Dexamethasone phosphate (as sodium)8mg/2mL solution for injection(Demo S.A.), CV006

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCTDexamethasone phosphate/DEMO 4 mg / mL solution for injection

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 millilitre (mL) of solution for injection contains 3.32 mg of dexamethasone (as dexamethasone sodium
phosphate) which is equivalent to 4.00 mg of dexamethasone phosphate or 4.37 mg dexamethasone sodium
phosphate.
Each 2 mL of solution for injection contains 6.64 mg of dexamethasone (as dexamethasone sodium phosphate)
which is equivalent to 8.00 mg of dexamethasone phosphate or 8.74 mg dexamethasone sodium phosphate.
Each 5 mL of solution for injection contains 16.6 mg of dexamethasone (as dexamethasone sodium phosphate)
which is equivalent to 20.00 mg of dexamethasone phosphate or 21.85 mg dexamethasone sodium phosphate.
Excipients with known effectSodium: Each ampoule of 1 mL solution for injection contains 0.575 mg sodium. Each ampoule of 2 mL solution
for injection contains 1.150 mg sodium. Each ampoule of 5 mL solution for injection contains 2.875 mg sodium.
Propylene glycol: This medicinal product contains 20 mg propylene glycol (E 1520) in each mL of solution for
injection.
For the full list of excipients, see section 6.1

3.

PHARMACEUTICAL FORM

Solution for injection.
Clear and colourless solution.
pH: 7.00 – 8.50
Osmalility: approximately 80 – 90 mOsm/kg

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications
Corticosteroid
For use in certain endocrine and non-endocrine disorders responsive to corticosteroid therapy.
Intravenous or Intramuscular administration
Dexamethasone phosphate/DEMO 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

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(Hydrocortisone or cortisone is the first choice, but synthetic analogues may be used with mineralocorticoids whereapplicable and, in infancy, mineralocorticoid supplementation is particularly important)Non-endocrine disorders
Dexamethasone phosphate/DEMO may be used in the treatment of non-endocrine corticosteroid responsive
conditions, including:Allergy and anaphylaxis
Angioneurotic oedema and anaphylaxis
Gastrointestinal
Crohn's disease and ulcerative colitis
Infection (with appropriate antimicrobial therapy)
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 substitutefor, specific and supportive measures the patient may require. Dexamethasone has been shown to be beneficial whenused in the early treatment of shock, but it may not influence overall survival.
Treatment of COVID-19 disease caused by the new SARS-CoV-2 coronavirus strain
Dexamethasone phosphate/DEMO is indicated in the treatment of coronavirus disease 2019 (COVID-19) in adultand adolescent patients (aged 12 years and older with body weight at least 40 kg) who require supplemental oxygentherapy.
Subcutaneous administration
In palliative care, patients receiving corticosteroids for symptoms such as fatigue, anorexia, refractory nausea andvomiting or adjuvant analgesia and symptomatic treatment of cord compression or raised intracranial pressure,
Dexamethasone phosphate/DEMO may be administered subcutaneously (see section 4.2) as an alternative to the oralroute when the latter is unacceptable or no longer feasible.
Local administration
Dexamethasone phosphate/DEMO is suitable for intraarticular or soft-tissue injection as adjunctive therapy for shortterm administration in:
Soft-tissue disorders
Such as carpal tunnel syndrome and tenosynovitis
Intraarticular disorders
Such as rheumatoid arthritis and osteoarthritis with an inflammatory component.
Dexamethasone phosphate/DEMO may be injected intralesionally in selected skin disorders such as cystic acne
vulgaris, localised lichen simplex, and keloids.
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4.2 Posology and method of administration
Dexamethasone phosphate/DEMO can be given without mixing or dilution.
Alternatively, it can be added, without loss of potency, to sodium chloride, or dextrose, injection and given byintravenous infusion.
In neonates, especially the premature infant, only preservative-free solutions should be administered.
In palliative care, Dexamethasone phosphate/DEMO can be diluted with sodium chloride injection and given by
Continuous Subcutaneous Infusion (CSCI).
Infusion mixtures must be used within 24 hours and the usual aseptic techniques for injections should be observed.
All dosage recommendations are given in units of dexamethasone phospate.
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').
Intravenous and intramuscular injection
Usually the parenteral dosage ranges are one-third to one-half of the oral dose, given every 12 hours.
The usual initial dosage is 0.5 mg – 20 mg (0.125 mL – 5.0 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 dosage may be justified. In these circumstances, the slower rate of absorption by intramuscularadministration should be recognised.
Both the dose in the evening, which is useful in alleviating morning stiffness and the divided dosage regimen areassociated 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 byany 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 phosphate/DEMO by intravenous or intramuscular injection is 4
mg – 20 mg (1.0 mL – 5.0 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 2 mg – 4 mg (0.5 mL – 1.0 mL), repeated as necessary, should be sufficient.
The total daily dosage usually need not exceed 80 mg (20.0 mL), even in severe conditions.
When constant maximal effect is desired, dosage must be repeated at three-hour or four-hour intervals or maintainedby slow intravenous drip.
Intravenous or 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 2 mg – 6 mg/kg (0.5 mL – 1.5 mL/kg) bodyweight as a single intravenous injection. This may be repeatedin two to six hours if shock persists. Alternatively, this may be followed immediately by the same dose in an
intravenous infusion. Therapy with Dexamethasone phosphate/DEMO is an adjunct to and not a replacement for
conventional therapy.

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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, preoperative preparation of patients with increased intracranialpressure secondary to brain tumour: initially 10 mg (2.5 mL) intravenously, followed by 4 mg (1.0 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 phosphate/DEMO are recommended for initiating short-term intensive therapy foracute life-threatening cerebral oedema. Following the high-loading dose schedule of the first day therapy, the doseis 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 oral dexamethasone as soon as possible (seetable below).
Management of recurrent or inoperable brain tumours:
Maintenance therapy should be determined for each patient; 2 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 50 mg (12.5 mL) i.v.
1st day
8 mg (2.0 mL) i.v. every 2 hours
2nd day
8 mg (2.0 mL) i.v. every 2 hours
3rd day
8 mg (2.0 mL) i.v. every 2 hours
4th day
4 mg (1.0 mL) i.v. every 2 hours
5th-8th days 4 mg (1.0 mL) i.v. every 4 hours
Thereafter decrease by daily reduction of 4 mg (1.0 mL)
Children (35 kg and over):Initial dose 25 mg (6.25 mL) i.v.
1st day
4 mg (1.0 mL) i.v. every 2 hours
2nd day
4 mg (1.0 mL) i.v. every 2 hours
3rd day
4 mg (1.0 mL) i.v. every 2 hours
4th day
4 mg (1.0 mL) i.v. every 4 hours
5th-8th days 4 mg (1.0 mL) i.v. every 6 hours
Thereafter decrease by daily reduction of 2 mg (0.5 mL)
Children (below 35 kg):
Initial dose 20 mg (5.0 mL) i.v.
1st day
4 mg (1.0 mL) i.v. every 3 hoursnd
2 day
4 mg (1.0 mL) i.v. every 3 hours
3rd day
4 mg (1.0 mL) i.v. every 3 hours
4th day
4 mg (1.0 mL) i.v. every 6 hours
5th-8th days 2 mg (0.5 mL) i.v. every 6 hours
Thereafter decrease by daily reduction of 1 mg (0.25 mL)
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:
Second day:Dexamethasone phosphate/DEMO 4 mg – 8 mg (1.0 mL – 2.0 mL) intramuscularly
Two 500 microgram dexamethasone tablets twice a day4

Dexamethasone phosphate (as sodium)8mg/2mL solution for injection(Demo S.A.), CV006

Third day:
Fourth day:Fifth day:
Sixth day:Seventh day:Eighth day:

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Two 500 microgram dexamethasone tablets twice a day
One 500 microgram dexamethasone tablet twice a day
One 500 microgram dexamethasone tablet twice a day
One 500 microgram dexamethasone tablet once daily
One 500 microgram dexamethasone tablet once daily
Reassessment day

For the treatment of Covid-19
Adult patients 6 mg IV, once a day for up to 10 days.
Paediatric population
Paediatric patients (adolescents aged 12 years and older) are recommended to take 6 mg/dose IV once a day for up
to 10 days.
Duration of treatment should be guided by clinical response and individual patient requirements.
Elderly, renal impairment, hepatic impairment
No dose adjustment is needed.
Subcutaneous administration
In palliative care, subcutaneous Dexamethasone phosphate/DEMO may be administered by injection or Continuous
Subcutaneous Infusion (CSCI). Doses usually range between 4.8 mg to 19.3 mg over 24 hours, taking into
consideration local clinical guidelines, and should be titrated according to the response.
Intraarticular or intralesional 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
Large joint (e.g. knee)
Small joints (e.g. interphalangeal, temporomandibular)
Tendon sheaths*
Soft-tissue infiltration
Ganglia

DEXAMETHASONE DOSE
2 mg – 4 mg
(0.5 mL – 1.0 mL)
0.8 mg – 1 mg
(0.2 mL – 0.25 mL)
0.4 mg – 1 mg
(0.1 mL – 0.25 mL)
2 mg – 6 mg
(0.5 mL – 1.5 mL)
1 mg – 2 mg
(0.25 mL – 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.
Paediatric population:
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 isrequired to avoid life threatening reactions (see 'Undesirable effects').
4.3 Contraindications
Systemic fungal infection; systemic infection unless specific anti-infective therapy is employed; hypersensitivity to
the active ingredient or any other component of this medication. Administration of live virus vaccines (see 'Special
warnings and precautions for use').
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4.4 Special warnings and precautions for use
In post marketing experience tumour lysis syndrome (TLS) has been reported in patients with haematologicalmalignancies 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 tocytotoxic 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 highdoses/systemic exposure (see also section 4.5 pharmacokinetic interactions that can increase the risk of side
effects), although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most
reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary.
Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop,
especially if depressed mood or suicidal ideation is suspected. Patients/carers should also be alert to possible
psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic
steroids, although such reactions have been reported infrequently.
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 depressiveor manic-depressive illness and previous steroid psychosis.
Frequent intraarticular injections over a prolonged period may lead to joint destruction with bone necrosis.
Intraarticular injection of corticosteroid may produce systemic adverse reactions including adrenal suppression.
Undesirable effects may be minimised by using the lowest effective dose for 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 andcongestive failure.
Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, retention of salt andwater and increased excretion of potassium, but these effects are less likely to occur with synthetic derivates, except
when used in large doses. Dietary salt restrictions 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 surgicalprocedures), 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 oftreatment, 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, thecurrent 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 three 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 to6Dexamethasone phosphate (as sodium)8mg/2mL solution for injection(Demo S.A.), CV006

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relapse on withdrawal of systemic corticosteroids but there is uncertainty about hypothalamic-pituitary adrenal(HPA) suppression, the dose of systemic corticosteroids 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 three weeks is appropriate if it
is considered that the disease is unlikely to relapse. Abrupt withdrawal of doses of up to 6 mg daily of
dexamethasone for three weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority ofpatients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should beconsidered even after courses lasting three weeks or less:• patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than three
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 6 mg daily of dexamethasone,• patients repeatedly taking doses in the evening.
Patients should carry 'steroid treatment' cards, which give clear guidance on the precautions to be taken to minimiserisk 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 contraindicated 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 phosphate/DEMO in active tuberculosis should be restricted to those cases offulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease inconjunction with an appropriate antituberculosis regimen. If the corticosteroids are indicated in patients with latenttuberculosis or tuberculin reactivity, close observation is necessary as reactivation may occur. During prolonged
corticosteroid therapy, these patients should receive prophylacticantimicrobial therapy. Corticosteroids may masksome signs of infection and new infections may appear during their use. Suppression of the inflammatory response
and immune function increasing 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 anincreased 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 month; this should begiven 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 oreven 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.
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Corticosteroids may activate latent amoebiasis or strongyloidiasis or exacerbate active disease. Therefore, it isrecommended 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 tothe 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 ofsystemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk ofsystemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid sideeffects.
In COVID-19 patients, systemic corticosteroids should not be stopped for patients who are already treated withsystemic (oral) corticosteroids for other reasons (e.g. patients with chronic obstructive pulmonary disease) but notrequiring supplemental oxygen.
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 witha 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 gastrointestinal 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 fluids is necessary to exclude a septic process.
A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever and malaise aresuggestive 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 intraarticular injections have been reported to cause development of Charcot-like arthropathies.
Paediatric population
Preterm neonates:
Available evidence suggests long-term neurodevelopmental adverse events after early treatment (< 96 hours) ofpremature infants with chronic lung disease at starting doses of 0.25mg/kg twice daily.
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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.
Dexamethasone has been used to treat and prevent chronic lung disease in preterm infants (unlicensed use).
Clinical trials have shown no long term benefit in reducing time to discharge, the incidence of chronic lung diseaseor mortality. Recent trials have suggested an association between the use of dexamethasone in preterm infants andthe 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.
Sodium content
This medicinal product contains 241.5 mg sodium per maximum single dose, equivalent to 12.075 % of the WHO
recommended maximum daily intake of 2 g sodium for an adult.
Propylene glycol content
This medicinal product contains 20 mg propylene glycol (E 1520) in each mL.
Medical monitoring is required in patients with impaired renal or hepatic functions because various adverse events
attributed to propylene glycol have been reported such as renal dysfunction (acute tubular necrosis), acute renal
failure and liver dysfunction.
Co-administration with any substrate for alcohol dehydrogenase, such as ethanol, may induce adverse effects inchildren less than 5 years old.
Co-administration with any substrate for alcohol dehydrogenase, such as ethanol, may induce serious adverse
effects in neonates.
See also Section 4.6 – Fertility, pregnancy and lactation.
4.5 Interaction with other medicinal products and other forms of interaction
Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinaemia.
The renal clearance of salicylates is increased by corticosteroids and therefore salicylate dosage should be reduced
along with steroid withdrawal.
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 interfere with dexamethasone suppression tests whichshould be interpreted with caution during administration of these drugs.
False-negative results in the dexamethasone suppression test in patients being treated with indometacin have beenreported.
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 thesame time, in order to avoid spontaneous bleeding.
The desired effects of hypoglycaemic agents (including insulin) are antagonised by corticosteroids.
When corticosteroids are administered concomitantly with potassium-depleting diuretics, patients should beobserved closely for development of hypokalaemia.
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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) aremetabolised by CYP3A. Medicinal products that induce CYP3A activity, such as dexamethasone, may increase theclearance 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 aresult 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, intrauterine growth retardation and effects on brain growth and development. There is no evidence thatcorticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate/lip in man. See also
section 5.3 Preclinical safety data.
However, when administered for prolonged periods or repeatedly during pregnancy, corticosteroids may increase
the risk of intrauterine 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 therisks.
When corticosteroids are essential however, patients with normal pregnancies may be treated as though they werein non-gravid state.
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.
While propylene glycol has not been shown to cause reproductive or developmental toxicity inanimals or humans, it may reach the foetus and was found in milk. As a consequence,administration of propylene glycol to pregnant or lactating patients should be considered on a case by case basis.
4.7 Effects on ability to drive and use machines
Not applicable.
4.8 Undesirable effects
The incidence of predictable undesirable effects, including hypothalamic-pituitary-adrenal suppression, correlateswith 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 intraarticular use').
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Gastrointestinal:
Peptic ulcer with possible perforation and haemorrhage, perforation of the small and large bowel, particularly inpatients 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 hyperpigmentation.
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 labilemood, and suicidal thoughts), psychotic reactions (including mania, delusions, hallucinations, and aggravation ofschizophrenia), 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 andchildren. In adults, the frequency of severe reactions has been estimated to be 5-6%. Psychological effects have beenreported on withdrawal of corticosteroids; the frequency is unknown.
Endocrine:
Menstrual irregularities, amenorrhoea, development of Cushingoid state, suppression of growth in children andadolescents, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress as in trauma,
surgery or illness), decreased carbohydrate tolerance, manifestation 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 intraocular pressure, papilloedema, corneal or scleral thinning,
exacerbation of ophthalmic viral disease, glaucoma exophthalmos, rare instances of blindness associated withintralesional therapy around the face and head, retinopathy of prematurity, chorioretinopathy.
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.

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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 the National Organisation for Medicines, 284 Mesogion Av., 155 62 Cholargos,
Athens, Tel.: +30 213 2040380/337, Fax: +30 210 6549585, Website: http://www.eof.gr.
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 thatwould 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 group: Corticosteroids for systemic use, plain preparations, glucocorticoids
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 gastrointestinal 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 disordersof 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 ordesoxycorticosterone.
The RECOVERY trial (Randomised Evaluation of COVid-19 thERapY,)1 is an investigator-initiated, individuallyrandomised, controlled, open-label, adaptive platform trial to evaluate the effects of potential treatments in patients
hospitalised with COVID-19. The trial was conducted at 176 hospital organizations in the United Kingdom. There
were 6425 Patients randomised to receive either dexamethasone (2104 patients) or usual care alone (4321 patients).
89% of the patients had laboratory-confirmed SARS-CoV-2 infection. At randomization, 16% of patients werereceiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were receiving oxygen
only (with or without non invasive ventilation), and 24% were receiving neither. The mean age of patients was
66.1+/-15.7 years. 36% of the patients were female. 24% of patients had a history of diabetes, 27% of heart disease
and 21% of chronic lung disease.
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Primary endpoint
Mortality at 28 days was significantly lower in the dexamethasone group than in the usual care group, with deaths
reported in 482 of 2104 patients (22.9%) and in 1110 of 4321 patients (25.7%), respectively (rate ratio, 0.83; 95%
confidence interval [CI], 0.75 to 0.93; P<0.001).
In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients
receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and in thosereceiving supplementary oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95%
CI, 0.72 to 0.94).
There was no clear effect of dexamethasone among patients who were not receiving any respiratory support at
randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55).
Secondary endpoints
Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group(median, 12 days vs. 13 days) and a greater probability of discharge alive within 28 days (rate ratio, 1.10; 95% CI,
1.03 to 1.17).
In line with the primary endpoint the greatest effect regarding discharge within 28 days was seen among patients
who were receiving invasive mechanical ventilation at randomization (rate ratio 1.48; 95% CI 1.16, 1.90), followedby oxygen only (rate ratio, 1.15 ;95% CI 1.06-1.24) with no beneficial effect in patients not receiving oxygen (rateratio, 0.96 ; 95% CI 0.85-1.08).

1

www.recoverytrial.net

SafetyThere were four serious adverse events (SAEs) related to study treatment: two SAEs of hyperglycaemia, one SAEof steroid-induced psychosis and one SAE of an upper gastrointestinal bleed. All events resolved.
Subgroup analyses
Effects of allocation to DEXAMETHASONE on 28−day mortality, by age and respiratory support received at
randomisation2

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Effects of allocation to DEXAMETHASONE on 28−day mortality, by respiratory support received at
randomisation and history of any chronic disease.3

2, 3(source: Horby P. et al., 2020; https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1 ; doi:
https://doi.org/10.1101/2020.06.22.20137273)
5.2 Pharmacokinetic properties
The biological half-life of dexamethasone in plasma is about 190 minutes. Binding of dexamethasone to plasma
proteins is less than for most other corticosteroids and is estimated to be about 77%. Up to 65% of a dose is
excreted in the urine in 24 hours, the rate of excretion being increased following concomitant administration ofphenytoin. The more potent halogenated corticosteroids, such as dexamethasone, appear to cross the placental
barrier with minimal inactivation.

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5.3 Preclinical safety data
In animal studies, cleft palate was observed in rats, mice, hamsters, rabbits, dogs and primates; not in horses andsheep. 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 theseeffects were seen at high dosages.

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Propylene glycol (E1520),
Disodium edetate,
Sodium hydroxide (for pH adjustment),
Water for injections.
6.2 Incompatibilities
Dexamethasone is physically incompatible with daunorubicin, doxorubicin, vancomycin, diphenhydramine (withlorazepam and metoclopramide) and metaraminol bitartrate and should not be admixed with solutions containing
these drugs. It is also incompatible with doxapram and glycopyrrolate in syringe and with ciprofloxacin, idarubicinand midazolam in Y-site injections (1:1 mixture).
6.3 Shelf life
As packaged for sale: 24 months.
In use: Chemical and physical in-use stability has been demonstrated for 24 h at 25°C, protected from light, when
diluted with the diluents stated in Section 6.6. Dilutions should be used within 24 hours and discarded after use.
From a microbiological point of view, the product should be used immediately after opening. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normallynot be longer than 24 h at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Any unused portion of the product should be discarded immediately after use.
6.4 Special precautions for storage
Store below 25°C.
Do not refrigerate or freeze.
Keep the ampoule in the outer carton in order to protect from light.
For storage conditions after dilution of the medicinal product, see Section 6.3.
6.5 Nature and contents of container
Type I clear glass ampoule containing 1 mL solution for injection.
Type I clear glass ampoule containing 2 mL solution for injection.
Type I clear glass ampoule containing 5 mL solution for injection.
Pack sizes of 1, 5, 10, 20, 50 and 100 ampoules of 1 mL solution for injection
Pack sizes of 1, 5, 10, 20, 50 and 100 ampoules of 2 mL solution for injection
Pack sizes of 1, 5, 10, 20, 50 and 100 ampoules of 5 mL solution for injection
Not all pack sizes may be marketed.

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6.6 Special precautions for disposal and other handling
When Dexamethasone phosphate/DEMO is given by intravenous infusion, dextrose 5% w/v in water and sodium
chloride 0.9% w/v have been recommended as diluents. The exact concentration of dexamethasone per infusion
container should be determined by the desired dose, patient fluid intake and drip rate required.
This medicinal product is preservative-free.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
After opening, any remaining unused solution should not be stored and should be discarded immediately.

7.

MARKETING AUTHORISATION HOLDER

DEMO S.A. Pharmaceutical Industry
21st km National Road Athens-Lamia
145 68 Krioneri, Attiki, Greece
T: +30 210 8161802, F: +30 210 8161587

8. MARKETING AUTHORISATION NUMBER(S)Reg. No. in Greece: 22062/17-03-2021 GR

9.

DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORIZATION

Date of first authorisation: 17/03/2021
Date of latest renewal: –10. DATE OF REVISION OF THE TEXT
04/202116