Solu-Medrol (Methylprednisolone Sodium)

SOLU-MEDROL®

Pharmacia & Upjohn

Methylprednisolone Sodium

Succinate Glucocorticoid

Action and Clinical

Like other corticosteroids, methylprednisolone exerts its effect by its anti-inflammatory action.:

Methylprednisolone is a potent anti-inflammatory steroid. It has a greater anti-inflammatory potency than prednisolone and has less tendency than prednisolone to induce sodium and water retention.

Methylprednisolone sodium succinate has the same metabolic and anti-inflammatory actions as methylprednisolone. When given parenterally and in equimolar quantities, the 2 compounds are equivalent in biologic activity. The relative potency of methylprednisolone and hydrocortisone, following i.v. administration, is at least 4 to 1. This is in good agreement with the relative oral potency of methylprednisolone and hydrocortisone.

The metabolism and excretion of methylprednisolone is similar to that of other corticosteroids. It influences carbohydrate, protein, fat and purine metabolism, electrolyte and water balance, and the functional capacities of the cardiovascular system, the kidney, skeletal muscle, the nervous system and other organs and tissues. Like other corticosteroids, methylprednisolone endows the organism with the capacity to resist not a few but all types of noxious stimuli and environmental change.

Indications And Clinical Uses:

I.V. administration of methylprednisolone is indicated in situations in which a rapid and intense hormonal effect is required. These include the following:

Hypersensitivity and dermatologic conditions: status asthmaticus, anaphylactic reactions, drug reactions, contact dermatitis, urticaria, generalized neurodermatitis, reactions to insect bites, pemphigus foliaceous and vulgaris, exfoliative dermatitis, erythema multiforme.

As adjunctive therapy in: acute systemic lupus erythematosus, acute rheumatic fever, acute gout.

Ulcerative colitis: In addition to the above conditions, colonic instillations of methylprednisolone in retention enemas or by continuous drip, have been shown to be a useful adjunct in the treatment of patients with ulcerative colitis.

In anaphylactic reactions: Epinephrine or norepinephrine should be administered first for an immediate hemodynamic effect followed by i.v. injection of methylprednisolone and other accepted procedures. There is evidence that the corticoids through their prolonged hemodynamic effect are of value in preventing recurrent attacks of acute anaphylactic reactions.

In sensitivity reactions: Such as in serum sickness, allergic dermatosis (urticaria) and reactions to insect bites, methylprednisolone is capable of providing relief within 1/2 to 2 hours. In some asthmatic patients it may be advantageous to administer methylprednisolone by slow i.v. drip over a period of hours.

As adjunctive therapy in fulminating acute systemic lupus erythematosus and acute rheumatic fever, and to relieve pain during the acute manifestations of gout: Methylprednisolone may be given by slow i.v. administration over a period of several minutes. Thereafter, the patient should be placed on i.m. or oral therapy as required for continued relief of symptoms. In these conditions, other accepted measures of therapy should also be instituted.

Shock: In severe hemorrhagic or traumatic shock adjunctive use of i.v. methylprednisolone may aid in achieving hemodynamic restoration. (Although there are no well-controlled [double-blind placebo] clinical trials, data from experimental animal models indicate that methylprednisolone may be useful in hemorrhagic and traumatic shock. See also Warnings regarding septic shock.) Corticoid therapy should not replace standard methods of combating shock, but present evidence indicates that concurrent use of large doses of corticoids with other measure may improve survival rates.

Organ Transplants: Corticosteroids both parenterally and orally in high doses have been used following organ transplantation as part of multi-faceted attempts to reduce the rejection phenomenon. Methylprednisolone is suitable for such indications.

Cerebral Edema: Corticosteroid therapy as an adjunct to the usual forms of therapy for cerebral edema has been used for many years. Cerebral edema associated with acute craniocerebral injuries and intracranial hematomas of traumatic origin, has been treated with methylprednisolone with some improvement in overall survival rate and reduction of permanent disability following such conditions. Administration of methylprednisolone immediately prior to intracranial surgery and in the immediate postoperative period has reduced the duration of postoperative complications related to cerebral edema.

Acute Spinal Cord Injury: The use of methylprednisolone in high doses has resulted in improvement in motor and sensory recovery. Treatment should begin within 8 hours of injury.

Contra-Indications:

Except when used for short-term or emergency therapy as in acute sensitivity reactions, methylprednisolone is contraindicated in patients with arrested tuberculosis, herpes simplex keratitis, acute psychoses, Cushing’s syndrome, peptic ulcer, markedly elevated serum creatinine, vaccinia and varicella. Also contraindicated for systemic fungal infections and known hypersensitivity to the ingredients.WarningWarnings:

Warnings in Clinical States:

Recent studies do not establish the efficacy of methylprednisolone in septic shock, and suggest that increased mortality may occur in some subgroups at higher risk (i.e., elevated serum creatinine greater than 2.0 mg% or secondary infections).

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.

Because rare instances of anaphylactoid (e.g., bronchospasm) reactions have occurred in patients receiving parenteral corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of allergy to any drug.

Bacteriostatic Water for Injection included in the Act-O-Vials contains benzyl alcohol. Benzyl alcohol has been reported to be associated with a fatal Gasping Syndrome in premature infants.

The recommended diluent for reconstitution of the vials is Bacteriostatic Water for Injection, which can contain benzyl alcohol. Benzyl alcohol has been reported to be associated with fatal “Gasping Syndrome” in premature infants.

Precautions:

The existence of diabetes, osteoporosis, renal insufficiency, chronic psychosis, diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, hypertension, myasthenia gravis or predisposition to thrombophlebitis requires that methylprednisolone be administered with extreme caution. The same caution should also be used in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess or other pyogenic infections.:

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, and therefore these patients should be treated with caution.

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.

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 complication increases.

Adequate adrenocortical supportive therapy including ACTH must be employed promptly if the patient is subjected to any unusual stress such as surgery, trauma or severe infection.

Since methylprednisolone, like prednisolone, suppresses endogenous adrenocortical activity, it is highly important that the patient receiving methylprednisolone be under careful observation, not only during the course of treatment but for some time after treatment is terminated.

There are reports of cardiac arrhythmias and/or circulatory collapse and/or cardiac arrest following the rapid administration or large i.v. doses of methylprednisolone (greater than 0.5 g administered over a period of less than 10 minutes). Bradycardia has been reported during or after the administration of large doses of methylprednisolone, and may be unrelated to the speed or duration of infusion.

Dosage must be decreased or discontinued gradually when the drug has been administered for more than a few days.

Patients should be advised to inform subsequent physicians of the prior use of methylprednisolone.

Convulsions have been reported with concurrent use of methylprednisolone and cyclosporine. Since concurrent administration of these agents results in a mutual inhibition of metabolism, it is possible that convulsions and other adverse events associated with the individual use of either drug may be more apt to occur.

An acute myopathy has been described with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevations of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.

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

Drug Interactions :

Table I includes the common interactions seen with Solu-Medrol and other drug products. Methylprednisolone, like all glucocorticoids, can cause the following effects when administered in combination with these products. This table is meant to serve as a guide to professionals when considering a rational course of therapy.

Table I–Solu-Medrol

Common Interactions Seen with Solu-Medrol and Other Drug Products

Class of Drug Drug(s) Involved Affects Therapy of Drugs Clinical Implication Mechanism

Antibiotic/Antifungal therapy Troleandomycin Erythromycin Ketoconazole Methylprednisolone Enhanced clinical effects and side effects of methylprednisolone Enzyme inhibition: Reduced MP elimination

Rifampin Methylprednisolone May reduce efficacy; dosage adjustment may be required. Enzyme induction, increased clearance

Anticholinesterase

Neostigmine,

pyridostigmineAnticholinesterasePrecipitation of myasthenic crisis

Anticoagulants

Oral anticoagulants or heparinAnticoagulantIncreased or decreased clotting. Monitor response. Adjust dose.

Anticonvulsants e.g., phenobarbital, phenytoin Methylprednisolone May reduce methylprednisolone efficacy. Monitor clinical response. Adjust dose if necessary. Enzyme induction: increased clearance of methylprednisolone

Antidiabetic Drugs e.g., insulin, glibenclamide, metformin Antidiabetic May impair glucose control. Monitor glucose levels and adjust dose of antidiabetic therapy. Diabetogenic effects of corticosteroid

Antihypertensive Agents All antihypertensives Antihypertensive May result in partial loss of hypertensive control. Mineralocorticoid effect of corticosteroid leading to raised blood pressure

Diuretics All potassium losing diuretics e.g., furosemide Enhanced toxicity. Monitor K + levels and supplement if necessary. Potassium loss

Cardioactive drugs Digoxin and related glycosides Digoxin Potentiation of digoxin toxicity Corticosteroid induced potassium loss (mineralocorticoid effect)

Immunizing Agents Live vaccine: poliomyelitis, BCG, mumps, measles, rubella, smallpox Vaccine May see increased toxicity from vaccine. Disseminated viral disease may occur. Corticosteroid induced immunosuppression

Killed Virulent Vaccines Vaccine Reduced response to vaccine Impaired immune response

Immuno- suppressants Methotrexate Azathioprine Methylprednisolone May allow reduced dose of corticosteroid. Synergistic effect on disease state

Cyclosporine (CYA) Both Monitor cyclosporine A levels. Adjust dose as necessary. Mutual inhibition of metabolism

Neuromuscular Blocking Agents

PancuroniumPancuroniumPartial reversal of neuromuscular

block

Psychotherapeutic Anxiolytics Antipsychotics CNS active drug Recurrence or poor control of CNS symptoms. May require dose adjustment. CNS effects of corticosteroid

Salicylates Salicylate Apparent decrease in salicylate efficacy or salicylate toxicity upon reduction of corticosteroid dose. Increased clearance and decreased plasma level

Sympathomimetic Agents e.g., salbutamol Increased efficacy and potentially increased toxicity Increased response to sympathetic agents

Pregnancy: Some animal studies have shown that corticosteroids, when administered to the mother at high doses, may cause fetal malformations. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, the use of this drug during pregnancy, in nursing mothers and 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. Newborn infants of mothers who received such therapy during pregnancy should be observed for signs of hypoadrenalism and appropriate measures instituted if such signs are present. No effect is known upon labor and delivery.

Lactation: Because prednisolone is excreted in breast milk it is reasonable to assume that all corticosteroids are. No specific data are available for methylprednisolone sodium succinate.

Adverse Reactions:

:The following adverse reactions have been reported with the systemic use of corticosteroid preparations (e.g., methylprednisolone). Their inclusion in this list does not necessarily indicate that the specific event has been observed with methylprednisolone.

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

Musculoskeletal: steroid myopathy, muscle weakness, osteoporosis, pathologic fractures, vertebral compression fractures, aseptic necrosis of femoral and humeral heads, tendon rupture–particularly of the Achilles tendon.

Gastrointestinal: peptic ulcer with possible perforation and hemorrhage, gastric hemorrhage, pancreatitis, esophagitis, perforation of the bowel, transient nausea, vomiting or dysgeusia (with rapid administration of large doses).

Increases in ALT, AST 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, thin fragile skin.

Endocrine: decreased carbohydrate tolerance, manifestations of latent diabetes mellitus, increased requirements for insulin or oral hypoglycemic agents in diabetics, menstrual irregularities, development of Cushingoid State, suppression of pituitary-adrenal axis, suppression of growth in children.

Metabolic: negative nitrogen balance due to protein catabolism.

Neurological: increased intracranial pressure, pseudotumor cerebri, psychic derangements, seizures.

Ophthalmic: posterior subcapsular cataracts, increased intraocular pressure, exophthalmos.

Immunological: masking of infections, latent infections becoming active, opportunistic infections, hypersensitivity reactions including anaphylaxis, may suppress reactions to skin tests.

The following additional reactions are related to parenteral corticosteroid therapy: anaphylactic reaction with or without circulatory collapse, cardiac arrest, bronchospasm, cardiac arrhythmias, hypotension or hypertension.

Symptoms And Treatment Of Overdose :

There is no clinical symptom of acute overdosage with this drug. Methylprednisolone is dialyzable. Continuous overdosage would require careful gradual reduction of dosage in order to prevent the occurrence of acute adrenal insufficiency.

Dosage And Administration:

As adjunctive therapy in life-threatening conditions (e.g., shock states), the recommended dose of methylprednisolone is 30 mg/kg, given i.v. over a period of at least 30 minutes. The large doses may be repeated every 4 to 6 hours for up to 48 hours.

Acute Spinal Cord Injury: For treatment of acute spinal cord injury, administer i.v. 30 mg methylprednisolone/kg of body weight in a bolus dose over a 15-minute period, followed by a 45-minute pause, and then a continuous infusion of 5.4 mg/kg/hour for 23 hours. There should be a separate i.v. site for the infusion pump. The treatment should begin within 8 hours of injury.

In other indications, initial dosage will vary from 10 to 500 mg depending on the clinical problem being treated. Larger doses may be required for short-term management of severe, acute conditions. Therapy may be initiated by administering methylprednisolone i.v. over a period of at least 5 minutes (e.g., doses up to 250 mg) to at least 30 minutes (e.g., doses greater than 250 mg). Subsequent doses may be given i.v. or i.m. at intervals dictated by the patient’s response and clinical condition. Corticosteroid therapy is an adjunct to, and not replacement for, conventional therapy.

Methylprednisolone in doses of 40 to 120 mg administered as retention enemas or by continuous drip 3 to 7 times weekly for periods of 2 or more weeks have been shown to be a useful adjunct in the treatment of some patients with ulcerative colitis. Many patients can be controlled with 40 mg administered in from 30 to 300 mL of water depending on the degree of involvement of the inflamed colonic mucosa. Other accepted therapeutic measures should, of course, be instituted.

Methylprednisolone may be administered by i.v. or i.m. injection or by i.v. infusion, the preferred method for initial emergency use being i.v. injection. To administer i.v. (or i.m.) injection, prepare solution as directed.

Compatibility: The compatibility and stability of methylprednisolone in solutions and with other drugs in i.v. admixtures is dependent on admixture pH, concentration, time, temperature, and the ability of methylprednisolone to solubilize itself. Thus, to avoid compatibility and stability problems, whenever possible it is recommended that methylprednisolone be administered separate from other drugs and as either i.v. push, through an i.v. medication chamber, or as an i.v. piggy-back solution.

Preparation of Solutions: To prepare solutions for i.v. infusion, first reconstitute methylprednisolone as directed. The medication may be administered in dilute solutions by admixing the reconstituted product with Dextrose 5% in Water, 0.9% Sodium Chloride (NS), Dextrose 5% in 0.45% Sodium Chloride. Dilute solution concentrations of 0.25 mg/mL or greater solution are physically and chemically stable for 48 hours.

Each Act-O-Vial (AOV) or vial of Solu-Medrol delivers after reconstitution with the diluent supplied or as directed (see Table II).

Table II–Solu-Medrol

Composition

Solu-Medrol 40 mg AOV 125 mg AOV 500 mg AOV 1 g AOV 40 mg Vial 125 mg Vial 500 mg Vial 1 g Vial

Powder

Deliverable Volume 1 mL 2 mL 4 mL 8 mL 1 mL 2 mL 8 mL 16 mL

Methylprednisolone (as sodium succinate) 40 mg 125 mg 500 mg 1 g 40 mg 125 mg 500 mg 1 g

Monobasic sodium phosphate anhydrous 1.6 mg 1.6 mg 6.4 mg 12.8 mg 1.84 mg 1.84 mg 6.4 mg 12.8 mg

Dibasic sodium phosphate dried 17.5 mg 17.4 mg 69.6 mg 139.2 mg 17.46 mg 17.4 mg 69.6 mg 139.2 mg

Lactose Hydrous 25 mg — — — 25 mg — — —

Diluent

Benzyl Alcohol 8.8 mg 17.6 mg 33.7 mg 66.8 mg — — — —

Sterile Water for Injection q.s. q.s. q.s. q.s. — — — —

Legend: AOV=Act-O-Vial.

When needed, the pH of each formula was adjusted with sodium hydroxide so that the pH of the reconstituted solution is within the range of 7 to 8.

Stability and Storage: Store unreconstituted sterile powder at room temperature (15 to 30°C). Store reconstituted solution at room temperature (15 to 30°C). Use reconstituted solution within 48 hours after mixing. Protect unreconstituted sterile powder and reconstituted solution from light.

Reconstituted Solutions: Directions for using the Act-O-Vial system: Press down on plastic activator to force diluent into the lower compartment. Gently agitate to effect solution. Remove plastic tab covering centre of stopper. Sterilize top of stopper with suitable germicide. Insert needle squarely through centre of stopper until tip is just visible. Invert vial and withdraw dose. See Table III.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Table III–Solu-Medrol

Reconstitution Table

Size Volume of Diluent to be Added Nominal Concentration per mL

40 mg AOV Entire contents supplied 40 mg/mL

125 mg AOV Entire contents supplied 62.5 mg/mL

500 mg AOV Entire contents supplied 125 mg/mL

1 g AOV Entire contents supplied 125 mg/mL

40 mg Vial 1 mL 40 mg/mL

125 mg Vial 2 mL 62.5 mg/mL

500 mg Vial 8 mL 62.5 mg/mL

1 g Vial 16 mL 62.5 mg/mL

Legend: AOV=Act-O-Vial.

Availability And Storage:

SuppliedAct-O-Vials: 40 mg: Each mL (when mixed) contains: methylprednisolone (as methylprednisolone sodium succinate) 40 mg, monobasic sodium phosphate anhydrous 1.6 mg, dibasic sodium phosphate dried 17.5 mg, lactose hydrous 25 mg and bacteriostatic water for injection q.s. In diluent, benzyl alcohol 8.8 mg with sterile water for injection q.s. Vial packs of 10.

125 mg: Each 2 mL (when mixed) contains: methylprednisolone (as methylprednisolone sodium succinate) 125 mg, monobasic sodium phosphate 1.6 mg, dibasic sodium phosphate dried 17.4 mg, and bacteriostatic water for injection q.s. In diluent benzyl alcohol 17.6 mg with sterile water for injection q.s. Vial packs of 10.

500 mg: Each 4 mL (when mixed) contains: methylprednisolone (as methylprednisolone sodium succinate) 500 mg, monobasic sodium phosphate anhydrous 6.4 mg, dibasic sodium phosphate dried 69.6 mg and bacteriostatic water for injection q.s. In diluent benzyl alcohol 33.7 mg with sterile water for injection q.s. Vial packs of 5.

1 g: Each 8 mL (when mixed) contains: methylprednisolone (as methylprednisolone sodium succinate) 1 g, monobasic sodium phosphate anhydrous 12.8 mg, dibasic sodium phosphate dried 139.2 mg and bacteriostatic water for injection q.s. In diluent benzyl alcohol 66.8 mg with sterile water for injection q.s. Single vials.

Vials: 40 mg: Reconstitute with 1 mL Bacteriostatic Water for Injection USP (benzyl alcohol as preservative) or Sterile Water for Injection. Each mL (when mixed) contains: methylprednisolone (as methylprednisolone sodium succinate) 40 mg, monobasic sodium phosphate anhydrous 1.84 mg, dibasic sodium phosphate dried 17.46 mg, lactose hydrous 25 mg and diluent q.s. Vial packs of 25.

125 mg: Reconstitute with 2 mL Bacteriostatic Water for Injection USP (benzyl alcohol as preservative) or Sterile Water for Injection. Each 2 mL (when mixed) contains: methylprednisolone (as methylprednisolone sodium succinate) 125 mg, monobasic sodium phosphate anhydrous 1.84 mg, dibasic sodium phosphate dried 17.4 mg and diluent q.s. Vial packs of 25.

500 mg: Reconstitute with 8 mL Bacteriostatic Water for Injection USP (benzyl alcohol as preservative) or Sterile Water for Injection. Each 8 mL (when mixed) contains: methylprednisolone (as methylprednisolone sodium succinate) 500 mg, monobasic sodium phosphate anhydrous 6.4 mg, dibasic sodium phosphate dried 69.6 mg and diluent q.s. Vial packs of 5.

1 g: Reconstitute with 16 mL Bacteriostatic Water for Injection USP (benzyl alcohol as preservative) or Sterile Water for Injection. Each 16 mL (when mixed) contains: methylprednisolone (as methylprednisolone sodium succinate) 1 g, monobasic sodium phosphate anhydrous 12.8 mg, dibasic sodium phosphate dried 139.2 mg and diluent q.s. Single vials.

SOLU-MEDROL® Pharmacia & Upjohn Methylprednisolone Sodium Succinate Glucocorticoid

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