METYPRESOL 125 mg Powder for Injection; METYPRESOL 500 mg Powder for Injection; METYPRESOL 1 g Powder for Injection; INTRAMED METYPRESOL DILUENT (2 mL; 7,5 mL; 15 mL) vial

INDICATIONS CONTRA-INDICATIONS DOSAGE SIDE-EFFECTS PREGNANCY OVERDOSE IDENTIFICATION PATIENT INFORMATION

METYPRESOL 125 mg Powder for Injection
METYPRESOL 500 mg Powder for Injection
METYPRESOL 1 g Powder for Injection
INTRAMED METYPRESOL DILUENT (2 mL; 7,5 mL; 15 mL) vial

SCHEDULING STATUS:
S4

PROPRIETARY NAME:
(and dosage form):

METYPRESOL 125 mg Powder for Injection
METYPRESOL 500 mg Powder for Injection
METYPRESOL 1 g Powder for Injection
INTRAMED METYPRESOL DILUENT (2 mL; 7,5 mL; 15 mL) vial

COMPOSITION:
Metypresol 125 mg contains methylprednisolone sodium succinate equivalent to methylprednisolone 125 mg.
Metypresol 500 mg contains methyl prednisolone sodium succinate equivalent to methylprednisolone 500 mg.
Metypresol 1 g contains methylprednisolone sodium succinate equivalent to methylprednisolone 1 g Intramed Metypresol Diluent contains Water for Injection 2 mL (7,5 mL; 15 mL).

PHARMACOLOGICAL CLASSIFICATION:
A.21.5.1 Corticosteroids and analogues.

PHARMACOLOGICAL ACTION:
Metypresol is a glucocorticoid with an anti-inflammatory potency of 5 relative to hydrocortisone while its sodium retaining potency is 0,5 compared with hydrocortisone. It has an intermediate duration of action (12 to 36 hours).

INDICATIONS:

–	Serious acute allergic reaction as supplement to primary therapy such as adrenaline.
–	Status asthmaticus.
–	Cerebral oedema associated with neoplasms.
–	Suppression of graft rejection reactions following transplantation.
–	Malignant haematologic diseases (e.g. acute lymphoblastic leukaemia) in conjunction with antineoplastic agents.
–	Haematologic dyscrasias (e.g. acute autoimmune hemalytic anaemia idiopathic thrombocytopenic purpurea).

CONTRA-INDICATIONS:

–	Acute infections including herpes simplex and herpes zoster, ulceration of the eye, varicella, vaccinia.
–	Psychoses.
–	Peptic ulcer.
–	Cushing's syndrome.
–	Osteoporosis.
–	Severe psychoneuroses.
–	Vaccination with live vaccine.
	Metypresol should be used only with great caution in the presence of congestive heart failure, in patients with diabetes mellitus, infectious diseases, chronic renal failure, and in uraemia, and in elderly persons.
	Patients with active or doubtfully quiescent tuberculosis should not be given Metypresol except, very rarely, as an adjunct to treatment with antitubercular drugs. Patients with quiescent tuberculosis should be observed closely and should receive chemoprophylaxis if corticosteroid therapy is prolonged.

DOSAGE AND DIRECTIONS FOR USE:
Metypresol 125 mg:
Acute allergic reactions; status asthmaticus; cerebral oedema.
Adults: Initial dose will vary from 10 to 40 mg depending on the clinical problem being treated. The injection may be repeated 2 to 3 times per 24 hours.
The following is a suggested dosage schedule of cerebral oedema:

	Dose (mg)	Route	Interval In hours	Duration
Pre-operative	20	IM	3 to 6	24 hours
During surgery	20 to 40	IV	Hourly	24 hours
Postoperative	20	IM	3	24 hours
	16	IM	3	24 hours
	12	IM	3	24 hours
	8	IM	3	24 hours
	4	IM	3	24 hours
	4	IM	6	24 hours
	4	IM	10	24 hours

Children: The dosage must be reduced for children. Dosage should be governed more by the severity of the condition and response of the patient than by age and size. It should be not less than 0,5 mg per kg every 24 hours.
The initial dosage should be given intravenously over a period of one to several minutes. The dosage of Metypresol should be reduced gradually once the patient's condition is under control.

Metypresol 500 mg and 1 g:
Suppression of graft injection reaction: 0,5 to 2,0 g IV every 24 to 28 hours (30 mg/kg/day).
Because of the risk of arrhythmias, Metypresol should be given by infusion in cases of myocardial damage.

Reconstitution:
The solvent, Intramed Metypresol Diluent, should be added aseptically to the vial containing the powder.

Metypresol 125 mg:	Reconstitution with 2 mL sterile Intramed Metypresol Diluent gives a solution of 125 mg/2 mL.
Metypresol 500 mg:	Reconstitution with 7,5 mL sterile Intramed Metypresol Diluent gives a solution of 500 mg/8 mL.
Metypresol 1 g:	Reconstitution with 15 mL sterile Intramed Metypresol Diluent gives a solution of 1 g/16 mL.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:

–	Cardiovascular collapse has been reported following the rapid intravenous injection of large doses of Metypresol.
–	Metypresol should not be injected into the deltoid muscle since it may cause subcutaneous atrophy.

The side effects associated with the use of corticosteroids result from excessive action on electrolyte balance, excessive action on other aspects of metabolism including gluconeogenesis, the action on tissue repair and healing, and an inhibitory effect on the secretion of corticotrophin by the anterior lobe of the pituitary gland.

Metypresol appears in mothers milk and may result in growth suppression in endogenous corticoid – production suppression and may cause other undesirable effects. Mothers should be advised against nursing. There is insufficient data to assess potential problems if administered during pregnancy, but this drug caused harm in animal studies.

Disturbances in the electrolyte balance are manifest in the retention of sodium and water, with oedema and hypertension and an increased excretion of potassium with the possibility of hypokalaemic alkalosis. In extreme cases cardiac failure may be induced.

Disturbances of electrolyte balances are less frequent with Metypresol, which has little mineralocorticoid activity.

Metypresol can lower the resistance of infections mask some signs of infections and new infections may appear during their use. Furthermore wound healing can be delayed.

Metypresol may cause posterior subcapaular cataract.

Other excessive metabolic effects lead to mobilisation of calcium and phosphorous, with osteoporosis and spontaneous fractures, nitrogen depletion, and hyperglycaemia with accentuation or precipitation of the diabetic state. The insulin requirements of the patients are increased. Increased appetite is often reported.

Acute adrenal insufficiency may occur during prolonged use or on cessation of treatment and may be precipitated by an infection or trauma.

Growth retardation in children has been reported.

Large doses of Metypresol may produce symptoms typical of hyperactivity of the adrenal cortex, with moon face, sometimes with hirsutism, buffalo hump, flushing, increased bruising, striae and acne, sometimes leading to a fully developed Cushing’s Syndrome.

Other side effects include amenorrhoea, hyperhidrosis, mental and neurological disturbances, (insomnia, euphoria, psychosis, excitement), intracranial hypertension, acute pancreatitis and aseptic necrosis of bone. An increase in the coagulability of blood may lead to thromboembolic complications.

The administration of Metypresol may also cause a reduction in the number of circulating lymphocytes.

Muscular weakness is an occasional side effect of Metypresol, particularly when taken in large doses. Strict aseptic technique is mandatory.

While on Metypresol therapy patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients who are receiving Metypresol because of possible hazards of neurological complications and lack of antibody response.

Children are at special risk of infection and may require prophylaxis with immunoglobulin. There is an enhanced effect of corticosteroids in patients with hypothyroidism and in those with cirrhosis.

With prolonged Metypresol therapy care should be taken in the case of patients with a history of ulcers, psychiatric derangements, severe hypertension, osteoporosis, predisposition to thrombosis, renal insufficiency and active tuberculosis. Patients with latent or manifest diabetes, bacterial infection, osteoporosis, recurrent thrombophlebitis, as well as children and pregnant women require close surveillance.

During long courses of therapy, patients should be seen regularly and, in particular, checked for hypertension, glycosuria, hypokalaemia, gastric discomfort and mental changes.

Sodium intake may need to be reduced and potassium supplements may be necessary. Monitoring of the fluid intake and output, and daily weight records may give early warning of fluid retention, back pain may signify osteoporosis; children are at special risk from raised intracranial pressure; infections should be treated as an emergency.

Measures to compensate for the adrenals' inability to respond to stress, include doubling the dose to cover minor intercurrent illnesses or similar stresses (with intramuscular administration to cover vomiting).

Concurrent administration of barbiturates, phenytoin, or rifampicin may enhance the metabolism and reduce the effects of Metypresol.

Response to anticoagulants maybe reduced and on some occasions enhanced by Metypresol.

Concurrent administration of Metypresol and the potassium-depleting diuretics, such as the thiazides or furosemide may cause excessive potassium loss.

Metypresol may increase or decrease the motility and number of spermatozoa in some patients.

Because instances of anaphylactoid 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.

The administration of Metypresol should not be discontinued suddenly, but tailed off over a period, because the administration of Metypresol suppresses the secretion of corticosteroids in the adrenal cortex.

IDENTIFICATION
Metypresol 125 mg contains a white crystalline powder in a 2 mL glass vial.
Metypresol 500 mg contains a while crystalline powder in a 15 mL glass vial.
Metypresol 1 g contains a white crystalline powder in a 20 mL glass vial.
Intramed Metypresol Diluent is a clear, colourless liquid in 2 mL (15 mL, 20 mL) glass vial.

PRESENTATION:
Single vials of powder packed together with a single vial of the required volume of Intramed Metypresol Diluent.

STORAGE INSTRUCTIONS:
Metypresol powder and reconstituted solution should be stored in a cool place (below 25°C). The reconstituted solution should be used within 8 hours. Protect from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS:

Metypresol 125 mg:	S/21.5.1/340
Metypresol 500 mg:	S/21.5.1/341
Metypresol 1 g:	S/21.5.1/342

Intramed Metypresol Diluent: Z/34/54

NAME AND BUSINESS ADDRESS OF APPLICANT:
INTRAMED (Pty) Ltd
6 Gibaud Road
6001 Port Elizabeth

DATE OF PUBLICATION OF THIS PACKAGE INSERT:

13 August 1987	12-241/10-93
	Tradepak P.E.