This information is intended for use by health professionals

1. Name of the medicinal product

Dexamethasone 2mg/5ml Oral Solution

2. Qualitative and quantitative composition

Each 5 ml of oral solution contains 2 mg dexamethasone as dexamethasone sodium phosphate.

Excipients with known effect:

Each 5 ml of solution contains:

∗ 1.75 g maltitol (E965)

∗ 500 mg sorbitol (E420)

∗ 470 mg propylene glycol (E1520)

∗ approximately 7.6 mg ethanol

∗ 5 mg benzoic acid

∗ 1.5mg sodium

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Oral solution.

A colourless solution with a mint flavour and odour.

4. Clinical particulars
4.1 Therapeutic indications

Neurology

Cerebral oedema (only with symptoms of intracranial pressure evidenced by computerised tomography) caused by a brain tumour, neuro-surgical intervention, cerebral abscess.

Pulmonary and respiratory diseases:

Acute asthma exacerbations when use of an oral corticosteroid (OCS) is appropriate, croup.

Dermatology

Initial treatment of extensive, severe, acute, skin diseases responding to glucocorticoids, e.g. erythroderma, pemphigus vulgaris.

Autoimmune disorders/rheumatology

Initial treatment of autoimmune disorders like systemic lupus erythematodes.

Active phases of systemic vasculitides like panarteritis nodosa (treatment duration should be limited to two weeks in cases of concomitant positive hepatitis B serology).

Severe progressive course of active rheumatoid arthritis, e.g. fast proceeding destructive forms and/or extraarticular manifestations.

Severe systemic course of juvenile idiopathic arthritis (Still's disease).

Haematological disorder

Idiopathic thrombocytopenic purpura in adults.

Infectology

Tuberculous meningitis only in conjunction with anti-infective therapy.

Dexamethasone Oral Solution is indicated in the treatment of coronavirus disease 2019 (COVID-19) in adult and adolescent patients (aged 12 years and older with body weight at least 40kg) who require supplemental oxygen therapy.

Oncology

Palliative treatment of neoplastic diseases.

Prophylaxis and treatment of emesis induced by cytostatics, emetogenic chemotherapy within antiemetic treatment.

Treatment of symptomatic multiple myeloma, acute lymphoblastic leukemia,

Hodgkin's disease and non-Hodgkin's lymphoma in combination with other medicinal products.

Various

Prevention and treatment of postoperative vomiting, within antiemetic treatment.

4.2 Posology and method of administration

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').

The initial dosage varies from 0.5 – 10 mg (equivalent to 1.25 ml – 25ml of product) a day depending on the disease being treated. In more severe diseases, doses higher than 10 mg may be required. The dose should be titrated to the individual patient response and disease severity. In order to minimize side effects, the lowest effective possible dose should be used.

Unless otherwise prescribed, the following dosage recommendations apply:

The below mentioned dosing recommendations are given for guidance only. The initial and daily doses should always be determined based on individual patient response and disease severity. If high doses are required other presentations may be more suitable.

- Cerebral oedema: Initial dose and duration of treatment depending on the cause and severity, 6-16 mg (up to 24 mg) / day orally, divided into 3-4 individual doses.

- Acute asthma: Adults: 16 mg / day for two days. Children: 0.6 mg / kg body weight for one or two days.

- Acute skin diseases: Depending on the nature and extent of the disease daily doses of 8-40 mg, in some cases up to 100 mg, which should be followed by down titration according to clinical need.

- Active phase of rheumatic system disorders: Systemic lupus erythematosus 6-16 mg / day.

- Active rheumatoid arthritis with severe progressive course form: running at fast destructive forms 12-16 mg /day, with extra-articular manifestations 6-12 mg / day.

- Idiopathic thrombocytopenic purpura: 40 mg for 4 days in cycles.

- Tuberculous meningitis: Patients with grade II or III disease received intravenous treatment for four weeks (0.4 mg per kilogram per day for week 1, 0.3 mg per kilogram per day for week 2, 0.2 mg per kilogram per day for week 3, and 0.1 mg per kilogram per day for week 4) and then oral treatment for four weeks, starting at a total of 4 mg per day and decreasing by 1 mg each week. Patients with grade I disease received two weeks of intravenous therapy (0.3 mg per kilogram per day for week 1 and 0.2 mg per kilogram per day for week 2) and then four weeks of oral therapy (0.1 mg per kilogram per day for week 3, then a total of 3 mg per day, decreasing by 1 mg each week).

- Palliative treatment of neoplastic diseases: Initial dose and duration of treatment depending on the cause and severity, 3-20 mg / day. Very high doses up to 96 mg may also be used for palliative treatment.

- Prophylaxis and treatment of emesis induced by cytostatics, emetogenic chemotherapy within antiemetic treatment: 8-20 mg dexamethasone prior to chemotherapy treatment, then 4-16 mg/day on day 2 and 3.

- Prevention and treatment of postoperative vomiting, within antiemetic treatment: single dose of 8 mg before the surgery.

- Treatment of symptomatic multiple myeloma, acute lymphoblastic leukemia, Hodgkin's disease and non-Hodgkin's lymphoma in combination with other medicinal products: the usual posology is 40 mg or 20 mg once per day.

- Childhood Croup:

Children: 0.15mg/kg-0.6 mg/kg in a single dose.. A second dose may be administered after 12 hours, if considered necessary by the treating physician.

Dexamethasone Oral Solution is not recommended for use in neonates aged ≤ 28 days (see section 4.4).

Doses of up to 0.6mg/kg dexamethasone have been used safely in clinical studies. However, a maximum dose of 10mg (25ml Dexamethasone 2mg/5ml Oral Solution) is recommended.

The following dosage chart should be followed for the treatment of childhood croup at a dose of 0.15mg/kg.

Approximate age

(mths/yrs)

Approximate weight

(kg)

Volume of Dexamethasone 2mg/5ml Oral Solution (ml)

Min

Max

Min

Max

1mth

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

The dose and administration frequency varies with the therapeutic protocol and the associated treatment(s). Dexamethasone administration should follow instructions for dexamethasone administration when described in the Summary of Product Characteristics of the associated treatment(s). If this is not the case, local or international treatment protocols and guidelines should be followed. Prescribing physicians should carefully evaluate which dose of dexamethasone to use, taking into account the condition and disease status of the patient.

For the treatment of COVID-19

Adult patients 6mg IV or PO, once a day for up to 10 days.

Paediatric population

Paediatric patients (adolescents aged 12 years and older) are recommended to take 6mg/dose IV or PO 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.

Renal impairment

Patients undergoing active hemodialysis may show an increased clearance of drug via the dialysate and thus require an adjustment of steroid dose.

Hepatic impairment

In patients with severe liver disease dose adjustment may be necessary. In patients with a severe liver impairment, the biological effects of dexamethasone may be potentiated due to its slower metabolism (prolonged plasma half-life) and hypoalbuminaemia (increased plasma levels of free drug), which may also cause more side effects.

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 (osteoporosis, diabetes mellitus, hypertension, reduced immunity, psychological changes). In such patients, the plasma concentrations of dexamethasone may be higher and its excretion slower than in younger patients, therefore its dose should be reduced accordingly.

Paediatric population

The excretion of dexamethasone is approximately equal in children and adults if dosage is adjusted to their body area. Dosage should be planned bearing in mind possible effects upon growth and development and for signs of adrenal suppression.

Long term treatment

For the long-term treatment of several conditions, after initial therapy, glucocorticoid treatment should be switched from dexamethasone to prednisone/prednisolone to reduce suppression on the function of the adrenal cortex.

Discontinuation of treatment

Acute adrenocortical failure may occur after abrupt discontinuation of long-term treatment with large doses of glucocorticoids. Therefore, glucocorticoid doses should be gradually reduced in such cases and treatment should be discontinued gradually. (see section 4.4)

4.3 Contraindications

• Hypersensitivity to dexamethasone or any of the excipients listed in section 6.1.

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

• Stomach ulcer or duodenal ulcer.

Vaccination with live vaccines during treatment with large therapeutic doses of dexamethasone (and other corticosteroids) is contraindicated due to the possibility of viral infection (see section 4.4 and 4.5).

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').

Adrenocortical insufficiency

An adrenocortical insufficiency, which is caused by glucocorticoid treatment, can, depending on the dose and length of treatment, remain for many months, and in some cases more than a year, after discontinuation of treatment. During treatment with dexamethasone for specific physical stress conditions (trauma, surgery, childbirth, etc.), a temporary increase in dose may be required. Because of the possible risk in stressful conditions, a corticosteroid ID should be made for patients undergoing long-term treatment. Even in cases of prolonged adrenocortical insufficiency after discontinuation of treatment, the administration of glucocorticoids can be necessary in physically stressful situations. An acute therapy-induced adrenocortical insufficiency can be minimized by slow dose reduction until a planned discontinuation time.

Treatment with dexamethasone should only be implemented in the event of the strongest indications and, if necessary, additional targeted anti-infective treatment administered for the following illnesses:

- Acute viral infections (Herpes zoster, Herpes simplex, Varicella, herpetic keratitis)

- HBsAG-positive chronic active hepatitis

- Approx. 8 weeks prior through 2 weeks after vaccinations with live vaccines (see section 4.3 and 4.5)

- Systemic mycoses and parasitosis (e.g. Nematodes)

- Poliomyelitis

- Lymphadenitis after BCG vaccination

- Acute and chronic bacterial infections

- With a history of tuberculosis (reactivation risk) use only under tuberculostatic protection

- Known or suspected Strongyloidiasis (threadworm infestation). Treatment with glucocorticoids may lead to lead to Strongyloides hyperinfection and dissemination with widespread larval migration.

In addition, treatment with dexamethasone should only be implemented under strong indications and, if necessary, additional specific treatment must be implemented for:

- Gastrointestinal ulcers

- Severe osteoporosis (as corticosteroids have a negative effect on the calcium balance)

- Difficult to regulate high blood pressure

- Difficult to regulate diabetes mellitus

- Psychiatric disorders (including history)

- Angle closure glaucoma and wide-angle glaucoma

- Corneal ulcerations and corneal injuries

- Severe heart failure

Anaphylactic reaction

Serious anaphylactic reactions may occur.

Tendinitis

The risk of tendinitis and tendon rupture is increased in patients treated concomitantly with glucocorticoids and fluoroquinolones.

Myasthenia gravis

Pre-existing myasthenia gravis may initially deteriorate in the beginning of dexamethasone treatment.

Intestinal perforation

Because of the risk of an intestinal perforation, dexamethasone must only be used under urgent indication and under appropriate monitoring for:

- Severe ulcerative colitis with threatened perforation

- Diverticulitis

- Entero-anastomosis (immediately postoperative)

Signs of peritoneal irritation after gastrointestinal perforation may be absent in patients receiving high doses of glucocorticoids.

Diabetes

A higher need for insulin, or oral antidiabetics, must be taken into consideration when administering dexamethasone to diabetics.

Cardiovascular disorders

Regular blood pressure monitoring is necessary during treatment with dexamethasone, particularly during administration of higher doses and with patients with difficult to regulate high blood pressure. Because of the risk of deterioration, patients with severe cardiac insufficiency should be carefully monitored.

Bradycardia may occur in patients treated with high doses of dexamethasone.

Caution should be exercised when using corticosteroids in patients who have recently suffered myocardial infarction as myocardial rupture has been reported.

Infections

Treatment with dexamethasone can conceal the symptoms of an existing, or developing infection thereby making a diagnosis more difficult. The prolonged use of even small amounts of dexamethasone leads to an increased risk of infection, even by microorganisms which otherwise rarely cause infections (so-called opportunistic infections).

Vaccination

Vaccinations with inactivated vaccine are always possible. However, it should be noted that the immune reaction and thereby the success of inoculation, can be affected by higher doses of corticoids.

Regular checkups with doctors (including vision checkups in three-month intervals) are advised during long-term treatment with dexamethasone.

Metabolic disorders

At high doses, sufficient calcium intake and sodium restriction, as well as serum potassium levels should be monitored. Depending on the length and dosage of the treatment, a negative influence on calcium metabolism can be expected, so that an osteoporosis prophylaxis is recommended. This applies, above all, to co-existing risk factors like familial disposition, increased age, after menopause, insufficient protein and calcium intake, heavy smoking, excessive alcohol intake, as well as insufficient exercise. Prevention consists of sufficient calcium and vitamin D intake and physical activity. Additional medical treatment should be considered in the event of pre-existing osteoporosis.

Corticosteroids should be used cautiously in patients with migraine, as corticosteroids may cause fluid retention.

Psychological changes

Psychological changes are manifested in various forms, the most common being euphoria. Depression, psychotic reactions and suicidal tendencies may also appear.

These illnesses can be serious. Usually they start within a few days or weeks of starting the medicine. They are more likely to happen at high doses. Most of these problems go away if the dose is lowered or the medicine is stopped. However, if problems do happen, they might need treatment. In a few cases, mental health problems have happened when doses are being lowered or stopped.

Cerebral oedema or increased intracranial pressure

Corticosteroids should not be used in conjunction with a head injury since they will probably not be of benefit or may even do harm.

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.

Prolonged use of corticosteroids may cause posterior subcapsular cataracts, glaucoma with possible damage to the optic nerve and can increase the risk of secondary ocular infections due to fungi or viruses.

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

Tumour lysis syndrome

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.

Discontinuation of treatment

Glucocorticoid doses should be gradually reduced.

The following risks should be considered upon interruption or discontinuation of long-term glucocorticoid administration:

- Exacerbation or recurrence of the underlying disease, acute adrenal insufficiency, corticosteroid withdrawal syndrome (A 'withdrawal syndrome' may include fever, muscle and joint pain, inflammation of the nose lining (rhinitis), weight loss, itchy skin and inflammation of the eye (conjunctivitis)).

- Certain viral diseases (chickenpox, measles) in patients treated with glucocorticoids, may be very severe.

- Children and immunocompromised persons without previous chickenpox or measles infection are particularly at risk.

If these people have contact with people infected with measles or chickenpox while undergoing treatment with dexamethasone, a preventative treatment should be introduced if necessary.

Systemic corticosteroids should not be stopped for patients who are already treated with systemic (oral) corticosteroids for other reasons (e.g. patients with chronic obstructive pulmonary disease) but not requiring supplemental oxygen.

Other

Pheochromocytoma crisis, which can be fatal, has been reported after administration of systemic corticosteroids.

Corticosteroids should only be administered to patients with suspected or identified pheochromocytoma after an appropriate risk/benefit evaluation.

Paediatric population

Corticosteroids cause a dose-dependent inhibition of growth in infancy, childhood and adolescence since corticosteroids may give rise to early closing of the epiphyses, which may be irreversible.

Therefore, during long-term treatment with dexamethasone, the indication should be very strongly presented in children and their growth rate should be checked regularly.

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.

Elderly

The adverse effects of systemic corticosteroids may be associated with more serious consequences in old age, especially osteoporosis, hypertension, hypokalaemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.

Excipient Warnings

Maltitol and sorbitol: Patients with rare hereditary problems of fructose intolerance should not take this medicine.

This medicine contains 94 mg propylene glycol in each ml, which is equivalent to 470 mg/ 5 ml. Co-administration with any substrate for alcohol dehydrogenase such as ethanol may induce serious adverse effects in neonates.

This product contains small amounts of ethanol (alcohol), less than 100mg per dose.

Influence of diagnostic tests

Glucocorticoids can suppress skin reaction to allergy testing. They can also affect the nitroblue tetrazolium test for bacterial infections and cause false-negative results.

Note on doping

The use of doping tests when taking dexamethasone can lead to positive results.

Dexamethasone contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Prior to the use of Dexamethasone in combination with any other medicinal product, reference should be made to the Summary of Product Characteristics of that product.

Pharmacodynamic interactions

Patients taking NSAIDs should be monitored, as NSAIDs may increase the incidence and/or severity of gastric ulcers. Acetylsalicylic acid should be used carefully in combination with corticosteroids in hypoprothrombinaemia.

The renal clearance of salicylates is increased by corticosteroids. Therefore, the dosage of salicylates may be reduced once the steroids are discontinued. Steroid withdrawal may result in salicylate intoxication due to the increase of salicylate concentration in the serum.

Corticosteroids reduce the effect of antidiabetic agents such as insulin, sulfonylurea, and metformin. Hyperglycaemia and diabetic ketoacidosis may occur occasionally.

Therefore, at the beginning of treatment, diabetics should have more frequent blood and urine tests.

The hypokalemic effect of acetazolamide, loop diuretics, thiazide diuretics, kaliuretics, amphotericin B injections (glucomineral)-corticosteroids, tetracosactide and laxatives will increase. Hypokalemia promotes cardiac arrhythmias, especially torsade de pointes, and increases the toxicity of cardiac glycosides. Before the start of corticosteroid treatment, hypokalemia should be corrected and patients should be monitored clinically, for electrolytes and by electrocardiography. Furthermore, there are case reports in which the simultaneous use of amphotericin B and hydrocortisone led to an enlarged heart and heart failure.

Antiulcer drugs: Carbenoxolone increases the risk of hypokalemia.

Chloroquine, hydroxychloroquine and mefloquine: Increased risk of myopathies and cardiomyopathies.

Concomitant administration of ACE inhibitors creates an increased risk of blood disorders.

The blood pressure-lowering effects of antihypertensive drugs may be affected by corticosteroids. The dose of the anti-hypertensive treatment may have to be adjusted during the treatment with dexamethasone.

Thalidomide: Great care should be taken during co-administration with thalidomide, a there have been reported cases of toxic epidermal necrolysis.

The effect of vaccinations may be reduced during treatment with dexamethasone.

Vaccination with live vaccines during treatment with large therapeutic doses of dexamethasone (and other corticosteroids) is contraindicated due to the possibility of viral infection. In this case, vaccination should be postponed for at least 3 months after the completion of treatment with corticosteroids. Other types of immunisation during treatment with large therapeutic doses of corticosteroids are dangerous due to the risk of neurological complications and decreased or absent increase in the antibody titers (in comparison with expected values) and therefore a smaller protective effect. However, patients who have received corticosteroids locally (parenteral) or for a short period of time (less than 2 weeks), in smaller doses may be immunised.

Cholinesterase inhibitors: Concomitant use of cholinesterase inhibitors and corticosteroids may cause serious muscle weakness in patients with myasthenia gravis. If possible, cholinesterase inhibitors should be discontinued at least 24 hours before the start of corticosteroid therapy.

The risk of tendinitis and tendon rupture is increased in patients treated concomitantly with glucocorticoids and fluoroquinolones.

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.

Pharmacokinetic interactions

Effects of other medicinal products on dexamethasone:

Dexamethasone is metabolized via the cytochrome P450 3A4 (CYP3A4).

The administration of dexamethasone with inducers of CYP3A4, such as ephedrine, barbiturates, rifabutin, rifampicin, phenytoin, and carbamazepine can lead to reduced plasma concentrations of dexamethasone, so the dose must be increased.

Aminoglutethimide can accelerate the reduction of dexamethasone and reduce its efficacy. If necessary, the dexamethasone dosage should be adjusted.

Bile acid resins, such as cholestyramine, may decrease the absorption of dexamethasone.

Topically applied gastrointestinal drugs, antacids, activated charcoal: Decreased glucocorticoid resorption has been described during co-administration of prednisolone and dexamethasone. Therefore, the administration of glucocorticoids and topically applied gastrointestinal drugs, antacids, activated charcoal should be postponed (with an interval of at least two hours).

The administration of dexamethasone with inhibitors of CYP3A4, such as azoleantifungals (e.g. ketoconazole, itraconazole), HIV protease inhibitors (e.g. ritonavir) and macrolide antibiotics (e.g. erythromycin) may lead to increased plasma concentrations and reduced clearance of dexamethasone. If required, the dexamethasone dose should be reduced.

Ketoconazole may not only increase the plasma concentration of dexamethasone by inhibition of CYP3A4, but also suppress adrenal corticosteroid synthesis and cause adrenal insufficiency upon discontinuation of corticosteroid treatment.

Estrogens, including oral contraceptives, may inhibit the metabolism of certain corticosteroids and thus enhance their effect.

Effects of dexamethasone on other medicinal products

Dexamethasone is a moderate inducer of CYP3A4. The administration of dexamethasone with substances metabolized by CYP3A4 can lead to increased clearance and decreased plasma concentrations of these substances.

Tuberculostatics: A reduction of isoniazid plasma concentrations was observed during concurrent use of prednisolone. Patients taking isoniazid should be monitored closely.

Cyclosporine: Concomitant administration of cyclosporine and corticosteroids may lead to an increased effect of both substances. There is an increased risk of cerebral seizures.

Praziquantel: Reduced praziquantel plasma concentrations create a risk of treatment failure due to the increased hepatic metabolism of dexamethasone.

Oral anticoagulants (coumarin): Concomitant corticosteroid therapy may either potentiate or lead to a weakening of the effect of oral anticoagulants. In case of high doses or of treatment lasting over 10 days there is a risk of bleeding specific to corticosteroid therapies (gastrointestinal mucosa, vascular fragility). Patients who use corticosteroids combined with oral anticoagulants should be closely monitored (controls on day 8, then every two weeks during and after treatment).

Atropine and other anticholinergics: Intraocular pressure increases may be noted during co-administration with dexamethasone.

Non-depolarizing muscle relaxants: the muscle relaxing effect may last longer.

Somatotropin: the effect of the growth hormone can be reduced.

Protirelin: Reduced increase in TSH may be noted during administration of protirelin.

4.6 Fertility, pregnancy and lactation

Pregnancy

Dexamethasone crosses the placenta. Administration of corticosteroids to pregnant animals can cause abnormalities in 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 Section 5.3). Long-term or repeated corticosteroid therapy in pregnancy increases the risk of intrauterine growth retardation. In newborns exposed to corticosteroids in the prenatal period, there is an increased risk of adrenal insufficiency, which under normal circumstances undergoes spontaneous postnatal regression, and is rarely of clinical significance. Dexamethasone should be prescribed during pregnancy, and particularly in the first trimester, only if the benefit outweighs the risks for the mother and child.

Breast-feeding

Corticosteroids are excreted in breast milk. There is insufficient information on the excretion of dexamethasone in human milk. A risk to the newborns/infants cannot be excluded. Infants of mothers taking high doses of systemic corticosteroids for prolonged periods may have a degree of adrenal suppression.

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

Dexamethasone decreases testosterone biosynthesis and endogenous ACTH secretion which has an effect on the spermatogenesis and the ovarian cycle.

4.7 Effects on ability to drive and use machines

There have been no studies on the effects on the ability to drive and use machines.

Dexamethasone may cause confusional state, hallucinations, dizziness, somnolence, fatigue, syncope and blurred vision (see section 4.8). If affected, patients should be instructed not to drive, use machines or perform hazardous tasks while being treated with dexamethasone.

4.8 Undesirable effects

The incidence of anticipated adverse effects correlates with the relative potency of the substance, dose, time of day of administration and duration of treatment. During a short-term therapy, in compliance with the dosage recommendations and close monitoring of patients, the risk of side effects is low.

The usual side effects of short-term dexamethasone treatment (days/weeks) include weight gain, psychological disorders, glucose intolerance and transitory adrenocortical insufficiency. Long-term dexamethasone treatment (months/years) usually causes central obesity, skin fragility, muscle atrophy, osteoporosis, growth retardation and long-term suprarenal insufficiency. (see also section 4.4 Special warnings and precautions for use)

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

System Organ Class

Infections and infestations

Increased susceptibility to, or exacerbation of, (latent) infections* (including septicaemia, tuberculosis, eye infections, chickenpox, measles, fungal and viral infections) with masking of clinical symptoms, opportunistic infections.

Blood and lymphatic system disorders

Leukocytosis, lymphopenia, eosinopenia, polycythemia, abnormal coagulation

Immune system disorders

Hypersensitivity reactions including anaphylaxis, immunosuppression (see also under “Infections and parasitic diseases”)

Endocrine disorders

Suppression of the hypothalamic- pituitary-adrenal axis and induction of Cushing's syndrome (typical symptoms: full-moon face, plethora, truncal obesity), secondary adrenal and pituitary insufficiency* (particularly in times of stress, as in trauma, surgery or illness), growth suppression in infancy, childhood and adolescence, menstrual irregularity and amenorrhoea, hirsutism

Metabolism and nutrition disorders

Weight gain, negative protein and calcium balance*, increased apetite, sodium and water retention*, potassium loss*(caution: rhythm disorders), hypokalaemic alkalosis manifestation of latent diabetes mellitus, impaired carbohydrate tolerance with increased dose requirements of antidiabetic therapy*, hypercholesterolemia, hypertriglyceridaemia.

Psychiatric disorders*

Psychological dependence, depression, insomnia, aggravated schizophrenia, mental illness, from euphoria to manifest psychosis

Nervous system disorders

Increased intracranial pressure with papilloedema in children (pseudotumor cerebri) usually following discontinuation of treatment; manifestation of latent epilepsy, increased seizures in overt epilepsy, vertigo, headache

Eye disorders

Elevated intraocular pressure, glaucoma*, papilloedema, cataract*, mainly with posterior subcapsular opacity, corneal and scleral atrophy, increased ophthalmic viral, fungal and bacterial infections, worsening of symptoms associated with corneal ulcers*, chorioretinopathy, blurred vision (see also section 4.4)

Cardiac disorders

Cardiac muscle rupture after recent history of myocardial infarction, congestive heart failure in predisposed patients, cardiac decompensation*

Vascular disorders

Hypertension, vasculitis, increased atherosclerosis and risk of thrombosis/thromboembolism (increase in coagulability of blood may lead to thromboembolic complications)

Respiratory, thoracic and mediastinal disorders

Hiccough

Gastrointestinal disorders

Dyspepsia, abdominal distension*, gastric ulcers with perforation and bleeding, acute pancreatitis, ulcerative esophagitis, oesophageal candidiasis, flatulence, nausea, vomiting

Skin and subcutaneous tissue disorders

Hypertrichosis, skin atrophy, telangiectasia, striae, erythema, steroid acne, petechiae, ecchymosis, allergic dermatitis, urticaria, angioneurotic oedema, thinning hair, pigment disorders, increased capillary fragility, perioral dermatitis, hyperhidrosis, tendency to bruise

Musculoskeletal and connective tissue disorders

Premature epiphyseal closure, osteoporosis, fractures of the spine and long bones, aseptic necrosis of the femoral and the humeral bones, tendon tears*, proximal myopathy, muscle weakness, loss of muscle mass

Reproductive system and breast disorders

Impotence

General disorders and administration site conditions

Reduced response to vaccination and skin tests. Delayed wound healing, discomfort, malaise, steroid withdrawal syndrome: a too rapid reduction in corticosteroid dose after prolonged treatment can lead to acute adrenal insufficiency, hypotension, and death. A withdrawal syndrome may present with fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and weight loss.

∗ See also section 4.4 Special warnings and precautions for use

Description of selected adverse reactions

Adrenocortical insufficiency

An adrenocortical insufficiency, which is caused by glucocorticoid treatment, can, depending on the dose and length of treatment, remain for many months and in some cases more than a year, after discontinuation of treatment. (see section 4.4 Special warnings and precautions for use)

Psychological changes

Psychological changes are manifested in various forms, the most common being euphoria. Depression, psychotic reactions and suicidal tendencies may also appear. These illnesses can be serious. Usually they start within a few days or weeks of starting the medicine. They are more likely to happen at high doses. Most of these problems go away if the dose is lowered or the medicine is stopped. (see section 4.4 Special warnings and precautions for use)

Infections

Treatment with dexamethasone can conceal the symptoms of an existing, or developing infection thereby making a diagnosis more difficult and can lead to an increased risk of infection. (see section 4.4 Special warnings and precautions for use)

Intestinal perforation

Corticosteroids can be associated with an increased risk of colonic perforation in severe ulcerative colitis with threatened perforation, diverticulitis and entero-anastomosis (immediately postoperative).

Signs of peritoneal irritation after gastrointestinal perforation may be absent in patients receiving high doses of glucocorticoids. (see section 4.4 Special warnings and precautions for use)

Cardiovascular disorders

Bradycardia, deterioration of severe cardiac insufficiency and difficult to regulate high blood pressure may occur. Caution should be exercised when using corticosteroids in patients who have recently suffered myocardial infarction as myocardial rupture has been reported. (see section 4.4 Special warnings and precautions for use)

Paediatric population

Corticosteroids cause a dose-dependent inhibition of growth in infancy, childhood, and adolescence since corticosteroids may give rise to early closing of the epiphyses, which may be irreversible. (see section 4.4 Special warnings and precautions for use)

Elderly

The adverse effects of systemic corticosteroids can have serious consequences especially in old age, mainly osteoporosis, hypertension, hypokalemia, diabetes, susceptibility to infection and skin atrophy. (see section 4.4 Special warnings and precautions for use)

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms

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

Overdose or prolonged use may exaggerate glucocorticoid adverse effects.

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: Corticosteroids, for systemic use, glucocorticoids,

Mechanism of action

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.

It's 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.

The RECOVERY trial (Randomised Evaluation of COVid-19 thERapY,)1 is an investigator-initiated, individually randomised, 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 were receiving 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.

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 those receiving 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), followed by oxygen only (rate ratio, 1.15 ;95% CI 1.06-1.24) with no beneficial effect in patients not receiving oxygen (rate ratio, 0.96 ; 95% CI 0.85-1.08).

Safety

There were four serious adverse events (SAEs) related to study treatment: two SAEs of hyperglycaemia, one SAE of 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

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

1 www.recoverytrial.net

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

Absorption and distribution

Dexamethasone is well absorbed when given by mouth; peak plasma levels are reached between 1 and 2 hours after ingestion and show wide inter-individual variations. The mean plasma half-life is 3.6 ± 0.9h. 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. They cross the placenta and may be excreted in small amounts in breast milk.

Biotransformation

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

Elimination

Dexamethasone and its metabolites are excreted in the urine.

5.3 Preclinical safety data

Studies in animals have shown that glucocorticoids increase the incidence of cleft palate, spontaneous abortions and intrauterine growth retardation. In some cases these divergences were combined with defects of the central nervous system and of the heart. In non-human primates, minor cranial skeletal abnormalities were observed. These effects were observed after use of high doses of dexamethasone.

6. Pharmaceutical particulars
6.1 List of excipients

Benzoic acid (E210)

Propylene glycol (E1520)

Citric acid monohydrate (E330)

Sodium citrate (E331)

Maltitol liquid (E965)

Sorbitol liquid (non-crystallising) (E420)

Garden mint flavour

Ethanol

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Unopened: 24 months

After first opening: 3 months

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Bottle: 75ml and 150ml amber soda glass (PhEur, Type III) bottles.

Closure: 28mm white push and turn cap with expanded polyethylene (EPE) liner.

Each pack will contain a 5mL dispensing syringe and bottle adapter.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

7. Marketing authorisation holder

Wockhardt UK Ltd

Ash Road North

Wrexham, LL13 9UF

United Kingdom.

8. Marketing authorisation number(s)

PL 29831/0604

9. Date of first authorisation/renewal of the authorisation

18/10/2019

10. Date of revision of the text

31/12/2020