Methyl Prednisolone Sodium Succcinate

Indications
When oral therapy is not feasible, and the strength, dosage form and route of administration of the drug reasonably lend the preparation to the treatment of the condition, this Sterile Powder is indicated for intravenous or intramuscular use in the following conditions:
Endocrine Disorders: Primary and secondary adrenocortical, Acute adrenocortical insufficiency 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.
Anti - inflammatory treatment:
Rheumatic Disorders: As adjunctive therapy for short term administration (to tide the patient over an acute episode or exacerbation) in: post – traumatic osteoarthritis, synovitis in osteoarthritis, rheumatoid arthritis, Including juvenile rheumatoid arthritis (Selected cases may require low – dose maintenance therapy), acute and Sub-acute 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 Iupus erythematosus (and Iupus 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).
Opthalmic Diseases: Severe acute and chronic allergic and inflammatory processes involving the eye, such as: herpes zoster Opthalmicus, iritis, iridocyclitis, chorioretinitis, diffuse posterior uveitis and choroiditis optic neuritis, sympathetic ophathalmia, anterior segment inflammation, allergic conjunctivitis, allergic corneal marginal ulcers, and 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.
Edematous States: To induce dieresis or remission of proteinuria in the nephritic syndrome, without uremia,of the idiopathic type or that due to lupus erythematosus. Immunosuppressive Treatment: Organ Transplantation.
Hematological and Oncological Disorders:
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.
Oncological Diseases: For palliative management of: leukaemias and lymphomas in adults, acute leukaemia of childhood.
Treatment or shock states: 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.)
Nervous System: Cerebral oedema from tumour –primary or metastatic and /or associated with surgical or radiation therapy, Acute exacerbation of multiple sclerosis, Acute spinal chord injury.
Cardiovascular Conditions-
Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy.
Trichinosis with neurologic or myocardial involvement.

Therapeutic Class
Glucocorticoids

Pharmacology
Glucocorticoids diffuse across cell membranes and complex with specific cytoplasmic receptors. These complex then enter the cell nucleus, bind to DNA (chromatin), and stimulate transcription of mRNA and subsequent protein synthesis of various enzyme thought to be ultimately responsible for the numerous effects of glucocorticoids after systemic use. Glucocorticoids not only have an important influence on inflammatory and immune process, but also affect the carbohydrate, protein and fat metabolism. They also act on the cardiovascular system, the skeletal muscles and the central nervous system.
Methylprednisolone, the sodium succinate ester of methyl-prednisolone, is rapidly and extensively hydrolyzed in vivo by cholinesterase to free methylprednisolone.
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. Methylprednisolone 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 500 mg dose to patients with lupus cerebritis.
Total body clearance following intravenous or intramuscular injection of methylprednisolone to healthy adult volunteers is approximately 15 – 16 L/hr. Methylprednisolone is hemodialisable.

Dosage & Administration
As adjunctive therapy in life threatening conditions the recommended dose of Methylprednisolone is 30 mg/kg of body weight administered intravenously 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 (lupus nephritis, rheumatoid arthritis)-
Suggested schedules:
Rheumatic disorders: 1 gm/day for one, two, three or four days IV or 1 gm/month for six month IV.
Systemic lupus erythematosus: 1 gm/day for three days IV.
Multiple sclerosis: 1 gm/day for three days IV or 1 gm/day for five days IV.
Oedematous states e.g. glomerulonephritis, lupus nephritis: 30 mg/kg every other day for four days IV or 1 gm/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 Methylprednisolone 125 mg 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-
Mild to moderately emetogenic chemotherapy: Administer Methylprednisolone 250 mg 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 Methylprednisolone for increased effect.
Severely emetogenic chemotherapy: Administer Methylprednisolone 250 mg IV over at least five minutes with appropriate doses of metoclopramide or a butyrophenone one hour before chemotherapy, then Methylprednisolone 250 mg 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 30 mg/kg as an IV bolus over a 15-minute period, followed by a 45-minute pause and then a continuous IV infusion of 5.4 mg/kg/h for 23 hours.
For patients initiated on treatment within 3 to 8 hours of injury: Administer 30 mg/kg as an IV bolus over a 15 minute period, followed by a 45-minute pause, and then a continuous IV infusion of 5.4 mg/kg/h for 47 hours.
In other indications: Initial dosage will vary from 10-500 mg depending on the clinical problem being treated. Larger doses may be required for short term management of severe, acute conditions. The initials dose up to 250 mg should be given intravenously over a period of at least five minutes and if greater than 250 mg, should be given over at least 30 minutes. It should not be less than 0.5 mg 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 0.5 mg per kg every 24 hours. Methylprednisolone (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 diluents provided.

Interaction
The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporine and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. Convulsions have been reported with concurrent use of methylprednisolone and cyclosporine. Drugs that induce hepatic enzymes such as Phenobarbital, phenytoin and rifampin may increase the clearance of methylprednisolone and may require increase in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycine and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulant is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation induces should be monitored to maintain the desired anticoagulant effect.

Contraindications
Systemic fungal infections. Known hypersensitivity to components.

Side Effects
he 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 heamorrhage, 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.
Opthalmic: 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.

Pregnancy & Lactation
Labour and Delivery: No effect known
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. Some animal studies have shown that corticosteroids when administered to the mother at high dose, may cause fetal malformations. Corticosteroids should be used during pregnancy only if clearly needed. If a chronic treatment with corticosteroids has to be stopped during pregnancy (as with other chronic treatments), this should occur gradually (see also dosage and administration). Corticosteroids readily cross the placenta. New born infants born of mother, who have received substantial doses of corticosteroids during pregnancy, should be carefully observed and evaluated for sings of adrenal insufficiency. In case of labor and delivery no effects are known. Corticosteroids are excreted in breast milk.

Precautions & Warnings
-Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation.
-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.
-Corticosteroids should be used with caution in non-specific ulcerative colitis.
-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.
-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.
-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 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.
Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission.
-Carcinogenesis, mutagenesis, impairment of fertility. There is no evidence that corticosteroids are carcinogenic, mutagenic or impair fertility.

Use in Special Populations
Use in children: Use in children may cause growth retardation in infancy, childhood and adolescence.

Overdose Effects
There is no clinical syndrome of acute over dosage with Methylprednisolone sodium Succcinate. Chronic over dosage induces typical Cushing symptoms Methylprednisolone is dialyzable.

Storage Conditions
Protect from light. Store unreconstituted product at controlled room temperature (20° to 25°C). Store solution at controlled room temperature (20° to 25° C). Use solution within 48 hours after mixing.