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

Obodence 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 (Chinese hamsterovary cells) by recombinant DNA technology.

This medicine contains 44 mg sorbitol (E420) 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 with a pH between 4.9 and 5.5 and an osmolality of 266 -326 mOsmol/kg.

Treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures. Inpostmenopausal women denosumab 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 risk offractures (see section 5.1). In men with prostate cancer receiving hormone ablation, denosumabsignificantly 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 once every 6months into the thigh, abdomen or upper arm.

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

Patients treated with Obodence 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 renal impairment(Glomerular filtration rate, GFR < 30 mL/min).

The safety and efficacy of denosumab have not been studied in patients with hepatic impairment (see section5.2).

Obodence 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 4.4 and5.3). 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 number of theadministered 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 by adequateintake of calcium and vitamin D before initiating therapy. Clinical monitoring of calcium levels isrecommended before each dose and, in patients predisposed to hypocalcaemia within two weeks, after theinitial dose. If any patient presents with suspected symptoms of hypocalcaemia during treatment (seesection 4.8 for symptoms) calcium levels should be measured. Patients should be encouraged to reportsymptoms 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 ofinitiating 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 at greaterrisk of developing hypocalcaemia. The risks of developing hypocalcaemia and accompanying parathyroidhormone elevations increase with increasing degree of renal impairment. Severe and fatal cases have beenreported. Adequate intake of calcium, vitamin D and regular monitoring of calcium is especially important inthese 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 they developsigns or symptoms of cellulitis.

ONJ has been reported rarely in patients receiving denosumab for osteoporosis (see section 4.8).

The start of treatment/new treatment course should be delayed in patients with unhealed open soft tissuelesions in the mouth. A dental examination with preventive dentistry and an individual benefit-riskassessment 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 potentcompounds), route of administration (higher risk for parenteral administration) and cumulative doseof bone resorption therapy.

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

- concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to headand neck.

- poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasivedental procedures (e.g. tooth extractions).

All patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups, andimmediately report any oral symptoms such as dental mobility, pain or swelling or non-healing of sores ordischarge during treatment with denosumab. While on treatment, invasive dental procedures should beperformed 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 thetreating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of treatmentshould 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 forosteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factorssuch as infection or trauma. The possibility of osteonecrosis of the external auditory canal should beconsidered in patients receiving denosumab who present with ear symptoms including chronic earinfections.

Atypical fractures of the femur

Atypical femoral fractures have been reported in patients receiving denosumab (see section 4.8). Atypicalfemoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of thefemur. Specific radiographic findings characterise these events. Atypical femoral fractures have also beenreported 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, protonpump inhibitors). These events have also occurred without antiresorptive therapy. Similar fractures reportedin association with bisphosphonates are often bilateral; therefore, the contralateral femur should beexamined in denosumab-treated patients who have sustained a femoral shaft fracture. Discontinuation ofdenosumab therapy in patients suspected to have an atypical femur fracture should be considered pendingevaluation 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 suchsymptoms should be evaluated for an incomplete femoral fracture.

Long-term antiresorptive treatment

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

Following denosumab discontinuation, decrease in bone mineral density (BMD) is expected (see section5.1), leading to an increased risk for fractures. Thus, monitoring of BMD is recommended, and alternativetreatment 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 fromsolid tumours).

Hypercalcaemia in paediatric patients

Denosumab should not be used in paediatric patients (age < 18). Serious hypercalcaemia has been reported.

Some clinical trial cases were complicated by acute renal injury.

Warnings for excipients

This medicine contains 44 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 betaken 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 is metabolisedby cytochrome P450 3A4 (CYP3A4). This indicates that denosumab should not alter the pharmacokineticsof 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 denosumabwere not altered by previous alendronate therapy, based on data from a transition study (alendronate todenosumab).

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

Obodence 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 Obodence. Any effects of Obodence are likely to be greater during the second and thirdtrimesters of pregnancy since monoclonal antibodies are transported across the placenta in a linear fashionas 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 of the mammarygland leading to impaired lactation post-partum (see section 5.3). A decision on whether to abstain frombreast-feeding or to abstain from therapy with Obodence should be made, taking into account the benefit ofbreast-feeding to the newborn/infant and the benefit of Obodence therapy to the woman.

No data are available on the effect of denosumab on human fertility. Animal studies do not indicate direct orindirect harmful effects with respect to fertility (see section 5.3).

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

The most common side effects with denosumab (seen in more than one patient in ten) are musculoskeletalpain 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 selectedadverse reactions) have been observed in patients taking denosumab.

The data in table 1 below describe adverse reactions reported from phase II and III clinical trials in patientswith osteoporosis and breast or prostate cancer patients receiving hormone ablation; and/or spontaneousreporting.

The following convention has been used for the classification of the adverse reactions (see table 1): verycommon (≥ 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 eachfrequency grouping and system organ class, adverse reactions are presented in order of decreasingseriousness.

Table 1. Adverse reactions reported in patients with osteoporosis and breast or prostate cancer patientsreceiving 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 hypersensitivity

Rare Anaphylactic reaction1

Metabolism and nutrition disorders Rare Hypocalcaemia1

Nervous system disorders Common Sciatica

Common Constipation

MedDRA system organ class Frequency category Adverse reactions

Gastrointestinal disorders 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 Very common Pain in extremitydisorders Very common Musculoskeletal pain1

Rare Osteonecrosis of the jaw1

Rare Atypical femoral fractures1

Not Known Osteonecrosis of the externalauditorycanal21 See section Description of selected adverse reactions.2 See section 4.4.

In a pooled analysis of data from all phase II and phase III placebo-controlled studies, influenza-like illnesswas reported with a crude incidence rate of 1.2% for denosumab and 0.7% for placebo. Although thisimbalance was identified via a pooled analysis, it was not identified via a stratified analysis.

In two phase III placebo-controlled clinical trials in postmenopausal women with osteoporosis,approximately 0.05% (2 out of 4 050) of patients had declines of serum calcium levels (less than 1.88mmol/L) following denosumab administration. Declines of serum calcium levels (less than 1.88 mmol/L)were not reported in either the two phase III placebo-controlled clinical trials in patients receiving hormoneablation 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 ofhypocalcaemia 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 intervalprolongation, tetany, seizures and altered mental status (see section 4.4). Symptoms of hypocalcaemia indenosumab clinical studies included paraesthesias or muscle stiffness, twitching, spasms and musclecramps.

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 of4 041] versus denosumab [1.5%, 59 out of 4 050]); in men with osteoporosis (placebo [0.8%, 1 out of 120]versus denosumab [0%, 0 out of 120]); in breast or prostate cancer patients receiving hormone ablation(placebo [1.7%, 14 out of 845] versus denosumab [1.4%, 12 out of 860]). Skin infections leading 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 denosumab. These cases werepredominantly cellulitis. Skin infections reported as serious adverse reactions were similar in the placebo(0.6%, 5 out of 845) and the denosumab (0.6%, 5 out of 860) groups in the breast and prostate cancerstudies.

ONJ has been reported rarely, in 16 patients, in clinical trials in osteoporosis and in breast or prostate cancerpatients receiving hormone ablation including a total of 23 148 patients (see section 4.4). Thirteen of these

ONJ cases occurred in postmenopausal women with osteoporosis during the phase III clinical trial extensionfollowing treatment with denosumab for up to 10 years. Incidence of ONJ was 0.04% at 3 years, 0.06% at 5years and 0.44% at 10 years of denosumab treatment. The risk of ONJ increased with duration of exposureto denosumab.

The risk of ONJ has also been assessed in a retrospective cohort study among 76 192 postmenopausalwomen newly initiating treatment with denosumab. 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 receiving androgendeprivation 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 postmenopausalwomen or men with osteoporosis and in women undergoing aromatase inhibitor therapy for non-metastaticbreast cancer.

Drug-related hypersensitivity reactions

In the post-marketing setting, rare events of drug-related hypersensitivity, including rash, urticaria, facialswelling, erythema, and anaphylactic reactions have been reported in patients receiving denosumab.

Musculoskeletal pain

Musculoskeletal pain, including severe cases, has been reported in patients receiving denosumab in thepost-marketing setting. In clinical trials, musculoskeletal pain was very common in both denosumab andplacebo 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.

Denosumab 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) or receivingdialysis 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 receivingdialysis (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed 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 noadditional adverse reactions were observed.

Pharmacotherapeutic group: Drugs for treatment of bone diseases - Other drugs affecting bone structure andmineralisation, ATC code: M05BX04

Obodence is a biosimilar medicinal product. Detailed information is available on the website of the

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

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

Denosumab 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 maintained over thedosing interval. At the end of each dosing interval, CTX reductions were partially attenuated from maximalreduction of ≥ 87% to approximately ≥ 45% (range 45-80%), reflecting the reversibility of denosumab’seffects on bone remodelling once serum levels diminish. These effects were sustained with continuedtreatment. 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 initiatingprimary denosumab treatment.

Anti-denosumab antibodies may develop during denosumab treatment. No apparent correlation of antibodydevelopment with pharmacokinetics, clinical response or adverse event has been observed.

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 vertebral fractures)with baseline bone mineral density (BMD) T-scores at the lumbar spine or total hip between -2.5 and -4.0and a mean absolute 10-year fracture probability of 18.60% (deciles: 7.9-32.4%) for major osteoporoticfracture and 7.22% (deciles: 1.4-14.9%) for hip fracture. Women with other diseases or on therapies thatmay 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

Denosumab significantly reduced the risk of new vertebral fractures at 1, 2 and 3 years (p < 0.0001) (seetable 2).

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

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

Placebo Denosumab 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

Denosumab 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 to 0.7% inthe denosumab group at 3 years.

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

Effect on all clinical fractures

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

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

Proportion of women with fracture Absolute risk Relative risk(%)+ reduction (%) (95% reduction (%) (95%

Placebo Denosumab CI) 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, denosumab 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 bydenosumab over 3 years were consistent regardless of the 10-year baseline fracture risk.

Effect on bone mineral density

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

denosumab 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 denosumab, BMD returned to approximatelypre-treatment levels and remained above placebo within 18 months of the last dose. These data indicate thatcontinued treatment with denosumab is required to maintain the effect of the medicinal product. Re-initiation of denosumab resulted in gains in BMD similar to those when denosumab was first administered.

Open-label extension study in the treatment of postmenopausal osteoporosis

A total of 4 550 women (2 343 denosumab & 2 207 placebo) who missed no more than one dose ofinvestigational product in the pivotal study described above and completed the month 36 study visit agreedto enrol in a 7-year, multinational, multicentre, open-label, single-arm extension study to evaluate the long-term safety and efficacy of denosumab. All women in the extension study were to receive denosumab 60 mgevery 6 months, as well as daily calcium (at least 1 g) and vitamin D (at least 400 IU). A total of 2 626subjects (58% of the women included in the extension study i.e. 34% of the women included in the pivotalstudy) completed the extension study.

In patients treated with denosumab for up to 10 years, BMD increased from the pivotal study baseline by21.7% at the lumbar spine, 9.2% at the total hip, 9.0% at the femoral neck, 13.0% at the trochanter and 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 patientstreated 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 of newvertebral and non-vertebral fractures were approximately 6.8% and 13.1% respectively, in patients whoremained on denosumab treatment for 10 years (n = 1 278). Patients who did not complete the study forany reason had higher on-treatment fracture rates.

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

Clinical efficacy and safety in men with osteoporosis

Efficacy and safety of denosumab once every 6 months for 1 year were investigated in 242 men aged 31-84years. Subjects with an eGFR < 30 mL/min/1.73 m2 were excluded from the study. All men receivedcalcium (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. Denosumab significantly increased BMD at all clinical sites measured, relative to placebo at 12months: 4.8% at lumbar spine, 2.0% at total hip, 2.2% at femoral neck, 2.3% at hip trochanter, and 0.9% atdistal 1/3 radius (all p < 0.05). Denosumab increased lumbar spine BMD from baseline in 94.7% of men at 1year. Significant increases in BMD at lumbar spine, total hip, femoral neck and hip trochanter wereobserved 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 mass whowere either naïve to osteoporosis therapies or had transitioned from previous alendronate therapy following1-3 years treatment with denosumab. Fifty nine women participated in the bone biopsy sub-study at month24 (n = 41) and/or month 84 (n = 22) of the extension study in postmenopausal women with osteoporosis.

Bone histology was also evaluated in 17 men with osteoporosis following 1 year treatment with denosumab.

Bone biopsy results showed bone of normal architecture and quality with no evidence of mineralisationdefects, woven bone or marrow fibrosis. Histomorphometry findings in the extension study inpostmenopausal women with osteoporosis showed that the antiresorptive effects of denosumab, as measuredby 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 denosumab 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) whowere at increased risk of fracture (defined as > 70 years, or < 70 years with a BMD T-score at the lumbarspine, total hip, or femoral neck < -1.0 or a history of an osteoporotic fracture). All men received calcium(at least 1 000 mg) and vitamin D (at least 400 IU) supplementation daily.

Denosumab 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, total hip,femoral neck and the hip trochanter 1 month after the initial dose.

Denosumab 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% absoluterisk reduction) at 3 years (all p < 0.01).

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

Efficacy and safety of denosumab once every 6 months for 2 years were investigated in women with non-metastatic breast cancer (252 women aged 35-84 years) and baseline BMD T-scores between -1.0 to -2.5 atthe lumbar spine, total hip or femoral neck. All women received calcium (at least 1 000 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. denosumab 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 hip trochanter,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 denosumab 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 its equivalentfor ≥ 3 months prior to study enrolment; n = 505) and glucocorticoid-initiating (≥ 7.5 mg daily prednisoneor its equivalent for < 3 months prior to study enrolment; n = 290). Patients were randomised (1:1) toreceive either denosumab 60 mg subcutaneously once every 6 months or oral risedronate 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, denosumab demonstrated a greater increase in lumbar spine

BMD compared to risedronate at 1 year (denosumab 3.6%, risedronate 2.0%; p < 0.001) and 2 years(denosumab 4.5%, risedronate 2.2%; p < 0.001). In the glucocorticoid-initiating subpopulation, denosumabdemonstrated a greater increase in lumbar spine BMD compared to risedronate at 1 year (denosumab 3.1%,risedronate 0.8%; p < 0.001) and 2 years (denosumab 4.6%, risedronate 1.5%; p < 0.001).

In addition, denosumab 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 subject incidence ofnon-vertebral fracture was 4.3% (denosumab) versus 2.5% (risedronate). At 2 years, the correspondingnumbers 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 in childrenwith osteogenesis imperfecta, aged 2 to 17 years, 52.3% male, 88.2% Caucasian. A total of 153 subjectsinitially received subcutaneous (SC) denosumab 1 mg/kg, up to a maximum of 60 mg, every 6 months for36 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 inextremity (37.9%), back pain (32.7%), and hypercalciuria (32.0%). Hypercalcaemia was reported duringevery 6 months (19%) and every 3 months (36.7%) dosing. Serious adverse events of hypercalcaemia(13.3%) were reported during every 3 months dosing.

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

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

In one multicentre, randomised, double-blind, placebo-controlled, parallel-group study conducted in 24paediatric patients with glucocorticoid-induced osteoporosis, aged 5 to 17 years, evaluating change frombaseline in lumbar spine BMD Z -score, safety and effectiveness were not established hence denosumabshould not be used for this indication.

The European Medicines Agency has waived the obligation to submit the results of studies with thereference medicinal product containing denosumab in all subsets of the paediatric population in thetreatment of bone loss associated with sex hormone ablative therapy, and in subsets of the paediatricpopulation below the age of 2 in the treatment of osteoporosis (See section 4.2 for information on paediatricuse).

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 a60 mg subcutaneous dose, maximum serum denosumab concentrations (Cmax) of 6 mcg/mL (range 1-17mcg/mL) occurred in 10 days (range 2-28 days).

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

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 denosumabdetected at 6 months post-dose.

No accumulation or change in denosumab pharmacokinetics with time was observed upon subcutaneousmultiple-dosing of 60 mg once every 6 months. Denosumab pharmacokinetics were not affected by theformation of binding antibodies to denosumab and were similar in men and women. Age (28-87 years), raceand disease state (low bone mass or osteoporosis; prostate or breast cancer) do not appear to significantlyaffect 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 turnovermarkers and BMD increases were consistent across a wide range of body weight.

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

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

No specific study in patients with hepatic impairment was performed. In general, monoclonal antibodies arenot eliminated via hepatic metabolic mechanisms. The pharmacokinetics of denosumab is not expected to beaffected by hepatic impairment.

Denosumab 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 and every 6months dosing, mean serum denosumab trough concentrations were observed to be higher for children 11 to17 years of age, while children 2 to 6 years of age had the lowest mean trough concentrations.

In single and repeated dose toxicity studies in cynomolgus monkeys, denosumab doses resulting in 100 to150 times greater systemic exposure than the recommended human dose had no impact on cardiovascularphysiology, male or female fertility, or produced specific target organ toxicity.

Standard tests to investigate the genotoxicity potential of denosumab have not been evaluated, since suchtests are not relevant for this molecule. However, due to its character it is unlikely that denosumab has anypotential 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 lymph nodeformation was observed in the foetus. An absence of lactation due to inhibition of mammary glandmaturation (lobulo-alveolar gland development during pregnancy) was also observed in knockout micelacking RANK or RANKL.

In a study of cynomolgus monkeys dosed with denosumab during the period equivalent to the first trimesterat AUC exposures up to 99-fold higher than the human dose (60 mg every 6 months), there was no evidenceof 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 AUC exposures119-fold higher than the human dose (60 mg every 6 months), there were increased stillbirths and postnatalmortality; abnormal bone growth resulting in reduced bone strength, reduced haematopoiesis, and toothmalalignment; absence of peripheral lymph nodes; and decreased neonatal growth. A no observed adverseeffect level for reproductive effects was not established. Following a 6 month period after birth, bonerelated changes showed recovery and there was no effect on tooth eruption. However, the effects on lymphnodes and tooth malalignment persisted, and minimal to moderate mineralisation in multiple tissues wasseen in one animal (relation to treatment uncertain). There was no evidence of maternal harm prior tolabour; adverse maternal effects occurred infrequently during labour. Maternal mammary glanddevelopment 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. Calcium levelswere transiently decreased and parathyroid hormone levels transiently increased in ovariectomised monkeystreated 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 fracture calluscompared to control, but biomechanical strength was not adversely affected.

Knockout mice (see section 4.6) lacking RANK or RANKL exhibited decreased body weight, reduced bonegrowth and lack of tooth eruption. In neonatal rats, inhibition of RANKL (target of denosumab therapy)with high doses of a construct of osteoprotegerin bound to Fc (OPG-Fc) was associated with inhibition ofbone growth and tooth eruption. These changes were partially reversible in this model when dosing with

RANKL inhibitors was discontinued. Adolescent primates dosed with denosumab at 27 and 150 times (10and 50 mg/kg dose) the clinical exposure had abnormal growth plates. Therefore, treatment with denosumabmay impair bone growth in children with open growth plates and may inhibit eruption of dentition.

Histidine

Histidine hydrochloride monohydrate

Sorbitol (E420)

Polysorbate 20

Water for injections

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

3 years.

Once removed from the refrigerator, Obodence may be stored at temperature up to a maximum of 25°C fora single period of up to 60 days, but not exceeding the original expiry date. If not used within this period ofup to 60 days, Obodence may be returned to the refrigerator for 28 days for future use.

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-dose pre-filled syringe made from type I glass with stainless steel 29 gaugeneedle with needle guard, a rubber needle shield (elastomer), a rubber plunger stopper (bromobutyl rubber)and a plastic plunger rod.

Pack size of one pre-filled syringe, presented in unblistered packaging

- 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 room temperature (upto 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.

Samsung Bioepis NL B.V.

Olof Palmestraat 102616 LR Delft

The Netherlands

EU/1/24/1890/001

Date of first authorisation: 12 February 2025

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

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