INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
AP METHYLPRED (powder for injection)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

AP METHYLPRED (powder for injection)

Each 8 mL (when reconstituted) contains Methylprednisolone Sodium Succinate 662.5 mg equivalent to 500 mg Methylprednisolone.

PHARMACOLOGICAL CLASSIFICATION:
A 21.5.1 Corticosteroids and analogues

PHARMACOLOGICAL ACTION:
Pharmacodynamics: Methylprednisolone is a corticosteroid with mainly glucocorticoid activity. Corticosteroids have multiple mechanisms of action including anti-inflammatory activity, immunosuppressive properties, and antiproliferative actions. They have broad anti-inflammatory effects on cellular immunity resulting from decreased formation, release and activity of the mediators of inflammation (e.g. kinins, histamine, liposomal enzymes, prostaglandins, leukotrienes).
Methylprednisolone has a potent anti-inflammatory action. The relative potency of methylprednisolone sodium succinate and hydrocortisone sodium succinate is at least four to one.
Pharmacokinetics:
Methylprednisolone is highly protein bound and is metabolised primarily by the liver, and to a lesser extent by the kidney. It is excreted in the urine.
The elimination half-life ranges from 3,5 hours in normal healthy adults and is independent of the route of administration.

INDICATIONS:
AP METHYLPRED is indicated for conditions that require a rapid, potent corticosteroid effect, such as:

•	Allergic disorders, the severity of which necessitates the use of intravenous (IV) therapy, such as bronchial asthma, angioedema or anaphylaxis.
•	Collagen disorders, for the treatment of exacerbations thereof. This includes conditions such as systemic lupus erythematosis, polyarteritis nodosa, and systemic dermatomyositis.
•	Dermatological disorders which respond to steroids and are severe.
•	Endocrine disorders, primary and secondary adrenocortical-deficiency states, although hydrocortisone and cortisone are preferred as replacement therapy because of their significant mineralocorticoid activity. Synthetic analogues must be used in conjunction with mineralocorticoids where applicable, especially in infancy.
•	Gastro-intestinal diseases, such as severe ulcerative colitis, during the critical period. Long-term use is not recommended.
•	Haematological disorders, such as idiopathic thrombocytopenia purpura (IV therapy only).
•	Neoplastic diseases. Indicated in conjunction with appropriate specific cancer therapy for palliative management of leukaemias and lymphomas in adults. It is also indicated for use as adjunctive therapy for nausea and vomiting associated with cancer therapy.
•	Neurological disorders, such as cerebral oedema, especially when associated with primary or metastatic brain tumour, craniotomy, or head injury. Acute exacerbations of multiple sclerosis.
•	Organ transplant rejection. Treatment and prophylaxis thereof.
•	Rheumatic disorders , including rheumatic fever, especially if carditis is present. It is indicated as adjunctive therapy during an acute episode or exacerbation.
•	Spinal cord injury, acute. Must be given within 8 hours of injury.
•	Shock, due to adrenocortical insufficiency, although hydrocortisone is the medicine of choice.
•	Progressive glomerulonephritis.

CONTRA-INDICATIONS:
AP METHYLPRED is contra-indicated in patients with:

•	Hypersensitivity to methylprednisolone or to any components of the formulation.
•	Systemic fungal infections.
•	Acute psychosis.
•	Peptic ulcer.
•	Osteoporosis (unless considered to be lifesaving).

AP METHYLPRED should not be used in the treatment of septic shock, especially in patients with raised serum creatinine levels or a secondary infection, as increased mortality may occur.

WARNINGS AND PRECAUTIONS:
Rapid intravenous administration of high doses of AP METHYLPRED has been reported to cause angioedema and/or anaphylactic reactions, seizures, and sudden death associated with cardiac arrhythmias (more than 0,5 g administered over a period of less than 10 minutes). Bradycardia, possibly unrelated to the speed of infusion, has been reported during and after administration of AP METHYLPRED. Monitoring of the electrocardiogram (ECG) is recommended. Equipment, medications, and trained personnel necessary for treating these complications should be immediately available.
Tuberculosis, (active positive skin test, latent, or history of) may be exacerbated or reactivated by AP METHYLPRED, appropriate antitubercular chemotherapy or prophylaxis should be administered concurrently.
Concurrent use of AP METHYLPRED and ciclosporin may cause convulsions (see INTERACTIONS).
AP METHYLPRED may mask signs of infection, or new infections may appear.
Patients on AP METHYLPRED require an increase in dosage prior to, during, and for a time following exposure to emotional or physical stress such as severe infection or surgery.
Infants born of mothers who have received prolonged therapy with high doses of AP METHYLPRED should be carefully monitored for signs of adrenal insufficiency (see PREGNANCY AND LACTATION).
Patients on AP METHYLPRED, especially in high doses, should not be immunized because of the possible risk of neurological complications and a lack of antibody response (see INTERACTIONS).
AP METHYLPRED should be used with caution in:

•	Diverticulitis.
•	Non-specific ulcerative colitis, if there is a risk of impending perforation, abscess or other infection.
•	Recent intestinal anastamoses.
•	Active or latent peptic ulcer.
•	Myasthenia gravis, as muscle weakness may initially be increased, leading to possible respiratory distress.
•	Osteoporosis.
•	Renal function impairment.
•	Hypertension.
•	Ocular herpes simplex, as this may result in corneal perforation.
•	Acute psychosis, which may be aggravated.
•	Glucose intolerance.

Decrease or discontinue the dosage gradually if AP METHYLPRED has been administered for more than a few days.
Effects on ability to drive and use machines: None stated.

INTERACTIONS:
Concomitant use of AP METHYLPRED with:-

•	Ciclosporin may result in seizures, especially with high doses in combination with AP METHYLPRED, as the metabolism of both is inhibited. Adverse effects are therefore more likely to occur (see WARNINGS AND PRECAUTIONS).
•	Medicines that induce hepatic enzymes, such as rifampicin, carbamazepine, or phenytoin, may result in reduced efficacy of AP METHYLPRED.
•	Medicines such as erythromycin and ketoconazole that inhibit metabolism, may result in an increase in AP METHYLPRED's adverse effects.
•	Live vaccines may potentiate the replication of the vaccine virus. Also, immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members. Caution should also be exercised with other vaccines (see WARNINGS AND PRECAUTIONS).
•	Salicylates may result in an increase in excretion of salicylates, which may require increased doses of salicylates. On withdrawal of AP METHYLPRED, salicylate poisoning may occur. Caution is recommended when salicylates are used concurrently with AP METHYLPRED in patients with hypoprothrombinaemia.
•	Nondepolarising neuromuscular blocking agents, such as pancuronium may enhance the blockade of nondepolarizing neuromuscular blocking agents, possibly leading to increased or prolonged respiratory depression or paralysis.
•	Other immunosuppressant agents may increase the risk of infection.
•	Diuretics, especially potassium-depleting diuretics, may result in severe hypokalaemia. Monitoring of serum potassium concentration and cardiac function is recommended.
•	Digoxin may increase the risk of cardiac arrhythmias associated with hypokalaemia.
•	Antidiabetic agents, oral and insulin, may require dosage adjustment of both agents as AP METHYLPRED may increase blood glucose concentration. Dosage readjustment of the hypoglycaemic agent also may be required when AP METHYLPRED is discontinued.
•	Coumarin anticoagulants may result in an enhanced anticoagulant effect. Monitoring of INR is recommended.
•	Anticholinesterase agents may produce severe weakness in patients with myasthenia gravis. Anticholinesterase agents should be withdrawn at least 24 hours before initiating therapy with AP METHYLPRED.
•	Carbonic anhydrase inhibitors or amphotericin B may result in severe hypokalaemia. Serum potassium concentrations and cardiac function should be monitored.
•	Antihypertensives may result in reduced hypotension.

PREGNANCY AND LACTATION:
Safety and efficacy in pregnancy and lactation has not been established (see WARNINGS AND PRECAUTIONS).
AP METHYLPRED is excreted in breastmilk and high doses may cause adrenal suppression of the infant.

DOSAGE AND DIRECTIONS FOR USE:
Therapy with AP METHYLPRED is an adjunct to, and not a replacement for, conventional therapy.
Adults: In life-threatening conditions, the recommended dose of AP METHYLPRED is 30 mg/kg, given intravenously (IV) over a period of at least 30 minutes. The dose may be repeated if necessary, every 46 hours for up to 48 hours.
Pulse dosing may be used in corticosteroid-responsive conditions that have exacerbated and are unresponsive to standard therapy. AP METHYLPRED should be administered over at least 30 minutes and may be repeated if there has been no improvement within a week after therapy, or as the patient's condition dictates. The suggested schedules are:
Multiple sclerosis: 1 g/day IV for 3 or 5 days.
Oedematous states: such as lupus nephritis: 30 mg/kg IV on alternate days for 4 days, or 1 g/day for 3, 5 or 7 days.
Systemic lupus erythematosis: 1 g/day IV for 3 days.

The doses for specific conditions are as follows:
Acute spinal injury:
Therapy should begin within 8 hours of injury. As adjunct therapy, 30 mg/kg body weight of AP METHYLPRED should be administered intravenously as a bolus over 15 minutes, followed after 45 minutes by a continuous infusion of 5,4 mg/kg body weight per hour, for twenty-three hours, and then stopped abruptly. There should be a separate intravenous site for the infusion pump.
As adjunctive therapy for the prevention of nausea and vomiting due to mild to moderate emetogenic cancer chemotherapy:
250 mg AP METHYLPRED IV over at least 5 minutes, 2 hours before chemotherapy, at the start of therapy and at the time of discharge.
As adjunctive therapy for severely emetogenic chemotherapy:
250 mg AP METHYLPRED IV over at least 5 minutes with appropriate doses of metoclopramide or a butyrophenone, one hour before chemotherapy, 250 mg AP METHYLPRED IV at the start of therapy and at the time of discharge.
In other indications, the initial dose varies from 10 to 500 mg depending on the severity of the condition being treated. Initial doses of up to 250 mg should be given intravenously over at least 5 minutes, and over at least 30 minutes if the dose is more than 250 mg. Thereafter, doses can be given either intravenously or intramuscularly in schedules determined by the patient's response and clinical condition.
Infants and children:
The dosage should be reduced, but it should depend on the severity of the condition and the response to the treatment, rather than on the age and size of the patient. The dose should however not be less than 0,5 mg/kg every 24 hours.
If AP METHYLPRED is used for more than a few days, the dosage must be decreased or discontinued gradually (see WARNINGS AND PRECAUTIONS).
Patients on prolonged therapy with AP METHYLPRED should have the following tests done at regular intervals: urinalysis, 2 hour postprandial blood sugar and blood pressure. Weight should also be monitored and patients with severe dyspepsia or a history of ulcers, should preferably have an upper gastro-intestinal X-ray.

Preparation of solution:
To prepare the solution for intravenous infusion, first reconstitute AP METHYLPRED with 8 ml water for injection.
Administer as above (over at least 5 minutes if the dose is 250 mg or less and over at least 30 minutes if the dose is more than 250 mg).
Subsequent doses may be withdrawn and administered in the same way.
The medication may be administered in dilute solutions by adding the reconstituted product to 5 % dextrose solution, 0,9 % sodium chloride solution, or 5 % dextrose solution + 0,9 % sodium chloride solution. This will then be chemically and physically stable for 48 hours.
AP METHYLPRED should be administered separately from other medicines, either as an IV push through, an IV medication chamber or as an IV “piggy-back” solution, in order to avoid compatibility and stability problems.
Inspect the product visually for particulate matter and discolouration before administering.

SIDE-EFFECTS:
The risk of adverse effects increases with the size of the dose and the duration of treatment and many adverse effects only occur with long-term use. This should be taken into account when determining the treatment regimen for the individual patient, including whether to use daily or intermittent doses. AP METHYLPRED should be administered slowly if given intravenously to avoid cardiac arrhythmias and circulatory collapse (see WARNINGS AND PRECAUTIONS).
Infections and infestations:
Frequency unknown: opportunistic infections.
Blood and lymphatic system disorders:
Frequency unknown: thrombo-embolism due to increased coagulability.
Immune system disorders:
Frequency unknown: masking of infections, reactivation of latent infections, especially tuberculosis (see WARNINGS AND PRECAUTIONS), hypersensitivity reactions, including anaphylaxis, suppression of skin test reactions.
Endocrine disorders:
Less frequent: manifestation of latent diabetes mellitus and increased requirements for hypoglycaemic agents, increased sweating.
Frequency unknown: adrenal suppression, Cushing's syndrome effects including filling or rounding out of the face, menstrual irregularities. Relative adrenocortical insufficiency, especially in times of stress due to trauma, severe illness or surgery (see WARNINGS AND PRECAUTIONS), growth suppression in children.
Metabolic and nutritional disorders:
Frequency unknown: sodium and fluid retention, electrolyte imbalance, hypokalaemic alkalosis, impaired carbohydrate tolerance, protein catabolism with negative nitrogen balance.
Psychiatric disorders:
Rare: psychic disturbances.
Nervous system disorders:
More frequent: nervousness, insomnia.
Less frequent: vertigo, seizures.
Frequency unknown: increased intracranial pressure, pseudotumour cerebri.
Eye disorders:
Frequency unknown: posterior subcapsular cataracts, increased intraocular pressure, exophthalmos.
Cardiac disorders:
Rare: congestive heart failure, cardiac arrhythmias and bradycardia (see WARNINGS AND PRECAUTIONS).
Vascular disorders:
Frequency unknown: hypertension.
Respiratory, thoracic and mediastinal disorders:
Frequency unknown: bronchospasm.
Gastro-intestinal disorders:
Frequent: gastro-intestinal irritation with nausea and vomiting.
Frequency unknown: pancreatitis, peptic ulceration or intestinal perforation, oesophagitis.
Skin and subcutaneous tissue disorders:
Rare: generalised allergic reaction (skin rash or hives), local reaction or infection at injection site, flushing of face or cheeks, changes in skin colour or hypopigmentation.
Frequency unknown: acne, striae, cutaneous or subcutaneous tissue atrophy, petechiae, ecchymosis, impaired wound healing, thin fragile skin, thinning of hair and scalp, purpura.
Musculoskeletal, connective tissue and bone disorders:
Frequency unknown: avascular necrosis, muscle weakness, osteoporosis or bone fractures (pathological, vertebral compression and spontaneous), steroid myopathy.

Withdrawal symptoms:
Too rapid a reduction of dosage of AP METHYLPRED following prolonged treatment may cause acute, possibly life-threatening adrenal insufficiency and/or a withdrawal syndrome not related to hypothalamic-pituitary-adrenal (HPA) axis suppression. Symptoms include lowgrade fever, muscle or joint pain, weight loss.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Symptoms of overdose:
(See Side-effects).
Treatment of overdose:
Treatment is symptomatic and supportive. AP METHYLPRED is dialyzable.

IDENTIFICATION:
A white to off white lyophilized plug or powder filled in flint vial, plugged with a light grey rubber plug and sealed with a light green flip off aluminium seal.

PRESENTATION:
Packed in a flint vial, plugged with a dark grey rubber plug and sealed with a light green flip off aluminium seal.
Available in pack sizes of 1's.

STORAGE INSTRUCTIONS:
Store in a dry cool place below 25ºC. Protected from light. Use solution within 48 hours after mixing.
KEEP OUT OF THE REACH OF CHILDREN.

REGISTRATION NUMBER:
A40/21.5.1/0524

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION:
PHARMACARE LIMITED
Building 12, Healthcare Park, Woodlands Drive, Woodmead, Sandton, 2148

DATE OF PUBLICATION OF PACKAGE INSERT:
18 July 2006

New addition to this site: July 2008
Source: Pharmaceutical Industry
SAEPI HOME PAGE      TRADE NAME INDEX      GENERIC NAME INDEX      FEEDBACK
Information presented by Malahyde Information Systems © Copyright 1996-2008