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Data Sheet

MEDROL®

Methylprednisolone tablets, 4mg and 100mg

Presentation

MEDROL tablets 4mg (methylprednisolone) are white flat elliptical coded "MEDROL 4" on one side, double scored on the reverse.

Length 8mm, Width 5.5mm, thickness 2mm.

MEDROL tablets 100mg are light blue, round, biconvex cross-scored, coded "Upjohn 3379".

Uses

Actions

Methylprednisolone is a potent anti-inflammatory steroid. It has greater anti-inflammatory potency than prednisolone even less tendency than prednisolone to induce sodium and water retention. The relative potency of methylprednisolone to hydrocortisone is at least four to one.

Pharmacokinetics

The mean elimination half-life ranges from 2.4 to 3.5 hours in normal, healthy adults and appears to be independent of the route of administration.

The mean oral time of peak concentration was 1.1 - 2.2 hours.

Methylprednisolone is widely distributed throughout the body and is described by a two-compartment model. The mean volume of distribution reported in 34 adult volunteers ranged from 41 to 61.5 L.

MEDROL readily crosses the blood-brain barrier into the central nervous system with peak CSF levels being 5 - 6% of the corresponding plasma levels. Methylprednisolone peak CSF levels occurred within five minutes to one hour after IV administration of a 500mg dose to patients with lupus cerebritis.

Methylprednisolone crosses the placental barrier. Although there is no data regarding methylprednisolone passage into breast milk of humans, it is present in breast milk of animals.

Methylprednisolone is metabolized in the liver to inactive metabolites, the major ones being 20B-hydroxymethyl-prednisolone and 20B-hydroxy-6a-methylprednisone.

Methylprednisolone clearance is altered by concurrent administration of troleandomycin, erythromycin, rifampin, anticonvulsants, and theophylline. No dosing adjustments are necessary in renal failure. Methylprednisolone is hemodializable.

Following IV administration of radiolabelled 6-methylprednisolone to six cancer patients, 75% of total reactivity was recovered in the urine after 96 hours and 9% in the faeces after five days. Twenty percent of the total dose was excreted in the bile, but the time course was not cited.

Indications

MEDROL (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).

Non-Endocrine Disorders:

  1. Rheumatic Disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in:
  2. Collagen Diseases: During an exacerbation or as maintenance therapy in selected cases of:
  3. Dermatologic Diseases:
  4. Allergic States:
  5. Ophthalmic Diseases: Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as:
  6. Respiratory Diseases:
  7. Haematologic Disorders:
  8. Neoplastic Diseases: For palliative management of:
  9. Edematous States:To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uraemia, of the idiopathic type or that due to lupus erythematosus.
  10. Gastrointestinal Diseases: To tide the patient over a critical period of the disease in:
  11. Nervous system:
  12. Miscellaneous: Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy. Trichinosis with neurologic or myocardial involvement.
  13. Organ Transplantations

Dosage and Administration

The initial dosage of MEDROL Tablets may vary from 4mg to 48mg 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. Clinical situations in which high dose therapy may be indicated include multiple sclerosis (200 mg/day), cerebral oedema (200 - 1,000 mg/day), and organ transplantation (up to 7 mg/kg/day). 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, MEDROL should be discontinued and the patient transferred to other appropriate therapy. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.

It should be emphasised that dosage requirements are variable and must be individualised on the basis of the disease under treatment and the response of the patient. After a favourable 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 MEDROL for a period of time consistent with the patient's condition.

Multiple Sclerosis: In treatment of acute exacerbations of multiple sclerosis daily doses of 200mg of prednisolone for a week followed by 80mg every other day for one month have been shown to be effective (4mg of methylprednisolone is equivalent to 5mg of prednisolone).

ADT Alternate Day Therapy: Alternate day therapy is a corticosteroid dosing regimen in which twice the usual daily dose of corticosteroid is administered every other morning. The purpose of this mode of therapy is to provide a patient requiring long-term pharmacologic dose treatment with the beneficial effects of corticoids while minimising 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:

  1. The anti-inflammatory or therapeutic effect of corticoids persists longer than their physical presence and metabolic effects, and
  2. Administration of the corticosteroid every other morning allows for re-establishment of more nearly normal hypothalamic-pituitary-adrenal (HPA) activity on the off-corticosteroid day.

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 corticosteroids.
  2. ADT is a therapeutic technique primarily designed for patients in whom long-term pharmacologic corticosteroid therapy is anticipated.
  3. In less severe disease processes in which corticosteroid 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:
    (i) Change to ADT and then gradually reduce the amount of corticosteroid given every other day, or
    (ii) Following control of the disease process reduce the daily dose of corticosteroid to the lowest effective level as rapidly as possible and then change over to an alternate day schedule. Theoretically, course (i) 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 corticosteroids for long periods of time (eg. 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 a minimum.
  5. As indicated above, certain corticosteroids, because of their prolonged suppressive effect on adrenal activity, are not recommended for alternate day therapy (eg. dexamethasone and betamethasone).
  6. The maximal activity of the adrenal cortex is between 2.00am and 8.00am, and it is minimal between 4.00pm 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 individualise 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-corticosteroid day. Other symptomatic therapy may be 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 a full suppressive daily divided corticosteroid 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 minimised by ADT, as in any therapeutic situation, the physician must carefully weigh the benefit risk ratio for each patient in whom corticosteroid therapy is being considered.

Contraindications

Systemic fungal infections.

Known hypersensitivity to MEDROL tablets or to methylprednisolone.

Warnings and Precautions

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. There may be decreased resistance and inability to localize infection when corticosteroids are used.Infections with any pathogen including viral, bacterial, fungal, protozoan or helminthic infections, in any location in 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. 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.

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. Allergic reactions (e.g. angioedema) may occur.

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 non-immunosuppressive doses of corticosteroids.

The use of MEDROL (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.

There is no universal agreement on whether corticosteroids per se are responsible for peptic ulcers encountered during therapy; however, glucocorticoid therapy may mask the symptoms of peptic ulcer so that perforation or hemorrhage may occur without significant pain.

Osteoporosis is a common but infrequently recognised adverse effect associated with a long-term use of large doses of glucocorticoid.

Growth may be suppressed in children receiving long-term daily, divided dose glucocorticoid therapy and use of such regimen should be restricted to the most urgent indication. Alternate day glucocorticoid therapy usually avoids or minimises this side effect.

Host defenses are impaired in patients receiving large doses of glucocorticoids and this effect increases susceptibility to fungus infections as well as bacterial and viral infections.

Usage in pregnancy: Some animal studies have shown that corticosteroids, when administered to the mother at high doses, may cause fetal malformations. Adequate human reproductive studies have not been done with corticosteroids. Therefore the use of this drug in pregnancy, nursing mothers, or women of childbearing potential requires that the benefits of the drug be carefully weighed against the potential risk to the mother and embryo or fetus. Since there is inadequate evidence of safety in human pregnancy, this drug should be used in pregnancy only if clearly needed.

Corticosteroids readily cross the placenta. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy must be carefully observed and evaluated for signs of adrenal insufficiency. There are no known effects of corticosteroids on labor and delivery.

Nursing mothers: Corticoids are excreted in breast milk.

General Precautions:

Drug-induced 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.

Corticosteroids should be used with caution in nonspecific ulcerative colitis if there is a probability of impending performation, abscess or other pyogenic infection; diverticulitis; fresh intestinal anastomoses; active or latent peptic ulcer; renal insufficiency; hypertension; osteoporosis; or myasthenia gravis.

Because 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.

Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission.

Carcinogenesis, mutagenesis, impairment of fertility: There is no evidence that corticosteroids are carcinogenic, mutagenic, or impair fertility.

Adverse Effects

The following are typical for all systemic corticosteroids. Their inclusion in this list does not necessarily indicate that the specific event has been observed with this particular medicine.

Fluid and Electrolyte Disturbances:

Musculoskeletal:

Gastrointestinal:

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:

Neurological:

Endocrine:

Ophthalmic:

Metabolic:

Immune System:

Interactions

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 use of either medicine may be more apt to occur. Convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Medicines that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the clearance of methylprednisolone and may require increase in methylprednisolone dose to achieve the desired response. Medicines 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 a decrease in 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 hypothrombinemia. 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.

Overdosage

There is no clinical syndrome of acute overdose with MEDROL (methylprednisolone). Methylprednisolone is dialysable.

Pharmaceutical Precautions

Medrol 100mg: Store at or below 25°C.

Medrol 4mg: Store below 25°C.

Medicine Classification

Prescription medicine

Package Quantities

MEDROL Tablets 4mg are available in bottles of 100

MEDROL tablets 100mg are available in bottles of 20

Name and Address

Pfizer New Zealand Ltd
P O Box 3998
Ellerslie
Auckland
New Zealand

Toll Free Number:  0800 736 363

Date Of Preparation

6th June 2005

(Ref: CPS 12/12/94)