Dexamethasone Sodium Phosphate Injection USP 8mg/2ml

Name of the medicinal product

Dexamethasone Sodium Phosphate Injection USP 4mg/1ml Taj Pharma
Dexamethasone Sodium Phosphate Injection USP 8mg/2ml Taj Pharma
Dexamethasone Sodium Phosphate Injection USP 20mg/5ml Taj Pharma
Dexamethasone Sodium Phosphate Injection USP 100mg/10ml Taj Pharma
Dexamethasone Sodium Phosphate Injection USP 120mg/30ml Taj Pharma

Qualitative and quantitative composition

a) Dexamethasone Sodium Phosphate Injection USP 4mg/1ml
Each ml contains:
Dexamethasone Phosphate               4mg
Sodium sulfite                                   1mg
Benzyl alcohol                                  10mg
Water of injection                             q.s

b) Dexamethasone Sodium Phosphate Injection USP 8mg/2ml
Each ml contains:
Dexamethasone Phosphate               4mg
Sodium sulfite                                   1mg
Benzyl alcohol                                  10mg
Water of injection                             q.s

c) Dexamethasone Sodium Phosphate Injection USP 20mg/5ml
Each ml contains:
Dexamethasone Phosphate               4mg
Sodium sulfite                                   1mg
Benzyl alcohol                                  10mg
Water of injection                             q.s

d) Dexamethasone Sodium Phosphate Injection USP 100mg/10ml
Each ml contains:
Dexamethasone Phosphate               10mg
Sodium sulfite                                   1mg
Benzyl alcohol                                  10mg
Water of injection                             q.s

e) Dexamethasone Sodium Phosphate Injection USP 120mg/30ml
Each ml contains:
Dexamethasone Phosphate              4mg
Sodium sulfite                                   1mg
Benzyl alcohol                                  10mg
Water of injection                             q.s

For the full list of excipients, see section 6.1.

Pharmaceutical form

Solution for injection

Colourless aqueous solution

Clinical particulars

4.1 Therapeutic indications

Corticosteroid

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

Systemic (intravenous or intramuscular) administration

Dexamethasone solution for injection is recommended for systemic administration by intravenous or intramuscular injection when oral therapy is not feasible or desirable in the following conditions:

Endocrine disorders

Primary or secondary adrenocortical insufficiency

(Hydrocortisone or cortisone is the first choice, but synthetic analogues may be used with mineralocorticoids where applicable and, in infancy, mineralocorticoid supplementation is particularly important)

Non-endocrine disorders

Dexamethasone solution for injection may be used in the treatment of non-endocrine corticosteroid-responsive conditions, including:

Allergy and anaphylaxis

Angioneurotic oedema and anaphylaxis

Gastrointestinal disorders

Crohn’s disease and ulcerative colitis

Infection (with appropriate chemotherapy)

Miliary tuberculosis and endotoxic shock

Neurological disorders

Raised intracranial pressure secondary to cerebral tumours and infantile spasms. In addition, dexamethasone for injection is used as an adjunct in the control of cerebral oedema caused by brain tumours or associated with neurosurgery, but not in those cases where the oedema is caused by head injury.

Respiratory disorders

Bronchial asthma and aspiration pneumonitis.

Skin disorders

Toxic epidermal necrolysis

Shock

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

Local administration

Dexamethasone solution for injection is suitable for intra-articular or soft-tissue injection as adjunctive therapy for short-term administration in:

Soft-tissue disorders

Such as carpal tunnel syndrome and tenosynovitis

Intra-articular disorders

Such as rheumatoid arthritis and osteoarthritis with an inflammatory component

Dexamethasone solution for injection may be injected intralesionally in selected skin disorders such as cystic acne vulgaris, localised lichen simplex, and keloids.

4.2 Posology and method of administration

Dosage requirements are variable and must be individualized on the basis of the disease under treatment and the response of the patient.

In neonates, especially the premature infant, only preservative-free solutions should be administered.

Posology

Intravenous and Intramuscular Injection

Usually the parenteral dose is one-third to one half the oral dose, given every 12 hours. The usual initial dosage of dexamethasone solution for injection is 0.4 mg – 16.6 mg (0.1 ml – 4.4 ml) and varies depending on the specific disease entity being treated. In situations of less severity, lower doses will generally suffice. However, in certain overwhelming, acute, life-threatening situations, dosages exceeding the usual recommended dosages have been used. In these circumstances, the slower rate of absorption by intramuscular administration should be recognized.

Both the dose in the evening, which is useful in alleviating morning stiffness and the divided dosage regimen are associated with greater suppression of the hypothalamo-pituitary-adrenal axis. After a favourable response is noted, the proper maintenance dosage should be determined by decreasing the initial dosage by small amounts at appropriate intervals to the lowest dosage which will maintain an adequate clinical response. Chronic dosage should preferably not exceed 500 micrograms dexamethasone daily. Close monitoring of the drug dosage is needed.

If the drug is to be stopped after it has been given for more than a few days, it is recommended that it be withdrawn gradually rather than stopped abruptly.

Whenever possible, the intravenous route should be used for the initial dose and for as many subsequent doses as are given while the patient is in shock (because of the irregular rate of absorption of any medicament administered by any other route in such patients). When the blood pressure responds, use the intramuscular route until oral therapy can be substituted. For the comfort of the patient, not more than 2 ml should be injected intramuscularly at any one site.

In emergencies, the usual dose is 3.3 mg to 16.6 mg (0.9 ml to 4.4 ml) I.V. or I.M. (in shock use only the I.V. route). This dose may be repeated until adequate response is noted.

After initial improvement, single doses of 1.7 mg to 3.3 mg (0.4 ml to 0.9 ml) should be repeated as necessary. The total daily dosage usually need not exceed 66.4 mg (17.5 ml), even in severe conditions.

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

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

Adults and Elderly

Once the disease is under control the dosage should be reduced or tapered off to the lowest suitable level under continuous monitoring and observation of the patient (see section 4.4).

For acute life-threatening situations (e.g. anaphylaxis, acute severe asthma) substantially higher dosages may be needed..

Shock (Of Haemorrhagic, Traumatic, or Surgical Origin)

The usual dose is 1.7 to 5 mg/kg (0.4 ml – 1.3 ml/kg) body weight given as a single intravenous injection. This may be repeated in 2 to 6 hours, if shock persists. As an alternative, this may be followed immediately by the same dose in an intravenous infusion. Therapy with dexamethasone solution for injection is an adjunct to, and not a replacement for, conventional therapy.

Administration of high dose corticosteroid therapy should be continued only until the patient’s condition has stabilized and usually no longer than 48 to 72 hours.

Cerebral Oedema

Associated with primary or metastatic brain tumour, pseudo-tumour cerebri or preoperative preparation of patients with increased intracranial pressure secondary to brain tumour:

Initially 8.3 mg (2.2 mL) dexamethasone solution for injection intravenously followed by 3.3 mg (0.9 mL) intramuscularly every 6 hours until symptoms of cerebral oedema subside. Response is usually noted within 12 to 24 hours: dosage may be reduced after 2 to 4 days and gradually discontinued over a period of 5 to 7 days.

High doses of dexamethasone solution for injection are recommended for initiating short-term intensive therapy for acute life-threatening cerebral oedema. Following the high loading dose schedule of the first day of therapy, the dose is scaled down over the 7 to 10 day period of intensive therapy and subsequently reduced to zero over the next 7 to 10 days. When maintenance therapy is required, this should be changed to oral dexamethasone as soon as possible.

Suggested high dose schedule in cerebral oedema is listed in the chart below:

Adults
• Initial Dose	41.5 mg (10.9 ml), I.V.
• 1st day	6.6 (1.7 ml) mg, I.V. every 2 hours
• 2nd day	6.6 (1.7 ml) mg, I.V. every 2 hours
• 3rd day	(1.7 ml) mg, I.V. every 2 hours
• 4th day	3.3 mg (0.9 ml), I.V. every 2 hours
• 5th to 8th day	3.3 mg (0.9 ml), I.V. every 4 hours
• Thereafter	decrease by daily reduction of 3.3 mg (0.9 ml)
Children (35 kg and over)
• Initial Dose	20.8 mg (5.5 ml), I.V.
• 1st day	3.3 mg (0.9 ml), I.V. every 2 hours
• 2nd day	3.3 mg (0.9 ml), I.V. every 2 hours
• 3rd day	3.3 mg (0.9 ml), I.V. every 2 hours
• 4th day	3.3 mg (0.9 ml), I.V. every 4 hours
• 5th to 8th day	3.3 mg (0.9 ml), I.V. every 6 hours
• Thereafter	decrease by daily reduction of 1.7 mg (0.4 ml)
Children (below 35 kg)
• Initial Dose	16.6 mg (4.4 ml), I.V.
• 1st day	3.3 mg (0.9 ml), I.V. every 3 hours
• 2nd day	3.3 mg (0.9 ml), I.V. every 3 hours
• 3rd day	3.3 mg (0.9 ml), I.V. every 3 hours
• 4th day	3.3 mg (0.9 ml), I.V. every 6 hours
• 5th to 8th day	1.7 mg 0.4 ml), I.V. every 6 hours
• Thereafter	decrease by daily reduction of 0.83 mg (0.2 ml)

For palliative management of patients with recurrent or inoperable brain tumours

Maintenance therapy should be individualized with dexamethasone solution for injection or dexamethasone tablets. A dosage of 1.7 mg (0.4 ml) 2 or 3 times a day may be effective.

Dual Therapy

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

		Total Daily Dosage
1st day	0.9 ml to 1.7 ml of dexamethasone injection intramuscularly	3.3 to 6.6 mg
2nd day	two 0.5 mg dexamethasone tablets b.i.d.	4 tablets
3rd day	two 0.5 mg dexamethasone tablets b.i.d.	4 tablets
4th day	one 0.5 mg dexamethasone tablet b.i.d.	2 tablets
5th day	one 0.5 mg dexamethasone tablet b.i.d.	2 tablets
6th day	one 0.5 mg dexamethasone tablet.	1 tablets
7th day	one 0.5 mg dexamethasone tablet.	1 tablets
8th day	follow-up visit/reassessment day

Intra-Articular, Intralesional, and Intra-Bursal Injection

Intra-articular, intralesional, and intra-bursal injections generally are employed when affected joints or areas are limited to one or two sites.

Some of the usual single doses are:

Site of Injection	Volume of Injection (mL)	Amount of Dexamethasone (mg)
Large Joints (e.g., Knee)	0.4 to 0.9	1.7 – 3.3
Small Joints (e.g., Interphalangeal, Temporomandibular)	0.17 to 0.21	0.66 – 0.8
Bursae	0.4 to 0.7	1.7 – 2.5
Tendon Sheaths*	0.09 to 0.21	0.33 – 0.8
Soft-tissue Infiltration	0.4 to 1.3	1.7 – 5.0
Ganglia	0.21 to 0.4	0.8 – 1.7

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

The frequency of injection varies from once every 3 to 5 days to once every 2 to 3 weeks, depending on the response to treatment.

Special Populations

Paediatric population

Dosage requirements are variable and may have to be changed according to individual needs.

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

Use in the elderly

Treatment of elderly patients, particularly if long term, should be planned bearing in mind the more serious consequences of the common side effects of corticosteroids in old age, especially osteoporosis, diabetes, hypertension, hypokalaemia, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life threatening reactions.

Method of administration

Dexamethasone solution for injection may be administered intravenously, intramuscularly, or by local injection (intra-articular or soft tissue). For administration by intravenous infusion: see section on compatibility with infusion fluids. With intravenous administration high plasma levels can be obtained rapidly.

Rapid intravenous injection of massive doses of glucocorticoids may sometimes cause cardiovascular collapse; the injection should therefore be given slowly over a period of several minutes.

Intra-articular injections should be given under strictly aseptic conditions.

4.3 Contraindications

Systemic infection unless specific anti-infective therapy is employed.

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

Local injection of a glucocorticoid is contraindicated in bacteraemia and systemic fungal infections, unstable joints, infection at the injection site e.g. septic arthritis resulting from gonorrhoea or tuberculosis.

4.4 Special warnings and precautions for use

A Patient Information Leaflet should be supplied with this product.

Severe allergic reactions. Rare instances of anaphylactoid/anaphylactic reactions with a possibility of shock have occurred in patients receiving parenteral corticosteroid therapy. Appropriate precautionary measures should be taken with patients who have a history of allergic reactions to corticosteroids.

Tumor 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. 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.

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 for 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 psychosis.

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.

After parenteral administration of glucocorticoids serious anaphylactoid reactions, such as glottis oedema, urticaria and bronchospasm, have occasionally occurred, particularly in patients with a history of allergy. If such an anaphylactoid reaction occurs, treat the patient with adrenaline and positive pressure ventilation.

Corticosteroids should not be used for the management of head injury or stroke because it is unlikely to be of any benefit and may even be harmful.

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. (See also section 4.2).

Preterm neonates

Available evidence suggests long-term neurodevelopment adverse events after early treatment (<96 hours) of premature infants with chronic lung disease at starting doses of 0.25 mg/kg twice daily.

Dexamethasone withdrawal

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 1 mg dexamethasone is reached, dose reduction should be slower to allow the HPA-axis to recover.

Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks is appropriate if it is considered that the disease is unlikely to relapse. Abrupt withdrawal of doses of up to 6 mg 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 6 mg daily of dexamethasone.
Patients repeatedly taking doses in the evening.

During prolonged therapy any intercurrent illness, trauma or surgical procedure will require a temporary increase in dosage; if corticosteroids have been stopped following prolonged therapy they may need to be temporarily re-introduced.

Patients 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.

Anti-inflammatory/Immunosuppressive effects and Infection

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.

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 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. Patients should be advised to take particular care to avoid exposure to measles and to seek immediate medical advice if exposure occurs; prophylaxis with intramuscular normal immunoglobin may be needed.

Live vaccines should not be given to individuals with impaired immune responsiveness. The antibody response to other vaccines may be diminished.

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.

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:

Osteoporosis (post-menopausal females are particularly at risk)
Hypertension or congestive heart failure
Existing or previous history of severe affective disorders (especially previous steroid psychosis)
Diabetes mellitus (or a family history of diabetes)
History of tuberculosis, since glucocorticoids may induce reactivation
Glaucoma (or a family history of glaucoma)
Previous corticosteroid-induced myopathy
Liver failure
Renal insufficiency
Epilepsy
Gastro-intestinal ulceration
Migraine
Certain parasitic infestations in particular amoebiasis
Incomplete statural growth since glucocorticoids on prolonged administration may accelerate epiphyseal closure
Patients with Cushing’s syndrome

In the treatment of conditions such as tendinitis or tenosynovitis care should be taken to inject into the space between the tendon sheath and the tendon as cases of ruptured tendon have been reported.

Paediatric population

Corticosteroids cause dose-related growth retardation in infancy, childhood and adolescence, which may be irreversible.

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

Use in the Elderly

The common 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.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium- free’.

4.5 Interaction with other medicinal products and other forms of interaction

Rifampicin, rifabutin, ephedrine, carbamazepine, phenylbutazone, phenobarbital, phenytoin, primidone, and aminoglutethimide enhance the metabolism of corticosteroids and its therapeutic effects may be reduced.

Dexamethasone is a moderate inducer of CYP 3A4. Co-administration of dexamethasone with other drugs that are metabolized by CYP 3A4 (e.g., indinavir, erythromycin) may increase their clearance, resulting in decreased plasma concentrations.

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.

The effects of anticholinesterases are antagonised by corticosteroids in myasthenia gravis.

The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives, cardiac glycosides and diuretics are antagonised by corticosteroids, and the hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics and carbenoxolone are enhanced.

The efficacy of coumarin anticoagulants may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.

The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication. There may be interaction with salicylates in patients with hypoprothrombinaemia.

4.6 Fertility, pregnancy and lactation

Pregnancy

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

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and effects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate/lip in man (see also 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.

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.

4.7 Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

Local adverse reactions include post-injection flare, and a painless destruction of the joint reminiscent of Charcot’s arthropathy especially with repeated intra-articular injection.

The incidence of predictable undesirable effects, including hypothalamic-pituitary-adrenal suppression correlates with the relative potency of the drug, dosage, timing of administration and the duration of treatment. Cases of ruptured tendon have been reported (see section 4.4).

Local injection of glucocorticoid may produce systemic effects.

Endocrine/metabolic

Suppression of the hypothalamic-pituitary-adrenal axis, premature epiphyseal closure, growth suppression in infancy, childhood and adolescence, menstrual irregularity and amenorrhoea, Cushingoid faces, hirsutism, weight gain, impaired carbohydrate tolerance with increased requirement for anti-diabetic therapy, negative protein and calcium balance, increased appetite

Anti-inflammatory and Immunosuppressive effects

Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, diminished lymphoid tissue and immune response, opportunistic infections, recurrence of dormant tuberculosis and decreased responsiveness to vaccination and skin tests (see section 4.4)

Musculoskeletal

Osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, tendon rupture

Proximal myopathy

Fluid and electrolyte disturbance

Sodium and water retention, hypertension, potassium loss, hypokalaemic alkalosis

Neuropsychiatric

A wide range of psychiatric reactions including affective disorders (such as irritable, euphoric, depressed and labile mood, and suicidal thoughts), psychotic reactions (including mania, delusions, hallucinations, and aggravation of schizophrenia), behavioural disturbances, irritability, anxiety, sleep disturbances, and cognitive dysfunction including confusion and amnesia have been reported. Reactions are common and may occur in both adults and children. In adults, the frequency of severe reactions has been estimated to be 5 – 6%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown.

Increased intra-cranial pressure with papilloedema in children (pseudotumour cerebri), usually after treatment withdrawal, aggravation of epilepsy, psychological dependence

Ophthalmic

Increased intra-ocular pressure, glaucoma, papilloedema, posterior subcapsular cataracts, corneal or scleral thinning, exacerbation of opthalmic viral or fungal diseases, chorioretinopathy

Eye disorders

Vision, blurred (see also section 4.4)

Gastrointestinal

Dyspepsia, peptic ulceration with perforation and haemorrhage, acute pancreatitis, candidiasis

Dermatological

Impaired healing, skin atrophy, bruising, telangiectasia, striae, increased sweating and acne

General

Hypersensitivity, including anaphylaxis and angioedema, have been reported. Leucocytosis. Thromboembolism.

A transient burning or tingling sensation mainly in the perineal area following intravenous injection of large doses of corticosteroid phosphates.

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.

4.9 Overdose

It is difficult to define an excessive dose of a corticosteroid as the therapeutic dose will vary according to the indication and patient requirements. Massive IV corticosteroid doses given as a pulse in emergencies are relatively free from hazardous effects.

Exaggeration of corticosteroid related adverse effects may occur. Treatment should be asymptomatic and supportive as necessary.

Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Corticosteroids for systemic use, Glucocorticoids.

Dexamethasone is a synthetic adrenocorticoid with approximately a 7 times higher anti-inflammatory potency than prednisolone and 30 times that of hydrocortisone. Adrenocorticoids act on the HPA at specific receptors on the plasma membrane. On other tissues the adrenocorticoids diffuse across cell membranes and complex with specific cytoplasmic receptors which enter the cell nucleus and stimulate protein synthesis. Adrenocorticoids have anti-allergic, antitoxic, antishock, antipyretic and immunosuppressive properties. Dexamethasone has only minor mineralocorticoid activities and does therefore, not induce water and sodium retention.

5.2 Pharmacokinetic properties

Absorption

After administration of Dexamethasone solution for injection, dexamethasone sodium phosphate is rapidly hydrolysed to dexamethasone. After an IV dose of 20 mg dexamethasone plasma levels peak within 5 minutes.

Distribution

Dexamethasone is bound (up to 77%) by plasma proteins, mainly albumin. There is a high uptake of dexamethasone by the liver, kidney and adrenal glands.

Biotransformation and Elimination

Metabolism in the liver is slow and excretion is mainly in the urine, largely as unconjugated steroids. The plasma half-life is 3.5 – 4.5 hours but as the effects outlast the significant plasma concentrations of steroids the plasma half-life is of little relevance and the use of biological half-life is more applicable. The biological half-life of dexamethasone is 36 – 54 hours; therefore, dexamethasone is especially suitable in conditions where continuous glucocorticoid action is desirable.

5.3 Preclinical safety data

In animal studies, cleft palate was observed in rats, mice, hamsters, rabbits, dogs and primates; not in horses and sheep. In some cases these divergences were combined with defects of the central nervous system and of the heart. In primates, effects in the brain were seen after exposure. Moreover, intra-uterine growth can be delayed. All these effects were seen at high dosages.

Pharmaceutical particulars

6.1 List of excipients

Glycerol

Disodium edetate

Water for injections

Sodium hydroxide or

Phosphoric acid

6.2 Incompatibilities

None known.

6.3 Shelf life

As packaged for sale

2 years

The product should be used immediately after first opening.

Following dilution with infusion fluids (see section 6.6):

Chemical and physical in-use stability of dilutions has been demonstrated for at least 24 hours, at 25°C (room temperature)

From a microbiological point of view, the product should be used immediately.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

As packaged for sale

Store in a refrigerator (2 °C – 8 °C). Do not freeze. Store in the original package.

Following dilution with infusion fluids:

See section 6.3.

6.5 Nature and contents of container

2 ml colourless glass vial containing 1 ml of solution. Available in cartons of 1 or 10 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Dexamethasone solution for injection may be diluted with the following solutions for injection or infusion:

Sodium Chloride 0.9% infusion

Glucose 5% Infusion

Compound Sodium Lactate Infusion

Hartmann’s Solution for Injection

Ringer-Lactate Solution for Injection

Ringer’s Solution for injection

Sorbitol 5% Injection

Invert Sugar 10% Injection

Rheomacrodex

Using these infusion fluids, Dexamethasone solution for injection can also be injected into the infusion line without causing precipitation of the ingredients. (See also section 4.2).

For single use only.

Discard any unused solution after use.

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

The product should only be used when the solution is clear and particle free.

7.Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Package leaflet: Information for the patient

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

Keep this leaflet. You may need to read it
If you have any further questions, ask your doctor or
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section

What is in this leaflet
What Dexamethasone is and what it is used for
What you need to know before you use Dexamethasone
How you use Dexamethasone
Possible side effects
How to store Dexamethasone
Contents of the pack and other information

1.What Dexamethasone is and what it is used for

The name of your medicine is Dexamethasone. This belongs to a group of medicines called corticosteroids.

Corticosteroids are hormones that are found naturally in your body that help to keep you healthy and well. Boosting your body with extra corticosteroid, such as Dexamethasone, is an effective way to treat various illnesses involving inflammation in the body. Dexamethasone lowers inflammation, which could otherwise go on making your condition worse. You must take this medicine regularly to get maximum benefit from it.

Dexamethasone is given by injection to patients unable to take a tablet form of the medicine. When given into a vein or muscle, dexamethasone reduces inflammation and suppresses the immune system and is used normally for patients with:

severe allergic reactions causing swelling of the face and throat, low blood pressure and collapse (angioneurotic oedema and anaphylaxis), severe exacerbation of bronchial asthma (such as status asthmaticus), hypersensitivity reaction to other medications
shock caused by infection or severe tuberculosis (also with anti-infective treatments e.g. antibiotics)
raised pressure in the skull caused by tumours or infantile spasms

Dexamethasone can be used

to control cerebral oedema (swelling in the brain) caused by brain tumour or after neurosurgery, but not in cases of head

Sometimes, the injection is given into the painful area itself e.g. inflammation of the joints (rheumatoid arthritis and osteoarthritis).

What you need to know before you use Dexamethasone

Do not use Dexamethasone:

if you are allergic to dexamethasone or any of the other ingredients of this medicine (listed in section 6). The signs of an allergic reaction include a rash, itching or shortness of breath
if you have an infection that affects the whole body
if you have an infection of a joint
if you have unstable joints. This is a condition where joints, such as the knee, can suddenly give

Do not have this medicine if any of the above apply to you.

Warnings and precautions

Talk to your doctor or pharmacist before using Dexamethasone:

If you have ever had severe depression or manic depression (bipolar disorder). This includes having had depression before while taking steroid medicines like Dexamethasone
If any of your close family has had these illnesses

If either of these applies to you, talk to a doctor before having this medicine.

Mental problems while having Dexamethasone

Mental health problems can happen while having steroids like Dexamethasone (see also section 4).

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

Talk to a doctor if you (or someone taking this medicine), show any signs of mental problems. This is particularly important if you are depressed, or might be thinking about suicide. In a few cases, mental problems have happened when doses are being lowered or stopped.

Take special care with Dexamethasone

Before you have Dexamethasone, tell your doctor if:

You have had allergic reactions with a corticosteroid treatment. Severe allergic reactions (including shock) have been seen with injected
You have a cancer of the blood because you may be at risk of a very rare, potentially life- threatening condition resulting from a sudden breakdown of tumour
You have symptoms of tumour lysis syndrome such as muscle cramping, muscle weakness, confusion, visual loss or disturbances and shortness of breath, in case you suffer from haematological malignancy
You have kidney or liver problems
You have high blood pressure or heart disease
You have diabetes or there is a family history of diabetes
You have thinning of the bones (osteoporosis), particularly if you are a female who has been through the menopause
You have had muscle weakness with this or other steroids in the past
You have raised eye pressure (glaucoma) or there is a family history of glaucoma
You have a stomach (peptic) ulcer
You have mental problems or you have had a mental illness which was made worse by this type of medicine such as ‘steroid psychosis’
You have epilepsy
You have migraines
You have an infection with parasites
You have tuberculosis (TB)
You have stunted growth
You have ‘Cushing’s syndrome’
You have had a head injury
You have had a stroke
Contact your doctor if you experience blurred vision or other visual

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before having Dexamethasone.

If you develop an infection while you are having this medicine, you should talk to your doctor. Please tell any doctor, dentist or person who may be giving you treatment that you are currently taking steroids or have taken them in the past.

If you are living in the UK, you should always carry a blue ‘steroid card’ which gives clear guidance on the special care to be taken when you are taking this medicine. Show this to any doctor, dentist or person who may be giving you treatment. Even after your treatment has finished you must tell anyone who is giving you treatment that you have taken steroids in the past.

Do not use Dexamethasone for the treatment of Acute Respiratory Distress Syndrome (ARDS; a serious lung disease) if you have been diagnosed with this condition for over 2 weeks.

Dexamethasone and viral infections

While you are having this kind of medicine, you should not come into contact with anyone who has chicken pox, shingles or measles if you have not had these illnesses. This is because you may need specialist treatment if you get these diseases. If you think you may have had exposure to any of these diseases, you should talk to your doctor straight away. You should also tell your doctor if you have ever had infectious diseases such as measles or chicken pox and if you have had any vaccinations for these conditions in the past.

Please tell a doctor or anyone giving you treatment, such as at a hospital, if:

You have an accident

You are ill

You need any surgery. This includes any surgery you may have at your dentist’s

You need to have a vaccination

If any of the above apply to you, you should tell your doctor or the person treating you even if you have stopped having this medicine.

Children

If a child is having this medicine, it is important that the doctor monitors their growth and development regularly.

Dexamethasone should not be routinely given to premature babies with respiratory problems.

Other medicines and Dexamethasone

Please tell your doctor if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. Other medicines can affect the way Dexamethasone works or Dexamethasone can affect the way they work. In particular:
Medicines to treat heart and blood problems, such as warfarin, high blood pressure medicine, and water tablets (diuretics)
Antibiotics such as rifampicin and rifabutin
Medicines that are broken down in the body by an enzyme in the liver (CYP 3A4) such as HIV protease inhibitors (e.g indinavir) or certain antibiotics (e.g. erythromycin)
Some medicines may increase the effects of Dexamethasone and your doctor may wish to monitor you carefully if you are taking these medicines (including some medicines for HIV: ritonavir, cobicistat)
Medicines to treat epilepsy, such as phenytoin, carbamazepine, phenobarbitone and primidone
Medicines that control pain or lower inflammation, such as aspirin or phenylbutazone
Medicines used to treat diabetes
Medicines used to lower potassium levels
Medicines used to treat myasthenia
Anti-cancer treatments, such as aminoglutethimide
Ephedrine used to relieve symptoms of a blocked nose
Acetazolamide used for glaucoma
Carbenoxolone sometimes used for

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

Driving and using machines

Dexamethasone is not likely to affect you being able to drive or use any tools or machines.

Dexamethasone contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium- free’.

How you have Dexamethasone

Dexamethasone is normally given by a doctor or a nurse. It will be given as an injection into a muscle, tendon or joint. It can also be given as an injection into a vein. The dose depends on your illness and how bad it is. Your doctor will decide the correct dosage for you and how and when the injection will be given

If you use more Dexamethasone than you should

If you think you have been given too much Dexamethasone, tell your doctor straight away. The following effects may happen:

Swelling of the throat
Skin reaction
Difficulty breathing

Since the injection will be given to you by a doctor or nurse, it is unlikely that you will be given too much or that you will miss a dose. If you think you have been given too much or that you have missed a dose, please contact your doctor immediately.

If you stop using Dexamethasone

It can be dangerous to have your treatment with Dexamethasone Injection stopped abruptly. After prolonged therapy your body may have gotten used to the administration of this medicine and may have reduced the normal production of hormones like the one contained in this medicine. How your treatment is stopped will depend on the disease you are being treated for and how much Dexamethasone Injection you have been given.If you need to stop this treatment, follow your doctor’s advice.. If you stop having this medicine too quickly, your condition may get worse.

It may be necessary to reduce the amount of medicine you are given gradually until you stop having it altogether. Your doctor has to make sure that the disease you have been treated for is unlikely to relapse. Dosage reduction must be adjusted if you are subjected to unusual stress (e.g. another illness, trauma or surgical procedures).

When the treatment is stopped too quickly, you may feel ‘withdrawal symptoms’. These may include headache, problems with your vision (including pain or swelling in the eye), feeling or being sick, fever, pain in your muscles and joints, swelling in the inside of your nose, weight loss, itchy skin and conjunctivitis. Too rapid a reduction following prolonged treatment can lead to insufficiency of hormone production in the adrenal gland and low blood pressure (symptoms of which can be tiredness, dizziness, headache, palpitation). In extreme cases, this may be fatal.

In a few cases, mental health problems have occurred when doses are being lowered or stopped

– see section 4 below.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Dexamethasone can also cause side effects when you stop using it.

See section 3, ‘If you stop having Dexamethasone’

Serious side effects: tell a doctor straight away

Steroids including Dexamethasone can cause serious mental health problems. These are common in both adults and children. They can affect about 5 in every 100 people taking medicines like Dexamethasone. These include:

Feeling depressed, including thinking about suicide
Feeling high (mania) or moods that go up and down
Feeling anxious, having problems sleeping, difficulty in thinking or being confused and losing your memory
Feeling, seeing or hearing things that do not exist. Having strange and frightening thoughts, changing how you act or having feelings of being alone

If you notice any of these problems, talk to a doctor straight away.

If you have an allergic reaction to Dexamethasone see a doctor straight away

An allergic reaction may include:

Any kind of skin rash or itching of the skin
Difficulty in breathing or collapse
Swelling of the face, lips, tongue and/or throat with difficulty in swallowing or breathing (angioedema).

If you get any of the following side effects see your doctor as soon as possible:

Stomach and gut problems: stomach ulcers which may perforate or bleed, indigestion, having more of an appetite than usual, diarrhoea, feeling or being sick
Inflamed pancreas: this may cause severe pain in the back or tummy
Problems with salts in your blood such as too much sodium or low potassium or calcium. You may have water retention
Heart and blood problems: high blood pressure, blood clots
Bone problems: thinning of the bones (osteoporosis) with an increased risk of fractures, bone disease, damaged tendons, damage to the joint where the injection was given
Recurring infections that get worse each time such as chicken pox and thrush
Skin problems: wounds that heal more slowly, bruising, acne, sweating more than usual. Burning, redness and swelling where the injection was given. This does not last long
Eye problems: increased pressure in the eye including glaucoma, eye disorders such as cataracts, eye infections, visual disturbances, loss of vision, blurred vision
Hormone problems: irregular or missing periods, stunted growth in children and teenagers, swelling of the face (called a ‘Cushingoid’ or ‘moon’ face). It may affect your diabetes and you may notice you start needing higher doses of the medicine you take for diabetes. Your body may not be able to respond normally to severe stress such as accidents, surgery or illness, growth of extra body hair (particularly in women), increased appetite or weight gain
Nervous system problems: fits or epilepsy may become worse, severe unusual headache with visual problems, being unable to sleep, feeling depressed, extreme mood swings, schizophrenia may become worse, headache or problems with your vision (including eye pain or swelling)

Reporting of side effects

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, tell your doctor or pharmacist.

How to store Dexamethasone

Keep this medicine out of the sight and reach of children

Do not use this medicine after the expiry date which is stated on the label and carton after “EXP”. The expiry date refers to the last day of that month.

Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the original package

After first opening, the product should be used immediately to avoid microbial contamination. When diluted with infusion fluids, chemical and physical in-use stability of dilutions has been demonstrated for at least 24 hours, at 25°C (room temperature). If not used immediately, in-use storage conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

Contents of the pack and other information What Dexamethasone contains

The active ingredient is dexamethasone (as sodium phosphate). Each 1 ml contains 3.8 mg dexamethasone (as sodium phosphate) which is equivalent to 5.0 mg dexamethasone sodium phosphate

The other ingredients are glycerol, disodium edetate, water for injections and sodium hydroxide or phosphoric acid

What Dexamethasone looks like and contents of the pack

Dexamethasone is a clear, colourless liquid. It comes in vials containing 1 ml of solution. Vials are available in packs of 1 or 10. Not all pack sizes may be marketed.