Drugs List

Therapeutic Indications

Uses

Giant cell tumour of bone: treatment
Prevention of skeletal related events in advanced malignancy involving bone

Prevention of skeletal related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with advanced malignancies involving bone.

Treatment of adults and skeletally mature adolescents with giant cell tumour of the bone that is unresectable or where surgical resection is likely to result in severe morbidity.

Administration

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

Contraindications

Children under 12 years
Breastfeeding
Hypocalcaemia
Pregnancy
Unhealed lesions from dental or oral surgery

Precautions and Warnings

Children aged 12 to 18 years
Renal dialysis
Renal impairment - creatinine clearance below 30 ml/minute

Children under 18: Use only in skeletally mature adolescents in GCT of bone
Consider a dental exam & appropriate preventive dentistry before treatment
Correct serum calcium levels before commencing treatment
Ensure adequate vitamin D and calcium supplementation
Treatment to be administered under the supervision of a specialist
Giant cell tumour of bone: Risk of hypercalcaemia following discontinuation
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
Consider discontinuation if atypical femoral fracture occurs
Consider withholding treatment if osteonecrosis of the jaw occurs
Not licensed for all indications in all age groups
Female: Contraception required during & for at least 5 months after therapy
Advise patient on need for adequate dental hygiene & regular dental checks
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 denosumab. In clinical trials, the incidence of ONJ was higher with longer duration of exposure and ONJ has also been diagnosed after discontinuing treatment, most cases within 5 months after last dose. The majority of subjects treated with denosumab with confirmed ONJ had a history of tooth extraction, poor oral hygiene or use of dental appliance. Other risk factors include cancer, co-morbidities (e.g. anaemia, coagulopathies, infection), smoking and concomitant therapies, such as chemotherapy and corticosteroids.

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.

Atypical femoral fractures have been reported rarely in patients treated with denosumab. 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. Patients who report new or unusual thigh, hip or groin pain should be evaluated for an incomplete femoral fracture.

Rebound hypercalcaemia requiring hospitalisation and complicated by acute renal injury has been reported in patients who were being treated for giant tumour cell of bone. These cases were reported up to 9 months after discontinuation of denosumab. Patients should be monitored for signs and symptoms of hypercalcaemia after discontinuation and calcium and vitamin D supplementation requirements reviewed.

Pregnancy and Lactation

Pregnancy

Denosumab is contraindicated in pregnancy.
The manufacturer states that the use of denosumab during pregnancy is not recommended. In addition, women should be advised not to become pregnant for at least 5 months after treatment with denosumab.
There are no adequate data from the use of denosumab in pregnant women. Limited data from animal studies suggest low risk of reproductive toxicity.

Lactation

Denosumab is contraindicated in breastfeeding.
The manufacturer recommends that a decision on whether to abstain from breastfeeding or to abstain from therapy with denosumab should be made.
It is unknown whether denosumab is excreted in human milk. Although the molecular weight suggests that excretion into breast milk will be inhibited, the long serum half-life may favour excretion (Briggs et al, 2015).

Side Effects

Anaphylactic reaction
Atypical femoral fracture
Cataracts
Cellulitis
Constipation
Diarrhoea
Diverticulitis
Dyspnoea
Ear infection
Eczema
Erythema
Facial swelling
Hyperhidrosis
Hypersensitivity reactions
Hypocalcaemia
Hypophosphataemia
Lichenoid drug eruptions
Musculoskeletal pain
New primary malignancy
Osteonecrosis (primarily of the jaw)
Osteonecrosis of the external auditory canal
Painful extremities
Rash
Rebound hypercalcaemia
Sciatica
Upper respiratory tract infection
Urinary tract infections
Urticaria

Presentation

Injection of denosumab containing 120mg in 1.7ml.
This product has been produced by recombinant technology using Chinese Hamster Ovary (CHO) cell lines.

Drugs List

Therapeutic Indications

Uses

Giant cell tumour of bone: treatment
Prevention of skeletal related events in advanced malignancy involving bone

Prevention of skeletal related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with advanced malignancies involving bone.

Treatment of adults and skeletally mature adolescents with giant cell tumour of the bone that is unresectable or where surgical resection is likely to result in severe morbidity.

Dosage

Calcium 500mg and vitamin D 400 IU daily supplementation is required in all patients, unless hypercalcaemia is present.

Adults

Children

Administration

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

Contraindications

Children under 12 years
Breastfeeding
Hypocalcaemia
Pregnancy
Unhealed lesions from dental or oral surgery

Precautions and Warnings

Children aged 12 to 18 years
Renal dialysis
Renal impairment - creatinine clearance below 30 ml/minute

Children under 18: Use only in skeletally mature adolescents in GCT of bone
Consider a dental exam & appropriate preventive dentistry before treatment
Correct serum calcium levels before commencing treatment
Ensure adequate vitamin D and calcium supplementation
Treatment to be administered under the supervision of a specialist
Giant cell tumour of bone: Risk of hypercalcaemia following discontinuation
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
Consider discontinuation if atypical femoral fracture occurs
Consider withholding treatment if osteonecrosis of the jaw occurs
Not licensed for all indications in all age groups
Female: Contraception required during & for at least 5 months after therapy
Advise patient on need for adequate dental hygiene & regular dental checks
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 denosumab. In clinical trials, the incidence of ONJ was higher with longer duration of exposure and ONJ has also been diagnosed after discontinuing treatment, most cases within 5 months after last dose. The majority of subjects treated with denosumab with confirmed ONJ had a history of tooth extraction, poor oral hygiene or use of dental appliance. Other risk factors include cancer, co-morbidities (e.g. anaemia, coagulopathies, infection), smoking and concomitant therapies, such as chemotherapy and corticosteroids.

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.

Atypical femoral fractures have been reported rarely in patients treated with denosumab. 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. Patients who report new or unusual thigh, hip or groin pain should be evaluated for an incomplete femoral fracture.

Rebound hypercalcaemia requiring hospitalisation and complicated by acute renal injury has been reported in patients who were being treated for giant tumour cell of bone. These cases were reported up to 9 months after discontinuation of denosumab. Patients should be monitored for signs and symptoms of hypercalcaemia after discontinuation and calcium and vitamin D supplementation requirements reviewed.

Pregnancy and Lactation

Pregnancy

Denosumab is contraindicated in pregnancy.
The manufacturer states that the use of denosumab during pregnancy is not recommended. In addition, women should be advised not to become pregnant for at least 5 months after treatment with denosumab.
There are no adequate data from the use of denosumab in pregnant women. Limited data from animal studies suggest low risk of reproductive toxicity.

Lactation

Denosumab is contraindicated in breastfeeding.
The manufacturer recommends that a decision on whether to abstain from breastfeeding or to abstain from therapy with denosumab should be made.
It is unknown whether denosumab is excreted in human milk. Although the molecular weight suggests that excretion into breast milk will be inhibited, the long serum half-life may favour excretion (Briggs et al, 2015).

Side Effects

Anaphylactic reaction
Atypical femoral fracture
Cataracts
Cellulitis
Constipation
Diarrhoea
Diverticulitis
Dyspnoea
Ear infection
Eczema
Erythema
Facial swelling
Hyperhidrosis
Hypersensitivity reactions
Hypocalcaemia
Hypophosphataemia
Lichenoid drug eruptions
Musculoskeletal pain
New primary malignancy
Osteonecrosis (primarily of the jaw)
Osteonecrosis of the external auditory canal
Painful extremities
Rash
Rebound hypercalcaemia
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: August 2018

Reference Sources

Summary of Product Characteristics: Xgeva 120 mg solution for injection. Amgen Ltd. Revised April 2019.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.

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

MHRA Drug Safety Update June 2018
Available at: https://www.mhra.gov.uk
Last accessed: 26 June 2018

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 201