Denosumab (Xgeva▼, Prolia); intravenous bisphosphonates: osteonecrosis of the jaw—further measures to minimise risk

Patient reminder cards about the risk of osteonecrosis of the jaw are being introduced; denosumab 120 mg is now contraindicated in patients with unhealed lesions from dental or oral surgery.

• From: Medicines and Healthcare products Regulatory Agency
• Published: 20 July 2015

• Therapeutic area: Cancer, Dentistry, Endocrinology, diabetology and metabolism, Obstetrics, gynaecology and fertility, Rheumatology

Before prescribing denosumab or intravenous bisphosphonates:

• give patients the patient reminder card for their medicine
• explain the risk of osteonecrosis of the jaw and advise patients on precautions to take—advise patients to:
  • tell their doctor if they have any problems with their mouth or teeth before starting treatment; if they wear dentures they should make sure their dentures fit properly before starting treatment
  • maintain good oral hygiene and get routine dental check-ups during treatment
  • tell their doctor and dentist that they are receiving denosumab or an intravenous bisphosphonate if they need dental treatment or dental surgery
  • tell their doctor and dentist immediately if they have any problems with their mouth or teeth during treatment (eg loose teeth, pain, swelling, non-healing sores or discharge)
• do not prescribe denosumab 120 mg (cancer indication) to patients with unhealed lesions from dental or oral surgery

Please continue to report suspected side effects to denosumab, bisphosphonates or any other medicines on a Yellow Card.

Indication

Denosumab and bisphosphonates are used to treat osteoporosis, Paget’s disease, and as part of some cancer regimens, particularly for metastatic bone cancer and multiple myeloma. Individual bisphosphonates and denosumab-containing medicines have different indications; please check the summary of product characteristics of the medicine in question.

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) is a known side effect of denosumab and bisphosphonates (see Drug Safety Update articles from November 2009 and September 2014). To date, we have received 45 Yellow Card reports of ONJ in people taking denosumab (all doses) and 323 reports in people taking a bisphosphonate.^{[footnote 1]}

In patients treated for osteoporosis (regardless of route of administration), the risk of ONJ is small compared with that in patients treated with the higher doses used for cancer-related conditions. Other drug-specific risk factors for ONJ include drug potency (higher risk for highly potent compounds such as zoledronate, pamidronate and denosumab), route of administration (higher risk for parenteral administration) and cumulative dose.

Patient reminder cards and denosumab 120 mg contraindication

MHRA and other EU medicines regulators have reviewed measures to minimise the risk of ONJ in patients taking denosumab or bisphosphonates. The review recommended introducing patient reminder cards^{[footnote 2]} for denosumab and intravenous bisphosphonates to inform patients of the risk of ONJ and precautions to take before and during treatment. The review of ONJ and denosumab also recommended that denosumab 120 mg should be contraindicated in patients with unhealed lesions from dental or oral surgery.

Oral bisphosphonates: reminder of precautions to take

All bisphosphonates are associated with a risk of ONJ. Therefore before prescribing oral bisphosphonates, we remind you to tell patients to maintain good oral hygiene, attend routine dental check-ups and immediately report any oral symptoms such as dental mobility, pain, or swelling to a doctor and dentist.

Further information

European Medicines Agency announcement, March 2015 (accessed 15 July 2015).

Content of reminder card as approved by the European Committee on Medicinal Products for Human Use (accessed 15 July 2015).

Content of Prolia (denosumab) patient card

Content of Xgeva (denosumab 120 mg) patient card

Content of Aclasta (zoledronic acid) patient reminder card

Content of Zometa (zoledronic acid) patient reminder card

Content of zoledronic acid 4 mg patient card

Content of zoledronic acid 5 mg patient card

Content of ibandronic acid 2 mg, 4 mg, and 6 mg patient card

Content of ibandronic acid 3 mg patient card

Content of pamidronate disodium patient card

Article citation: Drug Safety Update volume 8 issue 12 July 2015: 1.

1. Yellow Card reports are reports of suspected adverse drug reactions (ADRs) submitted voluntarily by healthcare professionals and members of the public in the UK. The number of reports received should not be used to determine the incidence of an ADR. This is because neither the total number of ADRs occurring, nor the number of patients using the drug is known. ADR reporting rates are influenced by the seriousness of ADRs, their ease of recognition, and the extent of use of a particular drug, and may be stimulated by publicity about a drug. ↩

2. The reminder cards are being sent by licence-holders for individual products separately and will therefore become available at different times. You can view the content of the reminder cards via the links above. ↩

Published 20 July 2015