Methylprednisolone Sodium Succinate

When oral therapy is not feasible, and the strength, dosage form, and route of administration of the drug reasonably lend the preparation to the treatment of the condition, the

of methylprednisolone sodium succinate for injection is indicated as follows:

Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, serum sickness, transfusion reactions.

Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome).

Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance), congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsuppurative thyroiditis.

To tide the patient over a critical period of the disease in regional enteritis (systemic therapy) and ulcerative colitis.

Acquired (autoimmune) hemolytic anemia, congenital (erythroid) hypoplastic anemia (Diamond-Blackfan anemia), idiopathic thrombocytopenic purpura in adults (intravenous administration only; intramuscular administration is contraindicated), pure red cell aplasia, selected cases of secondary thrombocytopenia.

Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy.

For the palliative management of leukemias and lymphomas.

Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor, or craniotomy.

Sympathetic ophthalmia, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids.

To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus.

Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis.

As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, temporal arteritis, polymyositis, and systemic lupus erythematosus.

Use only Bacteriostatic Water For Injection with Benzyl Alcohol when reconstituting methylprednisolone sodium succinate for injection (see

). 

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

This preparation may be administered by intravenous injection, by intravenous infusion, or by intramuscular injection, the preferred method for initial emergency use being intravenous injection. Following the initial emergency period, consideration should be given to employing a longer acting injectable preparation or an oral preparation.

There are reports of cardiac arrhythmias and/or cardiac arrest following the rapid administration of large intravenous doses of  methylprednisolone sodium succinate for injection (

). Bradycardia has been reported during or after the administration of large doses of methylprednisolone sodium succinate, and may be unrelated to the speed or duration of infusion. When high dose therapy is desired, the recommended dose of methylprednisolone sodium succinate for injection is 30 mg/kg . This dose may be repeated every 4 to 6 hours for 48 hours.

In general, high dose corticosteroid therapy should be continued only until the patient’s condition has stabilized; usually not beyond 48 to 72 hours.

In other indications, initial dosage will vary from 10 mg to 40 mg of methylprednisolone depending on the specific disease entity being treated. However, in certain overwhelming, acute, life-threatening situations, administrations in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages.

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. 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 the corticosteroid 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.

Methylprednisolone sodium succinate for injection may be administered by intravenous or intramuscular injection or by intravenous infusion, the preferred method for initial emergency use being intravenous injection. To administer by intravenous (or intramuscular) injection, prepare solution as directed. The desired dose may be administered intravenously over a period of several minutes. If desired, the medication may be administered in diluted solutions by adding Water for Injection or other suitable diluent (see below) to the single-dose vial and withdrawing the indicated dose.

To prepare solutions for intravenous infusion, first prepare the solution for injection as directed. This solution may then be added to indicated amounts of 5% dextrose in water, isotonic saline solution, or 5% dextrose in isotonic saline solution. From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user. Chemical and physical stability of the further diluted product has been demonstrated within 4 hours of preparation if stored below 25°C or within 24 hours of preparation if stored at 2° to 8°C.

In pediatric patients, the initial dose of methylprednisolone may vary depending on the specific disease entity being treated. The range of initial doses is 0.11 mg/kg/day to 1.6 mg/kg/day in three or four divided doses (3.2 mg/m²bsa/day to 48 mg/m²bsa/day).

The National Heart, Lung, and Blood Institute (NHLBI) recommended dosing for systemic

in pediatric patients whose asthma is uncontrolled by inhaled corticosteroids and long-acting bronchodilators is 1 mg/kg/day to 2 mg/kg/day in single or divided doses. It is further recommended that short course, or “burst” therapy, be continued until the patient achieves a peak expiratory flow rate of 80% of his or her personal best or until symptoms resolve. This usually requires 3 to 10 days of treatment, although it can take longer. There is no evidence that tapering the dose after improvement will prevent a relapse.

Dosage may be reduced for infants and children but should be governed more by the severity of the condition and response of the patient than by age or size. It should not be less than 0.5 mg per kg every 24 hours.

Dosage must be decreased or discontinued gradually when the drug has been administered for more than a few days. If a period of spontaneous remission occurs in a chronic condition, treatment should be discontinued. Routine laboratory studies, such as urinalysis, two-hour postprandial blood sugar, determination of blood pressure and body weight and a chest X-ray should be made at regular intervals during prolonged therapy. Upper GI X-rays are desirable in patients with an ulcer history or significant dyspepsia.

In treatment of acute exacerbations of multiple sclerosis, daily doses of 160 mg of methylprednisolone for a week followed by 64 mg every other day for 1 month have been shown to be effective (see

).

Cortisone, 25	Triamcinolone, 4
Hydrocortisone, 20	Paramethasone, 2
Prednisolone, 5	Betamethasone, 0.75
Prednisone, 5	Dexamethasone, 0.75
Methylprednisolone, 4

Protect from light.

Store unreconstituted product at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Store reconstituted solution (not further diluted) at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature], and use it within 48 hours.

See section

, for storage of further diluted solution.

The following adverse reactions have been reported with methylprednisolone sodium succinate or other corticosteroids:

Allergic or hypersensitivity reactions, anaphylactoid reaction, anaphylaxis, angioedema.

Leukocytosis.

Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see ), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis.

Acne, allergic dermatitis, burning or tingling (especially in the perineal area after intravenous injection), cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria.

Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients.

Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention.

Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis.

Hepatitis (see ).

Negative nitrogen balance due to protein catabolism.

Aseptic necrosis of femoral and humeral heads, Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, postinjection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures.

Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration (see ).

Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, rare instances of blindness associated with periocular injections.

Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, injection site infections following non-sterile administration (see ), malaise, moon face, weight gain.

Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression.

When corticosteroids are administered concomitantly with potassium-depleting agents (i.e. amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure.

Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance (see , ).

Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.

Co-administration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect.

Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required.

Serum concentrations of isoniazid may be decreased.

Cholestyramine may increase the clearance of corticosteroids.

Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use.

Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia.

Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect.

Drugs which induce cytochrome P450 3A4 enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased.

Drugs which inhibit cytochrome P450 3A4 have the potential to result in increased plasma concentrations of corticosteroids.

Ketoconazole has been reported to significantly decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects.

Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids.

Corticosteroids may suppress reactions to skin tests.

Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see ).

Methylprednisolone sodium succinate for injection, USP is an anti-inflammatory glucocorticoid, which contains methylprednisolone sodium succinate, USP as the active ingredient. Methylprednisolone sodium succinate, USP, is the sodium succinate ester of methylprednisolone, and it occurs as a white, or nearly white, odorless hygroscopic, amorphous solid. It is very soluble in water and in alcohol; it is insoluble in chloroform and is very slightly soluble in acetone.

The chemical name for methylprednisolone sodium succinate is pregna-1,4-diene-3,20-dione,21-(3-carboxy-1-oxopropoxy)-11,17-dihydroxy-6-methyl-monosodium salt, (6α, 11β), and the molecular weight is 496.53 g/mol. The structural formula is represented below:

 

Methylprednisolone sodium succinate, USP is soluble in water; it may be administered in a small volume of diluent and is well suited for intravenous use in situations where high blood levels of methylprednisolone are required rapidly.

Methylprednisolone sodium succinate for injection, USP is available in below formulations:

Formulations

40 mg (Single-Dose Vial) —Each mL (when mixed) contains methylprednisolone sodium succinate, USP equivalent to 40 mg methylprednisolone, USP. Also contains benzyl alcohol; lactose hydrous, 25 mg; monobasic sodium phosphate anhydrous, 1.6 mg; and dibasic sodium phosphate dried, 17.46 mg.

125 mg (Single-Dose Vial) —Each 2 mL (when mixed) contains methylprednisolone sodium succinate, USP equivalent to 125 mg methylprednisolone, USP. Also contains benzyl alcohol; monobasic sodium phosphate anhydrous, 1.6 mg; and dibasic sodium phosphate dried, 17.4 mg.

- Use only Bacteriostatic Water for Injection with Benzyl Alcohol when reconstituting Methylprednisolone Sodium Succinate for Injection, USP.

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