This information is intended for use by health professionals

1. Name of the medicinal product

Prednisolone 5mg Suppositories

2. Qualitative and quantitative composition

One suppository contains 5mg prednisolone as the sodium phosphate ester.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Suppository

Cream coloured, oval shaped waxy suppositories

4. Clinical particulars
4.1 Therapeutic indications

Prednisolone is a glucocorticosteroid which is about four times as potent as hydrocortisone on a weight for weight basis.

Prednisolone 5mg Suppositories are indicated for the treatment of haemorrhagic and granular proctitis and the anal complications of Crohn's disease.

4.2 Posology and method of administration

Posology

Adults and paediatric population:

One suppository inserted at night and one in the morning after defaecation. When the response is good, treatment is usually continued for some months. If symptoms recur later, treatment should be resumed.

Method of administration:

Rectal

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Systemic or local infection unless specific anti-infective therapy is employed.

4.4 Special warnings and precautions for use

Although Prednisolone 5mg Suppositories are applied locally, it should be borne in mind that there is likely to be substantial systemic absorption, especially when the bowel is inflamed.

Undesirable effects may be minimised by using for a minimum period. Frequent patient review is required to monitor therapeutic effect against disease activity.

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.

Chickenpox is of particular concern since this normally minor illness may be fatal in immunosuppressed patients. Patients 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 should be advised to take particular care to avoid exposure to measles and to seek immediate medical advice if exposure occurs. Prophylaxis with intramuscular normal immunoglobulin may be needed.

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

Corticosteroid treatment may reduce the response of the pituitary adrenal axis to stress, and relative insufficiency can persist for up to a year after withdrawal of prolonged therapy. Withdrawal of corticosteroids after prolonged therapy must therefore always be gradual to avoid acute adrenal insufficiency, being tapered off over weeks or months according to the dose and duration of treatment. During prolonged therapy any intercurrent illness, trauma or surgical procedure will require a temporary increase in dosage. If corticosteroids have been stopped following prolonged therapy they may need to be temporarily re-introduced.

Use with caution in patients with myasthenia gravis, non-specific ulcerative colitis, diverticulitis and fresh intestinal anastomoses.

Special precautions:

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

A. Osteoporosis (post-menopausal females are particularly at risk).

B. Hypertension or congestive heart failure.

C. Existing or previous history of severe affective disorders (especially previous steroid psychosis).

D. Diabetes mellitus (or a family history of diabetes).

E. History of tuberculosis.

F. Glaucoma (or a family history of glaucoma).

G. Previous corticosteroid-induced myopathy.

H. Liver failure - blood levels of corticosteroid may be increased, (as with other drugs which are metabolised in the liver).

I. Renal insufficiency.

J. Epilepsy.

K. Peptic ulceration.

L. Hypothyroidism.

M. Recent myocardial infarction.

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.

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 pharmacokinetic interactions that can increase the risk of side effects), 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 also 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.

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.

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

Systemic absorption of prednisolone should be borne in mind, especially when there is local inflammation. Thus the following interactions are possible:

Co-treatment with CYP3A inhibitors, including cobicistat-containing products, 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.

Analgesics:

Increased risk of gastro-intestinal bleeding and ulceration with aspirin and NSAIDs; the renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication.

Antibacterials:

Rifamycins accelerate metabolism of corticosteroids (reduced effect); erythromycin inhibits metabolism of methylprednisolone and possibly other corticosteroids.

Fluoroquinolones:

Increased risk of tendon rupture.

Anticoagulants:

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.

Antidiabetics:

Antagonism of hypoglycaemic effect.

Antiepileptics:

Carbamazepine, phenobarbital, phenytoin and primidone accelerate metabolism of corticosteroids (reduced effect).

Antifungals:

Increased risk of hypokalaemia with amphotericin (avoid concomitant use unless corticosteroids are required to control reactions); ketoconazole inhibits metabolism of methylprednisolone and possibly other corticosteroids.

Antihypertensives:

Antagonism of hypotensive effect.

Anticholinesterases:

Decreased effect of anticholinesterases in myasthenia gravis.

Antivirals:

Ritonavir possibly increases plasma concentration of prednisolone.

Cardiac Glycosides:

Increased toxicity if hypokalaemia occurs with corticosteroids.

Ciclosporin:

Increased plasma concentrations of prednisolone.

Cytotoxics:

Increased risk of haematological toxicity with methotrexate.

Diuretics:

Antagonism of diuretic effect; acetazolamide, loop diuretics, and thiazides increased risk of hypokalaemia.

Hormone antagonists:

Aminoglutethimide accelerates metabolism of corticosteroids (reduced effect).

Licorice:

Increased corticosteroid levels.

Mifepristone:

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

Neuromuscular blockers:

Antagonism of the neuromuscular blockade.

Oral Contraceptives:

Alteration in the plasma protein binding and metabolism of prednisolone caused by oestrogens, with or without progesterone, can result in exposure of women to increased levels of unbound prednisolone for prolonged periods of time.

Somatropin:

The growth promoting effect of somatropin may be inhibited.

Sympathomimetics:

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

Theophylline:

Increased risk of hypokalaemia.

Ulcer-healing drugs:

Carbenoxolone increases the risk of hypokalaemia.

Vaccines:

Live vaccines should not be given to individuals with impaired immune response as a result of treatment with large doses of corticosteroids.

4.6 Fertility, pregnancy and lactation

Pregnancy:

There is inadequate evidence of safety in human pregnancy. Topical administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate and intrauterine growth retardation. There may therefore be a very small risk of such effects in the human foetus. Also, hypoadrenalism may occur in the neonate. 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 and infants of mothers taking pharmacological doses of steroids should be monitored carefully for signs of adrenal suppression.

4.7 Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

A wide range of psychiatric reactions including affective disorder (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 any may occur in both adults and children. In adults, the frequency of severe reactions has been estimated to the 5-6%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is Not known.

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

System organ class

Frequency

Undesirable effects

Infections and infestations

Not known

Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis (see section 4.4).

Blood and lymphatic system disorders

Not known

leukemoid reactions, Leucocytosis

Immune system disorders

Not known

Hypersensitivity including anaphylaxis has been reported.

Endocrine disorders

Not known

Menstrual irregularity and amenorrhoea, Cushingoid facies, hirsutism, impaired carbohydrate tolerance with increased requirement for antidiabetic therapy. Negative protein and calcium balance.

Metabolism and nutrition disorders

Not known

Sodium and water retention, potassium loss, hypokalaemic alkalosis, increased appetite, weight gain, alteration in lipid levels (increases in total cholesterol, low density lipoproteins and triglycerides)

Psychiatric disorders

Not known

Psychological dependence

Nervous system disorders

Not known

Dizziness, headache, aggravation of epilepsy

Eye disorders

Not known

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

Vision, blurred (see also section 4.4)

Cardiac disorders

Not known

Myocardial rupture following recent myocardial infarction.

Vascular disorders

Not known

Hypertension, Thromboembolism

Gastrointestinal disorders

Not known

Nausea, hiccups, dyspepsia, peptic ulceration with perforation and haemorrhage, acute pancreatitis, candidiasis.

Skin and subcutaneous tissue disorders

Not known

Skin atrophy, bruising, telangiectasia, striae, acne, dermatitis and toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders

Not known

Osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, tendon rupture, proximal myopathy.

General disorders and administration site conditions

Not known

Impaired healing

.

Withdrawal symptoms and signs:

Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and in severe cases this could be fatal.

A 'withdrawal syndrome' may also occur including; fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.

Paediatric population

Suppression of the hypothalamic-pituitary-adrenal axis, growth suppression in infancy, childhood and adolescence.

Increased intracranial pressure with papilloedema in children (pseudotumor cerebri), usually after treatment withdrawal.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Treatment is unlikely to be needed in cases of acute overdosage.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Prednisolone sodium phosphate is an active corticosteroid with topical anti-inflammatory activity.

ATC: A07E A01

5.2 Pharmacokinetic properties

Biotransformation:

Corticosteroids are metabolised mainly in the liver but also in the kidney and are excreted in the urine.

Synthetic corticosteroids such as prednisolone have increased potency when compared with the natural corticosteroids, due to their slower metabolism and lower protein-binding affinity.

5.3 Preclinical safety data

None stated.

6. Pharmaceutical particulars
6.1 List of excipients

Witepsol H15

6.2 Incompatibilities

None known

6.3 Shelf life

2 years

6.4 Special precautions for storage

Store below 25°C

6.5 Nature and contents of container

Fin sealed plastic cavities moulded from 100 micron non-toxic PVC. Each cartoned plastic mould contains 10 suppositories (2 strips of 5 suppositories).

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

RPH Pharmaceuticals AB

Lagervägen 7

136 50 Jordbro

Sweden

8. Marketing authorisation number(s)

PL 36301/0055

9. Date of first authorisation/renewal of the authorisation

23/02/1993 / 19/05/2003

10. Date of revision of the text

31/10/2017