Denosumab interacts in the following cases:
The safety and efficacy of denosumab have not been studied in patients with hepatic impairment.
Patients with severe renal impairment (creatinine clearance <30 mL/min) or receiving dialysis are at greater risk of developing hypocalcaemia. The risks of developing hypocalcaemia and accompanying parathyroid hormone elevations increase with increasing degree of renal impairment. Adequate intake of calcium, vitamin D and regular monitoring of calcium is especially important in these patients.
There are no or limited amount of data from the use of denosumab in pregnant women. Studies in animals have shown reproductive toxicity.
Denosumab is not recommended for use in pregnant women and women of child-bearing potential not using contraception. Women should be advised not to become pregnant during and for at least 5 months after treatment with denosumab. Any effects of Prolia are likely to be greater during the second and third trimesters of pregnancy since monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester.
It is unknown whether denosumab is excreted in human milk. 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) during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum. A decision on whether to abstain from breast-feeding or to abstain from therapy with denosumab should be made, taking into account the benefit of breast-feeding to the newborn/infant and the benefit of denosumab therapy to the woman.
No data are available on the effect of denosumab on human fertility. Animal studies do not indicate direct or indirect harmful effects with respect to fertility.
Denosumab has no or negligible influence on the ability to drive and use machines.
The most common side effects with denosumab (seen in more than one patient in ten) are musculoskeletal pain and pain in the extremity. Uncommon cases of cellulitis, rare cases of hypocalcaemia, hypersensitivity, osteonecrosis of the jaw and atypical femoral fractures (see description of selected adverse reactions) have been observed in patients taking denosumab.
The data in table 1 below describe adverse reactions reported from phase II and III clinical trials in patients with osteoporosis and breast or prostate cancer patients receiving hormone ablation; and/or spontaneous reporting.
The following convention has been used for the classification of the adverse reactions (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 osteoporosis and breast or prostate cancer patients receiving hormone ablation:
| MedDRA system organ class | Frequency category | Adverse reactions |
|---|---|---|
| Infections and infestations | Common | Urinary tract infection |
| Common | Upper respiratory tract infection | |
| Uncommon | Diverticulitis1 | |
| Uncommon | Cellulitis1 | |
| Uncommon | Ear infection | |
| Immune system disorders | Rare | Drug hypersensitivity1 |
| Rare | Anaphylactic reaction1 | |
| Metabolism and nutrition disorders | Rare | Hypocalcaemia1 |
| Nervous system disorders | Common | Sciatica |
| Gastrointestinal disorders | Common | Constipation |
| Common | Abdominal discomfort | |
| Skin and subcutaneous tissue disorders | Common | Rash |
| Common | Eczema | |
| Common | Alopecia | |
| Uncommon | Lichenoid drug eruptions1 | |
| Very rare | Hypersensitivity vasculitis | |
| Musculoskeletal and connective tissue disorders | Very common | Pain in extremity |
| Very common | Musculoskeletal pain1 | |
| Rare | Osteonecrosis of the jaw1 | |
| Rare | Atypical femoral fractures1 | |
| Not Known | Osteonecrosis of the external auditory canal |
1 See section Description of selected adverse reactions.
In a pooled analysis of data from all phase II and phase III placebo-controlled studies, influenza-like illness was reported with a crude incidence rate of 1.2% for denosumab and 0.7% for placebo. Although this imbalance was identified via a pooled analysis, it was not identified via a stratified analysis.
In two phase III placebo-controlled clinical trials in postmenopausal women with osteoporosis, approximately 0.05% (2 out of 4,050) of patients had declines of serum calcium levels (less than 1.88 mmol/L) following denosumab administration. Declines of serum calcium levels (less than 1.88 mmol/L) were not reported in either the two phase III placebo-controlled clinical trials in patients receiving hormone ablation or the phase III placebo-controlled clinical trial in men with osteoporosis.
In the post-marketing setting, rare cases of severe symptomatic hypocalcaemia have been reported predominantly in patients at increased risk of hypocalcaemia receiving denosumab, with most cases occurring in the first weeks of initiating therapy. Examples of the clinical manifestations of severe symptomatic hypocalcaemia have included QT interval prolongation, tetany, seizures and altered mental status. Symptoms of hypocalcaemia in denosumab clinical studies included paraesthesias or muscle stiffness, twitching, spasms and muscle cramps.
In phase III placebo-controlled clinical trials, the overall incidence of skin infections was similar in the placebo and the denosumab groups: in postmenopausal women with osteoporosis (placebo [1.2%, 50 out of 4,041] versus denosumab [1.5%, 59 out of 4,050]); in men with osteoporosis (placebo [0.8%, 1 out of 120] versus denosumab [0%, 0 out of 120]); in breast or prostate cancer patients receiving hormone ablation (placebo [1.7%, 14 out of 845] versus denosumab [1.4%, 12 out of 860]). Skin infections leading to hospitalisation were reported in 0.1% (3 out of 4,041) of postmenopausal women with osteoporosis receiving placebo versus 0.4% (16 out of 4,050) of women receiving denosumab. These cases were predominantly cellulitis. Skin infections reported as serious adverse reactions were similar in the placebo (0.6%, 5 out of 845) and the denosumab (0.6%, 5 out of 860) groups in the breast and prostate cancer studies.
ONJ has been reported rarely, in 16 patients, in clinical trials in osteoporosis and in breast or prostate cancer patients receiving hormone ablation including a total of 23,148 patients. Thirteen of these ONJ cases occurred in postmenopausal women with osteoporosis during the phase III clinical trial extension following treatment with denosumab for up to 10 years. Incidence of ONJ was 0.04% at 3 years, 0.06% at 5 years and 0.44% at 10 years of denosumab treatment. The risk of ONJ increased with duration of exposure to denosumab.
The risk of ONJ has also been assessed in a retrospective cohort study among 76,192 postmenopausal women newly initiating treatment with denosumab. The incidence of ONJ was 0.32% (95% confidence interval [CI]: 0.26, 0.39) among patients using denosumab up to 3 years and 0.51% (95% CI: 0.39, 0.65) among patients using denosumab up to 5 years of follow-up.
In the osteoporosis clinical trial programme, atypical femoral fractures were reported rarely in patients treated with denosumab.
In a single phase III placebo-controlled clinical trial in patients with prostate cancer receiving androgen deprivation therapy (ADT), an imbalance in diverticulitis adverse events was observed (1.2% denosumab, 0% placebo). The incidence of diverticulitis was comparable between treatment groups in postmenopausal women or men with osteoporosis and in women undergoing aromatase inhibitor therapy for non-metastatic breast cancer.
In the post-marketing setting, rare events of drug-related hypersensitivity, including rash, urticaria, facial swelling, erythema, and anaphylactic reactions have been reported in patients receiving denosumab.
Musculoskeletal pain, including severe cases, has been reported in patients receiving denosumab in the post-marketing setting. In clinical trials, musculoskeletal pain was very common in both denosumab and placebo groups. Musculoskeletal pain leading to discontinuation of study treatment was uncommon.
Lichenoid drug eruptions (e.g. lichen planus-like reactions) have been reported in patients in the post-marketing setting.
Denosumab should not be used in paediatric patients (age <18). Serious hypercalcaemia has been reported. Some clinical trial cases were complicated by acute renal injury.
In clinical studies, patients with severe renal impairment (creatinine clearance <30 mL/min) or receiving dialysis were at greater risk of developing hypocalcaemia in the absence of calcium supplementation. Adequate intake of calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis.
Overall safety profile is consistent in all approved indications for denosumab.
Hypocalcaemia has very commonly been reported following denosumab administration, mostly within the first 2 weeks. Hypocalcaemia can be severe and symptomatic (see 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 denosumab are musculoskeletal pain. Cases of osteonecrosis of the jaw (see description of selected adverse reactions) have been commonly observed in patients taking denosumab.
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 2): 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 2. Adverse reactions reported in patients with advanced malignancies involving bone, multiple myeloma, or with giant cell tumour of bone:
| MedDRA system organ class | Frequency category | Adverse reactions |
|---|---|---|
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | Common | New primary malignancy1 |
| Immune system disorders | Rare | Drug hypersensitivity1 |
| Rare | Anaphylactic reaction1 | |
| Metabolism and nutrition disorders | Very common | Hypocalcaemia1,2 |
| Common | Hypophosphataemia | |
| Uncommon | Hypercalcaemia following treatment discontinuation in patients with giant cell tumour of bone | |
| Respiratory, thoracic and mediastinal disorders | Very common | Dyspnoea |
| Gastrointestinal disorders | Very common | Diarrhoea |
| Common | Tooth extraction | |
| Skin and subcutaneous tissue disorders | Common | Hyperhidrosis |
| Uncommon | Lichenoid drug eruptions1 | |
| Musculoskeletal and connective tissue disorders | Very common | Musculoskeletal pain1 |
| Common | Osteonecrosis of the jaw1 | |
| Uncommon | Atypical femoral fracture1 | |
| Not known | Osteonecrosis of the external auditory canal3 |
1 See section Description of selected adverse reactions
2 See section Other special populations
3 Class effect
A higher incidence of hypocalcaemia among subjects treated with denosumab compared to zoledronic acid has been observed in SRE prevention clinical studies.
The highest incidence of hypocalcaemia was observed in a phase III study in patients with multiple myeloma. Hypocalcaemia was reported in 16.9% of patients treated with denosumab 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 denosumab 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 denosumab and 0.1% of patients treated with zoledronic acid.
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 denosumab 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 denosumab 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 denosumab and 0.2% of patients treated with zoledronic acid.
In two phase II single-arm clinical studies in patients with giant cell tumour of bone, hypocalcaemia was reported in 5.7% of patients. None of the adverse events was considered serious. In the post-marketing setting, severe symptomatic hypocalcaemia (including fatal cases) has been reported, with most cases occurring in the first weeks of initiating therapy. Examples of clinical manifestations of severe symptomatic hypocalcaemia have included QT interval prolongation, tetany, seizures and altered mental status (including coma). Symptoms of hypocalcaemia in clinical studies included paraesthesias or muscle stiffness, twitching, spasms and muscle cramps.
In clinical studies, the incidence of ONJ was higher with longer duration of exposure; ONJ has also been diagnosed after stopping treatment with denosumab 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 studies.
A higher incidence of ONJ among subjects treated with denosumab compared to zoledronic acid has been observed in SRE prevention clinical studies. The highest incidence of ONJ was observed in a phase III study in patients with multiple myeloma. In the double-blind treatment phase of this study, ONJ was confirmed in 5.9% of patients treated with denosumab (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 study, the patient-year adjusted incidence of confirmed ONJ in the denosumab 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 studies in patients with advanced malignancies involving bone, ONJ was confirmed in 1.8% of patients treated with denosumab (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. Most subjects were receiving or had received chemotherapy.
The studies in patients with breast or prostate cancer included a denosumab 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-randomised, retrospective, observational study in 2 877 patients with cancer treated with denosumab 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 denosumab 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 denosumab was 6.6% (95% CI: 4.2, 10.0; median follow up time of 13 months [range 0.2 – 60]).
In a phase III study in patients with non-metastatic prostate cancer (a patient population for which denosumab 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 study in patients with giant cell tumour of bone (Study 6), ONJ was confirmed in 6.8% of patients, including one adolescent (median number of 34 doses; range 4 – 116). At the completion of the study, median time on study 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).
In the post-marketing setting, events of hypersensitivity, including rare events of anaphylactic reactions, have been reported in patients receiving denosumab.
In the clinical study programme, atypical femoral fractures have been reported uncommonly in patients treated with denosumab and the risk increased with longer duration of treatment. Events have occurred during treatment and up to 9 months after treatment was discontinued.
In the post-marketing setting, musculoskeletal pain, including severe cases, has been reported in patients receiving denosumab. In clinical studies, musculoskeletal pain was very common in both the denosumab and zoledronic acid treatment groups. Musculoskeletal pain leading to discontinuation of study treatment was uncommon.
In the primary double blind treatment phases of four phase III active-controlled clinical studies in patients with advanced malignancies involving bone, new primary malignancy was reported in 54/3 691 (1.5%) of patients treated with denosumab (median exposure of 13.8 months; range: 1.0 – 51.7) and 33/3 688 (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.
Lichenoid drug eruptions (e.g. lichen planus-like reactions), have been reported in patients in the post-marketing setting.
Denosumab was studied in an open-label study that enrolled 28 skeletally mature adolescents with giant cell tumour of bone. Based on these limited data, the adverse event profile appeared to be similar to adults.
Clinically significant hypercalcaemia after treatment discontinuation has been reported in the post-marketing setting in paediatric patients.
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. The risk of developing hypocalcaemia during denosumab 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 hypocalcaemia despite calcium supplementation. The overall incidence of clinically significant hypocalcaemia was 9%.
Accompanying increases in parathyroid hormone have also been observed in patients receiving denosumab 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.
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