Medrone Tablets 100mg

1. Name Of The Medicinal Product

Medrone^® Tablets 100 mg.

2. Qualitative And Quantitative Composition

Each Medrone Tablet contains 100 mg methylprednisolone Ph. Eur.

3. Pharmaceutical Form

Tablet

4. Clinical Particulars

4.1 Therapeutic Indications

Medrone is a potent corticosteroid with an anti-inflammatory activity at least five times that of hydrocortisone. An enhanced separation of glucocorticoid and mineralocorticoid effect results in a reduced incidence of sodium and water retention.

Medrone is indicated for conditions requiring glucocorticoid activity such as:-

1. Collagen diseases/arteritis

Systemic lupus erythematosus

Systemic dermatomyositis (polymyositis)

Rheumatic fever with severe carditis

Giant cell arteritis/polymyalgia rheumatica

2. Dermatological diseases

Pemphigus vulgaris

3. Allergic states

Bronchial asthma

4. Respiratory diseases

Pulmonary sarcoid

5. Haematological disorders

Idiopathic thrombocytopenic purpura

Haemolytic anaemia (autoimmune)

6. Neoplastic diseases

Leukaemia (acute and lymphatic)

Malignant lymphoma

7. Gastro-intestinal diseases

Crohn's disease

8. Miscellaneous

Tuberculous meningitis (with appropriate antituberculous chemotherapy)

Transplantation

4.2 Posology And Method Of Administration

The dosage recommendations shown in the table below are suggested initial daily doses and are intended as guides. The average total daily dose recommended may be given either as a single dose or in divided doses (excepting in alternate day therapy when the minimum effective daily dose is doubled and given every other day at 8.00 a.m.). It is envisaged that the 100 mg tablet will be used for high initial daily or alternate day doses in acute situations, with tapering of dosage achieved by using the 16 mg tablet.

Undesirable effects may be minimised by using the lowest effective dose for the minimum period (see Special warnings and special precautions for use).

The initial suppressive dose level may vary depending on the condition being treated. As soon as a satisfactory clinical response is obtained, the daily dose should be reduced gradually, either to termination of treatment in the case of acute conditions or to the minimal effective maintenance dose level in the case of chronic conditions. In chronic conditions it is important that the reduction in dosage from initial to maintenance dose levels be accomplished as clinically appropriate.

In alternate-day therapy, the minimum daily corticoid requirement is doubled and administered as a single dose every other day at 8.00 a.m. Dosage requirements depend on the condition being treated and response of the patient.

Elderly patients: Treatment of elderly patients, particularly if long-term, should be planned bearing in mind the more serious consequences of the common side-effects of corticosteroids in old age and close clinical supervision is required (see Special warnings and special precautions for use).

Children: In general, dosage for children should be based upon clinical response and is at the discretion of the clinician. Treatment should be limited to the minimum dosage for the shortest period of time. If possible, treatment should be administered as a single dose on alternate days (see Special warnings and special precautions for use).

Dosage Recommendations:

Indications	Recommended initial daily dosage
Systemic lupus erythematosus	20-100 mg
Systemic dermatomyositis	48 mg
Acute rheumatic fever	48 mg until ESR normal for one week.
Giant cell arteritis/polymyalgia rheumatica	64 mg
Pemphigus vulgaris	80-360 mg
Bronchial asthma	up to 64 mg single dose/alternate day up to 100 mg maximum.
Pulmonary sarcoid	32-48 mg on alternate days.
Haematological disorders and leukaemias	16-100 mg
Malignant lymphoma	16-100 mg
Crohn's disease	up to 48 mg per day in acute episodes.
Organ transplantation	up to 3.6 mg/kg/day

4.3 Contraindications

Methylprednisolone tablets are contraindicated in patients who have:

• systemic fungal infections

• systemic infections unless specific anti-infective therapy is employed

• hypersensitivity to the active substance or to any of the excipients

4.4 Special Warnings And Precautions For Use

Immunosuppressant Effects/Increased Susceptibility to Infections

Corticosteroids may increase susceptibility to infection, may mask some signs of infection, and new infections may appear during their use. Suppression of the inflammatory response and immune function increases the susceptibility to fungal, viral and bacterial infections and their severity. The clinical presentation may often be atypical and may reach an advanced stage before being recognised.

Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids.

Chickenpox is of serious 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 immunization 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.

Exposure to measles should be avoided. Medical advice must be sought immediately if exposure occurs. Prophylaxis with normal intramuscular immunoglobulin may be needed.

Similarly corticosteroids should be used with great care in patients with known or suspected parasitic infections such as Strongyloides (threadworm) infestation, which may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

The role of corticosteroids in septic shock has been controversial, with early studies reporting both beneficial and detrimental effects. More recently, supplemental corticosteroids have been suggested to be beneficial in patients with established septic shock who exhibit adrenal insufficiency. However, their routine use in septic shock is not recommended. A systematic review of short-course high-dose corticosteroids did not support their use. However, meta-analyses, and a review have suggested that longer courses (5-11 days) of low-dose corticosteroids might reduce mortality.

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

The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

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

Aspirin and nonsteroidal anti-inflammatory agents should be used cautiously in conjunction with corticosteroids.

Endocrine Effects

Adrenal cortical atrophy develops during prolonged therapy and may persist for months after stopping treatment. In patients who have received more than physiological doses of systemic corticosteroids (approximately 6 mg methylprednisolone) for greater than 3 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 of 6 mg methylprednisolone 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 3 weeks is appropriate if it considered that the disease is unlikely to relapse. Abrupt withdrawal of doses up to 32 mg daily of methylprednisolone for 3 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 3 weeks or less:

• 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. In addition, acute adrenal insufficiency leading to a fatal outcome may occur if glucocorticoids are withdrawn abruptly.

• Patients receiving doses of systemic corticosteroid greater than 32 mg daily of methylprednisolone.

• Patients repeatedly taking doses in the evening.

In drug-induced adrenocorticol insufficiency mineralocorticoid secretion may be impaired, therefore salt and/or a mineralocorticoid should be administered concurrently.

Glucocorticoids can produce or aggravate Cushing's syndrome, therefore glucocorticoids should be avoided in patients with Cushing's disease.

Particular care is required when considering the use of systemic corticosteroids in patients with hypothyroidism and frequent patient monitoring is necessary.

Metabolism and Nutrition Disorders

Corticosteroids, including methylprednisolone, can increase blood glucose, worsen pre-existing diabetes, and predispose those on long-term corticosteroid therapy to diabetes mellitus.

Particular care is required when considering the use of systemic corticosteroids in patients with Diabetes mellitus (or a family history of diabetes) and frequent patient monitoring is necessary.

Psychiatric Effects

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 treatment. Risks may be higher with high doses/systemic exposure (see also section 4.5), 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 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.

Nervous System Effects

Particular care is required when considering the use of systemic corticosteroids in patients with seizure disorders and myasthenia gravis and frequent patient monitoring is necessary.

Ocular Effects

Particular care is required when considering the use of systemic corticosteroids in patients with glaucoma (or a family history of glaucoma) and ocular herpes simplex as there is a fear of corneal perforation and frequent patient monitoring is necessary.

Prolonged use of corticosteroids may produce posterior 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.

Secondary fungal and viral infections of the eye may also be enhanced in patients receiving glucocorticoids.

Cardiac events

Systemic corticosteroids should be used with caution, and only if strictly necessary, in cases of congestive heart failure.

Particular care is required when considering the use of systemic corticosteroids in patients with recent myocardial infarction (myocardial rupture has been reported) and frequent patient monitoring is necessary.

Care should be taken for patients receiving cardioactive drugs such as digoxin because of steroid induced electrolyte disturbance/potassium loss (see section 4.8).

Vascular Effects

Particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary.

Hypertension Predisposition to thrombophlebitis

Gastrointestinal Effects

Particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary.

Peptic ulceration. Fresh intestinal anastomoses. Abscess or other pyogenic infections. Ulcerative colitis. Diverticulitis.

Hepatobiliary Effects

There is an enhanced effect of corticosteroids on patients with cirrhosis.

Particular care is required when considering the use of systemic corticosteroids in patients with liver failure or cirrhosis and frequent patient monitoring is necessary.

Musculoskeletal Effects

An acute myopathy has been reported with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (eg, myasthenia gravis), or in patients receiving concomitant therapy with anticholinergics, such as neuromuscular blocking drugs (eg pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevations of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.

Particular care is required when considering the use of systemic corticosteroids in patients with osteoporosis (post-menopausal females are particularly at risk) and frequent patient monitoring is necessary.

Renal and Urinary

Particular care is required when considering the use of systemic corticosteroids in patients with renal insufficiency and frequent patient monitoring is necessary.

Injury, poisoning and procedural complications

High doses of systemic corticosteroids should not be used for the treatment of traumatic brain injury.

Other

Undesirable effects may be minimised by using the lowest effective dose for the minimum period, and by administering the daily requirement as a single morning dose or whenever possible as a single morning dose on alternative days. Frequent patient review is required to appropriately titrate the dose against disease activity (see section 4.2).

Patients should carry 'Steroid Treatment' cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment

Use in children: Corticosteroids cause growth retardation in infancy, childhood and adolescence. . Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed. Treatment should be limited to the minimum dosage for the shortest possible time. In order to minimise suppression of the hypothalamo-pituitary-adrenal axis and growth retardation, treatment should be administered where possible as a single dose on alternate days (see section 4.2).

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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Methylprednisolone is a cytochrome P450 enzyme (CYP) substrate and is mainly metabolized by the CYP3A4 enzyme. CYP3A4 is the dominant enzyme of the most abundant CYP subfamily in the liver of adult humans. It catalyzes 6β-hydroxylation of steroids, the essential Phase I metabolic step for both endogenous and synthetic corticosteroids. Many other compounds are also substrates of CYP3A4, some of which (as well as other drugs) have been shown to alter glucocorticoid metabolism by induction (upregulation) or inhibition of the CYP3A4 enzyme.

Drug Class or Type - DRUG or SUBSTANCE	Interaction	Effect
Antibiotic, Antitubercular - RIFAMPIN - RIFABUTIN	CYP3A4 Inducer	CYP3A4 INDUCERS - Drugs that induce CYP3A4 activity generally increase hepatic clearance, resulting in decreased plasma concentration of medications that are substrates for CYP3A4. Coadministration may require an increase in methylprednisolone dosage to achieve the desired result.
Anticonvulsants - PHENOBARBITAL - PHENYTOIN - PRIMIDONE
Adrenocortical steroid synthesis inhibitor - AMINOGLUTETHIMIDE
Anticonvulsant - CARBAMAZEPINE	CYP3A4 Inducer (and Substrate)	CYP3A4 INDUCERS – see box above CYP3A4 SUBSTRATES - In the presence of another CYP3A4 substrate, the hepatic clearance of methylprednisolone may be inhibited or induced, with corresponding dosage adjustments required. It is possible that adverse events associated with the use of either drug alone may be more likely to occur with coadministration.
Macrolide Antibacterial - TROLEANDOMYCIN	CYP3A4 Inhibitor	CYP3A4 INHIBITORS - Drugs that inhibit CYP3A4 activity generally decrease hepatic clearance and increase the plasma concentration of CYP3A4 substrate medications, such as methylprednisolone. In the presence of a CYP3A4 inhibitor, the dose of methylprednisolone may need to be titrated to avoid steroid toxicity.
- GRAPEFRUIT JUICE
Calcium Antagonist - MIBEFRADIL
Histamine H2 receptor Antagonist - CIMETIDINE
Antiemetic - APREPITANT - FOSAPREPITANT	CYP3A4 Inhibitor (and Substrate)	CYP3A4 INHIBITORS – see box above CYP3A4 SUBSTRATES - In the presence of another CYP3A4 substrate, the hepatic clearance of methylprednisolone may be inhibited or induced, with corresponding dosage adjustments required. It is possible that adverse events associated with the use of either drug alone may be more likely to occur with coadministration. (1) Mutual inhibition of metabolism occurs with concurrent use of cyclosporine and methylprednisolone, which may increase the plasma concentrations of either or both drugs. Therefore, it is possible that adverse events associated with the use of either drug alone may be more likely to occur upon coadministration. (2) Protease inhibitors, such as indinavir and ritonavir, may increase plasma concentrations of corticosteroids. (3) Corticosteroids may induce the metabolism of HIV-protease inhibitors resulting in reduced plasma concentrations.
Antifungal - ITRACONAZOLE - KETOCONAZOLE
Calcium Channel Blocker - DILTIAZEM
Contraceptives (oral) - ETHINYLESTRADIOL/ NORETHINDRONE
Immunosuppressant - CICLOSPORIN (1)
Macrolide Antibacterial - CLARITHROMYCIN - ERYTHROMYCIN
Antivirals - HIV-PROTEASE INHIBITORS (2) (3)
Immunosuppressant - CYCLOPHOSPHAMIDE - TACROLIMUS	CYP3A4 Substrate	CYP3A4 SUBSTRATES - In the presence of another CYP3A4 substrate, the hepatic clearance of methylprednisolone may be inhibited or induced, with corresponding dosage adjustments required. It is possible that adverse events associated with the use of either drug alone may be more likely to occur with coadministration.
NSAIDs (nonsteroidal anti-inflammatory drugs) (4) - high-dose ASPIRIN (5) (acetylsalicylic acid)	Non-CYP3A4-mediated effects	(4) There may be increased incidence of gastrointestinal bleeding and ulceration when corticosteroids are given with NSAIDs. (5) Methylprednisolone may increase the clearance of high-dose aspirin. This decrease in salicylate serum levels could lead to an increased risk of salicylate toxicity when methylprednisolone is withdrawn.
Anticholinergics (6) - NEUROMUSCULAR BLOCKERS (7)	(6) An acute myopathy has been reported with the concomitant use of high doses of corticosteroids and anticholinergics, such as neuromuscular blocking drugs. (See section 4.4 Warnings and Precautions, Musculoskeletal, for additional information.) (7) Antagonism of the neuromuscular blocking effects of pancuronium and vecuronium has been reported in patients taking corticosteroids. This interaction may be expected with all competitive neuromuscular blockers.
Anticoagulants (oral)	The efficacy of coumarin anticoagulants may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.

Steroids may reduce the effects of anticholinesterases in myasthenia gravis. The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids, and the hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics and carbenoxolone are enhanced.

4.6 Pregnancy And Lactation

Pregnancy

The ability of corticosteroids to cross the placenta varies between individual drugs, however, methylprednisolone does cross the placenta.

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and affects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate in man, however, when administered for long 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.

Lactation

Corticosteroids are excreted in small amounts in breast milk, however, doses of up to 40 mg daily of methylprednisolone are unlikely to cause systemic effects in the infant. Infants of mothers taking higher doses than this may have a degree of adrenal suppression. Since adequate reproductive studies have not been performed in humans with glucocorticoids, these drugs should be administered to nursing mothers only if the benefits of therapy are judged to outweigh the potential risks to the infant.

4.7 Effects On Ability To Drive And Use Machines

The effect of corticosteroids on the ability to drive or use machinery has not been evaluated. There is no evidence to suggest that methylprednisolone tablets may affect the ability to drive and use machines. No deleterious effects of corticosteroids on driving or operating machinery ability is expected.

4.8 Undesirable Effects

MedDRA System Organ Class	Frequency†	Undesirable Effects
Infections and infestations	Common	Infection (including increased susceptibility and severity of infections with suppression of clinical symptoms and signs)
Not Known	Opportunistic infection, recurrence of dormant tuberculosis
Neoplasms benign, malignant and unspecified (including cysts and polyps)	Not Known	Kaposi's sarcoma
Blood and lymphatic system disorders	Not Known	Leucocytosis
Immune system disorders	Not Known	Drug hypersensitivity (including Anaphylactic reaction and Anaphylactoid reaction); Suppression of reactions to skin tests
Endocrine disorders	Common	Cushingoid
Not Known	Hypopituitarism
Metabolism and nutrition disorders	Common	Sodium retention; Fluid retention;
Not Known	Alkalosis hypokalaemic; Metabolic acidosis; Glucose tolerance impaired; increased requirements for insulin or oral hypoglycemic agents in diabetics; Increased appetite (which may result in Weight increased).
Psychiatric disorders	Common	Affective disorder (including Depressed mood and Euphoric mood)
Not Known	Psychotic disorder (including Mania, Delusion, Hallucination, and Schizophrenia [aggravation of]); Psychotic behaviour; Affective disorder (including Affect lability, Psychological dependence, Suicidal ideation); Mental disorder; Personality change; Mood swings; Confusional state; Abnormal behaviour; Anxiety; Insomnia; Irritibility.
Nervous system disorders	Not Known	Convulsions; Intracranial pressure increased (with Papilloedema [Benign intracranial hypertension]); Amnesia Cognitive disorder; Dizziness; Headache.
Eye disorders	Common	Cataract subcapsular
Not Known	Glaucoma, Exophthalmos, Corneal thinning; Scleral thinning
Ear and labyrinth disorders	Not Known	Vertigo
Cardiac disorders	Not Known	Cardiac failure congestive (in susceptible patients), Myocardial rupture following myocardial infarction
Vascular disorders	Common	Hypertension
Not Known	Hypotension, Embolism arterial
Respiratory, thoracic and mediastinal disorders	Not Known	Hiccups
Gastrointestinal disorders	Common	Peptic ulcer (with possible Peptic ulcer perforation and Peptic ulcer haemorrhage)
Not Known	Intestinal perforation; Gastric haemorrhage; Pancreatitis; Oesophagitis ulcerative; Abdominal distension; Oesophagitis; Abdominal pain; Diarrhoea; Dyspepsia, Nausea.
Skin and subcutaneous tissue disorders	Common	Skin atrophy, Acne
Not Known	Erythema; Angioedema; Pruritus; Urticaria Ecchymosis, Petechiae; Rash; Hirsutism, Hyperhidrosis; Skin striae, Telangiectasia.
Musculoskeletal and connective tissue disorders	Common	Muscular weakness; Growth retardation
Not Known	Pathologic fracture; Osteonecrosis; Muscle atrophy; Neuropathic arthropathy; Myopathy; Osteoporosis; Arthralgia; Myalgia.
Reproductive system and breast disorders	Not Known	Menstruation irregular
General disorders and administration site conditions	Common	Impaired healing
Not Known	Fatigue; Malaise Withdrawal symptoms - too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death (see section 4.4) A steroid “withdrawal syndrome,” seemingly unrelated to adrenocortical insufficiency, may also occur following abrupt discontinuance of glucocorticoids. This syndrome includes symptoms such as: anorexia, nausea, vomiting, lethargy, headache, fever, mylagia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules, weight loss, joint pain, desquamation, and/or hypotension. These effects are thought to be due to the sudden change in glucocorticoid concentration rather than to low corticosteroid levels.
Investigations	Common	Blood potassium decreased
Not Known	Intraocular pressure increased; Carbohydrate tolerance decreased; Alanine aminotransferase increased; Aspartate aminotransferase increased; Blood alkaline phosphatase increased; Urine calcium increased.
Injury, poisoning and procedural complications	Not Known	Tendon rupture (particularly of the Achilles tendon); Spinal compression fracture.

† Common (

The incidence of predictable undesirable side-effects associated with the use of corticosteroids, including hypothalamic-pituitary-adrenal suppression correlates with the relative potency of the drug, dosage, timing of administration and duration of treatment (see Section 4.4).

4.9 Overdose

Administration of methylprednisolone should not be discontinued abruptly but tailed off over a period of time. Appropriate action should be taken to alleviate the symptoms produced by any side-effect that may become apparent. It may be necessary to support the patient with corticosteroids during any further period of tra