Dexamethasone

Registered South African indications:

• Symptomatic multiple myeloma in combination with other appropriate medicines

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Active viral disease (especially viral hepatitis, herpes, varicella, shingles)
• Uncontrolled psychoses
• Use with live attenuated vaccines
• Active tuberculosis
• Coadministration with ciclosporin

South African recommendations

Caution in the following patient groups

• Renal impairment
• Hepatic impairment
• Elderly

Dose considerations

• Dexamethasone (tablet) is a high-dose glucocorticoid. This should be taken into consideration in the monitoring of the patient
• The benefit from dexamethasone treatment should be carefully and continuously weighed against actual and potential risks

Risk of infection

• Treatment with high-dose dexamethasone increases the risk of serious infections (bacterial, yeast, parasitic, or opportunistic), as the drug can mask signs of a developing infection. Patients must be closely monitored for infections, especially pneumonia. Active infectious disease requires appropriate anti-infective treatment, and active tuberculosis is a contraindication

Tuberculosis (quiescent/ dormant)

• Patients with quiescent/dormant tuberculosis should be closely observed and may require chemoprophylaxis if dexamethasone treatment is prolonged. Prophylactic anti-tuberculosis treatment is also required in cases of prior tuberculosis with major radiological sequelae or if the patient's previous full treatment course is uncertain

Strongyloidiasis

• There is a risk of severe strongyloidiasis. Patients from endemic areas (tropical, sub-tropical regions, southern Europe) should undergo a stool examination and parasite eradication if necessary, before initiating dexamethasone treatment

Viral diseases (varicella zoster, measles)

• Glucocorticoid treatment can aggravate certain viral diseases (varicella zoster, measles), especially in immunocompromised patients who have not previously had these diseases or have received glucocorticoids in the last three months. Patients must avoid contact with infected subjects and seek medical attention without delay, as preventive treatment (e.g., passive immunisation) may be necessary upon exposure

Vaccinations

• Dexamethasone should not be used with live attenuated vaccines (see Contraindications). While inactivated vaccines are usually possible, high glucocorticoid doses may diminish the immune response and, consequently, the effectiveness of the vaccination

Interference with laboratory tests

• Dexamethasone can suppress skin reactions in allergy testing and may cause false-negative results in the nitro blue tetrazolium (NBT) test for bacterial infections

Psychiatric disorders

• Potentially severe psychiatric adverse reactions (including depressed mood, suicidal ideation, and steroid psychoses) may occur, typically within days or weeks of starting dexamethasone; patients and carers should be warned and seek medical advice if symptoms develop. Particular care is required in patients with a history of severe affective disorders (depressive/manic-depressive illness) in themselves or their first-degree relatives
• Additionally, psychiatric disturbances may infrequently occur during or immediately after dose tapering/withdrawal. Insomnia may be minimised by morning administration

Tumour lysis syndrome (TLS)

• TLS has been reported in patients with haematological malignancies using dexamethasone. Patients at high risk (e.g. those with a high proliferative rate or high tumour burden) should be monitored closely, and appropriate precautions must be taken

Gastrointestinal disorders

• Treatment for active gastric or duodenal ulceration must be commenced before initiating dexamethasone. Prophylaxis should be considered for patients with a history of or risk factors for ulceration, haemorrhage, or perforation, and they should be clinically monitored, potentially including endoscopy

Eye disorders

• Systemic glucocorticoid treatment can cause chorioretinopathy, which may impair vision. Prolonged use of corticosteroids may produce subcapsular cataracts and glaucoma (with possible optic nerve damage), and enhance secondary ocular infections (fungal/viral). Particular care is needed for patients with glaucoma (or a family history of it) and those with ocular herpes simplex due to the risk of corneal perforation

Tendonitis

• Corticosteroids can favour the development of tendonitis and, in rare cases, tendon rupture. This risk is increased by the concomitant use of fluoroquinolone antimicrobials, in patients undergoing dialysis with secondary hyperparathyroidism or after renal transplantation

Phaeochromocytoma crisis

• Phaeochromocytoma crisis, which can be fatal, has been reported following systemic corticosteroid administration. Corticosteroids should only be given to patients with suspected or identified phaeochromocytoma after a careful risk/benefit evaluation

Use with other medicines (Risk of torsades de pointes)

• Concomitant use with medicines carrying a risk of torsades de pointes should be cautious due to an increased risk of ventricular dysrhythmia. Any hypokalaemia must be corrected, and patients should be monitored clinically, for electrolytes, and by electrocardiography

Long-term treatment (metabolic and cardiovascular)

• Long-term dexamethasone treatment requires a diet low in simple sugars and high in protein due to the drug's hyperglycaemic effect and protein catabolism. Water and sodium retention are common, potentially leading to hypertension, necessitating reduced sodium intake and blood pressure monitoring
• Potassium levels must be monitored, and supplementation given if there is a risk of cardiac arrhythmia or concurrent hypokalaemic medicinal products. Particular care is needed for patients with renal impairment, hypertension, or congestive heart failure

Long-term treatment (bone and endocrine)

• Depending on treatment duration, calcium metabolism may be impaired, requiring monitoring of calcium and vitamin D levels. Bisphosphonates should be considered for osteoporosis risk factors, especially in patients not already receiving them for multiple myeloma-related bone disease. Glucocorticoid therapy may reduce the effect of anti-diabetic and antihypertensive treatments, potentially requiring an increased dose of these medicines

Combination therapy (teratogens)

• When dexamethasone is used in combination with known teratogens (e.g., thalidomide, lenalidomide, pomalidomide, plerixafor), particular attention to pregnancy testing and prevention requirements is needed

Venous and arterial thromboembolic events

• Combining dexamethasone with thalidomide or its analogues significantly increases the risk of venous thromboembolism (DVT/PE) and arterial thromboembolism (MI/stroke) in multiple myeloma patients. Patients with known risk factors must be closely monitored, and all modifiable risk factors (e.g., smoking) should be minimised
• Caution is needed with concomitant use of erythropoietic medicinal products or hormone replacement therapy, and an Hb>12g/dl requires discontinuation of erythropoietics
• Prophylactic antithrombotic treatment is recommended, especially for patients with additional risk factors. If a thromboembolic event occurs, treatment must be discontinued and anticoagulation started; treatment may only be restarted once stabilised and a benefit/risk assessment is completed, with continuous anticoagulation therapy

Neutropenia and thrombocytopenia (combination therapy)

• The combination of dexamethasone with lenalidomide or pomalidomide in multiple myeloma patients is associated with a high incidence of grade 3/4 neutropenia and thrombocytopenia. Patients must be monitored for these haematological adverse reactions, including a complete blood count at baseline, weekly for the first 8 weeks, and monthly thereafter
• Patients must promptly report febrile episodes (febrile neutropenia), and doctors should be observant for signs of bleeding; dose reduction of the partner drug or use of growth factors may be required

Lactose warning

• As dexamethasone contains lactose, it may affect the glycaemic control of patients with diabetes mellitus. The medicine is contraindicated in patients with rare hereditary conditions such as galactose intolerance (e.g. galactosaemia), Lapp lactase deficiency, or glucose-galactose malabsorption

Effects on ability to drive and use machines

• Dexamethasone reduces the ability to drive and use machines. Dexamethasone may cause confusional state, hallucinations, dizziness, somnolence, fatigue, syncope and blurred vision
• If any of these effects occur, patients should be instructed not to drive, use machines or perform hazardous tasks while being treated with dexamethasone

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

South African registered indications and dosages

Symptomatic multiple myeloma in combination with other appropriate medicines

Treatment must be initiated and monitored under the supervision of medical practitioners experienced in the management of multiple myeloma (MM)

• Oral (tab): Usual dose: 40mg, once daily

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The dose and administration frequency varies with the therapeutic protocol and the associated treatment(s) used for MM. Dexamethasone administration should follow the appropriate protocol. Prescribing medical practitioners should take into account the condition and disease status of the patient

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Method of administration
For oral use. In order to minimise insomnia, the tablet should preferably be taken in the morning. Dexamethasone should be kept in the blister package until administration. Individual tablets in intact packaging should be separated from the blister using the perforation, e.g. for use in multi-compartment compliance aids

Not indicated for use in the paediatric population

Pregnancy

South African recommendations

• Contraindicated
• Based on human experience, dexamethasone as contained in dexamethasone is may cause congenital malformations, particularly intra-uterine growth retardation and rarely neonatal adrenal insufficiency, when administered during pregnancy
• Studies in animals have shown reproductive toxicity
• Dexamethasone should not be used during pregnancy unless the clinical condition of the woman requires treatment with dexamethasone

Combination therapy

• When dexamethasone is used in combination with known teratogens (e.g. thalidomide, lenalidomide, pomalidomide, plerixafor) particular attention to pregnancy testing and prevention requirements is needed

Women of childbearing potential

• Women should avoid becoming pregnant during dexamethasone treatment. Dexamethasone as contained in dexamethasone may cause congenital malformations
• Dexamethasone may be used with known teratogens (e.g. thalidomide, lenalidomide, pomalidomide, plerixafor), or with cytotoxic substances which are contraindicated in pregnancy
• Patients receiving dexamethasone in combination with products containing thalidomide, lenalidomide or pomalidomide should adhere to the pregnancy prevention programmes of those products

Contraception in males and females

• Women of childbearing potential and their male partners should take appropriate contraceptive measures. In particular, the requirements of the pregnancy prevention programme for combination treatment with thalidomide or its analogues must be followed
• The efficacy of oral contraceptives may be reduced during dexamethasone treatment

Breastfeeding

South African recommendations

• Contraindicated
• Women should not breastfeed their babies while taking dexamethasone
• Glucocorticoids are excreted in human milk and effects have been shown in breastfed newborns/infants of treated women

Fertility

South African recommendations

• Studies in animals have shown reductions in female fertility. No data on male fertility are available

South African recommendations

• Caution; no dose adjustment recommended
  Patients with renal insufficiency require appropriate monitoring

South African recommendations

• Caution; no information available
  Patients with hepatic impairment require appropriate monitoring and should be dosed with caution as there are no data

South African recommendations

• Caution; dose adjustment recommended
  In elderly and/or frail patients, it can be decided to prescribe another product containing a lower dose of dexamethasone, according to the appropriate treatment regimen
  The common adverse reactions to 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

Common

• Pneumonia
• Herpes zoster
• Upper respiratory tract infection
• Lower respiratory tract infection
• Oral candidiasis
• Oral fungal infection
• Urinary tract infection
• Herpes simplex
• Candidal infection

Not known

• Infection
• Sepsis

Blood and the Lymphatic System Disorders

Common

• Neutropenia
• Anaemia
• Thrombocytopenia
• Lymphopenia
• Leukopenia
• Leukocytosis

Uncommon

• Febrile neutropenia
• Pancytopenia
• Coagulopathy

Endocrine Disorders

Common

• Cushing's syndrome

Uncommon

• Hypothyroidism

Not known

• Adrenal atrophy
• Steroid withdrawal syndrome
• Adrenal insufficiency
• Hirsutism
• Menstrual irregularity

Metabolism and Nutrition Disorders

Very common

• Hyperglycaemia

Common

• Hypokalaemia
• Diabetes mellitus
• Anorexia
• Increased or decreased appetite
• Hypoalbuminaemia
• Fluid retention
• Hyperuricaemia

Uncommon

• Dehydration
• Hypocalcaemia
• Hypomagnesemia

Not known

• Impaired glucose tolerance
• Sodium retention
• Metabolic alkalosis

Psychiatric Disorders

Very common

• Insomnia

Common

• Depression
• Anxiety
• Aggression
• Confusional state
• Irritability
• Nervousness
• Mood alteration
• Agitation
• Euphoric mood

Uncommon

• Mood swings
• Hallucinations

Not known

• Mania
• Psychosis
• Behavioural disturbance

Nervous System Disorders

Common

• Peripheral neuropathy
• Dizziness
• Psychomotor hyperactivity
• Disturbance in attention
• Memory impairment
• Tremor
• Paraesthesia
• Headache
• Ageusia
• Dysgeusia
• Somnolence
• Lethargy
• Impaired balance
• Dysphonia

Uncommon

• Cerebrovascular accident
• Transient ischaemic attack
• Amnesia
• Coordination abnormal
• Ataxia
• Syncope

Not known

• Convulsions

Eye Disorders

Common

• Blurred vision
• Cataract

Uncommon

• Conjunctivitis
• Increased lacrimation

Not known

• Chorioretinopathy
• Glaucoma

Ear and Labyrinth Disorders

Common

• Vertigo

Cardiac Disorders

Common

• Atrial fibrillation
• Supraventricular extrasystoles
• Tachycardia
• Palpitations

Uncommon

• Myocardial ischaemia

Not known

• Congestive heart failure

Vascular Disorders

Common

• Venous thromboembolic reactions, predominantly deep vein thrombosis and pulmonary embolism
• Hypertension
• Hypotension
• Flushing
• Increased blood pressure
• Decreased diastolic blood pressure

Not known

• Purpura
• Bruising

Respiratory, Thoracic and Mediastinal Disorders

Common

• Bronchitis
• Cough
• Dyspnoea
• Pharyngolaryngeal pain
• Hoarseness
• Hiccough

Gastrointestinal Disorders

Very common

• Constipation

Common

• Vomiting
• Diarrhoea
• Nausea
• Dyspepsia
• Stomatitis
• Gastritis
• Abdominal pain
• Dry mouth
• Abdominal distension
• Flatulence

Not known

• Pancreatitis
• Gastrointestinal perforation
• Gastrointestinal haemorrhage
• Gastrointestinal ulcer

Hepato-biliary Disorders

Common

• Abnormal liver function tests
• Increased alanine aminotransferase

Skin and Subcutaneous Tissue Disorders

Common

• Rash
• Erythema
• Hyperhidrosis
• Pruritus
• Dry skin
• Alopecia

Uncommon

• Urticaria

Not known

• Skin atrophy
• Acne

Musculoskeletal, Connective Tissue and Bone Disorders

Very common

• Muscular weakness
• Muscle cramps

Common

• Myopathy
• Musculoskeletal pain
• Arthralgia
• Pain in extremity

Not known

• Pathological fracture
• Osteonecrosis
• Osteoporosis
• Tendon rupture

Renal and Urinary Disorders

Common

• Pollakiuria

Uncommon

• Renal failure

General Disorders and Administration Site Conditions

Very common

• Fatigue
• Asthenia
• Oedema (including peripheral and facial oedema)

Common

• Pain
• Mucosal inflammation
• Pyrexia
• Chills
• Malaise

Not known

• Impaired healing

Investigations

Common

• Decreased weight
• Increased weight

Combinations to be avoided due to safety concerns

• Ciclosporin
• Acetylsalicylic acid (aspirin) at doses ≥1g per dose or <3g per day (due to increased of risk of bleeding)
• Acetylsalicylic acid (aspirin) at doses ≥500mg per dose or <3g per day (due to increased risk of haemorrhage, ulcerations and gastro-intestinal perforation)
• Live attenuated vaccines

Combinations that require precaution due to safety concerns

• Hypokalaemic medicinal products
• Hypokalaemic diuretics (single or in combination)
• Laxatives
• Tetracosactide
• Intravenous amphotericin B
• Digitalis
• Medicines that carry a risk of torsades de pointes
• Erythropoietic medicines or other medicines that may increase the risk of thrombosis
• Hormone replacement therapy
• Thalidomide
• Analogues with dexamethasone
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Hypoglycaemic medicines
• Antihypertensive medicines
• Fluoroquinolones
• Methotrexate

Medicines that may reduce dexamethasone plasma concentration (and efficacy)

• CYP3A4 inducers
• Aminogluthetimide
• Anticonvulsants that are hepatic enzyme inducers
• Carbamazepine
• Fosphenytoin
• Phenobarbital
• Phenytoin
• Primidone
• Rifampicin
• Topical gastrointestinal medicines
• Antacids
• Activated carbon
• Cholestyramine
• Ephedrine

Medicines that may increase dexamethasone plasma concentration

• CYP3A4 inhibitors
• Aprepitant
• Fosaprepitant
• Clarithromycin
• Erythromycin
• Telithromycin
• Itraconazole
• Ketoconazole
• Posaconazole
• Voriconazole
• Nelfinavir
• Ritonavir

Effects of dexamethasone on other medicines

• Substances that are metabolised via CYP3A4
• Substances transported by P-gp
• Oral contraceptives
• Hormone replacement therapy
• Oral anticoagulants
• Docetaxel
• Cyclophosphamide
• Lapatinib
• Midazolam
• Ivermectin
• Rifabutin
• Indinavir
• Erythromycin
• Isoniazid
• Praziquantel

Other interactions

• Allergy test
• Nitro blue tetrazolium (NBT) test
  (See Interference with laboratory tests in Warnings and Precautions section)

• Full blood count (at baseline)
  - White blood cell count with differential count
  - Platelet count
  - Haemoglobin
  - Haematocrit
  - This monitoring should continue every week for the first 8 weeks of dexamethasone/lenalidomide treatment and monthly thereafter to monitor for cytopenia
• Electrolytes
  - Potassium levels
  - Calcium levels
• Hepatic function
• Renal function
• Ophthalmic examination
• Vitamin D levels

Specific cases may require

• Blood glucose
• Electrocardiography (ECG)
• Coagulation parameters
• Stool examination
• Endoscopy
• Blood pressure (long term therapy)

Additional Observations

• Infections
  - Patients should be closely monitored for the appearance of infections during treatment, as signs may be masked by dexamethasone
  - Patients should be informed of the signs and symptoms of pneumonia and advised to seek medical attention if they appear
  - Patients receiving combination therapy with thalidomide or its analogues should be advised to promptly report febrile episodes
• Thromboembolism
  - Patients with known risk factors for thromboembolism (especially when used in combination with thalidomide and its analogues) should be closely monitored
  - Be observant for the signs and symptoms of thromboembolism
  - Patients should seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling
• Bleeding
  - Be observant for signs and symptoms of bleeding, including petechiae and epistaxes
• Tumour Lysis Syndrome (TLS)
  - Patients at high risk of TLS should be monitored closely
• Mental status
  - Patients and/or carers should be warned that potentially severe psychiatric adverse reactions may occur
  - 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 during, or immediately after, dose tapering/withdrawal
  - Particular care is required in patients with existing or previous history of severe affective disorders or previous steroid psychoses

• Use of corticosteroids requires appropriate monitoring in patients with the following conditions:
  - Ulcerative colitis (due to perforation risk)
  - Recent intestinal anastomoses
  - Diverticulitis
  - Recent myocardial infarction (risk of left ventricular free wall rupture)
  - Diabetes mellitus (or family history)
  - Renal impairment
  - Hepatic impairment
  - Osteoporosis
  - Myasthenia gravis

Dexamethasone is a synthetic glucocorticoid; it combines high anti-inflammatory effects with low mineralocorticoid activity. It reduces the immune response. Dexamethasone has been shown to induce multiple myeloma cell death (apoptosis) via a downregulation of Nuclear Factor-κB activity and an activation of caspase-9 through second mitochondria-derived activator of caspase (Smac; an apoptosis-promoting factor) release. Dexamethasone also downregulated anti-apoptotic genes and increased IκB-α protein levels. Dexamethasone apoptotic activity is enhanced by the combination with thalidomides or its analogues and with proteasome inhibitor (e.g. bortezomib).