Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile

Overall safety profile is consistent in all approved indications for XGEVA.
Hypocalcemia has very commonly been reported following XGEVA administration, mostly within the first 2 weeks.
Hypocalcemia can be severe and symptomatic (see section 4.8 - description of selected adverse reactions). 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. Cases of osteonecrosis of the jaw (see sections 4.4 and 4.8 – description of selected adverse reactions) have been commonly observed in patients taking XGEVA.

Tabulated list of adverse reactions

The following convention has been used for the classification of the adverse reactions based on incidence rates in four phase III, two phase II clinical studies and post-marketing experience (see table 1): very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping and system organ class, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions reported in patients with advanced malignancies involving bone, multiple myeloma, or with giant cell tumor of bone

MedDRA system organ class                Frequency category                Adverse reactions Neoplasms benign, malignant and          Common                            New primary malignancy1 unspecified (including cysts and polyps)
Immune system disorders                  Rare                              Drug hypersensitivity1 Rare                              Anaphylactic reaction1
Metabolism and nutrition disorders       Very common                       Hypocalcemia1,2 Common                            Hypophosphatemia
Uncommon                          Hypercalcemia following treatment discontinuation in patients with giant cell tumor of bone3
Respiratory, thoracic and mediastinal Very common                          Dyspnea disorders
Gastrointestinal disorders            Very common                          Diarrhea Common                               Tooth extraction
Skin and subcutaneous tissue          Common                               Hyperhidrosis disorders                             Uncommon                             Lichenoid drug eruptions1 Musculoskeletal and connective        Very common                          Musculoskeletal pain1 tissue disorders                      Common                               Osteonecrosis of the jaw1 Uncommon                             Atypical femoral fracture1
Rare                                 Multiple vertebral fractures following treatment discontinuation3
Not known                         Osteonecrosis of the external auditory canal3,4
1
See section Description of selected adverse reactions
2
See section Other special populations
3
See section 4.4
4
Class effect

Description of selected adverse reactions

Hypocalcemia
A higher incidence of hypocalcemia among patients treated with denosumab compared to zoledronic acid has been observed in SRE prevention clinical trials.

The highest incidence of hypocalcemia was observed in a phase III trial in patients with multiple myeloma.
Hypocalcemia was reported in 16.9% of patients treated with XGEVA and 12.4% of patients treated with zoledronic acid. A grade 3 decrease in serum calcium levels was experienced in 1.4% of patients treated with XGEVA and 0.6% of patients treated with zoledronic acid. A grade 4 decrease in serum calcium levels was experienced in 0.4% of patients treated with XGEVA and 0.1% of patients treated with zoledronic acid.

In three phase III active-controlled clinical trials in patients with advanced malignancies involving bone, hypocalcemia was reported in 9.6% of patients treated with XGEVA and 5.0% of patients treated with zoledronic acid.

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 (see section 4.4).
In two phase II single-arm clinical trials in patients with giant cell tumor of bone, hypocalcemia was reported in 5.7% of patients. None of the adverse events was considered serious.

In the post-marketing setting, severe symptomatic hypocalcemia (including fatal cases) has been reported, with most cases occurring in the first weeks of initiating therapy. Examples of clinical manifestations of severe symptomatic hypocalcemia have included QT interval prolongation, tetany, seizures and altered mental status (including coma) (see section 4.4). Symptoms of hypocalcemia in clinical studies included paresthesias or muscle stiffness, twitching, spasms and muscle cramps.

Osteonecrosis of the jaw (ONJ)
In clinical trials, the incidence of ONJ was higher with longer duration of exposure; ONJ has also been diagnosed after stopping treatment with XGEVA with the majority of cases occurring within 5 months after the last dose. Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure were excluded from the clinical trials.

A higher incidence of ONJ among patients treated with denosumab compared to zoledronic acid has been observed in SRE prevention clinical trials. The highest incidence of ONJ was observed in a phase III trial in patients with multiple myeloma. In the double-blind treatment phase of this trial, ONJ was confirmed in 5.9% of patients treated with XGEVA (median exposure of 19.4 months; range: 1 - 52) and in 3.2% of patients treated with zoledronic acid. At the completion of the double-blind treatment phase of this trial, the patient-year adjusted incidence of confirmed ONJ in the XGEVA group (median exposure of 19.4 months; range: 1 - 52), was 2.0 per 100 patient-years during the first year of treatment, 5.0 in the second year, and 4.5 thereafter. The median time to ONJ was 18.7 months (range: 1 - 44).

In the primary treatment phases of three phase III active-controlled clinical trials 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 patients 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. Most patients were receiving or had received chemotherapy.

The trials 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). ONJ was confirmed in 6.9% of patients with breast cancer and prostate cancer during the extension treatment phase.

The patient-year adjusted overall incidence of confirmed ONJ was 1.1 per 100 patient-years during the first year of treatment, 3.7 in the second year and 4.6 thereafter. The median time to ONJ was 20.6 months (range: 4 - 53).

A non-randomized, retrospective, observational study in 2,877 patients with cancer treated with XGEVA or zoledronic acid in Sweden, Denmark, and Norway showed that 5-year incidence proportions of medically confirmed ONJ were 5.7% (95% CI: 4.4, 7.3; median follow-up time of 20 months [range: 0.2-60]) in a cohort of patients receiving XGEVA and 1.4% (95% CI: 0.8, 2.3; median follow-up time of 13 months [range: 0.1-60]) in a separate cohort of patients receiving zoledronic acid. Five-year incidence proportion of ONJ in patients switching from zoledronic acid to XGEVA was 6.6% (95% CI: 4.2, 10.0; median follow-up time of 13 months [range: 0.2-60]).

In a phase III trial 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 per 100 patient-years during the first year of treatment, 3.0 in the second year, and 7.1 thereafter.

In a long-term phase II open-label clinical trial in patients with giant cell tumor of bone (study 6, see section 5.1), ONJ was confirmed in 6.8% of patients, including one adolescent (median number of 34 doses; range: 4 – 116). At the completion of the trial, median time on trial including safety follow-up phase was 60.9 months (range: 0 – 112.6). The patient-year adjusted incidence of confirmed ONJ was 1.5 per 100 patient-years overall (0.2 per 100 patient-years during the first year of treatment, 1.5 in the second year, 1.8 in the third year, 2.1 in the fourth year, 1.4 in the fifth year, and 2.2 thereafter). The median time to ONJ was 41 months (range: 11 - 96).

Study 7 was conducted to continue to follow patients with GCTB who were treated in study 6 for an additional 5 or more years. ONJ was reported in 6 patients (11.8%) of the 51 exposed patients with median total 42 doses of denosumab. Three of these cases of ONJ were medically confirmed.

Drug related hypersensitivity reactions
In the post-marketing setting, events of hypersensitivity, including rare events of anaphylactic reactions, have been reported in patients receiving XGEVA.

Atypical fractures of the femur
In the clinical trial program overall, atypical femoral fractures have been reported uncommonly in patients treated with XGEVA and the risk increased with longer duration of treatment. Events have occurred during treatment and up to 9 months after treatment was discontinued (see section 4.4).

In the clinical trial program for GCTB, atypical femoral fractures have been reported commonly in patients treated with XGEVA. In study 6, incidence of confirmed AFF was 0.95% (5/526) in patients with giant cell tumor of bone. In the follow-up study 7, the incidence of confirmed AFF was 3.9% (2/51) of patients exposed to denosumab.

Musculoskeletal pain
In the post-marketing setting, musculoskeletal pain, including severe cases, has been reported in patients receiving XGEVA. In clinical trials, musculoskeletal pain was very common in both the denosumab and zoledronic acid treatment groups. Musculoskeletal pain leading to discontinuation of study treatment was uncommon.

New primary malignancy
In the primary double-blind treatment phases of four phase III active-controlled clinical trials in patients with advanced malignancies involving bone, new primary malignancy was reported in 54/3691 (1.5%) of patients treated with XGEVA (median exposure of 13.8 months; range: 1.0–51.7) and 33/3688 (0.9%) of patients treated with zoledronic acid (median exposure of 12.9 months; range: 1.0-50.8).

The cumulative incidence at one year was 1.1% for denosumab and 0.6% for zoledronic acid, respectively.

No treatment-related pattern in individual cancers or cancer groupings was apparent.
In patients with giant cell tumor of bone, incidence of new malignancy, including malignancies involving the bone and outside the bone was 3.8% (20/526) in study 6. In the follow-up study 7, the incidence was 11.8% (6/51) of patients exposed to denosumab.

Lichenoid drug eruptions
Lichenoid drug eruptions (e.g., lichen planus-like reactions), have been reported in patients in the post-marketing setting.

Pediatric population

XGEVA was studied in an open-label trial that enrolled 28 skeletally mature adolescents with giant cell tumor of bone. Based on these limited data, the adverse event profile appeared to be similar to adults.

Clinically significant hypercalcemia after treatment discontinuation has been reported in the post-marketing setting in pediatric patients (see section 4.4).

Other special populations

Renal impairment
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 hypocalcemia in the absence of calcium supplementation. The risk of developing hypocalcemia during XGEVA treatment is greater with increasing degree of renal impairment. In a clinical study in patients without advanced cancer, 19% of patients with severe renal impairment (creatinine clearance < 30 mL/min) and 63% of patients receiving dialysis developed hypocalcemia despite calcium supplementation. The overall incidence of clinically significant hypocalcemia was 9%.

Accompanying increases in parathyroid hormone have also been observed in patients receiving XGEVA with severe renal impairment or receiving dialysis. Monitoring of calcium levels and adequate intake of calcium and vitamin D is especially important in patients with renal impairment (see section 4.4).


Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/