Methylprednisolone Sodium Succinate for Injection (Teva Canada, 40 mg, ..., 1 G) Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES .............................................................................................. 2

TABLE OF CONTENTS ................................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ........................................................................ 4

1 INDICATIONS .......................................................................................................................... 4

1.1 Pediatrics ............................................................................................................................. 5

1.2 Geriatrics ............................................................................................................................. 5

2 CONTRAINDICATIONS ............................................................................................................ 5

4 DOSAGE AND ADMINISTRATION ............................................................................................ 6

4.1 Dosing Considerations ......................................................................................................... 6

4.2 Recommended Dose and Dosage Adjustment ..................................................................... 7

4.3 Reconstitution ..................................................................................................................... 8

4.4 Administration ..................................................................................................................... 9

5 OVERDOSAGE ........................................................................................................................ 9

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............................................ 9

7 WARNINGS AND PRECAUTIONS ........................................................................................... 10

7.1 Special Populations ............................................................................................................ 18

7.1.1 Pregnant Women ........................................................................................................... 18

7.1.2 Breast-feeding ................................................................................................................ 18

7.1.3 Pediatrics ........................................................................................................................ 19

7.1.4 Geriatrics ........................................................................................................................ 19

8 ADVERSE REACTIONS ........................................................................................................... 20

8.1 Adverse Reaction Overview ............................................................................................... 20

9 DRUG INTERACTIONS ........................................................................................................... 22

9.2 Drug Interactions Overview ............................................................................................... 22

9.4 Drug-Drug Interactions ...................................................................................................... 23

9.5 Drug-Food Interactions ...................................................................................................... 29

9.6 Drug-Herb Interactions ...................................................................................................... 29

9.7 Drug-Laboratory Test Interactions ..................................................................................... 29

10 CLINICAL PHARMACOLOGY ................................................................................................ 29

10.1 Mechanism of Action ....................................................................................................... 29

10.2 Pharmacodynamics.......................................................................................................... 29

10.3 Pharmacokinetics ............................................................................................................ 30

11 STORAGE, STABILITY AND DISPOSAL .................................................................................. 31

12 SPECIAL HANDLING INSTRUCTIONS .................................................................................... 32

PART II: SCIENTIFIC INFORMATION ......................................................................................... 33

13 PHARMACEUTICAL INFORMATION ..................................................................................... 33

14 CLINICAL TRIALS ................................................................................................................. 34

15 MICROBIOLOGY ................................................................................................................. 35

16 NON-CLINICAL TOXICOLOGY .............................................................................................. 35

17 SUPPORTING PRODUCT MONOGRAPHS ............................................................................. 36

PATIENT MEDICATION INFORMATION .................................................................................... 37

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

Intravenous administration of Methylprednisolone Sodium Succinate for Injection (methylprednisolone sodium succinate for injection) is indicated in situations in which a rapid and intense hormonal effect is required.

Methylprednisolone Sodium Succinate for Injection is indicated for:

• Hypersensitivity and dermatologic conditions

  • Status asthmaticus
  • Anaphylactic reactions
  • Drug reactions
  • Contact dermatitis
  • Urticaria
  • Generalized neurodermatitis
  • Reactions to insect bites
  • Pemphigus foliaceous and vulgaris
  • Exfoliative dermatitis

  • Erythema multiforme

    • 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 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 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 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 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

  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 for Injection 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 is suitable for such indications.

• Cerebral oedema of non traumatic origin

  Administration of methylprednisolone sodium succinate immediately prior to intracranial surgery and in the immediate post-operative period has reduced the duration of post-operative complications related to cerebral oedema.

1.1 Pediatrics

Methylprednisolone Sodium Succinate for Injection is contraindicated for use in premature infants (see 2 CONTRAINDICATIONS) and should be used with caution in the pediatric population (see 7 WARNINGS AND PRECAUTIONS, 7.1.3 Pediatrics).

1.2 Geriatrics

Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness.

2 CONTRAINDICATIONS

Methylprednisolone Sodium Succinate for Injection is contraindicated:

• in patients with known hypersensitivity to the ingredients. Methylprednisolone Sodium Succinate for Injection, 40 mg, include lactose produced from cow’s milk. This dosage form 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 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, as the Bacteriostatic Water for Injection that is indicated for reconstituting Methylprednisolone Sodium Succinate for Injection plain Vials products contains benzyl alcohol. See 7 WARNINGS AND PRECAUTIONS, 7.1.3 Pediatrics
• for intramuscular administration in idiopathic thrombocytopenic purpura.

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

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

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• Because complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used.
• The lowest possible dose of corticosteroid should be used to control the condition under treatment.
• Patients should be advised to inform subsequent health professionals of the prior use of methylprednisolone sodium succinate.
• The existence of diabetes, osteoporosis, renal insufficiency, chronic psychosis, cardiovascular disease, myasthenia gravis or predisposition to thrombophlebitis requires that Methylprednisolone Sodium Succinate for Injection be administered with extreme caution.

• Dosage adjustments may be required based on the following:

  • during remission
  • exacerbation of the disease process
  • the patient’s individual response to therapy
  • upon exposure of the patient to emotional or physical stress such as serious infection, surgery or injury. Methylprednisolone Sodium Succinate for Injection dosage may need to be increased during and after the stressful situation.
• 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.
• Pediatrics: Methylprednisolone Sodium Succinate for Injection is contraindicated for use in premature infants (see 2 CONTRAINDICATIONS) and should be used with caution in the pediatric population (see 7 WARNINGS AND PRECAUTIONS, 7.1.3 Pediatrics).

4.2 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 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 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 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 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.

4.3 Reconstitution

DIRECTIONS FOR RECONSTITUTION OF flip-top VIALS:

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.

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

Reconstitution Table

The reconstituted and diluted solution should be inspected visually for discolouration, haziness, particulate matter and leakage prior to administration. Discard unused portion.

Preparation of solution for IM or IV injection:

Loosen powder. Hold vial horizontally and rotate while directing the stream of diluent against the wall of the vial. Shake vial gently after all the diluent is added. Use solution only if it is clear.

Preparation of solutions for IV infusion:

First prepare the solution for injection as directed.

If desired, the medication may be administered in dilute solutions by admixing the reconstituted product with Dextrose 5% in Water, 0.9% Sodium Chloride, Dextrose 5% in 0.45% Sodium Chloride. Concentrations of 0.25 mg/mL or less are physically and chemically stable for 48 hours at 15°C 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 in solutions and with other drugs in intravenous admixtures is dependent on admixture pH, concentration, time, temperature, and ability of methylprednisolone to solubilize itself. Thus, to avoid compatibility and stability problems, whenever possible it is recommended that Methylprednisolone Sodium Succinate for Injection 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.

4.4 Administration

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 Methylprednisolone Sodium Succinate for Injection, reconstitute the vial as per instructions.

5 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.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table – Dosage Forms, Strengths, Composition and Packaging

Methylprednisolone Sodium Succinate for Injection is a sterile, lyophilized powder available as 40 mg (Box of 10 vials), 125 mg (Box of 10 vials), and 500 mg (Box of 5 vials) strengths of methylprednisolone per vial, and in 1 g of methylprednisolone per vial (Single vial).

The respective vials of methylPREDNISolone SODIUM SUCCINATE FOR INJECTION contain:

***Water is required in the manufacture of the bulk solution but is removed during the lyophilization process.

7 WARNINGS AND PRECAUTIONS

General

Methylprednisolone Sodium Succinate for Injection should not be administered by any route other than those listed under 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING. It is critical that, during administration of Methylprednisolone Sodium Succinate for Injection, 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 health professionals of the prior use of methylprednisolone sodium succinate.

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

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 possible tumorigenic and mutagenic potential (see 16 NON-CLINICAL TOXICOLOGY, Carcinogenesis and also 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 7 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.

Driving and Operating Machinery

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

Endocrine and Metabolism

Corticosteroid administration may result in hypothalamic-pituitary-adrenal (HPA) axis 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.

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 7 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.

In post marketing experience tumor lysis syndrome (TLS) has been reported in patients with malignancies, including hematological malignancies and solid tumors, following the use of systemic corticosteroids alone or in combination with other chemotherapeutic agents. Patients at high risk of TLS, such as patients with tumors that have a high proliferative rate, high tumor burden and high sensitivity to cytotoxic agents, should be monitored closely and appropriate precautions should be taken.

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. 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 (acetylsalicylic 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 2 CONTRAINDICATIONS; 9 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 2 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 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).

Monitoring and Laboratory Tests

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 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.

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 7 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.

Renal

Caution is required in patients with systemic sclerosis because an increased incidence of scleroderma renal crisis has been observed with corticosteroids, including methylprednisolone.

Corticosteroids should be used with caution in patients with renal insufficiency.

Reproductive Health: Female and Male Potential

• Fertility

Steroids may increase or decrease motility and number of spermatozoa in some patients (see 16 NON-CLINICAL PHARMACOLOGY).

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.

In patients receiving 40 mg Methylprednisolone Sodium Succinate for Injection 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 2 CONTRAINDICATIONS). If appropriate, administration of methylprednisolone sodium succinate 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.

Skin

Injection of Methylprednisolone Sodium Succinate for Injection 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.

7.1 Special Populations

7.1.1 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 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicity).

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

Since adequate human reproductive studies have not been done with methylprednisolone sodium succinate, Methylprednisolone Sodium Succinate for Injection 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 vials are reconstituted with Bacteriostatic Water for Injection USP (benzyl alcohol as preservative) as directed. Benzyl alcohol can cross the placenta.

7.1.2 Breast-feeding

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.

7.1.3 Pediatrics

Methylprednisolone Sodium Succinate for Injection is contraindicated for use in premature infants (see 2 CONTRAINDICATIONS). Benzyl alcohol can be introduced into the solution when Methylprednisolone Sodium Succinate for Injection 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.

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.

7.1.4 Geriatrics

See section 4 DOSAGE AND ADMINISTRATION, 4.1 Dosing Considerations, Geriatrics.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The following Adverse Reactions have been reported with the systemic use of methylprednisolone sodium succinate and other corticosteroid preparations.

9 DRUG INTERACTIONS

9.2 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.

9.4 Drug-Drug Interactions

The following table provides a list of drugs that may interact with methylprednisolone.

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, vencuronium bromide, rocuronium bromide, cisatracurium besylate, glycopyrrolate, propofol (see also 4 DOSAGE AND ADMINISTRATION, Compatibility).

9.5 Drug-Food Interactions

Interactions with food have not been established.

Grapefruit juice is a CYP3A4 inhibitor. See 9 DRUG INTERACTIONS, CYP3A4 INHIBITORS above.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Corticosteroids may suppress reactions to skin tests.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Corticosteroids bind to intracellular glucocorticoid receptors. The corticoid receptor complex mediates changes in gene expression that lead to multiple downstream effects over hours to days. Corticosteroid action results in inhibiting pro-inflammatory signals and promoting anti-inflammatory signals. Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit other inflammatory transcription factors, and they promote anti-inflammatory genes like interleukin-10.

Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. High doses of glucocorticoids for an extended period bind to mineralocorticoid receptors, raising sodium levels and decreasing potassium levels.

10.2 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.

10.3 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 9 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.

Elimination:

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.

11 STORAGE, STABILITY AND DISPOSAL

Unreconstituted Product:

Store at controlled room temperature 15°C to 25°C, protect from light.

Reconstituted Solutions:

Store at controlled room temperature 15°C to 25°C, protect from light.

When reconstituted with Sterile Water for Injection, (without bacteriostat), use as a single use vial. Use solution within 24 hours after mixing; discard unused solution.

Only facilities with recognized admixture programs, where dilutions are performed under aseptic conditions, should store the diluted product for more than 24 hours after initial puncture of the stopper particularly if Sterile Water for Injection is used as the reconstitution vehicle.

When reconstituted with Bacteriostatic Water for Injection, stored at controlled room temperature (15°C to 25°C), protected from light. The 40 mg vials, 125 mg vials, 500 mg vials, and 1 g vials, reconstituted as indicated in the Reconstitution Table, should be used within 48 hours. Discard unused solution.

Keep in a safe place out of the reach and sight of children.

12 SPECIAL HANDLING INSTRUCTIONS

This information is not available for this drug product.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Methylprednisolone sodium succinate (made 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 formula and molecular weight: C₂₆H₃₃NaO₈, 496.53 g/mol

Structural Formula:

OH O COCH₂OCO(CH₂)₂CO₂Na OH H Me H

Description: Methylprednisolone sodium succinate is a white or nearly white odourless, hygroscopic amorphous solid, mp (228° to 237°C), pKa of 4.6, partition coefficient (butyronitrile-water) of 0.03 at pH 8.5, very soluble in water and in alcohol, slightly soluble in acetone and practically insoluble in chloroform and ether.

14 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.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL 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 and Developmental 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.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. SOLU-MEDROL® Sterile Powder, 500 mg, 1 g Vials, Submission Control No. 280527, Product Monograph, Pfizer Canada ULC. (MAR 14, 2024)