denosumab: prescribing information – dosing, contraindications, interactions, side effects

Treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures. In postmenopausal women Prolia significantly reduces the risk of vertebral, non-vertebral and hip fractures.

Treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures (see section 5.1). In men with prostate cancer receiving hormone ablation, Prolia significantly reduces the risk of vertebral fractures.

Treatment of bone loss associated with long-term systemic glucocorticoid therapy in adult patients at increased risk of fracture (see section 5.1).

Posology

The recommended dose is 60 mg denosumab administered as a single subcutaneous injection once every 6 months into the thigh, abdomen or upper arm.

Patients must be adequately supplemented with calcium and vitamin D (see section 4.4).

Patients treated with Prolia should be given the package leaflet and the patient reminder card.

The optimal total duration of antiresorptive treatment for osteoporosis (including both denosumab and bisphosphonates) has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of denosumab on an individual patient basis, particularly after 5 or more years of use (see section 4.4).

Elderly (age ≥ 65)
No dose adjustment is required in elderly patients.

Renal impairment
No dose adjustment is required in patients with renal impairment (see section 4.4 for recommendations relating to monitoring of calcium).

No data is available in patients with long-term systemic glucocorticoid therapy and severe renal impairment (Glomerular filtration rate, GFR < 30 mL/min).

Hepatic impairment
The safety and efficacy of denosumab have not been studied in patients with hepatic impairment (see section 5.2).

Paediatric population
Prolia should not be used in children aged < 18 years because of safety concerns of serious hypercalcaemia, and potential inhibition of bone growth and lack of tooth eruption (see sections 4.4 and 5.3). Currently available data for children aged 2 to 17 years are described in sections 5.1 and 5.2.

Method of administration

For subcutaneous use.

Administration should be performed by an individual who has been adequately trained in injection techniques.

The instructions for use, handling and disposal are given in section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypocalcaemia (see section 4.4).

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 hypocalcaemia, 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 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 canal2
General disorders and administration site conditions
Uncommon
Injection site reactions3
1 See section Description of selected adverse reactions.
2 See section 4.4.
3 including injection site pain

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

Hypocalcaemia
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 hypocalcaemia resulting in hospitalisation, life-threatening events, and fatal cases 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 (see section 4.4).
Symptoms of hypocalcaemia in denosumab clinical studies included paraesthesias 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 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 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 18 patients, in clinical trials in osteoporosis and in breast or prostate cancer patients receiving hormone ablation including a total of 23 552 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.

The risk of ONJ has also been assessed in a retrospective cohort study among 76 192 postmenopausal women newly initiating treatment with Prolia. 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.

Atypical fractures of the femur
In the osteoporosis clinical trial programme, 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.

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

Other special populations

Paediatric population
Prolia should not be used in paediatric patients (age < 18). Serious hypercalcaemia has been reported (see section 5.1). 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 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 (see section 4.4).

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 Appendix V.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Calcium and vitamin D supplementation

Adequate intake of calcium and vitamin D is important in all patients.

Precautions for use

Hypocalcaemia
It is important to identify patients at risk for hypocalcaemia. Hypocalcaemia must be corrected by adequate intake of calcium and vitamin D before initiating therapy. Clinical monitoring of calcium levels is recommended before each dose and, in patients predisposed to hypocalcaemia within two weeks, after the initial dose. If any patient presents with suspected symptoms of hypocalcaemia during treatment (see section 4.8 for symptoms) calcium levels should be measured. Patients should be encouraged to report symptoms indicative of hypocalcaemia.

In the post-marketing setting, severe symptomatic hypocalcaemia (resulting in hospitalisation, life-threatening events, and fatal cases) have been reported. While most cases occurred in the first few weeks of initiating therapy, it has also occurred later.

Concomitant glucocorticoid treatment is an additional risk factor for hypocalcaemia.

Renal 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. Severe and fatal cases have been reported. Adequate intake of calcium, vitamin D and regular monitoring of calcium is especially important in these patients, see above.

Skin infections
Patients receiving denosumab may develop skin infections (predominantly cellulitis) leading to hospitalisation (see section 4.8). Patients should be advised to seek prompt medical attention if they develop signs or symptoms of cellulitis.

Osteonecrosis of the jaw (ONJ)
ONJ has been reported rarely in patients receiving Prolia for osteoporosis (see section 4.8).

The start of treatment/new treatment course should be delayed in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with denosumab in patients with concomitant risk factors.

The following risk factors should be considered when evaluating a patient’s risk of developing ONJ:
- potency of the medicinal product that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy.
- cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.
- concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck.
- poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures (e.g. tooth extractions).

All patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling or non-healing of sores or discharge during treatment with denosumab. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to denosumab administration.

The management plan of the patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

Osteonecrosis of the external auditory canal
Osteonecrosis of the external auditory canal has been reported with denosumab. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving denosumab who present with ear symptoms including chronic ear infections.

Atypical fractures of the femur
Atypical femoral fractures have been reported in patients receiving denosumab (see section 4.8).
Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal

regions of the femur. Specific radiographic findings characterise these events. Atypical femoral fractures have also been reported in patients with certain co-morbid conditions (e.g. vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and with use of certain medicinal products (e.g. bisphosphonates, glucocorticoids, proton pump inhibitors). These events have also occurred without antiresorptive therapy. Similar fractures reported in association with bisphosphonates are often bilateral; therefore, the contralateral femur should be examined in denosumab-treated patients who have sustained a femoral shaft fracture. Discontinuation of denosumab therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient based on an individual benefit-risk assessment. During denosumab treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture.

Long-term antiresorptive treatment
Long-term antiresorptive treatment (including both denosumab and bisphosphonates) may contribute to an increased risk for adverse outcomes such as osteonecrosis of the jaw and atypical femur fractures due to significant suppression of bone remodelling (see section 4.2).

Treatment discontinuation
Following denosumab discontinuation, decrease in bone mineral density (BMD) is expected (see section 5.1), leading to an increased risk for fractures. Thus, monitoring of BMD is recommended, and alternative treatment should be considered according to clinical guidelines.

Concomitant treatment with other denosumab-containing medicinal products
Patients being treated with denosumab should not be treated concomitantly with other denosumab-containing medicinal products (for prevention of skeletal related events in adults with bone metastases from solid tumours).

Hypercalcaemia in paediatric patients
Prolia should not be used in paediatric patients (age < 18). Serious hypercalcaemia has been reported.
Some clinical trial cases were complicated by acute renal injury.

Warnings for excipients
This medicine contains 47 mg sorbitol in each mL of solution. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

This medicinal product contains less than 1 mmol sodium (23 mg) per 60 mg that is to say essentially ‘sodium-free’.

This medicinal product contains 0.1 mg of polysorbate 20 in each mL of solution.
Polysorbates may cause allergic reactions.

In an interaction study, denosumab did not affect the pharmacokinetics of midazolam, which is metabolised by cytochrome P450 3A4 (CYP3A4). This indicates that denosumab should not alter the pharmacokinetics of medicinal products metabolised by CYP3A4.

There are no clinical data on the co-administration of denosumab and hormone replacement therapy (oestrogen), however the potential for a pharmacodynamic interaction is considered to be low.

In postmenopausal women with osteoporosis the pharmacokinetics and pharmacodynamics of denosumab were not altered by previous alendronate therapy, based on data from a transition study (alendronate to denosumab).

Pregnancy

There are no or limited amount of data from the use of denosumab in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Prolia 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 Prolia. 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.

Breast-feeding

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 see section 5.1) during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum (see section 5.3). A decision on whether to abstain from breast-feeding or to abstain from therapy with Prolia should be made, taking into account the benefit of breast-feeding to the newborn/infant and the benefit of Prolia therapy to the woman.

Fertility

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 (see section 5.3).

Prolia has no or negligible influence on the ability to drive and use machines.

There is no experience with overdose in clinical studies. Denosumab has been administered in clinical studies using doses up to 180 mg every 4 weeks (cumulative doses up to 1 080 mg over 6 months), and no additional adverse reactions were observed.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Drugs for treatment of bone diseases – Other drugs affecting bone structure and mineralisation, ATC code: M05BX04

Mechanism of action

Denosumab is a human monoclonal antibody (IgG2) that targets and binds with high affinity and specificity to RANKL, preventing activation of its receptor, RANK, on the surface of osteoclast precursors and osteoclasts. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function and survival, thereby decreasing bone resorption in cortical and trabecular bone.

Pharmacodynamic effects

Prolia treatment rapidly reduced the rate of bone turnover, reaching a nadir for the bone resorption marker serum type 1 C-telopeptides (CTX) (85% reduction) by 3 days, with reductions maintained over the dosing interval. At the end of each dosing interval, CTX reductions were partially attenuated from maximal reduction of ≥ 87% to approximately ≥ 45% (range 45-80%), reflecting the reversibility of Prolia’s effects on bone remodelling once serum levels diminish. These effects were sustained with continued treatment. Bone turnover markers generally reached pre-treatment levels within 9 months after the last dose. Upon re-initiation, reductions in CTX by denosumab were similar to those observed in patients initiating primary denosumab treatment.

Immunogenicity

In clinical studies, neutralising antibodies have not been observed for denosumab. Using a sensitive immunoassay < 1% of patients treated with denosumab for up to 5 years tested positive for non-neutralising binding antibodies with no evidence of altered pharmacokinetics, toxicity, or clinical response.

Clinical efficacy and safety in postmenopausal women with osteoporosis

Efficacy and safety of denosumab administered once every 6 months for 3 years were investigated in postmenopausal women (7 808 women aged 60-91 years, of which 23.6% had prevalent vertebral fractures) with baseline bone mineral density (BMD) T-scores at the lumbar spine or total hip between –2.5 and –4.0 and a mean absolute 10-year fracture probability of 18.60% (deciles: 7.9-32.4%) for major osteoporotic fracture and 7.22% (deciles: 1.4-14.9%) for hip fracture. Women with other diseases or on therapies that may affect bone were excluded from this study. Women received calcium (at least 1 000 mg) and vitamin D (at least 400 IU) supplementation daily.

Effect on vertebral fractures
Prolia significantly reduced the risk of new vertebral fractures at 1, 2 and 3 years (p < 0.0001) (see table 2).

Table 2. The effect of Prolia on the risk of new vertebral fractures

Proportion of women with fracture (%)
Absolute risk reduction (%)
(95% CI)
Relative risk reduction (%)
(95% CI)
Placebo n = 3 906
Prolia n = 3 902
0-1 year

Absorption

Following subcutaneous administration of a 1.0 mg/kg dose, which approximates the approved 60 mg dose, exposure based on AUC was 78% as compared to intravenous administration at the same dose level. For a 60 mg subcutaneous dose, maximum serum denosumab concentrations (Cmax) of 6 mcg/mL (range 1-17 mcg/mL) occurred in 10 days (range 2-28 days).

Biotransformation

Denosumab is composed solely of amino acids and carbohydrates as native immunoglobulin and is unlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids.

Elimination

After Cmax, serum levels declined with a half-life of 26 days (range 6-52 days) over a period of 3 months (range 1.5-4.5 months). Fifty-three percent (53%) of patients had no measurable amounts of denosumab detected at 6 months post-dose.

No accumulation or change in denosumab pharmacokinetics with time was observed upon subcutaneous multiple-dosing of 60 mg once every 6 months. Denosumab pharmacokinetics were not affected by the formation of binding antibodies to denosumab and were similar in men and women.
Age (28-87 years), race and disease state (low bone mass or osteoporosis; prostate or breast cancer) do not appear to significantly affect the pharmacokinetics of denosumab.

A trend was observed between higher body weight and lower exposure based on AUC and Cmax.
However, the trend is not considered clinically important, since pharmacodynamic effects based on bone turnover markers and BMD increases were consistent across a wide range of body weight.

Linearity/non-linearity

In dose ranging studies, denosumab exhibited non-linear, dose-dependent pharmacokinetics, with lower clearance at higher doses or concentrations, but approximately dose-proportional increases in exposures for doses of 60 mg and greater.

Renal impairment

Prevention of skeletal related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with advanced malignancies involving bone (see section 5.1).

Treatment of adults and skeletally mature adolescents with giant cell tumour of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

XGEVA should be administered under the responsibility of a healthcare professional.

Posology

Supplementation of at least 500 mg calcium and 400 IU vitamin D daily is required in all patients, unless hypercalcaemia is present (see section 4.4).

Patients treated with XGEVA should be given the package leaflet and the patient reminder card.

Prevention of skeletal related events in adults with advanced malignancies involving bone The recommended dose is 120 mg administered as a single subcutaneous injection once every 4 weeks into the thigh, abdomen or upper arm.

Giant cell tumour of bone
The recommended dose of XGEVA is 120 mg administered as a single subcutaneous injection once every 4 weeks into the thigh, abdomen or upper arm with additional 120 mg doses on days 8 and 15 of treatment of the first month of therapy.

Patients in the phase II study who underwent complete resection of giant cell tumour of bone did receive an additional 6 months of treatment following the surgery as per study protocol.

Patients with giant cell tumour of bone should be evaluated at regular intervals to determine whether they continue to benefit from treatment. In patients whose disease is controlled by XGEVA, the effect of interruption or cessation of treatment has not been evaluated, however limited data in these patients does not indicate a rebound effect upon cessation of treatment.

Renal impairment
No dose adjustment is required in patients with renal impairment (see sections 4.4 for recommendations relating to monitoring of calcium, 4.8 and 5.2).

Hepatic impairment
The safety and efficacy of denosumab have not been studied in patients with hepatic impairment (see section 5.2).

Elderly patients (age ≥ 65)
No dose adjustment is required in elderly patients (see section 5.2).

Paediatric population
The safety and efficacy of XGEVA have not been established in paediatric patients (age < 18) other than skeletally mature adolescents (aged 12-17 years) with giant cell tumour of bone.

XGEVA is not recommended in paediatric patients (age < 18) other than skeletally mature adolescents (aged 12-17 years) with giant cell tumour of bone (see section 4.4).

Treatment of skeletally mature adolescents with giant cell tumour of bone that is unresectable or where surgical resection is likely to result in severe morbidity: the posology is the same as in adults.

Inhibition of RANK/RANK ligand (RANKL) in animal studies has been coupled to inhibition of bone growth and lack of tooth eruption, and these changes were partially reversible upon cessation of RANKL inhibition (see section 5.3).

Method of administration

For subcutaneous use.

The XGEVA 120 mg/1.7 mL solution in a single use vial:
The administration of the 120 mg/1.7 mL vial should only be performed by a healthcare professional.

The XGEVA 120 mg/1.0 mL solution in a pre-filled syringe:
The administration using the 120 mg/1.0 mL pre-filled syringe can be administered by a patient or caregiver who has been trained in injection techniques by a healthcare professional. The first self-administration with the XGEVA pre-filled syringe should be supervised by a healthcare professional.

For instructions for use, handling and disposal see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Severe, untreated hypocalcaemia (see section 4.4).

Unhealed lesions from dental or oral surgery.

Summary of the safety profile

Overall safety profile is consistent in all approved indications for XGEVA.

Hypocalcaemia has very commonly been reported following XGEVA administration, mostly within the first 2 weeks. Hypocalcaemia 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 tumour of bone

MedDRA system organ class
Frequency category
Adverse reactions
Neoplasms benign, malignant and unspecified
(including cysts and polyps)
Common
New primary malignancy1

MedDRA system organ class
Frequency category
Adverse reactions
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 bone3 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 canal3,4 General disorders and administration site conditions Uncommon Injection site reactions5 1 See section Description of selected adverse reactions 2 See section Other special populations 3 See section 4.4 4 Class effect 5 Including injection site pain.

Description of selected adverse reactions

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

The highest incidence of hypocalcaemia was observed in a phase III trial in patients with multiple myeloma. Hypocalcaemia 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, hypocalcaemia 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 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) (see section 4.4). Symptoms of hypocalcaemia in clinical studies included paraesthesias 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-randomised, 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 tumour 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 subjects 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 programme 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 programme 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 tumour 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 tumour 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.

Paediatric population

XGEVA was studied in an open-label trial 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 (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 hypocalcaemia in the absence of calcium supplementation. The risk of developing hypocalcaemia 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 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 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 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 Appendix V.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Calcium and Vitamin D supplementation

Supplementation with calcium and vitamin D is required in all patients unless hypercalcaemia is present (see section 4.2).

Hypocalcaemia

Pre-existing hypocalcaemia must be corrected prior to initiating therapy with XGEVA.
Hypocalcaemia can occur at any time during therapy with XGEVA. Monitoring of calcium levels should be conducted (i) prior to the initial dose of XGEVA, (ii) within two weeks after the initial dose, (iii) if suspected symptoms of hypocalcaemia occur (see section 4.8 for symptoms). Additional monitoring of calcium level should be considered during therapy in patients with risk factors for hypocalcaemia, or if otherwise indicated based on the clinical condition of the patient.

Patients should be encouraged to report symptoms indicative of hypocalcaemia. If hypocalcaemia occurs while receiving XGEVA, additional calcium supplementation and additional monitoring may be necessary.

In the post-marketing setting, severe symptomatic hypocalcaemia (including fatal cases) has been reported (see section 4.8), with most cases occurring in the first weeks of initiating therapy, but can occur later.

Renal impairment

Patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis are at greater risk of developing hypocalcaemia. The risk of developing hypocalcaemia and accompanying elevations in parathyroid hormone increases with increasing degree of renal impairment. Regular monitoring of calcium levels is especially important in these patients.

Osteonecrosis of the jaw (ONJ)

ONJ has been reported commonly in patients receiving XGEVA (see section 4.8).

The start of treatment/new treatment course should be delayed in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with denosumab.

The following risk factors should be considered when evaluating a patient’s risk of developing ONJ:
- potency of the medicinal product that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy.
- cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.

• concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck.
• poor oral hygiene, periodontal disease, poorly fitting dentures, pre-existing dental disease, invasive dental procedures (e.g. tooth extractions).

All patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with denosumab. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to XGEVA administration.

The management plan of the patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of XGEVA treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with denosumab. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving denosumab who present with ear symptoms including chronic ear infections.

Atypical fractures of the femur

Atypical femoral fractures have been reported in patients receiving denosumab (see section 4.8).
Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur. Specific radiographic findings characterise these events. Atypical femoral fractures have also been reported in patients with certain co-morbid conditions (e.g. vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and with use of certain pharmaceutical agents (e.g.
bisphosphonates, glucocorticoids, proton pump inhibitors). These events have also occurred without antiresorptive therapy. Similar fractures reported in association with bisphosphonates are often bilateral; therefore the contralateral femur should be examined in denosumab-treated patients who have sustained a femoral shaft fracture. Discontinuation of XGEVA therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient based on an individual benefit-risk assessment. During denosumab treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture.

Hypercalcaemia following treatment discontinuation in patients with giant cell tumour of bone and in patients with growing skeletons

Clinically significant hypercalcaemia requiring hospitalisation and complicated by acute renal injury has been reported in XGEVA-treated patients with giant cell tumour of bone weeks to months following treatment discontinuation.

After treatment is discontinued, monitor patients for signs and symptoms of hypercalcaemia, consider periodic assessment of serum calcium and re-evaluate the patient’s calcium and vitamin D supplementation requirements (see section 4.8).

XGEVA is not recommended in patients with growing skeletons (see section 4.2). Clinically significant hypercalcaemia has also been reported in this patient group weeks to months following treatment discontinuation.

Others

Patients being treated with XGEVA should not be treated concomitantly with other denosumab containing medicinal products (for osteoporosis indications).

Patients being treated with XGEVA should not be treated concomitantly with bisphosphonates.

Malignancy in giant cell tumour of bone or progression to metastatic disease is an infrequent event and a known risk in patients with giant cell tumour of bone. Patients should be monitored for radiological signs of malignancy, new radiolucency or osteolysis. Available clinical data does not suggest an increased risk of malignancy in giant cell tumour of bone patients treated with XGEVA.

Warnings for excipients

This medicinal product contains sorbitol. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

This medicinal product contains less than 1 mmol sodium (23 mg) per 120 mg dose, that is to say essentially ‘sodium-free’.

This medicinal product contains 0.17 mg of polysorbate 20 in each 1.7 mL vial solution.
This medicinal product contains 0.1 mg of polysorbate 20 in each 1.0 mL PFS solution.
Polysorbates may cause allergic reactions.

Patients with Phenylketonuria (PKU)

The XGEVA 120 mg/1.7 mL solution in a single use vial does not contain phenylalanine. Patients with PKU should be administered XGEVA from the single use vial containing 120 mg in 1.7 mL solution.

Each XGEVA 120 mg/1.0 mL solution in a single dose pre-filled syringe contains 6.1 mg of phenylalanine. Phenylalanine may be harmful to patients with phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up because the body cannot remove it properly.

No interaction studies have been performed.

In clinical trials, XGEVA has been administered in combination with standard anti-cancer treatment and in patients previously receiving bisphosphonates. There were no clinically-relevant alterations in trough serum concentration and pharmacodynamics of denosumab (creatinine adjusted urinary N-telopeptide, uNTX/Cr) by concomitant chemotherapy and/or hormone therapy or by previous intravenous bisphosphonate exposure.

Pregnancy

There are no or limited amount of data from the use of denosumab in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

XGEVA 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 XGEVA. Any effects of XGEVA 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.

Breast-feeding

It is unknown whether denosumab is excreted in human milk. A risk to the newborns/infants cannot be excluded. Knockout mouse studies suggest absence of RANKL during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum (see section 5.3). A decision must be made on whether to abstain from breast-feeding or to abstain from XGEVA therapy taking into account the benefit of breast-feeding to the newborn/infant and the benefit of therapy for the woman.

Fertility

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 (see section 5.3).

XGEVA has no or negligible influence on the ability to drive and use machines.

There is no experience with overdose in clinical studies. XGEVA has been administered in clinical studies using doses up to 180 mg every 4 weeks and 120 mg weekly for 3 weeks.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Drugs for treatment of bone diseases – other drugs affecting bone structure and mineralisation, ATC code: M05BX04

Mechanism of action

RANKL exists as a transmembrane or soluble protein. RANKL is essential for the formation, function and survival of osteoclasts, the sole cell type responsible for bone resorption. Increased osteoclast activity, stimulated by RANKL, is a key mediator of bone destruction in metastatic bone disease and multiple myeloma. Denosumab is a human monoclonal antibody (IgG2) that targets and binds with high affinity and specificity to RANKL, preventing the RANKL/RANK interaction from occurring and resulting in reduced osteoclast numbers and function, thereby decreasing bone resorption and cancer-induced bone destruction.

Giant cell tumours of bone are characterised by neoplastic stromal cells expressing RANK ligand and osteoclast-like giant cells expressing RANK. In patients with giant cell tumour of bone, denosumab binds to RANK ligand, significantly reducing or eliminating osteoclast-like giant cells. Consequently, osteolysis is reduced and proliferative tumour stroma is replaced with non-proliferative, differentiated, densely woven new bone.

Pharmacodynamic effects

In phase II clinical studies of patients with advanced malignancies involving bone, subcutaneous (SC) dosing of XGEVA administered either every 4 weeks (Q4W) or every 12 weeks resulted in a rapid reduction in markers of bone resorption (uNTX/Cr, serum CTx), with median reductions of approximately 80% for uNTX/Cr occurring within 1 week regardless of prior bisphosphonate therapy or baseline uNTX/Cr level. In phase III clinical trials of patients with advanced malignancies involving bone, median uNTX/Cr reductions of approximately 80% were maintained through 49 weeks of XGEVA treatment (120 mg every Q4W).

Immunogenicity

In clinical studies, neutralising antibodies have not been observed for denosumab in advanced cancer patients or giant cell tumour of bone patients. Using a sensitive immunoassay < 1% of patients treated with denosumab for up to 3 years tested positive for non neutralising binding antibodies with no evidence of altered pharmacokinetics, toxicity, or clinical response.

Clinical efficacy and safety in patients with bone metastases from solid tumours

Absorption

Following subcutaneous administration, bioavailability was 62%.

Biotransformation

Denosumab is composed solely of amino acids and carbohydrates as native immunoglobulin and is unlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids.

Elimination

In patients with advanced cancer, who received multiple doses of 120 mg every 4 weeks an approximate 2-fold accumulation in serum denosumab concentrations was observed and steady-state was achieved by 6 months, consistent with time-independent pharmacokinetics. In patients with multiple myeloma who received 120 mg every 4 weeks, median trough levels varied by less than 8% between months 6 and 12. In patients with giant cell tumour of bone who received 120 mg every 4 weeks with a loading dose on days 8 and 15, steady-state levels were achieved within the first month of treatment. Between weeks 9 and 49, median trough levels varied by less than 9%. In patients who discontinued 120 mg every 4 weeks, the mean half-life was 28 days (range 14 to 55 days).

A population pharmacokinetic analysis did not indicate clinically significant changes in the systemic exposure of denosumab at steady-state with respect to age (18 to 87 years), race/ethnicity (Blacks, Hispanics, Asians and Caucasians explored), gender or solid tumour types or patients with multiple myeloma. Increasing body weight was associated with decreases in systemic exposure, and vice versa.
The alterations were not considered clinically-relevant, since pharmacodynamic effects based on bone turnover markers were consistent across a wide range of body weight.

Linearity/non-linearity

Denosumab displayed non-linear pharmacokinetics with dose over a wide dose range, but approximately dose-proportional increases in exposure for doses of 60 mg (or 1 mg/kg) and higher.