Data Sheet

SOLU MEDROL^®

Methylprednisolone sodium succinate for injection,

USP 40mg, 125mg, 500mg, 1000mg and 2000mg vials.

Presentation

SOLU MEDROL is a white crystalline powder available in the following pack sizes:

40mg - Act-o-vial (two compartment vial); each ml, when mixed, contains 40mg methylprednisolone sodium succinate in bacteriostatic water.

125mg - Act-o-vial (two compartment vial); each 2ml, when mixed, contains 125mg methylprednisolone sodium succinate in bacteriostatic water.

500mg - Act-o-vial (two compartment vial): each 4ml, when mixed, contains 500mg methylprednisolone sodium succinate in bacteriostatic water.

1000mg - Vial containing 1000mg methylprednisolone sodium succinate with a separate vial containing 15.6ml of bacteriostatic water.

2000mg - Vial containing 2000mg methylprednisolone sodium succinate with a separate vial containing 31.2ml of bacteriostatic water.

When reconstituted SOLU MEDROL is a clear aqueous solution.

Uses

Actions

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

Methylprednisolone sodium succinate has the same metabolic and anti-inflammatory actions as methylprednisolone. When given parenterally and in equimolar quantities, the two compounds are equivalent in biologic activity. The relative potency of SOLU MEDROL Sterile Powder (Methylprednisolone sodium succinate) and hydrocortisone sodium succinate, as indicated by depression of eosinophil count, following intra-venous administration, is at least four to one. This is in good agreement with the relative oral potency of methylprednisolone and hydrocortisone.

Pharmacokinetics

SOLU MEDROL, the sodium succinate ester of methyl-prednisolone, is rapidly and extensively hydrolysed in vivo by cholinesterases to free methylprednisolone.

After an intravenous infusion of SOLU MEDROL, 30mg/kg over a 20 minute period or 1gm over 30 to 60 minutes, peak methyl-prednisolone plasma concentrations of approximately 20mcg/ml were achieved. Peak methylprednisolone levels of 42-47mcg/ 100ml were reported following a single 40mg IV bolus injection to six adult male volunteers. Although with intramuscular (IM) injection lower peak levels are obtained than with intravenous (IV) injection, the plasma levels persist longer such that the extent of methylprednisolone absorption is equivalent with either route of administration. Peak methylprednisolone plasma levels of 33.67mcg/100ml were achieved in two hours after a single 40mg IM injection to 22 adult male volunteers.

The mean elimination half-life ranges from 2.4 to 3.5 hours in normal, healthy adults and appears to be independent of the route of administration.

Methylprednisolone is widely distributed throughout the body and is described by a two-compartment model. The mean volume of distribution reported in 34 adult volunteers ranged from 41 to 61.5. SOLU MEDROL readily crosses the blood-brain barrier into the central nervous system with peak CSF levels being 5 - 6% of the corresponding plasma levels. Methylprednisolone peak CSF levels occurred within five minutes to one hour after IV administration of a 500mg dose to patients with lupus cerebritis.

Methylprednisolone and the sodium succinate salt crosses the placental barrier. Although there is no data regarding methylprednisolone passage into breast milk of humans, it is present in breast milk of animals.

Methylprednisolone is metabolised in the liver to inactive metabolites, the major ones being 20B-hydroxymethylprednisone and 20 alpha-hydroxy-6a-methylprednisone.

Total body clearance following intravenous or intramuscular injection of methylprednisolone to healthy adult volunteers is approximately 15 - 16 L/hr. In adult volunteers receiving 40mg SOLU MEDROL, either IM or IV, renal clearance is 0.61 - 0.83 L/hr. Methylprednisolone clearance is altered by concurrent administration of troleandomycin, erythromycin, rifampin, anti-convulsants, and theophylline. No dosing adjustments are necessary in renal failure. Methylprednisolone is haemodialisable.

Following IV administration of radiolabelled 6α-methyl-prednisolone to six cancer patients, 75% of total reactivity was recovered in the urine after 96 hours and 9% in the faeces after five days. Twenty percent of the total dose was excreted in the bile, but the time course was not cited.

Indications

Endocrine Disorders -

Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogues may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance).

Acute adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; mineralocorticoid supplementation may be necessary, particularly when synthetic analogues are used).

Preoperatively and in the event of serious trauma or illness, in patients with known adrenal insufficiency or when adrenocortical reserve is doubtful.

congenital adrenal hyperplasia
nonsuppurative thyroiditis
hypercalcaemia associated with cancer

Rheumatic Disorders -

As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in:

post-traumatic osteoarthritis
synovitis of osteoarthritis
rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy)
acute and subacute bursitis
epicondylitis
acute non-specific tenosynovitis
acute gouty arthritis
psoriatic arthritis
ankylosing spondylitis

Collagen Diseases (Immune and Complex Diseases) -

During an exacerbation or as maintenance therapy in selected cases of:

systemic lupus erythematosus (and lupus nephritis)
acute rheumatic carditis
systemic dermatomyositis (polymyositis)
polyarteritis nodosa
Good pasture's syndrome

Dermatologic Diseases -

Pemphigus
severe erythema multiforme (Stevens-Johnson syndrome)
exfoliative dermatitis
bullous dermatitis herpetiformis
severe seborrhoeic dermatitis
severe psoriasis
mycosis fungoides

Allergic States -

Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in:

bronchial asthma
contact dermatitis
atopic dermatitis
serum sickness
seasonal or perennial allergic rhinitis
drug hypersensitivity reactions
urticarial transfusion reactions
acute non-infectious laryngeal oedema (epinephrine is the drug of first choice)

Ophthalmic Diseases -

Severe acute and chronic allergic and inflammatory processes involving the eye, such as:

herpes zoster ophthalmicus
iritis, iridocyclitis
chorioretinitis
diffuse posterior uveitis and choroiditis
optic neuritis
sympathetic ophthalmia
anterior segment inflammation
allergic conjunctivitis
allergic corneal marginal ulcers
keratitis

Gastrointestinal Diseases -

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

Respiratory Diseases -

symptomatic sarcoidosis
berylliosis
fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate anti-tuberculous chemotherapy
Loeffler's Syndrome not manageable by other means
aspiration pneumonitis

SOLU MEDROL is beneficial as adjunctive therapy in the treatment of AIDS patients with moderate to severe pneumocystis carinii pneumonia when given in the first 72 hours of initial anti-pneumocystis treatment. Due to the increased rate of reactivation of tuberculosis in AIDS patients, consideration should be given to the administration of antimycobacteria therapy if corticosteroids are used in this high risk group. The patient should also be observed for activation of other latent infections.

Haematologic Disorders -

acquired (autoimmune) haemolytic anaemia
idiopathic thrombocytopaenia purpura in adults (IV only; IM administration is contraindicated)
secondary thrombocytopaenia in adults
erythroblastopenia (RBC anaemia)
congenital (erythroid) hypoplastic anaemia

Neoplastic Diseases -

For palliative management of:
leukaemias and lymphomas in adults
acute leukaemia of childhood

Terminal Cancer -
To improve quality of life in patients with terminal cancer

Oedematous States -

To induce diuresis or remission of proteinuria in the nephrotic syndrome, without uraemia, of the idiopathic type or that due to lupus erythematosus.

Nervous System -
Cerebral oedema from tumour - primary or metastatic and/or associated with surgical or radiation therapy.
Acute exacerbations of multiple sclerosis.
Acute spinal chord injury. The treatment should begin within eight hours of injury.

Cardiovascular Conditions -

Shock secondary to adrenocortical insufficiency or shock unresponsive to conventional therapy when adrenal cortical insufficiency may be present. (Hydrocortisone is generally the drug of choice. When mineralocorticoid activity is undesirable, methylprednisolone may be preferred.)

Miscellaneous -

Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy.
Trichinosis with neurologic or myocardial involvement.
Organ Transplantation
Prevention of nausea and vomiting associated with cancer chemotherapy.

Dosage and Administration

As adjunctive therapy in life threatening conditions the recommended dose of SOLU MEDROL Sterile Powder is 30mg per kg of methylprednisolone sodium succinate, given IV over a period of at least 30 minutes. This dose may be repeated every 4 - 6 hours for up to 48 hours.

Pulse dosing for corticosteroid responsive diseases in exacerbation and/or unresponsive to standard therapy (eg. lupus nephritis, rheumatoid arthritis, etc.). Suggested schedules -

Rheumatic disorders: 1gm/day for one, two, three or four days IV or 1gm/month for six months IV.

Systemic lupus erythematosus: 1gm/day for three days IV.

Multiple sclerosis: 1gm/day for three days IV or 1gm/day for five days IV.

Oedematous states e.g. glomerulonephritis, lupus nephritis: 30mg/kg every other day for four days IV or 1gm/day for three, five or seven days IV.

The regimen should be administered over at least 30 minutes, and may be repeated if improvement has not occurred within a week after therapy or as patient's condition dictates.

Terminal Cancer - Quality of Life:

Prospective controlled studies have shown that SOLU MEDROL 125mg administered intravenously daily for up to eight weeks, significantly improves quality of life in patients with terminal cancer.

Prevention of nausea and vomiting associated with cancer chemotherapy. Suggested schedules: Mild to moderately emetogenic chemotherapy: Administer SOLU MEDROL 250mg IV over at least five minutes one hour before chemotherapy, at the initiation of chemotherapy, and at the time of discharge.

A chlorinated phenothiazine may also be used with the first dose of SOLU MEDROL for increased effect. Severely emetogenic chemotherapy: Administer SOLU MEDROL 250mg IV over at least five minutes with appropriate doses of metoclopramide or a butyrophenone one hour before chemotherapy, then SOLU MEDROL 250mg IV at the initiation of chemotherapy and at time of discharge.

Acute spinal cord injury Treatment should begin within 8 hours of injury.

For patients initiated on treatment within 3 hours of injury: Administer 30mg/kg as an IV bolus over a 15-minute period, followed by a 45-minute pause, and then a continuous IV infusion of 5.4mg/kg/h for 23 hours.

For patients initiated on treatment within 3 to 8 hours of injury: Administer 30mg/kg as an IV bolus over a 15-minute period, followed by a 45-minute pause, and then a continuous IV infusion of 5.4mg/kg/h for 47 hours.

There should be a separate intravenous site for the infusion pump.

Pneumocystis carinii pneumonia in patients with AIDS. A number of dosage schedules have been used. One approach is to administer 40mg SOLU MEDROL every 6 to 12 hours with gradual tapering over a maximum of 21 days or until the end of the pneumocystis therapy. Therapy should be started within 72 hours of initial anti-pneumocystis treatment.

In other indications, initial dosage will vary from 10 - 500mg depending on the clinical problem being treated. Larger doses may be required for short term management of severe, acute conditions. The initial dose, up to 250mg, should be given intravenously over a period of at least five minutes and if greater than 250mg, should be given over at least 30 minutes. It should not be less than 0.5mg per kg every 24 hours. Subsequent doses may be given intravenously or intra-muscularly at intervals dictated by the patient's response and clinical condition. Corticosteroid therapy is an adjunct to, and not a replacement for, conventional therapy.

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

SOLU MEDROL (methylprednisolone sodium succinate) may be administered by intravenous or intra-muscular injection, or by intravenous infusion, the preferred method for initial emergency use being intravenous injection. To administer by intravenous (or intramuscular) injection, prepare solution with the diluent provided.

Contraindications

Systemic fungal infections.

Known hypersensitivity to components.

Warnings and Precautions

Warnings

1. Recent studies do not establish the efficacy of SOLU-MEDROL in septic shock, and suggest that increased mortality may occur in some subgroups at higher risk (i.e. elevated creatinine greater than 2.0 mg % or secondary infections).
2. SOLU MEDROL (methylprednisolone sodium succinate) should not be used routinely to treat head injury as demonstrated by the results of a multicentre study. The study results revealed an increased mortality in the 2 weeks after injury in patients administered methylprednisolone sodium succinate compared to placebo (1.18 relative risk). A causal association with methylprednisolone sodium succinate treatment has not been established.
3. In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during and after the stressful situation is indicated.
4. Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localise infection when corticosteroids are used. Infections with any pathogen including viral, bacterial, fungal, protozoan or helminthic infections, in any location in the body, may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents that affect cellular immunity, humoral immunity, or neutrophil function. These infections may be mild, but can be severe and at times fatal. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases.
5. Usage in pregnancy: Some animal studies have shown that corticosteroids, when administered to the mother at high doses, may cause foetal malformations. Adequate human reproductive studies have not been done with corticosteroids. Therefore the use of this drug in pregnancy, nursing mothers, or women of child bearing potential requires that the benefits of the drug be carefully weighed against the potential risk to the mother and embryo or foetus. Since there is inadequate evidence of safety in human pregnancy, this drug should be used in pregnancy only if clearly needed.
   Corticosteroids readily cross the placenta. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy must be carefully observed and evaluated for signs of adrenal insufficiency. There are no known effects of corticosteroids on labour and delivery. Corticosteroids are excreted in breast milk.
6. Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered to patients receiving immunosuppressive doses of corticosteroids; however, the response to such vaccines may be diminished. Indicated immunisation procedures may be undertaken in patients receiving non-immunosuppressive doses of corticosteroids.
7. The use of SOLU-MEDROL Sterile Powder (methylprednisolone sodium succinate) in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with appropriate anti-tuberculosis regimen.
   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.
8. Because rare instances of anaphylactoid (eg, bronchospasm) reactions have occurred in patients receiving parenteral corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of allergy to any drug.
9. There are reports of cardiac arrhythmias and/or circulatory collapse and/or cardiac arrest following the rapid administration of large IV doses of methylprednisolone sodium succinate (greater than 0.5 gram administered over a period of less than 10 minutes). Bradycardia has been reported during or after the administration of large doses of methylprednisolone sodium succinate, and may be unrelated to the speed or duration of infusion.
10. This product contains benzyl alcohol. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants.

Precautions

1. General Precautions

1. Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation.
2. 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.
3. Corticosteroids should be used with caution in non-specific ulcerative colitis, if there is a probability of impending perforation, abscess or other pyogenic infection, also in diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, renal insufficiency, hypertension, osteoporosis, or myasthenia gravis.
4. 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.
5. Convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. 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.
6. An acute myopathy has been described with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (eg, myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (eg, pancuronium). This acute myopathy is generalised, 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.
7. Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission.

2. Carcinogenesis, mutagenesis, impairment of fertility
   There is no evidence that corticosteroids are carcinogenic, mutagenic, or impair fertility.
3. Labour and Delivery
   No effect known.
4. Nursing mothers
   Because prednisolone is excreted in breast milk, it is reasonable to assume that all corticosteroids are. No specific data is known for methylprednisolone sodium succinate.

Adverse Effects

The following are typical for all systemic corticosteroids. Their inclusion in this list does not necessarily indicate that the specific event has been observed with this particular formulation.

Fluid and Electrolyte Disturbances -
sodium retention
fluid retention
congestive heart failure in susceptible patients
potassium loss
hypokalaemic alkalosis
hypertension

Musculoskeletal -
muscle weakness
steroid myopathy
vertebral compression fractures
aseptic necrosis
pathologic fractures
osteoporosis
Tendon rupture, particularly of the Archilles tendon.

Gastrointestinal -
peptic ulcer with possible perforation and haemorrhage
gastric haemorrhage
pancreatitis
oesophagitis
perforation of the bowel

Dermatologic -
impaired wound healing
thin fragile skin
petechiae and ecchymoses

Neurological -
increased intracranial pressure
pseudotumor cerebri
psychic derangements
seizures

Endocrine -
menstrual irregularities
development of Cushingoid state
suppression of growth in children
suppression of pituitary-adrenal axis
decreased carbohydrate tolerance
- manifestations of latent diabetes mellitus
- increased requirements for insulin or oral hypoglycaemic agents in diabetes

Ophthalmic -
posterior subcapsular cataracts
increased intraocular pressure
exophthalmos

Metabolic -
negative nitrogen balance due to protein catabolism

Immune System -
masking of infections
latent infections becoming active
opportunistic infections
hypersensitivity reactions including anaphylaxis may suppress reactions to skin tests

The following additional reactions are related to parenteral corticosteroid therapy:

anaphylactic reaction with or without circulatory collapse, cardiac arrest, bronchospasm cardiac arrhythmias; hypotension or hypertension

Interactions

Methylprednisolone has a wide spectrum of clinical use and is therefore used with numerous concurrent drugs. The interactions summarised in the table on the following page are of known or likely clinical significance. The need for dosage adjustment of either medication will depend on the clinical situation, the dose regimen prescribed and the observed clinical response. The interactions listed have either pharmacokinetic or pharmacodynamic basis.

Overdosage

There is no clinical syndrome of acute overdosage with SOLU MEDROL (methylprednisolone sodium succinate). Methyl-prednisolone is dialyzable.

Pharmaceutical Precautions

Store below 25 degrees C. It is recommended that the reconstituted solution of SOLU MEDROL be used immediately upon preparation.

Medicine Classification

Prescription medicine.

Package Quantities

SOLU MEDROL is available in the following pack sizes -

40mg ACT-O-VIAL (25 units)
125mg ACT-O-VIAL (25 units)
500mg ACT-O-VIAL (1 unit)
1000mg vial with diluent (1 unit)
2000mg vial with diluent (1 unit)

Further Information

Compatibility and Stability -

The IV compatibility and stability of methylprednisolone sodium succinate solutions and with other drugs in intravenous admixtures is dependent on admixture pH, concentration, time, temperature and the ability of methylprednisolone to solubilise itself. Thus, to avoid compatibility and stability problems, whenever possible, it is recommended that SOLU MEDROL (methylprednisolone sodium succinate) be administered separate from other drugs and as either IV medication chamber, or as an IV "piggy-back" solution.

Preparation Of Solutions -

To prepare solutions for intravenous infusion, first reconstitute SOLU MEDROL (methylprednisolone sodium succinate) with the diluent provided . Therapy may be initiated by administering SOLU MEDROL (methylprednisolone sodium succinate) intravenously over a period of at least five minutes (eg, doses up to 250mg) to at least 30 minutes (eg, doses of 250mg or more). Subsequent doses may be withdrawn and administered similarly. If desired, the medication may be administered in dilute solutions by admixing the reconstituted product with dextrose in 5% in water, normal saline, dextrose 5% in 0.45% or 0.9% sodium chloride; the resulting solutions are physically and chemically stable for 48 hours.

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

SOLU MEDROL is a registered trademark.

Name and Address

Pfizer New Zealand Ltd
PO Box 3998
Auckland
NEW ZEALAND
Toll free number ; 0800 736 363

Date of Preparation

9 January 2005