Methylprednisolone Sodium Succinate for Injection, USP (Hospira Healthcare, 500 mg / 10 mL) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Intravenous administration of Methylprednisolone Sodium Succinate for Injection USP 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 (see text)
• Drug reactions
• Contact dermatitis
• Urticaria
• Generalized neurodermatitis
• Reactions to insect bites
• Pemphigus foliaceous and vulgaris
• Exfoliative dermatitis
• Erythema multiforme

In anaphylactic reactions, epinephrine or norepinephrine should be administered first for an immediate hemodynamic effect followed by intravenous injection of Methylprednisolone Sodium Succinate for Injection USP 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 Sodium Succinate for Injection USP is capable of providing relief within 1/2 to 2 hours. In some asthmatic patients it may be advantageous to administer Methylprednisolone Sodium Succinate for Injection USP by slow intravenous drip over a period of hours.

As adjunctive therapy in

• Acute systemic lupus erythematosus
• Acute rheumatic fever
• Acute gout

In these conditions, Methylprednisolone Sodium Succinate for Injection USP may be given by slow intravenous administration over a period of several minutes. Thereafter, the patient should be placed on intramuscular or oral therapy as required for continued relief of symptoms. In these conditions, other accepted measures of therapy should also be instituted.

Ulcerative colitis

In addition to the above conditions, colonic instillation of Methylprednisolone Sodium Succinate in retention enemas or by continuous drip, have been shown to be a useful adjunct in the treatment of patients with ulcerative colitis.

Shock

In severe hemorrhagic or traumatic shock, adjunctive use of intravenous methylprednisolone sodium succinate may aid in achieving hemodynamic restoration. Corticoid therapy should not replace standard methods of combating shock, but present evidence indicates that concurrent use of large doses of corticoids with other measures 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 Sodium Succinate for Injection USP is suitable for such indications.

Cerebral oedema of non traumatic origin

Administration of Methylprednisolone Sodium Succinate for Injection USP immediately prior to intracranial surgery and in the immediate post-operative period has reduced the duration of post-operative complications related to cerebral oedema.

CONTRAINDICATIONS

Methylprednisolone Sodium Succinate for Injection USP is contraindicated:

• for systemic fungal infections
• in patients administered with live or live attenuated vaccines while receiving immunosuppressive doses of corticosteroids.
• for intrathecal or epidural administration. Reports of serious medical events have been associated with these routes of administration.

• for use in premature infants because the diluent for reconstitution contains benzyl alcohol. See

  WARNINGS AND PRECAUTIONS, General; Pediatrics.

• Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura.

Except when used for short-term or emergency therapy, Methylprednisolone Sodium Succinate for Injection USP is contraindicated in patients with:

• arrested tuberculosis
• herpes simplex keratitis
• acute psychoses
• Cushing’s syndrome
• peptic ulcer
• markedly elevated serum creatinine
• vaccinia and varicella.

WARNINGS AND PRECAUTIONS

Methylprednisolone Sodium Succinate for Injection USP should not be used in premature infants. The diluent for reconstitution of the Vials contains benzyl alcohol which has been reported to be associated with fatal “Gasping Syndrome” in premature infants. 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 at which toxicity may occur is not known. See also CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS, Pediatrics.

Benzyl alcohol is potentially toxic when administered locally to neural tissue.

General

Methylprednisolone Sodium Succinate for Injection USP should not be administered by any route other than those listed under SUMMARY PRODUCT INFORMATION. It is critical that, during administration of Methylprednisolone Sodium Succinate for Injection USP, appropriate technique be used and care taken to assure proper route of administration.

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 Sodium Succinate for Injection USP.

Serious medical events have been reported in association with the intrathecal/epidural routes of administration (see CONTRAINDICATIONS and ADVERSE REACTIONS).

In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during and after the stressful situation is indicated.

The slower rate of absorption by intramuscular administration should be recognized.

The lowest possible dose of corticosteroid should be used to control the condition under treatment. 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.

The existence of diabetes, osteoporosis, renal insufficiency, chronic psychosis, hypertension, myasthenia gravis or predisposition to thrombophlebitis requires that Methylprednisolone Sodium Succinate for Injection USP be administered with extreme caution.

Carcinogenesis and Mutagenesis

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

Animal studies found corticosteroids to have a possible tumorigenic and mutagenic potential (See TOXICOLOGY, Carcinogenesis and also TOXICOLOGY, Mutagenesis).

Cardiovascular

There are reports of cardiac arrhythmias and/or circulatory collapse and/or cardiac arrest following the rapid administration of large intravenous doses of methylprednisolone sodium succinate (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 sodium succinate, and may be unrelated to the speed or duration of infusion.

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.

Thrombosis including venous thromboembolism has been reported to occur with corticosteroids. As a result, corticosteroids should be used with caution in patients who have or may be predisposed to thromboembolic disorders.

As sodium retention with resultant oedema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution, and only if strictly necessary, in patients with congestive heart failure. Corticosteroids should be used with caution in hypertension, or renal insufficiency. See also WARNINGS AND PRECAUTIONS, Endocrine and Metabolism.

Adverse effects of glucocorticoids on the cardiovascular system, such as dyslipidemia and hypertension, may predispose treated patients with existing cardiovascular risk factors to additional cardiovascular effects, if high doses and prolonged courses are used. Accordingly, corticosteroids should be employed judiciously in such patients and attention should be paid to risk modification and additional cardiac monitoring if needed.

Endocrine and Metabolism

Corticosteroid administration may result in hypothalamic-pituitary-adrenal (HPA) suppression (secondary adrenocortical insufficiency). The degree and duration of adrenocortical insufficiency produced is variable among patients and depends on the dose, frequency, time of administration and duration of glucocorticoid therapy. 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 may need to be reinstituted. In addition, acute adrenal insufficiency leading to a fatal outcome may occur if glucocorticoids are withdrawn abruptly.

Because glucocorticoids can produce or aggravate Cushing’s syndrome, glucocorticoids should be avoided in patients with Cushing’s disease.

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. See also WARNINGS AND PRECAUTIONS, Cardiovascular.

Corticosteroids, including methylprednisolone, can increase blood glucose, worsen pre-existing diabetes, and predispose those on long-term corticosteroid therapy to diabetes mellitus.

There is an enhanced effect of corticosteroids in patients with hypothyroidism. Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage.

Pheochromocytoma crisis, which can be fatal, has been reported after administration of systemic corticosteroids, including methylprednisolone. Corticosteroids should only be administered to patients with suspected or identified pheochromocytoma after an appropriate risk/benefit evaluation.

Gastrointestinal

Corticosteroids should be used with caution in non-specific ulcerative colitis if there is a probability of impending perforation, abscess or other pyogenic infection and in diverticulitis, fresh intestinal anastomoses, and active or latent peptic ulcer, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent.

Glucocorticoid therapy may mask the symptoms of peptic ulcer so that perforation or haemorrhage may occur without significant pain. In combination with NSAIDs, such as Aspirin (acetylsalicyclic acid), the risk of developing gastrointestinal ulcers is increased.

Hematologic

Aspirin (acetylsalicylic acid) should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.

Hepatic/Biliary/Pancreatic

Drug-induced liver injury such as acute hepatitis can result from cyclical pulsed intravenous methylprednisolone (usually at initial dose ≥ 1gm/day). The time to onset of acute hepatitis can be several weeks or longer. Resolution of the adverse event has been observed after treatment was discontinued.

There is an enhanced effect of corticosteroids in patients with cirrhosis.

High doses of corticosteroids may produce acute pancreatitis.

Immune

Corticosteroids may suppress the immune system and 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 organisms, 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.

Recent studies suggest that corticosteroids should not be used in septic shock (an unapproved indication), and suggest that increased mortality may occur in some subgroups at higher risk (e.g., elevated serum creatinine greater than 2.0 mg/dL or secondary infections).

Do not use intra-articularly, intrabursally or for intratendinous administration for local effect in the presence of acute local infection.

Fungal infections

Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. See also CONTRAINDICATIONS; DRUG INTERACTIONS.

Special pathogens

Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, Toxoplasma.

It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea.

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

Corticosteroids should not be used in cerebral malaria. There is currently no evidence of benefit from steroids in this condition.

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.

Vaccination

Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids (see CONTRAINDICATIONS). Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished. Indicated immunization procedures may be undertaken in patients receiving non immunosuppressive doses of corticosteroids.

While on corticosteroid therapy patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients who are on corticosteroids, especially in high doses, because of possible hazards of neurological complications and lack of antibody response.

Viral infections

Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with immune globulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents should be considered.

Recent studies do not support Methylprednisolone Sodium Succinate for Injection USP use during septic shock, and suggest that increased mortality may occur in some subgroups at higher risk (e.g., elevated serum creatinine greater than 2.0 mg/dL or secondary infections).

Musculoskeletal

An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g. myasthenia gravis, see WARNINGS AND PRECAUTIONS - Neurologic), or in patients receiving concomitant therapy with anticholinergics such as 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.

Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (e.g., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (e.g., postmenopausal women) before initiating corticosteroid therapy.

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

Neurologic

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.

Systemic corticosteroids are not indicated for, and therefore should not be used to treat traumatic brain injury. A multicenter study revealed an increased mortality at 2 weeks and 6 months after injury in patients administered methylprednisolone sodium succinate compared to placebo.

Corticosteroids should be used with caution in patients with seizure disorders.

Corticosteroids should be used with caution in patients with myasthenia gravis.

There have been reports of epidural lipomatosis in patients taking corticosteroids (including reports in children).

Ophthalmologic

Use of corticosteroids may produce posterior subcapsular cataracts and nuclear cataracts (particularly in children), exophthalmos, or increased intraocular pressure, which may result in glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored.

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 possible corneal perforation.

Corticosteroid therapy has been associated with central serous chorioretinopathy, which may lead to retinal detachment.

Psychiatric

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.

Potentially severe psychiatric adverse reactions may occur with systemic steroids. Symptoms typically emerge within a few days or weeks of starting treatment. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary.

Psychological effects have been reported upon withdrawal of corticosteroids; the frequency is unknown. Patients/caregivers should be encouraged to seek medical attention if psychological symptoms develop in the patient, especially if depressed mood or suicidal ideation is suspected. Patients/caregivers should be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids.

Sensitivity/Resistance

Allergic reactions may occur. Because rare instances of skin reactions and anaphylactic/anaphylactoid reactions have occurred in patients receiving corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of allergy to any drug (see ADVERSE REACTIONS).

Sexual Function/Reproduction

Steroids may increase or decrease motility and number of spermatozoa in some patients.

Skin

Injection of Methylprednisolone Sodium Succinate for Injection USP 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.

Special Populations

Pregnant Women: Corticosteroids readily cross the placenta. Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Administration of corticosteroids to pregnant animals can cause fetal malformations (cleft palate, skeletal malformations) and intra-uterine growth retardation (see TOXICOLOGY, Reproductive toxicity).

One retrospective study found an increased incidence of low birth weights in infants born of mothers receiving corticosteroids. Cataracts have been observed in infants born to mothers undergoing long-term treatment corticosteroids during pregnancy.

Since adequate human reproductive studies have not been done with methylprednisolone sodium succinate, Methylprednisolone Sodium Succinate for Injection USP should be used during pregnancy only at the lowest possible dose, only if clearly needed, where the potential benefit to the mother justifies the potential risk to the embryo or fetus.

Infants born to mothers who received substantial doses of corticosteroids during pregnancy should be observed for signs of hypoadrenalism and appropriate measures instituted if such signs are present. There are no known effects of corticosteroids on labour and delivery.

Benzyl alcohol can be introduced into the solution when Methylprednisolone Sodium Succinate for Injection USP Plain Vials are reconstituted with Bacteriostatic Water for Injection USP (benzyl alcohol as preservative) as directed.

Benzyl alcohol can cross the placenta.

Nursing Women: Corticosteroids are excreted in breast milk. Corticosteroids distributed into breast milk may suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects.

Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a careful benefit-risk assessment should be conducted and a decision should be made whether to discontinue nursing, or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatrics: Methylprednisolone Sodium Succinate for Injection USP is contraindicated for use in premature infants (see CONTRAINDICATIONS). Benzyl alcohol can be introduced into the solution, when Methylprednisolone Sodium Succinate for Injection USP Plain Vials are reconstituted with Bacteriostatic Water for Injection USP (benzyl alcohol as preservative). Benzyl alcohol has been associated with serious adverse events and death, particularly in pediatric patients, including the “gasping syndrome” in neonate and low-birth weight infants. The “gasping syndrome” is 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. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants, as well as patients receiving high doses (>90 mg/kg/day), 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.

Pediatric patients may experience a decrease in their growth velocity at low systemic doses and in the absence of laboratory evidence of HPA axis suppression. 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. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose.

Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed. 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.

Infants and children on prolonged corticosteroid therapy are at special risk from raised intracranial pressure.

High doses of corticosteroids may produce pancreatitis in children.

Geriatrics: In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Caution is recommended with prolonged corticosteroid treatment in the elderly due to a potential increased risk for osteoporosis, as well as increased risk for fluid retention with possible resultant hypertension.

Monitoring and Laboratory testing

Corticosteroids may suppress reactions to skin tests.

Since methylprednisolone suppresses endogenous adrenocortical activity, it is highly important that the patient receiving Methylprednisolone Sodium Succinate for Injection USP be under careful observation, not only during the course of treatment but for some time after treatment is terminated. Monitoring for signs and symptoms of drug-induced secondary adrenocortical insufficiency may be necessary for up to one year following cessation of long-term or high-dose corticosteroid therapy.

ADVERSE REACTIONS

The following Adverse Reactions have been reported with the systemic use of Methylprednisolone Sodium Succinate for Injection USP and other corticosteroid preparations.

The following adverse reactions have been reported with the following routes of administration:

Intrathecal/Epidural: Arachnoiditis, functional gastrointestinal disorder, bladder dysfunction, headache, meningitis, parapareisis/paraplegia, seizures, sensory disturbances.

DRUG INTERACTIONS

Overview

Methylprednisolone is a cytochrome P450 enzyme (CYP) substrate and is mainly metabolized by the CYP3A enzyme. CYP3A4 is the dominant enzyme of the most abundant CYP subfamily in the liver of adult humans. It catalyzes 6β-hydroxylation of steroids, the essential Phase I metabolic step for both endogenous and synthetic corticosteroids. Many other compounds are also substrates of CYP3A4, some of which (as well as other drugs) have been shown to alter glucocorticoid metabolism by induction (upregulation) or inhibition of the CYP3A4 enzyme.

CYP3A4 INHIBITORS – Drugs that inhibit CYP3A4 activity generally decrease hepatic clearance and increase the plasma concentration of CYP3A4 substrate medications, such as methylprednisolone. In the presence of a CYP3A4 inhibitor, the dose of methylprednisolone may need to be titrated to avoid steroid toxicity.

CYP3A4 INDUCERS – Drugs that induce CYP3A4 activity generally increase hepatic clearance, resulting in decreased plasma concentration of medications that are substrates for CYP3A4. Coadministration may require an increase in methylprednisolone dosage to achieve the desired result.

CYP3A4 SUBSTRATES – In the presence of another CYP3A4 substrate, the hepatic clearance of methylprednisolone may be affected, with corresponding dosage adjustments required. It is possible that adverse events associated with the use of either drug alone may be more likely to occur with coadministration.

NON-CYP3A4-MEDIATED EFFECTS – Other interactions and effects that occur with methylprednisolone are described in the Table below.

Drug-Drug Interactions

The following table provides a list and description of the most common and/or clinically important drug interactions or effects with methylprednisolone.

neuromuscular blocking effects of pancurinium and vecuronium has been reported in patients taking corticosteroids. This interaction may be expected with all

competitive

neuromuscular blockers.

Incompatibilities

To avoid compatibility and stability problems, it is recommended that methylprednisolone sodium succinate be administered separately from other compounds that are administered via the IV route of administration. Drugs that are physically incompatible in solution with methylprednisolone sodium succinate include, allopurinol sodium, doxapram hydrochloride, tigecycline, diltiazem hydrochloride, calcium gluconate, vecuronium bromide, rocuronium bromide, cisatracurium besylate, glycopyrrolate, propofol (see also DOSAGE AND ADMINISTRATION, Compatibility).

Drug-Food Interactions

Interactions with food have not been established.

Grapefruit juice is a CYP3A4 inhibitor. See DRUG INTERACTIONS, CYP3A4 INHIBITORS above.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Skin tests: Corticosteroids may suppress reactions to skin tests.

Drug-Lifestyle Interactions

Dizziness, vertigo, visual disturbances and fatigue are possible side effects associated with corticosteroid use. If affected, patients should not drive or operate machinery.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Corticosteroid therapy is an adjunct to, and not replacement for, conventional therapy.

As adjunctive therapy in life threatening conditions (e.g., shock states), the recommended dose of Methylprednisolone Sodium Succinate for Injection USP is 30 mg per kg, given intravenously over a period of at least 30 minutes. This large dose may be repeated every 4 - 6 hours for up to 48 hours.

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 Sodium Succinate for Injection USP intravenously 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 intravenously or intramuscularly at intervals dictated by the patient's response and clinical condition.

Methylprednisolone Sodium Succinate for Injection USP in doses of 40 to 120 mg administered as retention enemas or by continuous drip three to seven times weekly for periods of two 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 of Methylprednisolone Sodium Succinate for Injection USP administered in from 1 to 10 fluid ounces of water depending on the degree of involvement of the inflamed colonic mucosa. Other accepted therapeutic measures should, of course, be instituted.

Administration

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 intravenous (or intramuscular) injection, prepare solution as per instructions.

Reconstitution:

1. 1. Remove the protective plastic flip-top seal.
2. 2. Swab the rubber stopper with an antiseptic solution and introduce the required quantity of the diluent by means of a syringe into the vial.
3. 3. Shake the vial thoroughly to dissolve the powder content.
4. 4. Withdraw the dose in the usual manner with the help of a syringe, unused portion should be discarded.

Reconstitute with Sterile Water for Injection, or, if required, Bacteriostatic Water for Injection as follows:

RECONSTITUTION TABLE

The supplied Bacteriostatic Water for Injection in each pack of Methylprednisolone Sodium Succinate for Injection USP contains benzyl alcohol as preservative. SEE WARNINGS AND PRECAUTIONS, Pediatrics.

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

Store powder or reconstituted solution at 15 to 25 C. When reconstituted with Bacteriostatic Water for Injection, the resulting solution may be stored for up to 48 hours at 15 -25 C. When reconstituted with Sterile Water for Injection, the resulting solution may be stored for up to 24 hours at 15 -25 C due to risk of microbial contamination. The solution with a slight haze should be discarded. The vials are single dose vials. Discard unused portion.

To prepare solutions for IV infusion:

First prepare the solution for injection as directed. Further dilution should be done immediately after reconstitution.

If desired, the medication may be administered in diluted solutions by admixing the reconstituted product with 0.9% Sodium Chloride Injection or with Dextrose 5% Injection. Concentrations of 1mg/mL are physically and chemically stable for 24 hours at 15 to 25 C.

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

Compatibility

The compatibility and stability of Methylprednisolone Sodium Succinate for Injection USP, in solutions and with other drugs in intravenous 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 Sodium Succinate for Injection USP 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.

OVERDOSAGE

Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. Continuous overdosage would require careful gradual reduction of dosage in order to prevent the occurrence of acute adrenal insufficiency.

Methylprednisolone is dialyzable.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Pharmacodynamics

Methylprednisolone is a potent anti-inflammatory steroid.

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

The metabolism and excretion of methylprednisolone sodium succinate 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.

Exceeding prednisolone in anti-inflammatory potency and having even less tendency than prednisolone to induce retention of sodium and water, methylprednisolone sodium succinate offers the use of lower doses with an enhanced split between anti-inflammatory and mineralocorticoid activities. Thus methylprednisolone sodium succinate may be indicated for emergency use in patients in whom increased sodium retention would be hazardous.

The relative potency of methylprednisolone sodium succinate and hydrocortisone sodium succinate, as indicated by depression of eosinophil count, following intravenous administration, is at least four to one. This is in good agreement with the relative oral potency of methylprednisolone and hydrocortisone. Studies indicate that the administration of methylprednisolone results in an appreciable prolongation of plasma steroid levels over those obtained following equivalent doses of hydrocortisone or prednisolone. The following table illustrates this prolongation of blood levels expressed as the half-life in minutes of the 17- hydroxy-corticosteroid levels obtained following intravenous administration of methylprednisolone, prednisolone and hydrocortisone.

Pharmacokinetics

Methylprednisolone pharmacokinetics are linear, independent of the route of administration.

Absorption: After a 40 mg intramuscular dose of methylprednisolone sodium succinate to fourteen healthy adult male volunteers, the average peak concentration of 454 mg/mL was achieved at 1 hour. At 12 hours, the methylprednisolone plasma concentration declined to 31.9 mg/mL. No methylprednisolone was detected 18 hours after dosing. Based on the area under the time-concentration curve, an indication of total drug absorbed, intramuscular methylprednisolone sodium succinate was found to be bioequivalent to the same dose administered intravenously.

The sodium succinate ester of methylprednisolone is rapidly and extensively converted to the active methylprednisolone moiety after all routes of administration. Extent of absorption of free methylprednisolone following IV and IM administrations were found to be bioequivalent and significantly greater than those following administration of the oral solution and oral methylprednisolone tablets. Since the extent of methylprednisolone absorbed following the IV and IM treatment was equivalent, in spite of the greater amount of the hemisuccinate ester reaching the general circulation after IV administration, it appears that the ester is converted in the tissue after IM injection, with subsequent absorption as free methylprednisolone.

Distribution: Methylprednisolone is widely distributed into the tissues, crosses the blood-brain barrier and is secreted in breast milk. Its apparent volume of distribution is approximately 1.4 L/kg. The plasma protein binding of methylprednisolone in humans is approximately 77%.

Metabolism: In humans, methylprednisolone is metabolized in the liver to inactive metabolites, primarily 20α-hydroxymethylprednisolone and 20β-hydroxymethylprednisolone. Metabolism in the liver occurs primarily via the CYP3A4 (see DRUG INTERACTIONS).

Methylprednisolone, like many CYP3A4 substrates, may also be a substrate for the ATP-binding cassette (ABC) transport protein p-glycoprotein (P-gp), influencing tissue distribution and interactions with other medicines modulated by P-gp.

Excretion: The mean elimination half-life for total methylprednisolone is in the range of 1.8 to 5.2 hours. Total clearance is approximately 5 to 6 mL/min/kg.

STORAGE AND STABILITY:

Unreconstituted vials:

Store at 15 -25°C. Protect from light.

Reconstituted Solution:

When reconstituted with Bacteriostatic Water for Injection, the resulting solution may be stored for up to 48 hours at 15 -25 °C.

When reconstituted with Sterile Water for Injection, the resulting solution may be stored for up to 24 hours at 15 -25 °C due to risk of microbial contamination. The solution with a slight haze should be discarded. Discard unused portion.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Methylprednisolone Sodium Succinate for Injection USP is a sterile, lyophilized powder available in clear glass vial, equivalent to methylprednisolone 500 mg/vial and 1000 mg/vial.

Each pack of Methylprednisolone Sodium Succinate for Injection USP 500 mg per vial or 1000 mg per vial includes respectively a vial of 10 mL and 20 mL of Bacteriostatic Water for Injection (supplied as diluent) with Benzyl alcohol 0.9%v/v as preservative.

Composition

The respective vials of Methylprednisolone Sodium Succinate for Injection USP contain:

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: methylprednisolone sodium succinate for injection USP

(methylprednisolone sodium succinate is prepared in situ from methylprednisolone hemisuccinate with the aid of sodium hydroxide)

Chemical name: pregna-1,4-diene-3,20-dione,21-(3-carboxy-1-oxopropoxy)-11,17- dihydroxy-6-methyl-monosodium salt, (6α,11β)

Molecular mass: 496.53

Structural formula:

Physicochemical properties: white, or nearly white, odourless hygroscopic, amorphous solid, very soluble in water and in alcohol, insoluble in chloroform, very slightly soluble in acetone, melting point of 228° to 237°C, pka of 4.6, partition coefficient (butyronitrile-water) of 0.03 at pH 8.5

CLINICAL TRIALS

Hypersensitivity and Dermatologic Conditions

Status Asthmaticus

In a double-blind, placebo-controlled, randomized trial, the use of intravenous methylprednisolone (125 mg), given on presentation in the emergency room in addition to standard emergency treatments for asthma, reduced the need for hospital admission in acutely ill patients with bronchial asthma. Nine of 48 patients (19 percent) treated with methylprednisolone required hospital admission compared with 23 of 49 patients (47 percent) in the control group (p < 0.003).

Pemphigus Vulgaris

A small (n=15) retrospective study compared high-dose pulsed methylprednisolone sodium succinate to oral prednisone in patients with pemphigus vulgaris. Methylprednisolone sodium succinate was administered intravenously (n=9); the dose varied from 250 to 1000 mg/day for 2 to 5 days. Four of 6 responders to methylprednisolone sodium succinate maintained a remission without prednisone for almost 2 years. Patients in the control group (n=6) treated with prednisone required long-term treatment with higher doses of prednisone, and none of the patients maintained a long-term remission.

Acute Systemic Lupus Erythematosus

High-dose, intravenous methylprednisolone pulse therapy in 34 patients (30 adults and 4 adolescents) with lupus nephritis was evaluated. The 30 adult patients received 1 g of methylprednisolone intravenously over 30 minutes on 3 successive days, while the 4 adolescents received a 15 mg/kg/day dose for 3 days. Twelve of the 34 patients responded to treatment, as indicated by at least a 20% improvement in renal function and corresponding improvement in creatinine clearance levels. These improvements were maintained for at least 6 months in 60% of patients who responded to treatment.

Ulcerative Colitis

In a prospective, single-blind study of 60 patients with active ulcerative colitis, patients were randomized to receive either sucralfate enemas (20 g/100 ml) or methylprednisolone enemas (20 mg/100 ml). The enemas were administered twice daily for the first week and then once daily for three weeks. Results showed similar reductions in diarrhea and rectal bleeding at two weeks and at four weeks in the two groups. Sigmoidoscopic examination of the rectal mucosa demonstrated similar significant improvement in the macroscopic appearance of the rectal mucosa in both groups (8.28 to 6.20 in sucralfate group, p < 0.02; and 8.72 to 6.36 in the methylprednisolone treated group, p < 0.04). Histological assessment of the rectal biopsies taken at entry into the study and following four weeks of therapy also revealed similar improvements in the two groups.

Organ Transplants

A prospective, controlled study was conducted among 100 renal transplant patients to compare two different regimens of immunosuppressive therapy. In the study, 86 patients received kidneys from cadavers and 14 patients received kidneys from living, related donors. Patients were assigned to receive either double therapy (methylprednisolone plus cyclosporine) or triple therapy (methylprednisolone plus cyclosporine and azathioprine). In both groups, patients were given intravenous pulse doses of 0.5 g methylprednisolone at the moment of transplantation. Oral methylprednisolone was subsequently administered in a single morning dose of 16 mg until the end of the third month. Patients then received 12 mg/day oral methylprednisolone until the end of month 6, and a maintenance dosage of 8 mg/day thereafter. The results were similar with both regimens. No significant differences between groups were reported in the 2-year patient and kidney survival rates.

DETAILED PHARMACOLOGY

See ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics and Pharmacokinetics sections.

TOXICOLOGY

Acute Toxicology

The acute LD50 of methylprednisolone sodium succinate intraperitoneally in the mouse is 850 mg/kg. The oral LD50 of this drug in the rat is 5150 mg/kg. Dogs receiving single intravenous injections of methylprednisolone sodium succinate in doses of 4.4 to 6.4 mg/kg were free from clinical signs of drug intoxication during the 24 hour post-injection observation period.

Carcinogenesis:

Methylprednisolone has not been evaluated in rodent carcinogenicity studies.

Variable results have been obtained with other glucocorticoids tested for carcinogenicity in mice and rats. However, published data indicate that several related glucocorticoids including budesonide, prednisolone, and triamcinolone acetonide can increase the incidence of hepatocellular adenomas and carcinomas after oral administration in drinking water to male rats. These tumorigenic effects occurred at doses which were less than the typical clinical doses on a mg/m² basis.

Mutagenesis:

Methylprednisolone has not been evaluated for genotoxicity.

However, methylprednisolone sulfonate, which is structurally similar to methylprednisolone sodium succinate, was not mutagenic with or without metabolic activation in Salmonella typhimurium, or in a mammalian cell gene mutation assay using Chinese hamster ovary cells. Methylprednisolone suleptanate did not induce unscheduled DNA synthesis in primary rat hepatocytes. Moreover, a review of published data indicates that prednisolone farnesylate (PNF), which is structurally similar to methylprednisolone, was not mutagenic with or without metabolic activation in Salmonella typhimurium and Escherichia coli strains. In a Chinese hamster fibroblast cell line, PNF produced a slight increase in the incidence of structural chromosomal aberrations with metabolic activation at the highest concentration tested.

Reproductive toxicity:

Corticosteroids have been shown to reduce fertility when administered to rats. Male rats were administered corticosterone at doses of 0, 10, and 25 mg/kg/day by subcutaneous injection once daily for 6 weeks and mated with untreated females. The high dose was reduced to 20 mg/kg/day after Day 15. Decreased copulatory plugs were observed, which may have been secondary to decreased accessory organ weight. The numbers of implantations and live fetuses were reduced in untreated females mated with males treated at the administered doses of 10 and 25 mg/kg/day.

Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. In animal reproduction studies, glucocorticoids such as methylprednisolone have been shown to increase the incidence of malformations (cleft palate, skeletal malformations), embryo-fetal lethality (e.g., increase in resorptions), and intra-uterine growth retardation.

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