Summary of medicine characteristics - GLENSOLUDEX 4 MG SOLUBLE TABLETS
Glensoludex 4 mg soluble tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 4 mg dexamethasone as dexamethasone sodium phosphate.
The sodium content of Glensoludex 4 mg soluble tablets is 29.95 mg per tablet.
For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Soluble tablet
Glensoludex Soluble tablets 4 mg are salmon, oblong tablets
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Glensoludex is indicated for use in certain endocrine and non-endocrine disorders, in certain cases of cerebral oedema and for diagnostic testing of adrenocortical hyperfunction.
Endocrine disorders:
Endocrine exophthalmos.
Non-endocrine disorders:
Glensoludex may be used in the treatment of non-endocrine corticosteroid responsive conditions including:
Allergy and anaphylaxis: Anaphylaxis.
Arteritis collagenosis: Polymyalgia rheumatica, polyarteritis nodosa.
Haematological disorders: Haemolytic anaemia (also auto immune), leukaemia, myeloma, idiopathic thrombocytopenic purpura in adults, reticulolymphoproliferative disorders (see also under oncological disorders).
Gastroenterological disorders: For treatment during the critical stage in: ulcerative colitis (rectal only); regional enteritis (Crohn’s disease), certain forms of hepatitis.
Muscular disorders: Polymyositis.
Neurological disorders: Raised intra-cranial pressure secondary to cerebral tumours, acute exacerbations of multiple sclerosis.
Ocular disorders: Anterior and posterior uveitis, optic neuritis, chorioretinitis, iridocyclitis, temporal arteritis, orbital pseudotumour.
Renal disorders: Nephrotic syndrome.
Pulmonary disorders: Chronic bronchial asthma, aspiration pneumonitis, chronic obstructive pulmonary disease (COPD), sarcoidosis, allergic pulmonary disease such as farmer’s and pigeon breeder’s lung, Löffler’s syndrome, cryptogenic fibrosing alveolitis, croup.
Rheumatic disorders: Some cases or specific forms (Felty’s syndrome, Sjögren’s syndrome) of rheumatoid arthritis, including juvenile rheumatoid arthritis, acute rheumatism, lupus erythematosus disseminatus, temporal arteritis (polymyalgia rheumatica).
Skin disorders: Pemphigus vulgaris, bullous pemphigoid, erythrodermas, serious forms of erythema multiforme (Stevens-Johnson syndrome), mycosis fungoides, bullous dermatitis herpetiformis.
Oncological disorders: Lymphatic leukaemia, especially acute forms, malignant lymphoma (Hodgkin’s disease, non-Hodgkin’s lymphoma), metastasized breast cancer, hypercalcaemia as a result of bone metastasis or Kahler’s disease, Kahler’s disease.
Various: Intense allergic reactions; as immunosuppressant in organ transplantation; as an adjuvant in the prevention of nausea and vomiting and in the treatment of cancer with oncolytics that have a serious emetic effect.
Glensoludex 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 40 kg) who require supplemental oxygen therapy.
4.2 Posology and method of administration
Posology
In general, glucocorticoid dosage depends on the severity of the condition and response of the patient. Under certain circumstances, for instance in stress and changed clinical picture, extra dosage adjustments may be necessary. If no favourable response is noted within a couple of days, glucocorticoid therapy should be discontinued.
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 a day depending on the disease being treated. In more severe diseases, doses higher than 10 mg may be required. The initial dosage should be maintained or adjusted until the patient’s response is satisfactory. Both the dose in the evening, which is useful in alleviating morning stiffness, and the divided dosage regimen are associated with greater suppression of the hypothalamopituitary-adrenal axis. If satisfactory clinical response does not occur after a reasonable period of time, discontinue treatment with Glensoludex and transfer the patient to another therapy.
If the initial response is favourable, the maintenance dosage should be determined by lowering the dose gradually to the lowest dose required to maintain an adequate clinical response. Chronic dosage should preferably not exceed 2 mg Glensoludex daily.
Patients should be monitored for signs that may require dosage adjustment. These may be changes in clinical status resulting from remissions or exacerbations of the disease, individual drug responsiveness and the effect of stress (e.g. surgery, infection, trauma). During stress it may be necessary to increase dosage temporarily.
If the drug is to be stopped after more than a few days of treatment, it should be withdrawn gradually.
The following equivalents facilitate changing to dexamethasone from other glucocorticoids:
Milligram for milligram, dexamethasone is approximately equivalent to betamethasone, 4 to 6 times more potent than methylprednisolone and triamcinolone, 6 to 8 times more potent than prednisone and prednisolone, 25 to 30 times more potent than hydrocortisone, and about 35 times more potent than cortisone.
Raised intracranial pressure: Initial therapy is usually by injection using an intravenous formulation. When maintenance therapy is required, this should be changed to an oral formulation of dexamethasone as soon as possible. For the palliative management of patients with recurrent or inoperable brain tumours, maintenance dosage should be calculated individually. A dosage of 2 mg two or three times a day may be effective. The smallest dosage necessary to control symptoms should always be used.
Dexamethasone suppression tests:
1. Tests for Cushing’s syndrome:
2mg Glensoludex soluble tablets should be administered at 11 pm. Blood samples are then taken at 8 am the next morning for plasma cortisol determination.
Twenty four hour urine collection should be employed for 17-hydroxycorticosteroid excretion determination.
2. Test to distinguish Cushing’s syndrome caused by pituitary ACTH excess from the syndrome induced by other causes:
2 mg Glensoludex soluble tablets should be administered every 6 hours for 48 hours. Blood should be drawn at 8 am for plasma cortisol determination on the third morning.
Twenty four hour urine collection should be employed for 17-hydroxycorticosteroid excretion determination.
Paediatric population
Dosage should be limited to a single dose on alternate days to lessen retardation of growth and minimize suppression of hypothalamo-pituitary-adrenal axis.
Croup: Children: 0.15mg/kg-0.6 mg/kg in a single dose.
Elderly:
Treatment of elderly patients, particularly if long term, should be planned bearing in mind the more serious consequences of the common side effects of corticosteroids in old age.
Method of administration
Glensoludex soluble tablets should be dissolved in water. The soluble tablets should be dissolved in half a small glass of water and the solution drunk immediately after dissolution. A minimum volume of approximately 50 ml of water is sufficient for complete dissolution.
This formulation of Glensoludex is not suitable for subdivision of dose either as tablet or solution. The tablet strength(s) most appropriate for the prescribed dose should therefore be selected. During tapered dose reduction a change to a lower strength tablet may be needed. When a lower dose than 2mg is required, the patient should be prescribed an alternative formulation – such as an oral solution of dexamethasone sodium phosphate in a low strength formulation – to ensure optimal dose titration.
For the treatment of Covid-19
Adult patients 6 mg, 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 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.
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.
– Systemic fungal infections.
– Stomach ulcer or duodenal ulcer.
– Infection with tropical worms.
– Avoid live vaccines in patients receiving immunosuppressive doses (serum antibody response diminished).
In general no contraindications apply in conditions where the use of glucocorticoids may be lifesaving.
4.4 Special warnings and precautions for use
Patients should carry ‚Steroid treatment‘ cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.
Undesirable effects may be minimised by using the lowest effective dose for the minimum period, and by administering the daily requirement as a single morning dose or whenever possible as a single morning dose on alternative days. Frequent patient review is required to appropriately titrate the dose against disease activity. When reduction in dosage is possible, the reduction should be gradual (see section 4.2).
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. Patients 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.
Antiinflammatory/Immunosuppressive effects/Infection
Corticosteroids may exacerbate systemic fungal infections and should not be used unless they are needed to control drug reactions due to amphotericin. There have also been reports in which concomitant use of amphotericin and hydrocortisone was followed by cardiac enlargement and heart failure.
Administration of live virus vaccines is 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.
Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity. The clinical presentation may often be atypical, and serious infections such as septicaemia and tuberculosis may be masked and may reach an advanced stage before being recognised.
Appropriate antimicrobial therapy should accompany glucocorticoid therapy when necessary e.g. in tuberculosis and viral and fungal infections of the eye. There may be decreased resistance and inability to localise infection in patients on corticosteroids.
Chickenpox is ofparticular 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 nonimmune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.
Measles can have a more serious or even fatal course in immunosuppressed patients. In such children or adults particular care should be taken to avoid exposure to measles. If exposed, prophylaxis with intramuscular pooled immunoglobulin (IG) may be indicated. Exposed patients should be advised to seek medical advice without delay.
Corticosteroids may activate latent amoebiasis or strongyloidiasis or exacerbate active disease. Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis or Toxoplasma. It is recommended that these are ruled out before initiating corticosteroid therapy particularly in those patients who have spent time in the tropics or those with unexplained diarrhoea.
A report shows that the use of corticosteroids in cerebral malaria is associated with a prolonged coma and an increased incidence of pneumonia and gastrointestinal bleeding and therefore corticosteroids should not be used in cerebral malaria.
Eye disorders
Prolonged use of corticosteroids may produce subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses. Particular care is needed when treating patients with glaucoma (or family history of glaucoma) as well as when treating patients with ocular herpes simplex, because of possible corneal perforation.
Visual disturbance
Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.
Electrolyte disturbances
Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, retention of salt and water, and increased excretion of potassium, but these effects are less likely to occur with synthetic derivatives, except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary with corticosteroid therapy. All corticosteroids increase calcium excretion.
Particular care is needed when treating patients with renal impairment, hypertension and congestive heart failure.
Adrenal Suppression
Adrenal cortical atrophy develops during prolonged therapy and may persist for years after stopping treatment. Withdrawal of corticosteroids after prolonged therapy must therefore always be gradual to avoid acute adrenal insufficiency, being tapered off over weeks or months according to the dose and duration of treatment. In patients who have received more than physiological doses of systemic corticosteroids (approximately 1 mg dexamethasone for greater than 3 weeks, withdrawal should not be abrupt.
How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids but there is uncertainty about HPA suppression, the dose of systemic corticosteroid may be reduced rapidly to physiological doses. Once a daily dose of 1mg dexamethasone is reached, dose reduction should be slower to allow the HPA axis to recover.
Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks, is appropriate if it is considered that the disease is unlikely to relapse.
Abrupt withdrawal of doses of up to 6mg daily of dexamethasone for 3 weeks is unlikely to lead to clinically relevant HPA axis suppression in the majority of patients.
In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting 3 weeks or less:
Patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than 3 weeks.
When a short course has been prescribed within one year of cessation of long term therapy (months or years).
Patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy.
Patients receiving doses of systemic corticosteroid greater than 6mg daily of dexamethasone.
Patients repeatedly taking doses in the evening.
Intercurrent illness and stress
During prolonged therapy any intercurrent illness, trauma or surgical procedure will require a temporary increase in dosage; if corticosteroids have been stopped following prolonged therapy they may need to be temporarily reintroduced.
Patients under stress may require increased doses of corticosteroids prior, during and after the period of stressful situation.
Withdrawal symptoms
Stopping corticosteroids after prolonged therapy may cause withdrawal symptoms including fever, myalgia, arthralgia and malaise. This may occur in patients even without evidence of adrenal insufficiency.
Psychiatric reactions
Patients and/or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids (see section 4.8). Symptoms typically emerge within a few days or weeks of starting the treatment. Risks may be higher with high doses/systemic exposure (see also section 4.5 pharmacokinetic interactions that can increase the risk of side effects), although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary.
Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should also be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently.
Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid pyschosis.
General
In addition to the information given under the other headings, particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent monitoring is necessary:
a. Osteoporosis (post-menopausal females are particularly at risk).
b. Diabetes mellitus (or a family history of diabetes).
c. Hypertension or congestive heart failure
d. Existing or previous history of severe affective disorders (especially previous steroid psychosis)
e. Previous corticosteroid-induced myopathy.
f. History of tuberculosis
g. Glaucoma (or a family history of glaucoma)
h. Liver failure.
i. Epilepsy.
j. Renal insufficiency
k. Hypothyroidism
l. Peptic ulceration.
m. Migraine
n. Myasthenia gravis.
o. Non-specific ulcerative colitis, diverticulitis or fresh intestinal anastomosis.
p. History of allergy to corticosteroids.
q. Herpes simplex.
r. Certain parasitic infestations in particular amoebiasis.
s. Incomplete natural growth since glucocorticoids on prolonged administration may accelerate epiphyseal closure.
There is an enhanced effect of corticosteroids in patients with hypothyroidism and in those with cirrhosis.
Fat embolism has been reported as a possible complication of hypercortisonism.
Large doses of corticosteroids may mask the symptoms of gastrointestinal perforation.
Reports in the literature suggest an apparent association between use of corticosteroids and left-ventricular free-wall rupture after a recent myocardial infarction; therefore, corticosteroids should be used with great caution in these patients.
In rare cases, decrease or withdrawal of orally administered corticosteroids could reveal underlying disease that is accompanied by eosinophilia (e.g. Churg Strauss Syndrome) in patients with asthma.
The results of a randomised, placebo-controlled study suggest an increase in mortality if methylprednisolone therapy starts more than two weeks after the onset of Acute Respiratory Distress Syndrome (ARDS). Therefore, treatment of ARDS with corticosteroids should be initiated within the first two weeks of onset of ARDS.
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.
Hypersensitivity
Rare cases of anaphylactoid or hypersensitivity reactions such as glottis oedema, urticaria and bronchospasm have been reported especially with parenteral administration of corticosteroids and in patients with a history of allergy. Prophylactic measures should be taken especially if the patient has a history of allergic reactions to medicines.
If such an anaphylactoid reaction occurs, the following measures are recommended: immediate slow intravenous injection of 0.1–0.5ml of adrenaline (solution of 1:1000: 0.1–0.5mg adrenaline dependent on body weight), intravenous administration of aminophylline and artificial respiration if necessary.
Paediatric population
Corticosteroids cause a dose-dependent inhibition of growth in infancy, childhood, and adolescence, which may be irreversible. On prolonged administration glucocorticoids may accelerate epiphyseal closure.
Treatment should be limited to the minimum dose for the shortest period. Therefore, during long-term treatment with Glensoludex 4 mg soluble tablets, its use should be very clearly justified in children and their growth rate should be checked regularly.
Preterm neonates
Available evidence suggests long-term neurodevelopmental adverse events after early treatment (<96 hours) of premature infants with chronic lung disease at starting doses of 0.25 mg/kg twice daily.
Pheochromocytoma crisis
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.
Use in the elderly
The adverse effects of systemic corticosteroids can have serious consequences especially in old age, mainly osteoporosis, hypertension, hypokalaemia, diabetes, susceptibility to infection and skin atrophy. Close clinical monitoring is required to prevent life-threatening reactions.
Note on doping
The use of doping tests when taking Glensoludex 4 mg soluble tablets can lead to positive results.
Excipient Warnings
This medicinal product contains 29.95 mg sodium per tablet, equivalent to 1.5% of the WHO recommended maximum daily intake of 2 g sodium for an adult. To be taken into consideration by patients on a controlled sodium diet.
Glensoludex contains Sunset yellow, a colourant agent which can cause allergic reactions.
4.5 Interaction with other medicinal products and other forms of interaction
Effects of other medicinal products on dexamethasone:
Dexamethasone is metabolised via cytochrome P450 3A4 (CYP3A4). Concomitant administration of dexamethasone with inducers of CYP3A4, such as phenytoin, barbiturates (e.g. primidone and phenobarbital), ephedrine, rifabutin, carbamazepine and rifampicin may lead to decreased plasma concentrations of dexamethasone and the dose may need to be increased.
Co-treatment with CYP3A inhibitors, such as ketoconazole, ritonavir and erythromycin, including cobicistat-containing products, may lead to increased plasma concentrations of dexamethasone and it is expected to increase the risk of systemic products. 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.
Dexamethasone reduces the plasma concentration of the antiviral drugs indinavir and saquinavir.
Patients taking methotrexate and dexamethasone have an increased risk of haematological toxicity.
These interactions may also interfere with dexamethasone suppression tests, which therefore should be interpreted with caution during administration of substances that affect the metabolism of dexamethasone.
Ketoconazole may increase plasma concentrations of dexamethasone by inhibition of CYP3A4, but may also suppress corticosteroid synthesis in the adrenal and thereby cause adrenal insufficiency at withdrawal of corticosteroid treatment.
Ephedrine may increase the metabolic clearance of corticosteroids, resulting in decreased plasma levels. An increase of the corticosteroid dose might be necessary.
False-negative results in the dexamethasone suppression test in patients being treated with indometacin have been reported.
Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance.
Anticholinesterases: Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
Colestyramine: Colestyramine may decrease the absorption of dexamethasone.
Oestrogens, including oral contraceptives: Oestrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect.
Aminoglutethimide: Decrease of dexamethasone efficacy, due to its metabolism increase. An adjustment of dexamethasone dosage may be required.
Gastrointestinal topicals, antacids, charcoal: A decrease in digestive absorption of glucocorticoids have been reported with prednisolone and dexamethasone. Therefore, glucocorticoids should be taken separately from gastrointestinal topicals, antacids or charcoal, with an interval between treatment of at least two hours.
Effects of dexamethasone on other medicinal products
Dexamethasone is a moderate inducer of CYP3A4. Concomitant administration of dexamethasone with substances that are metabolised via CYP3A4 could lead to increased clearance and decreased plasma concentrations of these substances.
The renal clearance of salicylates is increased by corticosteroids and therefore, salicylate dosage should be reduced once the steroids are discontinued. Steroid withdrawal may result in salicylate intoxication.
The desired effects of anti-hypertensives and diuretics are antagonised by corticosteroids.
The hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics, amphotericin B injection, potassium depleting agents, corticosteroids (glucomineralo), tetracosactide and carbenoxolone are enhanced. Hypokalaemia predisposes to cardiac arrhythmia especially “torsade de pointes” and increase the toxicity of cardiac glycosides. Hypokalaemia should be corrected before corticosteroid treatment initiation. In addition, there have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure.
Sultopride has been linked to ventricular arrhythmias, especially torsade de pointes. This combination is not recommended.
Patients taking NSAIDs should be monitored since the incidence and/or severity of gastro-ulceration may increase. Aspirin should also be used cautiously in conjunction with corticosteroids in hypoprothrombinaemia.
Ciclosporin: Increased activity of both ciclosporin and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use.
Thalidomide: Co-administration with thalidomide should be employed cautiously, as toxic epidermal necrolysis has been reported with concomitant use.
Influence on diagnostic tests: Glucocorticoids can suppress skin reaction to allergy testing. Corticosteroids may affect the nitroblue tetrazolium test for bacterial infection and produce false-negative results
Live attenuated vaccines: Risk of fatal systemic disease.
Praziquantel: Decrease in praziquantel plasma concentrations, with a risk of treatment failure, due to its hepatic metabolism increased by dexamethasone.
Oral anticoagulants: Possible impact of corticosteroid therapy on the metabolism of oral anticoagulants and on clotting factors. At high doses or with treatment for more than 10 days, there is a risk of bleeding specific to corticosteroid therapy (gastrointestinal mucosa, vascular fragility). Patients taking corticosteroids associated with oral anticoagulants should be closely monitored (biological investigations on 8th day, then every 2 weeks during treatment and after treatment discontinuation).
Insulin, sulfonylureas, metformin: Increase in blood glucose, with sometimes diabetic ketosis. The desired effects of hypoglycaemic agents are antagonised by corticosteroids since they impair carbohydrate tolerance. Therefore, blood and urine self-monitoring should be reinforced by the patient, in particular at the start of treatment.
Isoniazid: Serum concentrations of isoniazid may be decreased. A decrease in plasma isoniazid levels have been reported with prednisolone. The suggested mechanism is an increase in hepatic metabolism of isoniazid and a decrease in the hepatic metabolism of isoniazid and a decrease in the hepatic metabolism of glucocorticoids. Patients taking isoniazid should be closely monitored.
4.6 Fertility, pregnancy and lactation
Pregnancy
Since adequate human reproduction studies have not been performed with corticosteroids, Glensoludex should not be used during pregnancy for maternal indications, unless it is clearly necessary. The lowest effective dose needed to maintain adequate disease control should be used.
Patients with preeclampsia or fluid retention require close monitoring.
Dexamethasone crosses the placenta. Placental transfer in considerable: foetal serum concentrations are similar to maternal concentrations.
When corticosteroids are essential however, patients with normal pregnancies may be treated as though they were in the non-gravid state.
Administration of corticosteroids to pregnant animals can cause abnormalities 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). 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.
Breastfeeding
Glucocorticoids are excreted in small amounts in breast milk and may suppress growth, interfere with endogenous corticosteroid production or cause other unwanted effects. A decision on whether to continue/discontinue breast feeding or to continue/discontinue therapy with dexamethasone should be made taking into account the benefit of breast feeding to the child and the benefit of dexamethasone therapy to the woman.
4.7 Effects on ability to drive and use machines
There are some side effects associated with this product that may affect some patients' ability to drive or operate machinery (see section 4.8)
4.8 Undesirable effects
The incidence of predictable undesirable effects, including hypothalamic-pituitaryadrenal suppression correlates with the relative potency of the substance, dosage, timing of administration and duration of treatment (see section 4.4).
The following side effects have been reported; their frequency is unknown
| System Organ Class | |
| Infections and infestations | Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence |
| of dormant tuberculosis. Decreased resistance of infection. | |
| Blood and lymphatic system disorders | Leucocytosis lymphopaenia, eosinopaenia, polycythaemia |
| Immune system disorders | Hypersensitivity including anaphylaxis has been reported. Decreased responsiveness to vaccination and skin tests. |
| Endocrine disorders | Menstrual irregularities and amenorrhoea, suppression of the hypothalamic-pituitary-adrenal axis, premature epiphyseal closure, development of Cushing's syndrome (typical symptoms: full-moon face, plethora, truncal obesity), hirsutism, secondary adrenocortical and pituitary insufficiency (particularly in times of stress, as trauma, surgery or illness). Negative protein and calcium balance. |
| Metabolism and nutrition disorders | Sodium and water retention, potassium loss (caution: rhythm disorders), hypokalaemic alkalosis, increased calcium excretion. Increased appetite. manifestation of latent diabetes mellitus, Impaired carbohydrate tolerance with increased requirement forantidiabetic therapy, hypercholesterolemia, hypertriglyceridaemia |
| Psychiatric disorders | Psychological dependence, depression, insomnia, aggravation of schizophrenia and psychic disturbances ranging from euphoria to frank psychotic manifestations. A wide range of psychiatric reactions including affective disorders (such as irritable, euphoric, depressed and labile mood and suicidal thoughts), psychotic reactions (including mania, delusions, hallucinations and aggravation of schizophrenia), behavioural disturbances, irritability, anxiety, sleep disturbances and cognitive dysfunction including confusion and amnesia have been reported. Reactions are common and may occur in both adults and children. In adults, the frequency of severe reactions has been estimated to be 56%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown |
| Nervous system disorders | Convulsions and aggravation of epilepsy, vertigo, headache, increased intracranial pressure with papilloedema in children (pseudotumour cerebri) usually after treatment withdrawal/discontinuation. |
| Eye disorders | Posterior subcapsular cataracts, increased intraocular pressure, glaucoma, papilloedema, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal and bacterial infections, exophthalmos. worsening of symptoms associated with corneal ulcers, Vision blurred (see also section 4.4) Frequency not known: Chorioretinopathy |
| Cardiac disorders | Myocardial rupture following recent myocardial infarction. Congestive heart failure in susceptible patients |
| Vascular disorders | Thromboembolism, hypertension, vasculitis and increased atherosclerosis |
| Respiratory, thoracic and mediastinal disorders | Hiccups |
| Gastrointestinal disorders | Dyspepsia, peptic ulcers with perforation and haemorrhage, candidiasis, acute pancreatitis. Abdominal distension and vomiting. Oesophageal ulceration, flatulence. Perforation of the small and large bowel particularly in patients with inflammatory bowel |
| disease. Nausea | |
| Skin and subcutaneous disorders | Impaired wound healing, hypertrichosis, thin fragile skin, petechiae and ecchymoses, erythema, striae, telangiectasia, acne, increased sweating, suppressed reaction to skin tests, other cutaneous reactions such as allergic dermatitis, urticaria, angioneurotic oedema, thinning scalp hair pigment disorders, increased capillary fragility, perioral dermatitis |
| Musculoskeletal and connective tissue disorders | Osteoporosis, vertebral and long bone fractures, avascular necrosis, tendon rupture. Proximal myopathy. Muscle weakness, aseptic necrosis of femoral and humeral heads, loss of muscle mass. Growth suppression in infants, children and adolescents, proximal myopathy, muscle weakness, loss of muscle mass |
| General disorders and administration site conditions | Malaise, abnormal fat deposits, steroid withdrawal syndrome (see section 4.4) |
| Injury, poisoning and procedural complications | Bruising |
| Investigations | Increased or decreased motility and number of spermatozoa, weight gain. |
Withdrawal symptoms and signs
Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death (see section 4.4).
A ‚withdrawal syndrome‘ may also occur including, fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 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
4.9 OverdoseReports of acute toxicity and/or deaths following overdosage with glucocorticoids are rare. No antidote is available. Treatment is probably not indicated for reactions due to chronic poisoning unless the patient has a condition that would render him unusually susceptible to ill effects from corticosteroids. In this case, the stomach should be emptied and symptomatic treatment should be instituted as necessary. Anaphylactic and hypersensitivity reactions may be treated with epinephrine (adrenaline), positivepressure artificial respiration and aminophylline. The patient should be kept warm and quiet. The biological half life of dexamethasone in plasma is about 190 minutes.
5.1 Pharmacodynamic properties
ATC Code: H02A B02
Pharmacotherapeutic Group: Glucocorticoids
Dexamethasone is a synthetic glucocorticoid whose anti-inflammatory potency is 7 times greater than prednisolone. Like other glucocorticoids, dexamethasone also has anti-allergic, antipyretic and immunosuppressive properties.
Dexamethasone has practically no water and salt-retaining properties and is, therefore, particularly suitable for the use in patients with cardiac failure or hypertension. Because of its long biological half-life (36–54 hours), dexamethasone is especially suitable in conditions where continuous glucocorticoid action is desired.
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).
| Dexamethasone | Usual Care | Rate or Risk Ratio | |
| Outcome | (N = 2104) | {N = 4321) | (95% Cl) |
| no./total no. of patients (%) | |||
| Primary outcome | |||
| Mortality at 28 days | 432/2104 (22.9) | 1110/4321 (25.7) | 0.83 (0.75–0.93) |
| Secondary outcomes | |||
| Discharged from hospital within 28 days | 1413/2104 (67.2) | 2745/4321 (63.5) | 1.10 (1.03–1.17) |
| Invasive mechanical ventilation or deathÿ | 456/1780 (25.6) | 994/3638 (27.3) | 0.92 (0.84–1.01) |
| Invasive mechanical ventilation | 102/1780 (5.7} | 285/3638 (7.8) | 0.77 (0.62–0.95) |
| Death | 387/1780 (21.7) | 827/3638 (22.7) | 0.93 (0.84–1.03) |
Rate ratios have been adjusted for age with respect to the outcomes of 28-day mortality and hospital discharge. Risk ratios have been adjusted for age with respect to the outcome of receipt of invasive mechanical ventilation or death and its subcomponents.
Ÿ Excluded from this category are patients who were receiving invasive mechanical ventilation at randomization.
Dexamethasone Usual care RR (95% Cl)
| No oxygen (Xj= 0.70; p=0.40} .-70 1D/1Q7 1 | „________1 ffl AO 9 |
| >70 <an 25/114 791 R.A/994 | ■ ^1 4A (n RR 9 ARI |
| ■>ftn 84/1 QO Î9R 4%.\ Q9/A4R (OR 4%) | – 1 HA CO 7A—1 4Q) |
| Subtotal 89/501 (17.8%) 145/1034(14.0%) - Oxygen only (x^=2.54; p=0.11) <70 53/675(7.9%) 193/1473 (13.1%) ----■---- ->7n 1O4/3OA ¿34 n%\ 17R/ari /33A°z1'i ____■ | ------ 1.19(0.91–1.55) 0.58 (0.43–0.78) 0 qr ro 77 1 or) |
| ■>ftn 141/9QR (47 311/AOO /A1 R%\ - — | – n RA fO 70 1 04 \ |
| Subtotal 298/1279 (23.3%) 682/2604(26.2%) O Mechanical ventilation (%^= 0.28; p=0.60) <70 ’ 66/269 (24.5%) 217/569 (38.1%) ----■---- >70 <=80 26/49 (53 1%) 58/104 (55 8%) ■ | 0.82 (0.72–0.94) 0.61 (0.46–0.81) 0 85 (0 53–1 34) |
| >on 3/fi (RH 0%\ R/1D /80 tl%’i ________________ | O 3Q fO 10—1 47) |
| Subtotal 95/324 (29.3%) 283/683 (41.4%) All participants 482/2104 (22.9%) 1110/4321 (25.7%) o | 0.64 (0.51–0.81) 0.83 (0.75–0.93) p<0.001 |
| o's 0.75 Dexamethasone better | 1'5 2 Usual care better |
Effects of allocation to DEXAMETHASONE on 28-day mortality, by respiratory support received at randomisation and history of any chronic disease.3
Dexamethasone Usual care RR (95% Cl)
No oxygen (Xi= 0–08; p=0.78) Prior disease 65/313(20.8*%»)
No prior disease 24/1 88 (12 8%)
Subtotal 89/501 (17.8%)
100/598 (16.7%)
45/436 (10.3%)
145/1034 (14.0%)
Oxygen only {■¿^=2.OS; p=O.15)
Prior disease 221/702(31.5%)
No prior disease 77/577 (13.3%)
Subtotal 298/1279(23.3%)
481/1473 (32.7%)
201/1131 (17.8%)
682/2 604 (26.2%)
Mechanical ventilationtxï= ’62:p=O.22)
| Prior disease | 51/1 59 | (32.1%) | 150/546 | (43.4%) |
| No prior disease | 44/1 65 | (26.7%) | 133/337 | (39.5%) |
| Subtotal | 95/324 | <29.3%) | 2 63/683 | <41.4%) |
| All participants | 462/21 04 | (22.9%) | 1111 9/4321 | (25.7%) |
Dexamethasone Usual care better better
1.22 (0.89–1.66)
1.12 (0.68–1.83)
1.19 (0.91–1.55)
0.88 (0.75–1.03)
0.70 (0.54–0 91 )
0.62 (0.72–0.94)
0.75 (0.54—1.02)
0.56 (0.40–0.78)
0.64 (0.51 –0.81 )
0.63 (0.75–0.93) p-: 0.001
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 interindividual variations. In healthy subjects a plasma half life of 3–6 hours has been observed, however in studies of patients this can be reduced to under 2 hours. Dexamethasone is bound (to about 77%) to plasma proteins, mainly albumins. Percentage protein binding of dexamethasone, unlike that of cortisol, remains practically unchanged with increasing steroid concentrations. Corticosteroids are rapidly distributed to all body tissues.
Biotransformation
Dexamethasone is metabolised mainly in the liver but also in the kidney.
Elimination
Dexamethasone and its metabolites are excreted in the urine.
5.3 Preclinical safety data
5.3 Preclinical safety dataIn animal studies, cleft palate was observed in rats, mice, hamsters, rabbits, dogs and primates: not in horses and sheep. In some cases these divergences were combined with defects of the central nervous system and of the heart. In primates, effects in the brain were seen after exposure. Moreover, intra-uterine growth can be delayed. All these effects were seen at high dosages.
6.1 List of excipients
Sodium Bicarbonate
Disodium Citrate 1.5Hydrate
Povidone K30
Sodium Saccharin
Sodium Benzoate
Yellow Sunset (E110)
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3
2 years
6.4
Special precautions for storage Store below 25°C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
Alu-alu blisters foil blisters packed in cartons containing 10, 30, 50 or 100 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
6.6 Special precautions for disposalAny unused medicinal product or waste material should be disposed of in accordance with local requirements.
Glenmark Pharmaceuticals Europe Limited
Laxmi House, 2B Draycott Avenue
Kenton, Middlesex
HA3 0BU
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 25258/0162
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION
14/09/2015