XBRYK 120mg 70mg / ml solution for injection medication leaflet

Xbryk 120 mg solution for injection

Each vial contains 120 mg of denosumab in approximately 1.7 mL of solution (70 mg/mL).

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

Excipient with known effects

Each 1.7 mL of solution contains 74.8 mg sorbitol (E420).

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 and may contain trace amounts of translucent to whiteproteinaceous particles.

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

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

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

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

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

Prevention of skeletal related events in adults with advanced malignancies involving bone

The recommended dose is 120 mg administered as a single subcutaneous injection once every 4 weeks intothe thigh, abdomen or upper arm.

Giant cell tumour of bone

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

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

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

No dose adjustment is required in patients with renal impairment (see section 4.4 for recommendationsrelating to monitoring of calcium, pct. 4.8 and 5.2).

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

Elderly patients (age ≥ 65)

No dose adjustment is required in elderly patients (see section 5.2).

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

Xbryk is not recommended in paediatric patients (age < 18) other than skeletally mature adolescents (aged12-17 years) with giant cell tumour of bone (see section 4.4).

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

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

For subcutaneous use.

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

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

Severe, untreated hypocalcaemia (see section 4.4).

Unhealed lesions from dental or oral surgery.

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

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

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

Patients should be encouraged to report symptoms indicative of hypocalcaemia. If hypocalcaemia occurswhile receiving denosumab, additional calcium supplementation and additional monitoring may benecessary.

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

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

ONJ has been reported commonly in patients receiving denosumab (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.

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, pre-existing 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 ofdenosumab treatment should be considered until the condition resolves and contributing risk factors aremitigated 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 pharmaceutical agents (e.g. bisphosphonates, glucocorticoids,proton pump inhibitors). These events have also occurred without antiresorptive therapy. Similar fracturesreported in 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.

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

Clinically significant hypercalcaemia requiring hospitalisation and complicated by acute renal injury hasbeen reported in denosumab-treated patients with giant cell tumour of bone weeks to months followingtreatment discontinuation.

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

Denosumab is not recommended in patients with growing skeletons (see section 4.2). Clinically significanthypercalcaemia has also been reported in this patient group weeks to months following treatmentdiscontinuation.

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

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

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

Warnings for excipients

This medicinal product contains 74.8 mg sorbitol in each vial. 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 120 mg dose, that is to say essentially‘sodium-free’.

No interaction studies have been performed.

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

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).

Xbryk 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 Xbryk. Any effects of Xbryk are likely to be greater during the second and third trimesters ofpregnancy since monoclonal antibodies are transported across the placenta in a linear fashion as pregnancyprogresses, with the largest amount transferred during the third trimester.

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

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

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

Hypocalcaemia has very commonly been reported following denosumab administration, mostly within thefirst 2 weeks. Hypocalcaemia can be severe and symptomatic (see section 4.8 - description of selectedadverse reactions). The decreases in serum calcium were generally appropriately managed by calcium andvitamin D supplementation. The most common adverse reactions with denosumab are musculoskeletal pain.

Cases of osteonecrosis of the jaw (see sections 4.4 and section 4.8 - description of selected adversereactions) have been commonly observed in patients taking denosumab.

The following convention has been used for the classification of the adverse reactions based on incidencerates in four phase III, two phase II clinical studies and post-marketing experience (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 advanced malignancies involving bone, multiple myeloma,or with giant cell tumour of bone

MedDRA system organ class Frequency category Adverse reactions

Neoplasms benign, malignant and Common New primary malignancy1unspecified (including cysts andpolyps)

Immune system disorders Rare Drug hypersensitivity1

Rare Anaphylactic reaction1

Metabolism and nutrition disorders Very common Hypocalcaemia1, 2

Common Hypophosphataemia

Uncommon Hypercalcaemia following treatmentdiscontinuation in patients with giantcell tumour of bone3

Respiratory, thoracic and Very common Dyspnoeamediastinal disorders

Gastrointestinal disorders Very common Diarrhoea

Common Tooth extraction

Skin and subcutaneous tissue disorders Common Hyperhidrosis

Uncommon Lichenoid drug eruptions1

Musculoskeletal and connective tissue Very common Musculoskeletal pain1disorders Common Osteonecrosis of the jaw1

Uncommon Atypical femoral fracture1

Not known Osteonecrosis of the external auditorycanal3,41 See section Description of selected adverse reactions2 See section Other special populations3 See section 4.44 Class effect

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

The highest incidence of hypocalcaemia was observed in a phase III trial in patients with multiple myeloma.

Hypocalcaemia was reported in 16.9% of patients treated with denosumab and 12.4% of patients treatedwith zoledronic acid. A grade 3 decrease in serum calcium levels was experienced in 1.4% of patientstreated with denosumab and 0.6% of patients treated with zoledronic acid. A grade 4 decrease in serumcalcium levels was experienced in 0.4% of patients treated with denosumab and 0.1% of patients treatedwith zoledronic acid.

In three phase III active-controlled clinical trials in patients with advanced malignancies involving bone,hypocalcaemia was reported in 9.6% of patients treated with denosumab and 5.0% of patients treated withzoledronic acid.

A grade 3 decrease in serum calcium levels was experienced in 2.5% of patients treated with denosumab and1.2% of patients treated with zoledronic acid. A grade 4 decrease in serum calcium levels was experiencedin 0.6% of patients treated with denosumab and 0.2% of patients treated with zoledronic acid (see section4.4).

In two phase II single-arm clinical trials in patients with giant cell tumour of bone, hypocalcaemia wasreported in 5.7% of patients. None of the adverse events was considered serious.

In the post-marketing setting, severe symptomatic hypocalcaemia (including fatal cases) has been reported,with most cases occurring in the first weeks of initiating therapy. Examples of clinical manifestations ofsevere symptomatic hypocalcaemia have included QT interval prolongation, tetany, seizures and alteredmental status (including coma) (see section 4.4). Symptoms of hypocalcaemia in clinical studies includedparaesthesias or muscle stiffness, twitching, spasms and muscle cramps.

In clinical trials, the incidence of ONJ was higher with longer duration of exposure; ONJ has also beendiagnosed after stopping treatment with denosumab with the majority of cases occurring within 5 monthsafter the last dose. Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jawcondition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedurewere excluded from the clinical trials.

A higher incidence of ONJ among patients treated with denosumab compared to zoledronic acid has beenobserved in SRE prevention clinical trials. The highest incidence of ONJ was observed in a phase III trial inpatients with multiple myeloma. In the double-blind treatment phase of this trial, ONJ was confirmed in5.9% of patients treated with denosumab (median exposure of 19.4 months; range 1 - 52) and in 3.2% ofpatients treated with zoledronic acid. At the completion of the double-blind treatment phase of this trial, thepatient-year adjusted incidence of confirmed ONJ in the denosumab group (median exposure of 19.4months; range 1 - 52), was 2.0 per 100 patient-years during the first year of treatment, 5.0 in the secondyear, and 4.5 thereafter. The median time to ONJ was 18.7 months (range: 1 - 44).

In the primary treatment phases of three phase III active-controlled clinical trials in patients with advancedmalignancies involving bone, ONJ was confirmed in 1.8% of patients treated with denosumab (medianexposure of 12.0 months; range: 0.1 - 40.5) and 1.3% of patients treated with zoledronic acid. Clinicalcharacteristics of these cases were similar between treatment groups. Among patients with confirmed ONJ,most (81% in both treatment groups) had a history of tooth extraction, poor oral hygiene, and/or use of adental appliance. Most patients were receiving or had received chemotherapy.

The trials in patients with breast or prostate cancer included a denosumab extension treatment phase(median overall exposure of 14.9 months; range: 0.1 - 67.2). ONJ was confirmed in 6.9% of patients withbreast cancer and prostate cancer during the extension treatment phase.

The patient-year adjusted overall incidence of confirmed ONJ was 1.1 per 100 patient-years during the firstyear of treatment, 3.7 in the second year and 4.6 thereafter. The median time to ONJ was 20.6 months(range: 4 - 53).

A non-randomised, retrospective, observational study in 2 877 patients with cancer treated with denosumabor zoledronic acid in Sweden, Denmark, and Norway showed that 5-year incidence proportions of medicallyconfirmed ONJ were 5.7% (95% CI: 4.4, 7.3; median follow up time of 20 months [range 0.2 - 60]) in acohort of patients receiving denosumab and 1.4% (95% CI: 0.8, 2.3; median follow up time of 13 months[range 0.1 - 60]) in a separate cohort of patients receiving zoledronic acid. Five-year incidence proportionof ONJ in patients switching from zoledronic acid to denosumab was 6.6% (95% CI: 4.2, 10.0; medianfollow up time of 13 months [range 0.2 - 60]).

In a phase III trial in patients with non-metastatic prostate cancer (a patient population for whichdenosumab is not indicated), with longer treatment exposure of up to 7 years, the patient-year adjustedincidence of confirmed ONJ was 1.1 per 100 patient-years during the first year of treatment, 3.0 in thesecond year, and 7.1 thereafter.

In a long-term phase II open-label clinical trial in patients with giant cell tumour of bone (study 6, seesection 5.1), ONJ was confirmed in 6.8% of patients, including one adolescent (median number of 34 doses;range 4 - 116). At the completion of the trial, median time on trial including safety follow- up phase was60.9 months (range: 0 - 112.6). The patient-year adjusted incidence of confirmed ONJ was 1.5 per 100patient-years overall (0.2 per 100 patient-years during the first year of treatment, 1.5 in the second year, 1.8in the third year, 2.1 in the fourth year, 1.4 in the fifth year, and 2.2 thereafter). The median time to ONJ was41 months (range: 11 - 96).

Study 7 was conducted to continue to follow subjects with GCTB who were treated in study 6 for anadditional 5 or more years. ONJ was reported in 6 patients (11.8%) of the 51 exposed patients with mediantotal 42 doses of denosumab. Three of these cases of ONJ were medically confirmed.

Drug related hypersensitivity reactions

In the post-marketing setting, events of hypersensitivity, including rare events of anaphylactic reactions,have been reported in patients receiving denosumab.

Atypical fractures of the femur

In the clinical trial programme overall, atypical femoral fractures have been reported uncommonly inpatients treated with denosumab and the risk increased with longer duration of treatment. Events haveoccurred during treatment and up to 9 months after treatment was discontinued (see section 4.4).

In the clinical trial programme for GCTB, atypical femoral fractures have been reported commonly inpatients treated with denosumab. In study 6, incidence of confirmed AFF was 0.95% (5/526) in patientswith giant cell tumour of bone. In the follow up study 7, the incidence of confirmed AFF was 3.9% (2/51)of patients exposed to denosumab.

Musculoskeletal pain

In the post-marketing setting, musculoskeletal pain, including severe cases, has been reported in patientsreceiving denosumab. In clinical trials, musculoskeletal pain was very common in both the denosumab andzoledronic acid treatment groups. Musculoskeletal pain leading to discontinuation of study treatment wasuncommon.

New primary malignancy

In the primary double-blind treatment phases of four phase III active-controlled clinical trials in patientswith advanced malignancies involving bone, new primary malignancy was reported in 54/3 691 (1.5%) ofpatients treated with denosumab (median exposure of 13.8 months; range: 1.0 - 51.7) and 33/3 688 (0.9%)of patients treated with zoledronic acid (median exposure of 12.9 months; range: 1.0 - 50.8).

The cumulative incidence at one year was 1.1% for denosumab and 0.6 % for zoledronic acid, respectively.

No treatment-related pattern in individual cancers or cancer groupings was apparent.

In patients with giant cell tumour of bone, incidence of new malignancy, including malignancies involvingthe bone and outside the bone was 3.8% (20/526) in study 6. In the follow up study 7, the incidence was11.8% (6/51) of patients exposed to denosumab.

Lichenoid drug eruptions

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

Denosumab was studied in an open-label trial that enrolled 28 skeletally mature adolescents with giant celltumour of bone. Based on these limited data, the adverse event profile appeared to be similar to adults.

Clinically significant hypercalcaemia after treatment discontinuation has been reported in the post-marketingsetting in paediatric patients (see section 4.4).

In a clinical study of patients without advanced cancer with severe renal impairment (creatinine clearance< 30 mL/min) or receiving dialysis, there was a greater risk of developing hypocalcaemia in the absence ofcalcium supplementation. The risk of developing hypocalcaemia during denosumab treatment is greaterwith increasing degree of renal impairment. In a clinical study in patients without advanced cancer, 19% ofpatients with severe renal impairment (creatinine clearance < 30 mL/min) and 63% of patients receivingdialysis developed hypocalcaemia despite calcium supplementation. The overall incidence of clinicallysignificant hypocalcaemia was 9%.

Accompanying increases in parathyroid hormone have also been observed in patients receiving denosumabwith severe renal impairment or receiving dialysis. Monitoring of calcium levels and adequate intake ofcalcium and vitamin D is especially important in patients with renal impairment (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 and 120 mg weekly for 3 weeks.

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

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

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

RANKL exists as a transmembrane or soluble protein. RANKL is essential for the formation, function andsurvival 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 multiplemyeloma. Denosumab is a human monoclonal antibody (IgG2) that targets and binds with high affinity andspecificity to RANKL, preventing the RANKL/RANK interaction from occurring and resulting in reducedosteoclast numbers and function, thereby decreasing bone resorption and cancer-induced bone destruction.

Giant cell tumours of bone are characterised by neoplastic stromal cells expressing RANK ligand andosteoclast-like giant cells expressing RANK. In patients with giant cell tumour of bone, denosumab binds to

RANK ligand, significantly reducing or eliminating osteoclast-like giant cells. Consequently, osteolysis isreduced and proliferative tumour stroma is replaced with non-proliferative, differentiated, densely wovennew bone.

In phase II clinical studies of patients with advanced malignancies involving bone, subcutaneous (SC)dosing of denosumab administered either every 4 weeks (Q4W) or every 12 weeks resulted in a rapidreduction in markers of bone resorption (uNTx/Cr, serum CTx), with median reductions of approximately80% for uNTx/Cr occurring within 1 week regardless of prior bisphosphonate therapy or baseline uNTx/Crlevel. In phase III clinical trials of patients with advanced malignancies involving bone, median uNTx/Crreductions of approximately 80% were maintained through 49 weeks of denosumab treatment (120 mgevery Q4W).

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 patients with bone metastases from solid tumours

Efficacy and safety of 120 mg denosumab SC every 4 weeks or 4 mg zoledronic acid (dose-adjusted forreduced 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: adultswith breast cancer (study 1), other solid tumours or multiple myeloma (study 2), and castrate-resistantprostate cancer (study 3). Within these active-controlled clinical trials, safety was evaluated in 5,931patients. Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw conditionrequiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure, were noteligible for inclusion in these studies. The primary and secondary endpoints evaluated the occurrence of oneor more skeletal related events (SREs). In studies demonstrating superiority of denosumab to zoledronicacid, patients were offered open-label denosumab in a pre-specified 2-year extension treatment phase. An

SRE was defined as any of the following: pathologic fracture (vertebral or non-vertebral), radiation therapyto bone (including the use of radioisotopes), surgery to bone, or spinal cord compression.

Denosumab reduced the risk of developing a SRE, and developing multiple SREs (first and subsequent) inpatients with bone metastases from solid tumours (see table 2).

Table 2. Efficacy results in patients with advanced malignancies involving bone

Study 2

Study 1 Study 3 Combined advanced

Other solid tumours**

Breast cancer Prostate cancer canceror multiple myeloma

Denosumab Zoledronic Denosumab Zoledronic Denosumab Zoledronic Denosumab Zoledronicacid acid acid acid

N 1 026 1 020 886 890 950 951 2 862 2 861

First SRE

Median time NR 26.4 20.6 16.3 20.7 17.1 27.6 19.4(months)

Difference in NA 4.2 3.5 8.2median time(months)

HR (95% CI) 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/ RRR (%)

Non- < 0.0001†/0.0101† 0.0007†/0.0619† 0.0002†/0.0085† < 0.0001/< 0.0001inferiority/ Superiorityp-values

Proportion of 30.7 36.5 31.4 36.3 35.9 40.6 32.6 37.8patients (%)

First and subsequent SRE*

Mean 0.46 0.60 0.44 0.49 0.52 0.61 0.48 0.57number/patient

Rate ratio 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(95% CI) /

RRR (%)

Superiority p- 0.0012† 0.1447† 0.0085† < 0.0001value

SMR per 0.45 0.58 0.86 1.04 0.79 0.83 0.69 0.81

Year

N 1 026 1 020 886 890 950 951 2 862 2 861

First SRE or HCM

Median time NR 25.2 19.0 14.4 20.3 17.1 26.6 19.4(months)

HR (95% CI) 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/ RRR (%)

Superiority p- 0.0074 0.0215 0.0134 < 0.0001

Study 2

Study 1 Study 3 Combined advanced

Other solid tumours**

Breast cancer Prostate cancer canceror multiple myelomavalue

First radiation to bone

Median time NR NR NR NR NR 28.6 NR 33.2(months)

HR (95% CI)/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

RRR (%)

Superiority p- 0.0121 0.0256 0.0071 < 0.0001value

NR = not reached; NA = not available; HCM = hypercalcaemia of malignancy; SMR = skeletal morbidity rate; HR = Hazard Ratio;

RRR = Relative Risk Reduction †Adjusted p-values are presented for studies 1, 2 and 3 (first SRE and first and subsequent SREendpoints); *Accounts for all skeletal events over time; only eventsoccurring ≥ 21 days after the previous event are counted.

** Including NSCLC, renal cell cancer, colorectal cancer, small cell lung cancer, bladder cancer, head and neck cancer,

GI/genitourinary cancer and others, excluding breast and prostate cancer.

Figure 1. Kaplan-Meier plots of time to first on-study SRE

Disease progression and overall survival with bone metastases from solid tumours

Disease progression was similar between denosumab and zoledronic acid in all three studies and in the pre-specified analysis of all three studies combined.

In studies 1, 2 and 3, overall survival was balanced between denosumab and zoledronic acid in patients withadvanced 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 othersolid tumours or multiple myeloma (hazard ratio and 95% CI was 0.95 [0.83, 1.08]). A post-hoc analysis instudy 2 (patients with other solid tumours or multiple myeloma) examined overall survival for the 3 tumourtypes used for stratification (non-small cell lung cancer, multiple myeloma, and other). Overall survival waslonger for denosumab 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 denosumab 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 acombined pre-specified analysis from studies 1, 2 and 3, overall survival was similar between denosumaband zoledronic acid (hazard ratio and 95% CI 0.99 [0.91, 1.07]).

Effect on pain

The time to pain improvement (i.e. ≥ 2-point decrease from baseline in BPI-SF worst pain score) was similarfor denosumab and zoledronic acid in each study and the integrated analyses. In a post-hoc analysis of thecombined dataset, the median time to worsening pain (> 4-point worst pain score) in patients with mild orno pain at baseline was delayed for denosumab compared to zoledronic acid (198 versus 143 days) (p =0.0002).

Clinical efficacy in patients with multiple myeloma

Denosumab was evaluated in an international, randomised (1:1), double-blind, active-controlled studycomparing denosumab with zoledronic acid in patients with newly diagnosed multiple myeloma, study 4.

In this study, 1 718 multiple myeloma patients with at least one bone lesion were randomised to receive 120mg denosumab subcutaneously every 4 weeks (Q4W) or 4 mg zoledronic acid intravenously (IV) every 4weeks (dose-adjusted for renal function). The primary outcome measure was demonstration of non-inferiority of time to first on study skeletal related event (SRE) as compared to zoledronic acid. Secondaryoutcome measures included superiority of time to first SRE, superiority of time to first and subsequent SRE,and overall survival. An SRE was defined as any of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cordcompression.

Across both study arms, 54.5% of patients intended to undergo autologous PBSC transplantation, 95.8%patients utilised/planned to utilise a novel anti-myeloma agent (novel therapies include bortezomib,lenalidomide, or thalidomide) in first-line therapy, and 60.7% of patients had a previous SRE. The numberof patients across both study arms with ISS stage I, stage II, and stage III at diagnosis were 32.4%, 38.2%,and 29.3%, respectively.

The median number of doses administered was 16 for denosumab and 15 for zoledronic acid.

Efficacy results from study 4 are presented in figure 2 and table 3.

Figure 2. Kaplan-Meier plot for time to first on-study SRE in patients with newly diagnosed multiple myeloma

Table 3. Efficacy results for denosumab compared to zoledronic acid in patients with newly diagnosed multiplemyeloma

Denosumab Zoledronic Acid(N = 859) (N = 859)

First SRE

Denosumab Zoledronic Acid(N = 859) (N = 859)

Number of patients who had SREs (%) 376 (43.8) 383 (44.6)

Median time to SRE (months) 22.8 (14.7, NE) 23.98 (16.56, 33.31)

Hazard ratio (95% CI) 0.98 (0.85, 1.14)

First and subsequent SRE

Mean number of events/patient 0.66 0.66

Rate ratio (95% CI) 1.01 (0.89, 1.15)

Skeletal morbidity rate per year 0.61 0.62

First SRE or HCM

Median time (months) 22.14 (14.26, NE) 21.32 (13.86, 29.7)

Hazard ratio (95% CI) 0.98 (0.85, 1.12)

First radiation to bone

Hazard ratio (95% CI) 0.78 (0.53, 1.14)

Overall survival

Hazard ratio (95% CI) 0.90 (0.70, 1.16)

NE = not estimable

HCM = hypercalcaemia of malignancy

Clinical efficacy and safety in adults and skeletally mature adolescents with giant cell tumour of bone

The safety and efficacy of denosumab was studied in two phase II open-label, single-arm trials (studies 5and 6) that enrolled 554 patients with giant cell tumour of bone that was either unresectable or for whichsurgery would be associated with severe morbidity and a prospective, multicentre, open label, phase IVstudy (study 7) that provided long term safety follow up for patients who completed study 6. Patientsreceived 120 mg denosumab subcutaneously every 4 weeks with a loading dose of 120 mg on days 8 and15. Patients who discontinued denosumab then entered the safety follow-up phase for a minimum of 60months. Retreatment with denosumab while in safety follow-up was allowed for patients who initiallydemonstrated a response to denosumab (e.g. in the case of recurrent disease).

Study 5 enrolled 37 adult patients with histologically confirmed unresectable or recurrent giant cell tumourof bone. The main outcome measure of the trial was response rate, defined as either at least 90% eliminationof giant cells relative to baseline (or complete elimination of giant cells in cases where giant cells represent< 5% of tumour cells), or a lack of progression of the target lesion by radiographic measurements in caseswhere histopathology was not available. Of the 35 patients included in the efficacy analysis, 85.7% (95%

CI: 69.7, 95.2) had a treatment response to denosumab. All 20 patients (100%) with histology assessmentsmet response criteria. Of the remaining 15 patients, 10 (67%) radiographic measurements showed noprogression of the target lesion.

Study 6 enrolled 535 adult or skeletally mature adolescents with giant cell tumour of bone. Of thesepatients, 28 were aged 12-17 years. Patients were assigned to one of three cohorts: cohort 1 includedpatients with surgically unsalvageable disease (e.g. sacral, spinal, or multiple lesions, including pulmonarymetastases); cohort 2 included patients with surgically salvageable disease whose planned surgery wasassociated with severe morbidity (e.g. joint resection, limb amputation, or hemipelvectomy); cohort 3included patients previously participating in study 5 and rolled over into this study. The primary objectivewas to evaluate the safety profile of denosumab in patients with giant cell tumour of bone. The secondaryoutcome measures of the study included time to disease progression (based on investigator assessment) forcohort 1 and proportion of patients without any surgery at month 6 for cohort 2.

In cohort 1 at the final analysis, 28 of the 260 treated patients (10.8%) had disease progression. In cohort 2,219 of the 238 (92.0%; 95% CI: 87.8%, 95.1%) evaluable patients treated with denosumab had notundergone surgery by month 6. Of the 239 subjects in cohort 2 with baseline target lesion location or on-study location not in lungs or soft tissue, a total of 82 subjects (34.3%) were able to avoid on- study surgery.

Overall, efficacy results in skeletally mature adolescents were similar to those observed in adults.

Study 7 enrolled 85 adult patients who were previously enrolled and completed study 6. Patients wereallowed to receive denosumab treatment for GCTB, and all patients were followed for 5 years. The primaryobjective was to evaluate the long-term safety profile of denosumab in patients with giant cell tumour of thebone.

Effect on pain

In the final analysis cohorts 1 and 2 combined, a clinically meaningful reduction in worst pain (i.e. ≥ 2-pointdecrease from baseline) was reported for 30.8% of patients at risk (i.e. those who had a worst pain score of ≥2 at baseline) within 1 week of treatment, and ≥ 50% at week 5. These pain improvements were maintainedat all subsequent evaluations.

The European Medicines Agency has waived the obligation to submit the results of studies with the referencemedicinal product containing denosumab in all subsets of the paediatric population in the prevention ofskeletal related events in patients with bone metastases and subsets of the paediatric population below the ageof 12 in the treatment of giant cell tumour of bone (see section 4.2 for information on paediatric use).

In study 6, denosumab has been evaluated in a subset of 28 adolescent patients (aged 13-17 years) withgiant cell tumour of bone who had reached skeletal maturity defined by at least 1 mature long bone (e.g.

closed epiphyseal growth plate of the humerus) and body weight ≥ 45 kg. One adolescent patients withsurgically unsalvageable disease (N=14) had disease recurrence during initial treatment. Thirteen of the 14patients with surgically salvageable disease whose planned surgery was associated with severe morbidityhad not undergone surgery by month 6.

Following subcutaneous administration, bioavailability was 62%.

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.

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

A population pharmacokinetic analysis did not indicate clinically significant changes in the systemicexposure of denosumab at steady-state with respect to age (18 to 87 years), race/ethnicity (Blacks,

Hispanics, Asians and Caucasians explored), gender or solid tumour types or patients with multiplemyeloma. Increasing body weight was associated with decreases in systemic exposure, and vice versa. Thealterations were not considered clinically-relevant, since pharmacodynamic effects based on bone turnovermarkers were consistent across a wide range of body weight.

Denosumab displayed non-linear pharmacokinetics with dose over a wide dose range, but approximatelydose-proportional increases in exposure for doses of 60 mg (or 1 mg/kg) and higher. The non-linearity islikely due to a saturable target-mediated elimination pathway of importance at low concentrations.

In studies of denosumab (60 mg, n = 55 and 120 mg, n = 32) in patients without advanced cancer but withvarying degrees of renal function, including patients on dialysis, the degree of renal impairment had noeffect on the pharmacokinetics of denosumab; thus dose adjustment for renal impairment is not required.

There is no need for renal monitoring with denosumab dosing.

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.

No overall differences in safety or efficacy were observed between geriatric patients and younger patients.

Controlled clinical studies of denosumab in patients with advanced malignancies involving bone over age 65revealed similar efficacy and safety in older and younger patients. No dose adjustment is required in elderlypatients.

In skeletally-mature adolescents (12-17 years of age) with giant cell tumour of bone who received 120 mgevery 4 weeks with a loading dose on days 8 and 15, the pharmacokinetics of denosumab were similar tothose observed in adult patients with GCTB.

Since the biological activity of denosumab in animals is specific to nonhuman primates, evaluation ofgenetically engineered (knockout) mice or use of other biological inhibitors of the RANK/RANKLpathway, such as OPG-Fc and RANK-Fc, were used to evaluate the pharmacodynamic properties ofdenosumab in rodent models.

In mouse bone metastasis models of oestrogen receptor positive and negative human breast cancer, prostatecancer and non-small cell lung cancer, OPG-Fc reduced osteolytic, osteoblastic, and osteolytic/osteoblasticlesions, delayed formation of de novo bone metastases, and reduced skeletal tumour growth. When OPG-Fcwas combined with hormonal therapy (tamoxifen) or chemotherapy (docetaxel) in these models, there wasadditive inhibition of skeletal tumour growth in breast, and prostate or lung cancer respectively. In a mousemodel of mammary tumour induction, RANK-Fc reduced hormone-induced proliferation in mammaryepithelium and delayed tumour formation.

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 single and repeated dose toxicity studies in cynomolgus monkeys, denosumab doses resulting in 2.7 to 15times greater systemic exposure than the recommended human dose had no impact on cardiovascularphysiology, male or female fertility, or produced specific target organ toxicity.

In a study of cynomolgus monkeys dosed with denosumab during the period equivalent to the first trimesterof pregnancy, denosumab doses resulting in 9 times greater systemic exposure than the recommendedhuman dose did not induce maternal toxicity or foetal harm during a period equivalent to the first trimester,although foetal lymph nodes were not examined.

In another study of cynomolgus monkeys dosed with denosumab throughout pregnancy at systemicexposures 12-fold higher than the human dose, there were increased stillbirths and postnatal mortality;abnormal bone growth resulting in reduced bone strength, reduced haematopoiesis, and tooth malalignment;absence of peripheral lymph nodes; and decreased neonatal growth. A no observed adverse effect level forreproductive effects was not established. Following a 6 month period after birth, bone related changesshowed recovery and there was no effect on tooth eruption. However, the effects on lymph nodes and toothmalalignment persisted, and minimal to moderate mineralisation in multiple tissues was seen in one animal(relation to treatment uncertain). There was no evidence of maternal harm prior to labour; adverse maternaleffects occurred infrequently 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.

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.

In preclinical studies knockout mice lacking RANK or RANKL had an absence of lactation due toinhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy) andexhibited impairment of lymph node formation. Neonatal RANK/RANKL knockout mice exhibiteddecreased body weight, reduced bone growth, altered growth plates and lack of tooth eruption.

Reduced bone growth, altered growth plates and impaired tooth eruption were also seen in studies ofneonatal rats administered RANKL inhibitors, and these changes were partially reversible when dosing of

RANKL inhibitor was discontinued. Adolescent primates dosed with denosumab at 2.7 and 15 times (10 and50 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.

4 years.

Once removed from the refrigerator, Xbryk may be stored at temperature up to a maximum of 25°C for asingle period of up to 60 days, but not exceeding the original expiry date. If not used within this period of upto 60 days, Xbryk 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 vial in the carton in order to protect from light.

1.7 mL solution in a single use vial (type I glass) with stopper (chlorobutyl rubber) and seal (aluminium)with flip-off cap.

Pack sizes of one or three.

Not all pack sizes may be marketed.

* Before administration, the Xbryk solution should be inspected visually. The solution may containtrace amounts of translucent to white proteinaceous particles. Do not inject the solution if it is cloudyor discoloured.

* Do not shake.

* To avoid discomfort at the site of injection, allow the vial to reach room temperature (up to 25ºC)before injecting and inject slowly.

* The entire contents of the vial should be injected.

* A 27 gauge needle is recommended for the administration of denosumab.

* The vial should not be re-entered.

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/1/24/1889/001

EU/1/24/1889/002

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/.