COMPOSITION:

Each tablet contains 5 mg or 10 mg prednisolone.

PHARMACOLOGICAL CLASSIFICATION:

 Adrenal Hormones and Synthetic Substitutes.

PHARMACODYNAMIC EFFECTS:

Prednisolone is one of the highly potent glucocorticoid steroids having anti-inflammatory, hormonal and metabolic effects qualitatively similar to those of hydrocortisone.

Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli.

PHARMACOKINETICS:

Absorption: Prednisolone is readily and almost completely absorbed from the GI tract after oral administration.

Distribution: Peak plasma concentrations are obtained 1-2 hours after oral administration. Prednisolone is extensively bound to plasma proteins, although less so than hydrocortisone. Prednisolone crosses the placenta and small amounts are excreted in breast milk.

Metabolism: Prednisolone is mainly metabolised in the liver and has a usual plasma half-life of 2-3 hours. Its initial absorption, but not its overall bioavailability, is affected by food, hepatic or renal impairment and certain drugs.

Excretion: It is excreted in the urine as free and conjugated metabolites, together with an appreciable proportion of unchanged prednisolone.

INDICATIONS:

Prednisolone is indicated in the management of all conditions deemed likely to benefit from short or long term glucocorticoid therapy. These include:

Allergic states: Severe, incapacitating allergies unresponsive to conventional treatment; asthma serum sickness; drug hypersensitivity reactions.

Collagen disorders: E.g. systemic lupus erythematosus, polymyositis, polymyalgia rheumatica and temporal (giant cell) arteritis, mixed connective tissue disease syndrome, acute rheumatic carditis.

Rheumatic disorders: Usually given as an adjunctive therapy for short term administration during an acute episode or exacerbation of rheumatoid arthritis, psoriatic arthritis.

Skin conditions: Life-threatening or incapacitating skin conditions such as pemphigus and exfoliative dermatitis.

Neoplastic disease: Leukaemias and lymphomas in adults, acute leukaemia of childhood.

Gastro-Intestinal disease: During acute exacerbation in ulcerative colitis and regional ileitis (Crohn's Disease).

Respiratory disease: Sarcoidosis (especially with hypercalcaemia), fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculosis chemotherapy.

Haematological disorders: Various blood dyscrasiaseg selected cases of haemolyticanaemia, thrombocytopenic purpura.

Miscellaneous: Nephrotic syndrome.

CONTRAINDICATIONS:

• Hypersensitivity to any ingredients in the formulation.
• Systemic infections unless specific anti-infective therapy is employed.
• Patients with ocular herpes simplex due to the possibility of perforation.
• One of the excipients of the tablet is lactose; hence patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

ADVERSE EFFECTS:

A wide range of psychiatric reactions including affective disorders (such as irritable, euphoric, depressed and labile mood, and suicidal thoughts), psychotic reactions (including mania, delusions, hallucinations, and aggravation of schizophrenia), behavioural disturbances, irritability, anxiety, sleep disturbances, and cognitive dysfunction including confusion and amnesia have been reported.

Body as a Whole: Leucocytosis, hypersensitivity including anaphylaxis, thromboembolism, fatigue, malaise.

Cardiovascular: congestive heart failure in susceptible patients, hypertension

Gastro-intestinal: Dyspepsia, nausea, peptic ulceration with perforation and haemorrhage, abdominal distension, abdominal pain, increased appetite which may result in weight gain, diarrhoea, oesophageal ulceration, oesophageal candidiasis, acute pancreatitis.

Musculo-skeletal: Proximal myopathy, osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, tendon rupture, myalgia.

Metabolic/Nutritional: Sodium and water retention, hypokalaemic alkalosis, potassium loss, negative nitrogen and calcium balance.

Skin/Appendages: Impaired healing, hirsutism, skin atrophy, bruising, striae, telangiectasia, acne, increased sweating, may suppress reactions to skin tests, pruritis, rash, urticaria.

Endocrine: Suppression of the hypothalamo-pituitary adrenal axis particularly in times of stress, as in trauma, surgery or illness, growth suppression in infancy, childhood and adolescence, menstrual irregularity and amenorrhoea. Cushingoid facies, weight gain, impaired carbohydrate tolerance with increased requirement for antidiabetic therapy, manifestation of latent diabetes mellitus, Increased appetite.

Central and Peripheral Nervous System: Euphoria, psychological dependence, depression, insomnia, dizziness, headache, vertigo. Raised intracranial pressure with papilloedema (pseudotumor cerebri) in children, usually after treatment withdrawal. Aggravation of schizophrenia. Aggravation of epilepsy.

Vision: Increased intra-ocular pressure, glaucoma, papilloedema, posterior subcapsular cataracts, exophthalmos, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal disease.

Anti-inflammatory and immunosuppressive effects: Increases susceptibility to, and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis.

Withdrawal symptoms: Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death. A steroid “withdrawal syndrome” ,This syndrome includes symptoms such as: anorexia, nausea, vomiting, lethargy, headache, fever, joint pain, desquamation, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules ,weight loss, and/or hypotension.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES:

If insufficient sleep occurs, the likelihood of impaired alertness may be increased, patients should make sure they are not affected before driving or operating machinery.

WARNINGS AND PRECAUTIONS:

• Patients/and or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids.
• Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected.
• 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.
• Caution is necessary when corticosteroids, including prednisolone, are prescribed to patients with the following conditions and frequent patient monitoring is necessary:

• Diabetes mellitus or in those with a family history of diabetes.
• Glaucoma or in those with a family history of glaucoma.
• Hypertension or congestive heart failure.
• Liver failure.
• Epilepsy.
• Osteoporosis: This is of special importance in post-menopausal females who are at particular risk.
• Patients with a history of severe affective disorders and particularly those with a previous history of corticosteroid induced psychoses.
• Peptic ulceration.
• Previous steroid myopathy.
• Glucocorticoids should be used cautiously in patients with myasthenia gravis receiving anticholinesterase therapy.
• Corticosteroids should be used with caution in patients with thromboembolic disorders.
• Renal insufficiency.
• Tuberculosis: The emergence of active tuberculosis can, however, be prevented by the prophylactic use of antituberculous therapy.
• Recent myocardial infarction (rupture).
• Chickenpox: 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.
• Measles: Patients are advised to avoid exposure to measles, medical advice should be sought if exposure occurs.
• Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity.
• The effect of corticosteroids may be enhanced in patients with hypothyroidism in those with chronic liver disease with impaired hepatic function.
• Live vaccines should not be given to individuals with impaired immune responsiveness. The antibody response to other vaccines may be diminished.
• Adrenal cortical atrophy develops during prolonged therapy and may persist for years after stopping treatment.

WITHDRAWAL:

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 40mg daily of prednisolone.

• Patients repeatedly taking doses in the evening.

During prolonged therapy any intercurrent illness, trauma or surgical procedure will require a temporary increase in dosage; if corticosteroids have been stopped following prolonged therapy they may need to be temporarily reintroduced.

DRUG INTERACTIONS:

• Antacids can reduce the absorbtion of prednisolone if given in high doses.Indigestion remedies should not be taken at the same time of day as Prednisolone.

• Rifampicin, rifabutin, carbamazepine, phenobarbital, phenytoin, primidone, carbimazole and aminoglutethimide enhance the metabolism of corticosteroids and its therapeutic effects may be reduced. Therefore it may be necessary to adjust the dose of prednisolone accordingly.

• The desired effects of hypoglycaemic agents (including insulin), antihypertensives and diuretics are antagonised by corticosteroids.

• The hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics, beta-2-agonists, theophylline and carbenoxolone are enhanced.

• 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.

• Ciclosporin increases the plasma concentration of prednisolone.

• The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication.

• NSAIDs such as indometacin may increase the risk of GI ulceration. The possiblity of GI ulceration should be considered with concomitant use with any other NSAIDs.

• Aspirin should be used cautiously in conjunction with glucocorticoids in patients with hypoprothrombinaemia. Concurrent use of aspirin and prednisolone may result in an increased risk of gastrointestinal ulceration and subtherapeutic aspirin serum concentrations.

• Antifungals: Increased risk of hypokalaemia with amphotericin. Avoid concomitant use. Ketoconazole reduces the metabolic and renal clearances of methylprednisolone, this may also occur with prednisolone.

• Mifepristone reduces the effect of corticosteroids for 3-4 days after administration.

• Methotrexate may have a steroid sparing effect. There is evidence that the toxicity of methotrexate is increased.

• Etoposide metabolism may be inhibited by corticosteroids in vitro. This may lead to an increase in both efficacy and toxicity of the etoposide. Monitoring would be prudent.

• Corticosteroids should not be used concurrently with retinoids and tetracyclines due to increased intracranial pressure.

• Oestrogens and progestogens increase plasma concentrations of corticosteroids.

PREGNANCY AND LACTATION:

Pregnancy:As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks.

Patients with pre-eclampsia or fluid retention require close monitoring.

Lactation:Corticosteroids are excreted in small amounts in breast milk. However doses of up to 40mg daily of prednisolone 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 breast feeding are likely to out-weigh any theoretical risk. Monitoring of the infant for adrenal suppression is advised.

DOSAGE AND ADMINISTRATION:

For oral administration.

The daily dose should be taken in the morning after breakfast.

Adults

20-40mg daily (acute conditions up to 80mg daily) reducing gradually to maintenance level when symptoms have subsided. Maintenance dosage is usually 5-20mg daily reached in about two weeks by reduction of the daily dosage by 5mg or 2.5mg, two or three times a week.

Children

Fractions of adult dosage may be used (eg 75% at 12 years, 50% at 7 years and 25% at 1 year), but clinical factors must be taken into consideration.

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 asingle dose on alternate days.

Elderly

Treatment of elderly patients, especially if long-term, should be planned bearing in mind the more serious consequences of the common side-effects of corticosteroids in old age, particularly diabetes, hypertension, hypokalaemia, osteoporosis, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.

Specific dosage guidelines The following recommendations for some corticosteroid-responsive disorders are for guidance only. Acute or severe disease may require initial high dose therapy with reduction to the lowest effective maintenance dose as soon as possible. Dosage reductions should not exceed 5-7.5mg daily during chronic treatment.

- Allergic and skin disorders Initial doses of 5-15mg daily are commonly adequate.

- Collagenosis Initial doses of 20-30mg daily are frequently effective. Those with more severe symptoms may require higher doses.

- Rheumatoid arthritis The usual initial dose is 10-15mg daily. The lowest daily maintenance dose compatible with tolerable symptomatic relief is recommended.

- Blood disorders and lymphoma An initial daily dose of 15-60mg is often necessary with reduction after an adequate clinical or haematological response. Higher doses may be necessary to induce remission in acute leukaemia.

OVERDOSAGE:

In the event of an overdosage, supportive and symptomatic therapy is indicated.

Serum electrolytes should be monitored.