Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Amdipharm UK Limited, Capital House, 85 King William Street, London, EC4N 7BL, United Kingdom
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.
Vaccination with live vaccines (see section 4.4).
Patients with ocular herpes simplex due to the possibility of perforation.
Intra-articular and periarticular injections of this medicine, when the joint or surrounding tissues are infected.
Injection into tendon sheaths and bursae when infection is present.
Injection directly into tendons.
Injection into spinal or other non-diarthrodial joints.
A patient information leaflet should be supplied with this product.
Patients should carry “steroid treatment” cards which give clear guidance on the precautions to be taken to minimise risk and provide details of prescriber, drug, dosage and duration of treatment.
Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission.
Chronic immunosuppression (e.g. in the setting of organ transplantation), has been associated with an increased risk of malignancy.
Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity. The resultant opportunistic infections may be fatal. 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.
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 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 special 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. Killed vaccines or toxoids may be given though their effects may be attenuated.
Caution is necessary when corticosteroids, including prednisolone, are prescribed to patients with the following conditions and frequent patient monitoring is necessary:
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 pharmacokinetic interactions that can increase the risk of side effects), 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 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 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.
In patients who have received more than physiological doses of systemic corticosteroids (approximately 7.5mg prednisolone or equivalent) 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 HPA suppression, the dose of systemic corticosteroid may be reduced rapidly to physiological doses. Once a daily dose equivalent to 7.5mg of prednisolone 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 40mg daily of prednisolone or equivalent 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:
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 reintroduced.
This medicine contains sodium: This medicinal product contains less than 1mmol sodium (23mg) per dose, i.e. essentially sodium free.
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.
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).
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 (HPA) axis and growth retardation (see section 4.2).
Caution is required in patients with systemic sclerosis because of an increased incidence of (possibly fatal) scleroderma renal crisis with hypertension and decreased urinary output observed with a daily dose of 15 mg or more prednisolone. Blood pressure and renal function (s-creatinine) should therefore be routinely checked. When renal crisis is suspected, blood pressure should be carefully controlled.
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.
Concomitant use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with corticosteroids increases the risk of gastro-intestinal bleeding and ulceration.
Aspirin should be used cautiously in conjunction with glucocorticoids in patients with hypoprothrombinaemia. Concurrent use of aspirin and prednisolone may result in an increased risk of gastrointestinal ulceration and sub therapeutic aspirin serum concentrations.
The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication.
The efficacy of coumarin anticoagulants and warfarin may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.
The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids.
Oestrogens and other oral contraceptives may potentiate the effects of glucocorticoids and dosage adjustments may be required if oral contraceptives are added to or withdrawn from a stable dosage regimen.
Antifungals: There is an increased risk of hypokalaemia with amphotericin, and concomitant use should be avoided. Ketoconazole reduces the metabolic and renal clearance of methylprednisolone and this may also occur with prednisolone.
Erythromycin may inhibit the metabolism of some corticosteroids.
Ciclosporin increases plasma concentration of prednisolone. The same effect is possible with ritonavir.
Rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone, ephedrine and aminoglutethimide enhance the metabolism of corticosteroids and its therapeutic effects may be reduced. Therefore, it may be necessary to adjust the dose of prednisolone accordingly.
Mifepristone may reduce the effect of corticosteroids for 3-4 days.
The growth promoting effect of somatotropin may be inhibited by the concomitant use of corticosteroids.
Steroids may reduce the effects of anticholinesterases in myasthenia gravis and cholecystographic x-ray media.
The hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics, and carbenoxolone are enhanced by corticosteroids.
There is also an increased risk of hypokalaemia with the simultaneous use of theophylline and if high doses of corticosteroids are given with high doses of bambuterol, fenoterol, formoterol, ritodrine, salbutamol, salmeterol and terbutaline.
The toxicity of cardiac glycosides is increased if hypokalaemia occurs with corticosteroids.
Concomitant use with methotrexate may increase the risk of haematological toxicity.
Etoposide metabolism may be inhibited by corticosteroids in vitro. This may lead to an increase in both efficacy and toxicity of etoposide. Monitoring would be prudent.
Corticosteroids should not be used concurrently with retinoids and tetracyclines due to increased intracranial pressure.
High doses of corticosteroids impair the immune response and so live vaccines should be avoided (see section 4.4).
The ability of corticosteroids to cross the placenta varies between individual drugs. However, 88% of prednisolone is inactivated as it 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 pre-natal 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.
Corticosteroids are excreted in small amounts in breast milk. However, doses of up to 40mg daily of prednisolone 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. Monitoring of the infant for adrenal suppression is advised.
This medicine has no or negligible influence on the ability to drive and use machines.
The incidence of predictable undesirable effects, including hypothalamo-pituitary-adrenal (HPA) 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 available data).
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).
Not known: Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission.
Not known: Leukocytosis.
Not known: Hypersensitivity including anaphylaxis has been reported.
Not known: Suppression of the HPA axis. Cushingoid. Impaired carbohydrate intolerance with increased requirement for anti-diabetic therapy, manifestation of latent diabetes mellitus.
Not known: Sodium and water retention, hypokalaemia, hypokalaemic alkalosis, increased appetite, negative protein and calcium balance.
Not known: Euphoric mood, psychological dependence, depressed mood, insomnia, aggravation of schizophrenia.
Not known: Dizziness, headache. Aggravation of epilepsy.
Not known: Glaucoma, papilloedema, posterior subcapsular cataracts, central serous chorioretinopathy, exophthalmos, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal diseases and vision, blurred (see also section 4.4).
Not known: Vertigo.
Not known: Myocardial rupture following recent myocardial infarction. Congestive cardiac failure (in susceptible patients).
Not known: Hypertension, embolism.
Not known: Hiccups.
Not known: Dyspepsia, nausea, vomiting, abdominal distension, abdominal pain, diarrhoea, oesophageal ulceration, candidiasis, pancreatitis acute. Peptic ulceration with perforation and haemorrhage.
Not known: Skin Atrophy, skin striae, acne, telangiectasia, hyperhidrosis, rash, pruritus, urticaria, hirsutism.
Not known: Myopathy, osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, myalgia.
Not known: Scleroderma renal crisis*
Not known: Menstruation irregular, amenorrhoea.
Not known: Impaired healing, malaise.
Not known: Weight increased.
Not known: Tendon rupture, contusion (bruising).
a 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.
* Scleroderma renal crisis: Amongst the different subpopulations the occurrence of scleroderma renal crisis varies. The highest risk has been reported in patients with diffuse systemic sclerosis. The lowest risk has been reported in patients with limited systemic sclerosis (2%) and juvenile onset systemic sclerosis (1%).
Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute 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.
In some instances, withdrawal symptoms may involve or resemble a clinical relapse of the disease for which the patient has been undergoing treatment.
Other effects that may occur during withdrawal or change of corticosteroid therapy include benign intracranial hypertension with headache and vomiting and papilloedema caused by cerebral oedema.
Latent rhinitis or eczema may be unmasked.
Increased intracranial pressure with papilloedema in children (pseudotumour cerebri) - usually after treatment withdrawal.
Growth retardation in infancy, childhood and adolescence.
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.
Not applicable.
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