The information below is based on the summary of product characteristics approved by regulatory authorities. For full details from the SmPC please click here https://www.medicines.org.uk/emc/product/1740/smpc#PRODUCTINFO; ECCO Consensus on UC, 2017; ECCO Consensus on Crohn’s Disease 2013; ECCO Toolkit

Additional related ECCO e-Learning resources can be found under IBD Curriculum Topic 6.1-6.11

Introduction and Mechanism of Action

Systemic steroids are synthetic or semi-synthetic glucocorticoids, which have potent anti-inflammatory effects in disorders of many organ systems. Glucocorticoids cause also profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli. They have specifically primary glucocorticoid and minor mineralocorticoid effects. As a glucocorticoid receptor agonist, systemic steroids promote protein catabolism, gluconeogenesis, capillary wall stability, renal excretion of calcium, and suppress immune and inflammatory responses.

Systemic steroids are generally completely absorbed after oral administration, and reach peak plasma concentrations after 1-3 hours. There is however wide inter-subject variation suggesting impaired absorption in some individuals. Plasma half-life is about 3 hours in adults and somewhat less in children. Its initial absorption, but not its overall bioavailability, is affected by food. Prednisolone has a biological half-life lasting several hours, making it suitable for alternate-day administration regimens.

They show dose dependent pharmacokinetics, with an increase in dose leading to an increase in volume of distribution and plasma clearance. The degree of plasma protein binding determines the distribution and clearance of free, pharmacologically active drug. Reduced doses are necessary in patients with hypoalbuminaemia. They are primarily transformed in the liver and excreted in the urine as free and conjugated metabolites, together with small amounts of unchanged prednisolone.

Therapeutic indications

In ulcerative colitis, systemic corticosteroids are appropriate in patients with moderate to severe activity and in those with mild activity who do not respond to mesalamine. Intravenous systemic steroids represent the first choice in severe ulcerative colitis.

In Crohn’s disease, they are appropriate in patients with moderate to severe activity.

Dosing, administration

Systemic steroids should be given at the lowest effective dose for the minimum period in order to minimise side effects. In children, they should be used only when specifically indicated, in a minimum dosage and for the shortest possible time.

There is no clear indication on the maximum dosage of systemic steroids in IBD. Dosage should not exceed 1 mg/kg or 60 mg/day at the beginning of the treatment. Abrupt withdrawal of doses of up to 40mg daily of prednisolone, or equivalent for 3 weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. For those who exceed these doses or time of exposure, gradual withdrawal should be considered. Dosage reductions should not exceed 5-7.5mg daily during chronic treatment. This gradual withdrawal should also be considered even after courses lasting 3 weeks or less in:

• 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 40mg daily of prednisolone (or equivalent).

• patients repeatedly taking doses in the evening, although steroids should be taken in the morning to be consistent with the normal biocycle of endogenous steroidal production by the adrenal gland.

In IBD patients, calcium and vitamin D (1500-2000 International Unit /day) supplementation should be given during steroid treatment.

Contraindications

• Hypersensitivity to the active substance
• Systemic infections unless specific anti-infective therapy is employed.
• Patients with ocular herpes simplex due to the possibility of perforation.

Adverse effects

General: Increased susceptibility to and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis; impaired healing, withdrawal symptoms

Blood disorders: Leucocytosis

Hypersensitivity including anaphylaxis, fatigue, malaise

Endocrine disorders: Cushingoid facies, weight gain, impaired carbohydrate tolerance with increased requirement for antidiabetic therapy, manifestation of latent diabetes mellitus, menstrual irregularity and amenorrhoea

Metabolism and nutrition disorders: Sodium and water retention, hypokalaemic alkalosis, potassium loss, negative nitrogen and calcium balance

Psychiatric disorders: Euphoria, psychological dependence, depression, insomnia, dizziness, headache, vertigo, aggravation of schizophrenia, aggravation of epilepsy

Eye disorders: Increased intra-ocular pressure, glaucoma, papilloedema, posterior subcapsular cataracts, exophthalmos, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal disease and vision, blurred

Cardiac disorders: Congestive heart failure in susceptible patients, hypertension

Vascular disorders: Thromboembolism

Gastrointestinal disorders: Dyspepsia, nausea, peptic ulceration with perforation and haemorrhage, abdominal distension, abdominal pain, increased appetite which may result in weight gain, diarrhoea, oesophageal ulceration, oesophageal candidiasis, acute pancreatitis

Skin and subcutaneous tissue disorders: Hirsutism, skin atrophy, bruising, striae, telangiectasia, acne, increased sweating, may suppress reactions to skin tests, pruritis, rash, urticaria

Musculoskeletal and connective tissue disorders: Proximal myopathy, osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, tendon rupture, myalgia

Renal and urinary disorders: Scleroderma renal crisis

Laboratory parameters and Monitoring

Before treatment:

• Assess disease activity by appropriate tests before start of treatment
• Measure blood pressure, and serum glucose, creatinine, and electrolytes before start of treatment
• Consider a Dual Emission X-ray Absorptiometry (DEXA), if risk factors for osteoporosis are identified and a baseline DEXA is not available

Follow up:

• Consider annual or biennial DEXA if in prolonged or repeated exposure to steroids is unavoidable
• Check vitamin D status

Interactions with other Drugs

Co-treatment with CYP3A inhibitors 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.

Patients with diabetes mellitus receiving concurrent insulin and/or oral hypoglycemic agents may require dosage adjustments of such therapy.

Concomitant administration of ulcerogenic drugs such as indomethacin during corticosteroid therapy may increase the risk of GI ulceration. Although concomitant therapy with salicylate and corticosteroids does not appear to increase the incidence or severity of GI ulceration, the possibility of this effect should be considered.

Serum salicylate concentrations may decrease when corticosteroids are administered concomitantly. The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication.

Response to anticoagulants may be reduced or less often, enhanced by corticosteroids. Close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.

Carbamazepine, phenobarbital, phenytoin and primidone accelerate metabolism of corticosteroids and may reduce their effect.

Rifamycin accelerate metabolism of corticosteroids and thus may reduce their effect. Erythromycin inhibits metabolism of methylprednisolone and possibly other corticosteroids.

Risk of hypokalaemia may be increased with amphotericin; ketoconazole inhibits metabolism of methylprednisolone and possibly other corticosteroids.

Ritonavir possibly increases plasma concentrations of prednisolone and other corticosteroids.

Cardiac Glycosides Increased toxicity if hypokalaemia occurs with corticosteroids.

Ciclosporin: Concomitant administration of prednisolone and ciclosporin may result in decreased plasma clearance of prednisolone (i.e. increased plasma concentration of prednisolone). The need for appropriate dosage adjustment should be considered when these drugs are administered concomitantly.

Increased risk of haematological toxicity with methotrexate.

Effect of corticosteroids may be reduced for 3-4 days after mifepristone.

Live vaccines should not be given to individuals with impaired immune responsiveness. The antibody response to other vaccines may be diminished.

Oestrogens may potentiate the effects of glucocorticoids and dosage adjustments may be required if oestrogens are added to or withdrawn from a stable dosage regimen.

Growth promoting effect of growth hormones may be inhibited.

Increased risk of hypokalaemia if high doses of corticosteroids given with high doses of bambuterol, fenoteral, formoteral, ritodrine, salbutamol, salmeterol and terbutaline.

The desired effects of hypoglycaemic agents (including insulin), antihypertensives and diuretics are antagonised by corticosteroids; and the hypokalaemic effect of acetazolamide, loop diuretics, thiazide diuretics, carbenoxolone and theophylline are enhanced.

Special situations (e.g. pregnancy)

Pregnancy

About 88% of prednisolone is inactivated as it crosses the placenta. 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 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.

Breast-feeding

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 receiving 40mg or more daily should be monitored for signs of adrenal suppression but the benefits of breast-feeding are likely to outweigh any theoretical risk.

Equivalence among systemic steroids
Molecule	Equivalent dose (mg)
Betamethasone	3
Dexamethasone	3.75
Methylprednisolone	20
Triamcinolone	20
Prednisone	25
Prednisolone	25
Hydrocortisone	100