Drugs List

Therapeutic Indications

Uses

Treatment of bone loss associated with hormone ablation in prostate cancer
Treatment of osteoporosis in men to prevent fractures
Treatment of osteoporosis in postmenopausal women to prevent fractures

Administration

For subcutaneous administration to the thigh, abdomen or upper arm.

Contraindications

Children under 18 years
Breastfeeding
Hypocalcaemia
Pregnancy

Precautions and Warnings

Renal dialysis
Renal impairment - creatinine clearance below 30 ml/minute
Unhealed lesions from dental or oral surgery

Calcium supplements may be required if risk of calcium/vitamin D deficiency
Consider a dental exam & appropriate preventive dentistry before treatment
Correct serum calcium levels before commencing treatment
Needle cover contains a derivative of latex
Treatment to be administered under the supervision of a specialist
Dental check-ups advisable during long-term treatment
Ensure patient's dietary intake of calcium and vitamin D is adequate
Evaluate benefit/risk in long term use ( > 5 years)
Monitor serum calcium levels regularly from starting treatment
Advise patient to report any ear pain, discharge or infection
Advise patient to report any new thigh, hip or groin pain
Advise patient to report signs of hypocalcaemia
Consider osteonecrosis of external auditory canal if ear symptoms occur
Patient should report signs or symptoms of cellulitis to doctor immediately
Consider discontinuation if atypical femoral fracture occurs
Consider withholding treatment if osteonecrosis of the jaw occurs
Advise patient of need for high oral hygiene standards
Advise patient to report any dental mobility, pain or swelling
Give patient package leaflet and patient reminder card
Patient to inform dentist of denosumab use: avoid invasive procedures

Hypocalcaemia can occur at any time during therapy with denosumab, but it is most likely to occur within the first weeks after treatment is initiated. Monitoring of calcium levels should be conducted prior to initiation and within two weeks of the first dose in all patients treated with denosumab. Additional monitoring is required in patients who develop symptoms of hypocalcaemia during treatment. Regular monitoring of calcium levels is important in patients with severe renal impairment (creatinine clearance below 30 ml/minute) or receiving dialysis and should also be considered in patients with additional risk factors for hypocalcaemia.

Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates and denosumab, most cases have been in patients with advanced malignancies involving bone. This risk is increased in patients on long-term denosumab therapy. In studies patients who developed ONJ had known risk factors, including a diagnosis of cancer with bone lesions, concomitant therapies (e.g., chemotherapy, antiangiogenic biologics, corticosteroids, radiotherapy to head and neck), poor oral hygiene, invasive dental procedures including extractions and dental implants, co-morbid disorders (e.g., pre-existing dental disease, anaemia, coagulopathy, infection) and previous treatment with bisphosphonates.

Dental examination with appropriate preventative procedures and an individual benefit-risk assessment is recommended prior to denosumab therapy in patients with risk factors for ONJ. While on treatment, patients should avoid invasive dental procedures if possible, especially in close proximity to the start of treatment with denosumab. The start of treatment or a new course of treatment should be delayed in patients with unhealed open soft tissue lesion in the mouth. Good oral hygiene practices and regular routine dental check-ups should be maintained during treatment with denosumab.

In patients with ear symptoms (such as chronic ear infections) or those with suspected cholesteatoma, consider the possibility of osteonecrosis of the external auditory canal. Possible risk factors include steroid use and chemotherapy, with or without local risk factors such as infection or trauma.

For patients who develop ONJ during treatment, dental surgery may exacerbate the condition. If ONJ occurs during treatment with denosumab, use clinical judgement and guide the management plan of each patient based on individual benefit/risk evaluation. The management plan for patients with ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

Atypical femoral fractures have been reported in patients receiving denosumab. This risk is increased in patients on long-term denosumab therapy. Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur. Similar fractures reported in association with bisphosphonates are often bilateral; therefore the contralateral femur should be examined in denosumab treated patients who have sustained a femoral shaft fracture, Consider discontinuation of denosumab therapy in patients suspected to have an atypical femoral fracture pending an individual risk/benefit assessment. During denosumab therapy, advise patients to report new or unusual thigh, hip or groin pain. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture.

Cases of increased risk of multiple vertebral fractures has been reported in patients within 18 months of discontinuing or delaying denosumab treatment, patients with a previous vertebral fracture may be at a higher risk. Specialist review is required before a patient stops treatment with denosumab.

Pregnancy and Lactation

Pregnancy

Denosumab is contraindicated in pregnancy.

There are no adequate data from the use of denosumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. In genetically engineered mice in which RANKL has been turned off by gene removal (a 'knockout mouse'), studies suggest absence of RANKL (the target of denosumab) could interfere with the development of lymph nodes in the foetus and could lead to postnatal impairment of dentition and bone growth.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Denosumab is contraindicated in breastfeeding.

It is unknown whether denosumab is excreted in human milk.

Knockout mouse studies suggest absence of RANKL during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum. 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.

The UK Drugs in Lactation Advisory Service states that due to the drug's properties, low levels are anticipated in human breast milk which are likely to be degraded in the infant's gastrointestinal tract.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal discomfort
Anaphylactic reaction
Atypical femoral fracture
Cataracts
Cellulitis
Constipation
Diverticulitis
Ear infection
Eczema
Erythema
Facial swelling
Hypersensitivity reactions
Hypocalcaemia
Infections
Musculoskeletal pain
Osteonecrosis (primarily of the jaw)
Osteonecrosis of the external auditory canal
Painful extremities
Rash
Sciatica
Upper respiratory tract infection
Urinary tract infections
Urticaria

Presentation

Denosumab injection 60 mg in 1 ml
This product has been produced by recombinant technology using Chinese Hamster Ovary (CHO) cell lines.

Drugs List

Therapeutic Indications

Uses

Treatment of bone loss associated with hormone ablation in prostate cancer
Treatment of osteoporosis in men to prevent fractures
Treatment of osteoporosis in postmenopausal women to prevent fractures

Dosage

Adults

Administration

For subcutaneous administration to the thigh, abdomen or upper arm.

Contraindications

Children under 18 years
Breastfeeding
Hypocalcaemia
Pregnancy

Precautions and Warnings

Renal dialysis
Renal impairment - creatinine clearance below 30 ml/minute
Unhealed lesions from dental or oral surgery

Calcium supplements may be required if risk of calcium/vitamin D deficiency
Consider a dental exam & appropriate preventive dentistry before treatment
Correct serum calcium levels before commencing treatment
Needle cover contains a derivative of latex
Treatment to be administered under the supervision of a specialist
Dental check-ups advisable during long-term treatment
Ensure patient's dietary intake of calcium and vitamin D is adequate
Evaluate benefit/risk in long term use ( > 5 years)
Monitor serum calcium levels regularly from starting treatment
Advise patient to report any ear pain, discharge or infection
Advise patient to report any new thigh, hip or groin pain
Advise patient to report signs of hypocalcaemia
Consider osteonecrosis of external auditory canal if ear symptoms occur
Patient should report signs or symptoms of cellulitis to doctor immediately
Consider discontinuation if atypical femoral fracture occurs
Consider withholding treatment if osteonecrosis of the jaw occurs
Advise patient of need for high oral hygiene standards
Advise patient to report any dental mobility, pain or swelling
Give patient package leaflet and patient reminder card
Patient to inform dentist of denosumab use: avoid invasive procedures

Hypocalcaemia can occur at any time during therapy with denosumab, but it is most likely to occur within the first weeks after treatment is initiated. Monitoring of calcium levels should be conducted prior to initiation and within two weeks of the first dose in all patients treated with denosumab. Additional monitoring is required in patients who develop symptoms of hypocalcaemia during treatment. Regular monitoring of calcium levels is important in patients with severe renal impairment (creatinine clearance below 30 ml/minute) or receiving dialysis and should also be considered in patients with additional risk factors for hypocalcaemia.

Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates and denosumab, most cases have been in patients with advanced malignancies involving bone. This risk is increased in patients on long-term denosumab therapy. In studies patients who developed ONJ had known risk factors, including a diagnosis of cancer with bone lesions, concomitant therapies (e.g., chemotherapy, antiangiogenic biologics, corticosteroids, radiotherapy to head and neck), poor oral hygiene, invasive dental procedures including extractions and dental implants, co-morbid disorders (e.g., pre-existing dental disease, anaemia, coagulopathy, infection) and previous treatment with bisphosphonates.

Dental examination with appropriate preventative procedures and an individual benefit-risk assessment is recommended prior to denosumab therapy in patients with risk factors for ONJ. While on treatment, patients should avoid invasive dental procedures if possible, especially in close proximity to the start of treatment with denosumab. The start of treatment or a new course of treatment should be delayed in patients with unhealed open soft tissue lesion in the mouth. Good oral hygiene practices and regular routine dental check-ups should be maintained during treatment with denosumab.

In patients with ear symptoms (such as chronic ear infections) or those with suspected cholesteatoma, consider the possibility of osteonecrosis of the external auditory canal. Possible risk factors include steroid use and chemotherapy, with or without local risk factors such as infection or trauma.

For patients who develop ONJ during treatment, dental surgery may exacerbate the condition. If ONJ occurs during treatment with denosumab, use clinical judgement and guide the management plan of each patient based on individual benefit/risk evaluation. The management plan for patients with ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

Atypical femoral fractures have been reported in patients receiving denosumab. This risk is increased in patients on long-term denosumab therapy. Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur. Similar fractures reported in association with bisphosphonates are often bilateral; therefore the contralateral femur should be examined in denosumab treated patients who have sustained a femoral shaft fracture, Consider discontinuation of denosumab therapy in patients suspected to have an atypical femoral fracture pending an individual risk/benefit assessment. During denosumab therapy, advise patients to report new or unusual thigh, hip or groin pain. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture.

Cases of increased risk of multiple vertebral fractures has been reported in patients within 18 months of discontinuing or delaying denosumab treatment, patients with a previous vertebral fracture may be at a higher risk. Specialist review is required before a patient stops treatment with denosumab.

Pregnancy and Lactation

Pregnancy

Denosumab is contraindicated in pregnancy.

There are no adequate data from the use of denosumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. In genetically engineered mice in which RANKL has been turned off by gene removal (a 'knockout mouse'), studies suggest absence of RANKL (the target of denosumab) could interfere with the development of lymph nodes in the foetus and could lead to postnatal impairment of dentition and bone growth.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Denosumab is contraindicated in breastfeeding.

It is unknown whether denosumab is excreted in human milk.

Knockout mouse studies suggest absence of RANKL during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum. 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.

The UK Drugs in Lactation Advisory Service states that due to the drug's properties, low levels are anticipated in human breast milk which are likely to be degraded in the infant's gastrointestinal tract.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal discomfort
Anaphylactic reaction
Atypical femoral fracture
Cataracts
Cellulitis
Constipation
Diverticulitis
Ear infection
Eczema
Erythema
Facial swelling
Hypersensitivity reactions
Hypocalcaemia
Infections
Musculoskeletal pain
Osteonecrosis (primarily of the jaw)
Osteonecrosis of the external auditory canal
Painful extremities
Rash
Sciatica
Upper respiratory tract infection
Urinary tract infections
Urticaria

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: September 2014

Reference Sources

Summary of Product Characteristics: Prolia. Amgen Ltd. Revised June 2017.

MHRA Drug Safety Update August 2020
Available at: https://www.mhra.gov.uk
Last accessed: 10 November 2020

MHRA Drug Safety Update June 2017
Available at: https://www.mhra.gov.uk
Last accessed: 21 June 2017

MHRA Drug Safety Update July 2015
Available at: https://www.mhra.gov.uk
Last accessed: 06 August 2015

MHRA Drug Safety Update September 2014
Available at: https://www.mhra.gov.uk
Last accessed: 15 October 2014

MHRA Drug Safety Update February 2013
Available at: https://www.mhra.gov.uk
Last accessed: 11 September 2014

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 26 October 2018

UK Drugs in Lactation Advisory Service.
Available at: https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Last accessed: 12 September 2014