OSENVELT 120mg 70mg / ml injectible solution medication leaflet

Osenvelt 120 mg solution for injection

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

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

Excipient with known effects

Each 1.7 mL of solution contains 79.9 mg sorbitol (E420) which is equivalent to 47 mg/mL and0.17 mg polysorbate 20 (E432) which is equivalent to 0.1 mg/mL.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear, colourless to pale yellow solution with pH of 5.2.

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

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

Denosumab 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,unless hypercalcaemia is present (see section 4.4).

Patients treated with denosumab 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 weeksinto the thigh, abdomen or upper arm.

Giant cell tumour of bone

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

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

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

No dose adjustment is required in patients with renal impairment (see sections 4.4 forrecommendations relating 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 (seesection 5.2).

Elderly patients (age ≥ 65)

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

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

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

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

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

RANKL inhibition (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 numberof the administered product should be clearly recorded.

Calcium and Vitamin D supplementation

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

Pre-existing hypocalcaemia must be corrected prior to initiating therapy with denosumab.

Hypocalcaemia can occur at any time during therapy with denosumab. Monitoring of calcium levelsshould be conducted (i) prior to the initial dose of denosumab, (ii) within two weeks after the initialdose, (iii) if suspected symptoms of hypocalcaemia occur (see section 4.8 for symptoms). Additionalmonitoring of calcium level should be considered during therapy in patients with risk factors forhypocalcaemia, or if otherwise indicated based on the clinical condition of the patient.

Patients should be encouraged to report symptoms indicative of hypocalcaemia. If hypocalcaemiaoccurs while receiving denosumab, additional calcium supplementation and additional monitoring maybe necessary.

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

Patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis are atgreater risk of developing hypocalcaemia. The risk of developing hypocalcaemia and accompanyingelevations in parathyroid hormone increases with increasing degree of renal impairment. Regularmonitoring of calcium levels 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 softtissue lesions in the mouth. A dental examination with preventive dentistry and an individualbenefit-risk assessment is recommended prior to treatment with denosumab.

The following risk factors should be considered when evaluating a patient’s risk of developing ONJ:

* potency of the medicinal product that inhibits bone resorption (higher risk for highly potentcompounds), route of administration (higher risk for parenteral administration) and cumulativedose of bone resorption therapy.

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

* concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy tohead and neck.

* poor oral hygiene, periodontal disease, poorly fitting dentures, pre-existing dental disease,invasive dental procedures (e.g. tooth extractions).

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

The management plan of the patients who develop ONJ should be set up in close collaborationbetween the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporaryinterruption of denosumab treatment should be considered until the condition resolves andcontributing 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 factorsfor osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local riskfactors such as infection or trauma. The possibility of osteonecrosis of the external auditory canalshould be considered in patients receiving denosumab who present with ear symptoms includingchronic ear infections.

Atypical fractures of the femur

Atypical femoral fractures have been reported in patients receiving denosumab (see section 4.8).

Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphysealregions of the femur. Specific radiographic findings characterise these events. Atypical femoralfractures have also been reported in patients with certain co-morbid conditions (e.g. vitamin Ddeficiency, rheumatoid arthritis, hypophosphatasia) and with use of certain pharmaceutical agents (e.g.bisphosphonates, glucocorticoids, proton pump inhibitors). These events have also occurred withoutantiresorptive therapy. Similar fractures reported in association with bisphosphonates are oftenbilateral; therefore the contralateral femur should be examined in denosumab-treated patients whohave sustained a femoral shaft fracture. Discontinuation of denosumab therapy in patients suspected tohave an atypical femur fracture should be considered pending evaluation of the patient based on anindividual benefit-risk assessment. During denosumab treatment, patients should be advised to reportnew or unusual thigh, hip, or groin pain. Patients presenting with such symptoms should be evaluatedfor an incomplete femoral fracture.

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 injuryhas been reported in denosumab-treated patients with giant cell tumour of bone weeks to monthsfollowing treatment 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 Dsupplementation requirements (see section 4.8).

Denosumab is not recommended in patients with growing skeletons (see section 4.2). Clinicallysignificant hypercalcaemia has also been reported in this patient group weeks to months followingtreatment discontinuation.

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 anda known risk in patients with giant cell tumour of bone. Patients should be monitored for radiologicalsigns of malignancy, new radiolucency or osteolysis. Available clinical data does not suggest anincreased risk of malignancy in giant cell tumour of bone in patients treated with denosumab.

Warnings for excipients

This medicine contains 79.9 mg sorbitol in each vial, which is equivalent to 47 mg/mL. The additiveeffect of concomitantly administered products containing sorbitol (or fructose) and dietary intake ofsorbitol (or fructose) should be taken into account.

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

This medicine contains 0.17 mg of polysorbate 20 in each vial which is equivalent to 0.1 mg/mL.

Polysorbates may cause allergic reactions. Tell your doctor if you have any known allergies.

No interaction studies have been performed.

In clinical trials, denosumab has been administered in combination with standard anti-cancer treatmentand in subjects previously receiving bisphosphonates. There were no clinically-relevant alterations intrough serum concentration and pharmacodynamics of denosumab (creatinine adjusted urinary

N-telopeptide, uNTX/Cr) by concomitant chemotherapy and/or hormone therapy or by previousintravenous bisphosphonate exposure.

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

Denosumab is not recommended for use in pregnant women and women of child-bearing potential notusing contraception. Women should be advised not to become pregnant during and for at least5 months after treatment with denosumab. Any effects of denosumab are likely to be greater during thesecond and third trimesters of pregnancy since monoclonal antibodies are transported across theplacenta in a linear fashion as pregnancy progresses, with the largest amount transferred during thethird 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). Adecision must be made on whether to abstain from breast-feeding or to abstain from denosumabtherapy taking into account the benefit of breast-feeding to the newborn/infant and the benefit oftherapy for the woman.

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

Denosumab 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 withinthe first 2 weeks. Hypocalcaemia can be severe and symptomatic (see section 4.8 - description ofselected adverse reactions). The decreases in serum calcium were generally appropriately managed bycalcium and vitamin D supplementation. The most common adverse reactions with denosumab aremusculoskeletal pain. Cases of osteonecrosis of the jaw (see sections 4.4 and 4.8 - description ofselected adverse reactions) have been commonly observed in patients taking denosumab.

The following convention has been used for the classification of the adverse reactions based onincidence rates in four phase III, two phase II clinical studies and post-marketing experience (seetable 1): very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100),rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000) and not known (cannot be estimated from theavailable data. Within each frequency grouping and system organ class, adverse reactions arepresented in order of decreasing seriousness.

Table 1. Adverse reactions reported in patients with advanced malignancies involving bone,multiple myeloma, or with giant cell tumour of bone

MedDRA system organ class Frequency category Adverse reactions

Neoplasms benign, malignant Common New primary malignancy1and unspecified (including cystsand polyps)

Immune system disorders Rare Drug hypersensitivity1

Rare Anaphylactic reaction1

Metabolism and nutrition Very common Hypocalcaemia1,2disorders Common Hypophosphataemia

Uncommon Hypercalcaemia followingtreatment discontinuation inpatients with giant cell tumour ofbone3

Respiratory, thoracic and Very common Dyspnoeamediastinal disorders

Gastrointestinal disorders Very common Diarrhoea

Common Tooth extraction

Skin and subcutaneous tissue Common Hyperhidrosisdisorders Uncommon Lichenoid drug eruptions1

Musculoskeletal and connective Very common Musculoskeletal pain1tissue disorders Common Osteonecrosis of the jaw1

Uncommon Atypical femoral fracture1

Not known Osteonecrosis of the externalauditory canal3,41 See section Description of selected adverse reactions2 See section Other special populations3 See section 4.44 Class effect

A higher incidence of hypocalcaemia among subjects treated with denosumab compared to zoledronicacid has been observed in SRE prevention clinical trials.

The highest incidence of hypocalcaemia was observed in a phase III trial in patients with multiplemyeloma. Hypocalcaemia was reported in 16.9% of patients treated with denosumab and 12.4% ofpatients treated with zoledronic acid. A grade 3 decrease in serum calcium levels was experienced in1.4% of patients treated with denosumab and 0.6% of patients treated with zoledronic acid. A grade 4decrease in serum calcium levels was experienced in 0.4% of patients treated with denosumab and0.1% of patients treated with zoledronic acid.

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

A grade 3 decrease in serum calcium levels was experienced in 2.5% of patients treated withdenosumab and 1.2% of patients treated with zoledronic acid. A grade 4 decrease in serum calciumlevels was experienced in 0.6% of patients treated with denosumab and 0.2% of patients treated withzoledronic acid (see section 4.4).

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 beenreported, with most cases occurring in the first weeks of initiating therapy. Examples of clinicalmanifestations of severe symptomatic hypocalcaemia have included QT interval prolongation, tetany,seizures and altered mental status (including coma) (see section 4.4). Symptoms of hypocalcaemia inclinical studies included paraesthesias 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 within5 months after the last dose. Patients with prior history of ONJ or osteomyelitis of the jaw, an activedental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasivedental procedure were excluded from the clinical trials.

A higher incidence of ONJ among subjects treated with denosumab compared to zoledronic acid hasbeen observed in SRE prevention clinical trials. The highest incidence of ONJ was observed in aphase III trial in patients with multiple myeloma. In the double-blind treatment phase of this trial, ONJwas confirmed in 5.9% of patients treated with denosumab (median exposure of 19.4 months; range1 - 52) and in 3.2% of patients treated with zoledronic acid. At the completion of the double-blindtreatment phase of this trial, the patient-year adjusted incidence of confirmed ONJ in the denosumabgroup (median exposure of 19.4 months; range 1 - 52), was 2.0 per 100 patient-years during the firstyear of treatment, 5.0 in the second year, and 4.5 thereafter. The median time to ONJ was 18.7 months(range: 1 - 44).

In the primary treatment phases of three phase III active-controlled clinical trials in patients withadvanced malignancies involving bone, ONJ was confirmed in 1.8% of patients treated withdenosumab (median exposure of 12.0 months; range: 0.1 - 40.5) and 1.3% of patients treated withzoledronic acid. Clinical characteristics of these cases were similar between treatment groups. Amongsubjects with confirmed ONJ, most (81% in both treatment groups) had a history of tooth extraction,poor oral hygiene, and/or use of a dental appliance. Most subjects were receiving or had receivedchemotherapy.

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 patientswith breast cancer and prostate cancer during the extension treatment phase.

The patient-year adjusted overall incidence of confirmed ONJ was 1.1 per 100 patient-years during thefirst year of treatment, 3.7 in the second year and 4.6 thereafter. The median time to ONJ was20.6 months (range: 4 - 53).

A non-randomised, retrospective, observational study in 2,877 patients with cancer treated withdenosumab or zoledronic acid in Sweden, Denmark, and Norway showed that 5-year incidenceproportions of medically confirmed ONJ were 5.7% (95% CI: 4.4, 7.3; median follow up time of20 months [range 0.2-60]) in a cohort 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 receivingzoledronic acid. Five-year incidence proportion of ONJ in patients switching from zoledronic acid todenosumab was 6.6% (95% CI: 4.2, 10.0; median follow up time of 13 months [range 0.2-60]).

In a phase III trial in patients with non-metastatic prostate cancer (a patient population for 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 of34 doses; range 4 - 116). At the completion of the trial, median time on trial including safetyfollow-up phase was 60.9 months (range: 0 - 112.6). The patient-year adjusted incidence of confirmed

ONJ was 1.5 per 100 patient-years overall (0.2 per 100 patient-years during the first year of treatment,1.5 in the second year, 1.8 in the third year, 2.1 in the fourth year, 1.4 in the fifth year, and 2.2thereafter). The median time to ONJ was 41 months (range: 11 - 96).

Drug related hypersensitivity reactions

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

Atypical fractures of the femur

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

Musculoskeletal pain

In the post-marketing setting, musculoskeletal pain, including severe cases, has been reported inpatients receiving denosumab. In clinical trials, musculoskeletal pain was very common in both thedenosumab and zoledronic acid treatment groups. Musculoskeletal pain leading to discontinuation ofstudy treatment was uncommon.

New primary malignancy

In the primary double blind treatment phases of four phase III active-controlled clinical trials inpatients with advanced malignancies involving bone, new primary malignancy was reported in54/3691 (1.5%) of patients treated with denosumab (median exposure of 13.8 months; range: 1.0-51.7)and 33/3688 (0.9%) of patients treated with zoledronic acid (median exposure of 12.9 months; range:1.0-50.8).

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

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

Lichenoid drug eruptions

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

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

Clinically significant hypercalcaemia after treatment discontinuation has been reported in thepost-marketing setting in paediatric patients (see section 4.4).

In a clinical study of patients without advanced cancer with severe renal impairment (creatinineclearance < 30 mL/min) or receiving dialysis, there was a greater risk of developing hypocalcaemia inthe absence of calcium supplementation. The risk of developing hypocalcaemia during denosumabtreatment is greater with increasing degree of renal impairment. In a clinical study in patients withoutadvanced cancer, 19% of patients with severe renal impairment (creatinine clearance < 30 mL/min)and 63% of patients receiving dialysis developed hypocalcaemia despite calcium supplementation.

The overall incidence of clinically significant hypocalcaemia was 9%.

Accompanying increases in parathyroid hormone have also been observed in patients receivingdenosumab with severe renal impairment or receiving dialysis. Monitoring of calcium levels andadequate intake of calcium 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. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

Osenvelt 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, functionand survival of osteoclasts, the sole cell type responsible for bone resorption. Increased osteoclastactivity, stimulated by RANKL, is a key mediator of bone destruction in metastatic bone disease andmultiple myeloma. Denosumab is a human monoclonal antibody (IgG2) that targets and binds withhigh affinity and specificity to RANKL, preventing the RANKL/RANK interaction from occurringand resulting in reduced osteoclast numbers and function, thereby decreasing bone resorption andcancer-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, denosumabbinds to RANK ligand, significantly reducing or eliminating osteoclast-like giant cells. Consequently,osteolysis is reduced and proliferative tumour stroma is replaced with non-proliferative, differentiated,densely woven new bone.

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 ofapproximately 80% for uNTX/Cr occurring within 1 week regardless of prior bisphosphonate therapyor baseline uNTX/Cr level. In phase III clinical trials of patients with advanced malignanciesinvolving bone, median uNTX/Cr reductions of approximately 80% were maintained through 49weeks of denosumab treatment (120 mg every Q4W).

Anti-denosumab antibodies may develop during denosumab treatment. No apparent correlation ofantibody development 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-adjustedfor reduced renal function) IV every 4 weeks were compared in three randomised, double-blind,active-controlled studies, in IV-bisphosphonate naïve patients with advanced malignancies involvingbone: adults with breast cancer (study 1), other solid tumours or multiple myeloma (study 2), andcastrate-resistant prostate cancer (study 3). Within these active-controlled clinical trials, safety wasevaluated in 5,931 patients. Patients with prior history of ONJ or osteomyelitis of the jaw, an activedental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasivedental procedure, were not eligible for inclusion in these studies. The primary and secondary endpointsevaluated the occurrence of one or more skeletal related events (SREs). In studies demonstratingsuperiority of denosumab to zoledronic acid, patients were offered open-label denosumab in apre-specified 2-year extension treatment phase. An SRE was defined as any of the following:pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use ofradioisotopes), surgery to bone, or spinal cord compression.

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

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

Study 1 Study 2 Study 3 Combinedbreast cancer other solid prostate cancer advanced cancertumours** ormultiple myelomadenosumab 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 8.2

Study 1 Study 2 Study 3 Combinedbreast cancer other solid prostate cancer advanced cancertumours** ormultiple myelomadenosumab zoledronic denosumab zoledronic denosumab zoledronic denosumab zoledronicacid acid acid acid

N 1,026 1,020 886 890 950 951 2,862 2,861median 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-inferiority < 0.0001†/0.0101† 0.0007†/0.0619† 0.0002†/0.0085† < 0.0001/< 0.0001/ Superiorityp-values

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

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 0.0012† 0.1447† 0.0085† < 0.0001p-value

SMR per Year 0.45 0.58 0.86 1.04 0.79 0.83 0.69 0.81

First SRE or HCM

Median time 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 0.0074 0.0215 0.0134 < 0.0001p-value

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 0.0121 0.0256 0.0071 < 0.0001p-value

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 SRE endpoints); *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 neckcancer, GI/genitourinary cancer and others, excluding breast and prostate cancer.

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

Dmab = Denosumab 120 mg Q4W

ZA = Zoledronic Acid 4 mg Q4W

N = Number of subjects randomised

* = Statistically significant for superiority; ** = Statistically significant for non-inferiority

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 thepre-specified analysis of all three studies combined.

In studies 1, 2 and 3, overall survival was balanced between denosumab and zoledronic acid inpatients with advanced malignancies involving bone: patients with breast cancer (hazard ratio and95% CI was 0.95 [0.81, 1.11]), patients with prostate cancer (hazard ratio and 95% CI was 1.03 [0.91,1.17]), and patients with other solid tumours or multiple myeloma (hazard ratio and 95% CI was 0.95[0.83, 1.08]). A post-hoc analysis in study 2 (patients with other solid tumours or multiple myeloma)examined overall survival for the 3 tumour types used for stratification (non-small cell lung cancer,multiple myeloma, and other). Overall survival was longer for denosumab in non-small cell lungcancer (hazard ratio [95% CI] of 0.79 [0.65, 0.95]; n = 702) and longer for zoledronic acid in multiplemyeloma (hazard ratio [95% CI] of 2.26 [1.13, 4.50]; n = 180) and similar between denosumab andzoledronic acid in other tumour types (hazard ratio [95% CI] of 1.08 (0.90, 1.30); n = 894). This studydid not control for prognostic factors and anti-neoplastic treatments. In a combined pre-specifiedanalysis from studies 1, 2 and 3, overall survival was similar between denosumab and 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) wassimilar for denosumab and zoledronic acid in each study and the integrated analyses. In a post-hocanalysis of the combined dataset, the median time to worsening pain (> 4-point worst pain score) inpatients with mild or no 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 toreceive 120 mg denosumab subcutaneously every 4 weeks (Q4W) or 4 mg zoledronic acidintravenously (IV) every 4 weeks (dose-adjusted for renal function). The primary outcome measurewas demonstration of non-inferiority of time to first on study skeletal related event (SRE) as comparedto zoledronic acid. Secondary outcome measures included superiority of time to first SRE, superiorityof time to first and subsequent SRE, and overall survival. An SRE was defined as any of thefollowing: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the useof radioisotopes), surgery to bone, or spinal cord compression.

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 includebortezomib, lenalidomide, or thalidomide) in first-line therapy, and 60.7% of patients had a previous

SRE. The number of patients across both study arms with ISS stage I, stage II, and stage III atdiagnosis 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 diagnosedmultiple myeloma

N = Number of subjects randomised

Table 3. Efficacy results for denosumab compared to zoledronic acid in patients with newlydiagnosed multiple myeloma

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

First SRE

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 5 and 6) that enrolled 554 patients with giant cell tumour of bone that was either unresectableor for which surgery would be associated with severe morbidity. Patients received 120 mg denosumabsubcutaneously every 4 weeks with a loading dose of 120 mg on days 8 and 15. Patients whodiscontinued denosumab then entered the safety follow-up phase for a minimum of 60 months.

Retreatment with denosumab while in safety follow-up was allowed for subjects 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 celltumour of bone. The main outcome measure of the trial was response rate, defined as either at least90% elimination of giant cells relative to baseline (or complete elimination of giant cells in caseswhere giant cells represent < 5% of tumour cells), or a lack of progression of the target lesion byradiographic measurements in cases where histopathology was not available. Of the 35 patientsincluded in the efficacy analysis, 85.7% (95% CI: 69.7, 95.2) had a treatment response to denosumab.

All 20 patients (100%) with histology assessments met response criteria. Of the remaining 15 patients,10 (67%) radiographic measurements showed no progression 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, includingpulmonary metastases); cohort 2 included patients with surgically salvageable disease whose plannedsurgery was associated with severe morbidity (e.g. joint resection, limb amputation, orhemipelvectomy); cohort 3 included patients previously participating in study 5 and rolled over intothis study. The primary objective was to evaluate the safety profile of denosumab in subjects withgiant cell tumour of bone. The secondary outcome measures of the study included time to diseaseprogression (based on investigator assessment) for cohort 1 and proportion of patients without anysurgery at month 6 for cohort 2.

In cohort 1 at the final analysis, 28 of the 260 treated patients (10.8%) had disease progression. Incohort 2, 219 of the 238 (92.0%; 95% CI: 87.8%, 95.1%) evaluable patients treated with denosumabhad not undergone surgery by month 6. Of the 239 subjects in cohort 2 with baseline target lesionlocation or on-study location not in lungs or soft tissue, a total of 82 subjects (34.3%) were able toavoid on-study surgery. Overall, efficacy results in skeletally mature adolescents were similar to thoseobserved in adults.

Effect on pain

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

The European Medicines Agency has waived the obligation to submit the results of studies withdenosumab in all subsets of the paediatric population in the prevention of skeletal related events inpatients with bone metastases and subsets of the paediatric population below the age of 12 in thetreatment 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)with giant cell tumour of bone who had reached skeletal maturity defined by at least 1 mature longbone (e.g. closed epiphyseal growth plate of the humerus) and body weight ≥ 45 kg. One adolescentsubject with surgically unsalvageable disease (N=14) had disease recurrence during initial treatment.

Thirteen of the 14 subjects with surgically salvageable disease whose planned surgery was associatedwith severe morbidity had 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 isunlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination areexpected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptidesand individual amino acids.

In subjects with advanced cancer, who received multiple doses of 120 mg every 4 weeks anapproximate 2-fold accumulation in serum denosumab concentrations was observed and steady-statewas achieved by 6 months, consistent with time-independent pharmacokinetics. In subjects withmultiple myeloma who received 120 mg every 4 weeks, median trough levels varied by less than 8%between months 6 and 12. In subjects with giant cell tumour of bone who received 120 mg every4 weeks with a loading dose on days 8 and 15, steady-state levels were achieved within the first monthof treatment. Between weeks 9 and 49, median trough levels varied by less than 9%. In subjects whodiscontinued 120 mg every 4 weeks, the mean half-life was 28 days (range 14 to 55 days).

A population pharmacokinetic analysis did not indicate clinically significant changes in the 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.

The alterations were not considered clinically-relevant, since pharmacodynamic effects based on boneturnover markers were consistent across a wide range of body weight.

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

The non-linearity is likely due to a saturable target-mediated elimination pathway of importance at lowconcentrations.

In studies of denosumab (60 mg, n = 55 and 120 mg, n = 32) in patients without advanced cancer butwith varying degrees of renal function, including patients on dialysis, the degree of renal impairmenthad no effect on the pharmacokinetics of denosumab; thus dose adjustment for renal impairment is notrequired. There is no need for renal monitoring with denosumab dosing.

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

No overall differences in safety or efficacy were observed between geriatric patients and youngerpatients. Controlled clinical studies of denosumab in patients with advanced malignancies involvingbone over age 65 revealed similar efficacy and safety in older and younger patients. No doseadjustment is required in elderly patients.

In skeletally-mature adolescents (12-17 years of age) with giant cell tumour of bone who received120 mg every 4 weeks with a loading dose on days 8 and 15, the pharmacokinetics of denosumab weresimilar to those observed in adult subjects 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,prostate cancer and non-small cell lung cancer, OPG-Fc reduced osteolytic, osteoblastic, andosteolytic/osteoblastic lesions, delayed formation of de novo bone metastases, and reduced skeletaltumour growth. When OPG-Fc was combined with hormonal therapy (tamoxifen) or chemotherapy(docetaxel) in these models, there was additive inhibition of skeletal tumour growth in breast, andprostate or lung cancer respectively. In a mouse model of mammary tumour induction, RANK-Fcreduced hormone-induced proliferation in mammary epithelium and delayed tumour formation.

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

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

In single and repeated dose toxicity studies in cynomolgus monkeys, denosumab doses resulting in 2.7to 15 times greater systemic exposure than the recommended human dose had no impact oncardiovascular physiology, 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 firsttrimester of pregnancy, denosumab doses resulting in 9 times greater systemic exposure than therecommended human dose did not induce maternal toxicity or foetal harm during a period equivalentto 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 toothmalalignment; absence of peripheral lymph nodes; and decreased neonatal growth. A no observedadverse effect level for reproductive effects was not established. Following a 6 month period afterbirth, bone related changes showed recovery and there was no effect on tooth eruption. However, theeffects on lymph nodes and tooth malalignment persisted, and minimal to moderate mineralisation inmultiple tissues was seen in one animal (relation to treatment uncertain). There was no evidence ofmaternal harm prior to labour; adverse maternal effects occurred infrequently during labour. Maternalmammary 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 fracturecallus compared 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 whendosing of RANKL inhibitor was discontinued. Adolescent primates dosed with denosumab at 2.7 and15 times (10 and 50 mg/kg dose) the clinical exposure had abnormal growth plates. Therefore,treatment with denosumab may impair bone growth in children with open growth plates and mayinhibit eruption of dentition.

Acetic acid*

Sodium acetate trihydrate (for pH adjustment)*

Sorbitol (E420)

Polysorbate 20 (E432)

Water for injections

* Acetate buffer is formed by mixing acetic acid with sodium acetate trihydrate

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

42 months.

Once removed from the refrigerator, Osenvelt may be stored at room temperature (up to 25°C) for upto 30 days in the original container, do not put it back in the refrigerator. It must be used within this30 day period.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

1.7 mL solution in a single use type 1 glass vial with a (butyl) rubber stopper and an aluminium sealwith a flip-off button.

Pack sizes of one, three or four vials.

Not all pack sizes may be marketed.

* Before administration, the Osenvelt solution should be inspected visually. Do not inject thesolution if it contains visible particles or is cloudy or discoloured.

* Do not shake.

* To avoid discomfort at the site of injection, allow the vial to reach room temperature (up to25ºC) 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.

Celltrion Healthcare Hungary Kft.1062 Budapest

Váci út 1-3. WestEnd Office Building B torony

Hungary

EU/1/24/1904/001

EU/1/24/1904/002

EU/1/24/1904/003

Date of first authorisation: 14 February 2025

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

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