4.4 Special warnings and precautions for use
Anti-inflammatory/ immunosuppressive effects and infection.
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. The immunosuppressive effects of corticosteroids, including prednisolone, may result in the activation or exacerbation of strongyloidiasis or fungal infection, or the activation of latent infection, or exacerbation of intercurrent infection involving other pathogens such as pneumocystis carinii. During prolonged therapy any intercurrent illness, trauma or surgical procedures will require a temporary increase in dosage, if corticosteroids have been stopped following prolonged therapy they may need to be temporarily re-introduced.
ChickenChickenpox 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 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 taking corticosteroids should be advised to take particular care to avoid exposure to measles and to seek immediate medical advice if exposure occurs.
4.5 Interactions with other medicinal products and other forms of interaction
Hepatic microsomal enzyme inducers: Rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone and aminoglutethimide enhance the metabolism of prednisolone and its therapeutic effects may be reduced.
Anticoagulants: The efficacy of coumarin anticoagulants may be enhanced or reduced by current concomitant corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.
Non-steroidal anti-inflammatory drugs (NSAIDs): There is an increased risk of gastro-intestinal bleeding and ulceration when corticosteroids are given with used concomitantly with NSAIDs, including aspirin. The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication.
Hormones: Oestrogens and progesterones may enhance the effects of corticosteroids and dosage adjustments may be required in some cases.
Prednisolone can inhibit the growth stimulating effect of somatropin.
Antibacterials: Corticosteroids can lower plasma concentrations of isoniazid and enhance its renal clearance.
Antifungals: Concomitant use with ketoconazole may inhibit the metabolism of prednisolone and enhance its adrenal suppressive effects. There is the potential for an increased risk of hypokalaemia when corticosteroids are used concomitantly with amphotericin.
Antineoplastics and immunosuppressants: Mutual inhibition of metabolism may occur between ciclosporin and prednisolone, and may increase the plasma concentration of either drug.
Antivirals: Plasma concentrations of prednisolone may be increased with antiviral drugs such as ritonavir and indinavir.
Vaccines: Concomitant use of high dose corticosteroids and live vaccines should be avoided. Corticosteroids may impair the immune response to other vaccines.
Neuromuscular blockers: Neuromuscular blocking effects may be antagonised by prednisolone in patients with adrenocortical insufficiency.
Cardiac glycosides: There is the potential for an increased risk of digitalis toxicity associated with hypokalaemia, when corticosteroids and cardiac glycosides are used concomitantly.
Sympathomimetics: There is an increased risk of hypokalaemia if high doses of corticosteroids are given with high doses of bambuterol, fenoterol, formoterol, reproterol, ritodrine, salbutamol, salmeterol, terbutaline and tulobuterol.
Thalidomide: The dosage of prednisolone needs to be reduced considerably when used with thalidomide. It has been suggested that prednisolone should not be given with thalidomide.
Intra-uterine devices (IUDs) –There is the potential for contraceptive failure in women using intra-uterine devices and receiving corticosteroid therapy.
Other: The desired effects of hypoglycaemic agents (including insulin), antihypertensives and diuretics are antagonised by corticosteroids and the hypokalaemic effects of acetazolamide loop diuretics, and thiazide diuretics are enhanced. The effect of corticosteroids may be reduced for 3 to 4 days after the use of mifepristone. There is the potential for an increased risk of hypokalaemia when corticosteroids and theophylline are used concomitantly.
4.6 Pregnancy and lactation
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. The use of corticosteroids, including prednisolone, during pregnancy may also result in stillbirth. 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 dose monitoring
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 4.4 Special Warnings and Precautions for use)
Endocrine/metabolic - suppression of the hypothalamic-pituitary-adrenal axis, growth suppression in infancy, childhood and adolescence, menstrual irregularity and amenorrhoea. Hirsutism, weight gain, impaired carbohydrate tolerance, hyperglycaemia, precipitation of diabetes mellitus or increased requirement for anti-diabetic therapy in pre-existing diabetes. Negative nitrogen and calcium balance. Increased appetite. Hypercholesterolaemia and hypertriglyceridaemia. High doses or prolonged administration of corticosteroids may cause Cushing’s syndrome.
Anti-inflammatory and immunosuppressive effects - increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis (see other special warnings and precautions).
Musculoskeletal - osteoporosis, vertebral and long bone fractures, tendon rupture. Proximal myopathy, muscular weakness, musclular atrophy and buffalo hump. Avascular osteonecrosis has been associated with long term or high dose corticosteroid therapy.
Fluid and electrolyte disturbance - sodium and water retention, potassium loss, hypokalaemic alkalosis, oedema.
Blood and lymphatic system disorders-corticosteroids have the potential to increase the coagulability of blood.
Vascular disorders - hypertension.
Neuropsychiatric - euphoria, psychological dependence, depression, insomnia, psychosis, and aggravation of schizophrenia, mania, delirium, nervousness and/or restlessness and hallucinations. Increased intra-cranial pressure with papilloedema in children (pseudotumour cerebri), usually after treatment withdrawal. Aggravation of epilepsy.
Ophthalmic - increased intra-ocular pressure, glaucoma, papilloedema, posterior subcapsular cataracts, corneal or scleral thinning, serious retinal detachment, exacerbation of ophthalmic viral of fungal diseases and sudden blindness. Potential for exophthalmos to occur with long-term administration of corticosteroids.
Gastrointestinal - dyspepsia, peptic ulceration with perforation and haemorrhage, acute pancreatitis, candidiasis, hiccups and nausea.
Dermatological - impaired healing, skin atrophy, bruising, telangiectasia, striae, acne, skin thinning, flushing, hyperhidrosis.
General - hypersensitivity including anaphylaxis, has been reported. Leucocytosis. Thromboembolism, myocardial rupture following recent myocardial infarction, increased risk of Stevens-Johnson syndrome or toxic epidermal necrolysis, tumour lysis syndrome.
Withdrawal symptoms and signs - too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death (see Special Warnings and Precautions for Use). A 'withdrawal syndrome' may also occur including, fever, myalgia, weakness, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules, loss of weight, mental changes, emotional changes, nausea, vomiting, hypotension, benign intracranial hypertension, dizziness, headache, and reappearance of disease symptoms.
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