Update section 4.8, following the submission of the PSUR. Entire section is changed, so changes are not bolded. Update Section 10.

4.8.      Undesirable Effects

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

The following side effects may be associated with the long-term systemic use of corticosteroids.

Infections and Infestations

Increased 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 disorders

Leukocytosis.

Immune system disorders

Hypersensitivity including anaphylaxis has been reported.

Endocrine disorders

Suppression of the HPA axis.

Cushingoid.

Impaired carbohydrate intolerance with increased requirement for anti-diabetic therapy, manifestation of latent diabetes mellitus.

Metabolism and nutrition disorders

Sodium and water retention, hypokalaemia, hypokalaemic alkalosis, increased appetite, negative protein and calcium balance.

Psychiatric disorders

Euphoric 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 disorders

Dizziness, headache.

Increased intracranial pressure with papilloedema in children (pseudotumour cerebri) -usually after treatment withdrawal.

Aggravation of epilepsy.

Eye disorders

Glaucoma, papilloedema, posterior subcapsular cataracts, central serous chorioretinopathy, exophthalmos, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal diseases.

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Myocardial rupture following recent myocardial infarction.

Congestive cardiac failure (in susceptible patients).

Vascular disorders

Hypertension, embolism.

Respiratory, thoracic and mediastinal disorders

Hiccups.

Gastrointestinal disorders

Dyspepsia, nausea, vomiting, abdominal distension, abdominal pain, diarrhoea, oesophageal ulceration, candidiasis, pancreatitis acute.

Peptic ulceration with perforation and haemorrhage.

Skin and subcutaneous tissue disorders

Skin Atrophy, skin striae, acne, telangiectasia, hyperhidrosis, rash, pruritus, urticaria, hirsutism.

Musculoskeletal and connective tissue disorders

Myopathy, osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, myalgia.

Growth retardation in infancy, childhood and adolescence.

Reproductive system and breast disorders

Menstruation irregular, amenorrhoea.

General disorders and administration site conditions

Impaired healing, malaise.

Investigations

Weight increased.

Injury, poisoning and procedural complications

Tendon rupture, contusion (bruising).

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 ‘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.

10.              Date of (Partial) Revision of the Text

March 2010

Addition of the following text:

Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy.  Discontinuation of corticosteroids may result in clinical remission.

Abrupt withdrawal of systemic corticosteroids treatment which has continued up to 3 weeks is appropriate if it is considered that the disease is unlikely to relapse.  Abrupt withdrawal of dose 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.  In the following patient groups, gradual withdrawal of systemic corticosteroid 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 years of cessation of long-term therapy (month or years).
• Patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy.
• Patients receiving doses of systemic corticosteroid greater than 40 mg daily of prednisolone (or equivalent).
•  Patients repeatedly taking doses in the evening.

Section 4.5 Interaction with other medicinal products and other forms of interaction

In the paragraph:

Serum levels of salicylates may increase considerably if corticosteroid therapy is withdrawn, possible causing intoxication. Since both salicylates and corticosteriods are ulcerogenic, it is possible that there will be an increased rate of gastrointestinal ulceration.  

The following text has been added:

There is an increased risk of gastrointestinal bleeding with aspirin and NSAIDs.

In the paragraph:

The desired actions of hypoglycaemic drugs (including insulin), antihypertensives and diuretics will be antagonised by corticosteroids.

The following text has been added:

The growth promoting effect of somatropin may be inhibited by corticosteroids.

In the paragraph:

The potassium-depleting effects of amphotericin, carbenoxolone and diuretics (acetazolamide, loop diuretics and thiazides) are enhanced by corticosteroids and signs of hypokalaemia should be looked for during their concurrent use.  

The following text has been added:

There is also an increased risk of hypokalaemia with the simultaneous use of theophylline, and if high doses of corticosteroids are given with high doses of bambuterol, fenoterol, ritodrine, salbutamol, salmeterol and terbutaline.

The toxicity of cardiac glycosides is increase if hypokalaemia occurs with corticosteroids.

In the paragraph:

The metabolism of corticosteroids may be enhanced and the therapeutic effects reduced by certain barbiturates (e.g. phenobarbitone), and by phenytoin, rifampicin, rifabutin, primidone, carbamazepine and aminoglutethimide.  

The following text has been added:

The effect of corticosteroids may be reduced for 3-4 days after taking mifepristone.

Ketoconazole may inhibit the metabolism of corticosteroids.

The plasma concentration of prednisolone and other corticosteroids may be increased by ritonavir, ciclosporin and oral contraceptives.

Under the section: Ophthalmic

The following paragraph:

Increased intra-ocular pressure, glaucoma, papilloedema, posterior subcapsular cataracts, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal diseases.

Has been changed to:

Increased intra-ocular pressure, glaucoma, papilloedema, posterior subcapsular cataracts, central serous chorioretinopathy, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal diseases.

Under the section: General

The following paragraph:

Hypersensitivity, including anaphylaxis, has been reported. Nausea, malaise, leucocytosis, thromboembolism.

Has been changed to:

Hypersensitivity, including anaphylaxis, has been reported. Nausea, malaise, leucocytosis, thromboembolism, hiccups, myocardial rupture following recent myocardial infarction.

Abrupt withdrawal of systemic corticosteriod treatment which has continued up to 3 weeks is appropriate if it is considered that the disease is unlikely to relapse. Abrupt withdrawal of doses of up to 40 mg daily of prednisolone (or equivalent) 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 coticosteroid 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 corticosteriod therapy,

• Patients receiving doses of systemic corticosteriod greater than 40 mg daily of prednisolone (or equivalent),

• Patients repeatedly taking doses in the evening.

Addition of the following text:

Withdrawal Symptoms

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.

10. Date of revision of the text

18 June 2002 17/11/2005