1. Name Of The Medicinal Product
Solu-Medrone 125 mg
2. Qualitative And Quantitative Composition
Solu-Medrone 125 mg : Methylprednisolone sodium succinate 165.8 mg equivalent to 125 mg of methylprednisolone.
3. Pharmaceutical Form
Powder for injection.
4. Clinical Particulars
4.1 Therapeutic Indications
Solu-Medrone is indicated to treat any condition in which rapid and intense corticosteroid effect is required such as:
1. Dermatological disease
Severe erythema multiforme (Stevens
2. Allergic states
Bronchial asthma
Severe seasonal and perennial allergic rhinitis
Angioneurotic oedema
Anaphylaxis
3. Gastro-intestinal diseases
Ulcerative colitis
Crohn's disease
4. Respiratory diseases
Aspiration of gastric contents
Fulminating or disseminated tuberculosis (with appropriate antituberculous chemotherapy)
5. Neurological disorders
Cerebral oedema secondary to cerebral tumour
Acute exacerbations of multiple sclerosis superimposed on a relapsing-remitting background.
6. Miscellaneous
T.B. meningitis (with appropriate antituberculous chemotherapy)
Transplantation
4.2 Posology And Method Of Administration
Solu-Medrone may be administered intravenously or intramuscularly, the preferred method for emergency use being intravenous injection given over a suitable time interval. When administering Solu-Medrone in high doses intravenously it should be given over a period of at least 30 minutes. Doses up to 250 mg should be given intravenously over a period of at least five minutes.
For intravenous infusion the initially prepared solution may be diluted with 5% dextrose in water, isotonic saline solution, or 5% dextrose in isotonic saline solution. To avoid compatibility problems with other drugs Solu-Medrone should be administered separately, only in the solutions mentioned.
Undesirable effects may be minimised by using the lowest effective dose for the minimum period (see Other special warnings and precautions).
Parenteral drug products should wherever possible be visually inspected for particulate matter and discoloration prior to administration.
Adults Dosage should be varied according to the severity of the condition, initial dosage will vary from 10 to 500 mg. In the treatment of graft rejection reactions following transplantation, a dose of up to 1 g/day may be required. Although doses and protocols have varied in studies using methylprednisolone sodium succinate in the treatment of graft rejection reactions, the published literature supports the use of doses of this level, with 500 mg to 1 g most commonly used for acute rejection. Treatment at these doses should be limited to a 48
Children In the treatment of high dose indications, such as haematological, rheumatic, renal and dermatological conditions, a dosage of 30 mg/kg/day to a maximum of 1 g/day is recommended. This dosage may be repeated for three pulses either daily or on alternate days. In the treatment of graft rejection reactions following transplantation, a dosage of 10 to 20 mg/kg/day for up to 3 days, to a maximum of 1 g/day, is recommended. In the treatment of status asthmaticus, a dosage of 1 to 4 mg/kg/day for 1
Elderly patients Solu-Medrone is primarily used in acute short
Detailed recommendations for adult dosage are as follows
In anaphylactic reactions adrenaline or noradrenaline should be administered first for an immediate haemodynamic effect, followed by intravenous injection of Solu-Medrone (methylprednisolone sodium succinate) with other accepted procedures. There is evidence that corticosteroids through their prolonged haemodynamic effect are of value in preventing recurrent attacks of acute anaphylactic reactions.
In sensitivity reactions Solu-Medrone is capable of providing relief within one half to two hours. In patients with status asthmaticus Solu-Medrone may be given at a dose of 40 mg intravenously, repeated as dictated by patient response. In some asthmatic patients it may be advantageous to administer by slow intravenous drip over a period of hours.
In graft rejection reactions following transplantation doses of up to 1 g per day have been used to suppress rejection crises, with doses of 500 mg to 1 g most commonly used for acute rejection. Treatment should be continued only until the patient's condition has stabilised; usually not beyond 48
In cerebral oedema corticosteroids are used to reduce or prevent the cerebral oedema associated with brain tumours (primary or metastatic).
In patients with oedema due to tumour, tapering the dose of corticosteroid appears to be important in order to avoid a rebound increase in intracranial pressure. If brain swelling does occur as the dose is reduced (intracranial bleeding having been ruled out), restart larger and more frequent doses parenterally. Patients with certain malignancies may need to remain on oral corticosteroid therapy for months or even life. Similar or higher doses may be helpful to control oedema during radiation therapy.
The following are suggested dosage schedules for oedemas due to brain tumour.
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Aim to discontinue therapy after a total of 10 days.
REFERENCES
1. Fox JL, MD. "Use of Methylprednisolone in Intracranial Surgery" Medical Annals of the District of Columbia, 34:261
2. Cantu RC, MD Harvard Neurological Service, Boston, Massachusetts. Letter on file, The Upjohn Company (February 1970).
In the treatment of acute exacerbations of multiple sclerosis in adults, the recommended dose is 1 g daily for 3 days. Solu-Medrone should be given as an intravenous infusion over at least 30 minutes.
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
4.3 Contraindications
Solu-Medrone is contra-indicated where there is known hypersensitivity to components, in systemic infection unless specific anti-infective therapy is employed and in cerebral oedema in malaria.
4.4 Special Warnings And Precautions For Use
Warnings and Precautions
1. A Patient Information Leaflet is provided in the pack by the manufacturer.
2. Undesirable effects may be minimised by using the lowest effective dose for the minimum period. Frequent patient review is required to appropriately titrate the dose against disease activity (see Posology and method of administration).
3. Adrenal cortical atrophy develops during prolonged therapy and may persist for months after stopping treatment. In patients who have received more than physiological doses of systemic corticosteroids (approximately 6 mg methylprednisolone) for greater than 3 weeks, withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids, but there is uncertainty about HPA suppression, the dose of systemic corticosteroid may be reduced rapidly to physiological doses. Once a daily dose of 6 mg methylprednisolone is reached, dose reduction should be slower to allow the HPA-axis to recover.
Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks is appropriate if it considered that the disease is unlikely to relapse. Abrupt withdrawal of doses up to 32 mg daily of methylprednisolone for 3 weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting 3 weeks or less:
• Patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than 3 weeks.
• When a short course has been prescribed within one year of cessation of long-term therapy (months or years).
• Patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy.
• Patients receiving doses of systemic corticosteroid greater than 32 mg daily of methylprednisolone.
• Patients repeatedly taking doses in the evening.
4. Patients should carry 'Steroid Treatment' cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.
5. Although Solu-Medrone is not approved in the UK for use in any shock indication, the following warning statement should be adhered to. Data from a clinical study conducted to establish the efficacy of Solu-Medrone in septic shock, suggest that a higher mortality occurred in subsets of patients who entered the study with elevated serum creatinine levels or who developed a secondary infection after therapy began. Therefore this product should not be used in the treatment of septic syndrome or septic shock.
6. There have been a few reports of cardiac arrhythmias and/or circulatory collapse and/or cardiac arrest associated with the rapid intravenous administration of large doses of Solu-Medrone (greater than 500 mg 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 and duration of infusion.
7. Corticosteroids may mask some signs of infection, and new infections may appear during their use. Suppression of the inflammatory response and immune function increases the susceptibility to fungal, viral and bacterial infections and their severity. The clinical presentation may often be atypical and may reach an advanced stage before being recognised.
8. Chickenpox is of serious concern since this normally minor illness may be fatal in immunosuppressed patients. Patients (or parents of children) without a definite history of chickenpox should be advised to avoid close personal contact with chickenpox or herpes zoster and if exposed they should seek urgent medical attention. Passive immunization with varicella/zoster immunoglobin (VZIG) is needed by exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.
9. Live vaccines should not be given to individuals with impaired immune responsiveness. The antibody response to other vaccines may be diminished.
10. The use of Solu-Medrone 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 an appropriate anti-tuberculous 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.
11. Rarely anaphylactoid reactions have been reported following parenteral Solu-Medrone therapy. Physicians using the drug should be prepared to deal with such a possibility. Appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of drug allergy.
12. Care should be taken for patients receiving cardioactive drugs such as digoxin because of steroid induced electrolyte disturbance/potassium loss (see Undesirable effects).
Special precautions
Particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary.
1. Osteoporosis (post-menopausal females are particularly at risk).
2. Hypertension or congestive heart failure.
3. Existing or previous history of severe affective disorders (especially previous steroid psychosis).
4. Diabetes mellitus (or a family history of diabetes).
5. History of tuberculosis.
6. Glaucoma (or a family history of glaucoma).
7. Previous corticosteroid-induced myopathy.
8. Liver failure or cirrhosis.
9. Renal insufficiency.
10. Epilepsy.
11. Peptic ulceration.
12. Fresh intestinal anastomoses.
13. Predisposition to thrombophlebitis.
14. Abscess or other pyogenic infections.
15. Ulcerative colitis.
16. Diverticulitis.
17. Myasthenia gravis.
18. Ocular herpes simplex, for fear of corneal perforation.
19. Hypothyroidism.
Use in children Corticosteroids cause growth retardation in infancy, childhood and adolescence, which may be irreversible. Treatment should be limited to the minimum dosage for the shortest possible time. In order to minimise suppression of the hypothalamo
Use in the elderly The common adverse effects of systemic corticosteroids may be associated with more serious consequences in old age, especially osteoporosis, hypertension, hypokalaemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
1. 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.
2. Drugs that induce hepatic enzymes, such as rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone, and aminoglutethimide enhance the metabolism of corticosteroids and its therapeutic effects may be reduced.
3. Drugs such as erythromycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance.
4. Steroids may reduce the effects of anticholinesterases in myasthenia gravis. The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids, and the hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics and carbenoxolone are enhanced.
5. The efficacy of coumarin anticoagulants may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.
6. The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication. Salicylates and non-steroidal anti-inflammatory agents should be used cautiously in conjunction with corticosteroids in hypothrombinaemia.
7. Steroids have been reported to interact with neuromuscular blocking agents such as pancuronium with partial reversal of the neuromuscular block.
4.6 Pregnancy And Lactation
Pregnancy
The ability of corticosteroids to cross the placenta varies between individual drugs, however, methylprednisolone does cross the placenta.
Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and affects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate in man, however, when administered for long periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. Hypoadrenalism may, in theory , occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential, however, patients with normal pregnancies may be treated as though they were in the non-gravid state.
Lactation
Corticosteroids are excreted in small amounts in breast milk, however, doses of up to 40 mg daily of methylprednisolone are unlikely to cause systemic effects in the infant. Infants of mothers taking higher doses than this may have a degree of adrenal suppression, but the benefits of breastfeeding are likely to outweigh any theoretical risk.
4.7 Effects On Ability To Drive And Use Machines
None stated.
4.8 Undesirable Effects
Under normal circumstances Solu-Medrone therapy would be considered as short-term. However, the possibility of side-effects attributable to corticosteroid therapy should be recognised, particularly when high-dose therapy is being used (see Special warnings and special precautions for use). Such side-effects include:
PARENTERAL CORTICOSTEROID THERAPY - Anaphylactic reaction with or without circulatory collapse, cardiac arrest, bronchospasm, cardiac arrhythmias, hypotension or hypertension.
GASTRO-INTESTINAL - Dyspepsia, peptic ulceration with perforation and haemorrhage, abdominal distension, oesophageal ulceration, oesophageal candidiasis, acute pancreatitis. Nausea, vomiting and bad taste in mouth may occur especially with rapid administration.
Increases in alanine transaminase (ALT, SGPT) aspartate transaminase (AST, SGOT) and alkaline phosphatase have been observed following corticosteroid treatment. These changes are usually small, not associated with any clinical syndrome and are reversible upon discontinuation.
ANTI-INFLAMMATORY AND IMMUNOSUPPRESSIVE EFFECTS - Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, may suppress reactions to skin tests, recurrence of dormant tuberculosis (see Special warnings and special precautions for use).
MUSCULOSKELETAL - Proximal myopathy, osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, tendon rupture.
FLUID AND ELECTROLYTE DISTURBANCE - Sodium and water retention, potassium loss, hypertension, hypokalaemic alkalosis, congestive heart failure in susceptible patients.
DERMATOLOGICAL - Impaired healing, petechiae and ecchymosis, skin atrophy, bruising, striae, telangiectasia, acne.
ENDOCRINE/METABOLIC - Suppression of the hypothalamo
NEUROPSYCHIATRIC - Euphoria, psychological dependence, mood swings, depression, personality changes, insomnia. Increased intra-cranial pressure with papilloedema in children (pseudotumour cerebri), usually after treatment withdrawal. Psychosis, aggravation of schizophrenia, seizures.
OPHTHALMIC - Increased intra
GENERAL - Leucocytosis, hypersensitivity including anaphylaxis, thrombo-embolism, malaise.
WITHDRAWAL SYMPTOMS - Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death. However, this is more applicable to corticosteroids with an indication where continuous therapy is given (see Special warnings and special precautions for use).
A 'withdrawal syndrome' may also occur including, fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.
4.9 Overdose
There is no clinical syndrome of acute overdosage with Solu-Medrone. Methylprednisolone is dialysable. Following chronic overdosage the possibility of adrenal suppression should be guarded against by gradual diminution of dose levels over a period of time. In such event the patient may require to be supported during any further stressful episode.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Medrone is a corticosteroid with an anti-inflammatory activity at least five times that of hydrocortisone. An enhanced separation of glucocorticoid and mineralocorticoid effect results in a reduced incidence of sodium and water retention.
5.2 Pharmacokinetic Properties
Methylprednisolone is extensively bound to plasma proteins, mainly to globulin and less so to albumin. Only unbound corticosteroid has pharmacological effects or is metabolised. Metabolism occurs in the liver and to a lesser extent in the kidney. Metabolites are excreted in the urine.
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.
Total body clearance following intravenous or intramuscular injection of methylprednisolone to healthy adult volunteers is approximately 15-16l/hour. Peak methylprednisolone plasma levels of 33.67 mcg/100 ml were achieved in 2 hours after a single 40 mg i.m. injection to 22 adult male volunteers.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium biphosphate and sodium phosphate.
The 40 mg vial also contains lactose.
6.2 Incompatibilities
None stated.
6.3 Shelf Life
Shelf-life of the medicinal product as packaged for sale: 60 months.
After reconstitution with Sterile Water for injections, use immediately, discard any remainder.
6.4 Special Precautions For Storage
Store below 25°C.
Refer to Section 4.2 Dosage and Administration. No diluents other than those referred to are recommended. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
6.5 Nature And Contents Of Container
Type I clear glass vial with butyl rubber plug and flip top seal.
Each vial of Solu-Medrone 125 mg contains the equivalent of 125 mg of methylprednisolone as the sodium succinate for reconstitution with 2 ml of Sterile Water for Injections.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Pharmacia Limited
Davy Avenue
Milton Keynes
MK5 8PH
UK
8. Marketing Authorisation Number(S)
Solu- Medrone 125 mg PL 0032/0034
9. Date Of First Authorisation/Renewal Of The Authorisation
PL 0032/ 0034, date of first authorisation: 21 February 1990
Last renewal date: 20 August 1996
10. Date Of Revision Of The Text
May 2001
Legal Category
POM.
