Adverse reactions : תופעות לוואי

4.8    Undesirable effects
Summary of the safety profile

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 hypocalcemia, hypersensitivity, osteonecrosis of the jaw and atypical femoral fractures (see sections 4.4 and 4.8 - description of selected adverse reactions) have been observed in patients taking denosumab.

Tabulated list of adverse reactions

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             Rare                            Hypocalcemia1 disorders
Nervous system disorders             Common                          Sciatica Gastrointestinal disorders           Common                          Constipation Common                          Abdominal discomfort
Skin and subcutaneous tissue         Common                          Rash disorders                            Common                          Eczema Common                          Alopecia
Uncommon                        Lichenoid drug eruptions1
Very rare                       Hypersensitivity vasculitis
Not known                       Drug reaction with eosinophilia and systemic symptoms
(DRESS) syndrome1
Musculoskeletal and                  Very common                     Pain in extremity connective tissue disorders          Very common                     Musculoskeletal pain1 Uncommon                        Multiple vertebral fractures1 following treatment discontinuation
Rare                            Osteonecrosis of the jaw1
Rare                            Atypical femoral fractures1
Not known                       Osteonecrosis of the external auditory canal2

1
See section Description of selected adverse reactions.
2
See section 4.4.

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.

Description of selected adverse reactions

Hypocalcemia
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 Prolia 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 hypocalcemia resulting in hospitalization, life-threatening events, and fatal cases have been reported, predominantly in patients at increased risk of hypocalcemia receiving denosumab, with most cases occurring in the first weeks of initiating therapy. Examples of the clinical manifestations of severe symptomatic hypocalcemia have included QT interval prolongation, tetany, seizures and altered mental status (see section 4.4).
Symptoms of hypocalcemia in denosumab clinical studies included paresthesias or muscle stiffness, twitching, spasms and muscle cramps.

Skin infections
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 Prolia [1.5%, 59 out of 4,050]); in men with osteoporosis (placebo [0.8%, 1 out of 120] versus Prolia [0%, 0 out of 120]); in breast or prostate cancer patients receiving hormone ablation (placebo [1.7%, 14 out of 845] versus Prolia [1.4%, 12 out of 860]). Skin infections leading to hospitalization 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 Prolia. 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 Prolia (0.6%, 5 out of 860) groups in the breast and prostate cancer studies.

Osteonecrosis of the jaw
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 (see section 4.4).
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.

Atypical fractures of the femur
In the osteoporosis clinical trial program, atypical femoral fractures were reported rarely in patients treated with denosumab (see section 4.4).

Diverticulitis
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.


Drug-related hypersensitivity reactions
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 Prolia.

Musculoskeletal pain
Musculoskeletal pain, including severe cases, has been reported in patients receiving Prolia 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.

Multiple vertebral fractures (MVF) following discontinuation of Prolia treatment In the osteoporosis clinical trial program, MVF were reported in patients following discontinuation of treatment with Prolia, particularly in those with a history of vertebral fracture.

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

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, have been reported in patients in the post-marketing setting.

Other special populations

Pediatric population
Prolia should not be used in pediatric patients (age < 18). Serious hypercalcemia has been reported.
Some clinical trial cases were complicated by acute renal injury.
Renal impairment
In clinical studies, patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis were at greater risk of developing hypocalcemia in the absence of calcium supplementation. Adequate intake of calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis (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