- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Anti-inflammatory/immunosuppressive effects and infectionKaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission. Chronic immunosupression (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.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 3 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 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. The antibody response to other vaccines may be diminished.Because of the possibility of fluid retention, care must be taken when corticosteroids are administered to patients with renal insufficiency or hypertension or congestive heart failure.Corticosteroids may worsen diabetes mellitus, osteoporosis, hypertension, glaucoma and epilepsy and therefore patients with these conditions or a family history of them should be monitored frequently.Care is required and frequent patient monitoring necessary where there is a history of severe affective disorders (especially a previous history of steroid psychosis), previous steroid myopathy, peptic ulceration, hypothyroidism, recent myocardial infarction or patients with a history of tuberculosis.In patients with liver failure, blood levels of corticosteroid may be increased, as with other drugs which are metabolised in the liver. Frequent patient monitoring is therefore necessary.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 infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.1Patients/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.1 PL06464/0914-0028; 01/04/2008
Erythromycin and ketoconazole may inhibit the metabolism of some corticosteroids.
Ciclosporin increases plasma concentration of prednisolone. The same effect is possible with ritonavir.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.The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids. The growth promoting effect of somatotropin may be inhibited by the concomittant use of corticosteroids.Steroids may reduce the effects of anticholinesterases in myasthenia gravis and cholecystographic x-ray media.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.Concomitant use of aspirin and Non Steroidal Anti-Inflammatory Drugs (NSAIDs) with corticosteroids increases the risk of gastro-intestinal bleeding and ulceration. The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication.The hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics, and carbenoxolone, are enhanced by corticosteroids. 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 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.High doses of corticosteroids impair the immune response and so live vaccines should be avoided (see also warnings).
Infections and InfestationsIncreased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis (see section 4.4).
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.
Blood and lymphatic system disordersLeukocytosis.
Immune system disordersHypersensitivity including anaphylaxis has been reported.
Endocrine disordersSuppression of the HPA axis.Cushingoid.Impaired carbohydrate intolerance with increased requirement for anti-diabetic therapy, manifestation of latent diabetes mellitus.
Metabolism and nutrition disordersSodium and water retention, hypokalaemia, hypokalaemic alkalosis, increased appetite, negative protein and calcium balance.
Psychiatric disordersEuphoric mood, psychological dependence, depressed mood, insomnia, aggravation of schizophrenia.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.
Nervous system disordersDizziness, headache. Increased intracranial pressure with papilloedema in children (pseudotumour cerebri) -usually after treatment withdrawal. Aggravation of epilepsy.
Eye disordersGlaucoma, papilloedema, posterior subcapsular cataracts, central serous chorioretinopathy, exophthalmos, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal diseases.
Ear and labyrinth disordersVertigo
Cardiac disordersMyocardial rupture following recent myocardial infarction.Congestive cardiac failure (in susceptible patients).
Vascular disordersHypertension, embolism.
Respiratory, thoracic and mediastinal disordersHiccups.
Gastrointestinal disordersDyspepsia, nausea, vomiting, abdominal distension, abdominal pain, diarrhoea, oesophageal ulceration, candidiasis, pancreatitis acute.Peptic ulceration with perforation and haemorrhage.
Skin and subcutaneous tissue disordersSkin Atrophy, skin striae, acne, telangiectasia, hyperhidrosis, rash, pruritus, urticaria, hirsutism.
Musculoskeletal and connective tissue disordersMyopathy, osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, myalgia. Growth retardation in infancy, childhood and adolescence.
Reproductive system and breast disordersMenstruation irregular, amenorrhoea.
General disorders and administration site conditionsImpaired healing, malaise.
Injury, poisoning and procedural complicationsTendon rupture, contusion (bruising).
Withdrawal SymptomsToo 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.
AbsorptionPrednisolone is readily absorbed from the gastrointestinal tract with peak plasma concentrations achieved by 1-2 hours after an oral dose. Plasma prednisolone is mainly protein bound (70-90%), with binding to albumin and corticosteroid-binding globulin. The plasma half-life of prednisolone, after a single dose, is between 2.5-3.5 hours.
DistributionThe volume of distribution and clearance of total and unbound prednisolone are concentration dependent, and this has been attributed to saturable protein binding over the therapeutic plasma concentration range.
MetabolismPrednisolone is extensively metabolised, mainly in the liver, but the metabolic pathways are not clearly defined.
ExcretionOver 90% of the prednisolone dose is excreted in the urine, with 7-30% as free prednisolone, and the remainder being recovered as a variety of metabolites.
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