Methylprednisolone Sodium Succinate

(Methylprednisolone)

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Methylprednisolone Sodium Succinate Prescribing Information

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

intravenous or intramuscular use

of methylprednisolone sodium succinate for injection, USP is indicated as follows:

Allergic states:

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.

Dermatologic diseases:

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

Endocrine disorders:

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.

Gastrointestinal diseases:

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

Hematologic disorders:

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.

Miscellaneous:

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

Neoplastic diseases:

For the palliative management of leukemias and lymphomas.

Nervous System:

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

Ophthalmic diseases:

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

Renal diseases:

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

Respiratory diseases:

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

Rheumatic disorders:

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.

NOTE: After mixing as directed, some of the methylprednisolone sodium succinate for injection, USP formulations contain benzyl alcohol (see DESCRIPTION, WARNINGS and PRECAUTIONS, Pediatric Use)

Because of possible physical incompatibilities, methylprednisolone sodium succinate for injection, USP should not be diluted or mixed with other solutions.

For reconstitution of methylprednisolone sodium succinate

for injection, use only Water for Injection or Bacteriostatic

Water for Injection with Benzyl Alcohol at room

temperature (see

DESCRIPTION

Methylprednisolone sodium succinate for injection, USP is an anti-inflammatory glucocorticoid, which contains methylprednisolone sodium succinate 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. The structural formula is represented below:

Referenced Image

Methylprednisolone sodium succinate 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 following strengths for intravenous or intramuscular administration:

40 mg (Single- Dose Vial)

Each mL (when mixed as directed) contains methylprednisolone sodium succinate equivalent to 40 mg methylprednisolone, also 1.6 mg monobasic sodium phosphate anhydrous; 17.46 mg dibasic sodium phosphate dried; and 25mg lactose hydrous.

This package does not contain diluent. The recommended diluents are Water for Injection USP or Bacteriostatic water for Injection USP. Bacteriostatic Water for Injection USP contains benzyl alcohol as a preservative.

125 mg (Single- Dose Vial)

Each 2 mL (when mixed as directed) contains methylprednisolone sodium succinate equivalent to 125 mg methylprednisolone; also 1.6 mg monobasic sodium phosphate anhydrous; and 17.4 mg dibasic sodium phosphate dried.

500mg (Multi-Dose)

Each 8 mL (when mixed as directed) contains methylprednisolone sodium succinate equivalent to 500 mg methylprednisolone; also 6.4 mg monobasic sodium phosphate anhydrous; 69.6 mg dibasic sodium phosphate dried.

This package does not contain diluent. Recommended diluent Bacteriostatic water for Injection contains benzyl alcohol as a preservative.

1 gram (Multi-Dose)

Each 16 mL (when mixed as directed) contains methylprednisolone sodium succinate equivalent to 1 gram methylprednisolone; also 12.8 mg monobasic sodium phosphate anhydrous; 139.2 mg dibasic sodium phosphate dried.

This package does not contain diluent. Recommended diluent Bacteriostatic water for Injection contains benzyl alcohol as a preservative.

2 gram (Single- Dose Vial)

Each 30.6 mL (when mixed as directed) contains methylprednisolone sodium succinate equivalent to 2 grams methylprednisolone; also 25.6 mg monobasic sodium phosphate anhydrous; 278 mg dibasic sodium phosphate dried.

This package does not contain diluent. Recommended diluent Bacteriostatic water for Injection contains benzyl alcohol as a preservative.

IMPORTANT –

Use only Water for Injection or Bacteriostatic Water for Injection with Benzyl Alcohol when reconstituting methylprednisolone sodium succinate for injection, USP.

Use within 48 hours after mixing.

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.

Prepare intravenous infusions only after reconstitution, use 5% dextrose in water, isotonic saline solution, or 5% dextrose in isotonic saline solution.

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, USP (

greater than 0.5 gram administered over a period of less than 10 minutes

). 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, USP sterile powder is 30 mg/kg

administered intravenously over at least 30 minutes.

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 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.

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. 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, USP 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 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°C 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 to 1.6 mg/kg/day in three or four divided doses (3.2 to 48 mg/m²bsa/day).

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

prednisone, prednisolone, or methylprednisolone

in pediatric patients whose asthma is uncontrolled by inhaled corticosteroids and long-acting bronchodilators is 1-2 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

PRECAUTIONS, Neurologic-psychiatric

For the purpose of comparison, the following is the equivalent milligram dosage of the various glucocorticoids:

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

These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered.

STORAGE CONDITIONS

Protect from light.

Store unreconstituted product at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

Store reconstituted solution (not further diluted) at controlled room temperature 20° to 25°C (68° to

77°F) [see USP], and use it within 48 hours.

See section

DOSAGE AND ADMINISTRATION

, for storage of further diluted solution.

Methylprednisolone sodium succinate for injection, USP Sterile Powder is contraindicated:

in systemic fungal infections and patients with known hypersensitivity to the product and its constituents. The methylprednisolone sodium succinate for injection, USP 40 mg presentation includes lactose monohydrate produced from cow’s milk. This presentation is therefore contraindicated in patients with a known or suspected hypersensitivity to cow’s milk or its components or other dairy products because it may contain trace amounts of milk ingredients.
for intrathecal administration. Reports of severe medical events have been associated with this route of administration.

Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura.

Additional contraindication for the use of methylprednisolone sodium succinate for injection, USP Sterile powder preserved with benzyl alcohol:

Formulations preserved with benzyl alcohol are contraindicated for use in premature infants. (see

WARNINGS

Serious Neurologic Adverse Reactions with Epidural Administration

Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids. Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke. These serious neurologic events have been reported with and without use of fluoroscopy. The safety and effectiveness of epidural administration of corticosteroids have not been established, and corticosteroids are not approved for this use.

General

Formulations with preservative (

see

DESCRIPTION) contain benzyl alcohol, which is potentially toxic when administered locally to neural tissue.

Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see

PRECAUTIONS, Pediatric Use

Injection of methylprednisolone sodium succinate may result in dermal and/or subdermal changes forming depressions in the skin at the injection site. In order to minimize the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections. Injection into the deltoid muscle should be avoided because of a high incidence of subcutaneous atrophy.

Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see

ADVERSE REACTIONS

In patients receiving the 40 mg presentation of methylprednisolone sodium succinate during the treatment for acute allergic conditions and where these symptoms worsen or any new allergic symptoms occur, consideration should be given to the potential for hypersensitivity reactions to cow’s milk ingredients (see

CONTRAINDICATIONS

).f appropriate, administration of methylprednisolone sodium succinate for injection, USP should be stopped, and the patient’s condition should be treated accordingly. Alternative treatments, including the use of corticosteroid formulations that do not contain ingredients produced from cow’s milk, should be considered for acute allergy management, where appropriate.

Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy who are subjected to any unusual stress before, during, and after the stressful situation.

Results from one multicenter, randomized, placebo-controlled study with methylprednisolone hemisuccinate, an intravenous corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of systemic corticosteroids, including methylprednisolone sodium succinate, should not be used for the treatment of traumatic brain injury.

Cardio-renal

Average and large doses of corticosteroids 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.

Literature reports suggest an apparent association between the use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.

There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure(see

CONTRAINDICATIONS

and

PRECAUTIONS, Drug Interactions,

Amphotericin B injection and potassium-depleting agents

Endocrine

Hypothalamic-pituitary adrenal (HPA) axis suppression, Cushing’s syndrome, and hyperglycemia. Monitor patients for these conditions with chronic use.

Corticosteroids can produce reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. 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.

Immunosuppression and Increased Risk of Infection

Corticosteroids, including methylprednisolone sodium succinate for injection, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens. Corticosteroids can:

• Reduce resistance to new infections

• Exacerbate existing infections

• Increase the risk of disseminated infections

• Increase the risk of reactivation or exacerbation of latent infections

• Mask some signs of infection

Corticosteroid-associated infections can be mild but can be severe and at times fatal. The rate of infectious complications increases with increasing corticosteroid dosages.

A study has failed to establish the efficacy of methylprednisolone sodium succinate in the treatment of sepsis syndrome and septic shock. The study also suggests that treatment of these conditions with methylprednisolone sodium succinate may increase the risk of mortality in certain patients (i.e., patients with elevated serum creatinine levels or patients who develop secondary infections after methylprednisolone sodium succinate).

Monitor for the development of infection and consider methylprednisolone sodium succinate for injection withdrawal or dosage reduction as needed.

Tuberculosis

If methylprednisolone sodium succinate for injection is used to treat a condition in patients with latent tuberculosis or tuberculin reactivity, reactivation of the disease may occur. Closely monitor such patients for reactivation. During prolonged methylprednisolone sodium succinate for injection therapy, patients with latent tuberculosis or tuberculin reactivity should receive chemoprophylaxis.

Varicella Zoster and Measles Viral Infections

Varicella and measles can have a serious or even fatal course in non-immune patients taking corticosteroids, including methylprednisolone sodium succinate for injection. In corticosteroid-treated patients who have not had these diseases or are non-immune, particular care should be taken to avoid exposure to varicella and measles:

• If a methylprednisolone sodium succinate for injection -treated patient is exposed to varicella, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If varicella develops, treatment with antiviral agents may be considered.

• If a methylprednisolone sodium succinate for injection -treated patient is exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated.

Hepatitis B Virus Reactivation

Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers treated with immunosuppressive dosages of corticosteroids, including methylprednisolone sodium succinate for injection.

Reactivation can also occur infrequently in corticosteroid-treated patients who appear to have resolved hepatitis B infection.

Screen patients for hepatitis B infection before initiating immunosuppressive (e.g., prolonged) treatment with methylprednisolone sodium succinate for injection. For patients who show evidence of hepatitis B infection, recommend consultation with physicians with expertise in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy.

Fungal Infections

Corticosteroids, including methylprednisolone sodium succinate for injection, may exacerbate systemic fungal infections; therefore, avoid methylprednisolone sodium succinate for injection use in the presence of such infections unless methylprednisolone sodium succinate for injection is needed to control drug reactions. For patients on chronic methylprednisolone sodium succinate for injection therapy who develop systemic fungal infections, methylprednisolone sodium succinate for injection withdrawal or dosage reduction is recommended.

Amebiasis

Corticosteroids, including methylprednisolone sodium succinate for injection, may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating methylprednisolone sodium succinate for injection in patients who have spent time in the tropics or patients with unexplained diarrhea.

Strongyloides Infestation

Corticosteroids, including methylprednisolone sodium succinate for injection, 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.

Cerebral Malaria

Avoid corticosteroids, including methylprednisolone sodium succinate for injection, in patients with cerebral malaria.

Drug-Induced Liver Injury

Rarely, high doses of cyclically pulsed intravenous methylprednisolone (usually for the treatment of exacerbations of multiple sclerosis at doses of 1 gram/day) can induce a toxic form of acute hepatitis. The time to onset of this form of steroid-induced liver injury can be several weeks or longer. Resolution has been observed after discontinuation of treatment. However, serious liver injury can occur, sometimes resulting in acute liver failure and death. Discontinue intravenous methylprednisolone if toxic hepatitis occurs. Since recurrence has occurred after re-challenge, avoid use of high dose intravenous methylprednisolone in patients with a history of toxic hepatitis caused by methylprednisolone.

Vaccination

Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines can not be predicted.

Immunization procedures may be undertaken in patients receiving corticosteroids as replacement therapy, e.g., for Addison’s disease.

Neurologic

Reports of severe medical events have been associated with the intrathecal route of administration (see

ADVERSE REACTIONS

Gastrointestinal

and

Neurologic/Psychiatric

Ophthalmic

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 bacteria, fungi, or viruses. The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should be used cautiously in patients with ocular herpes simplex because of corneal perforation. Corticosteroids should not be used in active ocular herpes simplex.

Kaposi’s Sarcoma

Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement of Kaposi’s sarcoma.

and

Pediatric Use

Some formulations of this product contain benzyl alcohol as a preservative(see

DESCRIPTION

). Carefully examine vials to determine formulation that is being used.

Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product ordinarily delivers amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. The risk of benzyl alcohol toxicity depends on the quantity administered and the hepatic capacity to detoxify the chemical. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

The efficacy and safety of corticosteroids in the pediatric population are based on the well-established course of effect of corticosteroids which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome (>2 years of age), and aggressive lymphomas and leukemias (>1 month of age). Other indications for pediatric use of corticosteroids, e.g., severe asthma and wheezing, are based on adequate and well-controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations.

The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see

ADVERSE REACTIONS

). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose.

Hypertrophic cardiomyopathy may develop after administration of methylprednisolone to prematurely born infants, therefore appropriate diagnostic evaluation and monitoring of cardiac function and structure should be performed.

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

Allergic reactions:

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

Blood and lymphatic system disorders:

Leukocytosis.

Cardiovascular:

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

WARNINGS

), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis.

Dermatologic:

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.

Endocrine:

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.

Fluid and electrolyte disturbances:

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

Gastrointestinal:

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.

Hepatobiliary:

Hepatitis (see

WARNINGS, Drug-Induced Liver Injury

Metabolic:

Negative nitrogen balance due to protein catabolism.

Musculoskeletal:

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

Neurologic/Psychiatric:

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

WARNINGS, Neurologic

Ophthalmic:

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

Other:

Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, injection site infections following non-sterile administration (see

WARNINGS

), malaise, moon face, weight gain.

Aminoglutethimide:

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

Amphotericin B injection and potassium-depleting agents:

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.

Antibiotics:

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

Drug Interactions

Hepatic Enzyme Inhibitors

Anticholinesterases:

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.

Anticoagulants, oral:

Coadministration 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.

Antidiabetics:

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

Antitubercular drugs:

Serum concentrations of isoniazid may be decreased.

Cholestyramine:

Cholestyramine may increase the clearance of corticosteroids.

Cyclosporine:

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

Digitalis glycosides:

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

Estrogens, including oral contraceptives:

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

Hepatic Enzyme Inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin):

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

Hepatic Enzyme Inhibitors (e.g., ketoconazole, macrolide antibiotics such as erythromycin and troleandomycin):

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

Ketoconazole:

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.

Nonsteroidal anti-inflammatory agents (NSAIDs):

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.

Skin tests:

Corticosteroids may suppress reactions to skin tests.

Vaccines:

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

WARNINGS, Immunosuppression and Increased Risk of Infection,

Vaccination

Referenced Image

Methylprednisolone sodium succinate for injection, USP is available in following strengths for intravenous or intramuscular administration:

40 mg (Single- Dose Vial)

125 mg (Single- Dose Vial)

500mg (Multi-Dose)

This package does not contain diluent. Recommended diluent Bacteriostatic water for Injection contains benzyl alcohol as a preservative.

1 gram (Multi-Dose)

This package does not contain diluent. Recommended diluent Bacteriostatic water for Injection contains benzyl alcohol as a preservative.

2 gram (Single- Dose Vial)

This package does not contain diluent. Recommended diluent Bacteriostatic water for Injection contains benzyl alcohol as a preservative.

IMPORTANT –

Use only Water for Injection or Bacteriostatic Water for Injection with Benzyl Alcohol when reconstituting methylprednisolone sodium succinate for injection, USP.

Use within 48 hours after mixing.

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.

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Methylprednisolone Sodium Succinate

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