4.1. Therapeutic indications

This presentation permits rapid use in emergency situations involving the following conditions:

Status asthmaticus and acute allergic reactions, including anaphylactic reaction to drugs. This medicine supplements the action of adrenaline.

Severe shock arising from surgical or accidental trauma or overwhelming infection.

Acute adrenal insufficiency caused by abnormal stress in Addison's disease, hypopituitarism, following adrenalectomy, and when adrenocortical function has been suppressed by prolonged corticosteroid therapy.

Soft tissue lesions such as tennis elbow, tenosynovitis, or bursitis.

Note: This medicine does not replace other forms of therapy for the treatment of shock and status asthmaticus.

4.2. Posology and method of administration

Posology

Undesirable effects may be minimised by using the lowest effective dose for the minimum period. Frequent patient review is required to titrate appropriately the dose against disease activity (see Section 4.4).

Systemic therapy in adults: 100 to 500mg hydrocortisone (1 to 5ml) administered by slow intravenous injection, taking at least half to one minute. This dose can be repeated three or four times in 24 hours, depending upon the condition being treated and the patient's response. Alternatively, This medicine may be given as an intravenous infusion. A clinical effect is seen in two to four hours, and it persists for up to eight hours after intravenous injection. The same dose can be given by intramuscular injection, but the response is likely to be less rapid, especially in shock.

Paediatric population: As a guide, infants up to 1 year may be given 25mg hydrocortisone intravenously; children 1 to 5 years, 50mg; 6 to 12 years, 100mg (1ml). This dose can be repeated three or four times in 24 hours depending upon the condition being treated and the patient's response.

Other uses: Local treatment of soft-tissue lesions - 100 to 200mg. This daily dose may be repeated on two or three occasions depending upon the patient's response.

This medicine is not recommended for intrathecal use.

Method of administration

Intravenous or intramuscular injection, or injection into soft tissues.

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.

Live virus immunisation.

This medicine should not be injected directly into tendons.

4.4. Special warnings and precautions for use

A patient information leaflet should be supplied with this product.

Patients should carry a 'steroid treatment card' which gives clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.

Suppression of the HPA-axis and other undesirable effects may be minimised by using the lowest effective dose for the minimum period (see Section 4.2). The pronounced hormonal effects associated with prolonged corticosteroid therapy will probably not be seen when this injection is used for short-term adjunctive therapy in shock. Frequent patient review is required to titrate appropriately the dose against disease activity.

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.

Using higher than normal doses of hydrocortisoneHigh (supra-physiological) dosages of hydrocortisone can cause elevation of blood pressure, salt and water retention, and increased 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.

In patients who have received more than physiological doses of

Corticosteroids should NOT be used in the treatment of cerebral oedema associated with acute head injury or cerebrovascular accident, as they are unlikely to be of benefit and may even be harmful.

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 transient illnesses such as low grade infection, fever of any aetiology, stressful situations such as minor surgical procedures, the daily 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.. If corticosteroids have been stopped following prolonged therapy they may need to be temporarily re-introduced.

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.

Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently (see section 4.5).

Average and large dosages of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increase excretion of potassium. 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, close observation is necessary as reactivation may occur. During prolonged corticosteroid therapy, these patients should receive prophylactic chemotherapy. The use of Hydrocortisone Tablets in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis.

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.

Thyroid-function

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

Thyrotoxic Periodic Paralysis (TPP) can occur in patients with hyperthyroidism and with hydrocortisone-induced hypokalaemia. TPP must be suspected in patients treated with hydrocortisone presenting signs or symptoms of muscle weakness, especially in patients with hyperthyroidism.

If TPP is suspected, levels of blood potassium must be immediately monitored and adequately managed to ensure the restoration of normal levels of blood potassium.

Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission.

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. New infections may appear during their use.

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.

Chickenpox is of particular concern since this normally minor illness may be fatal in immunosuppressed patients. Patients 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. If the patient is a child, parents must be given the above advice. 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 three 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 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 immunoglobulins may be needed.

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

Corticosteroids may increase or decrease motility and number of spermatozoa.

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 (active or latent);

l) recent myocardial infarction.

m) myasthenia gravis,

n) non-specific ulcerative colitis, diverticulitis, fresh intestinal anastomoses

o) signs of peritoneal irritation following gastro-intestinal perforation in patients receiving large doses of corticosteroids may be minimal or absent

p) thrombophlebitis

q) metastatic carcinoma

Renal Insufficiency or congestive heart failure

Because of the possibility of fluid retention, care must be taken when corticosteroids are administered to patients with renal insufficiency or congestive heart failure.

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

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

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.

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,).

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 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.

Withdrawal symptoms

Drug-induced secondary adrenocortical insufficiency may result from too rapid a withdrawal of corticosteroids and may be minimised by gradual reduction of dosage. 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 section 4.5).

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)-axis 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 for 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 corticosteroids greater than 160mg hydrocortisone.

• Patients repeatedly taking doses in the evening.

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

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.

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.

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per dosage, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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

Drug interactions: rifampicin, rifabutin, carbamazepine, certain barbiturates (e.g phenobarbital, phenytoin, primidone, ephedrine St. John's Wort and aminoglutethimide enhance the metabolism of corticosteroids and their therapeutic effects may be reduced.

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

Erythromycin and ketoconazole may inhibit the metabolism of corticosteroids.

Ketoconazole alone can inhibit adrenal corticosteroid synthesis and may cause adrenal insufficiency during corticosteroid withdrawal (see section 4.4).

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.

Ritonavir, may increase the plasma concentration of hydrocortisone. Efavirenz, and nevirapine may reduce 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 effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids.

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

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.

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. Aspirin should be used cautiously in conjunction with corticosteroids in patients with hypoprothrombinaemia. Concomitant use of salicylates or of non-steroidal anti-inflammatory drugs (NSAIDs) with corticosteroids increases the risk of gastrointestinal bleeding and ulceration.

The potassium-depleting effects of acetazolamide, loop diuretics, thiazide diuretics and carbenoxolone 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.

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

High doses of corticosteroids impair the immune response and so live vaccines should be avoided (see also section 4.4).

Corticosteroids may affect the nitroblue tetrazolium test for bacterial infection and produce false negative results.

Corticosteroids reduce absorption of calcium salts.

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

4.6. Fertility, pregnancy and lactation

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. 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.

Depression of hormone levels has been described in pregnancy but the significance of this finding is not clear.

Breast-feeding

Corticosteroids are excreted in breast milk, although no data are available for hydrocortisone. Doses of up to 160mg daily of hydrocortisone 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.

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.

4.7. Effects on ability to drive and use machines

Not relevant

Hydrocortisone has a minor influence on the ability to drive and use machines.

Hydrocortisone may cause fatigue, vertigo, visual field loss and muscle wasting and weakness. If affected, patients should not drive or operate machinery (see section 4.8).

4.8. Undesirable effects

Paraesthesia may occur following intravenous administration and is probably related to the rate of injection. It is often localised to the genital area but in some cases may radiate over the entire body. The unpleasant and sometimes painful sensation usually passes off within a few minutes and no sequelae have been reported. The effect seems to be related to the sodium phosphate salt of hydrocortisone.

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 adverse reactions are classified by system organ class and ranked under heading of frequency using the following convention: Not known (cannot be estimated from the available data).

System organ class

Frequency

Undesirable effects

Blood and lymphatic system disorders

Not known

Leucocytosis

Immune system disorders

Not known

Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis (see Section 4.4), Hypersensitivity, including anaphylaxis has been reported.

Endocrine disorders

Not known

Suppression of the hypothalamic-pituitary-adrenal axis, cushingoid faces, hirsutism, Negative protein and calcium balance.

Metabolism and nutrition disorders

Not known

Weight gain, Sodium and water retention, potassium loss, hypokalaemic alkalosis impaired carbohydrate tolerance with increased requirement for anti-diabetic therapy, Increased appetite.

Psychiatric disorders

Not known

Euphoria, psychological dependence, depression, insomnia

Nervous system disorders

Not known

Aggravation of epilepsy

Eye disorders

Not known

Increased intra-ocular pressure, glaucoma, papilloedema, posterior subcapsular cataracts, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal diseases.

Vision, blurred (see also section 4.4).

Cardiac disorders

Not known

Hypertrophic cardiomyopathy in prematurely born infants

Vascular disorders

Not known

Hypertension, Thrombo-embolism, Flushing

Gastrointestinal disorders

Not known

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

Skin and subcutaneous tissue disorders

Not known

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

Musculoskeletal and connective tissue disorders

Not known

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

Reproductive system and breast disorders

Not known

Menstrual irregularity and amenorrhoea

Investigations

Not known

Weight increased

Paediatric population

- growth suppression in infancy, childhood and adolescence

- aggravation of schizophrenia and increased intra-cranial pressure with papilloedema in children (pseudotumour cerebri), usually after treatment withdrawal.

Withdrawal symptoms and signs

Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to adrenal 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 loss of weight.

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 infections and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.

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.

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

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.

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