- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
PosologyThe recommended dose of XGEVA is 120 mg administered as a single subcutaneous injection once every 4 weeks into the thigh, abdomen or upper arm. 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 with renal impairmentNo dose adjustment is required in patients with renal impairment (see section 5.2). Experience in patients on dialysis or with severe renal impairment (creatinine clearance < 30 ml/min) is limited (see section 4.4 for recommendations relating to monitoring of calcium).
Patients with hepatic impairmentThe 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 populationXGEVA is not recommended in paediatric patients (age < 18) as the safety and efficacy of XGEVA in these patients have not been established. 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 administrationFor subcutaneous use.XGEVA should be administered under the responsibility of a healthcare professional.The instructions for use, handling and disposal are given in section 6.6.
Calcium and Vitamin D supplementationSupplementation with calcium and vitamin D is required in all patients unless hypercalcaemia is present (see section 4.2).
HypocalcaemiaPre-existing hypocalcaemia must be corrected prior to initiating therapy with XGEVA. Hypocalcaemia can occur at any time during therapy with XGEVA and most commonly occurs within the first 6 months of dosing. Patients with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis are at greater risk of developing hypocalcaemia. Monitoring of calcium levels in these patients is recommended. If hypocalcaemia occurs while receiving XGEVA, additional calcium supplementation may be necessary.In the post marketing setting, severe symptomatic hypocalcaemia (including fatal cases) has been reported (see section 4.8).
Osteonecrosis of the jawOsteonecrosis of the jaw (ONJ) has occurred in patients treated with XGEVA . In clinical trials, the incidence of ONJ was higher with longer duration of exposure (see section 4.8). Patients who developed ONJ in clinical studies generally had known risk factors for ONJ, including invasive dental procedures (e.g., tooth extraction, dental implants, oral surgery), poor oral hygiene or other pre-existing dental disease, advanced malignancies, infections, or concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors, radiotherapy to the head and neck). A dental examination with appropriate preventive dentistry should be considered prior to treatment with XGEVA in patients with active dental and jaw conditions (as listed above). While on treatment, patients should avoid invasive dental procedures if possible. Good oral hygiene practices should be maintained during treatment with XGEVA. Patients who are suspected of having or who develop ONJ while on XGEVA therapy should receive care by a dentist or oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. An individual risk/benefit evaluation should be done for each patient before prescribing XGEVA in patients with unavoidable risk factors for ONJ; and in patients who have developed ONJ during treatment with XGEVA.
Atypical fractures of the femurAtypical femoral fractures have been reported in patients receiving XGEVA (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 comorbid conditions (e.g. vitamin D deficiency, rheumatoid arthiritis, 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 XGEVA 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.
OthersPatients 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.
Warnings for excipientsPatients with rare hereditary problems of fructose intolerance should not use XGEVA.
PregnancyThere are no adequate data from the use of XGEVA in pregnant women. Reproductive toxicity was shown in a study of cynomolgus monkeys, dosed throughout pregnancy with denosumab at AUC exposures 12-fold higher than the human dose (see section 5.3). XGEVA is not recommended for use in pregnant women and women of childbearing potential not using contraception.Women who become pregnant during XGEVA treatment are encouraged to enrol in Amgen's Pregnancy Surveillance Programme. Contact details are provided in section 6 of the Package Leaflet.
Breast-feedingIt is unknown whether denosumab is excreted in human milk. 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 on whether to abstain from breast-feeding or to abstain from therapy with XGEVA should be made, taking into account the benefit of breast-feeding to the newborn/infant and the benefit of XGEVA therapy to the woman.Women who are nursing during XGEVA treatment are encouraged to enrol in Amgen's Lactation Surveillance Programme. Contact details are provided in section 6 of the Package Leaflet.
FertilityNo 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).
Summary of the safety profileThe safety of XGEVA was evaluated in:• 5,931 patients with advanced malignancies involving bone and is derived from active-controlled, clinical trials examining the efficacy and safety of XGEVA versus zoledronic acid in preventing the occurrence of skeletal related events. The adverse reactions are presented in table 1.
Tabulated list of adverse reactionsThe following convention has been used for the classification of the adverse reactions reported in three phase III and one phase II clinical studies (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) and very rare (< 1/10,000). 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
|MedDRA system organ class||Frequency category||Adverse reactions|
|Immune system disorder||Rare||Drug hypersensitivity1|
|Metabolism and nutrition disorders||Common||Hypocalcaemia1|
|Respiratory, thoracic and mediastinal disorders||Very common||Dyspnoea|
|Gastrointestinal disorders||Very common||Diarrhoea|
|Skin and subcutaneous tissues disorders||Common||Hyperhidrosis|
|Musculoskeletal and connective tissue disorders||Common||Osteonecrosis of the jaw1|
|Rare||Atypical femoral fracture1|
Description of selected adverse reactions
HypocalcaemiaIn 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).Symptoms of hypocalcaemia in clinical studies included paresthesias or muscle stiffness, twitching, spasms and muscle cramps.In the post-marketing setting, severe symptomatic hypocalcaemia (including fatal cases) has been reported.
Osteonecrosis of the jaw (ONJ)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 subjects with confirmed ONJ, most (81% in both treatment groups) had a history of tooth extraction, poor oral hygiene, and/or use of a dental appliance. In addition most subjects were receiving or had received chemotherapy. The 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). The patient-year adjusted incidence of confirmed ONJ was 1.1% during the first year of treatment and 4.1% thereafter. The median time to ONJ was 20.6 months (range: 4 - 53). Patients with certain identified risk factors for ONJ were excluded from participation in the pivotal studies.
Drug related hypersensitivity reactionsIn the post-marketing setting, events of hypersensitivity, including rare events of anaphylactic reactions, have been reported in patients receiving XGEVA.
Atypical fractures of the femurIn the clinical trial program, atypical femoral fractures were reported rarely in patients treated with denosumab (see section 4.4).
Other special populationsIn 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.
Reporting of suspected adverse reactionsReporting 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:
United KingdomYellow Card SchemeTel: Freephone 0808 100 3352Website: www.mhra.gov.uk/yellowcard
IrelandPharmacovigilance SectionIrish Medicines BoardKevin O'Malley HouseEarlsfort CentreEarlsfort TerraceIRL - Dublin 2Tel: +353 1 6764971Fax: +353 1 6762517Website: www.imb.iee-mail: email@example.com
Mechanism of actionRANKL 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.
Pharmacodynamic effectsIn phase II clinical studies of patients with advanced malignancies involving bone, subcutaneous (SC) dosing of XGEVA administered either every 4 weeks 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 the phase III clinical trials, median reductions of approximately 80% were maintained in uNTx/Cr after 3 months of treatment in 2075 XGEVA-treated advanced cancer patients naïve to IV-bisphosphonate.
ImmunogenicityIn clinical studies, neutralising antibodies have not been observed for XGEVA. 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 in patients with bone metastases from solid tumoursEfficacy and safety of 120 mg XGEVA SC every 4 weeks or 4 mg zoledronic acid (dose-adjusted for reduced renal function) IV every 4 weeks were compared in three randomised, double blind, active controlled studies, in IV-bisphosphonate naïve patients with advanced malignancies involving bone: adults with breast cancer (study 1), other solid tumours or multiple myeloma (study 2), and castrate-resistant prostate cancer (study 3). 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 not eligible for inclusion in these studies. The primary and secondary endpoints evaluated the occurrence of one or more skeletal related events (SREs). In studies demonstrating superiority of XGEVA to zoledronic acid, patients were offered open label XGEVA in a pre-specified 2-year extension treatment phase.XGEVA reduced the risk of developing a SRE, and developing multiple SREs (first and subsequent) in patients with bone metastases from solid tumours (see table 2).
Table 2: Efficacy results in patients with advanced malignancies involving bone
|Study 1breast cancer||Study 2 other solid tumours** or multiple myeloma||Study 3prostate cancer||Combinedadvanced cancer|
|XGEVA||zoledronic acid||XGEVA||zoledronic acid||XGEVA||zoledronic acid||XGEVA||zoledronic acid|
|Median time (months)||NR||26.4||20.6||16.3||20.7||17.1||27.6||19.4|
|Difference in median time (months)||NA||4.2||3.5||8.2|
|HR (95% CI) / RRR (%)||0.82 (0.71, 0.95) / 18||0.84 (0.71, 0.98) / 16||0.82 (0.71, 0.95) / 18||0.83 (0.76, 0.90) / 17|
|Non-inferiority / Superiority p-values||< 0.0001 / 0.0101||0.0007 / 0.0619||0.0002 / 0.0085||< 0.0001 / < 0.0001|
|Proportion of subjects (%)||30.7||36.5||31.4||36.3||35.9||40.6||32.6||37.8|
|First and subsequent SRE*|
|Rate ratio (95% CI) / RRR (%)||0.77 (0.66, 0.89) / 23||0.90 (0.77, 1.04) / 10||0.82 (0.71, 0.94) / 18||0.82 (0.75, 0.89) / 18|
|Superiority p-value||0.0012||0.1447||0.0085||< 0.0001|
|SMR per Year||0.45||0.58||0.86||1.04||0.79||0.83||0.69||0.81|
|First SRE or HCM|
|Median time (months)||NR||25.2||19.0||14.4||20.3||17.1||26.6||19.4|
|HR (95% CI) / RRR (%)||0.82 (0.70, 0.95) / 18||0.83 (0.71, 0.97) / 17||0.83 (0.72, 0.96) / 17||0.83 (0.76, 0.90) / 17|
|Superiority p-value||0.0074||0.0215||0.0134||< 0.0001|
|First radiation to bone|
|Median time (months)||NR||NR||NR||NR||NR||28.6||NR||33.2|
|HR (95% CI) / RRR (%)||0.74 (0.59, 0.94) / 26||0.78 (0.63, 0.97) / 22||0.78 (0.66, 0.94) / 22||0.77 (0.69, 0.87) / 23|
|Superiority p-value||0.0121||0.0256||0.0071||< 0.0001|
Disease progression and overall survivalDisease progression was similar between XGEVA and zoledronic acid in all three studies and in the pre-specified analysis of all three-studies combined.In all three studies overall survival was balanced between XGEVA and zoledronic acid in patients with advanced malignancies involving bone: patients with breast cancer (hazard ratio and 95% CI was 0.95 [0.81, 1.11]), patients with prostate cancer (hazard ratio and 95% CI was 1.03 [0.91, 1.17]), and patients with other solid tumours or multiple myeloma (hazard ratio and 95% CI was 0.95 [0.83, 1.08]). A post-hoc analysis in study 2 (patients with other solid tumours or multiple myeloma) examined overall survival for the 3 tumour types used for stratification (non-small cell lung cancer, multiple myeloma, and other). Overall survival was longer for XGEVA in non-small cell lung cancer (hazard ratio [95% CI] of 0.79 [0.65, 0.95]; n = 702) and longer for zoledronic acid in multiple myeloma (hazard ratio [95% CI] of 2.26 [1.13, 4.50]; n = 180) and similar between XGEVA and zoledronic acid in other tumour types (hazard ratio [95% CI] of 1.08 (0.90, 1.30); n = 894). This study did not control for prognostic factors and anti-neoplastic treatments. In a combined pre-specified analysis from studies 1, 2 and 3, overall survival was similar between XGEVA and zoledronic acid (hazard ratio and 95% CI 0.99 [0.91, 1.07]).
Effect on painThe time to pain improvement (i.e., ≥ 2 point decrease from baseline in BPI-SF worst pain score) was similar for denosumab and zoledronic acid in each study and the integrated analyses. In a post-hoc analysis of the combined dataset, the median time to worsening pain (> 4-point worst pain score) in patients with mild or no pain at baseline was delayed for XGEVA compared to zoledronic acid (198 versus 143 days) (p = 0.0002).
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with XGEVA in all subsets of the paediatric population in prevention of skeletal related events in patients with bone metastases (see section 4.2 for information on paediatric use).
AbsorptionFollowing SC administration, bioavailability was 62%.
BiotransformationDenosumab 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.
EliminationWith 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 subjects 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. 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-linearityDenosumab 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. The non-linearity is likely due to a saturable target-mediated elimination pathway of importance at low concentrations.
Renal impairmentIn a study of 55 patients without advanced cancer but with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics of denosumab. There is no need for renal monitoring when receiving XGEVA.
Hepatic impairmentNo specific study in patients with hepatic impairment was performed. In general, monoclonal antibodies are not eliminated via hepatic metabolic mechanisms. The pharmacokinetics of denosumab is not expected to be affected by hepatic impairment.
ElderlyNo overall differences in safety or efficacy were observed between geriatric patients and younger patients. Controlled clinical studies of XGEVA in patients with advanced malignancies involving bone over age 65 revealed similar efficacy and safety in older and younger patients. No dose adjustment is required in elderly patients.
Paediatric populationThe pharmacokinetic profile in paediatric populations has not been assessed.
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