Dexamethasone 2mg/ml Solution for Injection Taj Pharma

1. Name of the medicinal product

Dexamethasone 2mg/ml solution for injection Taj Pharma
Dexamethasone 4mg/ml solution for injection Taj Pharma
Dexamethasone 10mg/ml solution for injection Taj Pharma

2. Qualitative and quantitative composition

Each ml contains:
Dexamethasone sodium Phosphate (equivalent to 2mg dexamethasone Phosphate)
Sodium sulfite anhydrous                                  1mg
Sodium Citrate anhydrous                                19.4 mg
Benzyl alcohol                                                   10.42 mg
Water for injection                                              q.s

Each ml contains:
Dexamethasone sodium Phosphate (equivalent to 4mg dexamethasone Phosphate)
Sodium sulfite anhydrous                                  1mg
Sodium Citrate anhydrous                                19.4 mg
Benzyl alcohol                                                   10.42 mg
Water for injection                                              q.s

Each ml contains:
Dexamethasone sodium Phosphate (equivalent to 10mg dexamethasone Phosphate)
Sodium sulfite anhydrous                                  1mg
Sodium Citrate anhydrous                                 19.4 mg
Benzyl alcohol                                                   10.42 mg
Water for injection                                              q.s

For full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection

Clear and colourless solution

4. Clinical particulars

4.1 Therapeutic indications

Corticosteroid

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

Intravenous or Intramuscular administration

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

Endocrine disorders

Primary or secondary adrenocortical insufficiency

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

Non-endocrine disorders

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

Allergy and anaphylaxis

Angioneurotic oedema and anaphylaxis

Gastrointestinal

Crohn’s disease and ulcerative colitis

Infection (with appropriate chemotherapy)

Miliary tuberculosis and endotoxic shock

Neurological disorders

Raised intracranial pressure secondary to cerebral tumours and infantile spasms

Respiratory

Bronchial asthma and aspiration pneumonitis

Skin disorders

Toxic epidermal necrolysis

Shock

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

Subcutaneous administration

In palliative care, patients receiving corticosteroids for symptoms such as fatigue, anorexia, refractory nausea and vomiting or adjuvant analgesia and symptomatic treatment of cord compression or raised intracranial pressure, dexamethasone 3.3mg/ml solution for injection may be administered subcutaneously (see section 4.2) as an alternative to the oral route when the latter is unacceptable or no longer feasible.

Local administration

Dexamethasone 3.3 mg/ml solution for injection is suitable for intraarticular or soft-tissue injection as adjunctive therapy for short-term administration in:

Soft-tissue disorders

Such as carpal tunnel syndrome and tenosynovitis

Intraarticular disorders

Such as rheumatoid arthritis and osteoarthritis with an inflammatory component

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

4.2 Posology and method of administration

Dexamethasone 3.3 mg/ml solution for injection can be given without mixing or dilution.

Alternatively, it can be added, without loss of potency, to sodium chloride, or dextrose, injection and given by intravenous infusion.

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

In palliative care, Dexamethasone 3.3mg/ml solution for injection can be diluted with sodium chloride injection and given by Continuous Subcutaneous Infusion (CSCI).

Infusion mixtures must be used within 24 hours and the usual aseptic techniques for injections should be observed.

All dosage recommendations are given in units of dexamethasone base.

General considerations

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

Intravenous and intramuscular injection

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

The usual initial dosage is 0.4 mg – 16.6 mg (0.12 ml – 5.0 ml) a day. In situations of less severity, lower doses will generally suffice. However, in certain overwhelming, acute, life-threatening situations, administration in dosages exceeding the usual dosage may be justified. In these circumstances, the slower rate of absorption by intramuscular administration should be recognised.

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

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

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

In emergencies, the usual dose of Dexamethasone 3.3 mg/ml solution for injection by intravenous or intramuscular injection is 3.3 mg – 16.6 mg (1.0 ml – 5.0 ml) – in shock use only the i.v. route. This dose may be repeated until adequate response is noted.

After initial improvement, single doses of 1.7 mg – 3.3 mg (0.5 ml – 1.0 ml), repeated as necessary, should be sufficient. The total daily dosage usually need not exceed 66.4 mg (20.0 ml), even in severe conditions.

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

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

Shock (of haemorrhagic, traumatic, or surgical origin):

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

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

Cerebral oedema:

Associated with primary or metastatic brain tumour, preoperative preparation of patients with increased intracranial pressure secondary to brain tumour: initially 8.3 mg (2.5ml) intravenously, followed by 3.3 mg (1.0 ml) intramuscularly every six hours until symptoms of cerebral oedema subside. Response is usually noted within 12-24 hours; dosage may be reduced after two to four days and gradually discontinued over five to seven days.

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

Management of recurrent or inoperable brain tumours:

Maintenance therapy should be determined for each patient; 1.7 mg (0.5 ml) two or three times a day may be effective.

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

Suggested high-dose schedule in cerebral oedema

Adults:

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

Children (35 kg and over):

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

Children (below 35 kg):

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

Dual therapy:

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

Subcutaneous administration

In palliative care, subcutaneous Dexamethasone 3.3 mg/ml solution for injection may be administered by injection or Continuous Subcutaneous Infusion (CSCI). Doses usually range between 4 mg to 16 mg over 24 hours, taking into consideration local clinical guidelines, and should be titrated according to the response.

Intraarticular, intrabursal or intralesional injection

In general, these injections are employed when only one or two joints or areas are affected.

Some of the usual single doses are:

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

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

Paediatric population:

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

Use in the elderly:

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

4.3 Contraindications

Systemic fungal infection; systemic infection unless specific anti-infective therapy is employed; hypersensitivity to the active ingredient or any other component of this medication. Administration of live virus vaccines (see ‘Special warnings and precautions for use’).

4.4 Special warnings and precautions for use

In post marketing experience tumour lysis syndrome (TLS) has been reported in patients with haematological malignancies following the use of dexamethasone alone or in combination with other chemotherapeutic agents. Patient at high risk of TLS, such as patients with high proliferative rate, high tumour burden, and high sensitivity to cytotoxic agents, should be monitored closely and appropriate precaution taken.

Patients/and or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids (see section 4.8). Symptoms typically emerge within a few days or weeks of starting the treatment. Risks may be higher with high doses/systemic exposure (see also section 4.5 pharmacokinetic interactions that can increase the risk of side effects), although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary. Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should also be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such 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.

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

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

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

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 derivates, except when used in large doses. Dietary salt restrictions and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.

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

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

Stopping corticosteroids after prolonged therapy may cause withdrawal symptoms, including fever, myalgia, arthralgia and malaise. This may occur in patients even without evidence of adrenal insufficiency.

In patients who have received more than physiological doses of systemic corticosteroids (approximately 1 mg dexamethasone) for greater than three weeks, withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids but there is uncertainty about hypothalamic-pituitary adrenal (HPA) suppression, the dose of systemic corticosteroids may be reduced rapidly to physiological doses. Once a daily dose of 1 mg dexamethasone is reached, dose reduction should be slower to allow the HPA-axis to recover.

Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to three weeks is appropriate if it is considered that the disease is unlikely to relapse. Abrupt withdrawal of doses of up to 6 mg daily of dexamethasone for three weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting three weeks or less:

• patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than three weeks,
• when a short course has been prescribed within one year of cessation of long-term therapy (months or years),
• patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy,
• patients receiving doses of systemic corticosteroid greater than 6 mg daily of dexamethasone,
• patients repeatedly taking doses in the evening.

Patients should carry ‘steroid treatment’ cards, which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.

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

Administration of live virus vaccines is contraindicated in individuals receiving immunosuppressive doses of corticosteroids. If inactivated viral or bacterial vaccines are administered to individuals receiving immunosuppressive doses of corticosteroids, the expected serum antibody response may not be obtained. However, immunisation procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g. for Addison’s disease.

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

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

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

A report shows that the use of corticosteroids in cerebral malaria is associated with a prolonged coma and an increased incidence of pneumonia and gastro-intestinal bleeding.

Chickenpox is of particular concern, since this normally minor illness may be fatal in immunosuppressed patients. Patients (or parents of children) without a definite history of chickenpox should be advised to avoid close personal contact with chickenpox or herpes zoster and if exposed they should seek urgent medical attention. Passive immunisation with varicella/zoster immunoglobulin (VZIG) is needed by exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous three month; this should be given within ten days of exposure to chickenpox.

If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.

Measles can have a more serious or even fatal course in immunosuppressed patients. In such children or adults particular care should be taken to avoid exposure to measles. If exposed, prophylaxis with intramuscular pooled immunoglobulin (IG) may be indicated. Exposed patients should be advised to seek medical advice without delay.

Corticosteroids may activate latent amoebiasis or strongyloidiasis or exacerbate active disease. Therefore, it is recommended that latent or active amoebiasis and strongyloidiasis be ruled out, before initiating corticosteroid therapy in any patient at risk of or with symptoms of either condition.

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

Corticosteroids may increase or decrease motility and number of spermatozoa.

Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.

This medicinal product contains up to 1.9 mmol (or 43 mg) sodium per maximum single dose of the medicinal product (350 mg for a person with 70 kg bodyweight). To be taken into consideration by patients on a controlled sodium diet.

Special precautions:

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

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

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

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

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

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

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

Corticosteroids should not be injected into unstable joints.

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

Paediatric population

Preterm neonates:

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

Children:

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

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

Dexamethasone has been used to treat and prevent chronic lung disease in preterm infants (unlicensed use). Clinical trials have shown no long term benefit in reducing time to discharge, the incidence of chronic lung 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 should be made on an individual patient basis.

4.5 Interaction with other medicinal products and other forms of interaction

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

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

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

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

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

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

When corticosteroids are administered concomitantly with potassium-depleting diuretics, patients should be observed closely for development of hypokalaemia.

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

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

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

4.6 Fertility, pregnancy and lactation

Pregnancy

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

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, 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 also section 5.3 of the SmPC.

However, when administered for prolonged periods or repeatedly during pregnancy, corticosteroids may increase the risk of intrauterine growth retardation. Hypoadrenalism may, in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential however, patients with normal pregnancies may be treated as though they were in non-gravid state.

Lactation

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

None reported

4.8 Undesirable effects

The incidence of predictable undesirable effects, including hypothalamic-pituitary-adrenal suppression, correlates with the relative potency of the drug, dosage, timing of administration and the duration of treatment (see ‘Special warnings and precautions for use’).

Fluid and electrolyte disturbances:

Sodium retention, fluid retention, congestive heart failure in susceptible patients, potassium loss, hypokalaemic alkalosis, hypertension, increased calcium excretion (see ‘Special warnings and precautions for use’)

Musculoskeletal:

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

Gastrointestinal:

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

Dermatological:

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

Neurological:

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

Psychiatric:

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

Endocrine:

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

Anti-inflammatory and immunosuppressive effects:

Increased susceptibility and severity of infections with suppression of clinical symptoms and signs; opportunistic infections, recurrence of dormant tuberculosis (see ‘Special warnings and precautions for use’)

Ophthalmic:

Posterior subcapsular cataracts, increased intraocular pressure, papilloedema, corneal or scleral thinning, exacerbation of ophthalmic viral disease, glaucoma exophthalmos, rare instances of blindness associated with intralesional therapy around the face and head, retinopathy of prematurity, chorioretinopathy.

Metabolic:

Negative nitrogen balance due to protein catabolism, negative calcium balance

Cardiovascular:

Myocardial rupture following recent myocardial infarction (see ‘Special warnings and precautions for use’), hypertrophic cardio-myopathy in low birth weight infants

Other:

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

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

Withdrawal symptoms and signs

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

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Reports of acute toxicity and/or deaths following overdosage with glucocorticoids are rare. No antidote is available. Treatment is probably not indicated for reactions due to chronic poisoning, unless the patient has a condition that would render a patient unusually susceptible to ill effects from corticosteroids. In this case, symptomatic treatment should be instituted as necessary.

Anaphylactic and hypersensitivity reactions may be treated with adrenaline, positive-pressure artificial respiration and aminophylline. The patient should be kept warm and quiet.

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

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Glucocorticoids

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

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

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

5.2 Pharmacokinetic properties

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

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

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

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

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.

6. Pharmaceutical particulars

6.1 List of excipients

Propylene glycol,

disodium edetate,

sodium hydroxide solution

Water for Injections.

6.2 Incompatibilities

Dexamethasone is physically incompatible with daunorubicin, doxorubicin, vancomycin, diphenhydramine (with lorazepam and metoclopramide) and metaraminol bitartrate and should not be admixed with solutions containing these drugs. It is also incompatible with doxapram and glycopyrrolate in syringe and with ciprofloxacin, idarubicin and midazolam in Y-site injections (1:1 mixture).

6.3 Shelf life

2 years.

From a microbiological point of view, the product should be used immediately after opening. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 h at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Any unused portion of the product should be discarded immediately after use.

Chemical and physical in-use stability of dilutions has been demonstrated for 24 h at 25°C. Dilutions should be used within 24 hours and discarded after use.

6.4 Special precautions for storage

Keep container in the outer carton.

Do not freeze.

Store below 25°C.

Any unused portion should be discarded immediately after use.

6.5 Nature and contents of container

Type I clear glass ampoule containing 1 ml solution for injection.

Type I clear glass ampoule containing 2 ml solution for injection.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

When Dexamethasone 20 mg/ml solution for injection is given by intravenous infusion, dextrose 5% in water and sodium chloride 0.9% have been recommended as diluents. The exact concentration of dexamethasone per infusion container should be determined by the desired dose, patient fluid intake and drip rate required.

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

Dexamethasone 20mg/5 ml solution for injection Taj Pharma

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 again.
• If you have any further questions, ask your doctor or pharmacist.
• 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 4.

What is in this leaflet:

1. What Dexamethasone is and what it is used for
2. What you need to know before you use Dexamethasone
3. How to use Dexamethasone
4. Possible side effects
5. How to store Dexamethasone
6. Contents of the pack and other information

1. What Dexamethasone is and what it is used for

Dexamethasone 3.3 mg/ml, solution for injection contains the active substance dexamethasone (as sodium phosphate), which belongs to a group of medicines called steroids (specifically known as corticosteroids).

Corticosteroids occur naturally in the body and help to maintain health and well-being. Synthetic steroids such as dexamethasone work by mimicking some of their actions to treat disease.

Corticosteroids are given to patients for a variety of conditions where their abilities to reduce inflammation and suppress the immune system are valuable. These conditions may include Crohn’s disease, asthma, shock, anaphylaxis, tuberculosis, arthritis, osteoarthritis, and skin disorders including acne.

2. What you need to know before you use Dexamethasone

Do not use Dexamethasone:

• If you are allergic to dexamethasone, related substances or any of the other ingredients of this medicine (listed in section 6).
• If you have an infection, including one which could have been caused by a fungus (e.g. thrush), which is not being treated. However, your doctor may decide to treat you with Dexamethasone under certain circumstances.

If you are to be vaccinated by live virus vaccines.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before Dexamethasone is used.

• 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 taking dexamethasone.

• Mental health problems while taking dexamethasone

Mental health problems can happen while taking steroids like dexamethasone (see also section 4 Possible side effects).

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 health problems.

This is particularly important if you are depressed, or might be thinking about suicide. In a few cases, mental health problems have happened when doses are being lowered or stopped.

Patients taking Dexamethasone should avoid, if possible, close personal contact with people suffering from chickenpox, shingles or measles. If you think you may have been exposed to either disease, it is vital that you inform your doctor

immediately. You should also tell your doctor whether or not you have had common infectious diseases such as measles or chickenpox and of any vaccinations you have had. If you develop either disease, you will need specialist treatment from your doctor.

Corticosteroids may mask some signs of infection and new infections may appear during their use. Your doctors will try to use the smallest dose necessary to help you. However there may be times when an increase in dose will be needed. Any reduction in dose will need to be made more slowly than an increase. You should see your doctor if you develop any new infections while taking this medicine.

Take special care when using Dexamethasone if you have:

• Liver, kidney or heart problems (heart attack for example);
• High blood pressure;
• Epilepsy;
• A history of migraines;
• Osteoporosis (thinning of the bones);
• Had tuberculosis in the past;
• An under-active thyroid;
• Had amoebiasis in the past (infection specific to tropical countries which causes diarrhoea);
• A herpes infection of the eye;
• Diabetes (or a family history of diabetes);
• An eye disease called glaucoma (or a family history of glaucoma);
• Stomach ulcers;
• Experienced muscle weakness caused by previous steroid treatment;
• Suffered from myasthenia gravis (a disease causing weak muscles).

You should also tell your doctor if 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.

If you have an accident, fall ill, require any surgery (including at the dentist’s) or are to have any vaccinations (especially with so-called ‘live virus vaccines’) during or after treatment with Dexamethasone, you must tell the doctor treating you that you are taking or have taken steroids.

In the case of local injection of Dexamethasone (e.g. injection into a joint), your doctor will take special care to reduce the

particular risk of bacterial infection. This medicine should not be injected directly into an infected site. Please tell your doctor if you suffer from complications like a marked increase in pain

accompanied by local swelling, further restriction of joint motion, fever or malaise after a local injection of this medicine. Your doctor will have to check if you suffer from blood poisoning and take the appropriate action.

Injection into unstable joints should be avoided.

Please be advised not to over-use joints that are still diseased, even if you do not suffer pain.

IMPORTANT: all patients taking steroids drugs for more than a few days should carry “steroids treatment card”, which are

available from your pharmacist. These cards carry details of your medicine and your doctor.

Preterm neonates (premature babies) Dexamethasone should not be used routinely in preterm neonates with respiratory problems.

There may be an increased risk of the development of cerebral palsy when Dexamethasone is used to treat or prevent chronic lung disease in pre-term infants.

Children and adolescents

If the patient is an infant or a child, it is important that the doctor monitors his/her growth and development at intervals during treatment because this medicine can cause growth retardation.

Other medicines and Dexamethasone

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.

Some other medicines do not mix with Dexamethasone. Your doctor is aware of these and will adjust your treatment as necessary. However, it is very important that you tell your doctor all the medicines you are taking, including those obtained without a doctor’s prescription.

You should not be vaccinated with a live vaccine while having steroid therapy. Tell your doctor or pharmacist if you are planning to have a vaccination.

If you are taking any of the following medicines you should talk to your doctor before starting treatment with Dexamethasone:

• Aspirin or similar medicines;
• Phenytoin (used to treat epilepsy);
• Ephedrine (a nasal decongestant);
• Barbiturates (sedative drugs used to treat sleeplessness and epilepsy);
• Antibiotics called rifampicin and rifabutin (used to treat tuberculosis);
• Anticoagulant medicines which thin the blood;
• Medicines for diabetes;
• Certain diuretics (water tablets);
• A medicine called carbamazepine, used to treat epilepsy, pain and manic depression;
• An anticancer medicine called aminoglutethimide;
• Antiretroviral medicines e.g. ritonavir, darunavir, indinavir, lopinavir, saquinavir and efavirenz.

Pregnancy and breast-feeding

Tell your doctor if you are pregnant, trying to become pregnant or breast-feeding.

If you receive dexamethasone often or over a long period of time during pregnancy there may be a risk that the baby’s growth slows down. The baby may need careful observation for a short time after being born.

If you are given dexamethasone for a long time during breast- feeding then the baby’s growth may slow down and it may have other side effects (see Section 4). Your doctor will discuss this with you and decide whether you should receive dexamethasone.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Do not drive or use machines if you experience any side effect which may lessen your ability to do so.

Dexamethasone contains sodium.

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

3.  How to use Dexamethasone

You have been given or are about to be given Dexamethasone by a healthcare professional. This medicine will be given

as an injection either intravenously (injection into a vein), intramuscularly (injection into a muscle) or directly into a joint or soft tissue. Your doctor will decide what the appropriate dose for your condition is, and may alter your dose depending on how you respond. The usual initial dose ranges from

0.4 mg-16.6 mg (0.125-5 ml) per day, with repeat dosing depending on your condition.

For some patients the medicine may be given as an injection into the painful area itself, usually once every 3 to 5 days or once every 2-3 weeks depending on your response.

If you receive more Dexamethasone than you should

The times at which you are to have your injections will be set by your healthcare professional. Your doctor will monitor your response and condition to determine what treatment is needed. If you are concerned that you may have been given too much Dexamethasone by mistake, contact your doctor or healthcare professional immediately.

If you receive less Dexamethasone than you should

The times at which you are to have your injections will be set by your healthcare professional. Your doctor will monitor your response and condition to determine what treatment is needed. However, if you are concerned that you may have missed a dose, you should notify your healthcare professional as soon as possible.

INFORMATION FOR HEALTHCARE PROFESSIONALS

The following information is intended for medical or healthcare professionals only. Dexamethasone may be administered intravenously, intramuscularly or intraarticularly.

Dexamethasone is a clear, colourless to slightly yellowish liquid. The change of appearance of the solution from clear to yellowish is not a sign of deterioration of the product.

Incompatibilities

Dexamethasone (as sodium phosphate) is physically incompatible with daunorubicin, doxorubicin and vancomycin and should not be admixed with solutions containing these drugs. It is also incompatible with doxapram hydrochloride and glycopyrrolate in a syringe.

Instructions for use and handling

Dexamethasone can be diluted with the following infusion fluids:

• sodium chloride 0.9%
• anhydrous glucose 5%

If use of Dexamethasone is stopped

IMPORTANT : It can be dangerous to stop your treatment with Dexamethasone abruptly. How your treatment is stopped will depend on the disease you are being treated for and how much Dexamethasone you have been given. It may be necessary to reduce the amount of Dexamethasone you are given gradually until you stop having it altogether.

The symptoms that have been reported when treatment has been stopped too quickly included low blood pressure and in some cases, relapse of the disease for which the treatment was given.

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

4. Possible side effects

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

If you experience any of the following please contact your doctor immediately as you may need urgent medical attention:

• Severe allergic reaction which may include a sudden itchy rash, swelling of the extremities (such as your hands and feet) and a swelling of your mouth and throat (which may cause difficulty in breathing);
• Severe infection and/or fever which makes you feel very ill;
• If you experience sudden and (in cases of long-term therapy) unusual effects like a feeling you are going to faint, bleeding, extreme weakness, or a sudden pain in any of your organs.

The following unwanted side effects have been reported for Dexamethasone and are listed below according to the organs that are affected.

Psychiatric disorders (mental health problems) 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.

• 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 which 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.

Carers of patients receiving Dexamethasone should talk to a doctor immediately if the patient shows any signs of mental health problems. This is particularly important if the patient appears to be depressed, or mentions thoughts of suicide.

If you suffer from schizophrenia or epilepsy your symptoms may worsen.

Infections and infestations

You may experience more frequent and severe infections without noticing the symptoms as well as opportunistic infections (caused by a usually harmless microorganism in case of

an impaired immune system) or the recurrence of dormant tuberculosis.

Abnormal growth of tissue

You may develop sterile abscesses (enclosed collections of pus, likely to turn into hard solid lumps as they scar).

Blood systems

There may be an abnormal increase in the number of white blood cells.

Hormonal (endocrine disorders)

Menstrual irregularities, lack of menstruation, abnormal hair growth, development of Cushingoid state (symptoms of which include central obesity with thin arms, thinning of the skin with easy bruising, muscle wasting and weakness, high blood pressure, uncontrolled blood sugar, osteoporosis).

Children and adolescents may have suppressed growth. Your response to stress caused by trauma, surgery or illness may be reduced. You may also experience decreased carbohydrate tolerance, onset of latent diabetes mellitus, increased need for insulin or other medicines if you are diabetic.

Metabolism and nutrition disorders

You may notice that you gain weight or have an increased appetite. Your body may also have difficulty in handling nitrogen, calcium, sodium or potassium appropriately.

Nervous system disorders

You may feel increased pressure in your head with impaired vision, vertigo, headache or in preterm infants cerebral palsy (malformation of the brain) may occur.

Eye disorders

You may develop cataracts or feel increased pressure in the eye or notice abnormal bulging out of the eyeballs or thinning of the cornea or the white, outer coat of the eyeball. Your vision may become blurred due to congestion of the optic disc or glaucoma with possible damage to the optic nerves. Secondary eye infections due to fungi or viruses can occur as can rare instances of blindness associated with local therapy around the face and head. Premature babies may suffer retinopathy. You may also develop visual disturbances or loss of vision (chorioretinopathy).

Disorders of the blood vessels or heart

High blood pressure, blood clots in the veins. Susceptible patients may develop heart failure, or the heart tissue may rupture following a recent heart attack. In infants with a low birth weight a heart muscle disease (hypertrophic cardiomyopathy) may occur.

If you are treated for multiple myeloma with dexamethasone in combination with lenalidomide or thalidomide you will have an increased risk of thromboembolic events including: Deep vein thrombosis (a blood clot in the veins of your leg) – a symptom of this is leg pain; Pulmonary embolism (a blood clot in the arteries leading to your lungs) – a symptom of this is chest pain or shortness of breath.

Disorders of the stomach or the digestive system

You may suffer nausea, hiccups, heartburn or reflux or infection or inflammation of the tube that leads to your stomach. Peptic ulcer may occur with possible bleeding or perforation of the small and large bowel (particularly if you have inflammatory bowel disease). Your pancreas may become inflamed (pancreatitis) or your stomach may swell.

Skin disorders

Your skin may become thin or fragile with red or blood spots or bruising or it may become lighter or darker (hypo- or hyperpigmentation). Your face may become unusually red or

you may have acne, swelling around the eyes, mouth and hands, hives, allergic dermatitis or stretch marks. Wounds may take longer to heal, skin tests may be affected and you may sweat more. After injection into a vein you may feel a burning or tingling sensation especially in the perineal area (skin between anus and genital organs).

Muscle and bone disorders

You may suffer muscle weakness, loss of muscle mass, osteoporosis (loss of bone density) especially if you are postmenopausal, vertebral compression fractures (collapsing of a bone in the spine), aseptic necrosis of femoral and humeral heads (severe knee and hip joint problem, possibly requiring replacement joints), fracture of long bones, tendon rupture, post-injection flare (following local injection e.g. into a joint).

Reproductive system

The number and activity of spermatozoa may be affected in men.

General disorders

You may have a general ill feeling.

Many of these side effects are serious therefore please tell your doctor about your symptoms as soon as possible.

Please note that it is very important that you do not suddenly stop taking this medicine (even if you are suffering from a side effect) unless your doctor tells you to.

If you think this injection is causing you any problems, or you are at all worried, talk to your doctor, nurse or pharmacist.

Because of these potential side effects, you doctor will want to monitor you at intervals during your treatment.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse.

5.  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 ampoule and carton as “EXP”. The expiry date refers to the last day of that month.

Store below 25°C in the outer pack to protect from light.

Chemical and physical in-use stability has been demonstrated for 48 hours at 25°C protected from light when diluted with the infusion fluids listed in 6.6. From a microbiological point of view, the product should be used immediately. If not used

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

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

6.  Contents of the pack and other information

What Dexamethasone contains

The active substance is Dexamethasone (as sodium phosphate). Each 1 ml contains 3.3 mg dexamethasone (as sodium phosphate) which is equivalent to 4 mg dexamethasone phosphate or 4.37 mg dexamethasone sodium phosphate.

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

The other ingredients are: creatinine, sodium citrate, citric acid hydrate, sodium hydroxide, water for injection.

What Dexamethasone looks like and contents of the pack

Solution for injection in 1 ml or 2 ml colourless glass ampoules. Boxes of 5 or 10 ampoules of 1 ml and 2 ml.

Not all pack sizes may be marketed.

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