic anemia.

Neoplastic Diseases: For palliative management of: leukemias and lymphomas in adults, acute leukemia of childhood.

Edematous States: To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus.

Gastrointestinal Diseases: To tide the patient over a critical period of the disease in: ulcerative colitis, regional enteritis.

CNS: Acute exacerbations of multiple sclerosis.

Miscellaneous: Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy, trichinosis with neurologic or myocardial involvement.

Contra-Indications: Systemic fungal infections and known hypersensitivity to hydrocortisone or components of the tablet.

Manufacturers’ Warnings In Clinical States: In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during and after the stressful situation is indicated.

Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infections with any pathogen including viral, bacterial, fungal, protozoan or helminthic infections, in any location in the body, may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents that affect cellular immunity, humoral immunity, or neutrophil function. These infections may be mild, but can be severe and at times fatal. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases.

Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in nonimmune children or adults on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled i.m. immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered. Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppresion may lead to Strongyloides hyperinfection and dissemination with widespread larval migration often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.

Allergic reactions (e.g., angioedema) may occur.

Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.

Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered to patients receiving immunosuppressive doses of corticosteroids. However the response to such vaccines may be diminished. Indicated immunization procedures may be undertaken in patients receiving non-immunosuppressive doses of corticosteroids.

The use of hydrocortisone in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen.

If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

There is no universal agreement on whether corticosteroids per se are responsible for peptic ulcers encountered during therapy; however, glucocorticoid therapy may mask the symptoms of peptic ulcer so that perforation or hemorrhage may occur without significant pain.

Osteoporosis is a common but infrequently recognized adverse effect associated with a long-term use of large doses of glucocorticoid.

Growth may be suppressed in children receiving long-term daily, divided dose glucocorticoid therapy and use of such regimen should be restricted to the most urgent indications. Alternate day glucocorticoid therapy usually avoids or minimizes this side effect.

Host defenses are impaired in patients receiving large doses of glucocorticoids and this effect increases susceptibility to fungus infections as well as bacterial and viral infections.

Pregnancy and Lactation: Some animal studies have shown that corticosteroids, when administered to the mother at high doses, may cause fetal malformations. Adequate human reproduction studies have not been done with corticosteroids. Therefore, the use of this drug in pregnancy, nursing mothers or women of childbearing potential requires that the benefits of the drug be carefully weighed against the potential risk to the mother and embryo or fetus. Since there is inadequate evidence of safety in human pregnancy, this drug should be used in pregnancy only if clearly needed.

Corticosteroids readily cross the placenta. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy must be carefully observed and evaluated for signs of adrenal insufficiency. There are no known effects of corticosteroids on labour and delivery. Corticosteroids are excreted in breast milk.

Precautions: Drug induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.

There is an enhanced effect of corticosteroids on patients with hypothyroidism and in those with cirrhosis.

Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation.

The lowest possible dose of corticosteroid should be used to control the condition under treatment and when reduction in dosage is possible, the reduction should be gradual.

Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.

ASA and nonsteroidal anti-inflammatory agents should be used cautiously in conjunction with corticosteroids in patients with hypoprothrombinemia.

Corticosteroids should be used with caution in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess or other pyogenic infection; diverticulitis; fresh intestinal anastomoses; active or latent peptic ulcer; renal insufficiency; hypertension; osteoporosis; or myasthenia gravis.

Because complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used.

Convulsions have been reported with concurrent use of methylprednisolone and cyclosporine. Since concurrent administration of these agents results in a mutual inhibition of metabolism, it is possible that convulsions and other adverse events associated with the individual use of either drug may be more apt to occur.

Drug Interactions: The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose ASA. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when the corticosteroid is withdrawn. ASA should be used cautiously in conjunction with corticosteroids in patients suffering from hypothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect.

Information for the Patient: Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed medical advice should be sought without delay.

Adverse Reactions: Note: The following are typical for all systemic corticosteroids. Their inclusion in this list does not necessarily indicate that the specific event has been observed with this particular formulation.

Fluid and Electrolyte Disturbances: sodium retention; fluid retention; congestive heart failure in susceptible patients; potassium loss, hypokalemic alkalosis; hypertension.

Musculoskeletal: steroid myopathy; muscle weakness; osteoporosis; pathologic fractures; vertebral compression fractures, aseptic necrosis of femoral and humeral heads, loss of muscle mass, tendon rupture, particular of the Achilles.

Gastrointestinal: peptic ulcer with possible perforation and hemorrhage; pancreatitis; abdominal distention; ulcerative esophagitis; increases in AST, ALT and alkaline phosphatase have been observed following corticosteroid treatment. These changes are usually small, not associated with any clinical significance.

Dermatologic: impaired wound healing; petechiae and ecchymoses; thin fragile skin; increased sweating, facial erythema may suppress reactions to skin tests.

Metabolic: negative nitrogen balance due to protein catabolism.

Neurological: increased intracranial pressure; pseudotumor cerebri; psychic derangements and seizures; convulsions, vertigo and headache.

Endocrine: menstrual irregularities; development of cushingoid state; suppression of pituitary-adrenal axis particularly at times of stress as in trauma, surgery or illness; decreased carbohydrate tolerance; manifestations of latent diabetes mellitus; increased requirements for insulin or oral hypoglycemic agents in diabetes; suppression of growth in children.

Ophthalmic: posterior subcapsular cataracts; increased intraocular pressure; exophthalmos glaucoma.

Immune System: masking of infections; latent infections becoming active; opportunistic infections; hypersensitivity reactions including anaphylaxis; may suppress reactions to skin tests.

Dosage And Administration: The initial dosage may vary from 20 to 240 mg of hydrocortisone per day depending on the specific disease entity being treated. In situations of less severity, lower doses will generally suffice, while in selected patients higher initial doses may be required. The initial dosage should be maintained or adjusted until a satisfactory response is noted. If after a reasonable period of time there is a lack of satisfactory clinical response, hydrocortisone should be discontinued and the patient transferred to another appropriate therapy.

It should be emphasized that dosage requirements are variable and must be individualized on the basis of the disease under treatment and the response of the patient.

After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. It should be kept in mind that constant monitoring is needed in regard to drug dosage. Included in the situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment; in this latter situation it may be necessary to increase the dosage of hydrocortisone for a period of time consistent with the patient’s condition.

Availability And Storage: 10 mg: Each white, round, scored, compressed tablet, engraved “Cortef 10”, contains: hydrocortisone 10 mg. Nonmedicinal ingredients: calcium stearate, cornstarch, lactose, mineral oil, sorbic acid, sucrose.

20 mg: Each white, round, scored, compressed tablet, engraved “Cortef 20”, contains: hydrocortisone 20 mg. Nonmedicinal ingredients: calcium stearate, cornstarch, lactose, mineral oil, sorbic acid, sucrose. Sodium:

CORTEF® Pharmacia & Upjohn Hydrocortisone Corticosteroid

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