SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Cortistab Tablets 5mg

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 5 mg Cortisone Acetate Ph Eur.

3.    PHARMACEUTICAL FORM

A white, round biconvex tablet scored on one side.

4.    CLINICAL PARTICULARS

4.1    Therapeutic Indications

Cortistab Tablets are indicated in replacement therapy for such conditions as Addison’s disease, primary or secondary adrenal insufficiency or congenital adrenal hyperplasia.

4.2    Posology and Method of Administration

For oral administration.

In replacement therapy the normal daily dose is Adults: 12.5-37.5 mg in divided doses.

Children: 5-25 mg in divided doses.

Elderly: Steroids should be used cautiously in the elderly, since adverse effects are enhanced in old age.

In patients requiring replacement therapy, the daily doses should be given, where practicable, in two doses. The first dose in the morning should be larger than the second dose in the evening, thus simulating the normal diurnal rhythm of cortisol secretion.

After prolonged corticosteroid treatment, the function of the patient’s own adrenal cortices is often suppressed. To allow normal adrenal function to be restored, Cortistab dosage should be reduced gradually, e.g. by 5 to 12.5 mg every few days.

4.3 Contra-indications

Systemic fungal and viral infections, acute bacterial infections unless specific anti-infective therapy is given.

Cortistab Tablets are contra-indicated in patients with known hypersensitivity to any of the ingredients.

4.4 Special warnings and special precautions for use

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

During treatment, the patient should be observed for psychotic reactions, muscular weakness, eletrocardiographic changes, hypertension and untoward hormonal effects.

Cortico steroids may mask some signs of infection and new infections may appear during their use. There may be decreased resistance and inability to localise infection when corticosteroids are used.

Caution is necessary when prescribing corticosteroids in the following conditions:

a)    Previous history of tuberculosis or characteristic appearance on chest X-ray. The emergence of active tuberculosis can, however, be prevented by the prophylactic use of antituberculous therapy.

b)    Diabetes mellitus (or a family history of diabetes).

c)    Osteoporosis (post menopausal females are particularly at risk).

d)    Hypertension.

e)    History of severe affective disorders (especially previous history of steroid psychosis).

f)    Glaucoma (or a family history of glaucoma).

g)    Previous steroid myopathy

h)    Peptic ulceration.

i)    Epilepsy.

Use in children

Corticosteroids cause growth retardation in infancy, childhood and adolescence. Treatment should be limited to the minimum dosage for the shortest possible time, in order to minimise suppression of the hypothalamopituitary adrenal (HPA) axis and growth retardation. Treatment should be administered where possible as a single dose on alternate days.

Use in the elderly

Treatment of elderly patients, particularly if long-term, should be planned bearing in mind the more serious consequences of the common side effects of corticosteroids in old age, especially osteoporosis, diabetes, hypertension, susceptibility to infection and thinning of the skin.

Warning

Cortisone itself is inactive and must be converted in the liver toits active metabolite hydrocortisone. In some liver disorders therefore the bioavailability of Cortistab Tablets may be less reliable.

Patients/and or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids (see Section 4.8 Undesirable effects). 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 Interaction with other medicinal products and other forms of interaction), although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most adverse reactions resolve after either dose reduction or withdrawal of the medicine, 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 a 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.

4.5 Interaction with other medicinal products and other forms of interaction

Concurrent administration of barbiturates, Phenytoin, ephedrine or rifampicin may enhance the metabolism and reduce the effects of corticosteroids. Response to anticoagulants may be reduced and on some occasions, enhanced by corticosteroids. Administration of corticosteroids with potassium depleting diuretics such as thiazides or Furosemide, may cause excessive potassium loss.

Concurrent administration of corticosteroids with carbenoxolone or amphotericin increases the risk of hypokalaemia. Corticosteroids may antagonise the hypotensive effects of antihypertensives and hypoglycaemic effect of oral antidiabetics. Live vaccines should not be given to patients receiving high dose systemic corticosteroids therapy; killed vaccines or toxoids may be given although the response may be attenuated.

Serum levels of salicylates may increase considerably if corticosteroid therapy is withdrawn, possibly causing intoxication. Since both salicylates and corticosteroids are ulcerogenic, it is possible that there will be an increased rate of gastrointestinal ulceration.

There is some evidence that use of corticosteroids and methotrexate simultaneously may cause increased methotrexate toxicity and possibly death, although this combination of drugs has been used very successfully.

In patients treated with systemic corticosteroids, use of non-depolarising muscle relaxants can results in prolonged relaxation and acute myopathy. Risk factors for this include prolonged and high dose corticosteroids treatment, and prolonged paralysis (such as in an ITU setting).

Corticosteroids requirements may be reduced in patients taking estrogens (e.g. contraceptive products).

4.6 Pregnancy and Lactation

Pregnancy

The ability of corticosteroids to cross the placenta varies between individual drugs, however, cortisone readily 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 intrauterine growth retardation. Hypoadrenalism may, in theory, occur in the neonate following prenatal exposure to corticosteroids but is usually resolved 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 nongravid states.

Lactation

Corticosteroids are excreted in breast milk, although no data are available for cortisone. Doses of up to 200 mg daily of cortisone are unlikely to cause systemic effects in the infant. Infants of others 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.

No adverse effects known.

4.8 Undesirable effects

The following side effects may be associated with the long term systemic use of corticosteroids.

Gastrointestinal

Dyspepsia, peptic ulceration with perforation and haemorrhage, abdominal distension, oesophageal candidiasis, acute pancreatitis.

Musculoskeletal

Proximal myopathy, osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, tendon rupture.

Fluid and electrolyte disturbance

Sodium and water retention, hypertension, hypokalemic alkalosis.

Dermatological

Impaired healing, skin atrophy, bruising, striae, telangiectasia, acne, patechial haemorrhage, ecchymoses and erythema.

Endocrine/metabolic

Suppression of the hypothalamo-pituitary adrenal axis, growth suppression in childhood and adolescence, menstrual irregularity and amenorrhoea, cushingoid facies, hirsutism, weight gain, impaired carbohydrate tolerance and increase requirement for antidiabetics therapy, negative nitrogen balance.

Neuropsychiatric

Euphoria, psychological dependence, depression, insomnia. Intracranial hypertension in children, aggravation of schizophrenia.

Ophthalmic

Increased intra-ocular pressure, glaucoma, papilloedema, cataracts, posterior subcapsular cataracts, comeal or scleral thinning, exacerbation of ophthalmic viral disease.

General

Opportunistic infection, recurrence of dormant tuberculosis, leucocytosis, hypersensitivity, thromboembolism, increased appetite, nausea, malaise.

Withdrawal symptoms

Fever, myalgia, arthralgia, adrenal insufficiency.

Withdrawal

Withdrawal from glucocorticoid therapy, particularly if treatment has been longterm, may cause a variety of potentially serious symptoms. These effects, whilst only temporary, are due to drug-induced suppression of the HPA axis and may be avoided by very gradual withdrawal from corticosteroid therapy.

In patients who have received more than physiological doses of systemic corticosteroids (approximately 40 mg cortisone 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 corticosteroid may be reduced rapidly to physiological doses. Once a daily dose equivalent to 40 mg cortisone 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 3 weeks is appropriate if it is considered that the disease is unlikely to relapse. Abrupt withdrawal of doses of up to 200 mg daily of cortisone, or equivalent for 3 weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. In the flowing 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 200 mg daily of cortisone (or equivalent);

•    Patients repeatedly taking doses in the evening.

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 56%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown.

4.9 Overdose

Symptoms of overdosage include nausea, vomiting, sodium and water retention, hypoglycaemia and occasional gastrointestinal bleeding. Treatment is largely symptomatic, but gastrointestinal bleeding may be prevented by administration of Cimetidine 200-400 mg 6-hourly intravenously or Ranitidine 50 mg 6-hourly intravenously.

5.    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Cortisone acetate is an adrenal corticosteroid having glucocorticoid and some mineralocoticoid properties.

5.2    Pharmacokinetic properties

Cortisone acetate is readily absorbed from the gastrointestinal tract and the cortisone is rapidly converted in the liver to the active metabolite hydrocortisone. The biological half life of cortisone is only about 30 minutes.

5.3    Preclinical safety data

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

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose, maize starch, calcium stearate.

6.2    Incompatibilities

Not applicable

6.3    Shelf life

36 months.

6.4    Special precautions for storage

Store in a cool, dry place. Protect from light.

6.5    Nature and contents of container

An amber glass bottle having a tin-plate screw cap with waxed aluminiumfaced pulpboard liner. Each bottle contains 100 tablets.

6.6    Instructions for use, handling and disposal

None.

7    MARKETING AUTHORISATION HOLDER

Waymade plc

Trading as Sovereign Medical Sovereign House Miles Gray Road,

Basildon Essex SS14 3FR

8.    MARKETING AUTHORISATION NUMBER

PL 06464/0711

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 03/03/2011

10 DATE OF REVISION OF THE TEXT

03/03/2011