Xjeva solution for injection 70 mg/ml vial 1.7 ml No. 1

Instructions for Xjeva injection solution 70 mg/ml vial 1.7 ml No. 1

Composition

active ingredient: denosumab;

1 ml of solution contains 70 mg of denosumab; 1 vial (1.7 ml) contains 120 mg of denosumab;

Excipients: sorbitol (E 420), glacial acetic acid, sodium hydroxide, polysorbate 20, water for injections.

Dosage form

Solution for injection.

Main physicochemical properties: clear, colorless or yellowish solution, which may contain a small amount of translucent to white proteinaceous particles.

Pharmacotherapeutic group

Medicines for the treatment of bone diseases. Other medicines that affect bone structure and mineralization.

ATX code M05VX04.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

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

Giant cell tumors of the bone are characterized by the expression of RANK ligand by neoplastic stromal cells and RANK by osteoclast-like giant cells. In patients with giant cell tumor of the bone, denosumab binds to RANK ligand, significantly reducing or eliminating osteoclast-like giant cells. As a result, osteolysis is reduced and the proliferative tumor stroma is replaced by non-proliferative, differentiated, dense new bone.

Pharmacodynamic effects

In phase II clinical trials in patients with advanced bone-related malignancies, subcutaneous administration of Xgeva® every 4 weeks (Q4W) or every 12 weeks resulted in rapid reductions in markers of bone resorption (uNTx/Cr, serum CTx) with a mean reduction of approximately 80% in uNTx/Cr occurring within 1 week, regardless of prior bisphosphonate treatment or baseline uNTx/Cr. In phase III clinical trials in patients with advanced bone-related malignancies, the mean reduction in uNTx/Cr of approximately 80% was maintained through week 49 of treatment with Xgeva® (120 mg every 4 weeks (Q4W)).

Immunogenicity

In clinical studies, no neutralizing antibodies to denosumab were detected in patients with advanced cancer or giant cell tumor of bone. Using enzyme-linked immunosorbent assay, < 1% of patients treated with denosumab for up to 3 years tested positive for non-neutralizing binding antibodies without evidence of impaired pharmacokinetics, toxicity, or clinical response.

Clinical efficacy and safety in patients with bone metastases from solid tumors

The efficacy and safety of Xgeva® 120 mg subcutaneously every 4 weeks or zoledronic acid 4 mg (dose adjustment for renal impairment) intravenously every 4 weeks were compared in three randomized, double-blind, active-controlled studies in patients who were previously naïve to intravenous bisphosphonates and had advanced bone-involving malignancies: adults with breast cancer (study 1), other solid tumors or myeloma (study 2), and castration-resistant prostate cancer (study 3). Safety was evaluated in 5,931 patients in these active-controlled clinical studies. Patients with a history of osteonecrosis of the jaw (ONJ) or osteomyelitis of the jaw, patients with active dental or jaw disease requiring dental surgery, patients with non-healing wounds following dental/oral surgery, or patients with any planned invasive procedures were not eligible for inclusion in these studies. The primary and secondary endpoints assessed the occurrence of one or more skeletal events (SEs). In studies demonstrating superior efficacy of Xgeva® compared to zoledronic acid, patients were offered open-label Xgeva® in a pre-specified 2-year extension phase. SEs were defined as: pathological fracture (vertebral or non-vertebral), radiation therapy to bone (including radioisotopes), bone surgery, or spinal cord compression.

Xgeva® reduced the risk of developing CP and the development of multiple CPs (first and subsequent) in patients with bone metastases from solid tumors (see Table 1).

Table 1. Results of the efficacy study in patients with advanced bone-involving malignancies

ND – not reached; ND – data not available; HCM – hypercalcemia in malignant tumors; PCE – prevalence of skeletal events; RR – hazard ratio; RRR – relative risk reduction

† Adjusted p-values are presented from Studies 1, 2, and 3 (first CP, and endpoints of first and subsequent CPs). * Includes all skeletal events over time; only events occurring ≥ 21 days after the previous event are counted.

** Including NSCLC (non-small cell lung cancer), renal cell cancer, colorectal cancer, small cell lung cancer, bladder cancer, head and neck cancer, gastrointestinal/genitourinary system cancer and other sites, excluding breast cancer and prostate cancer.

Kaplan–Meier plots for time to first CP occurring during the study

Disease progression and overall survival in bone metastases from solid tumors

Disease progression was similar in the Xgeva® and zoledronic acid groups in all three studies and in the pre-specified pooled analysis of the three studies.

In Studies 1, 2 and 3, overall survival was comparable between the Xgeva® and zoledronic acid groups in patients with advanced bone-related malignancies: breast cancer patients (hazard ratio [95% CI] 0.95 [0.81, 1.11]), prostate cancer patients (hazard ratio [95% CI] 1.03 [0.91, 1.17]) and other solid tumours or myeloma patients (hazard ratio [95% CI] 0.95 [0.83, 1.08]). Post-hoc analysis in study 2 (patients with other solid tumors or myeloma) determined overall survival by the presence of one of 3 tumor types using stratification (non-small cell lung cancer, myeloma, and other). Overall survival was longer in the Xgeva® group in non-small cell lung cancer (hazard ratio [95% CI] 0.79 [0.65, 0.95]; n = 702), in the zoledronic acid group in myeloma (hazard ratio [95% CI] 2.26 [1.13, 4.50]; n = 180) and similar in the Xgeva® and zoledronic acid groups in other tumor types (hazard ratio [95% CI] 1.08 (0.90, 1.30); n = 894). This study was not controlled for prognostic factors and anticancer treatment. In a pooled pre-specified analysis of Studies 1, 2 and 3, overall survival was similar between Xgeva® and zoledronic acid (hazard ratio [95% CI] 0.99 [0.91, 1.07]).

Impact on pain

Clinical efficacy in patients with myeloma

In an international randomized (1:1) double-blind, active-controlled study, Xgeva® was compared with zoledronic acid in patients with newly diagnosed myeloma (Study 4).

In this study, 1,718 patients with multiple myeloma with at least one bone lesion were randomized to receive subcutaneous Xgeva® 120 mg every 4 weeks (Q4W) or intravenous zoledronic acid 4 mg every 4 weeks (dose adjusted based on renal function). The primary endpoint was non-inferiority of Xgeva® to zoledronic acid in the rate of first CR compared to zoledronic acid. Secondary endpoints included time to first CR, time to first and subsequent CR, and overall survival. CR was defined as pathological fracture (vertebral or nonvertebral), radiation therapy to bone (including radioisotopes), bone surgery, or spinal cord compression.

In both study arms, 54.5% of patients were scheduled to undergo autologous cord blood stem cell (PBSC) transplantation, 95.8% were using/planning to use a novel antimyeloma agent (bortezomib, lenalidomide, or thalidomide) as first-line therapy, and 60.7% had previously received CP. In both arms, the proportion of patients with International Staging System (ISS) stage I, II, and III myeloma disease at diagnosis was 32.4%, 38.2%, and 29.3%, respectively.

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

The efficacy results in Study 4 are presented in Figure 2 and Table 2.

Kaplan–Meier plots for time to first CP occurring in patients with newly diagnosed myeloma

Table 2. Efficacy results for Xgeva® compared to zoledronic acid in patients with newly diagnosed myeloma

NO – not suitable for assessment

GKZ – hypercalcemia in malignant tumors

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

The safety and efficacy of Xgeva® were studied in two open-label, non-comparative phase II studies (Studies 5 and 6) involving 554 patients with unresectable giant cell tumors of bone or for whom surgery was associated with severe morbidity. Xgeva® was administered subcutaneously at a dose of 120 mg every 4 weeks with a loading dose of 120 mg on days 8 and 15. After discontinuation of Xgeva®, patients entered a follow-up phase of at least 60 months to assess safety. Re-treatment with Xgeva® during the safety follow-up period was permitted for subjects who had an initial response to Xgeva® (e.g., in the event of disease recurrence).

Study 6 enrolled 535 skeletally mature adults or adolescents with giant cell tumor of bone. The age of 28 patients in this group ranged from 12 to 17 years. Patients were assigned to one of three cohorts: cohort 1 included patients with unresectable disease (e.g., sacral, spinal, or multiple tumor sites, including lung metastases); cohort 2 included patients with operable disease for whom planned surgery was associated with severe outcomes (e.g., joint resection, limb amputation, or hemipelvectomy); and cohort 3 included patients who crossed over to this study after participating in study 5. The primary objective was to evaluate the safety profile of denosumab in patients with giant cell tumor of bone. Secondary endpoints of the study included: for cohort 1 – time to disease progression (as assessed by the investigator); for cohort 2 – the proportion of patients who did not undergo any surgical intervention by month 6.

At the final analysis of data in cohort 1, 28 of 260 patients who received treatment had progressed (10.8%). In cohort 2, 219 of 238 (92.0% CI, 95% CI: 87.8%, 95.1%) evaluable patients treated with XGEVA® had not undergone surgery by month 6. In cohort 2, 82 (34.3%) of 239 patients with non-lung or non-soft tissue target tumours at baseline or during the study period had not undergone surgery during the study. Overall, the efficacy results in skeletally mature adolescents and adults were similar.

Impact on pain

In the final analysis of the pooled data from cohorts 1 and 2, a clinically meaningful reduction in severe pain (i.e., a ≥ 2-point reduction from baseline) was reported in 30.8% of at-risk patients (i.e., those with a worst severe pain score ≥ 2 from baseline) at week 1 of treatment and ≥ 50% at week 5. This pain reduction was maintained at all subsequent assessments.

Children

The European Medicines Agency has temporarily deferred the obligation to submit the results of studies with Xgeva® in all subsets of the paediatric population for the prevention of skeletal-related events in patients with bone metastases and in subsets of children aged up to 12 years in the treatment of giant cell tumours of bone (see section 4.2 for information on paediatric use).

In Study 6, Xgeva® was evaluated in a subgroup of 28 adolescents (aged 13 to 17 years) with giant cell tumor of bone with a mature skeletal system. Maturity was defined as complete maturation of at least 1 long bone (e.g., closed epiphyseal growth plate of the humerus) and a body weight ≥ 45 kg. One adolescent with unresectable disease (N = 14) relapsed during initial treatment. By Month 6, 13 of 14 patients with operable disease in whom planned surgery was associated with severe morbidity had not undergone surgery.

Pharmacokinetics.

Absorption

After subcutaneous administration, the bioavailability was 62%.

Biotransformation

Denosumab is composed exclusively of amino acids and carbohydrates, like natural immunoglobulin. It is therefore unlikely to be eliminated by hepatic metabolism. It is believed that its metabolism and elimination occur through the same pathways as immunoglobulin clearance, resulting in the breakdown of small proteins to individual amino acids.

Breeding

In patients with advanced cancer, multiple doses of 120 mg every 4 weeks resulted in an almost 2-fold increase in serum denosumab concentrations, with steady-state levels achieved by 6 months, consistent with time-independent pharmacokinetics. In subjects with multiple myeloma receiving 120 mg every 4 weeks, median trough concentrations differed by less than 8% at months 6 and 12. In patients with giant cell tumor of bone receiving 120 mg every 4 weeks with a loading dose on days 8 and 15, steady-state levels were achieved within the first month of treatment. At weeks 9 and 49, median trough concentrations differed by less than 9%. In patients who discontinued 120 mg every 4 weeks, the median half-life was 28 days (range: 14–55 days).

Population pharmacokinetic analysis did not indicate clinically meaningful changes in steady-state systemic exposure to denosumab based on age (18–87 years), race/ethnicity (dark skinned, Hispanic, Asian, and Caucasian patients were studied), gender, or solid tumor types or myeloma. Increased body weight was associated with decreased systemic exposure and vice versa. The changes were not considered clinically meaningful because the pharmacodynamic effects based on bone remodeling markers were consistent across a wide range of body weights.

Linearity/nonlinearity

Kidney failure

In studies of denosumab in patients (60 mg, n = 55 and 120 mg, n = 32) without advanced cancer but with varying degrees of renal function, including patients on dialysis, the degree of renal impairment did not affect the pharmacokinetics of denosumab; therefore, no dose adjustment is necessary in renal impairment. Monitoring of renal function is not required during treatment with Xgeva®.

Liver failure

No specific studies have been conducted in patients with hepatic impairment. In general, monoclonal antibodies are not eliminated by hepatic metabolism. Hepatic impairment is not expected to affect the pharmacokinetics of denosumab.

Elderly patients

No overall differences in safety or efficacy were observed between elderly and younger patients. Controlled clinical trials of Xgeva® in patients 65 years of age and older with advanced bone malignancies demonstrated similar efficacy and safety in both elderly and younger patients. No dose adjustment is necessary for elderly patients.

Children

In skeletally mature adolescents (aged 12 to 17 years) with giant cell tumor of bone who received 120 mg every 4 weeks with a loading dose on days 8 and 15, the pharmacokinetics of denosumab did not differ from those obtained in adult patients with giant cell tumor of bone.

Preclinical safety data.

Since the biological activity of denosumab in primates is specific, genetically modified mice (knockout technology) or other biological inhibitors of the RANK/RANKL pathway, such as OPG-Fc and RANK-Fc, were used to evaluate the pharmacodynamic properties of denosumab in rodent models.

In mouse models of bone metastases from estrogen receptor-positive and -negative breast cancer, prostate cancer, and human non-small cell lung cancer, OPG-Fc reduced osteolytic, osteoblastic, and osteolytic/osteoblastic destruction, delayed the formation of de novo bone metastases, and inhibited tumor growth in bone. When OPG-Fc was combined with hormonal therapy (tamoxifen) or chemotherapy (docetaxel), additional inhibition of bone cell growth of breast, prostate, or lung cancer, respectively, was observed. In a mouse model of induced mammary tumor, RANK-Fc reduced hormone-mediated proliferation of mammary epithelium and delayed tumor formation.

Standard tests to determine the genotoxic potential of denosumab were not performed because such tests are not relevant for this molecule. However, it is unlikely that denosumab has any genotoxic potential.

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

In single- and multiple-dose toxicity studies in cynomolgus monkeys, denosumab doses that produced systemic responses and were 2.7-15 times the recommended human dose had no effect on cardiovascular physiology, male or female reproductive function, or specific target organ toxicity.

In a study in cynomolgus monkeys treated with denosumab for a period equivalent to the first trimester of pregnancy, doses of denosumab that produced a systemic response and were 9 times the recommended human dose did not cause maternal or fetal toxicity for a period equivalent to the first trimester of pregnancy, although fetal lymph nodes were not examined.

In another study in cynomolgus monkeys treated with denosumab during pregnancy at systemic exposures 12 times the human dose, there were increased stillbirths and postnatal mortality; abnormal bone growth resulting in decreased bone strength, decreased hematopoiesis, and malocclusion; absence of peripheral lymph nodes; and neonatal growth retardation. The maximum dose that did not result in observable adverse effects was not established. At 6 months postpartum, bone-related changes showed a return to normal, and there was no effect on tooth eruption. However, effects on lymph nodes and occlusion persisted, and one animal had minimal to moderate mineralization of multiple tissues (relationship to treatment not apparent). There was no evidence of harm to the mother before delivery; adverse maternal reactions occurred infrequently during delivery. Maternal mammary gland development was normal.

In preclinical bone quality studies in monkeys, long-term treatment with denosumab resulted in decreased remodeling associated with improved bone strength and normal bone histology.

In preclinical studies, mice with RANK or RANKL gene knockouts failed to lactate due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy) and showed impaired lymph node formation. Newborn mice with RANK/RANKL gene knockouts showed reduced body weight, impaired bone growth, growth zone abnormalities, and absence of teething. Impaired bone growth, growth zone abnormalities, and absence of teething were also observed in studies of neonatal rats treated with RANKL inhibitors, and these changes were partially reversible upon withdrawal of the RANKL inhibitor. In adolescent primates treated with denosumab at doses 2.7 and 15 times (10 and 50 mg/kg) higher than the clinical dose, pathologically altered growth zones were observed. Thus, denosumab treatment may impair bone growth in children with open growth zones and may inhibit tooth eruption.

Indication

Prevention of skeletal events (pathological fracture, bone irradiation, spinal cord compression or bone surgery) in adult patients with advanced malignant tumors affecting the bone (see section 5.1).

Treatment of adults and adolescents with a mature skeletal system who have giant cell tumor of the bone that cannot be removed or if surgical resection is likely to result in severe consequences.

Contraindication

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

Severe untreated hypocalcemia (see section "Special warnings and precautions for use").

Lesions after dental or surgical interventions in the oral cavity that do not heal.

Interaction with other medicinal products and other types of interactions

Interaction studies have not been conducted. In clinical studies, Xgeva® was administered in combination with standard anticancer therapy and in the presence of prior bisphosphonate treatment. There were no clinically relevant changes in the trough serum concentrations and pharmacodynamics of denosumab (urinary N-telopeptide corrected for creatinine, uNTx/Cr) with concomitant chemotherapy and/or hormonal therapy or prior intravenous bisphosphonate administration.

Application features

Calcium and vitamin D supplementation. Calcium and vitamin D supplementation is necessary for all patients, except those with hypercalcemia (see section “Method of administration and dosage”).

Hypocalcemia. Pre-existing hypocalcemia should be corrected before initiating treatment with XGEVA®. Hypocalcemia may occur at any time during treatment with XGEVA®. Calcium levels should be monitored prior to the initial dose of XGEVA®, for two weeks after the initial dose, and if symptoms suggestive of hypocalcemia occur (see section 4.8 for symptoms). Additional calcium monitoring should be considered during treatment in patients with risk factors for hypocalcemia or as otherwise determined by the clinical status of the patient.

Patients should report symptoms suggestive of hypocalcemia. If hypocalcemia occurs during treatment with Xgeva®, additional calcium supplementation and additional monitoring of calcium levels may be required.

Severe symptomatic hypocalcemia (including fatalities) has been reported in post-marketing experience (see section 4.8), with the majority of cases occurring within the first weeks of treatment but may occur later.

Renal impairment. Patients with severe renal impairment (creatinine clearance < 30 ml/min) or patients on dialysis are at risk for hypocalcemia. The risk of hypocalcemia and concomitant elevation of parathyroid hormone increases with increasing degree of renal impairment. Continuous monitoring of calcium levels is particularly important in these patients.

Osteonecrosis of the jaw (ONJ): ONJ has been commonly reported in patients treated with Xgeva (see section 4.8).

Initiation of treatment/re-treatment should be delayed in patients with unhealed open soft tissue lesions in the oral cavity. A dental examination with appropriate preventive dental treatment and an individual benefit/risk assessment are recommended before starting denosumab.

When assessing a patient's risk of developing ONJ, the following risk factors should be considered:

the efficacy of the drug causing the inhibition of bone resorption (higher risk in case of use of potent drugs), the route of administration (higher risk in case of parenteral administration) and the total dose of drugs used to inhibit bone resorption;

cancer, comorbidities (e.g. anemia, coagulopathy, infection), smoking;

poor oral hygiene, periodontal disease, poorly fitting dentures, presence of dental disease, invasive dental intervention (e.g. tooth extraction).

All patients should maintain adequate oral hygiene, undergo periodic dental examinations, and promptly report any oral symptoms, such as tooth mobility, pain or swelling, non-healing or rupturing ulcers, during treatment with denosumab. During treatment, invasive dental procedures should be performed only after careful consideration and should be avoided immediately prior to initiation of Xgeva®.

The management plan for individual patients who develop ONJ should be developed in close collaboration between the treating physician and a dentist or maxillofacial surgeon experienced in the treatment of ONJ. Temporary discontinuation of XGEVA® treatment should be considered until the disease is resolved and, if possible, precipitating factors have been reduced.

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

Atypical hip fractures. Atypical hip fractures have been reported in patients receiving denosumab (see section 4.8). Atypical hip fractures may occur with little or no trauma to the subtrochanteric or diaphyseal region of the femur. Specific radiographic findings characterize these events. Atypical hip fractures have also been reported in patients with certain underlying conditions (such as vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and with certain pharmaceutical agents (e.g. bisphosphonates, glucocorticoids, proton pump inhibitors). These events have also occurred in the absence of antiresorptive therapy. Similar fractures reported with bisphosphonates are often bilateral; therefore, the contralateral hip should be examined in patients receiving denosumab with a confirmed femoral shaft fracture. Discontinuation of Xgeva® should be considered in patients with suspected atypical hip fracture based on an individual benefit/risk assessment. Patients should be advised to report new or unusual hip, hip, or groin pain during treatment with denosumab. Patients presenting with these symptoms should be evaluated for an incomplete hip fracture.

Hypercalcemia after drug discontinuation in patients with giant cell tumors of bone and growing bones: Clinically significant hypercalcemia requiring hospitalization and complicated by acute kidney injury has been reported with the use of XGEVA® in patients with giant cell tumors of bone weeks to months after discontinuation of treatment.

After discontinuation of treatment, patients should be monitored for signs and symptoms of hypercalcemia with periodic determination of serum calcium levels.