Prednisolone 1mg Tablets

Prednisolone 5mg Tablets

Prednisolone 1.0mg

Prednisolone 5.0mg

Excipients: Lactose.

For a full list of excipients, see section 6.1.

Tablet

White circular, flat faced tablets with break line and PL1 on one face and CP on the reverse.

White circular, flat faced tablets with break line and PL5 on one face and CP on the reverse.

Suppression of inflammatory and allergic disorders

Route of administration - Oral

Adults including the elderly

The lowest effective dose should be used for the minimum period in order to minimise side effects (see 4.4 Special Warnings and Precautions for use).

Initially:

5mg to 60mg daily in divided doses, as a single dose in the morning after breakfast, or as a double dose on alternate days. They should be taken with or after food. The dose can often be reduced within a few days but may need to be continued for several weeks or months.

Maintenance:

2.5 to 15mg daily, but higher doses may be needed. Cushingoid side-effects more likely above 7.5mg daily.

Children

Prednisolone should be used only when specifically indicated, in a minimal dosage and for the shortest possible time (see other special warnings and precautions)

Systemic infection unless specific anti-infective therapy is employed. Hypersensitivity to any ingredient.

A patient information leaflet should be supplied with this product.

Undesirable effects may be minimised by using the lowest effective dose for the minimum period, and by administering the daily requirement as a single morning dose or whenever possible as a single morning dose on alternate days. Frequent patient review is required to appropriately titrate the dose against disease activity (see dosage section)

Adrenal suppression.

Adrenal cortical atrophy develops during prolonged therapy and may persist for years after stopping treatment. Withdrawal of corticosteroids after prolonged therapy must therefore always be gradual to avoid acute adrenal insufficiency, being tapered off over weeks or months according to the dose and duration of treatment.

In patients who have received more than physiological doses of systemic corticosteroids (approximately 7.5mg prednisolone or equivalent) for longer than three 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. Recommendations for initial reduction have varied from as little as steps of 1mg monthly to 2.5mg to 5mg every three to seven days. Adrenal function should be monitored throughout. 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 hypothalamic-pituitary-adrenal (HPA) suppression, the dose of systemic corticosteroid may be reduced rapidly to physiological doses. Once a daily dose equivalent to 7.5mg of prednisolone 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 three weeks is appropriate if it is considered that the disease is unlikely to relapse. Abrupt withdrawal of doses of up to 40mg daily of prednisolone, or equivalent, for three 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 three weeks or less:

• Patients who have had repeated courses of systemic corticosteroids, particularly if taken for longer than three 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 (or equivalent),

• Patients repeatedly taking doses in the evening.

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.

Anti-inflammatory/ immunosuppressive effects and infection.

Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity. The clinical presentation may often be atypical and serious infections such as septicaemia and tuberculosis may be masked and may reach an advanced stage before being recognised. The immunosuppressive effects of corticosteroids, including prednisolone, may result in the activation or exacerbation of strongyloidiasis or fungal infection, or the activation of latent infection, or exacerbation of intercurrent infection involving other pathogens such as pneumocystis carinii. During prolonged therapy any intercurrent illness, trauma or surgical procedures will require a temporary increase in dosage, if corticosteroids have been stopped following prolonged therapy they may need to be temporarily re-introduced.

Chickenpox is of particular 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 immunisation with varicella zoster immunoglobulin (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.

Patients taking corticosteroids should be advised to take particular care to avoid exposure to measles and to seek immediate medical advice if exposure occurs.

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

Particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary.

a) osteoporosis (post menopausal females are particularly at risk)

b) hypertension or congestive heart failure

c) diabetes mellitus (or a family history of diabetes)

d) history of, or active tuberculosis

e) glaucoma (or a family history of glaucoma)

f) previous corticosteroid-induced myopathy

g) liver failure

h) renal insufficiency

i) epilepsy

j) peptic ulceration

k) hypothyroidism

l) recent myocardial infarction

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 the treatment. Risks may be higher with high doses/systemic exposure (see also section 4.5 pharmacokinetic interactions 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 also be alert to possible psychiatric disturbances that may occur either during or immediately after dose tampering/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 dose-related growth retardation in infancy, childhood and adolescence, which may be irreversible.

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.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Hepatic microsomal enzyme inducers: Rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone and aminoglutethimide enhance the metabolism of prednisolone and its therapeutic effects may be reduced.

Anticoagulants: The efficacy of coumarin anticoagulants may be enhanced or reduced by concomitant corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.

Non-steroidal anti-inflammatory drugs (NSAIDs): There is an increased risk of gastro-intestinal bleeding and ulceration when corticosteroids are used concomitantly with NSAIDs, including aspirin. The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication.

Hormones: Oestrogens may enhance the effects of corticosteroids and dosage adjustments may be required in some cases.

Prednisolone can inhibit the growth stimulating effect of somatropin.

Antibacterials: Corticosteroids can lower plasma concentrations of isoniazid and enhance its renal clearance.

Antifungals: Concomitant use with ketoconazole may inhibit the metabolism of prednisolone and enhance its adrenal suppressive effects. There is the potential for an increased risk of hypokalaemia when corticosteroids are used concomitantly with amphotericin.

Antineoplastics and immunosuppressants: Mutual inhibition of metabolism may occur between ciclosporin and prednisolone, and may increase the plasma concentration of either drug.

Antivirals: Plasma concentrations of prednisolone may be increased with antiviral drugs such as ritonavir and indinavir.

Vaccines: Concomitant use of high dose corticosteroids and live vaccines should be avoided. Corticosteroids may impair the immune response to other vaccines.

Neuromuscular blockers: Neuromuscular blocking effects may be antagonised by prednisolone in patients with adrenocortical insufficiency.

Cardiac glycosides: There is the potential for an increased risk of digitalis toxicity associated with hypokalaemia, when corticosteroids and cardiac glycosides are used concomitantly.

Sympathomimetics: There is an increased risk of hypokalaemia if high doses of corticosteroids are given with high doses of bambuterol, fenoterol, formoterol, reproterol, ritodrine, salbutamol, salmeterol, terbutaline and tulobuterol.

Thalidomide: The dosage of prednisolone needs to be reduced considerably when used with thalidomide. It has been suggested that prednisolone should not be given with thalidomide.

Intra-uterine devices (IUDs) –There is the potential for contraceptive failure in women using intra-uterine devices and receiving corticosteroid therapy.

Other: The desired effects of hypoglycaemic agents (including insulin), antihypertensives and diuretics are antagonised by corticosteroids and the hypokalaemic effects of acetazolamide loop diuretics, and thiazide diuretics are enhanced. The effect of corticosteroids may be reduced for 3 to 4 days after the use of mifepristone. There is the potential for an increased risk of hypokalaemia when corticosteroids and theophylline are used concomitantly.

Pregnancy

The ability of corticosteroids to cross the placenta varies between individual drugs, however, 88% of prednisolone is inactivated as it crosses the placenta.

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal 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/lip in man. However, when administered for prolonged periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. The use of corticosteroids, including prednisolone, during pregnancy may also result in stillbirth. 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. Patients with pre-eclampsia or fluid retention require dose 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 receiving 40mg or more daily should be monitored for signs of adrenal suppression but the benefits of breast- feeding are likely to outweigh any theoretical risk.

None

The incidence of predictable undesirable effects, including hypothalamic-pituitary-adrenal suppression correlates with the relative potency of the drug, dosage, timing of administration and the duration of treatment (see 4.4 Special Warnings and Precautions for use)

Endocrine/metabolic - suppression of the hypothalamic-pituitary-adrenal axis, growth suppression in infancy, childhood and adolescence, menstrual irregularity and amenorrhoea. Hirsutism, weight gain, impaired carbohydrate tolerance, hyperglycaemia, precipitation of diabetes mellitus or increased requirement for anti-diabetic therapy in pre-existing diabetes. Negative nitrogen and calcium balance. Increased appetite. Hypercholesterolaemia and hypertriglyceridaemia. High doses or prolonged administration of corticosteroids may cause Cushing's syndrome.

Anti-inflammatory and immunosuppressive effects - increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis (see other special warnings and precautions).

Musculoskeletal - osteoporosis, vertebral and long bone fractures, tendon rupture. Proximal myopathy, muscular weakness, musclular atrophy and buffalo hump. Avascular osteonecrosis has been associated with long term or high dose corticosteroid therapy.

Fluid and electrolyte disturbance - sodium and water retention, potassium loss, hypokalaemic alkalosis, oedema.

Blood and lymphatic system disorders-corticosteroids have the potential to increase the coagulability of blood.

Vascular disorders - hypertension.

Neuropsychiatric - 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. Reactions are common and may occur in both adults and children. In adults, the frequency of severe reactions has been estimated to be 5 – 6 %. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown. Psychological dependence, depression, insomnia, psychosis, delirium, and nervousness and/or restlessness have also been reported.

Increased intra-cranial pressure with papilloedema in children (pseudotumour cerebri), usually after treatment withdrawal. Aggravation of epilepsy.

Ophthalmic - increased intra-ocular pressure, glaucoma, papilloedema, posterior subcapsular cataracts, corneal or scleral thinning, serious retinal detachment, exacerbation of ophthalmic viral of fungal diseases and sudden blindness. Potential for exophthalmos to occur with long-term administration of corticosteroids.

Gastrointestinal - dyspepsia, peptic ulceration with perforation and haemorrhage, acute pancreatitis, candidiasis, hiccups and nausea.

Dermatological - impaired healing, skin atrophy, bruising, telangiectasia, striae, acne, skin thinning, flushing, hyperhidrosis.

General - hypersensitivity including anaphylaxis, has been reported. Leucocytosis. Thromboembolism, myocardial rupture following recent myocardial infarction, increased risk of Stevens-Johnson syndrome or toxic epidermal necrolysis, tumour lysis syndrome.

Withdrawal symptoms and signs - too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death (see Special Warnings and Precautions for Use). A 'withdrawal syndrome' may also occur including, fever, myalgia, weakness, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules, loss of weight, mental changes, emotional changes, nausea, vomiting, hypotension, benign intracranial hypertension, dizziness, headache, and reappearance of disease symptoms.

Treatment is unlikely to be needed; serum electrolytes should be monitored.

The major therapeutic use of prednisolone is based on the anti-inflammatory and immunosuppressive activities of glucocorticoids. The suppression of inflammatory response is independent of the initiating stimulus and the action is mainly local. Some important components of the mechanism underlying the anti-inflammatory effects of corticosteroids are:

(i) inhibition of the adherence of neutrophils and monocyte-macrophages to the capillary endothelial cells of the inflamed area,

(ii) blocking of the effect of macrophage migration inhibitory factor,

(iii) decreased activation of plasminogen to plasmin, and

(iv) inhibition of phospholipase A₂ activity thereby lowering the formation of prostaglandins, leukotrienes and related compounds.

This suppression of inflammatory response by corticoids may also be a key feature of the way they counteract complications that arise from cell-mediated immune reactions. An acute effect of such steroids is sequestration of lymphocytes from blood although lysis of tissues also occurs, e.g. in lymphatic malignancies. At therapeutic dose levels corticoids do not seem to have any significant effect on circulating antibodies or on the metabolism of complement.

The two major targets of glucocorticoids, such as prednisolone, would be the liver (induction of enzymes, e.g. those involved in gluconeogenesis and amino acid degradation) and the lymphatic system (growth inhibitory actions which ultimately may result in cell death). The central feature of these hormonal actions is the combination of the steroid with an intracellular receptor, producing conformational changes that expose the DNA-binding domain on the receptor. The binding of the steroid receptor complex to specific sequences, known as hormone response elements, brings about transcriptional activation or repression of specific genes.

Prednisolone is readily absorbed from the gastrointestinal tract and already exists in a metabolically active form.

Peak plasma concentrations of prednisolone are obtained one or two hours after administration by mouth, and it has a usual plasma half-life of two to four hours. Its initial absorption, but not its overall bioavailability, is affected by food.

Prednisolone is extensively bound to plasma proteins, although less so than hydrocortisone (cortisol).

Prednisolone is excreted in the urine as free and conjugated metabolites, together with an appreciable proportion of unchanged prednisolone. Prednisolone crosses the placenta and small amounts are excreted in breast milk.

Prednisolone has a biological half-life lasting several hours, intermediate between those of hydrocortisone (cortisol) and the longer acting glucocorticoids, such as dexamethasone. It is this intermediate duration of action that makes it suitable for the alternate day administration regimens that have been found to reduce the risk of adrenocortical insufficiency, yet provide adequate corticosteroid coverage in some disorders.

Teratogenic effects of glucocorticoids have not been demonstrated in the human. Although malignancies are known to arise in patients undergoing immunosuppression with corticosteroids, any role of these compounds in the induction of tumours remain uncertain. The classic toxic effects of prednisolone like drugs are given under adverse reactions.

Lactose

Maize starch

Stearic acid

Purified talc

Magnesium stearate

None

Three years

Do not store above 25^oC

50 tablets in amber glass bottles or 100, 500 and 1000 tablets in polypropylene or polyethylene containers.

28 or 56 tablets in blister pack strips of 250 micron white rigid PVC and 20 micron hard tempered aluminium foil coated with PVC compatible heat seal lacquer on the reverse side.

28 or 56 tablets in polypropylene or polyethylene containers in cartons.

Not applicable.

Wockhardt UK Ltd

Ash Road North

Wrexham Industrial Estate

Wrexham LL13 9UF

United Kingdom

Prednisolone 1mg Tablets - PL 29831/0177

Prednisolone 5mg Tablets – PL 29831/0178

20/06/2007

05/03/2008