This information is intended for use by health professionals

1. Name of the medicinal product

Martapan 2mg/5ml Oral Solution

2. Qualitative and quantitative composition

Each 5ml contains 2mg dexamethasone (as dexamethasone sodium phosphate).

Excipients with known effect:

Each 5 ml contains: -

0.061 mmol of sodium

0.6g of liquid sorbitol

1.4g of liquid maltitol

0.5g of Propylene glycol

0.005g of Benzoic acid

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Oral Solution

A colourless to faint yellow solution with odour of mint.

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, Löffler's syndrome, cryptogenic fibrosing alveolitis.

Rheumatic disorders: some cases or specific forms (Felty's syndrome, Sjörgen'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.

Childhood Croup:

Heterogeneous group of illnesses affecting the larynx, trachea and bronchi. Laryngotracheitis, laryngotracheobronchitis, laryngotracheobronchopneumonitis and spasmodic croup are included in the croup syndrome.

4.2 Posology and method of administration

Posology

Adults

General considerations

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 'Side effects').

Frequent patient review is required to appropriately titrate the dose against disease activity.

The usual dose in adults is 0.5-9 mg per day depending on the disease being treated. In more severe diseases, doses higher than 9mg may be required. 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 satisfactory clinical response does not occur after a reasonable period of time, discontinue treatment with dexamethasone and transfer the patient to another therapy.

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.

Patients should be monitored for signs that may require dosage adjustment. These may be changes in clinical status resulting from remissions or exacerbations of the disease, individual drug responsiveness and the effect of stress (e.g. surgery, infection, trauma). During stress it may be necessary to increase dosage temporarily.

If the drug is to be stopped 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 (1ml or 2ml) intramuscularly.

Second day: 1mg (2.5ml) Dexamethasone Oral Solution twice a day.

Third day: 1mg (2.5ml) Dexamethasone Oral Solution twice a day.

Fourth day: 500micrograms (1.25ml) Dexamethasone Oral Solution twice a day.

Fifth day: 500micrograms (1.25ml) Dexamethasone Oral Solution twice a day.

Sixth day: 500micrograms (1.25ml) Dexamethasone Oral Solution.

Seventh day: 500micrograms (1.25ml) 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.

Dexamethasone suppression tests:

1. Tests for Cushing's syndrome:

2mg (5ml) Dexamethasone Oral Solution should be administered at 11pm. Blood samples are

If greater accuracy is required, 500 micrograms (1.25ml) 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 (5ml) 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

Paediatric population

0.01-0.1 mg/kg of body weight daily.

Dosage should be limited to a single dose on alternate days to lessen retardation of growth and minimize suppression of hypothalamo-pituitary-adrenal axis.

Dexamethasone should only be administered to children with caution., The daily dose should be determined by the physician for each child individually.

Childhood Croup:

A single dose of 0.15mg/kg Dexamethasone Oral Solution is recommended. A second dose may be administered after 12 hours, if considered necessary by the treating physician.

Approximate age

(mths/yrs)

Approximate weight

(kg)

Volume of Martapan (ml)

Min

Max

Min

Max

0

2 mths

4

5.5

2

3 mths

6 mths

5.6

7.9

3

6 mths

12 mths

8

10.5

4

> 12 mths

2 yrs

10.6

13.3

5

> 2 yrs

4 yrs

13.4

16.2

6

> 4 yrs

7 yrs

16.3

22

8

> 7 yrs

9 yrs

22.1

27

10

> 9 yrs

12 yrs

27.1

41

15

> 12 yrs

14 yrs

42

55

20

> 14 yrs

56

68

25

Elderly:

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.

Method of administration

For oral 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

Avoid live vaccines in patients receiving immunosuppressive doses (serum antibody response diminished).

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

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 provides 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.

.

Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity. The clinical presentation may 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 is a normally minor illness but 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 immunoglobin (VZIG) is needed by exposed nonimmune 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 even 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 (IVIG) 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.

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. (see “withdrawal of prolonged therapy”).

Incurrent 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. This includes patients who have finished a course of systemic dexamethasone of less than three weeks duration in the week prior to the stress. Patients on systemic dexamethasone therapy who are at risk of adrenal suppression and are unable to take oral solution should receive parenteral dexamethasone cover during these periods.

Eye Disorders

Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerve 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.

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.

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, hypertension and congestive heart failure.

Use in children and adolescents:

Glucocorticoids 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. Therefore, Dexamethasone should only be used in children with caution.

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 glucocorticoids 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.

In post marketing experience tumour lysis syndrome (TLS) has been reported in patients with haematological malignancies following the use of dexamethasone alone or in combination with other chemotherapeutic agents. Patient at high risk of TLS, such as patients with high proliferative rate, high tumour burden, and high sensitivity to cytotoxic agents, should be monitored closely and appropriate precaution taken.

General

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

- Osteoporosis (post-menopausal women are particularly at risk);

- Diabetes mellitus (or a family history of diabetes);

- Previous corticosteroid-induced myopathy;

- Liver failure;

- Epilepsy;

- Peptic ulceration.

- myasthenia gravis

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

- 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.

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 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 aminophyline 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 pharmacokinetic interaction 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.

Patient/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 psychosis.

Withdrawal of prolonged therapy

In patients who have received dexamethasone for more than 3 weeks, withdrawal should not be abrupt. How dose reduction should be carried out (tapered off over weeks or months) depends largely on whether the disease is likely to relapse as the dose of systemic glucocorticoids is reduced. Clinical assessment of disease activity may therefore be needed during withdrawal. If the disease is unlikely to relapse on withdrawal but there is uncertainty about hypothalamus-pituitary-adrenal (HPA) suppression, the dose of systemic dexamethasone may be reduced rapidly to physiological doses. Once a daily dose of approx. 1 mg dexamethasone is reached, dose reduction should be slower to allow the HPA-axis to recover.

Abrupt withdrawal of systemic dexamethasone treatment, which has continued for up to 3 weeks, is appropriate if it is considered that the disease is unlikely to relapse.

Abrupt withdrawal of doses up to approx. 6 mg 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 dexamethasone therapy should be considered even after courses lasting 3 weeks or less:

• Patients who have had repeated courses of systemic dexamethasone (or other corticosteroids), particularly if taken for more 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 dexamethasone (or other corticosteroid) therapy.

• Patients receiving doses of systemic dexamethasone higher than approx. 6 mg.

• Patients repeatedly taking doses in the evening.

.

Withdrawal symptoms

Too rapid reduction of dexamethasone dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death. Characteristic symptoms of a “withdrawal syndrome” that may occur are fever, myalgia, malaise., arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight (see section 4.8).

Excipient Warnings

This product contains 0.6g sorbitol in each 5ml. When given according to the recommended dosage instructions, each dose may contain as much as 3 g of sorbitol. It also contains 1.4g liquid maltitol in each 5ml. When given according to the recommended dosage instruction, each dose may contain as much as 7g of maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. May have a mild laxative effect. Calorific value: 2.6kcal/g sorbitol and 2.3 kcal/g maltitol.

This medicine contains 5mg of benzoic acid in each 5ml. Benzoic acid may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks ago)

This product also contains 0.5g propylene glycol in each 5ml. Each dose may contain as much as 2.5g of propylene glycol. Propylene glycol in high doses may cause central nervous system side-effects, lactic acidosis, kidney and liver toxicity, increase in plasma osmolarity, and haemolytic reactions.This medicinal product contains 0.305 mmol of sodium per maximum daily dose. This medicinal product contains less than 1 mmol of sodium per maximum daily dose, that is to say essentially 'sodium-free'.

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 rifampicin, rifabutin, carbamazepine, barbiturates (e.g. primidone and phenobarbital), phenytoin, and ephedrine and aminoglutethimide enhance the metabolism of glucocorticoids and may lead to decreased plasma concentrations of dexamethasone and the dose may need to be increased.

Concomitant administration of inhibitors of CYP3A4 such as ketoconazole, ritonavir and erythromycin may lead to increased plasma concentrations of dexamethasone. Ketoconazole may also suppress corticosteroid synthesis in the adrenal and thereby cause adrenal insufficiency at withdrawal of corticosteroid treatment.

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.

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.

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.

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

Colestyramine: Colestyramine may decrease the absorption of dexamethasone.

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

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

Oral contraceptives (oestrogens) may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect

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 glucocorticoids and steroid withdrawal may result in salicylate intoxication.

The desired effects of hypoglycaemic agents (including insulin), antihypertensives 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.

Combination of corticosteroids with ulcer-inducing agents (e.g. NSAIDs) enhances the risk and/or severity of peptic ulceration. 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.

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

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

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intrauterine growth retardation and effects 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). However, when administered for prolonged periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. Hypoadrenalism. may, in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential however, patients with normal pregnancies may be treated as though they were in the non-gravid state.

Breast-feeding

Corticosteroids are excreted in small amounts into breast milk and may suppress growth, interfere with endogenous corticosteroid production or cause other unwanted effects. Infants of mothers taking high doses of systemic corticosteroids for prolonged periods may have a degree of adrenal suppression. A risk to the suckling child cannot be excluded.

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

Fertility

There are no data from the use of Dexamethasone on fertility.

4.7 Effects on ability to drive and use machines

Dexamethasone may cause side effects that may affect some patients'ability to drive or using machines (see 4.8 Undesirable effects). Caution should be exercised in driving and operating machinery.

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 duration of treatment (refer to Special Warnings and Precautions).

The following side effects have been reported; their frequency is unknown.

System organ class

Preferred Term(s) or Lower Level Terms

Blood and lymphatic system disorders

Leucocytosis

Endocrine disorders

Menstrual irregularities and amenorrhoea, suppression of the hypothalamo-pituitary adrenal axis, Adrenal suppression, 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.

Eye disorders

Papilloedema (in children with pseudotumour cerebri, usually after withdrawal), increased intra-ocular pressure, glaucoma, posterior subcapsular cataract, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal diseases, exopthalmos. Frequency rare: Vision blurred (see also section 4.4)

Frequency not known: Chorioretinopathy

Gastrointestinal disorders

Gastric ulcer (haemorrhage), Duodenal ulcer (haemorrhage), dyspepsia, peptic ulcer perforation, ulcerative oesophagitis, Acute pancreatitis, nausea, Abdominal distension and vomiting, hiccups. Perforation of the small and large bowel particularly in patients with inflammatory bowel disease.

General disorders and administration site conditions

Oedema, Impaired healing, Malaise, Abnormal fat deposits

Immune system disorders

Drug hypersensitivity, Anaphylactic reaction

Infections and infestations

Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infection, recurrence of dormant tuberculosis Varicella, exacerbation of opthalmic viral or fungal diseases, Candidiasis. Decreased resistance to infection

Investigations

Weight gain, Carbohydrate tolerance decreased, Intraocular pressure increased, increased or decreased motility and number of spermatozoa

Metabolism and nutrition disorders

Increased appetite, Diabetes mellitus inadequate control, Lipoprotein deficiency, Calcium deficiency, Sodium retention, Fluid retention, Hypokalaemia, hypokalaemic alkalosis. Impaired carbohydrate tolerance with increased requirement for anti-diabetic therapy.

Myocardial disorders

Myocardial rupture following recent myocardial infarction

Musculoskeletal and connective tissue disorders

Growth retardation (infancy, childhood and adolescence), muscle weakness, aseptic necrosis of femoral and humeral heads, loss of muscle mass. Osteoporosis, Osteonecrosis, proximal myopathy, Vertebral and long bone fracture, avascular necrosis, tendon rupture.

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 and hallucinations), behavioural disturbances, irritability, nervousness, 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.

Skin and subcutaneous tissue disorders

Impaired wound healing, thin fragile skin, petechiae and ecchymoses, erythema, striae, telangiectasia, acne, , , Skin atrophy, , Contusion, increased sweating, suppressed reaction to skin tests, other cutaneous reactions such as allergic dermatitis, urticaria, angioneurotic oedema, thinning scalp hair.

Vascular disorders

Hypertension, Thromboembolism

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 professionals are asked to report any suspected adverse reactions via the Yellow Card scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms

It is difficult to define an excessive dose of a corticosteroid as the therapeutic dose will vary according to indication and patient requirements. Exaggeration of corticosteroid related adverse effects may occur. Treatment should be asymptomatic and supportive as necessary.

Reports of acute toxicity and/or deaths following overdosage with glucocorticoids are rare.

Management

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

Pharmacodynamic effects

Dexamethasone is a highly potent and long-acting glucocorticoid with negligible sodium retaining properties and is therefore, particularly suitable for the use in patients with cardiac failure and hypertension. Its anti-inflammatory potency is 7 times greater than prednisolone and like other glucocorticoids, dexamethasone also has anti-allergic, antipyretic and immunosuppressive properties.

Dexamethasone has a biological half-life of 36 - 54 hours and therefore is suitable in conditions where continuous glucocorticoid action is required.

5.2 Pharmacokinetic properties

Absorption

Dexamethasone is well absorbed when given by mouth; peak plasma levels are reached between 1 and 2 hours after ingestion and show wide interindividual variations. The mean plasma half-life is 3.6 ± 0.9h.

Distribution

Dexamethasone is bound (to about 77%) to plasma proteins, mainly albumins. Percentage protein binding of dexamethasone, unlike that of cortisol, remains practically unchanged with increasing steroid concentrations.

Corticosteroids are rapidly distributed to all body tissues.

Biotransformation

Dexamethasone is metabolised mainly in the liver but also in the kidney.

The slower metabolism of the synthetic corticosteroids with their lower protein-binding affinity may account for their increased potency compared with the natural corticosteroids.

Elimination

Dexamethasone and its metabolites are excreted in the urine.

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.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

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, intra-uterine growth can be delayed. All these effects were seen at high dosages.

6. Pharmaceutical particulars
6.1 List of excipients

Benzoic acid (E210)

Propylene glycol (E1520)

Citric acid monohydrate

Liquid maltitol

Garden mint flavour (contains propylene glycol E1520)

Liquid sorbitol (non-crystallising)

Sodium citrate

Purified water

Citric acid 10% solution (pH adjustment)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

Shelf Life: 12 months

Shelf life after first opening the container: 28 days

6.4 Special precautions for storage

Do not store above 25°C.

Keep in the original container in order to protect from light.

6.5 Nature and contents of container

Bottles: 150ml in Amber Type III glass.

Closure: HDPE tamper evident, child resistant closure.

6.6 Special precautions for disposal and other handling

No special requirements for disposal

7. Marketing authorisation holder

Martindale Pharmaceuticals Ltd

Bampton Road

Harold Hill

Romford

Essex, RM3 8UG

UK

8. Marketing authorisation number(s)

PL 00156/0125

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 14/11/2011

10. Date of revision of the text

18/05/2018