SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Hydrocortistab Tablets Hydrocortisone 20 mg Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each Hydrocortisone 20 mg Tablet contains 20 mg    Hydrocortisone EP.

3    PHARMACEUTICAL FORM

A white, round, biconvex tablet scored on one side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Hydrocortisone Tablets are indicated for replacement therapy in primary and secondary adrenal insufficiency, Addison’s disease and congenital adrenal hyperplasia.

Hydrocortisone Tablets are also used for the emergency treatment of severe bronchial asthma, drug hypersensitivity reactions, serum sickness, angioneurotic oedema and anaphylaxis.

4.2.    Posology and method of administration

For oral administration.

Replacement therapy

Adults: 20-30 mg in divided doses is the normal daily requirement.

Children: 10-30 mg in divided doses is the normal daily requirement (see also section 4.4, Special Warnings and Precautions for Use).

In patients requiring replacement therapy, the daily dose should be given when 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.

60-80 mg every 4-6 hours for 24 hours then gradually reduce the dose over several days. Steroids should be used cautiously in the elderly, since adverse effects are enhanced in old age (see section 4.4, Special Warnings and Precautions for Use).

When long term treatment is to be discontinued, the dose should be gradually reduced over a period of weeks or months, depending on dosage and duration of therapy (see section 4.4, Special Warnings and Precautions for Use).

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 titrate the dose against disease activity.

4.3 Contraindications

Hydrocortisone Tablets are contraindicated in patients with known hypersensitivity to any of the ingredients. They are also contraindicated in patients with systemic infections (unless specific anti-infective therapy is employed) and in patients vaccinated with live vaccines.

4.4. Special warnings and precautions for use

A patient information leaflet should be supplied with this product.

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. 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 re-introduced.

Patients should carry ‘Steroid Treatment’ cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of the prescriber, drug, dosage and the duration of treatment.

Anti-inflammatory / immunosuppressive effects and infection

Suppression of inflammatory response and immune function increases the susceptibility to infections and their severity. The clinical presentation can often be atypical and serious infections such as septicaemia and tuberculosis may be masked and may reach an advanced stage before being recognised. New infections may appear during their use.

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 the previous 3 months; should this be confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.

Patients should be advised to take particular care to avoid exposure to measles and to seek immediate medical advice if exposure occurs. Prophylaxis with intramuscular normal immunoglobulin may be needed.

Live vaccines should not be given to individuals with impaired immune responsiveness caused by high doses of corticosteroids. Killed vaccines or toxoids may be given though their effects may be attenuated.

Particular care is required when prescribing systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary:

a)    Osteoporosis (postmenopausal females are particularly at risk)

b)    Hypertension or congestive heart failure.

c)    Existing or previous history of severe affective disorders (especially previous history of steroid psychosis).

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

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

f)    Glaucoma (or family history or glaucoma).

g)    Previous corticosteroid-induced myopathy.

h)    Liver failure.

i)    Renal insufficiency.

j)    Epilepsy.

k)    Peptic ulceration.

l)    Recent myocardial infarction

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

Corticosteroids should be used with caution in patients with hypothyroidism. Use in children:

Corticosteroids cause growth retardation in infancy, childhood and adolescence; this may be irreversible. Treatment should be limited to the minimum dosage for the shortest possible time, retardation (see section 4.2, Posology and Method of Administration).

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 (see section 4.2, Posology and Method of Administration).

Withdrawal symptoms:

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 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 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 HPS-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 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.

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. Interactions with other medicinal products and other forms of interaction

The metabolism of corticosteroids may be enhanced and the therapeutic effects reduced by certain barbiturates (e.g. phenobarbitone) and by phenytoin, rifampicin, rifabutin, primidone, carbamazepine and aminoglutethimide.

Mifepristone may reduce the effect of corticosteroids for 3-4 days.

Erythromycin and ketoconazole may inhibit the metabolism of corticosteroids.

Ritonavir may increase the plasma concentration of hydrocortisone.

Oestrogens and other oral contraceptives increase the plasma concentration of corticosteroids, and dosage adjustments may be required if oral contraceptives are added to or withdrawn from a stable dosage regimen.

The growth promoting effect of somatropin may be inhibited by the concomitant use of corticosteroids.

The desired actions of hypoglycaemic drugs (including insulin), antihypertensives and diuretics will be antagonised by corticosteroids.

The effectiveness of coumarin anticoagulants may be affected by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.

Serum levels of salicylates such as aspirin and benorilate, may increase considerably if corticosteroid therapy is withdrawn, possibly causing intoxication. Concomitant use of salicylates or of non-steroidal antiinflammatory drugs (NSAIDs) with corticosteroids increases the risk of gastrointestinal bleeding and ulceration.

The potassium-depleting effects of acetazolamide, thiazide diuretics and carbenxolone are enhanced by corticosteroids and signs of hypokalaemia

should be looked for during their concurrent use. The risk of hypokalaemia is increased with theophylline and amphotericin. Corticosteroids should not be given concomitantly with amphotericin, unless required to control reactions.

The risk of hypokalaemia also increases if high doses of corticosteroids are given with high doses of sympathomimetics e.g. bambuterol, fenoterol, formoterol, ritodrine, salbutamol, salmeterol and terbutaline. The toxicity of cardiac glycosides, e.g. digoxin, is increased if hypokalaemia occurs.

Concomitant use with methotrexate may increase the risk of haematological toxicity.

High doses of corticosteroids impair the immune response and so live vaccines should be avoided (see also section 4.4, Special Warnings and Precautions for Use).

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 intra-uterine growth retardation. Hypoadrenalism may, in theory, occur in the neonate following prenatal exposure to corticosteroids but it 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 non-gravid 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.

4.7. Effects on ability to drive and use machines

No adverse effects known.

4.8. Undesirable effects

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 section 4.4, Special Warnings and Precautions for Use).

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

Anti-inflammatory and immunosuppressive effects:

Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, and recurrence of dormant tuberculosis treatment (see section 4.4, Special Warnings and Precautions for Use).

Gastrointestinal:

Dyspepsia, peptic ulceration with perforation and haemorrhage, abnormal distension, oesophageal ulceration, 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, potassium loss, hypokalaemic alkalosis.

Dermatological:

Impaired healing, skin atrophy, bruising, striae, acne, telangiectasia.

Endocrine / metabolic:

Suppression of the hypothalamo-pituitary-adrenal axis, growth suppression in infancy, childhood and adolescence, menstrual irregularity and amenorrhoea. Cushingoid facies, hirsutism, weight gain, impaired carbohydrate tolerance with increased requirement for antidiabetic therapy, negative protein and calcium balance, and increased appetite.

Neuropsychiatric:

Euphoria, psychological dependence, depression, insomnia and aggravation of schizophrenia. Increased intracranial 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, exacerbation of ophthalmic viral or fungal diseases.

Cardiovascular:

Myocardial rupture following recent myocardial infarction.

General:

Hypersensitivity, including anaphylaxis has been reported. Nausea, malaise, leucocytosis, thromboembolism.

Withdrawal symptoms:

Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute renal insufficiency, hypotension and death (see section 4.4 Special warnings and precautions for use). A withdrawal syndrome may also occur including fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin modules and weight loss.

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.

4.9. Overdose

Overdosage may cause nausea and vomiting, sodium and water retention, hyperglycaemia and occasional gastrointestinal bleeding. Treatment need only be symptomatic although cimetidine (200-400 mg by slow intravenous injection every 6 hours) or ranitidine (50 mg by slow intravenous injection every 6 hours) may be administered to prevent gastrointestinal bleeding.

5 PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Hydrocortisone is an adrenal corticosteroid having glucocorticoid and some mineralocorticoid properties.

5.2. Pharmacokinetic properties

Hydrocortisone given by mouth is readily absorbed from the gastrointestinal tract. Hydrocortisone is extensively bound to plasma proteins and has a biological half-life of about 100 minutes. Hydrocortisone is metabolised in the liver and most body tissues to hydrogenated and degraded forms, such as tetrahydrocortisone and tetrahydrocortisol. These are excreted in the urine, mainly conjugated as glucuronides, together with a very small proportion of unchanged hydrocortisone.

5.3. Pre-clinical safety data

Not applicable.

6.1.    List of excipients

Lactose, pregelatinised starch and calcium stearate.

6.2.    Incompatibilities

None stated.

6.3. Shelf-life

36 months.

6.4. Special precautions for storage

Store in a cool dry place.

Nature and contents of container

6.6. Instructions for use, handling and disposal

None.

7    MARKETING AUTHORISATION HOLDER

Waymade Plc

t/a Sovereign Medical

Sovereign House,

Miles Gray Road,

Basildon,

Essex SS14 3FR.

8    MARKETING AUTHORISATION NUMBER(S)

PL 06464/0701.

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

13/01/2009

10 DATE OF REVISION OF THE TEXT

09/02/2015