Methylprednisolone 1000 mg powder and solvent for solution for injection/infusion

Each vial of powder contains methylprednisolone sodium succinate 1326.0 mg equivalent to 1000 mg of methylprednisolone. After reconstitution in water for injections, each ml of solution contains the equivalent of 59.6 mg of methylprednisolone.

Each vial of solvent contains 15.6 ml of water for injections.

Sodium content: the 1000 mg methylprednisolone vials contain the equivalent of 74.4 mg (3.2 mmol) of sodium.

For a full list of excipients, see section 6.1

Powder and solvent for solution for injection/infusion.

Each vial of methylprednisolone sodium succinate contains a white or almost white amorphous powder.

Each vial of solvent contains water for injections.

Methylprednisolone powder and solvent for injection/infusion is indicated to treat any condition in which rapid and intense corticosteroid effect is required such as:

1. Dermatological disease

Severe erythema multiforme (Stevens Johnson syndrome)

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

Methylprednisolone powder for injection/infusion may be administered intravenously or intramuscularly, the preferred method for emergency use being intravenous injection given over a suitable time interval. When administering Methylprednisolone sodium succinate in high doses intravenously it should be given over a period of at least 30 minutes. Doses up to 250mg 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 Methylprednisolone powder for injection/infusion 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 gram/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 - 72 hour period until the patient's condition has stabilised, as prolonged high dose corticosteroid therapy can cause serious corticosteroid induced side effects (see Undesirable effects and Special warnings and special precautions for use).

Children: In the treatment of high dose indications, such as haematological, rheumatic, renal and dermatological conditions, a dosage of 30mg/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 20mg/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 4mg/kg/day for 1- 3 days is recommended.

Elderly patients: Methylprednisolone sodium succinate powder for injection/infusion is primarily used in acute short term conditions. There is no information to suggest that a change in dosage is warranted in the elderly. However, treatment of elderly patients should be planned bearing in mind the more serious consequences of the common side-effects of corticosteroids in old age and close clinical supervision is required (see Special warnings and special precautions for use).

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 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 Methylprednisolone sodium succinate is capable of providing relief within one half to two hours. In patients with status asthmaticus Methylprednisolone sodium succinate 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 - 72 hours.

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.

Aim to discontinue therapy after a total of 10 days.

In the treatment of acute exacerbations of multiple sclerosis in adults, the recommended dose is 1000 mg daily for 3 days. Methylprednisolone powder for injection/infusion 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 term management of severe, acute conditions. The initial dose, up to 250 mg, should be given intravenously over a period of at least 5 minutes, doses exceeding 250 mg should be given intravenously over a period of at least 30 minutes. Subsequent doses may be given intravenously or intramuscularly at intervals dictated by the patient's response and clinical condition. Corticosteroid therapy is an adjunct to, and not replacement for, conventional therapy.

Methylprednisolone powder for injection/infusion 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.

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 Methylprednisolone powder for injection/infusion 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 methylprednisolone sodium succinate 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 methylprednisolone sodium succinate (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. Exposure to measles should be avoided. Medical advice should be sought immediately if exposure occurs. Prophylaxis with normal intramuscular immuneglobulin may be needed.

10. Live vaccines should not be given to individuals with impaired immune responsiveness. The antibody response to other vaccines may be diminished.

11. The use of Methylprednisolone powder for injection/infusion 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.

12. Rarely anaphylactoid reactions have been reported following parenteral methylprednisolone sodium succinate 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.

13. Care should be taken for patients receiving cardioactive drugs such as digoxin because of steroid induced electrolyte disturbance/potassium loss (see Undesirable effects).

14. Corticosteroids should not be used for the management of head injury or stroke because it is unlikely to be of benefit and may even be harmful.

15. Sodium content: each 1000mg of methylprednisolone contains the equivalent of 3.2 mmol (74.4 mg) of sodium. To be taken into consideration by patients on a controlled sodium diet.

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.

20. Recent myocardial infarction (myocardial rupture has been reported).

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

22. Patients and/or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids (see section 4.8). Symptoms typically emerge within a few days or weeks of starting treatment. Risks may be higher with high doses/systemic exposure (see also section 4.5 Interaction with Other Medicaments and Other Forms of Interaction that can increase the risk of side effects), although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary.

Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently.

Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis.

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 pituitary adrenal axis and growth retardation, treatment should be administered where possible as a single dose on alternate days.

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.

1. Convulsions have been reported with concurrent use of methylprednisolone and ciclosporin. 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 which inhibit the CYP3A4 enzyme, such as cimetidine, erythromycin, ketoconazole, itraconazole, diltiazem and mibefradil, may decrease the rate of metabolism of corticosteroids and hence increase the serum concentration.

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.

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 fetal development including cleft palate, intra-uterine growth retardation and effects 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.

None stated.

Under normal circumstances Methylprednisolone powder for injection/infusion 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, hypopigmentation or hyperpigmentation.

GASTRO-INTESTINAL

Dyspepsia, peptic ulceration with perforation and haemorrhage, abdominal distension, oesophageal ulceration, oesophageal candidiasis, acute pancreatitis, perforation of the bowel, gastric haemorrhage. 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, suppression of 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. Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy.

Discontinuation of corticosteroids may result in clinical remission.

ENDOCRINE/METABOLIC

Suppression of the hypothalamo pituitary adrenal axis, growth suppression in infancy, childhood and adolescence, menstrual irregularity and amenorrhoea. Cushingoid facies, hirsutism, weight gain, impaired carbohydrate tolerance with increased requirement for antidiabetic therapy, negative nitrogen and calcium balance. Increased appetite.

NEUROPSYCHIATRIC

A wide range of psychiatric reactions including affective disorders (such as irritable, euphoric, depressed and labile mood, psychological dependence and suicidal thoughts), psychotic reactions (including mania, delusions, hallucinations and aggravation of schizophrenia), behavioural disturbances, irritability, anxiety, sleep disturbances, seizures and cognitive dysfunction including confusion and amnesia have been reported for all corticosteroids. Reactions are common and may occur in both adults and children. In adults, the frequency of severe reactions was estimated to be 5-6%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown. Increased intra-cranial pressure with papilloedema in children (pseudotumour cerebri) has been reported, usually after treatment withdrawal of methylprednisolone.

OPHTHALMIC

Increased intra ocular pressure, glaucoma, papilloedema with possible damage to the optic nerve, cataracts, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal disease.

CARDIOVASCULAR

Myocardial rupture following a myocardial infarction.

GENERAL

Leucocytosis, hypersensitivity including anaphylaxis, thrombo-embolism, malaise, persistent hiccups with high doses of corticosteroids.

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.

There is no clinical syndrome of acute overdosage with Methylprednisolone powder for injection/infusion.

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.

ATC code H02AB04, Corticosteroids for systemic use, plain: mineralocorticoids: glucocorticoids.

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 15-16 litres/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.

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 15-16 litres/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.

There are no pre-clinical data of relevance to the prescriber, which are additional to those included in other sections.

Sodium phosphate dibasic.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Shelf-life of the medicinal product as packaged for sale: 18 months.

After reconstitution with Sterile Water for Injections, use immediately, discard any remainder.

This product does not require any special temperature storage conditions.

Keep the vials in the outer carton in order to protect from light.

Powder

Type I clear glass vial with butyl rubber plug and flip top seal.

Each vial contains the equivalent of 1000 mg of methylprednisolone as the sodium succinate for reconstitution with 15.6 ml of Water for Injections.

Solvent

Type I clear glass vial with butyl rubber plug and flip top seal.

Each vial contains 15.6 ml of Water for Injections.

After reconstitution, the solution should be clear and colourless. Parenteral drug products should wherever possible be visually inspected for particulate matter and discoloration prior to administration.

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, the reconstituted methylprednisolone solution should be administered separately, only in the solutions mentioned.

Beacon Pharmaceuticals Ltd, 85 High Street, Tunbridge Wells TN1 1YG.

PL 18157/0228

7 June 2011

7 June 2011