This monograph deals with the systemic use of corticosteroids by the oral, iv and im routes. It does not address local (e.g., intra-articular) use of corticosteroids.

Corticosteroids are synthetic analogues of hormones secreted by the adrenal cortex. They possess anti-inflammatory (glucocorticoid) and/or salt-retaining (mineralocorticoid) properties to varying degrees (see Table 1). Glucocorticoids affect almost all body systems and cause varied metabolic effects. They promote protein catabolism, gluconeogenesis, and redistribution of fat from peripheral to central areas of the body. They reduce intestinal absorption and increase renal excretion of calcium. Mineralocorticoids affect electrolyte and fluid balance by acting on the distal renal tubule to promote sodium reabsorption and potassium and hydrogen excretion.

The mechanism of action of corticosteroids is not fully understood. Glucocorticoids decrease inflammation through multiple mechanisms, including stabilization of leukocyte lysosomal membranes, inhibition of macrophage accumulation in inflamed areas, and reduction of capillary permeability. They suppress the body's immune responses through mechanisms such as reduction of activity and volume of the lymphatic system, decreased immunoglobulin and complement concentrations as well as decreased passage of immune complexes through basement membranes. They also stimulate the erythroid cells of bone marrow and lengthen the survival time of erythrocytes and platelets. The mechanism of action for the antiemetic effect of corticosteroids is not well established.

Most glucocorticoids in the form of free alcohols, ketones or acetates are readily absorbed when administered orally. With im administration, the rate of absorption of the lipid soluble acetate and acetonide esters is much slower than that of the water soluble sodium phosphate and sodium succinate salts. A water soluble corticosteroid salt should be administered iv to achieve a rapid onset of action.

In animal studies, most glucocorticoids have been shown to be removed rapidly from blood and distributed to muscles, liver, skin, intestine and kidneys. They bind to plasma proteins to varying extents. Because only unbound drug is pharmacologically active, patients with low serum albumin concentrations may be more susceptible to the effects of glucocorticoids than patients with normal serum albumin concentrations. Glucocorticoids cross the placenta and may be distributed into breast milk.

Cortisone and prednisone are reduced to their pharmacologically active forms, hydrocortisone and prednisolone respectively. These active compounds are then metabolized, primarily in the liver, to biologically inactive compounds. Inactive metabolites, primarily glucuronides and sulfates, are excreted by the kidneys. Small amounts of unmetabolized drug are excreted in urine and bile.

Table 1: Corticosteroids: Systemic

Comparative Properties

Drug	Biologic Half-Life (hours)	Equivalent Anti-inflammatory Dose (mg)a	Relative Mineralo-corticoid Potency
Glucocorticoids:
Short-acting	8 to 12
Cortisone		25	2
Hydrocortisone		20	2
Intermediate-acting	18 to 36
Methylprednisolone		4	0
Prednisolone		5	1
Prednisone		5	1
Triamcinolone		4	0
Long-acting	36 to 54
Betamethasone		0.6	0
Dexamethasone		0.75	0
Mineralocorticoid:
Fludrocortisone	12 to 24	10	125

^a. Equivalent doses are approximations and may not apply to all diseases or routes of administration. Duration of HPA axis suppression and degree of mineralocorticoid activities must be considered separately.

Endocrine Disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogues 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 some forms of cancer. Used parenterally in acute adrenal cortical insufficiency (hydrocortisone or cortisone is the drug of choice), preoperatively or in the event of serious trauma or illness with known adrenal insufficiency or when adrenal cortical reserve is doubtful, shock unresponsive to conventional therapy if adrenal cortical insufficiency exists or is suspected.

Rheumatic Disorders and Collagen Diseases: As adjunctive therapy for short-term administration (for acute episode or exacerbation) in: psoriatic and rheumatoid arthritis (selected cases may require low dose maintenance therapy), ankylosing spondylitis, acute and subacute bursitis, acute nonspecific tenosynovitis, acute gouty arthritis; for exacerbation or maintenance therapy in selected cases of systemic lupus erythematosus, acute rheumatic carditis, systemic dermatomyositis, polymyositis, polymyalgia rheumatica, giant-cell arteritis.

Dermatologic Diseases: Blistering immune diseases such as pemphigus vulgaris, bullous pemphigoid and acute severe contact dermatitis; widespread and recalcitrant atopic dermatitis; other inflammatory skin diseases such as lichen planus, vasculitis or acne fulminans.

Allergic Conditions: For short-term administration in the control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment such as seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, serum sickness and drug hypersensitivity reactions. Parenteral therapy is indicated for urticarial transfusion reactions, angioedema and anaphylaxis (epinephrine is the drug of choice).

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 (but not herpes simplex), iritis and iridocyclitis, chorioretinitis, anterior segment inflammation, diffuse posterior uveitis and choroiditis, optic neuritis, retrobulbar neuritis, sympathetic ophthalmia.

Respiratory Diseases: moderate to severe croup, symptomatic sarcoidosis, Löffler's syndrome not manageable by other means, berylliosis, fulminating or disseminated pulmonary tuberculosis when concurrently accompanied by appropriate antituberculous chemotherapy, aspiration pneumonitis, acute exacerbations of chronic obstructive pulmonary disease, diffuse interstitial pulmonary fibrosis (Hamman-Rich syndrome), adjunctive therapy in the treatment of selected cases of Pneumocystis jiroveci pneumonia (PJP) in patients with HIV.

Hematological Disorders: idiopathic thrombocytopenia purpura and secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, aplastic crisis, congenital (erythroid) hypoplastic anemia.

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

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

Gastrointestinal Diseases: as adjunctive therapy in the treatment of ulcerative colitis and regional enteritis (Crohn's disease).

Nervous System: acute exacerbations of multiple sclerosis. Dexamethasone may be used to treat patients with cerebral edema associated with primary or metastatic brain tumors, neurosurgery, pseudotumor cerebri and cerebral vascular accident (acute stroke) excluding intracerebral hemorrhage. Dexamethasone may also be used in the preoperative preparation of patients with increased intracranial pressure secondary to brain tumors or for palliation of patients with inoperable or recurrent brain neoplasms.

Organ Transplants: used in high dose concurrently with other immunosuppressive drugs to prevent rejection of transplanted organs and to prevent and treat graft versus host disease after bone marrow transplant.

Miscellaneous: tuberculosis meningitis with subarachnoid block or impending block when concurrently accompanied by appropriate antituberculous chemotherapy; acute bacterial meningitis; trichinosis with neurologic or myocardial involvement; postoperative dental inflammatory reactions; prevention of chemotherapy-associated nausea and vomiting. Recent guidelines suggest that corticosteroids are indicated in selected patients in septic shock (e.g., patients with relative adrenal insufficiency who require vasopressors to maintain adequate blood pressure). Dexamethasone is also used in the diagnostic testing of adrenocortical hyperfunction and antenatal prophylaxis of neonatal respiratory distress.

Hypersensitivity to the product and its constituents; systemic fungal infections; administration of live virus vaccines in patients receiving immunosuppressive corticosteroid doses.

Adrenal Suppression: Following prolonged therapy, abrupt discontinuation may result in a withdrawal syndrome and secondary adrenocortical insufficiency. Symptoms of adrenal insufficiency resulting from rapid withdrawal include: nausea, fatigue, anorexia, dyspnea, hypotension, hypoglycemia, myalgia, fever, malaise, arthralgia, dizziness, desquamation of skin and fainting. This type of relative insufficiency may persist for up to a year after discontinuation of therapy; therefore, in any stressful situation occurring during that period, reinstitute hormone therapy. If the patient is receiving corticosteroids already, the dosage may have to be increased. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid may be needed.

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

Gastrointestinal Effects: The association between peptic ulceration and corticosteroid therapy remains controversial. However, corticosteroid therapy may mask the symptoms of peptic ulcer. Perforation or hemorrhage may occur without significant pain.

Corticosteroids should be used with caution in patients with diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer and in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess or other pyogenic infection.

Hypersensitivity: Rare instances of anaphylactoid reactions have occurred in patients receiving parenteral corticosteroid therapy. Appropriate precautionary measures should be taken prior to parenteral administration, especially when the patient has a history of allergy to any drug. Some corticosteroid products contain tartrazine and sodium bisulfite, both of which may cause severe allergic reactions in susceptible individuals.

Immunosuppression: Immunization procedures should generally not be undertaken in patients receiving systemic corticosteroids, especially those on high doses, because of possible neurological complications and a lack of antibody response. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy. Corticosteroids may suppress reactions to patch tests.

Infections: When subjected to unusual stress, patients on corticosteroid therapy require increased dosage of rapidly-acting corticosteroids before, during and after the stressful situation.

Corticosteroids should only be used in active tuberculosis in cases of fulminating disseminated tuberculosis 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.

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. If corticosteroids have to be used in the presence of bacterial infections, institute appropriate anti-infective therapy. Patients exposed to certain infections (e.g., measles, chickenpox) should seek medical advice.

Corticosteroids may activate latent amebiasis. Amebiasis should be ruled out before giving corticosteroids to a patient who has spent time in the tropics or has unexplained diarrhea.

Ocular Effects: Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal ulceration and perforation. 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.

Renal Function Impairment: Edema may occur in the presence of renal disease with a fixed or decreased glomerular filtration rate. Caution is advised when corticosteroids are used in patients with renal insufficiency, acute glomerulonephritis and chronic nephritis.

Because complications of treatment with corticosteroids are dependent on the dosage regimen, a risk/benefit decision must be made in each individual case with respect to dose and duration of treatment and whether daily or intermittent therapy should be used. The lowest effective corticosteroid dose should be used to control the condition under treatment. Patients on long-term corticosteroid therapy who are subjected to unusual stress such as injury or surgery may require an increased dosage of corticosteroid during and after the stress.

When corticosteroids are used in myasthenia gravis, hospitalization with careful observation is recommended because a transient worsening of symptoms, possibly leading to respiratory distress, may precede clinical improvement.

Corticosteroid therapy can cause mental or mood disturbances including hypomania, mania, depression and psychosis. These reactions appear to be dose-related and more commonly seen in the first few weeks of therapy, but are sometimes seen following sharp decreases in corticosteroid dosage or during pulse therapy. Existing mood instability or psychotic tendencies may be aggravated by corticosteroids.

Avascular or aseptic necrosis of the femoral or humeral head has been associated with long-term corticosteroid treatment; however, it has also occurred in patients receiving high dose, short-term therapy. This adverse effect is more likely to occur in patients with a predisposing illness such as rheumatoid arthritis or systemic lupus erythematosis.

Systemic corticosteroid therapy has been associated with loss of bone density and osteoporosis, which are reversible after discontinuation of the corticosteroid. Adults chronically taking systemic corticosteroids should maintain an intake of at least 1500 mg of calcium and 800 IU of vitamin D daily, either through diet or supplementation, to prevent corticosteroid-induced osteoporosis. Some oral bisphosphonates are used to treat or prevent corticosteroid-induced osteoporosis and should be prescribed to patients at risk. (see Bisphosphonates: Oral, CPhA Monograh).

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

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

To minimize the likelihood and severity of dermal atrophy, corticosteroids should not be injected sc. Injections into the deltoid area or repeat injections into any one site should also be avoided.

The use of systemic corticosteroids in pregnant women has not been associated with an increased incidence of major fetal malformations. However, the incidence of oral cleft may be increased. Monitoring of neonates for signs of expected physiologic effects of exogenous corticosteroids is recommended, especially if high doses were used during pregnancy.

The extent of corticosteroid excretion in breast milk is thought to be clinically insignificant. The use of systemic corticosteroid therapy is generally considered to be compatible with breast-feeding. Caution is advised if extremely high doses are used.

Avoid prolonged therapy with systemic corticosteroids in infants and children if possible since corticosteroids may suppress growth. If deemed essential to institute chronic therapy, consider alternate day therapy to minimize this side effect. Growth and development should be closely monitored.

See Table 2.

Table 2: Corticosteroids: Systemic

Corticosteroid Drug Interactions

Drug(s) Involved	Description of Interaction	Action Required
Anticholinesterase agents (e.g., neostigmine, pyridostigmine)	Corticosteroids antagonize the effect of anticholinesterase agents, resulting in severe weakness in patients with myasthenia gravis.	Withdraw anticholinesterase medication if possible at least 24 hours prior to initiation of corticosteroid therapy.
Antidiabetic agents, including insulin	Corticosteroids may increase blood glucose concentrations.	Monitor blood glucose concentrations. Dose of antidiabetic agent may need to be increased.
Cyclosporine	Corticosteroid clearance may be decreased and plasma concentrations of cyclosporine may be increased through mutual inhibition of metabolism. Seizures have been reported in patients receiving high dose corticosteroid and cyclosporine concurrently.	Monitor cyclosporine levels closely; adjust dose of both medications if required.
Digoxin	Corticosteroid-induced potassium loss may potentiate digoxin toxicity.	Monitor serum potassium.
Estrogens	Corticosteroid clearance may be decreased.	Decrease corticosteroid dose if required.
Hepatic microsomal enzyme inducers (e.g., barbiturates, phenytoin, rifampin)	Corticosteroid clearance may be increased through enzyme induction.	Increase corticosteroid dose if required.
Hepatic microsomal enzyme inhibitors (e.g., erythromycin, ketoconazole)	Corticosteroid clearance may be decreased through enzyme inhibition.	Decrease corticosteroid dose if required.
Isoniazid	Corticosteroids may increase hepatic metabolism and/or excretion of isoniazid.	Increase isoniazid dose if required.
Oral anticoagulants	Corticosteroids may increase or decrease anticoagulant action.	Monitor INR and adjust anticoagulant dose if required.
Potassium-depleting diuretics (e.g., thiazides, furosemide, ethacrynic acid)	Corticosteroid potassium-wasting effect is enhanced.	Monitor serum potassium and add supplement if required.
Nonsteroidal anti-inflammatory drugs (NSAIDs)	ASA: Corticosteroids may increase renal clearance of salicylate, resulting in either a decrease in salicylate efficacy, or salicylate toxicity when corticosteroid dose is decreased or discontinued.	Monitor salicylate level.
	All NSAIDs (including low-dose ASA): Concomitant use may increase the risk of peptic ulceration.	Avoid concurrent administration. If deemed necessary, monitor closely for gastrointestinal side effects and consider prophylaxis with misoprostol or a proton pump inhibitor.
Vaccines or toxoids	Corticosteroids inhibit antibody response resulting in enhanced toxicity from or diminished response to vaccines or toxoids.	Avoid use of vaccines or toxoids in patients receiving immunosuppressive doses of corticosteroids (see Warnings).

Drug-Laboratory Test Interactions: Corticosteroids may decrease I¹³¹ uptake and produce false negative results in the nitroblue tetrazolium test for systemic bacterial infection.

thromboembolism; fat embolism; hypercholesterolemia; accelerated atherosclerosis; cardiac arrhythmias or ECG changes due to potassium deficiency; syncope; aggravation of hypertension; myocardial rupture following recent MI; reports of cardiac arrhythmias, fatal arrest or circulatory collapse following rapid administration of iv methylprednisolone greater than 0.5 g given over a period of less than 10 minutes.

impaired wound healing; thin fragile skin; petechiae and ecchymoses; facial erythema; striae; hirsutism; acneiform eruptions; suppressed reactions to skin tests; hypersensitivity reactions such as allergic dermatitis, urticaria, angioneurotic edema.

decreased carbohydrate tolerance; hyperglycemia; glycosuria; increased requirements for oral hypoglycemics or insulin in diabetes; manifestations of latent diabetes mellitus; menstrual irregularities; development of cushingoid state; suppression of growth in children; secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness; increased sweating.

sodium retention; fluid retention; congestive heart failure in susceptible patients; potassium loss; hypokalemic alkalosis; hypertension; hypocalcemia.

nausea, vomiting, anorexia which may result in weight loss; increased appetite which may result in weight gain; diarrhea or constipation, abdominal distention, pancreatitis, gastric irritation and ulcerative esophagitis; peptic ulcer with possible perforation and hemorrhage; perforation of the small and large bowel, particularly in inflammatory bowel disease.

leukocytosis, thrombocytopenia, lymphopenia.

Anaphylactic and hypersensitivity reactions occur occasionally and, depending on their severity, may be treated with antihistamines with or without epinephrine. General supportive measures should also be employed.

negative nitrogen balance due to protein catabolism.

aseptic necrosis of femoral and humeral heads; muscle weakness; steroid myopathy; loss of muscle mass; osteoporosis; spontaneous fractures including vertebral compression fractures and pathologic fractures of long bones.

seizures; increased intracranial pressure with papilledema (pseudotumor cerebri) in association with withdrawal of corticosteroid therapy; neuritis; paresthesias.

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

hallucinations; psychosis; euphoria; mood changes.

necrotizing angiitis, thrombophlebitis; aggravation or masking of infections; insomnia; anaphylactoid reactions. Burning or tingling of the perineal area may occur after iv injection of corticosteroids. Parenteral corticosteroid therapy has also produced hypo- or hyperpigmentation, scarring, induration, delayed pain or soreness, subcutaneous and cutaneous atrophy and sterile abscesses.

Because injections of slightly soluble corticosteroids may produce atrophy at the site of injection, im injections of these products should be made deeply into gluteal muscle; repeated im injections at the same site should be avoided and these products should not be administered sc.

Dosage ranges for corticosteroids are extremely wide and patient responses are quite variable. Dosage should be individualized according to the diagnosis, severity, prognosis, probable duration of disease, patient response and tolerance. For infants and children, the recommended dosage should be governed by the same considerations rather than by strict adherence to the ratio indicated by age or body weight.

Dosages used in various conditions are considered either physiologic (amount of corticosteroid normally secreted by the adrenal cortex daily) or pharmacologic (anything greater). See Table 3. Refer to Table 1 for equivalent doses for other corticosteroids.

Table 3: Corticosteroids: Systemic

Oral Prednisone Dosage (Adult)

Type of Dosage Range	Approximate Daily Dose
Physiologic	5 mg
Pharmacologic
Maintenance or Low Dose	5 to 15 mg
Moderate Dose	0.5 mg/kg
High Dose	1 to 3 mg/kg
Massive Dose	15 to 30 mg/kg

Dosage should be decreased or discontinued gradually when the drug has been administered for more than a few weeks to minimize the risk of adrenal insufficiency, as adrenal suppression has occurred after as little as 2 weeks of corticosteroid therapy. A number of different regimens for tapering corticosteroid therapy have been described. It has been suggested that the dosage be reduced by the equivalent of 2.5 to 5 mg of prednisone every 3 days to 2 weeks. An increase in dose followed by a more gradual withdrawal may be necessary if the disease flares up during tapering.

In the management of acute disorders, corticosteroid dosage should be sufficient to ensure that symptoms are controlled quickly, and treatment should be discontinued as soon as possible. In acute conditions where prompt relief is imperative, large doses are permissible and may be mandatory for a short period.

In chronic conditions requiring long-term therapy, use the lowest dosage that provides adequate but not necessarily complete relief. If a high dosage for prolonged periods is considered essential, observe patients closely for signs that might necessitate reduction in dosage or discontinuance of the drug. Chronic conditions are subject to periods of remission. When such periods occur, consider discontinuing corticosteroids gradually. Continued supervision of the patient after cessation of corticosteroids is essential since there may be a reappearance of severe manifestations of the disease.

Alternate day therapy in which a single dose is administered every other morning is considered by many clinicians to be the dosage regimen of choice for long-term corticosteroid treatment of most conditions; however, this remains controversial. Morning administration of the corticosteroid simulates the natural circadian rhythm of corticosteroid secretion which is high in the morning and low in the evening. This regimen provides relief of symptoms while minimizing adrenal suppression, cushingoid state, withdrawal symptoms and growth suppression in children. Intermediate-acting agents should be used for alternate day therapy (see Table 1). Dexamethasone is not suitable for every other day dosing to minimize adrenal suppression due to its long duration of effect.

The reader is referred to individual product monographs for more specific dosing information.