PROLIA 60mg / ml injection solution in pre-filled syringe medication leaflet

Prolia 60 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 60 mg of denosumab in 1 mL of solution (60 mg/mL).

Denosumab is a human monoclonal IgG2 antibody produced in a mammalian cell line (Chinesehamster ovary cells) by recombinant DNA technology.

This medicine contains 47 mg sorbitol in each mL of solution.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear, colourless to slightly yellow solution.

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

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

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

The recommended dose is 60 mg denosumab administered as a single subcutaneous injection onceevery 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 andbisphosphonates) has not been established. The need for continued treatment should be re-evaluatedperiodically 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.

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

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

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

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

For subcutaneous use.

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

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).

In order to improve the traceability of biological medicinal products, the name and the batch numberof 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

It is important to identify patients at risk for hypocalcaemia. Hypocalcaemia must be corrected byadequate intake of calcium and vitamin D before initiating therapy. Clinical monitoring of calciumlevels is recommended before each dose and, in patients predisposed to hypocalcaemia withintwo weeks, after the initial dose. If any patient presents with suspected symptoms of hypocalcaemiaduring treatment (see section 4.8 for symptoms) calcium levels should be measured. Patients should beencouraged 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 fewweeks of initiating therapy, it has also occurred later.

Concomitant glucocorticoid treatment is an additional risk factor for hypocalcaemia.

Patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis are atgreater risk of developing hypocalcaemia. The risks of developing hypocalcaemia and accompanyingparathyroid hormone elevations increase with increasing degree of renal impairment. Severe and fatalcases have been reported. Adequate intake of calcium, vitamin D and regular monitoring of calcium isespecially important in these patients, see above.

Skin infections

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

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 softtissue lesions in the mouth. A dental examination with preventive dentistry and an individualbenefit-risk assessment is recommended prior to treatment with denosumab in patients withconcomitant 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 potentcompounds), route of administration (higher risk for parenteral administration) and cumulativedose of bone resorption therapy.

* cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.

* concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy tohead 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 ofsores or discharge during treatment with denosumab. While on treatment, invasive dental proceduresshould be performed only after careful consideration and be avoided in close proximity to denosumabadministration.

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

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with denosumab. Possible risk factorsfor osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local riskfactors such as infection or trauma. The possibility of osteonecrosis of the external auditory canalshould be considered in patients receiving denosumab who present with ear symptoms includingchronic 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 diaphysealregions of the femur. Specific radiographic findings characterise these events. Atypical femoralfractures have also been reported in patients with certain co-morbid conditions (e.g. vitamin Ddeficiency, rheumatoid arthritis, hypophosphatasia) and with use of certain medicinal products (e.g.

bisphosphonates, glucocorticoids, proton pump inhibitors). These events have also occurred withoutantiresorptive therapy. Similar fractures reported in association with bisphosphonates are oftenbilateral; therefore, the contralateral femur should be examined in denosumab-treated patients whohave sustained a femoral shaft fracture. Discontinuation of denosumab therapy in patients suspected tohave an atypical femur fracture should be considered pending evaluation of the patient based on anindividual benefit-risk assessment. During denosumab treatment, patients should be advised to reportnew or unusual thigh, hip, or groin pain. Patients presenting with such symptoms should be evaluatedfor an incomplete femoral fracture.

Long-term antiresorptive treatment

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

Concomitant treatment with other denosumab-containing medicinal products

Patients being treated with denosumab should not be treated concomitantly with otherdenosumab-containing medicinal products (for prevention of skeletal related events in adults withbone 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 concomitantlyadministered 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’.

In an interaction study, denosumab did not affect the pharmacokinetics of midazolam, which ismetabolised by cytochrome P450 3A4 (CYP3A4). This indicates that denosumab should not alter thepharmacokinetics 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 ofdenosumab were not altered by previous alendronate therapy, based on data from a transition study(alendronate to denosumab).

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

Prolia is not recommended for use in pregnant women and women of child-bearing potential not usingcontraception. Women should be advised not to become pregnant during and for at least 5 months aftertreatment with Prolia. Any effects of Prolia are likely to be greater during the second and thirdtrimesters of pregnancy since monoclonal antibodies are transported across the placenta in a linearfashion 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 see section 5.1) during pregnancy may interfere with maturation ofthe mammary gland leading to impaired lactation post-partum (see section 5.3). A decision on whetherto abstain from breast-feeding or to abstain from therapy with Prolia should be made, taking intoaccount the benefit of breast-feeding to the newborn/infant and the benefit of Prolia therapy to thewoman.

No data are available on the effect of denosumab on human fertility. Animal studies do not indicatedirect 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.

The most common side effects with denosumab (seen in more than one patient in ten) aremusculoskeletal pain and pain in the extremity. Uncommon cases of cellulitis, rare cases ofhypocalcaemia, hypersensitivity, osteonecrosis of the jaw and atypical femoral fractures (seesections 4.4 and 4.8 - description of selected adverse reactions) have been observed in patients takingdenosumab.

The data in table 1 below describe adverse reactions reported from phase II and III clinical trials inpatients with osteoporosis and breast or prostate cancer patients receiving hormone ablation; and/orspontaneous 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 theavailable data). Within each frequency grouping and system organ class, adverse reactions arepresented in order of decreasing seriousness.

Table 1. Adverse reactions reported in patients with osteoporosis and breast or prostate cancerpatients 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 Hypocalcaemia1disorders

MedDRA system organ class Frequency category Adverse reactions

Nervous system disorders Common Sciatica

Gastrointestinal disorders Common Constipation

Common Abdominal discomfort

Skin and subcutaneous tissue Common Rashdisorders Common Eczema

Common Alopecia

Uncommon Lichenoid drug eruptions1

Very rare Hypersensitivity vasculitis

Musculoskeletal and connective Very common Pain in extremitytissue disorders Very common Musculoskeletal pain1

Rare Osteonecrosis of the jaw1

Rare Atypical femoral fractures1

Not Known Osteonecrosis of the external auditorycanal21 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-likeillness 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 stratifiedanalysis.

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 than1.88 mmol/L) following Prolia administration. Declines of serum calcium levels (less than1.88 mmol/L) were not reported in either the two phase III placebo-controlled clinical trials in patientsreceiving 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 inhospitalisation, life-threatening events, and fatal cases have been reported, predominantly in patients atincreased risk of hypocalcaemia receiving denosumab, with most cases occurring in the first weeks ofinitiating therapy. Examples of the clinical manifestations of severe symptomatic hypocalcaemia haveincluded 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 theplacebo 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 hormoneablation (placebo [1.7%, 14 out of 845] versus Prolia [1.4%, 12 out of 860]). Skin infections leading tohospitalisation were reported in 0.1% (3 out of 4 041) of postmenopausal women with osteoporosisreceiving placebo versus 0.4% (16 out of 4 050) of women receiving Prolia. These cases werepredominantly cellulitis. Skin infections reported as serious adverse reactions were similar in theplacebo (0.6%, 5 out of 845) and the Prolia (0.6%, 5 out of 860) groups in the breast and prostatecancer studies.

ONJ has been reported rarely, in 16 patients, in clinical trials in osteoporosis and in breast or prostatecancer 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 thephase 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 riskof ONJ increased with duration of exposure to denosumab.

The risk of ONJ has also been assessed in a retrospective cohort study among 76 192 postmenopausalwomen newly initiating treatment with Prolia. The incidence of ONJ was 0.32% (95% confidenceinterval [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 patientstreated with denosumab (see section 4.4).

Diverticulitis

In a single phase III placebo-controlled clinical trial in patients with prostate cancer receivingandrogen deprivation therapy (ADT), an imbalance in diverticulitis adverse events was observed(1.2% denosumab, 0% placebo). The incidence of diverticulitis was comparable between treatmentgroups in postmenopausal women or men with osteoporosis and in women undergoing aromataseinhibitor 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 thepost-marketing setting. In clinical trials, musculoskeletal pain was very common in both denosumaband placebo groups. Musculoskeletal pain leading to discontinuation of study treatment wasuncommon.

Lichenoid drug eruptions

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

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.

In clinical studies, patients with severe renal impairment (creatinine clearance < 30 mL/min) orreceiving dialysis were at greater risk of developing hypocalcaemia in the absence of calciumsupplementation. Adequate intake of calcium and vitamin D is important in patients with severe renalimpairment or receiving dialysis (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no experience with overdose in clinical studies. Denosumab has been administered in clinicalstudies 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.

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

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

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

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

Clinical efficacy and safety in postmenopausal women with osteoporosis

Efficacy and safety of denosumab administered once every 6 months for 3 years were investigated inpostmenopausal women (7 808 women aged 60-91 years, of which 23.6% had prevalent vertebralfractures) 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%) formajor osteoporotic fracture and 7.22% (deciles: 1.4-14.9%) for hip fracture. Women with otherdiseases 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) (seetable 2).

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

Proportion of women with fracture (%) Absolute risk Relative risk

Placebo Prolia reduction (%) reduction (%)n = 3 906 n = 3 902 (95% CI) (95% CI)0-1 year 2.2 0.9 1.4 (0.8, 1.9) 61 (42, 74)**0-2 years 5.0 1.4 3.5 (2.7, pct. 4.3) 71 (61, 79)**0-3 years 7.2 2.3 4.8 (3.9, 5.8) 68 (59, 74)*

*p < 0.0001, **p < 0.0001 - exploratory analysis

Effect on hip fractures

Prolia demonstrated a 40% relative reduction (0.5% absolute risk reduction) in the risk of hip fractureover 3 years (p < 0.05). The incidence of hip fracture was 1.2% in the placebo group compared to0.7% in the Prolia group at 3 years.

In a post-hoc analysis in women > 75 years, a 62% relative risk reduction was observed with Prolia(1.4% absolute risk reduction, p < 0.01).

Effect on all clinical fractures

Prolia significantly reduced fractures across all fracture types/groups (see table 3).

Table 3. The effect of Prolia on the risk of clinical fractures over 3 years

Proportion of women with Absolute risk Relative riskfracture (%)+ reduction (%) reduction (%)

Placebo Prolia (95% CI) (95% CI)n = 3 906 n = 3 902

Any clinical fracture1 10.2 7.2 2.9 (1.6, 4.2) 30 (19, 41)***

Clinical vertebral fracture 2.6 0.8 1.8 (1.2, 2.4) 69 (53, 80)***

Non-vertebral fracture2 8.0 6.5 1.5 (0.3, 2.7) 20 (5, 33)**

Major non-vertebral fracture3 6.4 5.2 1.2 (0.1, 2.2) 20 (3, 34)*

Major osteoporotic fracture4 8.0 5.3 2.7 (1.6, 3.9) 35 (22, 45)***

*p ≤ 0.05, **p = 0.0106 (secondary endpoint included in multiplicity adjustment), ***p ≤ 0.0001+ Event rates based on Kaplan-Meier estimates at 3 years.1 Includes clinical vertebral fractures and non-vertebral fractures.2 Excludes those of the vertebrae, skull, facial, mandible, metacarpus, and finger and toe phalanges.3 Includes pelvis, distal femur, proximal tibia, ribs, proximal humerus, forearm, and hip.4 Includes clinical vertebral, hip, forearm, and humerus fractures, as defined by the WHO.

In women with baseline femoral neck BMD ≤ -2.5, Prolia reduced the risk of non-vertebral fracture(35% relative risk reduction, 4.1% absolute risk reduction, p < 0.001, exploratory analysis).

The reduction in the incidence of new vertebral fractures, hip fractures and non-vertebral fractures by

Prolia over 3 years were consistent regardless of the 10-year baseline fracture risk.

Effect on bone mineral density

Prolia significantly increased BMD at all clinical sites measured, versus placebo at 1, 2 and 3 years.

Prolia increased BMD by 9.2% at the lumbar spine, 6.0% at the total hip, pct. 4.8% at the femoral neck,7.9% at the hip trochanter, 3.5% at the distal 1/3 radius and 4.1% at the total body over 3 years (allp < 0.0001).

In clinical studies examining the effects of discontinuation of Prolia, BMD returned to approximatelypre-treatment levels and remained above placebo within 18 months of the last dose. These dataindicate that continued treatment with Prolia is required to maintain the effect of the medicinalproduct. Re-initiation of Prolia resulted in gains in BMD similar to those when Prolia was firstadministered.

Open-label extension study in the treatment of postmenopausal osteoporosis

A total of 4 550 women (2 343 Prolia & 2 207 placebo) who missed no more than one dose ofinvestigational product in the pivotal study described above and completed the month 36 study visitagreed to enrol in a 7-year, multinational, multicentre, open-label, single-arm extension study toevaluate the long-term safety and efficacy of Prolia. All women in the extension study were to receive

Prolia 60 mg every 6 months, as well as daily calcium (at least 1 g) and vitamin D (at least 400 IU). Atotal of 2 626 subjects (58% of the women included in the extension study i.e. 34% of the womenincluded in the pivotal study) completed the extension study.

In patients treated with Prolia for up to 10 years, BMD increased from the pivotal study baselineby 21.7% at the lumbar spine, 9.2% at the total hip, 9.0% at the femoral neck, 13.0% at the trochanterand 2.8% at the distal 1/3 radius. The mean lumbar spine BMD T-score at the end of the study was−1.3 in patients treated for 10 years.

Fracture incidence was evaluated as a safety endpoint but efficacy in fracture prevention cannot beestimated due to high number of discontinuations and open-label design. The cumulative incidence ofnew vertebral and non-vertebral fractures were approximately 6.8% and 13.1% respectively, inpatients who remained on denosumab treatment for 10 years (n = 1 278). Patients who did notcomplete the study for any reason had higher on-treatment fracture rates.

Thirteen adjudicated cases of osteonecrosis of the jaw (ONJ) and two adjudicated cases of atypicalfractures of the femur occurred during the extension study.

Clinical efficacy and safety in men with osteoporosis

Efficacy and safety of Prolia once every 6 months for 1 year were investigated in 242 men aged31-84 years. Subjects with an eGFR < 30 mL/min/1.73 m2 were excluded from the study. All menreceived calcium (at least 1 000 mg) and vitamin D (at least 800 IU) supplementation daily.

The primary efficacy variable was percent change in lumbar spine BMD, fracture efficacy was notevaluated. Prolia significantly increased BMD at all clinical sites measured, relative to placebo at12 months: 4.8% at lumbar spine, 2.0% at total hip, 2.2% at femoral neck, 2.3% at hip trochanter, and0.9% at distal 1/3 radius (all p < 0.05). Prolia increased lumbar spine BMD from baseline in 94.7% ofmen at 1 year. Significant increases in BMD at lumbar spine, total hip, femoral neck and hiptrochanter were observed by 6 months (p < 0.0001).

Bone histology in postmenopausal women and men with osteoporosis

Bone histology was evaluated in 62 postmenopausal women with osteoporosis or with low bone masswho were either naïve to osteoporosis therapies or had transitioned from previous alendronate therapyfollowing 1-3 years treatment with Prolia. Fifty nine women participated in the bone biopsy sub-studyat month 24 (n = 41) and/or month 84 (n = 22) of the extension study in postmenopausal women withosteoporosis. Bone histology was also evaluated in 17 men with osteoporosis following 1 yeartreatment with Prolia. Bone biopsy results showed bone of normal architecture and quality with noevidence of mineralisation defects, woven bone or marrow fibrosis. Histomorphometry findings in theextension study in postmenopausal women with osteoporosis showed that the antiresorptive effects of

Prolia, as measured by activation frequency and bone formation rates, were maintained over time.

Clinical efficacy and safety in patients with bone loss associated with androgen deprivation

Efficacy and safety of Prolia once every 6 months for 3 years were investigated in men withhistologically confirmed non-metastatic prostate cancer receiving ADT (1 468 men aged 48-97 years)who were at increased risk of fracture (defined as > 70 years, or < 70 years with a BMD T-score at thelumbar spine, total hip, or femoral neck < -1.0 or a history of an osteoporotic fracture). All menreceived calcium (at least 1 000 mg) and vitamin D (at least 400 IU) supplementation daily.

Prolia significantly increased BMD at all clinical sites measured, relative to treatment with placebo at3 years: 7.9% at the lumbar spine, 5.7% at the total hip, 4.9% at the femoral neck, 6.9% at the hiptrochanter, 6.9% at the distal 1/3 radius and 4.7% at the total body (all p < 0.0001). In a prospectivelyplanned exploratory analysis, significant increases in BMD were observed at the lumbar spine, totalhip, femoral neck and the hip trochanter 1 month after the initial dose.

Prolia demonstrated a significant relative risk reduction of new vertebral fractures: 85% (1.6%absolute risk reduction) at 1 year, 69% (2.2% absolute risk reduction) at 2 years and 62% (2.4%absolute risk reduction) at 3 years (all p < 0.01).

Clinical efficacy and safety in patients with bone loss associated with adjuvant aromatase inhibitortherapy

Efficacy and safety of Prolia once every 6 months for 2 years were investigated in women withnon-metastatic breast cancer (252 women aged 35-84 years) and baseline BMD T-scores between

- 1.0 to -2.5 at the lumbar spine, total hip or femoral neck. All women received calcium (at least1 000 mg) and vitamin D (at least 400 IU) supplementation daily.

The primary efficacy variable was percent change in lumbar spine BMD, fracture efficacy was notevaluated. Prolia significantly increased BMD at all clinical sites measured, relative to treatment withplacebo at 2 years: 7.6% at lumbar spine, 4.7% at total hip, 3.6% at femoral neck, 5.9% at hiptrochanter, 6.1% at distal 1/3 radius and 4.2% at total body (all p < 0.0001).

Treatment of bone loss associated with systemic glucocorticoid therapy

Efficacy and safety of Prolia were investigated in 795 patients (70% women and 30% men) aged 20 to94 years treated with ≥ 7.5 mg daily oral prednisone (or equivalent).

Two subpopulations were studied: glucocorticoid-continuing (≥ 7.5 mg daily prednisone or itsequivalent for ≥ 3 months prior to study enrolment; n = 505) and glucocorticoid-initiating (≥ 7.5 mgdaily prednisone or its equivalent for < 3 months prior to study enrolment; n = 290). Patients wererandomised (1:1) to receive either Prolia 60 mg subcutaneously once every 6 months or oralrisedronate 5 mg once daily (active control) for 2 years. Patients received calcium (at least 1 000 mg)and vitamin D (at least 800 IU) supplementation daily.

In the glucocorticoid-continuing subpopulation, Prolia demonstrated a greater increase in lumbar spine

BMD compared to risedronate at 1 year (Prolia 3.6%, risedronate 2.0%; p < 0.001) and 2 years (Prolia4.5%, risedronate 2.2%; p < 0.001). In the glucocorticoid-initiating subpopulation, Proliademonstrated a greater increase in lumbar spine BMD compared to risedronate at 1 year (Prolia 3.1%,risedronate 0.8%; p < 0.001) and 2 years (Prolia 4.6%, risedronate 1.5%; p < 0.001).

In addition, Prolia demonstrated a significantly greater mean percent increase in BMD from baselinecompared to risedronate at the total hip, femoral neck, and hip trochanter.

The study was not powered to show a difference in fractures. At 1 year, the subject incidence of newradiological vertebral fracture was 2.7% (denosumab) versus 3.2% (risedronate). The subjectincidence of non-vertebral fracture was 4.3% (denosumab) versus 2.5% (risedronate). At 2 years, thecorresponding numbers were 4.1% versus 5.8% for new radiological vertebral fractures and 5.3%versus 3.8% for non-vertebral fractures. Most of the fractures occurred in the GC-C subpopulation.

A single-arm phase III study evaluated the efficacy, safety, and pharmacokinetics was conducted inchildren with osteogenesis imperfecta, aged 2 to 17 years, 52.3% male, 88.2% Caucasian. A total of153 subjects initially received subcutaneous (SC) denosumab 1 mg/kg, up to a maximum of 60 mg,every 6 months for 36 months. Sixty subjects transitioned to every 3 months dosing.

At month 12 of every 3 months dosing, the least squares (LS) mean (standard error, SE) change frombaseline in lumbar spine BMD Z-score was 1.01 (0.12).

The most common adverse events reported during every 6 months dosing were arthralgia (45.8%),pain in extremity (37.9%), back pain (32.7%), and hypercalciuria (32.0%). Hypercalcaemia wasreported during every 6 months (19%) and every 3 months (36.7%) dosing. Serious adverse events ofhypercalcaemia (13.3%) were reported during every 3 months dosing.

In an extension study (N = 75), serious adverse events of hypercalcaemia (18.5%) were observedduring every 3 months dosing.

The studies were terminated early due to the occurrence of life-threatening events and hospitalisationsdue to hypercalcaemia (see section 4.2).

In one multicentre, randomised, double-blind, placebo-controlled, parallel-group study conducted in24 paediatric patients with glucocorticoid-induced osteoporosis, aged 5 to 17 years, evaluating changefrom baseline in lumbar spine BMD Z-score, safety and effectiveness were not established hence

Prolia should not be used for this indication.

The European Medicines Agency has waived the obligation to submit the results of studies with Proliain all subsets of the paediatric population in the treatment of bone loss associated with sex hormoneablative therapy, and in subsets of the paediatric population below the age of 2 in the treatment ofosteoporosis. See section 4.2 for information on paediatric use.

Following subcutaneous administration of a 1.0 mg/kg dose, which approximates the approved 60 mgdose, exposure based on AUC was 78% as compared to intravenous administration at the same doselevel. For a 60 mg subcutaneous dose, maximum serum denosumab concentrations (Cmax) of6 mcg/mL (range 1-17 mcg/mL) occurred in 10 days (range 2-28 days).

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

After Cmax, serum levels declined with a half-life of 26 days (range 6-52 days) over a period of3 months (range 1.5-4.5 months). Fifty-three percent (53%) of patients had no measurable amounts ofdenosumab detected at 6 months post-dose.

No accumulation or change in denosumab pharmacokinetics with time was observed uponsubcutaneous multiple-dosing of 60 mg once every 6 months. Denosumab pharmacokinetics were notaffected 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) donot 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 onbone turnover markers and BMD increases were consistent across a wide range of body weight.

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

In a study of 55 patients with varying degrees of renal function, including patients on dialysis, thedegree of renal impairment had no effect on the pharmacokinetics of denosumab.

No specific study in patients with hepatic impairment was performed. In general, monoclonalantibodies are not eliminated via hepatic metabolic mechanisms. The pharmacokinetics of denosumabis not expected to be affected by hepatic impairment.

Prolia should not be used in paediatric populations (see sections 4.2 and 5.1).

In a phase III study of paediatric patients with osteogenesis imperfecta (N = 153), maximum serumdenosumab concentrations were observed on day 10 across all age groups. For every 3 months andevery 6 months dosing, mean serum denosumab trough concentrations were observed to be higher forchildren 11 to 17 years of age, while children 2 to 6 years of age had the lowest mean troughconcentrations.

In single and repeated dose toxicity studies in cynomolgus monkeys, denosumab doses resultingin 100 to 150 times greater systemic exposure than the recommended human dose had no impact oncardiovascular physiology, male or female fertility, or produced specific target organ toxicity.

Standard tests to investigate the genotoxicity potential of denosumab have not been evaluated, sincesuch tests are not relevant for this molecule. However, due to its character it is unlikely thatdenosumab has any potential for genotoxicity.

The carcinogenic potential of denosumab has not been evaluated in long-term animal studies.

In preclinical studies conducted in knockout mice lacking RANK or RANKL, impairment of lymphnode formation was observed in the foetus. An absence of lactation due to inhibition of mammarygland maturation (lobulo-alveolar gland development during pregnancy) was also observed inknockout mice lacking RANK or RANKL.

In a study of cynomolgus monkeys dosed with denosumab during the period equivalent to the firsttrimester at AUC exposures up to 99-fold higher than the human dose (60 mg every 6 months), therewas no evidence of maternal or foetal harm. In this study, foetal lymph nodes were not examined.

In another study of cynomolgus monkeys dosed with denosumab throughout pregnancy at AUCexposures 119-fold higher than the human dose (60 mg every 6 months), there were increasedstillbirths and postnatal mortality; abnormal bone growth resulting in reduced bone strength, reducedhaematopoiesis, and tooth malalignment; absence of peripheral lymph nodes; and decreased neonatalgrowth. A no observed adverse effect level for reproductive effects was not established. Following a6 month period after birth, bone related changes showed recovery and there was no effect on tootheruption. However, the effects on lymph nodes and tooth malalignment persisted, and minimal tomoderate mineralisation in multiple tissues was seen in one animal (relation to treatment uncertain).

There was no evidence of maternal harm prior to labour; adverse maternal effects occurredinfrequently during labour. Maternal mammary gland development was normal.

In preclinical bone quality studies in monkeys on long-term denosumab treatment, decreases in boneturnover were associated with improvement in bone strength and normal bone histology. Calciumlevels were transiently decreased and parathyroid hormone levels transiently increased inovariectomised monkeys treated with denosumab.

In male mice genetically engineered to express huRANKL (knock-in mice), which were subjected to atranscortical fracture, denosumab delayed the removal of cartilage and remodelling of the fracturecallus compared to control, but biomechanical strength was not adversely affected.

Knockout mice (see section 4.6) lacking RANK or RANKL exhibited decreased body weight, reducedbone growth and lack of tooth eruption. In neonatal rats, inhibition of RANKL (target of denosumabtherapy) with high doses of a construct of osteoprotegerin bound to Fc (OPG-Fc) was associated withinhibition of bone growth and tooth eruption. These changes were partially reversible in this modelwhen dosing with RANKL inhibitors was discontinued. Adolescent primates dosed with denosumab at27 and 150 times (10 and 50 mg/kg dose) the clinical exposure had abnormal growth plates. Therefore,treatment with denosumab may impair bone growth in children with open growth plates and mayinhibit eruption of dentition.

Acetic acid, glacial*

Sodium hydroxide (for pH adjustment)*

Sorbitol (E420)

Polysorbate 20

Water for injections

* Acetate buffer is formed by mixing acetic acid with sodium hydroxide

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

4 years.

Once removed from the refrigerator, Prolia may be stored at room temperature (up to 25°C) for up to30 days in the original carton. It must be used within this 30 days period.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the pre-filled syringe in the outer carton in order to protect from light.

One mL solution in a single use pre-filled syringe made from type I glass with stainless steel 27 gaugeneedle, with or without needle guard.

Pack size of one pre-filled syringe, presented in blistered (pre-filled syringe with or without a needleguard) or unblistered packaging (pre-filled syringe without a needle guard only).

Not all pack sizes may be marketed.

* Before administration, the solution should be inspected. Do not inject the solution if it containsparticles, or is cloudy or discoloured.

* Do not shake.

* To avoid discomfort at the site of injection, allow the pre-filled syringe to reach roomtemperature (up to 25°C) before injecting and inject slowly.

* Inject the entire contents of the pre-filled syringe.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Amgen Europe B.V.

Minervum 70614817 ZK Breda

The Netherlands

EU/1/10/618/001

EU/1/10/618/002

EU/1/10/618/003

Date of first authorisation: 26 May 2010

Date of latest renewal: 16 January 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.