Posted by Miguel (209.42.225.52) on February 21, 2000 at 18:54:39:
In Reply to: Prednisone dosage levels posted by David on February 21, 2000 at 18:21:15:
Description:
Prednisone tablets contain prednisone which is a glucocorticoid. Glucocorticoids are adrenocortical steroids, both naturally occurring and
synthetic, which are readily absorbed from the gastrointestinal tract. Prednisone is a white to practically white, odorless, crystalline powder. It
is very slightly soluble in water; slightly soluble in alcohol, in chloroform, in dioxane, and in methanol.
The chemical name for prednisone is pregna-1,4-diene-3,11,20-trione, 17,21-dihydroxy- and its molecular weight is 358.43.
Deltasone are available in 5 strengths: 2.5 mg, 5 mg, 10 mg, 20 mg and 50 mg. Inactive Ingredients: 2.5 mg: Calcium Stearate, Corn Starch,
Erythrosine Sodium, Lactose, Mineral Oil, Sorbic Acid and Sucrose. 5 mg: Calcium Stearate, Corn Starch, Lactose, Mineral Oil, Sorbic Acid and
Sucrose. 10 mg: Calcium Stearate, Corn Starch, Lactose, Sorbic Acid and Sucrose. 20 mg: Calcium Stearate, Corn Starch, FD&C Yellow No.
6, Lactose, Sorbic Acid and Sucrose. 50 mg: Corn Starch, Lactose, Magnesium Stearate, Sorbic Acid, Sucrose, and Talc.
Clinical Pharmacology:
Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement
therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their potent anti-inflammatory effects in disorders of
many organ systems.
Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli.
Indications and Usage:
Prednisone tablets are indicated in the following conditions:
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; Hypercalcemia associated with cancer;
Nonsuppurative thyroiditis
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 nonspecific 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; Systemic
dermatomyositis (polymyositis); Acute rheumatic carditis
Dermatologic Diseases: Pemphigus; Bullous dermatitis herpetiformis; Severe erythema multiforme (Stevens-Johnson syndrome);
Exfoliative dermatitis; Mycosis fungoides; Severe psoriasis; 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; Drug hypersensitivity reactions
Ophthalmic Diseases: Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: Allergic
corneal marginal ulcers; Herpes zoster ophthalmicus; Anterior segment inflammation; Diffuse posterior uveitis and choroiditis; Sympathetic
ophthalmia; Allergic conjunctivitis; Keratitis; Chorioretinitis; Optic neuritis; Iritis and iridocyclitis
Respiratory Diseases: Symptomatic sarcoidosis; Loeffler'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
Nervous System: 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
Contraindications:
Systemic fungal infections and known hypersensitivity to components.
Warnings:
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. Infections with any pathogen including
viral, bacterial, fungal, protozoan or helminthic infections, in any location of 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.1
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.2There may be decreased resistance and inability to localize infection when corticosteroids are used.
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.
Usage in pregnancy: Since adequate human reproduction studies have not been done with corticosteroids, the use of these drugs in
pregnancy, nursing mothers or women of childbearing potential requires that the possible benefits of the drug be weighed against the
potential hazards to the mother and embryo or fetus. Infants born of mothers who have received substantial doses of corticosteroids during
pregnancy, should be carefully observed for signs of hypoadrenalism.
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 nonimmunosuppressive
doses of corticosteroids.
The use of prednisone tablets 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 anti-tuberculous 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.
Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chicken pox and
measles, for example, can have a more serious or even fatal course in non-immune 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 chicken pox, prophylaxis with varicella zoster immune
globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See
the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents
may be considered.
Precautions:
Information for the Patient
Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients
should also be advised that if they are exposed, medical advice should be sought without delay.
General 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.
Steroids 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;
and myasthenia gravis.
Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed.
Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in
clinical remission.
Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple
sclerosis, they do not show that corticosteroids affect the ultimate outcome or natural history of the disease. The studies do show that
relatively high doses of corticosteroids are necessary to demonstrate a significant effect. (See DOSAGE AND ADMINISTRATION.)
Since 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 cyclosporin. Since concurrent use of these agents results in
a mutual inhibition of metabolism, it is possible that 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 aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is
withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. 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.
Adverse Reactions:
Fluid and Electrolyte Disturbances: Sodium retention; Fluid retention; Congestive heart failure in susceptible patients; Potassium loss;
Hypokalemic alkalosis; Hypertension
Musculoskeletal: Muscle weakness; Steroid myopathy; Loss of muscle mass; Osteoporosis; Tendon rupture, particularly of the Achilles
tendon; Vertebral compression fractures; Aseptic necrosis of femoral and humeral heads; Pathologic fracture of long bones
Gastrointestinal: Peptic ulcer with possible perforation and hemorrhage; Pancreatitis; Abdominal distention; Ulcerative esophagitis
Increases in alanine transaminase (ALT, SGPT), aspartate transaminase (AST, SGOT) and alkaline phosphatase have been observed following
corticosteroid treatment. These changes are usually small, not associated with any clinical syndrome and are reversible upon
discontinuation.
Dermatologic: Impaired wound healing; Thin fragile skin; Petechiae and ecchymoses; Facial erythema; Increased sweating; May suppress
reactions to skin tests
Metabolic: Negative nitrogen balance due to protein catabolism
Neurological: Increased intracranial pressure with papilledema (pseudo-tumor cerebri) usually after treatment; Convulsions; Vertigo;
Headache
Endocrine: Menstrual irregularities; Development of Cushingoid state; Secondary adrenocortical and pituitary unresponsiveness,
particularly in times of stress, as in trauma, surgery or illness; Suppression of growth in children; Decreased carbohydrate tolerance;
Manifestations of latent diabetes mellitus; Increased requirements for insulin or oral hypoglycemic agents in diabetics
Ophthalmic: Posterior subcapsular cataracts; Increased intraocular pressure; Glaucoma; Exophthalmos
Metabloic: Negative nitrogen balance due to protein catabolism.
Additional Reactions: Urticaria and other allergic, anaphylactic or hypersensitivity reactions
Dosage and Administration:
The initial dosage of prednisone tablets may vary from 5 mg to 60 mg of prednisone 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, Prednisone should be discontinued and the patient transferred to other 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 patients'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 Prednisone for
a period of time consistent with the patient's condition. If after long-term therapy the drug is to be stopped, it is recommended that it be
withdrawn gradually rather than abruptly.
Multiple Sclerosis
In the treatment of acute exacerbations of multiple sclerosis daily doses of 200 mg of prednisolone for a week followed by 80 mg every
other day for 1 month have been shown to be effective. (Dosage range is the same for prednisone and prednisolone.)
ADT (Alternate Day Therapy)
ADT is a corticosteroid dosing regimen in which twice the usual daily dose of corticoid is administered every other morning. The purpose of
this mode of therapy is to provide the patient requiring long-term pharmacologic dose treatment with the beneficial effects of corticoids
while minimizing certain undesirable effects, including pituitary-adrenal suppression, the Cushingoid state, corticoid withdrawal symptoms,
and growth suppression in children.
The rationale for this treatment schedule is based on two major premises: (a) the anti-inflammatory or therapeutic effect of corticoids
persists longer than their physical presence and metabolic effects and (b) administration of the corticosteroid every other morning allows for
re-establishment of more nearly normal hypothalamic-pituitary-adrenal (HPA) activity on the off-steroid day.
A brief review of the HPA physiology may be helpful in understanding this rationale. Acting primarily through the hypothalamus a fall in free
cortisol stimulates the pituitary gland to produce increasing amounts of corticotropin (ACTH) while a rise in free cortisol inhibits ACTH
secretion. Normally the HPA system is characterized by diurnal (circadian) rhythm. Serum levels of ACTH rise from a low point about 10 pm to
a peak level about 6 am. Increasing levels of ACTH stimulate adrenocortical activity resulting in a rise in plasma cortisol with maximal levels
occurring between 2 am and 8 am. This rise in cortisol dampens ACTH production and in turn adrenocortical activity. There is a gradual fall in
plasma corticoids during the day with lowest levels occurring about midnight.
The diurnal rhythm of the HPA axis is lost in Cushing's disease, a syndrome of adrenocortical hyperfunction characterized by obesity with
centripetal fat distribution, thinning of the skin with easy bruisability, muscle wasting with weakness, hypertension, latent diabetes,
osteoporosis, electrolyte imbalance, etc. The same clinical findings of hyperadrenocorticism may be noted during long-term pharmacologic
dose corticoid therapy administered in conventional daily divided doses. It would appear, then, that a disturbance in the diurnal cycle with
maintenance of elevated corticoid values during the night may play a significant role in the development of undesirable corticoid effects.
Escape from these constantly elevated plasma levels for even short periods of time may be instrumental in protecting against undesirable
pharmacologic effects.
During conventional pharmacologic dose corticosteroid therapy, ACTH production is inhibited with subsequent suppression of cortisol
production by the adrenal cortex. Recovery time for normal HPA activity is variable depending upon the dose and duration of treatment.
During this time the patient is vulnerable to any stressful situation. Although it has been shown that there is considerably less adrenal
suppression following a single morning dose of prednisolone (10 mg) as opposed to a quarter of that dose administered every 6 hours, there
is evidence that some suppressive effect on adrenal activity may be carried over into the following day when pharmacologic doses are used.
Further, it has been shown that a single dose of certain corticosteroids will produce adrenocortical suppression for two or more days. Other
corticoids, including methylprednisolone, hydrocortisone, prednisone, and prednisolone, are considered to be short acting (producing
adrenocortical suppression for 1 1/4 to 1 1/2 days following a single dose) and thus are recommended for alternate day therapy.
The following should be kept in mind when considering alternate day therapy:
Basic principles and indications for corticosteroid therapy should apply. The benefits of ADT should not encourage the indiscriminate
use of steroids.
ADT is a therapeutic technique primarily designed for patients in whom long-term pharmacologic corticoid therapy is anticipated.
In less severe disease processes in which corticoid therapy is indicated, it may be possible to initiate treatment with ADT. More
severe disease states usually will require daily divided high dose therapy for initial control of the disease process. The initial
suppressive dose level should be continued until satisfactory clinical response is obtained, usually four to ten days in the case of
many allergic and collagen diseases. It is important to keep the period of initial suppressive dose as brief as possible particularly
when subsequent use of alternate day therapy is intended. Once control has been established, two courses are available: (a) change
to ADT and then gradually reduce the amount of corticoid given every other day or (b) following control of the disease process reduce
the daily dose of corticoid to the lowest effective level as rapidly as possible and then change over to an alternate day schedule.
Theoretically, course (a) may be preferable.
Because of the advantages of ADT, it may be desirable to try patients on this form of therapy who have been on daily corticoids for
long periods of time (e.g., patients with rheumatoid arthritis). Since these patients may already have a suppressed HPA axis,
establishing them on ADT may be difficult and not always successful. However, it is recommended that regular attempts be made to
change them over. It may be helpful to triple or even quadruple the daily maintenance dose and administer this every other day rather
than just doubling the daily dose if difficulty is encountered. Once the patient is again controlled, an attempt should be made to
reduce this dose to a minimum.
As indicated above, certain corticosteroids, because of their prolonged suppressive effect on adrenal activity, are not recommended
for alternate day therapy (e.g., dexamethasone and betamethasone).
The maximal activity of the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight. Exogenous
corticosteroids suppress adrenocortical activity the least, when given at the time of maximal activity (am).
In using ADT it is important, as in all therapeutic situations to individualize and tailor the therapy to each patient. Complete control of
symptoms will not be possible in all patients. An explanation of the benefits of ADT will help the patient to understand and tolerate
the possible flare-up in symptoms which may occur in the latter part of the off-steroid day. Other symptomatic therapy may be added
or increased at this time if needed.
In the event of an acute flare-up of the disease process, it may be necessary to return to a full suppressive daily divided corticoid dose
for control. Once control is again established alternate day therapy may be re-instituted.
Although many of the undesirable features of corticosteroid therapy can be minimized by ADT, as in any therapeutic situation, the
physician must carefully weigh the benefit-risk ratio for each patient in whom corticoid therapy is being considered.
Store at controlled room temperature 15° to 30° C (59° to 86° F).
References:
1. Fekety R. Infections associated with corticosteroids and immunosuppressive therapy. In: Gorbach SL, Bartlett JG, Blacklow NR, eds.
Infectious Diseases. Philadelphia: WB Saunders Company 1992:1050-1.2. Stuck AE, Minder CE, Frey FJ. Risk of infectious complications in
patients taking glucocorticoids. Rev Infect Dis1989:11(6):954-63.
(The Upjohn Company, 12/94, 810 342 016, 691015)