WARNINGS SECTION.

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.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.. 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 child-bearing 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 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 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. Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Fluid and Electrolyte Disturbances Sodium retention Congestive heart failure in susceptible patients Hypertensiono Fluid retentiono Potassium losso Hypokalemic alkalosis Musculoskeletal Muscle weaknesso Loss of muscle masso Steroid myopathyo Osteoporosiso Tendon rupture, particularly of the Achilles tendono Vertebral compression fractureso Aseptic necrosis of femoral and humeral headso Pathologic fracture of long bones Gastrointestinal Peptic ulcer with possible perforation and hemorrhageo Pancreatitiso Abdominal distentiono 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.Dermatologico Impaired wound healingo Petechiae and ecchymoseso May suppress reactions to skin testso Thin fragile skino Facial erythemao Increased sweating Neurological Increased intracranial pressure with papilledema (pseudo-tumor cerebri) usually after treatmento Convulsionso Vertigoo HeadacheEndocrine Development of Cushingoid stateo Suppression of growth in childreno 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.. Sodium retention o Congestive heart failure in susceptible patients o Hypertension. Fluid retention. Potassium loss. Hypokalemic alkalosis o 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 o Peptic ulcer with possible perforation and hemorrhage. Pancreatitis. Abdominal distention. Ulcerative esophagitis o Impaired wound healing. Petechiae and ecchymoses. May suppress reactions to skin tests. Thin fragile skin. Facial erythema. Increased sweating o Increased intracranial pressure with papilledema (pseudo-tumor cerebri) usually after treatment. Convulsions. Vertigo. Headache. 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 o Menstrual irregularities o Decreased carbohydrate tolerance o Manifestations of latent diabetes mellitus o Increased requirements of insulin or oral hypoglycemic agents in diabetics o Posterior subcapsular cataracts o Increased intraocular pressure o Glaucoma o Exophthalmos o Negative nitrogen balance due to protein catabolism.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. The initial dosage of methylprednisolone tablets may vary from mg to 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 satisfactory response is noted. If after reasonable period of time there is 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 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 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 period of time consistent with the patients condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.Multiple SclerosisIn treatment of acute exacerbations of multiple sclerosis daily doses of 200 mg of prednisolone for week followed by 80 mg every other day for month have been shown to be effective (4 mg of methylprednisolone is equivalent to mg of prednisolone).ADT(R) (Alternate Day Therapy)Alternate day therapy is 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 reestablishment of more nearly normal hypothalamic-pituitary-adrenal (HPA) activity on the offsteroid day.A brief review of the HPA physiology may be helpful in understanding this rationale. Acting primarily through the hypothalamus fall in free cortisol stimulates the pituitary gland to produce increasing amounts of corticotropin (ACTH) while rise in free cortisol inhibits ACTH secretion. Normally the HPA system is characterized by diurnal (circadian) rhythm. Serum levels of ACTH rise from low point about 10 pm to peak level about am. Increasing levels of ACTH stimulate adrenal cortical activity resulting in rise in plasma cortisol with maximal levels occurring between am and am. This rise in cortisol dampens ACTH production and in turn adrenal cortical activity. There is gradual fall in plasma corticoids during the day with lowest levels occurring about midnight.The diurnal rhythm of the HPA axis is lost in Cushings disease, 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 disturbance in the diurnal cycle with maintenance of elevated corticoid values during the night may play 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 single morning dose of prednisolone (10 mg) as opposed to quarter of that dose administered every six 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 single dose of certain corticosteroids will produce adrenal cortical suppression for two or more days. Other corticoids, including methylprednisolone, hydrocortisone, prednisone, and prednisolone, are considered to be short acting (producing adrenal cortical suppression for 1/4 to 1/2 days following single dose) and thus are recommended for alternate day therapy.The following should be kept in mind when considering alternate day therapy:1.Basic principles and indications for corticosteroid therapy should apply. The benefits of ADT should not encourage the indiscriminate use of steroids.2.ADT is therapeutic technique primarily designed for patients in whom long-term pharmacologic corticoid therapy is anticipated.3.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.4.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 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 minimum.5.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).6.The maximal activity of the adrenal cortex is between am and am, and it is minimal between pm and midnight. Exogenous corticosteroids suppress adrenocortical activity the least, when given at the time of maximal activity (am).7.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 maybe added or increased at this time if needed.8.In the event of an acute flare-up of the disease process, it may be necessary to return to full suppressive daily divided corticoid dose for control. Once control is again established alternate day therapy may be reinstituted.9.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.. 1.Basic principles and indications for corticosteroid therapy should apply. The benefits of ADT should not encourage the indiscriminate use of steroids.. 2.ADT is therapeutic technique primarily designed for patients in whom long-term pharmacologic corticoid therapy is anticipated.. 3.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.. 4.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 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 minimum.. 5.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).. 6.The maximal activity of the adrenal cortex is between am and am, and it is minimal between pm and midnight. Exogenous corticosteroids suppress adrenocortical activity the least, when given at the time of maximal activity (am).. 7.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 maybe added or increased at this time if needed.. 8.In the event of an acute flare-up of the disease process, it may be necessary to return to full suppressive daily divided corticoid dose for control. Once control is again established alternate day therapy may be reinstituted.. 9.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.

GENERAL PRECAUTIONS SECTION.

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 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.Caution is required in patients with systemic sclerosis because an increased incidence of scleroderma renal crisis has been observed with corticosteroids, including methylprednisolone.Steroids should be used with caution in nonspecific ulcerative colitis, if there is 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.Kaposis 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 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, 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.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Methylprednisolone tablets are indicated in the following conditions: 1.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 hyperplasiaNonsuppurative thyroiditisHypercalcemia associated with cancer. 2.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 spondylitisAcute and subacute bursitisSynovitis of osteoarthritisAcute nonspecific tenosynovitisPost-traumatic osteoarthritisPsoriatic arthritisEpicondylitisAcute gouty arthritis. 3.Collagen Diseases. During an exacerbation or as maintenance therapy in selected cases of:Systemic lupus erythematosusSystemic dermatomyositis (polymyositis)Acute rheumatic carditis. 4.Dermatologic Diseases. Bullous dermatitis herpetiformisSevere erythema multiforme (Stevens-Johnson syndrome)Severe seborrheic dermatitisExfoliative dermatitisMycosis fungoidesPemphigusSevere psoriasis. 5.Allergic States. Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment:Seasonal or perennial allergic rhinitisDrug hypersensitivity reactionsSerum sicknessContact dermatitisBronchial asthmaAtopic dermatitis 6.Ophthalmic Diseases. Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as:Allergic corneal marginal ulcersHerpes zoster ophthalmicusAnterior segment inflammationDiffuse posterior uveitis and choroiditisSympathetic ophthalmiaKeratitisOptic neuritisAllergic conjunctivitisChorioretinitisIritis and iridocyclitis. 7.Respiratory Diseases. Symptomatic sarcoidosisBerylliosisLoefflers syndrome not manageable by other meansFulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapyAspiration pneumonitis. 8.Hematologic Disorders. Idiopathic thrombocytopenic purpura in adultsSecondary thrombocytopenia in adultsAcquired (autoimmune) hemolytic anemiaErythroblastopenia (RBC anemia)Congenital (erythroid) hypoplastic anemia. 9.Neoplastic Diseases. For palliative management of:Leukemias and lymphomas in adultsAcute leukemia of childhood. 10.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.. 11.Gastrointestinal Diseases. To tide the patient over critical period of the disease in:Ulcerative colitisRegional enteritis. 12.Nervous System. Acute exacerbations of multiple sclerosis 13.Miscellaneous. Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy.Trichinosis with neurologic or myocardial involvement.

PRECAUTIONS SECTION.

PRECAUTIONS. 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 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.Caution is required in patients with systemic sclerosis because an increased incidence of scleroderma renal crisis has been observed with corticosteroids, including methylprednisolone.Steroids should be used with caution in nonspecific ulcerative colitis, if there is 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.Kaposis 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 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, 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.