This information is intended for use by health professionals

1. Name of the medicinal product

Betnesol 4mg/ml Solution for Injection

Betamethasone 4mg/ml Solution for Injection

2. Qualitative and quantitative composition

Each ampoule contains 5.3mg of betamethasone sodium phosphate equivalent to 4mg betamethasone in 1ml of sterile aqueous solution.

Excipients with known effect

Sodium Metabisulphite contains 0.100 %w/v

Also contains approximately 0.678mg sodium per ml.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for Injection

1ml ampoules containing a clear colourless or pale yellow solution.

4. Clinical particulars
4.1 Therapeutic indications

Betamethasone is a glucocorticosteroid which is about eight to ten times as active as prednisolone on a weight-for-weight basis. It may be indicated in the following conditions:

Status asthmaticus and acute allergic reactions, including anaphylactic reactions to drugs. Betnesol Injection/Betamethasone Injection supplements the action of adrenaline.

Severe shock arising from surgical or accidental trauma or overwhelming infection.

Acute adrenal crisis caused by abnormal stress in Addison's disease, Simmonds' disease, hypopituitarism following adrenalectomy, and when adrenocortical function has been suppressed by prolonged corticosteroid therapy.

Soft tissue lesions such as tennis elbow, tenosynovitis and bursitis.

NB. Betnesol Injection/Betamethasone Injection does not replace other forms of therapy for the treatment of shock and status asthmaticus.

4.2 Posology and method of administration

Posology:

Systemic therapy in adults

4 to 20mg betamethasone (1 to 5ml) administered by slow intravenous injection over half to one minute. This dose can be repeated three or four times in 24 hours, or as required, depending upon the condition being treated and the patient's response.

Alternatively, Betnesol Injection/Betamethasone Injection may be given by intravenous infusion. The same dose can be given by deep intramuscular injection but the response is likely to be less rapid, especially in shock. This dose can be repeated three or four times in 24 hours depending upon the condition being treated and the patient's response.

Systemic therapy in paediatric population

Infants up to 1 year may be given 1mg betamethasone intravenously; children aged 1 to 5 years, 2mg; 6 to 12 years, 4mg (1ml). This dose can be repeated three or four times in 24 hours, depending upon the condition being treated and the patient's response.

Method of administration:

Betnesol Injection/Betamethasone Injection may be administered by slow intravenous injection, deep intramuscular injection or subconjunctival injection. Alternatively, Betnesol Injection/Betamethasone Injection may be given by intravenous infusion. Local injections of Betnesol Injection/Betamethasone Injection may be used when treating soft tissue lesions (see below).

The incidence of predictable undesirable effects, including hypothalamic-pituitary-adrenal (HPA) axis suppression correlates with the relative potency of the drug, dosage, timing of administration and the duration of treatment (see section 4.4).

Other routes

Local injections of 4 to 8mg Betnesol Injection/Betamethasone Injection may be used when treating soft tissue lesions in adults; children may require smaller doses. This dose can be repeated on two or three occasions depending upon the patient's response.

Betnesol Injection/Betamethasone Injection has also been administered sub-conjunctivally as a single injection of 0.5 to 1ml.

Intrathecal use is not recommended.

4.3 Contraindications

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

Systemic infections, unless specific anti-infective therapy is employed.

Betnesol Injection/Betamethasone Injection contains sodium metabisulphite (0.1% w/v) as a preservative and therefore should not be used to treat patients with known hypersensitivity to bisulphite, metabisulphite.

Betnesol Injection/Betamethasone Injection should not be injected directly into tendons.

4.4 Special warnings and precautions for use

A patient information leaflet should be supplied with this product.

Undesirable effects may be minimised by using the lowest effective dose for the minimum period and by administering the daily requirement as a single morning dose or whenever possible as a single morning dose on alternate days. Frequent patient review is required to appropriately titrate the dose against disease activity (see section 4.2).

Caution is advised with the use of corticosteroids in patients who have suffered a recent myocardial infarction because of the risk of myocardial rupture.

Caution is advised on the use of corticosteroids in patients with hypothyroidism or myasthenia gravis.

Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity. The clinical presentation may often be atypical and serious infections such as septicaemia and tuberculosis may be masked and may reach an advanced stage before being recognised.

Chickenpox is of particular concern since this normally minor illness may be fatal in immunosuppressed patients. Patients (or parents of children) without a definite history of chickenpox should be advised to avoid close personal contact with chickenpox or herpes zoster and if exposed they should seek urgent medical attention. Passive immunisation with varicella zoster immunoglobulin (VZIG) is needed by exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.

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

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

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

In the treatment of cerebral oedema due to tumour, gastrointestinal bleeding may occur and stool examination may be helpful in diagnosis.

Adrenal suppression:

Adrenal cortical atrophy develops during prolonged therapy and may persist for years after stopping treatment.

In patients who have received more than physiological doses of systemic corticosteroids (approximately 1mg betamethasone or equivalent) for greater than 3 weeks, withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as a dose of systemic corticosteroids is reduced. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids but there is uncertainty about HPA suppression, the dose of systemic corticosteroid may be reduced rapidly to physiological doses. Once a daily dose equivalent to 1mg betamethasone is reached, dose reduction should be slower to allow the HPA-axis to recover.

Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks is appropriate if it is considered that the disease is unlikely to relapse. Abrupt withdrawal of doses of up to 6mg daily of betamethasone, or equivalent for 3 weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting 3 weeks or less:

• Patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than 3 weeks,

• When a short course has been prescribed within one year of cessation of long-term therapy (months or years),

• Patients who have reasons for adrenocortical insufficiency other than exogenous corticosteroids therapy,

• Patients receiving doses of systemic corticosteroid greater than 6mg daily of betamethasone (or equivalent),

• Patients repeatedly taking doses in the evening.

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

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.

A. Osteoporosis (post-menopausal females are particularly at risk).

B. Hypertension or congestive heart failure.

C. Existing or previous history of severe affective disorders (especially previous steroid psychosis).

D. Diabetes mellitus (or a family history of diabetes).

E. History of, or active, tuberculosis.

F. Glaucoma (or a family history of glaucoma).

G. Previous corticosteroid-induced myopathy.

H. Liver failure - blood levels of corticosteroid may be increased, as with other drugs which are metabolised in the liver.

I. Renal insufficiency.

J. Epilepsy.

K. History of, or active, peptic ulceration.

L. Herpes simplex keratitis.

M. Diverticulitis.

N. Thromboembolic tendencies.

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.

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 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.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Paediatric population

Caution is advised in children as they are more susceptible to systemic toxicity from betamethasone.

Corticosteroids cause dose-related 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 HPA axis and growth retardation, consideration should be given to administration of a single dose on alternate days.

Elderly

The common adverse effects of systemic corticosteroids may be associated with more serious consequences in old age, especially osteoporosis, hypertension, hypokalaemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.

4.5 Interaction with other medicinal products and other forms of interaction

Steroids may reduce the effects of anticholinesterases in myasthenia gravis, cholecystographic X-ray media and non-steroidal anti-inflammatory agents.

Rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone, aminoglutethimide and ephedrine enhance the metabolism of corticosteroids; thus the corticosteroid therapeutic effect may be reduced.

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

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

The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication.

The risk of hypokalaemia is increased with theophylline, ulcer healing drugs such as carbenoxolone and antifungals such as amphotericin B.

Increased toxicity may result if hypokalaemia occurs in patients on cardiac glycosides.

Ritonavir and oral contraceptives may result in increased plasma concentrations or corticosteroids.

The effect of corticosteroids may be reduced for 3-4 days after mifepristone.

The growth promoting effect of somatropin may be inhibited by corticosteroids.

An increase in the incidence of gastrointestinal bleeding may occur if NSAIDS are taken concomitantly with corticosteroids.

Corticosteroids may antagonise the effects of neuromuscular blocking drugs such as vecuronium.

Concurrent use of corticosteroids and fluoroquinolones may result in increased risk of tendon rupture.

Concomitant use of betamethasone with quetiapine may result in the increased metabolism of quetiapine and, depending on the clinical response, a higher dose of quetiapine may need to be considered.

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.

Corticosteroids may enhance the metabolism of tretinoin resulting in decreased levels of tretinoin.

4.6 Fertility, pregnancy and lactation

Pregnancy

The ability of corticosteroids to cross the placenta varies between individual drugs, however, betamethasone readily crosses the placenta. Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and effects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate/lip in man. However, when administered for prolonged periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. Hypoadrenalism may, in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important. Myocardial hypertrophy and gastroesophageal reflux have been reported in association with in-utero exposure to betamethasone.

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. Patients with pre-eclampsia or fluid retention require close monitoring.

Betamethasone, systemically administered to a woman during pregnancy may result in a transient suppression of the foetal heart rate parameters and biophysical activities that are widely used for the assessment of foetal well – being. These characteristics can include a reduction in foetal breathing movements, body movements and heart rate.

Breast-feeding

Corticosteroids may pass into breast milk, although no data are available for betamethasone. Infants of mothers taking high doses of systemic corticosteroids for prolonged periods may have a degree of adrenal suppression

4.7 Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

The incidence of predictable undesirable effects, including hypothalamic-pituitary-adrenal (HPA) axis suppression, correlates with the relative potency of the drug, dosage, timing of administration and the duration of treatment (see section 4.4)

Not known: frequency cannot be estimated from the available data

System organ class

Frequency

Undesirable effects

Infections and infestations

Not known

Increased susceptibility to and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis (see section 4.4)

Endocrine disorders

Not known

Suppression of the HPA axis, growth suppression in infancy, childhood and adolescence, menstrual irregularity and amenorrhoea.

Metabolism and nutrition disorders

Not known

Cushingoid facies, hirsutism, weight gain, impaired carbohydrate tolerance with increased requirement for antidiabetic therapy*

Psychiatric disorders

Common

A wide range of psychiatric reactions**

Eye disorders

Not known

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

Vision, blurred (see also section 4.4)

Cardiac disorders

Not known

Myocardial rupture following recent myocardial infarction

Gastrointestinal disorders

Not known

Abdominal distension, oesophageal ulceration, nausea, dyspepsia, peptic ulceration with perforation and haemorrhage, acute pancreatitis, candidiasis

Skin and subcutaneous tissue disorders

Not known

Impaired healing, skin atrophy, bruising, telangiectasia, striae, acne, Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders

Not known

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

General disorders and administration site conditions

Not known

Hypersensitivity including anaphylaxis has been reported. Leucocytosis, Thrombo-embolism, Malaise, Hiccups

* Negative protein, nitrogen and calcium balance. Increased appetite. Hyperhidrosis. Increased high - density lipoprotein and low – density lipoprotein concentrations in the blood. Fluid and electrolyte disturbance (Sodium and water retention, hypertension, potassium loss, hypokalaemic alkalosis)

** Including affective disorder (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 the 5-6%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown. Psychological dependence. Increased intra-cranial pressure with papilloedema in children (pseudotumour cerebri), usually after treatment withdrawal. Aggravation of epilepsy.

Withdrawal symptoms and signs

Too rapid reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death (see “Special Warnings and Precautions for Use”).

A “withdrawal syndrome” may also occur including; fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.

Reporting of suspected adverse reactions

Reporting of 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

Management:

Should overdosage occur, the possibility of adrenal suppression should be minimised by a gradual reduction of dosage over a period of time. The patient may need support during any further trauma.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Betamethasone sodium phosphate is an active corticosteroid with topical anti-inflammatory activity.

ATC Code: HO2A B01

Betamethasone is a glucocorticoid which is about eight to ten times as active as prednisolone on a weight-for-weight basis

5.2 Pharmacokinetic properties

Corticosteroids are bound to plasma proteins in varying degrees.

Biotransformation:

Corticosteroids are metabolised primarily by the liver.

Elimination:

Corticosteroids are excreted by the kidneys.

5.3 Preclinical safety data

None stated

6. Pharmaceutical particulars
6.1 List of excipients

Disodium edetate

Sodium metabisulphite

Sodium chloride

Sodium hydroxide

Hydrochloric acid

Water for injection

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package in order to protect from light.

6.5 Nature and contents of container

1ml clear, one-point cut (OPC) colourless glass Type 1 Ph Eur ampoules packed in cartons of 5 ampoules

6.6 Special precautions for disposal and other handling

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

7. Marketing authorisation holder

RPH Pharmaceuticals AB

Lagervägen 7

136 50 Jordbro

Sweden

8. Marketing authorisation number(s)

PL 36301/0054

9. Date of first authorisation/renewal of the authorisation

22nd December 1992

10. Date of revision of the text

19/03/2018