Denosumab

Registered South African indications:

• Osteoporosis in postmenopausal women and in men at increased risk of fractures
• Bone loss
  - Treatment and prevention in prostate and breast cancer patients undergoing hormone ablation
  - Treatment of bone loss associated with long-term systemic glucocorticoid therapy in adult patients at increased risk of fracture

Contraindications
South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy 
• Breastfeeding 
• Hypocalcaemia 

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Hypocalcaemia

 Cautions
South African manufacturer recommendations

• Women of childbearing potential and for at least 5 months after treatment with denosumab
• Severe renal impairment (eGFR<30ml/min/1.73m²) 
  - Receiving dialysis
  - Increasing degree of renal impairment
• Hepatic impairment
• Inadequate intake of calcium and vitamin D supplementation
• Risk factors associated with developing osteonecrosis of the jaw (ONJ)
  - Potency of the medicinal agent that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy
  - Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection)
  - Smoking
  - Coadministration with corticosteroids and angiogenesis inhibitors
  - Concomitant therapies: chemotherapy and radiotherapy to head and neck
  - Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures e.g. tooth extractions
• Unhealed open soft tissue lesions in the mouth
• Patients with certain co-morbid conditions
  - Vitamin D deficiency
  - Rheumatoid arthritis
  - Hypophosphatasia
• History of vertebral fracture (See additional prescribing points)
• Latex allergy (See additional prescribing points)
• Sorbitol/fructose intolerance
• Prolonged use (including both denosumab and bisphosphonates)
• Coadministration with certain pharmaceutical agents (e.g. bisphosphonates, glucocorticoids, proton pump inhibitors)
• Coadministration with other denosumab containing medicinal agents

 International manufacturer recommendations

• Pregnancy
• Women of childbearing potential not using contraception and for at least 5 months after treatment with denosumab
• Breastfeeding
• Severe renal impairment (eGFR<30ml/min/1.73m²) 
  - Receiving dialysis
  - Increasing degree of renal impairment
• Hepatic impairment
• Inadequate intake of calcium and vitamin D supplementation
• Risk factors associated with developing osteonecrosis of the jaw (ONJ)
  - Potency of the medicinal agent that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy
  - Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection)
  - Smoking
  - Coadministration with corticosteroids and angiogenesis inhibitors
  - Concomitant therapies: chemotherapy and radiotherapy to head and neck
  - Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures e.g. tooth extractions
• Unhealed open soft tissue lesions in the mouth
• Risk factors for osteonecrosis of the external auditory canal
  - Coadministration with steroid
  - Chemotherapy and/or local risk factors such as infection or trauma
• Ear symptoms including chronic ear infections
• Patients with certain co-morbid conditions
  - Vitamin D deficiency
  - Rheumatoid arthritis
  - Hypophosphatasia
• Prolonged use (including both denosumab and bisphosphonates)
• Coadministration with certain pharmaceutical agents (e.g. bisphosphonates, glucocorticoids, proton pump inhibitors)
• Coadministration with other denosumab containing medicinal agents
• Coadministration with agents containing sorbitol (or fructose)

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

Osteoporosis in postmenopausal women and in men at increased risk of fractures
Bone loss
- Treatment and prevention in prostate and breast cancer patients undergoing hormone ablation
- Treatment of bone loss associated with long-term systemic glucocorticoid therapy in adult patients at increased risk of fracture

• SC: 60mg, as a single injection once every 6 months into the thigh, abdomen or upper arm

In postmenopausal women denosumab significantly reduces the risk of vertebral, non-vertebral and hip fractures. In patients with prostate cancer, denosumab reduces the incidence of vertebral fractures

Method of administration: For subcutaneous use. Administration should be performed by an individual who has been adequately trained in injection techniques

Patients must be adequately supplemented with calcium and vitamin D

The optimal total duration of antiresorptive treatment for osteoporosis (including both denosumab and bisphosphonates) has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of denosumab on an individual patient basis, particularly after ≥5 years of use

Instructions for use/handling: See additional prescribing points

Not established for use in children below 18 years

 Pregnancy
South African manufacturer recommendations

• Contraindicated
• There are no or limited amount of data from the use of denosumab in pregnant women. Studies in animals have shown reproductive toxicity
• Denosumab is not recommended for use in pregnant women and women of childbearing potential not using contraception. Women should be advised not to become pregnant during and for at least 5 months after treatment with denosumab. Any effects of denosumab are likely to be greater during the second and third trimesters of pregnancy since monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester

 International manufacturer recommendations

• Caution; not recommended
• There are no or limited amount of data on the use of denosumab in pregnant women. Studies in animals have shown reproductive toxicity
• Denosumab is not recommended for use in pregnant women and women of childbearing potential not using contraception. Women should be advised not to become pregnant during and for at least 5 months after treatment with denosumab. Any effects of denosumab are likely to be greater during the second and third trimesters of pregnancy since monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester

Breastfeeding
South African manufacturer recommendations

• Contraindicated 
• It is unknown whether denosumab is excreted in human milk. In genetically engineered mice in which receptor activator of nuclear factor kappa-Β ligand (RANKL) has been turned off by gene removal (a “knockout mouse”), studies suggest absence of RANKL (the target of denosumab) during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation postpartum
• A decision on whether to abstain from breastfeeding or to abstain from therapy with denosumab should be made, taking into account the benefit of breastfeeding to the newborn/infant and the benefit of denosumab therapy to the woman

International manufacturer recommendations

• Caution
• It is unknown whether denosumab is excreted in human milk. In genetically engineered mice in which receptor activator of nuclear factor kappa-Β ligand (RANKL) has been turned off by gene removal (a “knockout mouse”), studies suggest absence of RANKL (the target of denosumab) during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation postpartum
• A decision on whether to abstain from breastfeeding or to abstain from therapy with denosumab should be made, taking into account the benefit of breastfeeding to the newborn/infant and the benefit of denosumab therapy to the woman

Fertility 

• No data are available on the effect of denosumab on human fertility. Animal studies do not indicate direct or indirect harmful effects with respect to fertility

Renal Impairment 

• Mild to moderate: (eGFR≥30ml/min/1.73m²): No dose adjustment recommended 
• Severe: (eGFR<30ml/min/1.73m²): Caution; no dose adjustment recommended  
  No data is available in patients with long-term systemic glucocorticoid therapy and severe renal impairment

Hepatic Impairment

• Caution; no information available 

Elderly 

• No dose adjustment recommended 

Porphyria Information 

• Not porphyrinogenic (NP) 

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Sciatica
• Seizures
• Altered mental status

Cardiovascular Disorders 

• Prolonged QT interval 

Respiratory Disorders 

• Upper respiratory tract infection

Gastrointestinal Disorders 

• Osteonecrosis of the jaw
• Diverticulitis
• Constipation
• Abdominal discomfort

Genitourinary Disorders 

• Urinary tract infection

Endocrine and Metabolic Disorders 

• Hypocalcaemia

Musculoskeletal Disorders 

• Pain in extremity 
• Musculoskeletal pain
• Atypical femoral fractures
• Paraesthesias or muscle stiffness
• Twitching
• Spasms 
• Muscle cramps
• Tetany

Skin and Subcutaneous Tissue Disorders 

• Cellulitis
• Rash 
• Eczema 
• Alopecia 
• Lichenoid drug eruptions 
  - Lichen planus-like reactions
• Hypersensitivity vasculitis

Immune, Blood and Lymphatic System Disorders 

• Drug hypersensitivity
  - Rash
  - Urticaria
  - Facial swelling
  - Erythema
• Anaphylactic reactions

Sensory Disorders 

• Ear symptoms
  - Chronic ear infection
• Osteonecrosis of the external auditory canal

No significant interactions

• Renal function
• Electrolytes
• Oral examination
• Serial bone mineral density (BMD)
• Fasting serum C-terminal telopeptide (CTX)
• Urinary N-terminal telopeptide (NTX)

Specific cases may require

• Pregnancy status
• Dental examination
• Hepatitis B virus (HBV) screening (patients with cancer)
  - Hepatitis B surface antigen
  - Hepatitis B core antibody
  - Total Ig or IgG
  - Antibody to hepatitis B surface antigen

Additional observations

• Signs/symptoms of hypocalcemia, especially in patients predisposed to hypocalcemia 
  - Severe renal impairment
  - Thyroid/parathyroid surgery
  - Malabsorption syndromes
  - Hypoparathyroidism
• Signs/symptoms of hypercalcemia
  - Periodic serum calcium (after discontinuation in patients with growing skeletons and in patients with giant bone cell tumor)
• Infection
• Dermatologic reactions
• Signs/symptoms of hypersensitivity

Traceability

• In order to improve the traceability of biological medicinal agents, the name and the batch number of the administered product should be clearly recorded

Instructions for use/handling

• Before administration, the solution should be inspected. Do not inject the solution if it contains particles or is cloudy or discoloured
• Do not shake
• To avoid discomfort at the site of injection, allow the pre-filled syringe to reach room temperature (up to 25°C) before injecting and inject slowly. Inject the entire contents of the pre-filled syringe
• Any unused medicinal product or waste material should be disposed of

Multiple vertebral fractures (MVF) following discontinuation of denosumab treatment

• Multiple vertebral fractures (MVF) may occur following discontinuation of treatment with denosumab, particularly in patients with a history of vertebral fracture. Advise patients not to interrupt denosumab therapy without their physician’s advice. Evaluate the individual benefit/risk before discontinuing treatment with denosumab. If denosumab treatment is discontinued, consider transitioning to an alternative antiresorptive therapy

Latex allergy (South African manufacturer recommendations)

• The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions

Denosumab is a human monoclonal antibody immunoglobulin G2 (IgG2) that targets and binds with high affinity and specificity to receptor activator of nuclear factor kappa-Β ligand (RANKL), preventing activation of its receptor, receptor activator of nuclear factor kappa-Β (RANK), on the surface of osteoclast precursors and osteoclasts. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function and survival, thereby decreasing bone resorption in cortical and trabecular bone.

Pre-filled syringe (per ml) 60mg

• Prolia 60mg (Amgen) originator