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XGEVA (denosumab)

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Side effects & safety information

XGEVA® (DENOSUMAB) side effects & safety

Safety data are available from a total of 6,454 patients who received XGEVA® in clinical studies.[CHMP AR, pp. 74-75, 84; SmPC, p. 6]

Adverse events did not differ significantly between treatment groups in the three main clinical studies, where 96.2% of XGEVA® patients had one or more adverse effect in the pivotal studies, compared with 96.8% in the zoledronic acid group. The most common side effects in both groups were nausea, anaemia, fatigue, back pain, decreased appetite, asthenia, constipation, dyspnoea, diarrhoea, arthralgia, bone pain and vomiting. The most common XGEVA® side effect that led to withdrawal in the studies was osteonecrosis of the jaw (ONJ), followed by hypocalcaemia. Less renal impairment has been observed in patients on XGEVA® therapy compared with zoledronic acid. Long-term safety data are limited.[CHMP AR, pp. 74-75, 84]

Safety of XGEVA® has also been assessed in two phase II, single-arm clinical studies in patients with giant cell tumour of bone.[SmPC, p. 8]

Hypocalcaemia has commonly been reported following XGEVA® administration, mostly within the first 2 weeks. Hypocalcaemia can be severe and symptomatic. The decreases in serum calcium were generally appropriately managed by calcium and vitamin D supplementation. The most common adverse reactions with XGEVA® are musculoskeletal pain.[SmPC, p.6]

VERY COMMON XGEVA® (DENOSUMAB) SIDE EFFECTS (≥1/10) [SmPC, p. 7]

  • Dyspnoea
  • Diarrhoea
  • Musculoskeletal pain

COMMON XGEVA® (DENOSUMAB) SIDE EFFECTS (≥1/100 to <1/10) [SmPC, p. 7]

  • Hypocalcaemia
  • Hypophosphataemia
  • Tooth extraction
  • ONJ
  • Hyperhidrosis

RARE XGEVA® (DENOSUMAB) SIDE EFFECTS (≥1/10,000 to <1/1,000) [SmPC, p. 7]

  • Drug hypersensitivity
  • Anaphylactic reaction
  • Atypical femoral fracture

Description of selected XGEVA® (DENOSUMAB) side effects

Hypocalcaemia

In three phase III, active-controlled clinical studies in patients with advanced malignancies involving bone, hypocalcaemia was reported in 9.6% of patients treated with XGEVA® and 5.0% of patients treated with zoledronic acid.[SmPC, p. 7]

A grade 3 decrease in serum calcium levels was experienced in 2.5% of patients treated with XGEVA® and 1.2% of patients treated with zoledronic acid. A grade 4 decrease in serum calcium levels was experienced in 0.6% of patients treated with XGEVA® and 0.2% of patients treated with zoledronic acid.[SmPC, p. 7]

Symptoms of hypocalcaemia in clinical studies included paresthesias or muscle stiffness, twitching, spasms and muscle cramps. [SmPC, p. 7]

In the post-marketing setting, severe symptomatic hypocalcaemia (including fatal cases) has been reported.[SmPC, p. 7]

Osteonecrosis of the jaw (ONJ)

In clinical studies, the incidence of ONJ increased with length of exposure; ONJ has also been diagnosed after stopping treatment with XGEVA®, with the majority of cases occurring within 5 months after the last XGEVA® dose.[SmPC, p. 7]

In the primary treatment phases of three phase III, active-controlled clinical studies in patients with advanced malignancies involving bone, ONJ was confirmed in 1.8% of patients treated with XGEVA® (median exposure of 12.0 months; range 0.1–40.5) and 1.3% of patients treated with zoledronic acid. Clinical characteristics of these cases were similar between treatment groups. Among subjects with confirmed ONJ, most (81% in both treatment groups) had a history of tooth extraction, poor oral hygiene, and/or use of a dental appliance. In addition most subjects were receiving or had received chemotherapy. The studies in patients with breast or prostate cancer included an XGEVA® extension treatment phase (median overall exposure of 14.9 months; range 0.1–67.2). The patient-year adjusted overall incidence of confirmed ONJ was 1.1% during the first year of treatment, 3.7% in the second year and 4.6% per year thereafter. The median time to ONJ was 20.6 months (range: 4–53).[SmPC, p. 8]

In a phase III study in patients with non-metastatic prostate cancer (a patient population for which XGEVA® is not indicated), with longer treatment exposure of up to 7 years, the patient-year adjusted incidence of confirmed ONJ was 1.1% during the first year of treatment, 3.0% in the second year and 7.1% per year thereafter.[SmPC, p. 8]

In two phase II, single-arm clinical studies in patients with giant cell tumour of bone, ONJ occurred in 2.3% (12 of 523) of patients treated with XGEVA® (median overall exposure of 20.3 months; range: 0–83.4). The patient-year adjusted incidence of ONJ was 0.2% during the first year of treatment and 1.7% in the second year. The median time to ONJ was 19.4 months (range: 11–40). Based on duration of exposure, there are insufficient data in giant cell tumour of bone patients to assess risk of ONJ beyond 2 years.[SmPC, p. 8]

Drug-related hypersensitivity

In the post-marketing setting, events of hypersensitivity, including rare events of anaphylactic reactions, have been reported in patients receiving XGEVA®.[SmPC, p. 8]

Atypical fractures of the femur

In the clinical study program, atypical femoral fractures were reported rarely in patients treated with XGEVA®.[SmPC, p. 8]

Other special populations

In a clinical study of patients without advanced cancer with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis, there was a greater risk of developing hypocalcaemia in the absence of calcium supplementation.[SmPC, p. 8]

The most common XGEVA® (denosumab) side effect that led to withdrawal in the studies was osteonecrosis of the jaw (ONJ), followed by hypocalcaemia [CHMP AR, p. 84]

Fertility, pregnancy and breastfeeding 

Fertility 

No data are available on the effect of XGEVA® on human fertility. Animal studies do not indicate direct or indirect harmful effects. [SmPC, p. 7]

Pregnancy 

Adequate data on the use of XGEVA® in pregnancy are not available. XGEVA® use is not recommended in women who are pregnant or are of child-bearing potential and not using any highly effective contraception.[SmPC, pp. 5-6]

Breastfeeding 

It is not known whether XGEVA® is excreted in human breast milk. A risk/benefit analysis should be undertaken in women requiring XGEVA® therapy who are breastfeeding.[SmPC, p. 6]

XGEVA® (denosumab) should not be used in adult patients with severe untreated hypocalcaemia [CHMP AR, p. 86]

Safety in special populations

Renal impairment

No dose adjustment is necessary. Patients with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis are at greater risk of developing hypocalcaemia. Regular monitoring of calcium levels is especially important in these patients.[SmPC, pp. 3-4]

Hepatic impairment

XGEVA® use has not been specifically studied in patients with impaired hepatic function.[SmPC, p. 3]




Paediatric population

XGEVA® is not recommended in paediatric patients under the age of 18 years other than skeletally mature adolescents with giant cell tumour of bone.[SmPC, p. 3]

Ability to drive and use machines

XGEVA® has minimal or no effect on the ability to drive and use machines.[SmPC, p. 6]

Overdose

There are no data on XGEVA® overdose from clinical studies.[SmPC, p. 9]

Reporting of suspected adverse reactions 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in "Reporting of suspected adverse reactions Appendix V.”[SmPC, p. 9]

This medicinal product is subject to additional monitoring.
This will allow quick identification of new safety information.
Healthcare professionals are asked to report any suspected adverse reactions.