Methylprednisolone (1791)

Methylprednisolone is a glucocorticoid. Glucocorticoids are adrenocortical steroids, both naturally occurring and synthetic, which are readily absorbed from the gastrointestinal tract. Methylprednisolone occurs as a white to practically white, odorless, crystalline powder. It is sparingly soluble in alcohol, in dioxane, and in methanol, slightly soluble in acetone, and in chloroform, and very slightly soluble in ether. It is practically insoluble in water.

The chemical name for methylprednisolone is pregna-1,4-diene-3,20-dione, 11,17,21-trihydroxy-6-methyl-,(6α, 11β)- and the molecular weight is 374.48.

Each Medrol tablet for oral administration contains 2, 4, 8, 16, 24, or 32 mg of methylprednisolone.

Medrol Inactive ingredients:  2 mg: Calcium stearate, corn starch, erythrosine sodium, lactose, mineral oil, sorbic acid, sucrose. 4 and 16 mg: Calcium stearate, corn starch, lactose, mineral oil, sorbic acid, sucrose. 8 and 32 mg: Calcium stearate, corn starch, FD&C yellow no. 6, lactose, mineral oil, sorbic acid, sucrose. 24 mg: Calcium stearate, corn starch, FD&C yellow no. 5, lactose, mineral oil, sorbic acid, sucrose.

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.

Methylprednisolone is 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.

Nonsuppurative thyroiditis.

Hypercalcemia associated with cancer.

Rheumatic Disorders:  As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in:

Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy).

Ankylosing spondylitis.

Acute and subacute bursitis.

Synovitis of osteoarthritis.

Acute nonspecific tenosynovitis.

Post-traumatic osteoarthritis.

Psoriatic arthritis.

Epicondylitis.

Acute gouty arthritis.

Collagen Diseases:  During an exacerbation or as maintenance therapy in selected cases of:

Systemic lupus erythematosus.

Systemic dermatomyositis (polymyositis).

Acute rheumatic carditis.

Dermatologic Diseases:

Bullous dermatitis herpetiformis.

Severe erythema multiforme (Stevens-Johnson syndrome).

Severe seborrheic dermatitis.

Exfoliative dermatitis.

Mycosis fungoides.

Pemphigus.

Severe psoriasis.

Allergic States:  Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment:

Seasonal or perennial allergic rhinitis.

Drug hypersensitivity reactions.

Serum sickness.

Contact dermatitis.

Bronchial asthma.

Atopic dermatitis.

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.

Keratitis.

Optic neuritis.

Allergic conjunctivitis.

Chorioretinitis.

Iritis and iridocyclitis.

Respiratory Diseases:

Symptomatic sarcoidosis.

Berylliosis.

Loeffler's syndrome not manageable by other means.

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.

Systemic fungal infections and known hypersensitivity to components.

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

General

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.

The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. Convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin, and rifampin may increase the clearance of methylprednisolone and may require increases in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity.

Methylprednisolone 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 methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia.

The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect.

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

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

Gastrointestinal:  (1) Peptic ulcer with possible perforation and hemorrhage; (2) pancreatitis; (3) abdominal distention; (4) ulcerative esophagitis; and (5) 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, petechiae and ecchymoses, may suppress reactions to skin tests, thin fragile skin, facial erythema, increased sweating.

Neurological:  Increased intracranial pressure with papilledema (pseudo-tumor cerebri) usually after treatment, convulsions, vertigo, headache.

Endocrine:  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; menstrual irregularities; decreased carbohydrate tolerance; manifestations of latent diabetes mellitus; increased requirements of insulin or oral hypoglycemic agents in diabetics.

Ophthalmic:  Posterior subcapsular cataracts, increased intraocular pressure, glaucoma, exophthalmos.

Metabolic:  Negative nitrogen balance due to protein catabolism.

The following additional reactions have been reported following oral as well as parenteral therapy: urticaria and other allergic, anaphylactic, or hypersensitivity reactions.

The initial dosage of methylprednisolone may vary from 4-48 mg of methylprednisolone 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, methylprednisolone 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 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 methylprednisolone 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 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 (4 mg of methylprednisolone is equivalent to 5 mg of prednisolone).

ADT (Alternate Day Therapy)

Alternate day therapy 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 that their physical presence and metabolic effects and (b) administration of the corticosteroid every other morning allows for reestablishment 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 adrenal cortical activity resulting in a rise in plasma cortisol with maximal levels occurring between 2 and 8 AM. This rise in cortisol dampens ACTH production and in turn adrenal cortical 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 adrenal cortical 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 adrenal cortical suppression for 2 or more days. Other corticoids, including methylprednisolone, hydrocortisone, prednisone, and prednisolone, are considered to be short acting (producing adrenal cortical suppression for 1¼ to 1½ 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 4 to 10 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 reinstituted.

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.

References

Medrol tablets are available in:

2 mg:  Pink, elliptical, scored, imprinted "MEDROL 2".

4 mg:  White, elliptical, scored, imprinted "MEDROL 4".

8 mg:  Peach, elliptical, scored, imprinted "MEDROL 8".

16 mg:  White, elliptical, scored, imprinted "MEDROL 16".

24 mg:  Yellow, elliptical, scored, imprinted "MEDROL 24".

32 mg:  Peach, elliptical, scored, imprinted "MEDROL 32".

Storage:  Store at controlled room temperature 20-25°C (68-77°F).