Betamethasone Sodium Phosphate

Registered South African indications:

• Substitution therapy, for the treatment of adrenal insufficiency states in patients with a known or suspected adrenal insufficiency prior to surgery or if shock, severe trauma or other stressful conditions occur
• Symptomatic treatment of inflammatory conditions responsive to corticosteroid therapy

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Patients with systemic fungal infections
• In certain conditions ordinarily considered contraindicated to corticosteroid therapy (the anticipated clinical improvement must be weighed against the possibility of undesirable corticosteroid effects):
  • Osteoporosis
  • Marked emotional instability
  • Peptic ulcer
  • Tuberculosis
  • Acute viral infections, including acute ocular herpes simplex
  • Thromboembolic tendencies
  • Diverticulitis
  • Recent intestinal anastomosis
  • Acute and chronic infections
• Pregnancy
• Breastfeeding

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Known hypersensitivity to bisulphite, metabisulphite
• Systemic infections, unless specific anti-infective therapy is employed
• Should not be injected directly into tendons

South African recommendations

Caution in the following patient groups

• Renal impairment
• Hepatic impairment
• Elderly
• Paediatrics

• Gastrointestinal and renal risks:

  • Non-specific ulcerative colitis (especially if perforation, abscess, or pyogenic infection is suspected)
  • Diverticulitis or recent intestinal anastomoses
  • Active or latent peptic ulcer
  • Renal insufficiency
• Hypertension
• Osteoporosis
• Myasthenia gravis
• Recent myocardial infarction due to the risk of myocardial rupture
• Hypothyroidism
• Cirrhosis

Restricted administration

• Should not be administered intrathecally or subconjunctivally

Serious neurologic events with epidural injection

• Reports include spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke, some resulting in death. These have occurred with and without fluoroscopy. Epidural administration is not approved or established as safe or effective

Not for head injury or stroke management

• Corticosteroids should not be used for head injury or stroke, as they may be ineffective or harmful

Cerebral oedema and gastrointestinal bleeding

• In cerebral oedema due to a tumour, gastrointestinal bleeding may occur; stool examination may assist in diagnosis

Toxic effects from use or withdrawal

• Adverse effects can result from both prolonged use and abrupt withdrawal of high doses

Risk of anaphylactic reactions

• Less frequent but serious anaphylactoid/anaphylactic reactions, including shock, have been reported. Precautions are necessary for patients with a history of corticosteroid allergies

Use in Idiopathic Thrombocytopenic Purpura (ITP)

• Should be administered intramuscularly with caution in patients with idiopathic thrombocytopenic purpura

Intramuscular injection precautions

• Must be injected deeply into large muscle masses to avoid local tissue atrophy

Systemic effects from local injections

• Soft tissue, intralesional, and intra-articular administration may produce both local and systemic effects

Joint fluid examination before injection

• Any present joint fluid should be examined to exclude a septic process. Injection into previously infected joints should be avoided

Signs of septic arthritis

• Marked pain increase, local swelling, restricted joint motion, fever, and malaise may indicate septic arthritis. If confirmed, appropriate antimicrobial therapy should be initiated

Avoid injection into certain areas

• Corticosteroids should not be injected into unstable joints, infected areas, or intervertebral spaces

Risk of joint damage in osteoarthritis

• Repeated intra-articular injections in osteoarthritis may increase joint destruction

Avoid direct injection into tendons

• Avoid injecting corticosteroids directly into the substance of tendons because delayed appearance of tendon rupture has resulted

Post-injection joint care

• Patients should avoid overuse of treated joints after intra-articular corticosteroid therapy

Transition to oral therapy

• For long-term therapy, switching from parenteral to oral administration should be considered after assessing the benefits and risks

Dosage adjustments

• Adjustments may be necessary based on remission, exacerbation of the disease process, individual response, or exposure to physical/emotional stress such as infection, surgery, or injury. Monitoring may be required for up to a year after discontinuation of long-term or high-dose therapy

Risk of masked infections

• Corticosteroids may mask infection symptoms, reducing resistance and impairing the body's ability to localise infections

Ocular effects

• Prolonged use may cause posterior subcapsular cataracts (especially in children), glaucoma with potential optic nerve damage, and increased risk of secondary fungal or viral ocular infections

Electrolyte and blood pressure changes

• Can cause elevated blood pressure, salt and water retention, and potassium depletion. Effects are less common with synthetic corticosteroids unless used in large doses. Salt restriction and potassium supplementation may be necessary. Increased calcium excretion occurs with all corticosteroids

Vaccination considerations

• Live vaccines should not be administered during corticosteroid treatment
• Smallpox vaccination should be avoided
• Other immunisation procedures should be avoided in high-dose corticosteroid patients due to the risk of neurological complications and lack of antibody response
• Patients receiving corticosteroids for replacement therapy (e.g., Addison's disease) may undergo immunisation

Precautions for chickenpox and measles exposure

• Patients on immunosuppressive corticosteroid therapy should avoid exposure to chickenpox or measles
• If exposed, they should seek medical advice
• Prophylaxis with intramuscular normal immunoglobulin may be necessary

Tuberculosis risk

• Use in active tuberculosis should be limited to fulminating or disseminated tuberculosis cases, alongside appropriate anti-tuberculosis therapy
• Patients with latent tuberculosis or tuberculin reactivity require close monitoring due to potential reactivation
• Prolonged corticosteroid therapy may necessitate chemoprophylaxis. If using rifampicin, consider its effect on increasing corticosteroid metabolism, potentially requiring dose adjustments

Gradual dose reduction

• The lowest effective dose should be used to control the condition
• Gradual tapering is necessary to avoid medicine-induced secondary adrenocortical insufficiency
• Relative adrenocortical insufficiency may persist for months post-therapy; corticosteroid treatment may need to be resumed during periods of stress
• If mineralocorticosteroid secretion is impaired, concurrent administration of salt and/or a mineralocorticosteroid may be required
• Once a daily dose equivalent to 1mg betamethasone is reached, dose reduction should be slower to allow the HPA-axis to recover

Risk of adrenal atrophy

• Prolonged corticosteroid therapy can cause adrenal cortical atrophy, which may persist for years after stopping treatment

Gradual dose reduction required

• Patients who have received systemic corticosteroids at doses exceeding physiological levels (≥1 mg betamethasone or equivalent) for more than 3 weeks should not discontinue treatment abruptly
• The tapering schedule depends on the likelihood of disease relapse
• If the disease is unlikely to relapse but HPA-axis suppression is uncertain, the dose can be reduced rapidly to physiological levels before tapering more gradually

When abrupt withdrawal is appropriate

• If treatment lasted up to 3 weeks and disease relapse is unlikely, abrupt withdrawal may be considered
• Withdrawal of doses ≤6mg daily of betamethasone (or equivalent) for 3 weeks is unlikely to cause significant HPA-axis suppression in most patients

Patient groups requiring gradual withdrawal (even after ≤3 weeks of use)

• Patients with repeated corticosteroid courses, especially those lasting >3 weeks
• Patients who received a short course within one year of discontinuing long-term corticosteroid therapy
• Patients with pre-existing adrenal insufficiency from causes other than corticosteroid therapy
• Patients receiving doses >6 mg daily of betamethasone (or equivalent)
• Patients who routinely take corticosteroids in the evening

Need for increased dosage in stressful situations

• During prolonged therapy, any illness, trauma, or surgical procedure may necessitate a temporary increase in corticosteroid dosage
• If corticosteroids were recently discontinued after long-term therapy, they may need temporary reintroduction

Increased effects in certain conditions

• Effects may be enhanced in patients with hypothyroidism, myasthenia gravis, or cirrhosis

Ocular herpes simplex

• Cautious use is required due to the risk of corneal perforation

Psychiatric reactions

• Corticosteroid therapy may cause psychic derangements and aggravate existing emotional instability or psychotic tendencies
• Severe psychiatric adverse reactions, including depression and suicidal ideation, may occur within days or weeks of starting treatment
• Patients and caregivers should seek medical advice if psychological symptoms develop
• Particular care is needed in patients with a history of severe affective disorders or a family history of depressive or manic-depressive illness and previous steroid psychosis

Pheochromocytoma crisis

• Potentially fatal pheochromocytoma crisis has been reported after corticosteroid administration
• Corticosteroids should only be given after appropriate risk/benefit evaluation in patients with suspected or confirmed pheochromocytoma

Visual disturbance

• Blurred vision and other visual issues may occur
• Patients should be referred to an ophthalmologist if visual symptoms appear, as corticosteroids may contribute to cataracts, glaucoma, or central serous chorioretinopathy (CSCR)

Pregnancy and neonatal risks

• Not indicated for managing hyaline membrane disease after birth
• Should not be administered to pregnant women with pre-eclampsia, eclampsia, or placental damage

Fertility concerns

• May alter sperm motility and count in some patients

Ability to drive and use machines

• Patients should avoid hazardous tasks, such as driving or operating machinery, until they are aware of how betamethasone sodium phosphate affects them

Recommendations in other jurisdictions

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• Recent myocardial infarction (due to the risk of myocardial rupture)
• Hypothyroidism
• Myasthenia gravis
• Osteoporosis (post-menopausal females are particularly at risk)
• Hypertension or congestive heart failure
• Existing or previous history of severe affective disorders (especially previous steroid psychosis)
• Diabetes mellitus (or a family history of diabetes)
• History of, or active, tuberculosis
• Glaucoma (or a family history of glaucoma)
• Previous corticosteroid-induced myopathy
• Epilepsy
• History of, or active, peptic ulceration
• Herpes simplex keratitis
• Diverticulitis
• Thromboembolic tendencies

Minimising undesirable effects

• Use the lowest effective dose for the shortest duration possible
• Preferably administer the daily dose as a single morning dose or on alternate days when feasible
• Regular patient review is essential to adjust the dose based on disease activity

Risk of infection

• Corticosteroids suppress inflammation and immune function, increasing susceptibility to infections
• Serious infections such as septicaemia and tuberculosis may be masked and progress unnoticed

Chickenpox and herpes zoster precautions

• Chickenpox can be fatal in immunosuppressed patients
• Patients without a definite history of chickenpox should avoid close contact with infected individuals
• Urgent medical attention is required if exposed
• Passive immunisation with varicella-zoster immunoglobulin (VZIG) is needed within 10 days of exposure in exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months
• If chickenpox is confirmed, urgent specialist care is required. Corticosteroids should not be stopped and the dose may need to be increased

Vaccination precautions

• Live vaccines should not be given to individuals with impaired immune function
• The antibody response to other vaccines may be reduced
• Patients should take extra precautions to avoid measles exposure and seek immediate medical attention if exposed
• Prophylaxis with intramuscular normal immunoglobulin may be needed in case of exposure

Head injury

• Corticosteroids should not be used for managing head injury or stroke as they are unlikely to provide benefit and may be harmful

Cerebral oedema

• In patients with cerebral oedema due to tumours, gastrointestinal bleeding may occur. Stool examination may help in diagnosis

Pheochromocytoma crisis

• Fatal pheochromocytoma crisis has been reported after corticosteroid administration. Corticosteroids should only be given to patients with suspected or confirmed pheochromocytoma after a thorough risk/benefit evaluation

Adrenal suppression

• Adrenal cortical atrophy develops with prolonged corticosteroid therapy and may persist for years after stopping treatment
• Patients who have received more than physiological doses (≥1 mg betamethasone or equivalent) for more than 3 weeks should not stop treatment abruptly
• The speed of dose reduction depends on whether the underlying disease is likely to relapse

Withdrawal considerations

• Rapid dose reduction to physiological levels may be appropriate if HPA suppression is uncertain
• 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
• Gradual withdrawal is recommended in the following cases, even if treatment lasted less than 3 weeks:
  • Repeated corticosteroid courses, especially if exceeding 3 weeks
  • Short courses within one year of stopping long-term therapy (months or years)
  • Patients with pre-existing adrenocortical insufficiency (other than exogenous corticosteroids therapy)
  • Doses exceeding 6mg daily of betamethasone (or equivalent)
  • Evening doses taken repeatedly
• During prolonged therapy, any illness, trauma, or surgery may require a temporary dose increase
• If corticosteroids have been discontinued after long-term therapy, they may need to be temporarily reintroduced in response to stress or illness

Steroid treatment cards

• Patients should carry a 'steroid treatment' card providing details on prescriber, drug, dosage, and treatment duration, along with precautions to minimise risks

Psychiatric adverse reactions

• Severe psychiatric reactions can occur with systemic corticosteroid use
• Symptoms may develop within days to weeks of treatment initiation
• Higher doses and increased systemic exposure may increase risk
• Psychiatric reactions may include depressed mood or suicidal ideation
• Patients and carers should monitor for psychological symptoms and seek medical attention if concerning reactions develop
• Psychiatric symptoms may also occur during or after dose tapering or withdrawal
• Extra caution is required in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives, including:
  • Depression or manic-depressive illness
  • Previous steroid-induced psychosis

Visual disturbances

• Corticosteroid use (both systemic and topical) may cause blurred vision and other visual disturbances
• Referral to an ophthalmologist is advised if vision issues arise
• Potential eye conditions linked to corticosteroid use:
  • Cataract formation
  • Glaucoma
  • Central serous chorioretinopathy (CSCR)

Paediatric use

• Children are more susceptible to systemic toxicity from betamethasone
• Corticosteroids may cause dose-related growth retardation in infants, children, and adolescents
• Growth retardation may be irreversible
• To minimise suppression of the HPA axis and growth effects:
  • Use the lowest effective dose for the shortest duration
  • Consider alternate-day dosing where possible

Excipient precautions

• Medicinal product contains sodium metabisulphite which may rarely cause severe hypersensitivity reactions and bronchospasm
• The product contains less than 1mmol sodium (23mg) per 1ml, that is to say essentially 'sodium-free'

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Substitution therapy, for the treatment of adrenal insufficiency states in patients with a known or suspected adrenal insufficiency prior to surgery or if shock, severe trauma or other stressful conditions occur
Symptomatic treatment of inflammatory conditions responsive to corticosteroid therapy

• IV/IM/Intra-articularly/Intralesionally/As an infusion: Doses equivalent to 4-20mg
• Local injection into soft tissue: Doses equivalent to 4-8mg

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Dosage frequency and route of administration must be adjusted to the specific requirements of the patient, according to the disease, the severity of the condition, the response obtained and the patient’s tolerance to the product

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Rapid intravenous injection of massive doses of corticosteroids may sometimes cause cardiovascular collapse and injections should therefore be given slowly or by infusion

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Betamethasone sodium phosphate should not be administered intrathecally or subconjunctivally

Paed. forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Substitution therapy, for the treatment of adrenal insufficiency states in patients with a known or suspected adrenal insufficiency prior to surgery or if shock, severe trauma or other stressful conditions occur
Symptomatic treatment of inflammatory conditions responsive to corticosteroid therapy

• No specific recommendation provided

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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

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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

Pregnancy

South African recommendations

• Contraindicated
• Betamethasone sodium phosphate is contraindicated for use in pregnancy since the safety in pregnancy has not been established

Recommendations in other jurisdictions

• Caution; positive evidence of risk in animal studies
• 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
• Studies have shown an increased risk of neonatal hypoglycaemia following antenatal administration of a short course of betamethasone to women at risk for late preterm delivery

Breastfeeding

South African recommendations

• Contraindicated
• Betamethasone sodium phosphate is contraindicated for use in lactation since the safety in lactation has not been established

Recommendations in other jurisdictions

• Caution; no information available
• 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

Fertility

South African recommendations

• Betamethasone sodium phosphate may alter the motility and number of spermatozoa in some patients

Recommendations in other jurisdictions

• No information available

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no dose adjustment recommended

South African recommendations

• Caution; no dose adjustment recommended
  If rifampicin is used in a chemoprophylactic program, its enhancing effect on metabolic hepatic clearance of corticosteroids should be considered; adjustment in corticosteroid dosage may be required

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended
  Liver failure - blood levels of corticosteroid may be increased, as with other drugs which are metabolised in the liver

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no dose adjustment recommended
  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

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

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
  - 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)

Psychiatric Disorders

Common

• A wide range of psychiatric reactions
  • 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
  • Cognitive dysfunction including confusion and amnesia have been reported
  • 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

Eye Disorders

Not known

• Increased intra-ocular pressure
• Glaucoma
• Papilloedema
• Posterior subcapsular cataracts
• Corneal or scleral thinning
• Exacerbation of ophthalmic viral or fungal diseases
• Blurred vision

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

• Anticholinesterases
• Non-steroidal anti-inflammatory drugs
• Rifampicin
• Rifabutin
• Carbamazepine
• Phenobarbitone
• Phenytoin
• Primidone
• Aminoglutethimide
• Ephedrine
• Hypoglycaemic agents
• Insulin
• Antihypertensives
• Diuretics
• Acetazolamide
• Loop diuretics
• Thiazide diuretics
• Carbenoxolone
• Coumarin anticaogulants
• Theophylline
• Hypokalaemic agents
• Ulcer healing agents
• Antifungals
• Amphotericin B
• Salicylates
• Cardiac glucosides
• Ritonavir
• Oral contraceptives
• Mifepristone
• Somatropin
• Neuromuscular blocking agents
• Vecuronium
• Fluoroquinolones
• Quetiapine
• CYP3A inhibitors
• Cobicistat containing products
• Tretinoin
• Live vaccines
• Smallpox vaccine

Other interactions

• Cholecystographic X-ray media

None routine. Specific cases may require

• Growth (in children)
• Hepatitis B screening prior to initiation

Additional observations

• Injections site reactions
• Signs and symptoms of infection
• Latent or active amoebiasis prior to initiation in patients who have spent time in tropical climates or have unexplained diarrhoea
• Reactivation of tuberculosis in patients with latent tuberculosis or tuberculin reactivity

Betamethasone sodium phosphate is a glucocorticoid (potent suppressor of inflammation) and has the general properties of corticosteroids. It acts by controlling the rate of protein-synthesis. It forms a steroid-receptor complex with receptor proteins in target tissue, moving into the nucleus where it binds the chromatin and regulates transcription of certain genes in these tissues. In most examples transcription is enhanced, however, glucocorticoids may also decrease transcription of certain genes i.e., pro-opiomelanocortin that encodes ACTH (adrenocorticotropic hormone). This plays an important part in the negative feedback regulation of the HPA-axis (hypothalamic-pituitary-adrenal axis).

Injection (per ml) 4mg

• Betanoid Injection (Pharmacare)
• Celestone (Schering) originator (Discontinued 30/12/2018)
• Lenasone (Pharmacare)
• Pharma Q Betamethasone injection (Pharma Q)