Hydrocortisone 10 mg Tablets

Each tablet contains 10 mg hydrocortisone.

Excipient with known effect:

Each tablet contains 76 mg Lactose monohydrate.For the full list of excipients, see section 6.1.

Tablets

White, round, flat tablet with a breakline on one side and 'H' imprinted on other side.

The tablet can be divided into equal doses.

Corticosteroid

o As replacement therapy in congenital adrenal hyperplasia in children.

o For the emergency treatment of severe bronchial asthma, drug hypersensitivity reactions, serum sickness, angioneurotic oedema and anaphylaxis in adults and children.

Posology

Dosage must be individualised according to the response of the individual patient. The lowest possible dosage should be used.

Patients should be observed closely for signs that might require dosage adjustment, including changes in clinical status resulting from remissions or exacerbations of the disease, individual drug responsiveness and the effect of stress (e.g. surgery, infection, trauma). During stress it may be necessary to increase the dosage temporarily.

To avoid hypoadrenalism and/or a relapse of the underlying disease, it may be necessary to withdraw the drug gradually (see 4.4 'Special warnings and precautions for use').

Replacement therapy in congenital hyperplasia

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.

Acute emergencies

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.

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.

Pre-operative use

Anaesthetists must be informed if the patient is taking corticosteroids or has previously taken corticosteroids.

Method of Administration

For oral administration.

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

- Systemic fungal infections

- patients with systemic infections (unless specific anti-infective therapy is employed) and

- patients vaccinated with live vaccines.

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.

The lowest possible dosage of corticosteroids should be used and when reduction in dosage is possible, the reduction should be gradual.

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, 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 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.

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.

Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control life-threatening drug reactions due to amphotericin. Moreover, there have been cases reported in which concomitant use of amphotericin and hydrocortisone was followed by cardiac enlargement and congestive failure.

Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.

Patients with concomitant adrenal insufficiency and retroviral infection, such as HIV, need careful dose adjustment due to potential interaction with antiretroviral medicinal products and increased hydrocortisone dose due to the infection.

High (supra-physiological) dosages of hydrocortisone can cause elevation of blood pressure, salt and water retention and increase excretion of potassium. Long-term treatment with higher than physiological hydrocortisone doses can lead to clinical features resembling Cushing´s syndrome with increased adiposity, abdominal obesity, hypertension and diabetes and thus result in an increased risk of cardiovascular morbidity and mortality. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.

A report shows that the use of corticosteroids in cerebral malaria is associated with a prolonged coma and an increased incidence of pneumonia and gastro-intestinal bleeding.

If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, with previous history of tuberculosis or characteristic appearance on a chest x-ray, close observation is necessary as reactivation may occur. During prolonged corticosteroid therapy, these patients should receive prophylactic chemotherapy to prevent emergence of active tuberculosis.

The use of Hydrocortisone Tablets in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis.

Corticosteroids should be used with caution in renal insufficiency, hypertension, liver failure, diabetes or in those with a family history of diabetes, congestive heart failure, thrombophlebitis, exanthematous disease, chronic nephritis, acute glomerulonephritis, metastatic carcinoma, osteoporosis(postmenopausal patients are at special risk), severe affective disorders (particularly if there is a history of steroid-induced psychosis), epilepsy, previous steroid myopathy, glaucoma (or family history of glaucoma), myasthenia gravis, non-specific ulcerative colitis, diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer. Signs of peritoneal irritation following gastro-intestinal perforation in patients receiving large doses of corticosteroids may be minimal or absent.

Fat embolism has been reported as a possible complication of hypercortisonism.

There is an enhanced effect of corticosteroids in patients with hypothyroidism and in those with cirrhosis.

Prolonged courses of corticosteroids increase susceptibility to infections and their severity. The clinical presentation of infections may also be atypical.

Corticosteroids may mask some signs of infection and new infections may appear during their use. Some serious infection such as septicaemia and tuberculosis may reach an advanced stage before being recognised. There may be decreased resistance and inability to localise infection in patients on corticosteroids. Corticosteroids may affect the nitroblue tetrazolium test for bacterial infection and produce false negative results.

Corticosteroids may activate latent amoebiasis or strongyloidiasis or exacerbate active disease. Therefore, it is recommended that latent or active amoebiasis and strongyloidiasis be excluded before initiating corticosteroid therapy in any patient at risk of or with symptoms suggestive of either condition.

Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.

Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation.

Corticosteroids may increase or decrease motility and number of spermatozoa.

Diabetes may be aggravated, necessitating a higher insulin dosage. Latent diabetes mellitus may be precipitated.

Menstrual irregularities may occur, and this possibility should be mentioned to female patients.

Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroids, especially when a patient has a history of drug allergies.

Aspirin should be used cautiously in conjunction with corticosteroids in patients with hypoprothrombinaemia.

Withdrawal: Adrenal cortical atrophy develops during prolonged therapy and may persist for years after stopping treatment. Drug-induced secondary adrenocortical insufficiency may result from too rapid a withdrawal of corticosteroids and may be minimised by gradual reduction of dosage over weeks or months according to the dose and duration of treatment. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, corticosteroid therapy should be reinstated. If the patient is receiving steroids already, the dosage may have to be increased. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently (see 4.5 'Interactions with other medicinal products and other forms of interaction').

During transient illnesses such as low grade infection, fever of any aetiology, stressful situations such as minor surgical procedures, the daily replacement dose must be increased temporarily .The patient must be carefully informed how to act in these situations and also advised to immediately seek medical attention should an acute deterioration occur; especially in cases of gastroenteritis, vomiting and/or diarrhoea leading to fluid and salt loss, as well as to inadequate absorption of oral hydrocortisone.

Stopping corticosteroid, after prolonged therapy may cause withdrawal symptoms, including fever, myalgia, arthralgia and malaise. In patients who have received more than physiological doses of systemic corticosteroids (approximately 30mg hydrocortisone) for greater 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. 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 of 30mg hydrocortisone 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 160mg hydrocortisone 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 greater 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 160mg hydrocortisone,

• Patients repeatedly taking doses in the evening.

Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy; discontinuance of such therapy may result in remission of the disease

Patients with adrenal insufficiency should be monitored for thyroid dysfunction as both hypothyroidism and hyperthyroidism may markedly influence the exposure of administered hydrocortisone.

Live vaccines should not be given to individuals with impaired immune responsiveness caused by high doses of corticosteroids. The response to vaccines may be reduced and there is a risk of generalized infection with live vaccines. Killed vaccines or toxoids may be given though their effects may be attenuated.

Hypertrophic cardiomyopathy was reported after administration of hydrocortisone to prematurely born infants, therefore appropriate diagnostic evaluation and monitoring of cardiac function and structure should be performed.

Paediatric population

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 in order to minimise suppression of the hypothalamo-pituitary-adrenal axis and growth retardation (see section 4.2).

Growth and development of infants and children on prolonged corticosteroid therapy should be carefully monitored.

Excipient

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

Hydrocortisone 10 mg Tablets contains less than 1 mmol (23 mg) of sodium per tablet, that is to say essentially `sodium-free´.

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.

Drug interactions listed below have been reported in pharmacological doses of corticosteroids and may not occur at replacement therapy doses of corticosteroids.

Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinaemia. There is an increased risk of gastro-intestinal bleeding and ulceration when corticosteroids are given with aspirin and NSAIDs. Corticosteroids reduce plasma concentrations of salicylate and such an interaction may occur with pharmacological doses of glucocorticoids. Serum levels of salicylates, such as aspirin and benorilate, may increase considerably if corticosteroid therapy is withdrawn, possibly causing intoxication.

Phenytoin, ephedrine, rifabutin, carbamazepine, barbiturates, rifampicin, primidone, sympathomimetics, St. John's Wort and aminoglutethimide may enhance the metabolic clearance of corticosteroids, resulting in decreased blood levels and lessened physiological activity, thus requiring adjustment in corticosteroid dosage.

The prothrombin time should be checked frequently in patients who are receiving corticosteroids and coumarin anticoagulants at the same time because of reports of altered response to these anticoagulants. Studies have shown that the usual effect produced by adding corticosteroids is inhibition of response to coumarins, although there have been some conflicting reports of potentiation not substantiated by studies.

Ketoconazole alone can inhibit adrenal corticosteroid synthesis and may cause adrenal insufficiency during corticosteroid withdrawal (see 4.4 'Special warnings and precautions for use'). Potent CYP 3A4 inhibitors such as itraconazole, posaconazole, voriconazole, telithromycin, clarithromycin, and grapefruit juice can inhibit the metabolism of hydrocortisone, and thus increase blood levels. During long-term prophylactic treatment with any of the antibiotics, adjustment of the hydrocortisone dosage should be considered.

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 effects.

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

Corticosteroids antagonise the effects of diuretics. Glucocorticosteroids are necessary for free water clearance by the kidneys. When corticosteroids are administered concomitantly with potassium-depleting diuretics (e.g. acetazolamide, loop diuretics, thiazides), patients should be observed closely for development of hypokalaemia.

Moreover, corticosteroids may affect the nitroblue tetrazolium test for bacterial infection and produce false negative results.

Corticosteroids antagonise the hypotensive effects of beta-blockers, alpha-blockers, calcium channel blockers, clonidine, diazoxide, methyldopa, moxonidine, nitrates or nitroprusside, hydralazine, minoxidil, vasodilator antihypertensives, adrenergic neurone blockers, ACE inhibitors and angiotensin II receptor antagonists.

Corticosteroids increase risk of hypokalaemia when given with cardiac glycosides, theophylline and beta₂ sympathomimetics.

There is an increased risk of hypokalaemia when corticosteroids are given with amphotericin. Concomitant use of amphotericin with corticosteroids should be avoided unless amphotericin is needed 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.

The effect of corticosteroids may be reduced for 3-4 days after interaction with mifepristone.

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. Interactions of combined oral contraceptives may also apply to combined contraceptive patches.

Ritonavir may increase the plasma concentration of hydrocortisone. Efavirenz, and nevirapine may reduce the plasma concentration of hydrocortisone.

Corticosteroids reduce absorption of calcium salts.

Erythromycin possibly inhibits metabolism of corticosteroids.

Corticosteroids antagonise hypoglycaemic effect of antidiabetics (including insulin).

There is an increased risk of haematological toxicity when corticosteroids are given with methotrexate.

Corticosteroids may inhibit the growth promoting effect of somatropin.

High doses of corticosteroids impair immune response to vaccines; avoid concomitant use with live vaccines (see also section 4.4).

Corticosteroids possibly reduce the effects of sodium benzoate and sodium phenyl butyrate.

The clinical response needs to be monitored in patients given medicinal products affecting gastric emptying and motility.

Steroids may reduce the effects of anticholinesterases in myasthenia gravis and cholecystographic x-ray media.

Pregnancy

The ability of corticosteroids to cross the placenta varies between individual drugs; however, hydrocortisone readily 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.

Pregnant patients should be monitored closely if they develop fluid retention or pre-eclampsia.

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.

The dose of hydrocortisone should be carefully monitored during pregnancy in women with adrenal insufficiency. Dosing according to individual clinical response is recommended.

Breast-feeding

Corticosteroids are excreted in breast milk, although no data are available for hydrocortisone. Doses of up to 160 mg daily of hydrocortisone are unlikely to cause systemic effects in the infant. Infants of mothers taking high doses of systemic corticosteroids for prolonged periods may have a degree of adrenal suppression but the benefits of breast-feeding are likely to outweigh any theoretical risk.

Fertility

Patients with adrenal insufficiency have been shown to have reduced parity, which is most likely due to the underlying disease, but there is no indication that hydrocortisone in doses for replacement therapy will affect fertility.

Hydrocortisone has moderate influence on the ability to drive machines. It may cause vertigo, visual field loss and muscle wasting and weakness. If affected, patients should not drive or operate machinery (see section 4.8 'Undesirable effects').

Untreated and poorly replaced adrenal insufficiency may affect the ability to drive and use machines.

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).

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

Not known (cannot be estimated from the available data)

a) Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections and recurrence of dormant tuberculosis (see section 4.4).

b) 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.

Neoplasms benign, malignant and unspecified incl. cysts and polyps:

Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy.

Discontinuation of corticosteroids may result in clinical remission.

Paediatric population

Growth suppression in infancy, childhood and adolescence, increased intracranial pressure with papilloedema in children (pseudotumour cerebri), usually after treatment withdrawal.

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). A withdrawal syndrome may also occur including fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and weight loss.

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,

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms

Reports of acute toxicity and/or deaths following overdosage with glucocorticoids are rare. No antidote is available. Overdosage may cause nausea and vomiting, sodium and water retention, hyperglycaemia and occasional gastrointestinal bleeding.

Management

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.

Treatment is probably not indicated for reactions due to chronic poisoning unless the patient has a condition that would render him unusually susceptible to ill effects from corticosteroids. In this case, symptomatic treatment should be instituted as necessary.

Anaphylactic and hypersensitivity reactions may be treated with adrenaline, positive-pressure artificial respiration and aminophylline. The patient should be kept warm and quiet.

The biological half-life of hydrocortisone is about 100 minutes.

Pharmcotherapeutic group: Glucocorticoids

ATC code: H02AB

Glucocorticoids are adrenocortical steroids, both naturally-occurring and synthetic, which are readily absorbed from the gastro-intestinal tract.

Hydrocortisone is believed to be the principal corticosteroid secreted by the adrenal cortex. Naturally-occurring glucocorticosteroids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. They are also used for their potent anti-inflammatory effects in disorders of many organ systems. Glucocorticoids cause profound and varied metabolic effects. In addition they modify the body's immune responses to diverse stimuli.

Absorption

Hydrocortisone is readily absorbed from the gastro-intestinal tract and 90% or more of the drug is reversibly bound to protein.

Distribution

The binding is accounted for by two protein fractions. One, corticosteroid-binding globulin is a glycoprotein; the other is albumin.

Biotransformation

Hydrocortisone is metabolised in the liver and most body tissues to hydrogenated and degraded forms such as tetrahydrocortisone and tetrahydrocortisol which are excreted in the urine, mainly conjugated as glucuronides, together with a very small proportion of unchanged hydrocortisone. Hydrocortisone has a plasma half-life of about 100 minutes.

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.

Lactose monohydrate

Talcum

Potato starch

Gelatin

Sodium starch glycolate

Magnesium stearate

Not applicable

36 months

Do not store above 30° C. Keep the blister in the outer carton in order to protect from light.

PVC/PVdC aluminium blister containing 30 tablets.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Mibe Pharma UK Ltd

4 Coleman Street,

6th Floor,

London,

EC2R 5AR

UNITED KINGDOM

PL 49452/0002

14/04/2016

16/09/2020