REDIPRED Oral solution Ref.[50299] Active ingredients: Prednisolone

Adrenocorticol insufficiency

During prolonged corticosteroid therapy, adrenal suppression and atrophy may occur and secretion of corticotrophin may be suppressed. Duration of treatment and dosage appear to be important factors in determining suppression of the pituitary adrenal axis and response to stress on cessation of steroid treatment. The patient’s liability to suppression is also variable and depends on the dose, frequency, time of administration and duration of therapy. Some patients may recover normal function rapidly. In others, the production of hydrocortisone in response to the stress of infections, surgical operations or accident may be insufficient and death results.

Symptoms of adrenal insufficiency include: malaise, muscle weakness, mental changes, muscle and joint pain, desquamation of the skin, dyspnoea, anorexia, nausea and vomiting, fever, hypoglycaemia, hypotension and dehydration.

Abrupt withdrawal of corticosteroids therapy may precipitate acute adrenal insufficiency. In some cases, withdrawal symptoms may simulate a clinical relapse of the disease for which the patient has been under treatment. Therefore, withdrawal of corticosteroids should always be gradual. A degree of adrenal insufficiency may persist for 6 to 12 months; therefore in any situation of stress occurring during that period steroid therapy may need to be reinstituted. Since mineralocorticoid secretion may be impaired, treatment with salt and/or mineralcorticosteroid may also be needed.

Because prednisolone manifests little sodium retaining activity, the usual early sign of hydrocortisone overdosage (i.e. increase in bodyweight due to fluid retention) is not a reliable index of prednisolone overdosage. Hence recommended dose levels should not be exceeded, and all patients receiving prednisolone should be under close medical supervision. All precautions pertinent to the use of hydrocortisone apply to Redipred.

General precautions

Use with caution in patients with impaired hepatic function, a reduction of dosage may be necessary. In treating chronic liver disease with the drug, major adverse reactions such as vertebral collapse, diabetes, hypertension, cataracts and Cushing’s syndrome occur in about 30% of patients.

Use with caution in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess or other pyogenic infection. Caution must also be used in diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, renal insufficiency, hypertension and myasthenia gravis, when steroids are used as direct or adjunctive therapy.

Use with caution in patients with epilepsy, diabetes mellitus or in those with a family history of diabetes, uraemia and in the presence of diminished cardiac reserve or congestive heart failure. The possibility of the development of osteoporosis should be an important consideration in initiating and managing corticosteroid therapy, especially in post- menopausal women.

The risk of gastrointestinal ulceration or haemorrhage is increased when alcohol is used concurrently with glucocorticoids.

Patients with active or doubtfully quiescent tuberculosis should not be given prednisolone except as adjuncts to treatment with tuberculostatic drugs as reactivation of the disease may occur. Chemoprophylaxis is indicated during prolonged corticosteroid therapy.

During long courses of treatment, laboratory and metabolic studies should be made. Fluid retention should be watched for via a fluid balance chart and daily weighing. Sodium intake may need to be reduced to less than 1 g daily and potassium and calcium supplements may be necessary.

Anti-inflammatory/immunosuppressive effects and infection

Corticosteroids may mask some signs of latent infection (such as fever and inflammation) and new infections may appear during their use. There may be decreased resistance and inability to localise infection when corticosteroids are used. Susceptibility to infection is not specific for any particular bacterial or fungal pathogen.

Live vaccines are contraindicated in patients on high doses of corticosteroids and should be postponed until at least 3 months after stopping corticosteroid therapy. Other immunisation procedures should not be undertaken in patients on corticosteroid therapy, especially on high doses because of possible hazards of neurological complications and lack of antibody response. Immunisation procedures may be undertaken in patients receiving corticosteroids as replacement therapy.

Children who are on immunosuppressant drugs are more susceptible to infections than healthy children. Chicken pox and measles, for example, can have a more serious or even fatal course in children on immunosuppressant corticosteroids. In such children or in adults who have not had these diseases, particular care should be taken to avoid exposure. If exposed, they should seek urgent medical attention. Therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If chicken pox develops, treatment with antiviral agents may be considered.

Ocular effects

Prolonged use of corticosteroids may produce subcapsular cataracts and nuclear cataracts (particularly in children), exophthalmos or increased intraocular pressure, which may result in glaucoma with possible damage to the optic nerves.

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.

Corticosteroids should only be initiated in patients with ocular herpes simplex with appropriate viral cover by ophthalmologists because of the risk of corneal scaring loss of vision and corneal perforation.

Psychiatric effects

Patients and/or carers should be warned that potentially severe psychiatric reactions may occur. Symptoms typically emerge within a few days or weeks of starting treatment. Most patients recover after either dose reduction or withdrawal, although specific treatment may be necessary. Patients and/or carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected.

Particular care is required when considering the use of corticosteroids in patients with existing or previous history of severe affective disorders.

Psychic derangements range from euphoria, insomnia, mood swings, personality changes and severe depression to frank psychotic manifestations.

Use in children

Children on long term steroids must be carefully observed for potential serious adverse reactions such as obesity, growth retardation osteoporosis and adrenal suppression.

Children are at special risk from raised intracranial pressure.

Use in the elderly

Caution is recommended for elderly patients as they are more susceptible to adverse reactions, especially osteoporosis, diabetes, hypertension, hypokalaemia, susceptibility to infection and thinning of the skin.

Carcinogenicity / mutagenicity:

In male rats, administration of prednisolone in the drinking water at a daily dose of 0.4mg/kg for two years caused an increased incidence of hepatocellular tumours. Similar results were obtained with triamcinolone acetonide and budesonide, indicating a class effect of glucocorticosteroids. The hepatocarcinogenic response to these drugs does not appear to be related to genotoxic activity.

Other conditions

Caution is necessary when oral corticosteroids are used in patients with the following other conditions and frequent monitoring is necessary:

• Hypothyroidism
• Glaucoma
• Patients with a history of severe affective disorders particularly of steroid induced psychoses
• Previous steroid myopathy
• Patients with thromboembolic disorders
• Patients with Duchenne’s muscular dystrophy since transient rhabdomyolysis and myoblobinuria have been reported following strenuous physical activity.

The following drug interactions with corticosteroids have been selected on the basis of their potential clinical significance: antacids, antidiabetic agents (oral or insulin), digitalis glycosides, diuretics, drugs which induce hepatic microsomal enzymes, such as barbiturates, phenytoin and rifampicin, potassium supplements, sodium-containing medications of foods, somatropin, vaccines, live viruses or other immunisations.

Effects on laboratory tests

Glucocorticoids may decrease I131 uptake and protein-bound iodine concentrations, making it difficult to monitor the therapeutic response of patients receiving the drugs for thyroiditis. Glucocorticoids may produce false-negative results in the nitroblue tetrazolium test for systemic bacterial infection. Glucocorticoids may suppress reactions to skin tests.

Other interactions for oral and systemic corticosteroids

Pregnancy

Category A.

In animal experiments, corticosteroids have been found to cause malformations of various kinds (cleft palate, skeletal malformation) and abortion. These findings do not seem to be relevant to humans. Reduced placental and birth weight have been recorded in animals and humans after long term treatment. Since the possibility of suppression of the adrenal cortex in the newborn baby after long term treatment must be considered, the needs of the mother must be carefully weighted against the risk to the foetus when prescribing corticosteroids. The short term use of corticosteroids antepartum for the prevention of respiratory distress syndrome, does not seem to pose a risk to the foetus or the newborn infant. Maternal pulmonary oedema has been reported with tocolysis and fluid overload.

Lactation

Prednisolone is excreted in breast milk; therefore, administration to nursing mothers is not recommended.

Not relevant.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine.

Healthcare professionals are asked to report any suspected adverse reactions to https://nzphvc.otago.ac.nz/reporting/.

Short term administration of Redipred, even in massive dosages, is unlikely to produce harmful effects. The majority of adverse reactions from corticosteroids are those from withdrawal or from prolonged use of high doses.

More common reactions

Gastrointestinal

Adverse gastrointestinal effects of corticosteroids include nausea, vomiting, anorexia (which may result in weight loss), increased appetite (which may result in weight gain), diarrhoea or constipation, abdominal distension and gastric irritation.

Cardiovascular

The mineralocorticoid activity of a steroid may lead to salt and water retention which can also result in hypertension. Hypokalaemia can lead to arrhythmias and cardiac arrest.

Neurological

Adverse neurological effects have included headache, vertigo, insomnia, dizziness, restlessness and increased motor activity, ischaemic neuropathy, EEG abnormalities and seizures. Large doses can cause behavioural and personality changes ranging from nervousness, euphoria or mood swings to psychotic episodes which can include both manic and depressive states, paranoid states and acute toxic psychoses. It is no longer believed that previous psychiatric problems predispose to behavioural disturbances during therapy with glucocorticoids. Conversely, the absence of a history of psychiatric illness is no guarantee against the occurrence of psychosis during hormonal therapy.

Dermatological

Dermatological adverse effects of corticosteroids include impaired wound healing, facial plethora, increased sweating, easy bruising, hirsutism, an acneiform eruption on the face, chest and back, red striae on the thighs, buttocks and shoulders. Several months of high dose therapy can often result in thinning of skin. Dermatologic manifestations of hypersensitivity to the corticosteroids include hives and/or allergic dermatitis, urticaria and angioedema. Corticosteroid induced purpura resembles senile purpura. This purpura usually occurs on extensor surfaces, dorsum of the hand, and radial aspect of the forearm.

Endocrine

The endocrine effects of the glucocorticoids involve variously the hypothalamic pituitary adrenal axis, the parathyroid and thyroid. There are also metabolic effects, primarily involving the carbohydrates with increased requirement for antidiabetic therapy, manifestation of latent diabetes mellitus, increased appetite and weight gain. Retardation of growth by long term corticosteroid treatment in children. Cushing’s syndrome may result from prolonged elevation of plasma glucocorticoid levels. Corticosteroids have also been reported to increase or decrease motility and number of sperm in men. Disorders of menstruation are common. Antagonism occurs between the parathyroids and hypercorticism. Latent hypoparathyroidism may be unmasked by administration of corticosteroids. The phosphate retention occurring in renal failure caused by adrenal insufficiency may also make hypoparathyroidism manifest.

Biochemical

All glucocorticoids increase gluconeogenesis. Glucose tolerance and sensitivity to insulin are decreased but provided pancreatic islet function is normal carbohydrate metabolism will not be noticeably deranged. Steroid diabetes, has been reported to develop in one fifth of patients treated with high glucocorticoid dosage. High dose corticosteroid therapy may induce marked hypertriglyceridaemia with milky plasma.

Haematological

Corticosteroids will increase the total WBC count, with an increase in neutrophils and a decrease in monocytes, lymphocytes and eosinophils.

Immunological

The frequency and severity of clinical infections increase during glucocorticoid therapy.

Musculoskeletal

Osteoporosis and vertebral compression fractures can occur in patients of all ages. Osteoporosis is an indication for withdrawal of therapy. Myopathy, characterised by weakness of the proximal musculature of arms and legs and their associated shoulder and pelvic muscles, is occasionally reported in patients taking large doses of corticosteroids. It may occur soon after treatment is begun and be sufficiently severe to prevent ambulation. It is an indication for withdrawal of therapy. Avascular aseptic necrosis of bone has often been described and preferentially involves the femoral and humeral head.

Serious or life-threatening reactions

Suppression of the hypothalamic pituitary adrenal axis is one of the consequences of repeated administration of glucocorticoids. In some cases acute adrenal insufficiency after a period of glucocorticoid treatment has proved fatal. Less common reactions

Gastrointestinal

Pancreatitis and ulcerative oesophagitis can occur. Peptic ulceration is an occasional complication. The high incidence of haemorrhage and perforation in these ulcers and the insidious nature of their development make them severe therapeutic problems. Some investigators believe the available evidence does not support the conclusion that steroids cause ulcers. Others feel that only patients with rheumatoid arthritis have an increased incidence of ulcers. It has been proposed that the glucocorticoids alter the mucosal defence mechanism.

Neurological

Latent epilepsy can be rendered manifest by corticosteroid treatment. Long-term treatment may result in benign intracranial hypertension.

Ophthalmological

Prolonged use of glucocorticoids may result in posterior subcapsular cataracts (particularly in children), exophthalmos or increased intraocular pressure which may result in glaucoma or may occasionally damage the optic nerve and in rare cases, lead to blindness or rare diseases such as central serous chorioretinopathy (CSCR). Establishment of secondary fungal and viral infections of the eye may also be enhanced.

Withdrawal symptoms

Muscle weakness, hypoglycaemia, headache, nausea, vomiting, anorexia leading to weight loss, lethargy, fever, restlessness and muscle and joint pain. Muscle weakness and stiff joints may persist for three to six months after discontinuation of treatment. Too rapid a reduction of corticosteroids following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death.

Other adverse effects for oral and systemic corticosteroids

Not relevant.