Xgeva(denosumab狄迪诺塞麦)

1. Name of the drug

XGEVA 120 mg injection

2. Qualitative and quantitative composition of denosumab

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

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

Excipients with known effects

Each 1.7 mL solution contains 78 mg sorbitol (E420).

For a complete list of excipients, see section 6.1.

3. Drug form

Injection (injection).

Clear, colorless to slightly yellowish solution that may contain trace amounts of translucent white protein particles.

4. Clinical details

4.1 Therapeutic indications

Prevention of skeletal-related events (pathological fractures, radiation to bone, spinal cord compression, or orthopedic surgery) in adults with bone metastases from solid tumors.

Treatment of skeletally mature adolescents with unresectable giant cell tumors of the bone or where surgical resection may result in severe morbidity.

4.2 System and Methods of Administration

XGEVA should be administered by a healthcare professional.

Posology

All patients should be supplemented with at least 500 mg of calcium and 400 IU of vitamin D daily unless hypercalcemia is present (see section 4.4).

Patients receiving XGEVA should be provided with a package insert and a patient reminder card.

Prevention of Skeletal-Related Events in Adults with Bone Metastases from Solid Tumors

The recommended dose is 120 mg subcutaneously once every 4 weeks into the thigh, abdomen, or upper arm.

Giant Cell Tumor of Bone

The recommended dose of XGEVA is 120 mg subcutaneously once every 4 weeks into the thigh, abdomen, or upper arm, with an additional 120 mg dose on days 8 and 15 of the first month of treatment.

Patients who had completely resected giant cell tumors of bone in the Phase II study were treated for 6 months after surgery, per the study protocol.

Patients with giant cell tumors of bone should be evaluated periodically to determine if they continue to benefit from treatment. The effect of interrupting or stopping treatment has not been evaluated in patients with disease controlled by XGEVA, but limited data in these patients do not suggest a rebound effect at the end of treatment.

Renal Impairment

No dose adjustment is required in patients with renal impairment (see sections 4.4, 4.8 and 5.2 for recommendations on calcium monitoring).

Hepatic Impairment

The safety and efficacy of denosumab have not been studied (see section 5.2).

Elderly Patients (Age ≥ 65 years)

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

Pediatric Population

The safety and efficacy of XGEVA have not been established in pediatric patients (age < 18 years) other than skeletally mature adolescents with giant cell tumor of the bone.

XGEVA is not recommended for use in pediatric patients (age < 18 years) other than skeletally mature adolescents with giant cell tumor of the bone (see section 4.4).

Treatment of skeletally mature adolescents with giant cell tumor of the bone that is unresectable or for which surgical resection is likely to result in serious complications: the dosing is the same as for adults.

Inhibition of RANK/RANK ligand (RANKL) has been associated with inhibition of bone growth and lack of tooth eruption in animal studies, and these changes are partially reversible upon cessation of RANKL inhibition (see section 5.3).

Method of Administration

For subcutaneous use.

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

4.3 Contraindications

Hypersensitivity to the active substances or any of the excipients listed in section 6.1. Severe, untreated hypocalcemia (see section 4.4).

Unhealed lesions from dental or oral surgery.

4.4 Special Warnings and Precautions for Use

Calcium and Vitamin D Supplementation

All patients require calcium and vitamin D supplementation unless hypercalcemia is present (see section 4.2).

Hypocalcemia

Preexisting hypocalcemia must be corrected prior to initiating treatment with XGEVA. Hypocalcemia may occur at any time during treatment with XGEVA. (i) prior to the initial dose of XGEVA, (ii) within two weeks after the initial dose, and (iii) upon the development of suspected symptoms of hypocalcemia (see Symptoms section 4.8). Additional monitoring of calcium levels should be considered during treatment in patients with risk factors for hypocalcemia or as otherwise indicated based on the patient’s clinical condition.

Patients should be encouraged to report symptoms of hypocalcemia. If hypocalcemia develops while receiving XGEVA, additional calcium supplementation and additional monitoring may be required.

In the postmarketing setting, severe symptomatic hypocalcemia (including fatal cases) has been reported (see section 4.8), with the majority of cases occurring within the first week of initiation of treatment but can occur later.

Renal Impairment

Patients with severe renal impairment (creatinine clearance <30 mL/min) or those receiving dialysis are at increased risk for the development of hypocalcemia. The risk of developing hypocalcemia and concomitant elevations in parathyroid hormone increases with the degree of renal impairment. Regular monitoring of calcium levels is particularly important in these patients.

Osteonecrosis of the jaw (ONJ)

ONJ is commonly reported in patients receiving XGEVA (see section 4.8).

Patients with nonhealing open soft tissue lesions of the oral cavity should delay treatment/new courses of therapy. Prior to treatment with denosumab, dental examinations with preventive dentistry and an individual benefit-risk assessment are recommended.

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

Potency of the drug inhibiting bone resorption (higher risk with highly potent compounds), route of administration (higher risk with parenteral administration), and cumulative doses of bone resorption therapy.

Cancer, comorbidities (e.g., anemia, coagulation, infection), smoking.

Concomitant therapy: corticosteroids, chemotherapy, angiogenesis inhibitors, radiation therapy to the head and neck.

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

All patients should be encouraged to maintain good oral hygiene, receive regular dental examinations, and promptly report any oral symptoms such as dental mobility, pain or swelling, or non-healing ulcers or bleeding during treatment with denosumab. While on treatment, invasive dental procedures should only be performed after careful consideration and should be avoided as close to XGEVA administration as possible.

The management plan for patients who develop ONJ should be established in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of XGEVA treatment should be considered until the condition resolves and contributing risk factors are mitigated as much as possible.

Osteonecrosis of the External Auditory Canal

Osteonecrosis of the external auditory canal has been reported with denosumab. Possible risk factors for osteonecrosis of the external auditory canal include the use of steroids and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving denosumab who present with otic symptoms, including chronic ear infections.

Atypical Femoral Fractures

Atypical femoral fractures have been reported in patients receiving denosumab (see section 4.8). Atypical femoral fractures may occur in the subtrochanteric and diaphyseal regions with minimal or no trauma. Specific radiographic findings characterize these events. Atypical femur fractures have also been reported in patients with certain comorbidities (e.g., vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and those taking certain medications (e.g., bisphosphonates, glucocorticoids, proton pump inhibitors). These events have also occurred in the absence of antiresorptive therapy. Similar fracture reports associated with bisphosphonates are usually bilateral; therefore the contralateral femur should be examined in patients with femoral shaft fractures treated with denosumab. Discontinuation of XGEVA treatment in patients with suspected atypical femoral fracture should be considered based on an individual benefit-risk assessment for the patient. Patients should be advised to report new or unusual thigh, hip, or groin pain during denosumab treatment. Patients who develop such symptoms should be evaluated for an incomplete femur fracture.

Patients with bone growths

XGEVA is not recommended for use in patients with bone growths (see section 4.2). Clinically significant hypercalcemia has been reported in patients treated with XGEVA, with bone growth occurring weeks to months after treatment interruption.

Other

Patients treated with XGEVA should not be treated concomitantly with other denosumab-containing medicines (osteoporosis indication).

Patients treated with XGEVA should not be treated concomitantly with bisphosphonates.

Malignant giant cell tumor of bone or progression to metastatic disease is a rare event and a known risk in patients with giant cell tumor of bone. Patients should be monitored for radiographic signs of malignancy, new radiolucencies or osteolysis. Available clinical data do not suggest an increased risk of malignancy in patients with giant cell tumor of bone treated with XGEVA.

Warning about excipients

This medicine contains sorbitol. Patients with rare hereditary fructose intolerance should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per 120 mg, i.e., it is essentially “sodium-free”.

4.5 Interactions with other medicinal products and other forms of interaction

No interaction studies have been conducted.

In clinical trials, XGEVA has been used in combination with standard anticancer therapy, as well as in subjects previously treated with bisphosphonates. There are no clinically relevant alterations in trough concentrations and pharmacodynamics of denosumab (creatinine adjusted urinary N-terminal peptide, uNTx/Cr) by concomitant chemotherapy and/or hormonal therapy or prior intravenous bisphosphonate exposure.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited data on the use of denosumab in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3).

XGEVA is not recommended for use in pregnant women and women of reproductive potential without contraceptive use. Advise women not to become pregnant for at least the duration of pregnancy

After 5 months of treatment with XGEVA. Any effects of XGEVA may be greater in the second and third trimesters of pregnancy because the monoclonal antibody is transported to the placenta in a linear manner as pregnancy progresses, with maximal amounts transferred in the third trimester.

Lactation

It is unknown whether denosumab is excreted in human milk. Risk to the neonate/infant cannot be excluded. Knockout mouse studies suggest that RANKL deficiency during pregnancy may interfere with mammary gland maturation, leading to impaired lactation postpartum (see section 5.3). Decide whether to discontinue breastfeeding or to forgo XGEVA treatment taking into account the benefits of breastfeeding for the newborn/infant and the benefits of treatment for the woman.

Fertility

There are no data on the effects of denosumab on human fertility. Animal studies do not indicate direct or indirect adverse effects on fertility (see section 5.3).

4.7 Effects on Ability to Drive and Use Machines

XGEVA has no or negligible effects on the ability to drive and use machines.

4.8 Adverse Effects

Safety Summary Summary
The overall safety profile was consistent across all approved XGEVA indications.

Following XGEVA administration, hypocalcemia was commonly reported, mostly within the first 2 weeks. Hypocalcemia can be severe and symptomatic (see section 4.8 – Description of selected adverse reactions). Decreases in serum calcium are usually managed appropriately with calcium and vitamin D supplementation. The most common adverse reaction to XGEVA is musculoskeletal pain. Osteonecrosis of the jaw has been observed in patients taking XGEVA (see sections 4.4 and 4.8 – Description of selected adverse reactions).

List of adverse reactions
The following convention has been used to classify adverse reactions based on incidence in three Phase III, two Phase II clinical studies and post-marketing experience (see Table 1): very common (≥1/10), common (≥1/100 to <1/10), rare (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000) (<1/10,000). Within any frequency grouping and system organ class, adverse reactions are presented in order of decreasing severity.

Table 1: Adverse reactions reported in patients with advanced malignancies involving bone or giant cell tumors of bone
Organ class (MedDRA) Frequency category Adverse reactions
Immune system disorders Rare Drug hypersensitivity1
Rare Allergic reaction1
Metabolism and nutrition disorders Common Hypocalcemia1,2
Common Hypophosphatemia
Respiratory, chest and mediastinal disorders Common Dyspnea
Gastrointestinal disorders Common Diarrhea
Common Tooth loss
Skin and subcutaneous tissue disorders Common Hyperhidrosis
Musculoskeletal and connective tissue disorders Common Musculoskeletal pain1
Common Osteonecrosis of the jaw1
Rare Atypical femoral fracture1
Unknown Osteonecrosis of the external auditory canal3,4
1 See section Selected Adverse Reactions
2 See section Other Special Populations
3 See section 4.4
4 Typical Reactions

Description of Selected Adverse Reactions

Hypocalcemia

In three Phase III active-controlled clinical trials in patients with advanced malignancies involving the bone, hypocalcemia was reported in 9.6% of patients treated with XGEVA and 5.0% of patients treated with zoledronic acid.

Grade 3 decreases in serum calcium levels occurred in 2.5% of the XGEVA-treated group and 1.2% of the zoledronic acid-treated group. Grade 4 decreases in serum calcium levels occurred in 0.6% of the XGEVA-treated group and 0.2% of the zoledronic acid-treated group (see section 4.4).

In two Phase II single-arm clinical trials in patients with giant cell tumor of bone, hypocalcemia was reported in 5.7% of patients. None of the adverse events were considered serious.

In postmarketing surveillance, severe symptomatic hypocalcemia, including fatal cases, has been reported, with the majority of cases occurring within the first week of initiation of treatment. Clinical manifestations of severe symptomatic hypocalcemia include QT interval prolongation, tetany, seizures, and altered mental status (including coma) (see section 4.4). Symptoms of hypocalcemia in clinical studies include paresthesias or muscle stiffness, twitches, cramps, and muscle spasms.

Osteonecrosis of the jaw (ONJ)

In clinical trials, the incidence of ONJ was higher with longer exposure; ONJ was also diagnosed after discontinuation of XGEVA treatment, with the majority of cases occurring within 5 months of the last dose. Patients with a history of ONJ or a history of osteomyelitis of the jaw, active teeth or jaw conditions requiring oral surgery, unhealed dental/oral surgery, or any planned invasive dental procedure were excluded from clinical trials.

During the primary treatment phase of three Phase III active controlled clinical trials in patients with advanced malignancies undergoing bone therapy, 1.3% of patients treated with XGEVA (median 12.0 months; range: 0.1-40.5) and 1.3% of patients treated with zoledronic acid experienced ONJ. The clinical characteristics of these cases were similar between treatment groups. Among subjects with confirmed ONJ, the majority (81% in both treatment groups) had a history of tooth extraction, poor oral hygiene, and/or use of dental appliances. Most subjects were receiving or had received chemotherapy.

Trials in patients with breast or prostate cancer included an extended treatment phase with XGEVA (median overall exposure duration 14.9 months; range: 0.1-6

7.2). During the expansion phase, ONJ was diagnosed in 6.9% of patients with breast and prostate cancer.

The patient-year adjusted overall incidence of diagnosed ONJ was 1.1% in the first year of treatment, 3.7% in the second year, and 4.6% per year thereafter. The median duration of ONJ was 20.6 months (range: 4-53).

Two phase 1, single-arm clinical trials in patients with giant cell tumor of bone showed that 2.3% (12 of 523) of patients treated with XGEVA developed ONJ (median total exposure duration 20.3 months; range: 0-83.4). The patient-year adjusted overall incidence of ONJ was 0.2% in the first year of treatment and 1.7% in the second year. The median duration of ONJ was 19.4 months (range: 11-40). Data in patients with giant cell tumor of bone are insufficient to assess the risk of ONJ beyond 2 years based on duration of exposure.

In a Phase III clinical trial in patients with non-metastatic prostate cancer (a patient population for which XGEVA was not shown), with extended treatment duration of up to 7 years, the adjusted annual incidence rate for patients with confirmed ONJ was 1.1% in the first year of treatment, 3.0% in the second year, and 7.1% per year thereafter.

Drug-related hypersensitivity reactions
In the post-marketing setting, events of hypersensitivity reactions, including rare events of anaphylaxis, have been reported in patients treated with XGEVA.

Atypical femur fractures
In the clinical trial program, atypical femur fractures have occurred rarely in patients treated with denosumab (see section 4.4).

Musculoskeletal pain
In the post-marketing setting, patients treated with XGEVA have reported musculoskeletal pain, including severe cases. In clinical trials, musculoskeletal pain was highly common in the denosumab and zoledronic acid treatment groups. Musculoskeletal pain leading to discontinuation of study treatment was uncommon.

Pediatric population

XGEVA was studied in an open-label trial that enrolled 18 skeletally mature adolescents with giant cell tumors of bone. Based on these limited data, the adverse event profile appears to be similar to that in adults.

Other special populations

Renal impairment
In a clinical study in patients with advanced cancer without severe renal impairment (creatinine clearance <30 mL/min) or patients receiving dialysis, the risk of hypocalcemia was higher in the presence of calcium deficiency. The risk of hypocalcemia during XGEVA treatment increases with the degree of renal impairment. In clinical studies in patients without advanced cancer, 19% of patients with severe renal impairment (creatinine clearance <30 mL/min) and 63% of patients receiving dialysis developed hypocalcemia despite calcium supplementation. The overall incidence of clinically significant hypocalcemia was 9%.

Concomitant elevations in parathyroid hormone were also observed in patients receiving XGEVA with severe renal impairment or receiving dialysis. It is particularly important in patients with renal impairment to monitor calcium levels and to have adequate calcium and vitamin D intake (see section 4.4).

Reporting suspected adverse reactions

Post-marketing reporting of suspected adverse reactions of medicinal products is important. It allows for ongoing monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions through the national reporting systems listed in Annex V.

4.9 Overdose

There is no experience of overdose in clinical studies. XGEVA has been used in clinical studies at doses up to 180 mg every 4 weeks and 120 mg weekly for 3 weeks.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Drugs used to treat bone disorders – Other drugs affecting bone structure and mineralization, ATC code: M05BX04

Mechanism of Action

RANKL exists as a transmembrane or soluble protein. RANKL is essential for the formation, function, and survival of osteoclasts, the only cell type responsible for bone resorption. Increased osteoclast activity stimulated by RANKL is a key mediator of bone destruction in metastatic bone disease and multiple myeloma. Denosumab is a human monoclonal antibody (IgG2) that targets and binds to RANKL with high affinity and specificity, preventing the occurrence of RANKL/RANK interaction and leading to a decrease in osteoclast number and function, thereby reducing bone resorption and cancer-induced bone destruction.

Giant cell tumors of the bone are characterized by tumor stromal cells that express RANK ligands and osteoclast-like giant cells that express RANK. In patients with giant cell tumors of the bone, denosumab binds to RANK ligands and significantly reduces or eliminates osteoclast-like giant cells. As a result, osteolysis is reduced and proliferative tumor stroma is replaced by non-proliferative, densely differentiated new bone.

Pharmacodynamic Effects

In a Phase II clinical study in patients with advanced malignancies involving the bone, subcutaneous (SC) administration of XGEVA every 4 weeks or every 12 weeks resulted in rapid reductions, with a median reduction of approximately 80% in uNTx/Cr occurring within 1 week, in bone resorption markers (uNTx/Cr, serum CTx), regardless of prior bisphosphonate therapy or baseline uNTx/Cr levels. In a Phase III clinical trial, an approximately 80% median reduction in uNTx/Cr levels was maintained after 3 months of treatment in 2075 patients with advanced cancer who were not receiving IV-bisphosphonates.

Immunogenicity

In clinical studies, no neutralizing antibodies have been observed with denosumab. Using a sensitive immunoassay, <1% of patients treated with denosumab for up to 3 years tested positive for non-neutralizing binding antibodies, with no evidence of altered pharmacokinetics, toxicity, or clinical responses.

Clinical Efficacy and Safety in Patients with Bone Metastases from Solid Tumors

The efficacy and safety of 120 mg XGEVASC every 4 weeks or 4 mg zoledronic acid (dose adjusted for reduced renal function) IV every 4 weeks were evaluated in three randomized, double-blind comparative, active-controlled studies in patients with advanced malignancies involving bone following IV-bisphosphonate nab-resistant prostate cancer: adults with breast cancer (Study 1), other solid tumors or multiple myeloma (Study 2), and castration-resistant prostate cancer (Study 3). Safety was evaluated in 5,931 patients in these active-controlled clinical trials. Patients with a prior history of ONJ or osteomyelitis of the jaw, active dental or mandibular osteomyelitis requiring oral surgery, unhealed dental/oral surgery, or any planned invasive dental procedure were not eligible for inclusion in these studies. The primary and secondary endpoints evaluated the occurrence of one or more skeletal-related events (SREs). In the study demonstrating the superiority of XGEVA to zoledronic acid, patients were offered open-label XGEVA during the pre-specified 2-year extension treatment phase.

XGEVA reduced the risk of developing SREs and developed multiple SREs (first and subsequent) in patients with solid tumor bone metastases (see Table 2).

Table 2: Efficacy results involving patients with bone malignancies

Xgeva (denosumab) _ Hong Kong Jimin Pharmaceutical

Xgeva (denosumab) _ Hong Kong Jimin Pharmaceutical

NR = Not Reached; NA = Not Available; HCM = Hypercalcemia of Malignancy; SMR = Skeletal Morbidity; HR = Hazard Ratio; RRR = Relative Risk Reduction†Adjusted p-values ​​are listed for Studies 1, 2, and 3 (first SRE and first and subsequent SRE endpoints). *All skeletal events were recorded over time; only events occurring ≥21 days after the last event were counted.

**Includes NSCLC, renal cell carcinoma, colorectal cancer, small cell lung cancer, bladder cancer, head and neck cancer, gastrointestinal/genitourinary tract cancer, etc., excluding breast cancer and prostate cancer.

Figure 1. Kaplan-Meier time to first study SRE

ZA-Zoledronic acid 4mg Q4W
Dmab-Denosumab 120mg Q4W
Xgeva (denosumab)_Hong Kong Jimin Pharmaceutical
N=Number of subjects randomized
*=Statistical significance for superiority; **=Statistical significance for non-inferiority

Disease progression and overall survival

Disease progression was similar between XGEVA and zoledronic acid in all three studies and in the pre-specified analysis of all three studies combined.
In all three studies, overall survival was balanced between XGEVA and zoledronic acid in patients with advanced malignancies: patients with breast cancer (hazard ratio and 95% CI 0.95 [0.81, 1.11]), patients with prostate cancer (hazard ratio 95% CI 1.03 [0.91, 1.17]), patients with other solid tumors or multiple myeloma (hazard ratio 95% CI 0.95 [0.83, 1.08]). A post hoc analysis of Study 2 (patients with other solid tumors or multiple myeloma) examined overall survival in the 3 tumor types used for stratification (non-small cell lung cancer, multiple myeloma, and other). The hazard ratio [95% CI] for zoledronic acid in multiple myeloma was 0.79 [0.65, 0.95]; n = 702), overall survival was longer with XGEVA 2.26 [1.13, 4.50]; n = 180), and XGEVA and zoledronic acid were similar in the other tumor types (hazard ratio [95% CI] 1.08 (0.90, 1.30); n = 894). This study did not control for prognostic factors and antineoplastic therapy. In a prespecified analysis of the combination of studies 1, 2, and 3, overall survival was similar with XGEVA and zoledronic acid (hazard ratio and 95% CI 0.99 [0.91, 1.07]).

Effect on Pain

Time to pain improvement (i.e., a ≥2-point reduction from baseline in the BPI-SF worst pain score) was similar for denosumab and zoledronic acid in each study and in the combined analysis. In a post hoc analysis of the combined dataset, the median time to pain relief or freedom from pain (>4-point worst pain score) was delayed in the XGEVA group compared with zoledronic acid (198 days vs. 143 days) (p=0.0002).

Clinical Efficacy and Safety in Adults and Skeletically Mature Adolescents with Giant Cell Tumor of Bone

The safety and efficacy of XGEVA were investigated in two Phase II open-label, single-arm clinical trials (Studies 4 and 5) enrolling 529 patients with giant cell tumor of bone that was either unresectable or for which surgery would be associated with severe disease.

A total of 37 adult patients with histologically confirmed unresectable or recurrent giant cell tumor of bone were enrolled in Study 4. Response criteria included elimination of giant cells based on histopathology or lack of progression by radiography.

Of the 35 patients included in the efficacy analysis, 85.7% (95% CI: 69.7, 95.2) responded to XGEVA. All 20 patients (100%) responded histologically. Of the remaining 15 patients, 10 (67%) had no radiographic progression of the target lesion.

Study 5 enrolled 507 adults or skeletally mature adolescents with giant cell tumor of bone and evidence of measurable active disease.

In Cohort 1 (patients with surgically unsalvageable disease), the median time to disease progression had not been reached, with 21 of 258 treated patients experiencing disease progression. In Cohort 2 (patients with surgically salvageable disease with planned surgery associated with severe complications), 209 of 228 XGEVA evaluable patients had not undergone surgery at 6 months. A total of 225 patients were treated with giant cell tumor of bone (pulmonary metastases), 109 did not undergo surgery, and 84 had less extensive underlying disease than planned. The median time to surgery was 261 days.

After 305 patients were enrolled in Studies 4 and 5, retrospective analysis of imaging data was performed. One hundred and ninety had at least one evaluable time point response and were included in the analysis (Table 3). Overall, XGEVA resulted in an objective tumor response by any modality in 71.6% (95% CI 64.6, 77.9) of patients (Table 3), with the majority of responses measured by fluorodeoxyglucose PET activity or increased density on CT/HU, and only 25.1% of patients responding by RECIST. The median duration of response was 3.1 months (95% CI 2.89, 3.65). The median duration of response was uncertain (4 patients experienced disease progression after an objective response). Of the 190 subjects evaluable for objective tumor response, 55 subjects had surgical giant cell tumors of the bone, of which 40 subjects had complete resection.

Table 3: Objective treatment response in patients with giant cell tumor or bone
Xgeva (denosumab)_Hong Kong Jimin Pharmaceutical
1CI = Exact Confidence Interval
2RECIST1.1: Response Evaluation Criteria for Assessment of Tumor Burden in Solid Tumors Based on Computed Tomography (CT)/Magnetic Resonance Imaging (MRI)
3EORTC: Modified European Organization for Research and Treatment of Cancer criteria using fluorodeoxyglucose positron emission tomography (FDG-PET) to assess metabolic response
4Density/Size: Modified reverse Choi criteria for assessment of tumor size and density using CT/MRI-based Hounsfield units

Effect on Pain

Reported After 282 patients were enrolled, 31.4% of patients at risk (i.e., those with the worst pain score) in Study 5 Cohorts 1 and 2 reported a clinically meaningful reduction in worst pain (i.e., a reduction of ≥2 points from baseline to baseline ≥2) within 1 week of treatment and ≥50% at Week 5. Pain improvements were maintained at subsequent assessments. Baseline pretreatment analgesics in Cohorts 1 and 2 were scored using a seven-point scale, with 74.8% of patients reporting no or mild analgesic use (i.e., analgesia score ≤2) and 25.2% using strong opioids (i.e., analgesia score 3 to 7).

Pediatric population

The European Medicines Agency has waived submission of the results of the XGEVA study to all subsets of the pediatric population for the prevention of skeletal-related events in patients with bone metastases and for the subgroup of the pediatric population younger than 12 years of age with giant cell tumor of the bone (see section 4.2 for information on pediatric use).

In Study 5, XGEVA was evaluated in a subset of 18 adolescent patients (13-17 years of age) with giant cell tumor of the bone who had reached skeletal maturity defined by at least 1 mature long bone (e.g., closed epiphyseal growth plate of the humerus) and weighed ≥45 kg. Objective responses were observed in four of the six adolescents assessed with investigator assessment at the interim analysis of Study 5, with all 18 adolescent patients reporting stable disease or better (two complete responses, eight partial responses as best response, and eight stable disease). The European Medicines Agency has deferred the obligation to submit the final results of this study.

5.2 Pharmacokinetic properties

Absorption

After subcutaneous administration, the bioavailability was 62%.

Biotransformation

Denosumab is composed of individual amino acids and carbohydrates as native immunoglobulins and is unlikely to be eliminated by hepatic metabolism. Its metabolism and elimination are expected to follow the immunoglobulin clearance pathway, resulting in degradation to small peptides and individual amino acids.

Elimination

In subjects with advanced cancer, who received multiple doses of 120 mg every 4 weeks, an approximate 2-fold accumulation of denosumab in serum concentrations was observed and steady-state was achieved by 6 months, independent of time-dependent pharmacokinetics

consistent. In subjects with giant cell tumors who received 120 mg every 4 weeks with loading doses on days 8 and 15, steady-state levels were achieved within the first month of treatment. Less than 9% change between weeks 9 and 49, the median trough level. In subjects who discontinued 120 mg every 4 weeks, the mean half-life was 28 days (range 14 to 55 days).

Population pharmacokinetic analyzes did not demonstrate clinically significant changes in systemic exposure to denosumab at steady state relative to age (18 to 87 years), race/ethnicity (black, Hispanic, Asian, and white explored), sex, or solid tumors type. Increased body weight is associated with decreased systemic exposure and vice versa. This change is not considered clinically relevant because the effect on bone turnover markers is consistent across a wide range of body weights.

linear/nonlinear

Denosumab showed dose-to-dose nonlinear pharmacokinetics over a wide dose range, but with a roughly dose-proportional increase in exposure for doses of 60 mg (or 1 mg/kg) and higher. The nonlinearity may be due to the importance of a saturating target-mediated elimination pathway at low concentrations.

renal insufficiency

In one study, the pharmacokinetics of denosumab in patients without advanced cancer (60 mg, N=55 and 120 mg, N=32) but with varying degrees of renal function, including dialysis, affected the degree of renal impairment. There was no effect on denosumab; therefore no dose adjustment is required for renal impairment. No renal monitoring is necessary with XGEVA dosing.

Liver insufficiency

No specific studies were conducted in patients with hepatic impairment. In general, monoclonal antibodies are not eliminated by mechanisms of hepatic metabolism. The pharmacokinetics of denosumab are not expected to be affected by hepatic impairment.

elderly

No overall differences in safety and efficacy were observed between older and younger patients. A controlled clinical study of XGEVA in patients with bone-involving, advanced malignancies over 65 years of age found similar efficacy and safety in older and younger patients. No dose adjustment is required in elderly patients.

pediatric population

Pharmacokinetic properties have not been evaluated in the pediatric population.

5.3 Preclinical Safety Data

Since the biological activity of denosumab in animals is specific to non-human primates, evaluation of genetically engineered (knockout) mice or the use of other biological inhibitors of the RANK/RANKL pathway, such as OPG-Fc and RANK-Fc, For evaluation of the pharmacodynamic properties of denosumab in rodent models.

In mouse bone metastasis models of estrogen receptor-positive and -negative human breast cancer, prostate cancer, and non-small cell lung cancer, OPG-Fc reduces osteolytic, osteoblastic, and osteolytic/osteoblastic lesions, from Delayed formation of skull metastases, and reduced bone tumor growth. When OPG-Fc is used in combination with hormone therapy (tamoxifen) or chemotherapy (docetaxel) in these models, the additive backbone inhibits tumor growth in breast, and prostate or lung cancers respectively. In a mouse model of mammary tumor induction, RANK-Fc reduces hormone-induced proliferation in mammary epithelial cells and delays tumor formation.

Standard tests to investigate the genotoxic potential of denosumab were not evaluated because such tests are not relevant for this molecule. However, due to its characteristics it is unlikely that denosumab 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 resulted in systemic exposures 2.7 to 15 times greater than the recommended human dose at doses that had no effects on cardiovascular physiology, male or female fertility, or produced specific target organ toxicity.

In one study in cynomolgus monkeys administered denosumab during the first trimester of gestation, denosumab resulted in systemic exposure 9 times greater than the recommended human dose and did not cause maternal or fetal toxicity at doses equivalent to the first trimester. During the injury, although the fetal lymph nodes were not examined.

In another study of cynomolgus monkeys administered denosumab to systemic exposure throughout pregnancy at 12 times higher human doses, there were increased stillbirth and postpartum mortality, respectively; abnormal bone growth resulting in reduced bone strength, reduced hematopoiesis, and Malaligned teeth; absence of peripheral lymph nodes; and reduced neonatal growth. No observed adverse effect dose for reproductive effects has been established. Following the 6-month postnatal period, skeletal-related changes show a resurgence and have no impact on tooth eruption. However, effects in lymph nodes and dental malalignment persisted, and minimal to moderate mineralization in multiple tissues was noted in one animal (relative to treatment uncertain). There is no evidence of adverse maternal effects during labor; adverse maternal effects rarely occur during labor. Maternal breast development is normal.

In a long-term preclinical bone mass study in monkeys treated with denosumab, reductions in bone turnover were associated with improvements in bone strength and normal bone histology.

In male mice genetically engineered to express huRANKL (knock-in mice) that undergo transcortical fractures, denosumab delays cartilage removal and remodeling in the fracture callus compared with controls, but biomechanical strength is not adversely affected .

In preclinical studies knockout mice lacking RANK or RANKL had an absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy) and showed impairment of lymph node formation. Neonatal RANK/RANKL knockout mice show reduced 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 in neonatal rats administered RANKL inhibitors, and these changes were partially reversible when RANKL inhibitor administration was discontinued. Adolescent primates administered denosumab had abnormal growth plates at 2.7 and 15 times the clinical exposure (10 and 50 mg/kg doses). Therefore, treatment with denosumab may impair bone growth in children with open growth plates and may inhibit dentition eruption.

 

6. Drug details

6.1 List of excipients

Acetic acid, glacial acetic acid*
Sodium hydroxide (for pH adjustment)*
Sorbitol (E420)
Polysorbate 20
Water for Injection
*Acetate buffer is formed by mixing acetic acid and sodium hydroxide

6.2 not compatible

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

6.3 Shelf life

3 years.

Once removed from the refrigerator, XGEVA can be stored at room temperature (up to 25°C) for up to 30 days in the original container. It must be used within 30 days or so.

6.4 Special precautions for storage

Store in refrigerator (2℃-8℃).
Do not freeze.
Please wrap vials to protect from light.

6.5 Properties and contents of container

1.7 ml solution in single-use vials (Type I glass) with stopper (fluoropolymer-coated elastomer) and seal (aluminum) equipped with flip-top closure cap.

Available in one, three or four size packages.
Not all package sizes are available on the market.

6.6 Handling of special precautions, etc.

•Prior to administration, XGEVA solutions should be visually inspected. The solution may contain trace amounts of translucent white protein particles. If it is cloudy or no injection solution changes color.
•Don’t shake.
• To avoid discomfort at the injection site, allow the vial to come to room temperature (max 25°C) before injecting slowly.
•The entire contents of the vial should be injected.
•A 27-gauge needle is recommended for administration of denosumab.
•Vials should not be re-entered.

Any unused medicinal products or waste should be disposed of in accordance with local requirements.

7. Promotion of authorized holders

AmgenEuropeB.V.
Minervum7061
NL-4817ZKBreda
TheNetherlands

8.MARKETING authorization number (S)

EU/1/11/703/001
EU/1/11/703/002
EU/1/11/703/003

9. First authorization time/renewal time
First authorization July 13, 2011
Latest date updated: April 4, 2016

10.Date of revised text

Detailed information about this medicine is available on the European Medicines Agency’s website.