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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Dexamethasone 10mg/5ml Oral Solution

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5ml contains 10mg Dexamethasone (as dexamethasone sodium phosphate) 1ml contains 2mg Dexamethasone (as dexamethasone sodium phosphate)

Excipients with known effect:

Liquid maltitol 1375mg/5ml (275mg/ml)

Sorbitol liquid (non crystallising) 700mg/5ml (140mg/ml)

For a full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Oral Solution

A colourless to faint yellow solution.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Dexamethasone is a corticosteroid. It is designed for use in certain endocrine and non-endocrine disorders, in certain cases of cerebral oedema and for diagnostic testing of adrenocortical hyperfunction.

Endocrine disorders: Endocrine exophthalmos.

Non-endocrine disorders:

Dexamethasone may be used in the treatment of non-endocrine corticosteroid responsive conditions including:

Allergy and anaphylaxis: Anaphylaxis.

Arteritis collagenosis: Polymyalgia rheumatica, polyarteritis nodosa.

Haematological disorders: Haemolytic anaemia (also auto immune), leukaemia, myeloma, idiopathic thrombocytopenic purpura in adults, reticulolymphoproliferative disorders (see also under oncological disorders).

Gastroenterological disorders: For treatment during the critical stage in: ulcerative colitis (rectal only); regional enteritis (Crohn’s disease), certain forms of hepatitis.

Muscular disorders: Polymyositis.

Neurological disorders: Raised intra-cranial pressure secondary to cerebral tumours, acute exacerbations of multiple sclerosis.

Ocular disorders: Anterior and posterior uveitis, optic neuritis, chorioretinitis, iridocyclitis, temporal arteritis, orbital pseudotumour.

Renal disorders: Nephrotic syndrome

Pulmonary disorders: Chronic bronchial asthma, aspiration pneumonitis, chronic obstructive pulmonary disease (COPD), sarcoidosis, allergic pulmonary disease such as farmer’s and pigeon breeder’s lung, Loffler’s syndrome, cryptogenic fibrosing alveolitis.

Rheumatic disorders: some cases or specific forms (Felty’s syndrome, Sjorgen’s syndrome) of rheumatoid arthritis, including juvenile rheumatoid arthritis, acute rheumatism, lupus erythematosus disseminatus, temporal arteritis (polymyalgia rheumatica).

Skin disorders: Pemphigus vulgaris, bullous pemphigoid, erythrodermas, serious forms of erythema multiforme (Stevens-Johnson syndrome), mycosis fungoides, bullous dermatitis herpetiformis.

Oncological Disorders: lymphatic leukaemia, especially acute forms, malignant lymphoma (Hodgkin’s disease, non-Hodgkin’s lymphoma), metastasized breast cancer, hypercalcaemia as a result of bone metastasis or Kahler’s disease, Kahler’s disease.

Various: intense allergic reactions; as immunosuppressant in organ transplantation; as an adjuvant in the prevention of nausea and vomiting and in the treatment of cancer with oncolytics that have a serious emetic effect.

4.2 Posology and method of administration

Method of administration For oral use Posology

In general, glucocorticoid dosage depends on the severity of the condition and response of the patient. Under certain circumstances, for instance in stress and changed clinical picture, extra dosage adjustments may be necessary.

The prescribed amount of solution should be withdrawn from the bottle using the oral dosing syringe supplied.

Adults

The dosage should be titrated to the individual response and the nature of the disease. In order to minimise side effects, the lowest effective possible dosage should be used (see section 4.8).

Usually, daily oral dosages of 0.5 - 10 mg are sufficient. In some patients higher dosages may be temporarily required to control the disease. Once the disease is under control the dosage should be reduced or tapered off to the lowest suitable level under continuous monitoring and observation of the patient (see section 4.4).

The initial dosage should be maintained or adjusted until the patient’s response is satisfactory. Both the dose in the evening, which is useful in alleviating morning stiffness, and the divided dosage regimen are associated with greater suppression of the hypothalamo-pituitary-adrenal axis.

If the initial response is favourable, the maintenance dosage should be determined by lowering the dose gradually to the lowest dose required to maintain an adequate clinical response. Chronic dosage should preferably not exceed 1.5mg dexamethasone daily.

If no favourable response is noted within a couple of days, glucocorticoid therapy should be discontinued.

Patients should be monitored for signs that dosage adjustment is required. These may arise from a change in clinical status (e.g. remission or exacerbation of the condition), individual corticosteroid responsiveness or as a result of concomitant stress (e.g. surgery, infection, trauma). During periods of stress it may be necessary to increase the dose temporarily.

If the drug is to be discontinued after more than a few days of treatment, it should be withdrawn gradually.

The following equivalents facilitate changing to dexamethasone from other glucocorticoids:

Milligram for milligram, dexamethasone is approximately equivalent to betamethasone, 4 to 6 times more potent than methylprednisolone and triamcinolone, 6 to 8 times more potent than prednisone and prednisolone, 25 to 30 times more potent than hydrocortisone, and about 35 times more potent than cortisone.

Acute, self-limiting allergic disorders or acute exacerbations of chronic allergic disorders.

The following dosage schedule combining parenteral and oral therapy is suggested:

First day:    Dexamethasone sodium phosphate injection 4mg or 8mg (2ml or

4ml) intramuscularly.

Second day:    1mg (0.5ml) Dexamethasone Oral Solution twice a day.

Third day:    1mg (0.5ml) Dexamethasone Oral Solution twice a day.

Fourth day:    500micrograms (0.25ml) Dexamethasone Oral Solution twice a day.

Fifth day:    500micrograms (0.25ml) Dexamethasone Oral Solution twice a day.

Sixth day:    500micrograms (0.25ml) Dexamethasone Oral Solution.

Seventh day:    500micrograms (0.25ml) Dexamethasone Oral Solution.

Eighth day:    Re-assessment.

This schedule is designed to ensure adequate therapy during acute episodes whilst minimising the risk of overdosage in chronic cases.

Raised intracranial pressure: Initial therapy is usually by injection. When maintenance therapy is required, this should be changed to dexamethasone oral solution as soon as possible. For the palliative management of patients with recurrent or inoperable brain tumours, maintenance dosage should be calculated individually. A dosage of 2mg two or three times a day may be effective. The smallest dosage necessary to control symptoms should always be used.

Lower strength oral formulations may facilitate the administration of lower daily doses in the initial stages of treatment.

Dexamethasone suppression tests:

1. Tests for Cushing’s syndrome:

2mg (1ml) Dexamethasone Oral Solution should be administered at 11pm. Blood samples are then taken at 8am the next morning for plasma cortisol determination.

If greater accuracy is required, 500 micrograms (0.25ml) Dexamethasone Oral Solution should be administered every 6 hours for 48 hours. Blood should be drawn at 8am for plasma cortisol determination on the third morning.

24-hour urine collection should be employed for 17-hydroxycorticosteroid excretion determination.

2. Test to distinguish Cushing’s syndrome caused by pituitary ACTH excess from the syndrome induced by other causes:

2mg (1ml) Dexamethasone Oral Solution should be administered every 6 hours for 48 hours. Blood should be drawn at 8am for plasma cortisol determination on the third morning.

24-hour urine collection should be employed for 17-hydroxycorticosteroid excretion determination.

For a short dexamethasone suppression test, the use of lower strength oral formulations may facilitate the administration of lower doses.

Elderly

The elderly may be more susceptible to the side-effects of corticosteroids particularly during long-term therapy.

Paediatric population

Due to the strength of this formulation, this product is not indicated for paediatric use.

4.3 Contraindications

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

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

-    Systemic fungal infections.

- Stomach ulcer or duodenal ulcer

- Infection with tropical worms

In general no contraindications apply in conditions where the use of glucocorticoids may be life saving.

4.4 Special warnings and precautions for use

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.

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. When reduction in dosage is possible, the reduction should be gradual (Refer to ‘Posology and Administration’).

Anti-inflammatory/Immunosuppressive effects/Infection

Corticosteroids may exacerbate systemic fungal infections and should not be used unless they are needed to control drug reactions due to amphotericin. There have also been reports in which concomitant use of amphotericin and hydrocortisone was followed by cardiac enlargement and heart failure.

Administration of live virus vaccines is contra-indicated in individuals receiving immunosuppressive doses of corticosteroids. If inactivated viral or bacterial vaccines are administered to individuals receiving immunosuppressive doses of corticosteroids, the expected serum antibody response may not be obtained.

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.

Appropriate anti-microbial therapy should accompany glucocorticoid therapy when necessary e.g. in tuberculosis and viral and fungal infections of the eye. There may be decreased resistance and inability to localise infection in patients on corticosteroids.

Chickenpox is of particular 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 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.

Measles can have a more serious or even fatal course in immunosuppressed patients. In such children or adults particular care should be taken to avoid exposure to measles. If exposed, prophylaxis with intramuscular pooled immunoglobulin (IG) may be indicated. Exposed patients should be advised to seek medical advice without delay.

Corticosteroids may activate latent amoebiasis or strongyloidiasis or exacerbate active disease. Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis or Toxoplasma. It is recommended that these are ruled out before initiating corticosteroid therapy particularly in those patients who have spent time in the tropics or those with unexplained diarrhoea.

A report shows that the use of corticosteroids in cerebral malaria is associated with a prolonged coma and an increased incidence of pneumonia and gastro-intestinal bleeding and therefore corticosteroids should not be used in cerebral malaria.

Eye disorders

Prolonged use of corticosteroids may produce subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses. Particular care is needed when treating patients with glaucoma (or family history of glaucoma) as well as when treating patients with ocular herpes simplex, because of possible corneal perforation.

Electrolyte disturbances

Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, retention of salt and water, and increased excretion of potassium, but these effects are less likely to occur with synthetic derivatives, except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary with corticosteroid therapy. All corticosteroids increase calcium excretion.

Particular care is needed when treating patients with renal impairment, hypertention and congestive heart failure.

Adrenal Suppression

Adrenal cortical atrophy develops during prolonged therapy and may persist for years after stopping treatment. 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. In patients who have received more than physiological doses of systemic corticosteroids (approximately 1 mg dexamethasone) 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 1mg dexamethasone 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 is considered that the disease is unlikely to relapse.

Abrupt withdrawal of doses of up to 6mg daily of dexamethasone 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.

•    Patients receiving doses of systemic corticosteroid greater than 6mg daily of dexamethasone.

•    Patients repeatedly taking doses in the evening.

Intercurrent illness and stress

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.

Patients under stress may require increased doses of corticosteroids prior, during and after the period of stressful situation.

Withdrawal symptoms

Stopping corticosteroids after prolonged therapy may cause withdrawal symptoms including fever, myalgia, arthralgia and malaise. This may occur in patients even without evidence of adrenal insufficiency.

General

In addition to the information given under the other headings, particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary:

-    diabetes mellitus (or a family history of diabetes)

-    osteoporosis (especially post-menopausal females)

-    previous corticosteroid-induced myopathy

-    myasthenia gravis

-    non-specific ulcerative colitis, diverticulitis    or fresh intestinal anastomosis

-    peptic ulceration

-    liver failure

-    epilepsy

-    migraine

-    history of allergy to corticosteroids

-    herpes simplex

There is an enhanced effect of corticosteroids in patients with hypothyroidism and in those with cirrhosis.

Fat embolism has been reported as a possible complication of hypercortisonism.

Large doses of corticosteroids may mask the symptoms of gastro-intestinal perforation.

Reports in the literature suggest an apparent association between use of corticosteroids and left-ventricular free-wall rupture after a recent myocardial infarction; therefore, corticosteroids should be used with great caution in these patients.

In rare cases, decrease or withdrawal of orally administered corticosteroids could reveal underlying disease that is accompanied by eosinophilia (e.g. Churg Strauss Syndrome) in patients with asthma.

The results of a randomised, placebo-controlled study suggest an increase in mortality if methylprednisolone therapy starts more than two weeks after the onset of Acute Respiratory Distress Syndrome (ARDS). Therefore, treatment of ARDS with corticosteroids should be initiated within the first two weeks of onset of ARDS.

Hypersensitivity

Rare cases of anaphylactoid or hypersensitivity reactions such as glottis oedema, urticaria and bronchospasm have been reported especially with parenteral administration of corticosteroids and in patients with a history of allergy. Prophylactic measures should be taken especially if the patient has a history of allergic reactions to medicines.

If such an anaphylactoid reaction occurs, the following measures are recommended: immediate slow intravenous injection of 0.1-0.5ml of adrenaline (solution of 1: 1000: 0.1-0.5mg adrenaline dependent on body weight), intravenous administration of aminophylline and artificial respiration if necessary.

Psychiatric reactions

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

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 pyschosis.

Use in Children and Adolescents

This product is not indicated for use in children however corticosteroids can cause dose-related growth retardation in infancy, childhood and adolescence, which may be irreversible. On prolonged administration glucocorticoids may accelerate epiphyseal closure.

Treatment should be limited to the minimum dose for the shortest period.

Children and adolescents on prolonged therapy should be carefully monitored Preterm neonates:

Available evidence suggests long-term neurodevelopmental adverse events after early treatment (<96 hours) of premature infants with chronic lung disease at starting doses of 0.25mg/kg twice daily.

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.

Ingredients in the formulation

The product contains liquid maltitol and sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on dexamethasone:

Dexamethasone is metabolized via cytochrome P450 3A4 (CYP3A4). Concomitant administration of dexamethasone with inducers of CYP3A4, such as phenytoin, barbiturates (e.g. primidone and phenobarbital), ephedrine, rifabutin, carbamazepine and rifampicin may lead to decreased plasma concentrations of dexamethasone and the dose may need to be increased.

Dexamethasone reduces the plasma concentration of the antiviral drugs indinavir and saquinavir.

Patients taking methotrexate and dexamethasone have an increased risk of haematological toxicity.

Concomitant administration of inhibitors of CYP3A4 such as ketoconazole, ritonavir and erythromycin may lead to increased plasma concentrations of dexamethasone.

These interactions may also interfere with dexamethasone suppression tests, which therefore should be interpreted with caution during administration of substances that affect the metabolism of dexamethasone.

Ketoconazole may increase plasma concentrations of dexamethasone by inhibition of CYP3A4, but may also suppress corticosteroid synthesis in the adrenal and thereby cause adrenal insufficiency at withdrawal of corticosteroid treatment.

Ephedrine may increase the metabolic clearance of corticosteroids, resulting in decreased plasma levels. An increase of the corticosteroid dose might be necessary.

False-negative results in the dexamethasone suppression test inpatients being treated with indometacin have been reported.

Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance

Anticholinesterases: Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.

Colestyramine: Colestyramine may decrease the absorption of dexamethasone.

Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect

Aminoglutethimide: Decrease of dexamethasone efficacy, due to its metabolism increase. An adjustment of dexamethasone dosage may be required.

Gastrointestinal topicals, antacids, charcoal: A decrease in digestive absorption of glucocorticoids have been reported with prednisolone and dexamethasone. Therefore, glucocorticoids should be taken separately from gastrointestinal topicals, antacids or charcoal, with an interval between treatment of at least two hours.

Effects of dexamethasone on other medicinal products

Dexamethasone is a moderate inducer of CYP3A4. Concomitant administration of dexamethasone with substances that are metabolised via CYP3A4 could lead to increased clearance and decreased plasma concentrations of these substances.

The renal clearance of salicylates is increased by corticosteroids and therefore, salicylate dosage should be reduced along with steroidal withdrawal.

The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids.

The hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics, amphotericin B injection, potassium depleting agents, corticosteroids (gluco-mineralo), tetracosactide and carbenoxolone are enhanced. Hypokalaemia predisposes to cardiac arrhythmia especially “torsade de pointes” and increase the toxicity of cardiac glycosides. Hypokalemia should be corrected before corticosteroid treatment initiation. In addition, there have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure.

Sultopride has been linked to ventricular arrhythmias, especially torsade de pointes. This combination is not recommended.

Patients taking NSAID's should be monitored since the incidence and/or severity of gastro-ulceration may increase. Aspirin should also be used cautiously in conjunction with corticosteroids in hypoprothrombinaemia.

Antitubercular drugs: Serum concentrations of isoniazid may be decreased.

Ciclosporin: Increased activity of both ciclosporin and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use.

Thalidomide: Co-administration with thalidomide should be employed cautiously, as toxic epidermal necrolysis has been reported with concomitant use.

Corticosteroids may affect the nitrobuletetrazolium test for bacterial infection and produce false-negative results.

Vaccines attenuated live

Risk of fatal systemic disease

Praziquantel:

Decrease in praziquantel plasmatic concentrations, with a risk of treatment failure, due to its hepatic metabolism increased by dexamethasone.

Oral anticoagulants:

Possible impact of corticosteroid therapy on the metabolism of oral anticoagulants and on clotting factors. At high doses or with treatment for more than 10 days, there is a risk of bleeding specific to corticosteroid therapy (gastrointestinal mucosa, vascular fragility). Patients taking corticosteroids associated with oral anticoagulants should be closely monitored (biological investigations on 8th day, then every 2 weeks during treatment and after treatment discontinuation).

Insulin, sulfonylureas, metformin:

Increase in blood glucose, with sometimes diabetic ketosis, since corticosteroids impair carbohydrate tolerance. Therefore, blood and urine self-monitoring should be reinforced by the patient, in particular at the start of treatment

Isoniazid:

A decrease in plasma isoniazid levels have been reported with prednisolone. The suggested mechanism is an increase in hepatic metabolism of isoniazid and a decrease in the hepatic metabolism of isoniazid and a decrease in the hepatic metabolism of glucocorticoids. Patients taking isoniazid should be closely monitored.

4.6 Fertility, Pregnancy and lactation

Pregnancy

Since adequate human reproduction studies have not been performed with corticosteroids, dexamethasone should not be used during pregnancy for maternal indications, unless it is clearly necessary. The lowest effective dose needed to maintain adequate disease control should be used.

Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

Patients with pre-eclampsia or fluid retention require close monitoring.

Placental transfer in considerable: foetal serum concentrations are similar to maternal concentrations.

When corticosteroids are essential however, patients with normal pregnancies may be treated as though they were in the non-gravid state.

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intrauterine 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/lip in man.

See also section 5.3 of the SmPC.

Lactation

Corticosteroids are excreted in small amounts in breast milk and may suppress growth, interfere with endogenous corticosteroid production or cause other unwanted effects. A decision on whether to continue/discontinue breast feeding or to continue/discontinue therapy with dexamethasone should be made taking into account the benefit of breast feeding to the child and the benefit of dexamethasone therapy to the woman.

4.7 Effects on ability to drive and use machines

There are some side effects associated with this product that may affect some patients’ ability to drive or operate machinery (see section 4.8).

4.8 Undesirable effects

The incidence of predictable undesirable effects, including hypothalamic-pituitary-adrenal 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 have been reported; there frequency is unknown.

System Organ Class
Infections and infestations	Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis. Decreased resistance to infection.
Blood and lymphatic system disorders	Leucocytosis
Immune system disorders	Hypersensitivity including anaphylaxis has been reported. Decreased responsiveness to vaccination and skin tests.
Endocrine disorders	Menstrual irregularities and amenorrhoea, suppression of the hypothalamic-pituitary-adrenal axis, premature epiphyseal closure, development of Cushingoid state, hirsutism, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery or illness). Negative protein and calcium balance.
Metabolism and nutrition disorders	Sodium and water retention, potassium loss, hypokalaemic alkalosis, increased calcium excretion. Increased appetite. Impaired carbohydrate tolerance with increased requirement for anti-diabetic therapy.
Nervous system disorders	Convulsions and aggravation of epilepsy, vertigo, headache, increased intra-cranial pressure with papilloedema in children (Pseudotumour cerebri), usually after treatment withdrawal, psychological dependence, depression, insomnia, aggravation of schizophrenia and psychic disturbances ranging from euphoria to frank psychotic manifestations. 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.
Eye disorders	Posterior subcapsular cataracts, increased intra-ocular pressure, glaucoma, papilloedema, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal

	diseases, exopthalmos.
Cardiac disorders	Myocardial rupture following recent myocardial infarction. Congestive heart failure in susceptible patients.
Vascular disorders	Thromboembolism, hypertension
Gastrointestinal disorders	Dyspepsia, peptic ulceration with perforation and haemorrhage, acute pancreatitis, candidiasis. Abdominal distension and vomiting. Oesophageal ulceration. Perforation of the small and large bowel particularly in patients with inflammatory bowel disease. Nausea, hiccups.
Skin and subcutaneous tissue disorders	Impaired wound healing, thin fragile skin, petechiae and ecchymoses, erythema, striae, telangiectasia, acne, increased sweating, suppressed reaction to skin tests, other cutaneous reactions such as allergic dermatitis, urticaria, angioneurotic oedema, thinning scalp hair
Musculoskeletal and connective tissue disorders	Osteoporosis, vertebral and long bone fractures, avascular necrosis, tendon rupture. Proximal myopathy. Muscle weakness, aseptic necrosis of femoral and humeral heads, loss of muscle mass. Growth suppression in children and adolescents.
General disorders and administration site conditions	Malaise, abnormal fat deposits.
Injury and poisoning	Bruising.
Investigations	Increased or decreased motility and number of spermatozoa, weight gain.

Withdrawal symptoms and signs

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.

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 professional are asked to report any suspected adverse reactions via the national reporting system.

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

Reports of acute toxicity and/or deaths following overdosage with glucocorticoids are rare. No antidote is available. Treatment is probably not indicated for reactions due to chronic poisoning unless the patient has a condition that would render him unusually

susceptible to ill effects from corticosteroids. In this case, the stomach should be emptied and symptomatic treatment should be instituted as necessary. Anaphylactic and hypersensitivity reactions may be treated with epinephrine (adrenaline), positive-pressure artificial respiration and aminophylline. The patient should be kept warm and quiet. The biological half life of dexamethasone in plasma is about 190 minutes

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC Code: H02A B02

Pharmacotherapeutic Group: Corticosteroid

Dexamethasone is a synthetic glucocorticoid whose anti-inflammatory potency is 7 times greater than prednisolone. Like other glucocorticoids, dexamethasone also has anti-allergic, antipyretic and immunosuppressive properties.

Dexamethasone has practically no water and salt-retaining properties and is, therefore, particularly suitable for the use in patients with cardiac failure or hypertension. Because of its long biological half-life (36-54 hours), dexamethasone is especially suitable in conditions where continuous glucocorticoid action is desired.

5.2 Pharmacokinetic properties

Corticosteroids, are, in general, readily absorbed from the gastro-intestinal tract. They are also well absorbed from sites of local application. Water-soluble forms of corticosteroids are given by intravenous injection for a rapid response; more prolonged effects are achieved using lipid-soluble forms of corticosteroids by intramuscular injection.

Corticosteroids are rapidly distributed to all body tissues. They cross the placenta and may be excreted in small amounts in breast milk.

Most corticosteroids in the circulation are extensively bound to plasma proteins, mainly to globulin and less so to albumin. The corticosteroid-binding globulin has high affinity but low binding capacity, while the albumin has low affinity but large binding capacity. The synthetic corticosteroids are less extensively protein bound than hydrocortisone (cortisol). They also tend to have longer half-lives.

Corticosteroids are metabolised mainly in the liver but also in the kidney, and are excreted in the urine. The slower metabolism of the synthetic corticosteroids with their lower protein-binding affinity may account for their increased potency compared with the natural corticosteroids.

10mg/5ml Oral Solution

A bioequivalence study was performed on Dexamethasone 10mg/5ml Oral Solution against the brand leaders 2mg tables. Data is provided below to show that the two products are bioequivalent and interchangeable mg for mg.

Ratio	98.45%	97.93%	101.86%
90% Geometric C.I.	89.64% to 108.13%	88.37% to 108.52%	90.38% to 114.79%
Intra-Subject CV	12.84%	14.08%	16.41%

5.3 Preclinical safety data

In animal studies, cleft palate was observed in rats, mice, hamsters, rabbits, dogs and primates; not in horses and sheep. In some cases these divergences were combined with defects of the central nervous system and of the heart. In primates, effects in the brain were seen after exposure. Moreover, inter-uterine growth can be delayed. All these effects were seen at high doses.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Propylene Glycol (E1250)

Benzoic Acid (E210)

Citric Acid Monohydrate (E330)

Sodium Citrate (E331)

Liquid Maltitol (E965)

Sorbitol liquid (non crystallising) (E420)

Purified Water

6.2    Incompatibilities

Not applicable

6.3    Shelf life

Unopened: 17 months

Once opened: use within 1 month. Discard any unused solution.

6.4    Special precautions for storage

Do not store above 25°C. Do not refrigerate or freeze. Store in the original package in order to protect from light.

6.5    Nature and contents of container

Bottle: Amber (Type III glass)

Closure: HDPE, EPE wadded, child resistant closure

Dosing Device: Polypropylene body, purple HDPE plunger with a capacity of 5ml and dosage graduation at every 0.25ml.

Bottle Adaptor: Low density polyethylene

Pack size: 30ml or 150ml

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

The prescribed amount of solution should be withdrawn from the bottle using the oral dosing syringe supplied.

Do not use the product if solid particles are observed inside the solution.

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

7    MARKETING AUTHORISATION HOLDER

Rosemont Pharmaceuticals Ltd

Rosemont House

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 00427/0218

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10 DATE OF REVISION OF THE TEXT