Martapan 2mg/5ml Oral Solution
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Martapan 2mg/5ml Oral Solution
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 5ml contains 2mg dexamethasone (as dexamethasone sodium phosphate).
Each 5 ml contains 0.061 mmol of sodium, 0.6g of liquid sorbitol, 1.4g of liquid maltitol and 0.5g of Propylene glycol.
For full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Oral Solution
A colourless to faint yellow solution with odour of mint.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Indicated in a wide variety of disorders amenable to glucocorticoid therapy, as well as an adjunct in the control of cerebral oedema.
4.2 Posology and method of administration
The dosage of Dexamethasone Oral Solution depends on the severity of the condition and the response of the patient. Frequent patient review is required to appropriately titrate the dose against disease activity. If no favourable response is noted within a couple of days, continuation of glucocorticoid therapy should be discontinued.
Adults
The usual dose in adults is 0.5-10 mg per day. As soon as symptoms diminish, the dose should be reduced under continuous observation of the clinical picture to the lowest possible level, or tapered off completely by following the withdrawal schedule below.
During prolonged therapy any intercurrent illness, trauma or surgical procedure will require a temporary increase in dosage.
Children
0.01-0.1 mg/kg of body weight daily.
Dexamethasone should only be administered to children with caution, since glucocorticoids can induce growth retardation. The daily dose should be determined by the physician for each child individually.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Systemic infection unless specific anti-infective therapy is employed.
Avoid live vaccines in patients receiving immunosuppressive doses (serum antibody response diminished).
In general no contraindications apply in conditions where the use of glucocorticoids may be lifesaving.
4.4 Special warnings and precautions for use
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 (see “withdrawal of prolonged therapy”). 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.
Anti-inflammatory/Immunosuppressive effects: Glucocorticoid therapy is nonspecific, suppresses the symptoms and signs of disease and decreases the resistance to infections. 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. Strong antimicrobial therapy should accompany glucocorticoid therapy when necessary.
Vaccines should not be given to individuals with glucocorticoid therapy-induced immunosuppression. Vaccination with live vaccines, e.g. Chickenpox is of particular concern. Chickenpox is a normally minor illness but 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 immunization with varicella/zoster immunoglobin (VZIG) is needed by exposed nonimmune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and even 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 (IVIG) may be indicated. Exposed patients should be advised to seek medical advice without delay.
Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerve and may enhance the establishment of secondary ocular infections due to fungi or viruses.
Glucocorticoids can cause dose-related growth retardation in infancy, childhood and adolescence, which may be irreversible. Therefore, Dexamethasone should only be used in children with caution.
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.
The common adverse effects of systemic glucocorticoids 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.
Particular care is required when considering the use of systemic glucocorticoids in patients with the following conditions and frequent patient monitoring is necessary:
- Osteoporosis (post-menopausal women are particularly at risk);
- Hypertension or congestive heart failure;
- Diabetes mellitus (or a family history of diabetes);
- History of tuberculosis;
- Glaucoma (or a family history of glaucoma);
- Previous glucocorticoid-induced myopathy;
- Liver failure;
- Renal insufficiency;
- Epilepsy;
- Peptic ulceration.
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 interaction 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. Patient/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.
Withdrawal of prolonged therapy
In patients who have received dexamethasone for more than 3 weeks, withdrawal should not be abrupt. How dose reduction should be carried out (tapered off over weeks or months) depends largely on whether the disease is likely to relapse as the dose of systemic glucocorticoids is reduced. Clinical assessment of disease activity may therefore be needed during withdrawal. If the disease is unlikely to relapse on withdrawal but there is uncertainty about hypothalamus-pituitary-adrenal (HPA) suppression, the dose of systemic dexamethasone may be reduced rapidly to physiological doses. Once a daily dose of approx. 1 mg dexamethasone is reached, dose reduction should be slower to allow the HPA-axis to recover.
Abrupt withdrawal of systemic dexamethasone treatment, which has continued for up to 3 weeks, is appropriate if it is considered that the disease is unlikely to relapse.
Abrupt withdrawal of doses up to approx. 6 mg 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 dexamethasone therapy should be considered even after courses lasting 3 weeks or less:
• Patients who have had repeated courses of systemic dexamethasone (or other corticosteroids), particularly if taken for more than 3 weeks.
• When a short course has been prescribed within one year of cessation of longterm therapy (months or years).
• Patients who may have reasons for adrenocortical insufficiency other than exogenous dexamethasone (or other corticosteroid) therapy.
• Patients receiving doses of systemic dexamethasone higher than approx. 6 mg.
• Patients repeatedly taking doses in the evening.
Patients who during systemic treatment encounter stresses such as trauma, surgery or infection and who are at risk of adrenal insufficiency should receive additional systemic dexamethasone cover during these periods. This includes patients who have finished a course of systemic dexamethasone of less than three weeks duration in the week prior to the stress. Patients on systemic dexamethasone therapy who are at risk of adrenal suppression and are unable to take oral solution should receive parenteral dexamethasone cover during these periods.
Too rapid reduction of dexamethasone dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death. Characteristic symptoms of a “withdrawal syndrome” that may occur are fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight (see section 4.8).
Excipient Warnings
The medicine contains 0.6g sorbitol in each 5ml. When given according to the recommended dosage instructions, each dose may contain as much as 3 g of sorbitol. It also contains 1.4g liquid maltitol in each 5ml. When given according to the recommended dosage instruction, each dose may contain as much as 7g of maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. May have a mild laxative effect. Calorific value: 2.6kcal/g sorbitol and 2.3 kcal/g maltitol.
4.5 Interaction with other medicinal products and other forms of interaction
Rifampin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone, ephedrine and aminoglutethimide enhance the metabolism of glucocorticoids and the therapeutic effects may be reduced.
The desired effects of hypoglycaemic agents (including insulin), antihypertensives and diuretics are antagonised by glucocorticoids.
The effects of anticholinesterases are antagonised by glucocorticoids in myasthenia gravis.
Concurrent use of potassium-depleting diuretics (e.g. acetazolamide, loop diuretics, thiazide diuretics or carbenoxolone) and glucocorticoids may result in severe hypokalaemia.
The efficacy of coumarin anticoagulants may be enhanced by concurrent glucocorticoid therapy and close monitoring of the International Normalised Ratio or prothrombin time is required.
The renal clearance of salicylates is increased by glucocorticoids and steroid withdrawal may result in salicylate intoxication.
Combination of corticosteroids with ulcer-inducing agents (e.g. NSAIDs) enhances the risk of peptic ulceration.
Patients taking methotrexate and dexamethasone have an increased risk of haematological toxicity.
Antacids, especially those containing magnesium trisilicate have been reported to impair the gastrointestinal absorption of glucocorticoid steroids. Therefore, doses of one agent should be spaced as far as possible from the other.
Dexamethasone reduces the plasma concentration of the antiviral drugs indinavir and saquinavir.
Oral contraceptives (oestrogens and progestogens) increase plasma concentration of corticosteroids. The antiviral drug ritonavir also increases the plasma concentration of dexamethasone.
4.6 Fertility, Pregnancy and lactation
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 the 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. A risk to the suckling child cannot be excluded. Dexamethasone therapy is not recommended during breast feeding unless the potential benefit justifies the potential risk to the child.
Fertility
There are no data from the use of Dexamethasone on fertility.
4.7 Effects on ability to drive and use machines
Dexamethasone may cause side effects that may affect the ability to drive or using machines. Caution should be exercised in driving and operating machinery.
4.8 Undesirable effects
The incidence of predictable undesirable effects of glucocorticoids correlates with the dosage, timing of administration and duration of treatment.
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.
System organ class
Preferred Term(s) or Lower Level
|
Terms | |
|
Blood and lymphatic system disorders |
Leucocytosis |
|
Endocrine disorders |
Hypothalamo-pituitary disorder, Adrenal suppression, Cushingoid |
|
Eye disorders |
Papilloedema (in children with pseudotumour cerebri, usually after withdrawal), Glaucoma, subcapsular cataract, Corneal or scleral thinning |
|
Gastrointestinal disorders |
Gastric ulcer (haemorrhage), Duodenal ulcer (haemorrhage), dyspepsia, peptic ulcer perforation, Pancreatitis acute, nausea, Abdominal distension and vomiting, hiccups |
|
General disorders and administration site conditions |
Oedema, Impaired healing |
|
Immune system disorders |
Drug hypersensitivity, Anaphylactic reaction |
|
Infections and infestations |
Infection (aggravated), opportunistic infection, tuberculosis (reactivated), Varicella, exacerbation of opthalmic viral or fungal diseases, Candidiasis |
|
Injury, poisoning and procedural complications |
Vertebral and long bone fracture, Tendon rupture, Contusion |
|
Investigations |
Weight increased, Carbohydrate tolerance decreased, Intraocular pressure increased |
|
Metabolism and nutrition disorders |
Increased appetite, Diabetes mellitus inadequate control, Lipoprotein deficiency, Calcium deficiency, Sodium retention, Fluid retention, Hypokalaemia, Alkalosis hypokalaemic |
|
Myocardial disorders |
Myocardial rupture following recent myocardial infarction |
|
Musculoskeletal and connective tissue disorders |
Growth retardation (infancy, childhood and adolescence), Osteoporosis, Osteonecrosis, Myopathy |
|
Nervous system disorders |
Intracranial pressure increased (in children with pseudotumour cerebri, usually after withdrawal), Epilepsy aggravated |
|
Psychiatric disorders |
Nervousness, Euphoric mood, Drug dependence, Depression, Insomnia, Schizophrenia aggravated |
|
Reproductive system and |
Menstrual irregularity, Amenorrhoea |
|
breast disorders | |
|
Skin and subcutaneous tissue disorders |
Dermatitis allergic, Hirsutism, Skin atrophy, Telangiectasia, Skin striae, Acne |
|
Vascular disorders |
Hypertension, 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 section 4.4).
A 'withdrawal syndrome' may also occur including, fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.
4.9 Overdose
It is difficult to define an excessive dose of a corticosteroid as the therapeutic dose will vary according to indication and patient requirements. Exaggeration of corticosteroid related adverse effects may occur. Treatment should be asymptomatic and supportive as necessary.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC Code: H02A B02
Pharmacotherapeutic Group: Corticosteroid
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. Its 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
Corticosteroids, are, in general, readily absorbed from the gastro-intestinal tract.
They are also well absorbed from sites of local application. Water-soluble forms of corticosteroids are given by intravenous injection for a rapid response; more prolonged effects are achieved using lipid-soluble forms of corticosteroids by intramuscular injection.
Corticosteroids are rapidly distributed to all body tissues. They cross the placenta and may be excreted in small amounts in breast milk.
Most corticosteroids in the circulation are extensively bound to plasma proteins, mainly to globulin and less so to albumin. The corticosteroid-binding globulin has high affinity but low binding capacity, while the albumin has low affinity but large binding capacity. The synthetic corticosteroids are less extensively protein bound than hydrocortisone (cortisol). They also tend to have longer half-lives.
Corticosteroids are metabolised mainly in the liver but also in the kidney, and are excreted in the urine. The slower metabolism of the synthetic corticosteroids with their lower protein-binding affinity may account for their increased potency compared with the natural corticosteroids.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
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
Benzoic acid (E210)
Propylene glycol (E1520)
Citric acid monohydrate Liquid maltitol
Garden mint flavour (contains propylene glycol E1520) Liquid sorbitol (non-crystallising)
Sodium citrate Purified water
Citric acid 10% solution (pH adjustment)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
Shelf Life: 12 months
Shelf life after first opening the container: 28 days
6.4 Special precautions for storage
Do not store above 25°C.
Keep in the original container in order to protect from light.
6.5 Nature and contents of container
Bottles: 150ml in Amber Type III glass.
Closure: HDPE tamper evident, child resistant closure.
6.6 Special precautions for disposal
No special requirements
7 MARKETING AUTHORISATION HOLDER
Martindale Pharmaceuticals Ltd (T/S Martindale Pharma)
Bampton Road Harold Hill Romford Essex, RM3 8UG UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 00156/0125
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
14/11/2011
10 DATE OF REVISION OF THE TEXT
19/03/2013