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1. Dexamethasone Alapis 0.4 Mg/ Ml Oral Solution
2. Dexamethasone Alapis 0.4 Mg/ Ml Oral Solution

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Dexamethasone Alapis 0.4mg/ml Oral Solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution contains 0.4 mg of dexamethasone (as dexamethasone sodium phosphate).

Excipients:

Propylene glycol (E1520): 90 mg/ml

Liquid maltitol (E965): 275 mg/ml

Liquid sorbitol (non-crystallising) (E420): 140 mg/ml

Ethanol: 0.24 mg/ml

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Oral Solution

A colourless to faint yellow solution with mint odour.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Dexamethasone is a corticosteroid. It is designed for use in certain endocrine and non-endocrine disorders, in certain cases of cerebral oedema and for diagnostic testing of adrenocortical hyperfunction.

Endocrine disorders:

Endocrine exophthalmos.

Non-endocrine disorders:

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

Allergy and anaphylaxis: Anaphylaxis.

Arteritis collagenosis: Polymyalgia rheumatica, polyarteritis nodosa.

Haematological disorders: Haemolytic anaemia (also auto immune), leukaemia, myeloma, idiopathic thrombocytopenic purpura in adults,reticulolymphoproliferative disorders (see also under oncological disorders).

Gastroenterological disorders: For treatment during the critical stage in: ulcerative colitis (rectal only); regional enteritis (Crohn's disease), certain forms of hepatitis.

Muscular disorders: Polymyositis.

Neurological disorders: Raised intra-cranial pressure secondary to cerebral tumours, acute exacerbations of multiple sclerosis.

Ocular disorders: Anterior and posterior uveitis, optic neuritis, chorioretinitis, iridocyclitis, temporal arteritis, orbital pseudotumour.

Renal disorders: Nephrotic syndrome

Pulmonary disorders: Chronic bronchial asthma, aspiration pneumonitis, chronic obstructive pulmonary disease (COPD), sarcoidosis, allergic pulmonary disease such as farmer's and pigeon breeder's lung, Loffler's syndrome, cryptogenic fibrosing alveolitis.

Rheumatic disorders: some cases or specific forms (Felty's syndrome, Sjorgen's syndrome) of rheumatoid arthritis, including juvenile rheumatoid arthritis, acute rheumatism, lupus erythematosus disseminatus, temporal arteritis (polymyalgia rheumatica).

Skin disorders: Pemphigus vulgaris, bullous pemphigoid, erythrodermas, serious forms of erythema multiforme (Stevens-Johnson syndrome), mycosis fungoides, bullous dermatitis herpetiformis.

Oncological Disorders: lymphatic leukaemia, especially acute forms, malignant lymphoma (Hodgkin's disease, non-Hodgkin's lymphoma), metastasized breast cancer, hypercalcaemia as a result of bone metastasis or Kahler's disease, Kahler's disease.

Various: intense allergic reactions; as immunosuppressant in organ transplantation; as an adjuvant in the prevention of nausea and vomiting and in the treatment of cancer with oncolytics that have a serious emetic effect.

4.2 Posology and method of administration

Adults

General considerations:

The dosage should be titrated to the individual response and the nature of the disease. In order to minimise side effects, the lowest effective possible dosage should be used (see 'Side effects').

The initial dosage varies from 0.5 - 9mg a day depending on the disease being treated. In more severe diseases, doses higher than 9mg may be required. The initial dosage should be maintained or adjusted until the patient's response is satisfactory. Both the dose in the evening, which is useful in alleviating morning stiffness, and the divided dosage regimen are associated with greater suppression of the hypothalamo-pituitary-adrenal axis. If satisfactory clinical response does not occur after a reasonable period of time, discontinue treatment with dexamethasone and transfer the patient to another therapy.

If the initial response is favourable, the maintenance dosage should be determined by lowering the dose gradually to the lowest dose required to maintain an adequate clinical response. Chronic dosage should preferably not exceed 1.5mg dexamethasone daily.

Patients should be monitored for signs that may require dosage adjustment. These may be changes in clinical status resulting from remissions or exacerbations of the disease, individual drug responsiveness and the effect of stress (e.g. surgery, infection, trauma). During stress it may be necessary to increase dosage temporarily.

If the drug is to be stopped after more than a few days of treatment, it should be withdrawn gradually.

The following equivalents facilitate changing to dexamethasone from other glucocorticoids:

Milligram for milligram, dexamethasone is approximately equivalent to betamethasone, 4 to 6 times more potent than methylprednisolone and triamcinolone, 6 to 8 times more potent than prednisone and prednisolone, 25 to 30 times more potent than hydrocortisone, and about 35 times more potent than cortisone.

Acute, self-limiting allergic disorders or acute exacerbations of chronic allergic disorders.

The following dosage schedule combining parenteral and oral therapy is suggested:

First day:    Dexamethasone sodium phosphate injection 4mg or 8mg (1ml or

2ml) intramuscularly.

Second day:    1mg (2.5ml) Dexamethasone Alapis twice a day.

Third day:    1mg (2.5ml) Dexamethasone Alapis twice a day.

Fourth day:    500micrograms (1.25ml) Dexamethasone Alapis twice a day.

500micrograms (1.25ml) Dexamethasone Alapis twice a day. 500micrograms (1.25ml) Dexamethasone Alapis. 500micrograms (1.25ml) Dexamethasone Alapis. Re-assessment.

This schedule is designed to ensure adequate therapy during acute episodes whilst minimizing the risk of over dosage in chronic cases.

Raised intracranial pressure: Initial therapy is usually by injection. When maintenance therapy is required, this should be changed to dexamethasone oral solution as soon as possible. For the palliative management of patients with recurrent or inoperable brain tumours, maintenance dosage should be calculated individually. A dosage of 2mg two or three times a day may be effective. The smallest dosage necessary to control symptoms should always be used.

Dexamethasone suppression tests:

1.    Tests for Cushing's syndrome:

2mg (5ml) Dexamethasone Alapis should be administered at 11pm. Blood samples are then taken at 8am the next morning for plasma cortisol determination.

If greater accuracy is required, 500 micrograms (1.25ml) Dexamethasone Alapis should be administered every 6 hours for 48 hours. Blood should be drawn at 8am for plasma cortisol determination on the third morning.

24-hour urine collection should be employed for 17-hydroxycorticosteroid excretion determination.

2.    Test to distinguish Cushing's syndrome caused by pituitary ACTH excess from the syndrome induced by other causes:

2mg (5 ml) Dexamethasone Alapis should be administered every 6 hours for 48 hours. Blood should be drawn at 8am for plasma cortisol determination on the third morning.

24-hour urine collection should be employed for 17-hydroxycorticosteroid excretion determination.

Paediatric population:

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

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.

4.3 Contraindications

-    Hypersensitivity to dexamethasone or any of the excipients listed.

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

-    Systemic fungal infections.

-    Stomach ulcer or duodenal ulcer

-    Infection with tropical worms

4.4 Special warnings and precautions for use

An andrinocortical insufficiency, which is caused by glucocorticoid treatment, can, depending on the dose and length of treatment, remain for many months, and in some cases more than a year, after discontinuation of treatment. During treatment with Dexamethasone Alapis for specific physical stress conditions (trauma, surgery, childbirth, etc.), a temporary increase in dose may be required. Because of the possible risk in stressful conditions, a corticosteroid ID should be made for patients undergoing long-term treatment. Even in cases of prolonged andrinocortical insufficiency after discontinuation of treatment, the administration of glucocorticoids can be necessary in physically stressful situations. An acute therapy-induced andrinocortical insufficiency can be minimized by slow dose reduction until a planned discontinuation time. Treatment with Dexamethasone Alapis should only be implemented in the event of the strongest indications and, if necessary, additional targeted anti-infective treatment administered for the following illnesses:

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

-    HBsAG-positive chronic active Hepatitis

-    Approx. 8 weeks prior through 2 weeks after vaccinations with live vaccines

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

-    Poliomyelitis

-    Lymphadenitis after BCG vaccination

-    Acute and chronic bacterial infections

-    With a history of tuberculosis (reactivation cave!) Use only under tuberculostatic protection

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

-    Gastrointestinal ulcers

-    Severe osteoporosis

-    Difficult to regulate high blood pressure

-    Difficult to regulate Diabetes mellitus

-    Psychiatric disorders (including history)

-    Angle closure glaucoma and wide-angle glaucoma

-    Corneal ulcerations and corneal injuries

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

-    Severe ulcerative colitis with threatened perforation

-    Diverticulitis

-    Entero-anastomosis (immediately postoperative)

Signs of peritoneal irritation after gastrointestinal perforation may be absent in patients receiving high doses of glucocorticoids. A higher need for insulin, or oral antidiabetics, must be taken into consideration when administering Dexamethasone Alapis to diabetics. Regular blood pressure monitoring is necessary during treatment with Dexamethasone Alapis, particularly during administration of higher doses and with patients with difficult to regulate high blood pressure. Because of the risk of deterioration, patients with severe cardiac insufficiency should be carefully monitored. Treatment with Dexamethasone Alapis can conceal the symptoms of an existing, or developing infection thereby making a diagnosis more difficult.

The prolonged use of even small amounts of Dexamethasone leads to an increased risk of infection, even by microorganisms which otherwise rarely cause infections (so-called opportunistic infections). Vaccinations with inactivated vaccine are always possible. However, it should be noted that the immune reaction and thereby the success of inoculation, can be affected by higher doses of corticoids.

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

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

-    Exacerbation or recurrence of the underlying disease, acute adrenal insufficiency, corticosteroid withdrawal syndrome.

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

-    Children and immunocompromised persons without previous chickenpox or measles infection are particularly at risk. If these people have contact with people infected with measles or chickenpox while undergoing treatment with Dexamethasone Alapis, a preventative treatment should be introduced if necessary.

Paediatric population

Corticosteroids cause a dose-dependent inhibition of growth in infancy, childhood, and adolescence, which may be irreversible. Therefore, during long-term treatment with Dexamethasone Alapis, the indication should be very strongly presented in children and their growth rate should be checked regularly.

Use in the elderly

The adverse effects of systemic corticosteroids can have serious consequences especially in old age, mainly osteoporosis, hypertension, hypokalemia, diabetes, susceptibility to infection and skin atrophy. Close clinical monitoring is required to prevent life-threatening reactions.

Influence of diagnostic tests

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

Note on doping

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

Excipient Warnings

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Dexamethasone Alapis contains these kinds of sugar:

•    0.14 g sorbitol in each ml. When taken according to the dosage recommendations each dose supplies up to 3.15 g of sorbitol.

•    0.275 g maltitol in each ml. When taken according to the dosage recommendations each dose supplies up to 6.2 g of maltitol.

Dexamethasone Alapis contains 0.09 g propylene glycol in each ml. When taken according to the dosage recommendations each dose supplies up to 2 g of propylene glycol

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

(5.51 mg ethanol / 9 mg dexamethasone).

4.5 Interaction with other medicinal products and other forms of interaction

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

The administration of Dexamethasone with inducers of CYP3A4, such as ephedrine, barbiturates, Rifabutin, Rifampicin, phenytoin, and Carbamazepine can lead to reduced plasma concentrations of Dexamethasone, so the dose must be increased.

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

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

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

The administration of Dexamethasone with inhibitors of CYP3A4, such as Azole antifungals (e.g. Ketoconazole, Itraconazole), HIV protease inhibitors (e.g. Ritonavir) and macrolide antibiotics (e.g. erythromycin) may lead to increased plasma concentrations and reduced clearance of Dexamethasone. If required, the Dexamethasone dose should be reduced.

Ketoconazole may not only increase the plasma concentration of Dexamethasone by inhibition of CYP3A4, but also suppress adrenal corticosteroid synthesis and cause adrenal insufficiency upon discontinuation of corticosteroid treatment. Estrogens, including oral contraceptives, may inhibit the metabolism of certain corticosteroids and thus enhance their effect.

Effects of Dexamethasone on other drugs

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

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

The renal clearance of salicylates is increased by corticosteroids. Therefore, the dosage of salicylates may be reduced once the steroids are discontinued.

Corticosteroids reduce the effect of antidiabetic agents such as insulin, sulfonylurea, and metformin. Hyperglycaemia and diabetic ketoacidosis may occur occasionally. Therefore, at the beginning of treatment, diabetics should have more frequent blood and urine tests.

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

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

The blood pressure-lowering effects of antihypertensive drugs may be affected by corticosteroids.

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

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

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

The effect of vaccinations may be reduced during treatment with Dexamethasone. Live attenuated vaccines are not recommended for patients receiving immunosuppressive doses because of the risk of life-threatening generalized inoculation.

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

Chloroquine, Hydroxychloroquine and Mefloquine: Increased risk of myopathies and cardiomyopathies.

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

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

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

Non-depolarizing muscle relaxants: the muscle relaxing effect may last longer. Somatotropin: the effect of the growth hormone can be reduced.

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

4.6 Fertility, pregnancy and lactation

Pregnancy Dexamethasone crosses the placenta. In animal experiments, corticosteroids can cause abnormalities in foetal development, including cleft palate, intrauterine growth retardation and impairment of brain growth and development (see Section 5.3). Epidemiological studies suggest a positive association between systemic corticosteroid use and cleft palate in humans. Long-term or repeated corticosteroid therapy in pregnancy increases the risk of intrauterine growth retardation. In newborns exposed to corticosteroids in the prenatal period, there is an increased risk of adrenal insufficiency, which under normal circumstances undergoes spontaneous postnatal regression, and is rarely of clinical significance. Dexamethasone should be prescribed during pregnancy and particularly in the first trimester only if the benefit outweighs the risks for the mother and child.

Lactation

Glucocorticoids are excreted in breast milk. There are no known risks to infants. Nevertheless, extra caution should be exercised regarding its indication during pregnancy. Should the relevant condition require higher doses, treatment should be discontinued.

4.7 Effects on ability to drive and use machines

Dexamethasone Alapis has no or negligible influence on the ability to drive and use machines.

So far, there is no evidence that Dexamethasone Alapis affects the ability to drive or operate machinery.

4.8 Undesirable effects

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

Infections and infestations	Increased susceptibility to or exacerbation of (latent) infections with masking of clinical symptoms, opportunistic infections, reactivation of latent tuberculosis, exacerbation of eye infections, candidiasis
Blood and lymphatic system disorders	Leukocytosis, lymphopenia, eosinopenia, polycythemia
Immune system disorders	Hypersensitivity reactions including anaphylaxis, immunosuppression (see also under “Infections and parasitic diseases”)
Endocrine disorders	Suppression of the hypothalamic-pituitary-adrenal axis and induction of Cushing's syndrome (typical symptoms: full-moon face, plethora, truncal obesity), secondary adrenal and pituitary insufficiency (especially in stress such as trauma or surgery)
Metabolism and nutrition disorders	Weight gain, negative protein and calcium balance, increased appetite, sodium and water retention, potassium loss (caution: rhythm disorders), hypokalemic alkalosis, manifestation of latent diabetes mellitus, impaired carbohydrate tolerance with increased dose requirements of antidiabetic therapy, hypercholesterolemia, hypertriglyceridaemia
Psychiatric disorders	Psychological dependence, depression, insomnia, aggravated schizophrenia, mental illness, from euphoria to manifest psychosis
Nervous system disorders	Increased intracranial pressure with papilloedema in children (pseudotumor cerebri) usually following discontinuation of treatment; manifestation of latent epilepsy, increased seizures in overt epilepsy
Eye disorders	Elevated intraocular pressure, glaucoma, papilloedema, cataract, mainly with posterior subcapsular opacity, corneal and scleral atrophy, increased ophthalmic viral, fungal and bacterial infections, worsening of symptoms associated with corneal ulcers
Cardiac disorders	Cardiac muscle rupture after recent history of myocardial infarction, congestive heart failure in predisposed patients
Vascular disorders	Hypertension, vasculitis, increased atherosclerosis and risk of thrombosis/thromboembolism

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 him unusually susceptible to ill effects from corticosteroids. In this case, the stomach should be emptied and symptomatic treatment should be instituted as necessary. Anaphylactic and hypersensitivity reactions may be treated with epinephrine (adrenaline), positive-pressure artificial respiration and aminophylline. The patient should be kept warm and quiet. The biological half life of dexamethasone in plasma is about 190 minutes.

5 PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

ATC Code: H02A B02

Pharmacotherapeutic Group: Glucocorticoids

Dexamethasone is a highly potent and long-acting glucocorticoid with negligible sodium retaining properties and is therefore, particularly suitable for the use in patients with cardiac failure and hypertension. It's anti-inflammatory potency is 7 times greater than prednisolone and like other glucocorticoids, dexamethasone also has anti-allergic, antipyretic and immunosuppressive properties.

Dexamethasone has a biological half life of 36 - 54 hours and therefore is suitable in conditions where continuous glucocorticoid action is required.

5.2 Pharmacokinetic properties

Dexamethasone is well absorbed when given by mouth; peak plasma levels are reached between 1 and 2 hours after ingestion and show wide interindividual variations. The mean plasma half life is 3.6 ± 0.9h. Dexamethasone is bound (to about 77%) to plasma proteins, mainly albumins. Percentage protein binding of dexamethasone, unlike that of cortisol, remains practically unchanged with increasing steroid concentrations. Corticosteroids are rapidly distributed to all body tissues. Dexamethasone is metabolised mainly in the liver but also in the kidney. Dexamethasone and its metabolites are excreted in the urine.

5.3 Preclinical safety data

Studies in animals have shown that glucocorticoids increase the incidence of cleft palate, spontaneous abortions and intrauterine growth retardation. In non-human primates, minor cranial skeletal abnormalities were observed. These effects were observed after use of high doses of dexamethasone.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Benzoic acid (E210)

Propylene glycol (E1520)

Citric acid monohydrate Liquid maltitol

Liquid sorbitol (non-crystallising)

Sodium citrate (E331)

Garden mint flavour Purified water.

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years

After first opening: 3 months

6.4 Special precautions for storage

Do not store above 25°C.

Do not refrigerate

The storage at temperatures higher than 25°C could lead to precipitation inside the solution. Do not use the product if solid particles are observed inside the solution.

6.5 Nature and contents of container

Amber (Type III) glass bottle, with child-resistant closure, along with an oral syringe.

Capacity: 150 ml

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

ALAPIS S.A.

2, Aftokrators Nikolaou str.

176 71 Athens Greece

8    MARKETING AUTHORISATION NUMBER(S)

PL 35574/0013

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

06/11/2012

10    DATE OF REVISION OF THE TEXT

06/11/2012