Methylprednisolone

Physicians Total Care, Inc.

FULL PRESCRIBING INFORMATION: CONTENTS*

• METHYLPREDNISOLONE DESCRIPTION
• CLINICAL PHARMACOLOGY
• METHYLPREDNISOLONE INDICATIONS AND USAGE
• METHYLPREDNISOLONE CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
• METHYLPREDNISOLONE ADVERSE REACTIONS
• METHYLPREDNISOLONE DOSAGE AND ADMINISTRATION
• HOW SUPPLIED
• REFERENCES:

FULL PRESCRIBING INFORMATION

1003010102

Rx only

METHYLPREDNISOLONE DESCRIPTION

Methylprednisolone is a glucocorticoid. Glucocorticoids are adrenocortical steroids, both naturally occurring and synthetic, which are readily absorbed from the gastrointestinal tract. Methylprednisolone is 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, 11ß)-and the molecular weight is 374.48. The structural formula is represented below:

Each tablet, for oral administration, contains 4 mg methylprednisolone. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, cornstarch, lactose (anhydrous), magnesium stearate, microcrystalline cellulose, sodium starch glycolate and stearic acid.

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.

METHYLPREDNISOLONE INDICATIONS AND USAGE

Methylprednisolone 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 mineralocorticoid 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 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

METHYLPREDNISOLONE 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 infections 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.² There 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.

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 Methylprednisolone 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 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.

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

METHYLPREDNISOLONE ADVERSE REACTIONS

Sodium retention

Fluid retention

Congestive heart failure in susceptible patients

Potassium loss

Hypokalemic alkalosis

Hypertension

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

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.

Impaired wound healing

Petechiae and ecchymoses

Increased sweating

May suppress reactions to skin tests

Thin fragile skin

Facial erythema

Negative nitrogen balance due to protein catabolism

Increased intracranial pressure with papilledema (pseudotumor cerebri) usually after treatment

Convulsions

Vertigo

Headache

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

Posterior subcapsular cataracts

Increased intraocular pressure

Glaucoma

Exophthalmos

The following additional reactions are related to oral as well as parenteral therapy:

Urticaria and other allergic, anaphylactic or hypersensitivity reactions.

METHYLPREDNISOLONE DOSAGE AND ADMINISTRATION

The initial dosage of Methylprednisolone Tablets may vary from 4 mg to 48 mg 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.

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 (4 mg of Methylprednisolone is equivalent to 5 mg of prednisolone).

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 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 Alternate Day Therapy should not encourage the indiscriminate use of steroids.
• Alternate Day Therapy 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 Alternate Day Therapy. 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 Alternate Day Therapy 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 Alternate Day Therapy, it may be desirable to try patients on this form of therapy who have been on daily corticoid for long periods of time (e.g., patients with rheumatoid arthritis).
  Since these patients may already have a suppressed HPA axis, establishing them on Alternate Day Therapy 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 Alternate Day Therapy it is important, as in all therapeutic situations to individualize and tailor the therapy to all patients. An explanation of the benefits of Alternate Day Therapy 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 Alternate Day Therapy, as in any therapeutic situation, the physician must carefully weigh the benefit-risk ratio for each patient in whom corticoid therapy is being considered.

HOW SUPPLIED

MethylPREDNISolone 4 mg Tablets, USP are supplied as follows:

Bottles of 20         NDC 54868-2913-3
Bottles of 30         NDC 54868-2913-1
Bottles of 60         NDC 54868-2913-2
Bottles of 100      NDC 54868-2913-0

REFERENCES:

• Fekety R. Infections associated with corticosteroids and immunosuppressive therapy. In: Gorbach SL, Bartlett JG, Blacklow NR, eds. Infectious Diseases. Philadelphia: WBSaunders Company 1992:1050-1.
• Stuck AE, Minder CE, Frey FJ. Risk of infectious complications in patients taking glucocorticoids. Rev. Infect Dis. 1989:11(6):954-63.

Bottles of 20         NDC 54868-2913-3