| Verbiage [REMOVED], added or altered significantly as noted in bold below:
4.3. Contraindications
1It is 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.
Since joints and tissues injected with corticosteroids have an increased susceptibility to infection, local injections of Hydrocortistab should be carried out with full aseptic precautions.
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:
(d) Hypertension or congestive heart failure.
(e) Existing or previous history of severe affective disorders (especially previous history of steroid psychosis).
(g) Previous corticosteroid-induced myopathy.
(j) Liver failure.
(k) Renal insufficiency.
(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, in order to minimise suppression of the hypothalamo-pituitary-adrenal axis and growth retardation (see section 4.2, Posology and Method of Administration).
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.
4.5. Interactions with other Medicaments and other forms of Interaction
The metabolism of corticosteroids may be enhanced and the therapeutic effects reduced by certain barbiturates (e.g. phenobarbital) 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 are 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 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.
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.
4.8. 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).
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 (pseudotumor 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:
Opportunistic infection, recurrence of dormant tuberculosis, leucocytosis, , thromboembolism, increased appetite, nausea, malaise. Hypersensitivity, including anaphylaxis has been reported.
Withdrawal symptoms and signs:
[REMOVE Fever, myalgia, arthralgia, adrenal insufficiency.]
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.
4.9. Overdose
Overdosage is unlikely with Hydrocortistab Injection but there is no specific antidote available. 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.
10. DATE OF (PARTIAL) REVISION OF THE TEXT
April 2008
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