PREDNISOLONE TABLETS BP 5 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Prednisolone Tablets BP 5 mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 5 mg of prednisolone (micronised).

Excipient with known effect:

Each film-coated tablet contains 60.0 mg lactose.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet.

Prednisolone tablets BP 5 mg are white, flat bevelled edge tablets engraved with the company Logo on one side and A077 with a break-line on the other side.

4 CLINICAL PARTICULARS

4.1 Therapeutic 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

Eg 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 dyscrasias e.g. selected cases of haemolytic anaemia, thrombocytopenic purpura.

Miscellaneous

Nephrotic syndrome.

4.2 Posology and method of administration

Posology

In general, the appropriate individual dose must be determined by trial and error and requires regular re-evaluation according to the activity of the disease. The initial dose should be maintained or adjusted until the anticipated response is observed and then gradually reduced until the lowest dose given for the shortest possible time, which will maintain an adequate clinical response is reached. To minimise pituitary-adrenal suppression, the daily requirement should be taken as a single dose in the morning or whenever possible as a single morning dose on alternative days (see other special warnings and precautions). Abrupt withdrawal after courses of up to 3 weeks has not resulted in adverse reactions for most asthma patients taking other appropriate treatment. During prolonged therapy, dosage may need increasing during exacerbations of the disease or during periods of stress. When long-term therapy is to be stopped, dosage should be reduced gradually over a period of weeks to months depending on the dosage and length of therapy. Abrupt withdrawal of prolonged, high dosage corticosteroids is associated with risk of potentially life-threatening adrenal insufficiency. Withdrawal symptoms include fever, myalgia and arthralgia.

Adults

The initial dose of prednisolone may vary from 5 mg to 60 mg daily, depending on the disorder being treated. Divided daily dosage is usually employed. In long-term therapy the maintenance dose should be kept as low as possible to minimise side effects. Treatment should be constantly reviewed. Alternate day dosing (double dose every second day) may also be effective and minimises the degree of pituitary-adrenal suppression.

Paediatric population

Fractions of the adult daily dose may be given – 25% at one year, 50% at seven years and 75% at twelve years – though dosage will usually be determined by clinical response, as in adults. As an initial dose, 0.75–1 mg/kg daily in divided doses may be given.

Treatment should be limited to the lowest effective dose for the shortest possible time. Corticosteroids cause dose-related growth retardation in infancy, childhood and adolescence which may be irreversible. In order to minimise pituitary-adrenal suppression and growth retardation, doses should, where possible, be given on alternate days.

Elderly

The dosage should be the minimum required to achieve the desired effect since corticosteroid side effects such as diabetes, osteoporosis, hypokalaemia, hypertension, thinning of the skin and susceptibility to infection have more serious consequences in the elderly. Close clinical supervision is required to avoid life-threatening reactions.

Method of administration

The daily dose should be taken in the morning after breakfast. For further information with reference to dosage see warnings and precautions section.

For oral use.

4.3 Contraindications

– Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

– Systemic infections unless specific anti-infective therapy is employed.

– Patients with ocular herpes simplex due to the possibility of perforation.

4.4 Special warnings and precautions for use

A Patient Information Leaflet should be supplied with this product. Patients should carry “steroid treatment” cards which give clear guidance on the precautions to be taken to minimise risk and provide details of prescriber, drug, dosage and duration of treatment.

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 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.

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.

Renal insufficiency.

Tuberculosis: Those with a history of, or X-ray changes characteristic of tuberculosis. The emergence of active tuberculosis can, however, be prevented by the prophylactic use of antituberculous therapy.

Recent myocardial infarction (rupture).

Chickenpox: 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 special care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.

Measles: Patients are advised to avoid exposure to measles, medical advice should be sought if exposure occurs.

Prophylaxis with intramuscular normal immunoglobulin may be needed.

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 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.

Scleroderma renal crisis – Caution is required in patients with systemic sclerosis because of an increased incidence of (possibly fatal) scleroderma renal crisis with hypertension and decreased urinary output observed with a daily dose of 15 mg or more prednisolone. Blood pressure and renal function (s-creatinine) should therefore be routinely checked. When renal crisis is suspected, blood pressure should be carefully controlled.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Withdrawal

In patients who have received more than physiological doses of systemic corticosteroids (approximately 7.5 mg prednisolone or equivalent) 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 equivalent to 7.5 mg of prednisolone is reached, dose reduction should be slower to allow HPA-axis to recover.

Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks is appropriate if it is considered that the disease is unlikely to relapse. Abrupt withdrawal of doses of up to 40 mg daily of prednisolone, or equivalent 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 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 40 mg daily of prednisolone (or equivalent),

Patients repeatedly taking the 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.

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

4.5 Interaction with other medicinal products and other forms of interaction

Antacids can reduce the absorption 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 possibility of GI ulceration should be considered with concomitant use with any other NSAIDs.

Aspirin (acetylsalicylic acid) should be used cautiously in conjunction with glucocorticoids in patients with hypoprothrombi­naemia. Concurrent use of aspirin (acetylsalicylic acid) and prednisolone may result in an increased risk of gastrointestinal ulceration and subtherapeutic aspirin (acetylsalicylic acid) 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: The effects of corticosteroids may be reduced for 3–4 days after taking mifepristone.

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.

Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.

4.6 Fertility, pregnancy and lactation

Pregnancy

The ability of corticosteroids to cross 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 affects 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. 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 close monitoring.

Breast-feeding

Corticosteroids are excreted in small amounts in breast milk. However, doses of up to 40 mg 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 outweigh any theoretical risk. Monitoring of the infant for adrenal suppression is advised.

4.7 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.

4.8 Undesirable effects

The incidence of predictable undesirable side-effects, including hypothalamic -pituitary – adrenal suppression correlate with the relative potency of the drug, dosage, timing of administration and duration of treatment. 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 alternative days. Frequent patient review is required to appropriately titrate the dose against disease activity.

The following side effects have been observed and the frequencies are defined as follows: Very common (>1/10); Common (>1/100 to <1/10); Uncommon (>1/1,000 to <1/100); Rare (>1/10,000 to <1/1,000); Very rare (<1/10,000), Not known (cannot be estimated from the available data).

Immune system disorders: 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”.

Endocrine disorders: Cushingoid facies, growth suppression in infancy, childhood and adolescence, hirsutism, impaired carbohydrate tolerance with increased requirement for antidiabetic therapy, menstrual irregularity and amenorrhoea, negative protein and calcium balance, suppression of the hypothalamo-pituitary adrenal axis, and weight gain. Although the frequency is not known, there is a risk for Cushing Syndrome.

Metabolism and nutrition disorders: Hypertension, nocturia, hypokalaemic alkalosis, potassium loss, sodium and water retention, risk of congestive heart failure in susceptible patients.

Psychiatric Disorders: 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.

Intracranial pressure with papilloedema in children (pseudotumour cerebri) usually after treatment withdrawal, psychological dependence.

Eye disorders: Corneal or scleral thinning, scleral perforation, exacerbation of ophthalmic viral or fungal disease, glaucoma, increased intra-ocular pressure, papilloedema, posterior subcapsular cataracts, vision, blurred (frequency not known, see also section 4.4), central serous chorioretinopathy (frequency not known).

Cardiac disorders: Bradycardia* (frequency not known) Following high doses

Gastrointestinal disorders: Abdominal distension, acute pancreatitis, dyspepsia, nausea, increased appetite, oesophageal candidiasis, oesophageal ulceration, peptic ulceration with perforation and haemorrhage, perforation of the small bowel, particularly in patients with inflammatory bowel disease.

Skin and subcutaneous tissue disorders: Acne, bruising, impaired healing, skin atrophy, striae, telangiectasia.

Musculoskeletal and connective tissue disorders: A vascular osteonecrosis, osteoporosis, proximal myopathy, tendon rupture, vertebral and long bone fractures, muscle weakness, wasting and loss of muscle mass.

Renal and urinary disorders: Scleroderma renal crisis – Amongst the different subpopulations the occurrence of scleroderma renal crisis varies. The highest risk has been reported in patients with diffuse systemic sclerosis. The lowest risk has been reported in patients with limited systemic sclerosis (2%) and juvenile onset systemic sclerosis (1%) (Frequency ‘unknown’).

*see section c)

General disorders and administration site conditions: Hypersensitivity including anaphylaxis, leucocytosis, malaise, thromboembolism.

Withdrawal symptoms:

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, arthralgia, conjunctivitis, fever, loss of weight, myalgia, painful itchy skin nodules and rhinitis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

In the event of overdose, no specific antidote is available. Treatment is supportive and symptomatic.

Serum electrolytes should be monitored.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Corticosteroids for systemic use, plain, ATC Code: H02A B06.

Prednisolone is one of the highly potent glucocorticoid steroids having antiinflammatory, 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.

5.2 Pharmacokinetic properties

Absorption

Prednisolone is normally rapidly and almost completely absorbed from the GI tract after oral administration.

Distribution

Peak effects are achieved within 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.

Biotransformation

Prednisolone is mainly metabolised in the liver and has a usual plasma half-life of 2–3 hours. It has a biological half-life lasting several hours which makes it suitable for the alternate-day administration regimens which have been found to reduce the risk of adrenocortical insufficiency, yet provide adequate corticosteroid coverage in some disorders.

Its initial absorption, but not its overall bioavailability, is affected by food, hepatic or renal impairment and certain drugs.

Elimination

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

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Maize starch

Lactose

Pregelatinised maize starch

Magnesium stearate

Potable water

6.2 Incompatibilities

None known.

6.3 Shelf life

As packaged for sale:

– 3 years for product packed in opaque plastic containers [see 6.5 (a, b)];

– 2 years for product packed in blister packs [see 6.5 ©].

6.4 Special precautions for storage

Store below 25°C.

Store in the original package in order to protect from light and moisture.

6.5 Nature and contents of container

(a) opaque plastic containers composed of polypropylene tubes and polyethylene made tamper-evident closures, in pack sizes of 20, 50, 100, 250, 500, 1000 and 2500.

(b) opaque plastic containers with child resistant/tamper evident caps, composed of polypropylene and/or polyethylene, in pack sizes of 28, 56 and 84.

© blister packs composed of 20 MU hard temper aluminium foil and 200 MU white opaque PVC in pack size of 28, 56 and 84.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Crescent Pharma Limited

Key House Sarum Hill Basingstoke RG21 8SR UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 20416/0408

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

Date of first authorisation: 11 June 2004

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