This information is intended for use by health professionals

1. Name of the medicinal product

DEXAMETHASONE 3.3 mg/ml, solution for injection

2. Qualitative and quantitative composition

Each ml of solution contains 3.3 mg dexamethasone (as sodium phosphate) which is equivalent to 4 mg dexamethasone phosphate or 4.37 mg dexamethasone sodium phosphate.

Each 2 ml contains 6.6 mg dexamethasone (as sodium phosphate) which is equivalent to 8 mg dexamethasone phosphate or 8.74 mg dexamethasone sodium phosphate.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection.

4. Clinical particulars
4.1 Therapeutic indications

Corticosteroid.

For use in certain endocrine and non-endocrine disorders responsive to corticosteroid therapy.

Systemic administration: DEXAMETHASONE 3.3 mg/ml, solution for injection is recommended for systemic administration by intravenous or intramuscular injection when oral therapy is not feasible or desirable in the following conditions.

Endocrine disorders

Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice, but synthetic analogues may be used with mineralocorticoids where applicable and, in infancy, mineralocorticoid supplementation is particularly important).

Non-endocrine disorders

DEXAMETHASONE 3.3 mg/ml, solution for injection may be used in the treatment of non-endocrine corticosteroid- responsive conditions, including:

Allergy and anaphylaxis: Angioneurotic oedema and anaphylaxis.

Gastro-intestinal: Crohn's disease and ulcerative colitis.

Infection (with appropriate chemotherapy): Miliary tuberculosis and endotoxic shock.

Neurological disorders: Raised intracranial pressure secondary to cerebral tumours and infantile spasms.

Respiratory: Bronchial asthma and aspiration pneumonitis.

Skin disorders: Toxic epidermal necrolysis.

Shock: Adjunctive treatment where high pharmacological doses are needed. Treatment is an adjunct to, and not a substitute for, specific and supportive measures the patient may require. DEXAMETHASONE 3.3 mg/ml, solution for injection has been shown to be beneficial when used in the early treatment of shock, but it may not influence overall survival.

Local administration

DEXAMETHASONE 3.3 mg/ml, solution for injection is suitable for intra-articular or soft-tissue injection as adjunctive therapy for short-term administration in:

Soft-tissue disorders such as carpal tunnel syndrome and tenosynovitis.

Intra-articular disorders such as rheumatoid arthritis and osteoarthritis with an inflammatory component.

DEXAMETHASONE 3.3 mg/ml, solution for injection may be injected intralesionally in selected skin disorders such as cystic acne vulgaris, localised lichen simplex, and keloids.

4.2 Posology and method of administration

Method of administration

DEXAMETHASONE 3.3 mg/ml, solution for injection can be given without mixing or dilution, but, if preferred, can be added without loss of potency to sodium chloride injection or dextrose injection and given by intravenous drip. The infusion mixture must be used within 24 hours and the usual aseptic techniques for injections should be observed.

Solutions used for intravenous administration or further dilution of this product should be preservative-free when used in the neonate, especially the premature infant.

Posology

All dosage recommendations are given in units of dexamethasone base.

Intravenous and intramuscular injection

General considerations: Dosage must be individualised on the basis of the disease and the response of the patient. In order to minimise side effects, the lowest possible dosage adequate to control the disease process should be used (see 'Undesirable effects').

Usually the parenteral dosage ranges are one-third to one-half the oral dose, given every 12 hours.

The usual initial dosage is 0.4 mg-16.6 mg (0.125 ml-5 ml) a day. In situations of less severity, lower doses will generally suffice. However, in certain overwhelming, acute, life- threatening situations, administration in dosages exceeding the usual dosages may be justified. In these circumstances, the slower rate of absorption by intramuscular administration should be recognised.

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. After a favourable response is noted, the proper maintenance dosage should be determined by decreasing the initial dosage by small amounts at appropriate intervals to the lowest dosage which will maintain an adequate clinical response. Chronic dosage should preferably not exceed 500 micrograms dexamethasone daily. Close monitoring of the drug dosage is needed.

To avoid hypoadrenalism and / or a relapse of the underlying disease, it may be necessary to withdraw the drug gradually (see 'Special warnings and precautions for use').

Whenever possible, the intravenous route should be used for the initial dose and for as many subsequent doses as are given while the patient is in shock (because of the irregular rate of absorption of any medicament administered by any other route in such patients). When the blood pressure responds, use the intramuscular route until oral therapy can be substituted.

For the comfort of the patient, not more than 2 ml should be injected intramuscularly at any one site.

In emergencies, the usual dose of DEXAMETHASONE 3.3 mg/ml, solution for injection by intravenous or intramuscular injection is 3.3 mg-16.6 mg (1 ml-5 ml) (in shock use only the i.v. route). This dose may be repeated until adequate response is noted.

After initial improvement, single doses of 1.7 mg-3.3 mg (0.5 ml-1 ml), repeated as necessary, should be sufficient. The total daily dosage usually need not exceed 66.4 mg (20 ml), even in severe conditions.

When constant maximal effect is desired, dosage must be repeated at three-hour or four-hour intervals, or maintained by slow intravenous drip.

Intravenous and intramuscular injections are advised in acute illness. When the acute stage has passed, oral steroid therapy should be substituted as soon as feasible.

Shock (of haemorrhagic, traumatic, or surgical origin): Usually 1.7 mg- 5.0 mg/kg (0.5ml-1.5ml/kg) bodyweight as a single intravenous injection. This may be repeated in two to six hours if shock persists. Alternatively, this may be followed immediately by the same dose in an intravenous infusion. Therapy with DEXAMETHASONE 3.3 mg/ml, solution for injection is an adjunct to, and not a replacement for, conventional therapy.

Administration of these high doses should be continued only until the patient's condition has stabilised and usually no longer than 48-72 hours.

Cerebral oedema: Associated with primary or metastatic brain tumour, pre-operative preparation of patients with increased intracranial pressure secondary to brain tumour: initially 8.3 mg (2.5 ml) intravenously, followed by 3.3 mg (1 ml) intramuscularly every six hours until symptoms of cerebral oedema subside. Response is usually noted within 12-24 hours; dosage may be reduced after two to four days and gradually discontinued over five to seven days.

High doses of DEXAMETHASONE 3.3 mg/ml, solution for injection are recommended for initiating short-term intensive therapy for acute life-threatening cerebral oedema. Following the high-loading dose schedule of the first day of therapy, the dose is scaled down over the seven- to ten-day period of intensive therapy and subsequently reduced to zero over the next seven to ten days. When maintenance therapy is required, substitute with oral dexamethasone as soon as possible (see table below).

Palliative management of recurrent or inoperable brain tumours: Maintenance therapy should be determined for each patient; 1.7 mg (0.5 ml) two or three times a day may be effective.

The smallest dose necessary to control cerebral oedema should be used.

Suggested high-dose schedule in cerebral oedema

Adults:

Initial dose 41.5 mg-(12.5ml) i.v.

1st day

2nd day

3rd day

4th day

5th-8th days

6.6 mg (2.0ml) iv. every 2 hours

6.6 mg (2.0ml) i.v. every 2 hours

6.6 mg (2.0ml) i.v. every 2 hours

3.3 mg (1.0ml) i.v.every 2 hours

3.3 mg (1.0 ml) i.v. every 4 hours

Thereafter decrease by daily reduction of 3.3 (1.0ml) mg

Children (35 kg and over):

Initial dose 20.8 mg (6.25ml) i.v.

1st day

2nd day

3rd day

4th day

5th-8th days

3.3 mg (1.0ml) i.v. every 2 hours

3.3 mg (1.0ml) i.v. every 2 hours

3.3 mg (1.0ml) i.v. every 2 hours

3.3 mg (1.0ml)i.v. every 4 hours

3.3 mg (1.0ml) i.v. every 6 hours

Thereafter decrease by daily reduction of 1.7 mg (0.5ml)

Children (below 35 kg):

Initial dose 16.6 mg (5.0ml) i.v.

1st day

2nd day

3rd day

4th day

5th-8th days

3.3 mg (1.0ml) i.v. every 3 hours

3.3 mg (1.0ml) i.v. every 3 hours

3.3 mg (1.0ml) i.v. every 3 hours

3.3 mg (1.0ml) i.v. every 6 hours

1.7 mg (0.5ml) i.v. every 6 hours

Thereafter decrease by daily reduction of 0.83 mg (0.25ml)

Dual therapy: In acute self-limiting allergic disorders or acute exacerbations of chronic allergic disorders, the following schedule combining oral and parenteral therapy is suggested:

First day

DEXAMETHASONE 3.3 mg/ml, solution for injection, 3.3mg-6.6 mg (1ml-2 ml) intramuscularly

Second day

Two 500 microgram dexamethasone tablets twice a day

Third day

Two 500 microgram dexamethasone tablets twice a day

Fourth day

One 500 microgram dexamethasone tablets twice a day

Fifth day

One 500 microgram dexamethasone tablets twice a day

Sixth day

One 500 microgram dexamethasone tablet once daily

Seventh day

One 500 microgram dexamethasone tablet once daily

Eighth day

Reassessment day

Intrasynovial, intralesional, and soft-tissue injection: In general, these injections are employed when only one or two joints or areas are affected.

Some of the usual single doses are:

Site of injection

Amount of dexamethasone base

Large joints (e.g. knee)

1.7-3.3 mg (0.5-1 ml)

Small joints

(e.g. interphalangeal, temporomandibular)

0.66-0.8 mg (0.2-0.25 ml)

Bursae

1.7-2.5 mg (0.5-0.75 ml)

Tendon sheaths*

0.33-0.8 mg (0.1-0.25 ml)

Soft-tissue infiltration

1.7 mg-5.0 mg (0.5-1.5 ml)

Ganglia

0.8mg – 1.7 mg (0.25-0.5 ml)

* Injection should be made into the tendon sheath, and not directly into the tendon.

Frequency of injection, once every three to five days to once every two to three weeks, depending on response.

Use in children: Dosage should be limited to a single dose on alternate days to lessen retardation of growth and minimise suppression of the hypothalamo-pituitary-adrenal axis.

Use in the 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, especially osteoporosis, diabetes, hypertension, hypokalaemia, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life threatening reactions (see 'Undesirable effects').

4.3 Contraindications

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

Systemic fungal infection; systemic infection unless specific anti-infective therapy is employed. Administration of live virus vaccines (see 'Special warnings and Special Precautions for use').

4.4 Special warnings and precautions for use

Frequent intra-articular injections over a prolonged period may lead to joint destruction with bone necrosis. Intra-articular injection of corticosteroid may produce systemic adverse reactions including adrenal suppression.

Undesirable effects may be minimised by using the lowest effective dose for the minimum period. Frequent patient review is required to appropriately titrate the dose against disease activity. When reduction in dosage is possible, the reduction should be gradual (see 'Posology and Method of Administration').

Corticosteroids may exacerbate systemic fungal infections and, therefore, should not be used in the presence of such infections, unless they are needed to control drug reactions due to amphotericin. Moreover, there have been cases reported in which, concomitant use of amphotericin and hydrocortisone, was followed by cardiac enlargement and congestive failure.

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.

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 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 interactions 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.

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. All corticosteroids increase calcium excretion.

The slower rate of absorption by intramuscular administration should be recognised.

In patients on corticosteroid therapy subjected to unusual stress (e.g. intercurrent illness, trauma, or surgical procedures), dosage should be increased before, during and after the stressful situation. Drug-induced secondary adrenocortical insufficiency may result from too rapid withdrawal of corticosteroids and may be minimised by gradual dosage reduction, being tapered off over weeks and months, depending on the dose and duration of treatment, but may persist for up to a year after discontinuation of therapy. In any stressful situation during that period, therefore, corticosteroid therapy should be reinstated. If the patient is already receiving corticosteroids, the current dosage may have to be temporarily increased. Salt and/or a mineralocorticoid should be given concurrently, since mineralocorticoid secretion may be impaired.

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.

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 1 mg 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 ofdexamethasone,

• Patients repeatedly taking doses in the evening.

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.

Because anaphylactoid reactions have occurred, rarely, in patients receiving parenteral corticosteroid therapy, appropriate precautions should be taken prior to administration, especially when the patient has a history of allergy to any drug.

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. However, immunisation procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g. for Addison's disease.

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

The use of DEXAMETHASONE 3.3 mg/ml, solution for injection in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculosis regimen. If the corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation may occur. During prolonged corticosteroid therapy, these patients should receive prophylactic chemotherapy.

Corticosteroids may mask some signs of infection, and new infections may appear during their use. Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity. The clinical presentation may often be atypical, and serious infections such as septicaemia and tuberculosis may be masked and reach an advanced stage before being recognised. There may be decreased resistance, and inability to localise infection.

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.

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 three months; this should be given within ten 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. Therefore, it is recommended that latent or active amoebiasis and strongyloidiasis be ruled out, before initiating corticosteroid therapy in any patient at risk of, or with symptoms of either condition.

Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses. Corticosteroids may increase or decrease motility and number of spermatozoa.

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.

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: renal insufficiency, hypertension, diabetes or in those with a family history of diabetes, congestive heart failure, osteoporosis, previous steroid myopathy, glaucoma (or family history of glaucoma), myasthenia gravis, non-specific ulcerative colitis, diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, existing or previous history of severe affective disorders (especially previous steroid psychosis), liver failure, and epilepsy. Signs of peritoneal irritation, following gastro-intestinal perforation in patients receiving large doses of corticosteroids, may be minimal or absent. Fat embolism has been reported as a possible complication of hypercortisonism.

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

Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation.

Local steroid injection should be undertaken in an aseptic environment to reduce the particular risk of bacterial infection. Injection of a steroid into an infected site should be avoided.

Appropriate examination of joint fluid is necessary to exclude a septic process.

A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted.

Patients should understand the great importance of not over-using joints that are still diseased, despite symptomatic improvement.

Corticosteroids should not be injected into unstable joints.

Frequent intra-articular injections have been reported to cause development of Charcot-like arthropathies.

Paediatric population:

Preterm neonate:

Dexamethasone has been used 'off-label' to treat and prevent chronic lung disease in preterm infants. Clinical trials have shown a short term benefit in reducing ventilator dependence but no long term benefit in reducing time to discharge, the incidence of chronic lung disease or mortality. 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/hg twice daily. Recent trials have suggested an association between the use of dexamethasone in preterm infants and the development of cerebral palsy. In view of this possible safety concern, an assessment of the risk: benefit should be made on an individual patient basis.

Children:

Corticosteroids cause growth retardation in infancy, childhood and adolescence, which may be irreversible. Treatment should be limited to the minimum dosage for the shortest possible time. In order to minimise suppression of the hypothalamo-pituitary-adrenal axis and growth retardation, treatment should be limited, where possible, to a single dose on alternate days.

Growth and development of infants and children on prolonged corticosteroid therapy should be carefully monitored.

This medicine contains 0,4 mg of sodium per 1 ml ampoule and 0,8 mg of sodium per 2 ml ampoule (less than 23 mg per ampoule), i.e. it is essentially sodium free.

4.5 Interaction with other medicinal products and other forms of interaction

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

Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinaemia.

The incidence of gastro-intestinal ulceration is increased in patients receiving concomitant non-steroidal anti-inflammatory drugs and corticosteroids.

As phenytoin, barbiturates, ephedrine, rifabutin, carbamazepine, rifampicin, and aminoglutethimide may enhance the metabolic clearance of corticosteroids, resulting in decreased blood levels and reduced physiological activity, the dosage may have to be adjusted. These interactions may interfere with dexamethasone suppression tests, which should be interpreted with caution during administration of these drugs.

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

The efficacy of coumarin anticoagulants may be changed by concurrent corticosteroid treatment. The prothrombin time should be checked frequently in patients who are receiving corticosteroids and coumarin anticoagulants at the same time, in order to avoid spontaneous bleeding.

The desired effects of hypoglycaemic agents (including insulin), are antagonised by corticosteroids.

Diuretics are antagonised by corticosteroids and the hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics and carbenoxolone are enhanced. Patients receiving corticosteroids and potassium depleting diuretics and/or cardiac glycosides, should be monitored for hypokalaemia. This is of particular importance in patients receiving cardiac glycosides, since hypokalaemia increases the toxicity of these drugs. The effects of anti-hypertensive drugs are also antagonised by corticosteroids.

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

Antiretroviral protease inhibitors (ritonavir, darunavir, indinavir, lopinavir, saquinavir and efavirenz) are metabolised by CYP3A. Medicinal products that induce CYP3A activity, such as dexamethasone, may increase the clearance of medicines metabolised by CYP3A, resulting in lowered plasma concentrations.

Certain antiretroviral protease inhibitors (ritonavir, indinavir) may also be inhibitors of CYP3A themselves and as a result may increase the plasma concentration of dexamethasone.

4.6 Fertility, pregnancy and lactation

Pregnancy

The ability of corticosteroids to cross the placenta varies between individual drugs, however, dexamethasone readily crosses the placenta.

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine 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. 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.

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

Breast-feeding

Corticosteroids may pass into breast milk, although no data are available for dexamethasone. Infants of mothers taking high doses of systemic corticosteroids for prolonged periods may have a degree of adrenal suppression.

Suppression of growth or other adverse effects may occur.

Fertility

The effect of dexamethasone on fertility is unknown.

4.7 Effects on ability to drive and use machines

Steroids may cause vertigo, vision disorders or muscle weakness. If affected patients should be advised not to drive or operate 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 the duration of treatment (see 'Special warnings and precautions for use').

Fluid and electrolyte disturbances: Sodium retention, fluid retention, congestive heart failure in susceptible patients, potassium loss, hypokalaemic alkalosis, hypertension, increased calcium excretion (see 'Special warnings and precautions for use').

Musculoskeletal: Muscle weakness, steroid myopathy, loss of muscle mass, osteoporosis (especially in post-menopausal females), vertebral compression fractures, aseptic necrosis of femoral and humeral heads, pathological fracture of long bones, tendon rupture, and post- injection flare (following intra-articular use).

Gastro-intestinal: Peptic ulcer with possible perforation and haemorrhage, perforation of the small and large bowel, particularly in patients with inflammatory bowel disease, pancreatitis, abdominal distension, ulcerative oesophagitis, dyspepsia, oesophageal candidiasis.

Dermatological: Impaired wound healing, thin fragile skin, petechiae and ecchymoses, erythema, striae, telangiectasia, acne, increased sweating, possible suppression of skin tests, burning or tingling especially in the perineal area (after intravenous injection), other cutaneous reactions such as allergic dermatitis, urticaria, angioneurotic oedema, and hypo- or hyper-pigmentation.

Neurological: Convulsions, increased intracranial pressure with papilloedema (pseudotumour cerebri) usually after treatment, vertigo, headache. Cerebral palsy in pre-term infants.

Psychiatric: 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.

Endocrine: Menstrual irregularities, amenorrhoea, development of Cushingoid state, suppression of growth in children and adolescents, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery or illness), decreased carbohydrate tolerance, manifestations of latent diabetes mellitus, increased requirements for insulin or oral hypoglycaemic agents in diabetes, hirsutism.

Anti-inflammatory and immunosuppressive effects: Increased susceptibility and severity of infections with suppression of clinical symptoms and signs. Opportunistic infections, recurrence of dormant tuberculosis (see 'Special warnings and precautions for use').

Ophthalmic: Posterior subcapsular cataracts, increased intra-ocular pressure, papilloedema, corneal or scleral thinning, exacerbation of ophthalmic viral disease, glaucoma, exophthalmos, rare instances of blindness associated with intra-lesional therapy around the face and head, retinopathy of prematurity.

Metabolic: Negative nitrogen balance due to protein catabolism. Negative calcium balance.

Cardiovascular: Myocardial rupture following recent myocardial infarction (see 'Special warnings and precautions for use'). Hypertrophic cardio-myopathy in low birth-weight infants.

Other: Hypersensitivity, including anaphylaxis has been reported, leucocytosis, thrombo- embolism, weight gain, increased appetite, nausea, malaise, hiccups, and sterile abscess.

Multiple myeloma patients treated with lenalidomide or thalidomide in combination with dexamethasone have an increased risk of thromboembolic events including deep vein thrombosis and pulmonary embolism.

Withdrawal symptoms and signs

Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension, and death (see 'Special warnings and precautions for use').

In some instances, withdrawal symptoms may simulate a clinical relapse of the disease for which the patient has been undergoing treatment.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Reports of acute toxicity and/or deaths following overdosage with gluco-corticoids 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 a patient unusually susceptible to ill effects from corticosteroids. In this case, symptomatic treatment should be instituted as necessary.

Anaphylactic and hypersensitivity reactions may be treated with 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

Pharmacotherapeutic class: CORTICOSTEROIDS FOR SYSTEMIC USE, PLAIN; ATC Code: H02AB02.

Dexamethasone possesses the actions and effects of other basic glucocorticoids and is among the most active members of its class.

Glucocorticoids are adrenocortical steroids, both naturally occurring and synthetic, which are readily absorbed from the gastro-intestinal tract. They cause profound and varied metabolic effects and in addition, they modify the body's immune responses to diverse stimuli. Naturally-occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used primarily for their potent anti-inflammatory effects in disorders of many organ systems.

Dexamethasone has predominant glucocorticoid activity with little propensity to promote renal retention of sodium and water. Therefore it does not offer complete replacement therapy and must be supplemented with salt or desoxycorticosterone.

5.2 Pharmacokinetic properties

Absorption

Intramuscular injections of dexamethasone gives maximum plasma concentrations of dexamethasone at 1 hour. Dexamethasone is readily absorbed from the gastro-intestinal tract.

Distribution

The biological half-life of dexamethasone in plasma is about 190 minutes.

The more potent halogenated corticosteroids such as dexamethasone, appear to cross the placental barrier with minimal inactivation.

Biotransformation

Binding of dexamethasone to plasma proteins is less than for most other corticosteroids and is estimated to be about 77%.

Elimination

Up to 65% of a dose is excreted in the urine in 24 hours, the rate of excretion being increased following concomitant administration of phenytoin.

5.3 Preclinical safety data

Not relevant.

6. Pharmaceutical particulars
6.1 List of excipients

Creatinine, sodium citrate, citric acid hydrate, sodium hydroxide, water for injection.

6.2 Incompatibilities

Dexamethasone sodium phosphate is physically incompatible with daunorubicin, doxorubicin and vancomycin and should not be admixed with solutions containing these drugs. Also incompatible with doxapram HCl and glycopyrrolate in syringe.

6.3 Shelf life

2 years.

After opening: the product must be used immediately.

Chemical and physical in-use stability has been demonstrated for 48 hours at 25°C protected from light when diluted with the infusion fluids listed in 6.6. From a microbiological point of view, the product should be used immediately. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution and dilution have taken place in controlled validated aseptic conditions.

6.4 Special precautions for storage

Store below 25°C.

Store in the outer pack in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

Discard any unused product at the end of each operating session.

6.5 Nature and contents of container

1 ml clear glass ampoule. Box of 5 and 10 ampoules.

2 ml clear glass ampoule. Box of 5 and 10 ampoules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Use with infusion fluids

Dexamethasone can be diluted with the following infusion fluids:

sodium chloride 0.9%

glucose 5%

Using these infusion fluids, Dexamethasone Injection can also be injected into the infusion line without causing precipitation of the ingredients.

For single use only.

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

7. Marketing authorisation holder

PANPHARMA

Z.I. du Clairay

35133 Luitré

France

8. Marketing authorisation number(s)

PL 44124/0015

9. Date of first authorisation/renewal of the authorisation

10/07/2017

10. Date of revision of the text

13/09/2017