VAEST

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VAEEST (WYOST®)

Composition:

active substance: denosumab;

1 ml of solution contains 70 mg of denosumab;

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

Pharmaceutical form. Solution for injection.

Basic physicochemical properties: clear or slightly opalescent, colorless or slightly yellowish or slightly brown solution with pH from 4.9 to 5.5 and osmolality of 245–345 mOsmol/kg.

Pharmacotherapeutic group. Drugs for the treatment of bone diseases. Other drugs affecting bone structure and mineralization.

ATC code M05BX04.

Pharmacological Properties

Pharmacodynamics

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 the primary mediator of bone destruction in metastatic bone disease and multiple myeloma. Denosumab is a human monoclonal antibody (IgG2) that binds with high affinity and specificity to RANKL, thereby preventing the RANKL/RANK interaction, leading to reduced number and activity of osteoclasts, and consequently decreasing cancer-induced bone resorption and destruction.

Giant cell tumor of bone is characterized by expression of RANK ligand by neoplastic stromal cells and RANK by osteoclast-like giant cells. In patients with giant cell tumor of bone, denosumab binds to RANK ligand, substantially 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 connective tissue and new bone.

Pharmacodynamic effects

In Phase II clinical studies in patients with advanced malignancies involving bone, subcutaneous administration of denosumab every 4 weeks (Q4W) or every 12 weeks led to a rapid reduction in bone resorption markers (uNTx/Cr, serum CTx), with a mean reduction of approximately 80% in uNTx/Cr occurring within 1 week, regardless of prior bisphosphonate therapy or baseline uNTx/Cr levels. In Phase III clinical studies in patients with advanced malignancies involving bone, a mean reduction in uNTx/Cr of approximately 80% was maintained up to at least week 49 of denosumab treatment (120 mg every 4 weeks [Q4W]).

Immunogenicity

In clinical studies, neutralizing antibodies to denosumab were not detected in patients with advanced cancer or giant cell tumor of bone. Using an enzyme-linked immunosorbent assay, < 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 reaction.

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

The efficacy and safety of subcutaneously administered denosumab 120 mg every 4 weeks and intravenously administered zoledronic acid 4 mg (dose adjusted for impaired renal function) every 4 weeks were compared in three randomized, double-blind, active-controlled trials in patients who had not previously received intravenous bisphosphonates and who had advanced malignancy with bone involvement: adults with breast cancer (Study 1), other solid tumors or multiple myeloma (Study 2), and castration-resistant prostate cancer (Study 3). In these active-controlled clinical trials, safety was evaluated in 5,931 patients. Patients with a history of osteonecrosis of the jaw (ONJ) or osteomyelitis of the jaw, patients with active dental or jaw disease requiring dental surgical intervention, patients with non-healing oral or dental surgical wounds, or patients with any planned invasive procedures were excluded from these studies. The primary and secondary endpoints assessed the time to occurrence of one or more skeletal-related events (SREs). In studies demonstrating superior efficacy of denosumab compared to zoledronic acid, patients were offered open-label denosumab in a pre-specified 2-year extension phase of treatment. SREs were defined as follows: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including use of radioisotopes), surgery to bone, or spinal cord compression.

Denosumab reduced the risk of developing SREs and the risk of developing multiple SREs (first and subsequent) in patients with bone metastases from solid tumors (see Table 1).

Table 1. Efficacy results in patients with advanced malignancies involving bone

Notes

ND – not reached; NA – data not available; HCM – hypercalcaemia of malignancy; SSE – skeletal-related event rate; HR – hazard ratio; RRR – relative risk reduction.

† Adjusted p-values are from studies 1, 2, and 3 (first SRE, as well as endpoints for first and subsequent SREs).

* 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 carcinoma, colorectal cancer, small cell lung cancer, bladder cancer, head and neck cancer, gastrointestinal/genitourinary cancers and other solid tumours, excluding breast cancer and prostate cancer.

Fig. 1. Kaplan–Meier curves for time to first SRE during the study

Notes

Dmab – denosumab 120 mg every 4 weeks (Q4W).

ZOL – zoledronic acid 4 mg every 4 weeks (Q4W).

N – number of randomized patients.

* – statistically significant for greater efficacy.

** – statistically significant for non-inferior efficacy.

Disease progression and overall survival in patients with bone metastases from solid tumours

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

Overall survival in studies 1, 2, and 3 was comparable between the denosumab and zoledronic acid groups in patients with advanced malignancies and bone involvement: patients with breast cancer (hazard ratio [95% CI] 0.95 [0.81; 1.11]), patients with prostate cancer (hazard ratio [95% CI] 1.03 [0.91; 1.17]), and patients with other solid tumours or multiple myeloma (hazard ratio [95% CI] 0.95 [0.83; 1.08]). A post-hoc analysis in study 2 (patients with other solid tumours or multiple myeloma) assessed overall survival according to one of three tumour types using stratification (non-small cell lung cancer, multiple myeloma, and others). Overall survival was longer in the denosumab group for non-small cell lung cancer (hazard ratio [95% CI] 0.79 [0.65; 0.95]; n = 702), in the zoledronic acid group for multiple myeloma (hazard ratio [95% CI] 2.26 [1.13; 4.50]; n = 180), and similar in the denosumab and zoledronic acid groups for other tumour types (hazard ratio [95% CI] 1.08 [0.90; 1.30]; n = 894). This study was not controlled for prognostic factors or anti-cancer therapy. In the pre-specified pooled analysis of studies 1, 2, and 3, overall survival was similar between the denosumab and zoledronic acid groups (hazard ratio [95% CI] 0.99 [0.91; 1.07]).

Effect on pain

Time to pain reduction (i.e., a decrease of ≥ 2 points from baseline on the pain score of the modified Brief Pain Inventory–Short Form [BPI-SF]) was similar with denosumab and zoledronic acid in each study and in integrated analyses. In a post-hoc analysis of combined data, the median time to pain progression (> 4-point increase in pain score) in patients with mild or no pain at baseline was longer with denosumab compared to zoledronic acid (198 vs. 143 days) (p = 0.0002).

Clinical efficacy in patients with multiple myeloma

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

In this study, 1718 patients with multiple myeloma and at least one bone lesion were randomized to receive subcutaneous denosumab 120 mg every 4 weeks (Q4W) or intravenous zoledronic acid 4 mg every 4 weeks (dose adjusted according to renal function). The primary endpoint was to demonstrate non-inferiority of denosumab compared to zoledronic acid in time to first SRE. Secondary endpoints included superiority in time to first SRE, time to first and subsequent SREs, and overall survival. SREs were defined as: pathological fracture (vertebral or non-vertebral), radiation therapy to bone (including use of radiopharmaceuticals), surgery to bone, or spinal cord compression.

In both study groups, 54.5% of patients underwent autologous peripheral blood stem cell transplantation (PBSC), 95.8% used or planned to use a novel anti-myeloma agent (bortezomib, lenalidomide, or thalidomide) as first-line therapy, and 60.7% had experienced a prior SRE. In both groups, the proportion of patients with International Staging System (ISS) stage I, II, and III multiple myeloma at diagnosis was 32.4%, 38.2%, and 29.3%, respectively.

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

Efficacy results from study 4 are presented in Fig. 2 and Table 2.

Fig. 2. Kaplan–Meier curves for time to first SRE in patients with newly diagnosed multiple myeloma

Notes

N – number of randomized patients.

Table 2. Efficacy results for denosumab compared with zoledronic acid in patients with newly diagnosed multiple myeloma

Notes

NO – not evaluable.

HCM – hypercalcaemia of malignancy.

Clinical efficacy and safety in adults and children with mature skeletal systems with giant cell tumour of bone

The safety and efficacy of denosumab were evaluated in two open-label, non-comparative phase II studies (studies 5 and 6) involving 554 patients with unresectable giant cell tumour of bone or for whom surgery was associated with severe morbidity. A prospective, multicentre, open-label phase IV study (study 7) was also conducted to provide long-term safety follow-up for patients who completed study 6. Denosumab was administered subcutaneously at a dose of 120 mg every 4 weeks with loading doses of 120 mg on days 8 and 15. After discontinuation of denosumab treatment, patients transitioned into a subsequent long-term follow-up phase lasting at least 60 months to assess drug safety. Re-initiation of denosumab treatment during the safety follow-up period was permitted for study participants who had shown an initial response to denosumab (e.g., in case of disease recurrence).

Study 5 included 37 adult patients with histologically confirmed unresectable or recurrent giant cell tumours of bone. The primary endpoint was objective response, defined as elimination of giant cells by at least 90% compared to baseline (or complete elimination of giant cells if their proportion was less than 5% of tumour cells), or absence of progression of the target tumour lesion confirmed by radiographic imaging in the absence of histopathological data. Among the 35 patients included in the efficacy analysis, 85.7% (95% CI: 69.7; 95.2) responded to denosumab treatment. All 20 patients (100%) who had histopathological data available met the response criteria. Among the remaining 15 patients, 10 (67%) showed no progression of the target tumour lesion based on radiographic assessments.

Study 6 included 535 adults and children with mature skeletal systems with giant cell tumour 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 inoperable disease (e.g., sacral, spinal, or multiple tumour lesions, including lung metastases); cohort 2 included patients with operable disease for whom planned surgery was associated with severe morbidity (e.g., joint resection, limb amputation, or hemipelvectomy); cohort 3 included patients who transitioned into this study after participation in study 5. The primary objective was to evaluate the safety profile of denosumab in patients with giant cell tumour of bone. Secondary endpoints included: for cohort 1 – time to disease progression (as assessed by the investigator); for cohort 2 – proportion of patients who did not undergo any surgical intervention by month 6.

In the final analysis of cohort 1, disease progression was observed in 28 out of 260 treated patients (10.8%). In cohort 2, 219 out of 238 evaluable patients (92.0% CI, 95% CI: 87.8%, 95.1%) did not undergo surgical intervention by month 6. In cohort 2, 82 (34.3%) out of 239 patients, whose target tumour lesion was located outside the lungs and soft tissues at baseline or during study participation, did not undergo surgery during the study. Overall, efficacy results in children with mature skeletal systems and adults were similar.

Study 7 included 85 adult patients who had previously participated in and completed study 6. Patients were allowed to receive denosumab treatment for giant cell tumour of bone, and all patients were monitored for 5 years. The primary objective was to evaluate the long-term safety profile of denosumab in patients with giant cell tumour of bone.

Effect on pain

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

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of denosumab studies in all paediatric subpopulations for the prevention of skeletal events in patients with bone metastases and in children under 12 years of age for the treatment of giant cell tumours of bone (see section "Posology and method of administration" for information on paediatric use).

In study 6, denosumab was evaluated in a subgroup of 28 children (aged 13 to 17 years) with giant cell tumours of bone and mature skeletal systems. Maturity was defined by the completion of maturation of at least one long bone (e.g., closed epiphyseal growth plate of the humerus) and a body weight ≥ 45 kg. One child with inoperable disease (N = 14) experienced recurrence during initial treatment. By month 6, 13 out of 14 patients with operable disease, for whom planned surgery was associated with severe morbidity, had not undergone surgical treatment.

Pharmacokinetics

Absorption

After subcutaneous administration, bioavailability was 62%.

Biotransformation

Denosumab consists exclusively of amino acids and carbohydrates, similar to natural immunoglobulins. Therefore, it is unlikely to be eliminated via hepatic metabolism. Its metabolism and elimination are believed to occur via the same pathways as immunoglobulin clearance, resulting in the breakdown of small proteins into individual amino acids.

Elimination

In patients with advanced cancer receiving multiple doses of 120 mg every 4 weeks, serum denosumab concentrations increased nearly twofold, and steady state was reached by 6 months, consistent with time-independent pharmacokinetics. In patients 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 tumours of bone receiving 120 mg every 4 weeks with loading doses 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 receiving 120 mg every 4 weeks, the mean elimination half-life was 28 days (range: 14–55 days).

Population pharmacokinetic analysis did not indicate clinically relevant changes in systemic exposure to denosumab at steady state based on age (18–87 years), race/ethnic group (Black patients, patients of Latin American origin, patients of Asian origin, and Caucasian patients), patient sex, solid tumour types, or presence of multiple myeloma. Increased body weight was associated with decreased systemic exposure and vice versa. These changes were not considered clinically relevant, as pharmacodynamic effects based on bone remodelling markers were consistent across a wide range of body weights.

Linearity/non-linearity

Denosumab exhibited non-linear pharmacokinetics over a wide dose range, but nearly dose-proportional increases in exposure were observed for doses of 60 mg (or 1 mg/kg) and higher. Non-linearity is most likely due to a target-mediated elimination pathway that becomes saturated at low concentrations.

Renal impairment

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

Hepatic impairment

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

Elderly patients

No differences in safety or efficacy were observed between elderly and younger patients. Controlled clinical studies of denosumab in patients aged 65 years and older with advanced-stage malignancies involving bone demonstrated similar efficacy and safety in older and younger patients. No dose adjustment is required for elderly patients.

Paediatric population

In children with mature skeletal systems (aged 12 to 17 years) with giant cell tumour of bone receiving 120 mg every 4 weeks with loading doses on days 8 and 15, the pharmacokinetics of denosumab were similar to those observed in adult patients with giant cell tumour 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 oestrogen receptor-positive and -negative breast cancer, prostate cancer, and non-small cell lung cancer, OPG-Fc reduced osteolytic, osteoblastic, and mixed osteolytic/osteoblastic bone destruction, delayed the formation of de novo bone metastases, and suppressed tumour growth in bone. When OPG-Fc was combined with hormonal therapy (tamoxifen) or chemotherapy (docetaxel), additional suppression of bone metastasis growth from breast cancer, prostate cancer, or lung cancer, respectively, was observed. In a mouse model of hormone-induced mammary tumour, RANK-Fc reduced hormone-mediated mammary epithelial proliferation and delayed tumour formation.

Standard tests to determine the genotoxic potential of denosumab were not performed, as 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 repeat-dose toxicity studies in cynomolgus monkeys, doses of denosumab leading to systemic exposure 2.7–15 times higher than the recommended human dose did not affect cardiovascular physiology, male or female reproductive function, or cause specific target organ toxicity.

In a study in cynomolgus monkeys treated with denosumab during a period equivalent to the first trimester of human pregnancy, doses leading to systemic exposure 9 times higher than the recommended human dose did not cause toxic effects in the dam or foetus during the first trimester equivalent period, although foetal lymph nodes were not examined.

In another study in cynomolgus monkeys treated with denosumab throughout pregnancy with systemic exposure 12 times higher than the human dose, increased stillbirths and postnatal mortality were observed; pathological bone growth leading to reduced bone strength, decreased haematopoiesis, and malocclusion; absence of peripheral lymph nodes; and delayed neonatal growth. The maximum dose without observed adverse effects was not established. Six months after birth, bone-related changes returned to normal, and no effect on tooth eruption was observed. However, effects on lymph nodes and malocclusion persisted, and in one animal, minimal to moderate mineralisation of multiple tissues was observed (relationship to treatment not clear). There was no evidence of harm to the dam prior to delivery; adverse reactions in the dam were infrequent during delivery. Mammary gland development in the dam was normal.

In preclinical bone quality studies in monkeys with long-term denosumab treatment, reduced remodelling was associated with improved bone strength and normal bone histological parameters.

In male mice genetically modified to express huRANKL (knock-in mice) subjected to trans-cortical fracture, denosumab delayed cartilage tissue organisation and bone callus remodelling compared to controls, but biochemical strength was not adversely affected.

In preclinical studies, mice with blocked RANK or RANKL genes showed no lactation due to inhibition of mammary gland maturation (lobuloalveolar development during pregnancy) and demonstrated impaired lymph node formation. Newborn mice with blocked RANK/RANKL genes showed reduced body weight, impaired bone growth, growth plate abnormalities, and absence of tooth eruption. Impaired bone growth, growth plate abnormalities, and absence of tooth eruption were also observed in newborn rats treated with RANKL inhibitors, and these changes were partially reversible after discontinuation of the RANKL inhibitor. In adolescent primates treated with denosumab at doses 2.7 and 15 times higher (10 and 50 mg/kg) than the clinical dose, pathological changes in growth plates were observed. Thus, denosumab treatment may impair bone growth in children with open growth plates and may suppress tooth eruption.

Clinical characteristics

Indications

The medicinal product Vayest is indicated for:

• Prevention of skeletal events (pathological fracture, radiation to bone, spinal cord compression, or surgical intervention on bones) in adult patients with advanced stage malignancies involving bone (see section "Pharmacodynamics").
• Treatment of adults and children with mature skeletal systems who have unresectable giant cell tumor of bone or for whom surgical resection is likely to result in severe morbidity.

Contraindications

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

Severe untreated hypocalcemia (see section "Special precautions").

Osteonecrosis of the jaw following dental or surgical procedures in the oral cavity that has not healed.

Interaction with other medicinal products and other forms of interaction

Interaction studies have not been conducted. In clinical studies, denosumab was administered in combination with standard anti-cancer therapy and following prior treatment with bisphosphonates. There were no clinically significant changes in the minimum serum concentration or pharmacodynamics of denosumab (urinary N-telopeptide corrected for creatinine, uNTx/Cr) when administered concomitantly with chemotherapy and/or hormonal therapy or following prior intravenous administration of bisphosphonate.

Special precautions for use

Traceability

To improve traceability of biological medicinal products, the name and batch number of the administered medicinal product should be clearly documented.

Calcium and vitamin D supplementation. Calcium and vitamin D supplementation is necessary for all patients, except for patients with hypercalcaemia (see section "Posology and method of administration").

Hypocalcaemia. Pre-existing hypocalcaemia must be corrected prior to initiating treatment with Vaiest. Hypocalcaemia may occur at any time during treatment with Vaiest. Monitoring of calcium levels should be performed prior to the first dose of Vaiest, within two weeks after the initial dose, and when symptoms suggestive of hypocalcaemia occur (see section "Undesirable effects" for symptoms). Additional monitoring of calcium levels during treatment should be considered in patients with risk factors for hypocalcaemia or in other cases depending on the patient's clinical condition.

Patients should be advised to report symptoms suggestive of hypocalcaemia. If hypocalcaemia occurs during treatment with Vaiest, additional calcium supplementation and more frequent monitoring of calcium levels may be required.

During post-marketing use, severe symptomatic hypocalcaemia (including fatal cases) has been reported (see section "Undesirable effects"), with most cases occurring within the first weeks of treatment initiation, although cases may also occur later.

Renal impairment. Patients with severe renal impairment (creatinine clearance < 30 mL/min) or patients on dialysis are at increased risk of developing hypocalcaemia. The risk of hypocalcaemia and associated increase in parathyroid hormone levels increases with the severity of renal impairment. Continuous monitoring of calcium levels is particularly important in these patients.

Osteonecrosis of the jaw (ONJ). ONJ has been frequently reported in patients receiving denosumab (see section "Undesirable effects").

Initiation of treatment or a new course of treatment should be delayed in patients with non-healing open soft tissue lesions in the oral cavity. A dental examination with appropriate preventive dental treatment and individual benefit-risk assessment is recommended prior to starting denosumab.

Factors to consider when assessing the risk of ONJ include:

• Potency of the bone resorption-inhibiting medicinal product (higher risk with more potent agents), route of administration (higher risk with parenteral administration), and cumulative dose of bone resorption-inhibiting agents;
• Cancer, concomitant conditions (e.g., anaemia, coagulopathy, infection), smoking;
• Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, head and neck radiation therapy;
• Poor oral hygiene, periodontal disease, ill-fitting dentures, presence of dental disease, invasive dental procedures (e.g., tooth extraction).

All patients should maintain adequate oral hygiene, undergo regular dental examinations, and promptly report any oral symptoms such as tooth mobility, pain or swelling, non-healing or draining oral ulcers during denosumab treatment. Invasive dental procedures should only be performed during treatment after careful consideration and should be avoided immediately prior to initiating Vaiest.

Management of individual patients who develop ONJ should be planned in close collaboration between the treating physician and a dentist or maxillofacial surgeon experienced in managing ONJ. Temporary discontinuation of Vaiest should be considered until the condition resolves and, if possible, precipitating factors should be minimized.

Osteonecrosis of the external auditory canal. Osteonecrosis of the external auditory canal has been reported with denosumab use. Potential risk factors include steroid use, chemotherapy, and local risk factors such as infections and trauma. Osteonecrosis of the external auditory canal should be considered in patients receiving denosumab who present with symptoms related to the auditory organs, including chronic ear infections.

Atypical femoral fractures. Atypical femoral fractures have been reported in patients receiving denosumab (see section "Undesirable effects"). Atypical femoral fractures may occur with minimal or no trauma in the subtrochanteric or diaphyseal region of the femur. Specific radiographic findings characterize these events. Atypical femoral fractures have also been reported in patients with certain comorbidities (such as vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and with certain medications (e.g., bisphosphonates, glucocorticoids, proton pump inhibitors). These events have also occurred without anti-resorptive therapy. Similar fractures reported with bisphosphonate use are often bilateral; therefore, the contralateral femur should be examined in patients receiving denosumab who have a confirmed femoral shaft fracture. Discontinuation of Vaiest should be considered in patients suspected of having an atypical femoral fracture, based on individual benefit-risk assessment. Patients receiving denosumab should be advised to report new or unusual pain in the hip, groin, or thigh. Patients with such symptoms should be evaluated for incomplete femoral fractures.

Hypercalcaemia following discontinuation of treatment in patients with giant cell tumour of bone and in patients with growing skeleton. Clinically significant hypercalcaemia requiring hospitalization and complicated by acute kidney injury has been reported following denosumab use in patients with giant cell tumour of bone, occurring weeks or months after treatment discontinuation.

After stopping treatment, patients should be monitored for signs and symptoms of hypercalcaemia, with periodic measurement of serum calcium levels and reassessment of the need for additional calcium and vitamin D supplementation (see section "Undesirable effects").

Vaiest is not recommended for patients with growing skeleton (see section "Posology and method of administration"). Clinically significant hypercalcaemia has also been reported in this patient group, occurring weeks to months after discontinuation of the medicinal product.

Other conditions. Patients receiving Vaiest should not concurrently use other medicinal products containing denosumab (for osteoporosis).

Patients receiving Vaiest should not concurrently use bisphosphonates.

Malignant transformation of giant cell tumour or progression with metastasis is rare but a known risk in patients with giant cell tumour of bone. Patients should be monitored for radiological signs of malignancy, new areas of radiolucency, or osteolysis. Available clinical data do not indicate an increased risk of malignancy in patients with giant cell tumour of bone receiving denosumab.

Excipients. This medicinal product contains 78.9 mg of sorbitol per vial. The additive effect of concurrently administered medicinal products containing sorbitol (or fructose), and dietary intake of sorbitol (or fructose), should be considered.

This medicinal product contains less than 1 mmol sodium (23 mg) per 120 mg, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy. There are insufficient data on the use of denosumab in pregnant women. Reproductive toxicity has been demonstrated in animal studies (see section "Preclinical safety data").

Vaiest is not recommended for use in pregnant women or in women of childbearing potential who are not using contraception. Women should be advised to avoid pregnancy during treatment with Vaiest and for at least 5 months thereafter. Any effects of Vaiest are likely to be more pronounced during the second and third trimesters of pregnancy, as monoclonal antibodies cross the placenta more readily as pregnancy progresses, with the greatest transfer occurring during the third trimester.

Breastfeeding. It is unknown whether denosumab is excreted in human breast milk. A risk to newborns/infants cannot be excluded. Knockout mouse studies have shown that the absence of RANKL during pregnancy may affect mammary gland maturation, leading to impaired lactation after delivery (see section "Preclinical safety data"). A decision must be made whether to discontinue breastfeeding or to discontinue therapy with Vaiest, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility. Data on the effect of denosumab on human fertility are lacking. Animal studies have not shown direct or indirect harmful effects on fertility (see section "Preclinical safety data").

Effect on ability to drive and use machines

Vaiest has no or negligible effect on the ability to drive or use machines.

Dosage and Administration

The medicinal product Xgeva should be administered under the supervision of a physician.

Dosing.

An adequate daily intake of at least 500 mg of calcium and 400 IU of vitamin D should be ensured, except in cases of hypercalcemia (see section "Special Warnings and Precautions for Use").

Prevention of skeletal-related events in adults with advanced malignancies involving bone. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection once every 4 weeks in the thigh, abdomen, or upper arm.

Giant cell tumor of bone. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection once every 4 weeks in the thigh, abdomen, or upper arm. Additional doses of 120 mg are administered on days 8 and 15 of the first month of treatment.

Patients in a Phase II study who underwent complete surgical resection of giant cell tumor of bone received additional treatment for 6 months post-surgery according to the study protocol.

Patients with giant cell tumor of bone should be regularly evaluated to determine whether they continue to benefit from treatment. The effect of interrupting or temporarily discontinuing treatment has not been evaluated in patients with disease controlled by denosumab; however, limited data in these patients do not suggest a rebound effect after temporary treatment discontinuation.

Renal impairment. No dose adjustment is necessary for patients with renal impairment (see section "Special Warnings and Precautions for Use" for recommendations on monitoring calcium levels, section "Undesirable Effects," and subsection "Pharmacokinetics").

Hepatic impairment. The safety and efficacy of denosumab in patients with hepatic impairment have not been studied (see subsection "Pharmacokinetics").

Elderly patients (age ≥ 65 years). No dose adjustment is necessary for elderly patients (see subsection "Pharmacokinetics").

Administration method

For subcutaneous use only.

• Prior to administration, visually inspect the solution. Do not administer if the solution is cloudy or contains visible particles.
• Do not shake.
• To minimize injection site discomfort, allow the vial to warm to room temperature (up to 25 °C) before administration, and inject the solution slowly.
• Administer the entire contents of the vial.
• A 27-gauge needle is recommended for administration of denosumab.
• Do not re-puncture the vial with a needle.

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

Children

The safety and efficacy of denosumab in children (under 18 years of age) have not been established, except in children with mature skeletal systems (aged 12 to 17 years) who have giant cell tumor of bone.

Denosumab is not recommended for use in children under 18 years of age, except in children with mature skeletal systems (aged 12 to 17 years) who have giant cell tumor of bone (see section "Special Warnings and Precautions for Use").

Treatment of children with mature skeletal systems who have unresectable giant cell tumor of bone or for whom surgical resection is likely to result in severe morbidity: the dose is the same as that for adults.

Inhibition of receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL) in animal studies was associated with suppressed bone growth and failure of tooth eruption; these changes were partially reversible after cessation of RANKL inhibition (see subsection "Non-clinical Safety Data").

Overdose

Experience with overdose in clinical studies is lacking. Denosumab has been administered in clinical studies at doses up to 180 mg every 4 weeks and 120 mg every 3 weeks.

Adverse Reactions

Summary of safety profile

The overall safety profile is similar across all approved indications for denosumab.

Hypocalcemia was reported very commonly following administration of denosumab, primarily within the first two weeks. Hypocalcemia could be severe and symptomatic (see section "Description of selected adverse reactions"). Decreases in serum calcium levels were generally managed effectively with calcium and vitamin D supplementation. The most common adverse reaction with denosumab was musculoskeletal pain. Osteonecrosis of the jaw was reported commonly in patients receiving denosumab (see section "Special warnings and precautions for use" and section "Description of selected adverse reactions").

Summary table of adverse reactions

Classification of adverse reactions reported in four phase III clinical studies and two phase II clinical studies, as well as during post-marketing use (see Table 3): very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and not known (cannot be estimated from the available data). Within each frequency category and system organ class, adverse reactions are listed in order of decreasing severity.

Table 3. Adverse reactions reported in patients with advanced malignancies involving bone, multiple myeloma, or giant cell tumor of bone

1 See section "Description of specific adverse reactions".

2 See section "Other special patient groups".

3 See section "Special instructions for use".

4 Effect characteristic for this class of medicinal products.

Description of specific adverse reactions

Hypocalcaemia. A higher incidence of hypocalcaemia was observed in clinical trials for prevention of skeletal-related events (SREs) in patients receiving denosumab compared to patients receiving zoledronic acid.

The highest incidence of hypocalcaemia was observed in a phase III trial in patients with multiple myeloma. Cases of hypocalcaemia occurred in 16.9% of patients receiving denosumab and in 12.4% of patients receiving zoledronic acid. Grade 3 serum calcium reduction occurred in 1.4% and 0.6% of patients receiving denosumab and zoledronic acid, respectively, and grade 4 reduction occurred in 0.4% and 0.1%, respectively.

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

Grade 3 reductions in serum calcium levels occurred in 2.5% of patients receiving denosumab and in 1.2% of patients receiving zoledronic acid. Grade 4 reductions in serum calcium levels occurred in 0.6% of patients receiving denosumab and in 0.2% of patients receiving zoledronic acid (see section "Special instructions for use").

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

During post-marketing use, severe symptomatic hypocalcaemia (including fatal cases) has been reported, with most cases occurring within the first weeks after initiation of treatment. Clinical manifestations of severe symptomatic hypocalcaemia include QT interval prolongation, tetany, seizures, and mental status changes (including coma) (see section "Special instructions for use"). Symptoms of hypocalcaemia observed in clinical trials included paresthesia or muscle stiffness, muscle twitching, spasms, and muscle cramps.

Osteonecrosis of the jaw (ONJ). In clinical trials, the incidence of ONJ increased with longer duration of exposure to the drug; ONJ was also diagnosed after discontinuation of denosumab treatment, with most cases occurring within 5 months after the last dose. Patients with a history of ONJ or osteomyelitis of the jaw, active dental or jaw diseases requiring surgical intervention, non-healing oral wounds following dental/surgical procedures, or those planned for any invasive dental procedures were excluded from clinical trials.

A higher incidence of ONJ was observed in clinical trials for prevention of SREs in patients receiving denosumab compared to those receiving zoledronic acid. The highest incidence of ONJ occurred in a phase III trial in patients with multiple myeloma. In the double-blind treatment phase of this study, ONJ was confirmed in 5.9% of patients receiving denosumab (median exposure 19.4 months; range: 1–52) and in 3.2% of patients receiving zoledronic acid. At the end of the double-blind treatment phase, the patient-year adjusted incidence rate of confirmed ONJ cases in the denosumab group (median exposure 19.4 months; range: 1–52) was 2.0 per 100 patient-years during the first year of treatment, 5.0 during the second year, and 4.5 in subsequent years. The median time to onset of ONJ was 18.7 months (range: 1–44).

In the primary treatment phases of three active-controlled phase III clinical trials involving patients with advanced malignancies with bone metastases, ONJ was confirmed in 1.8% of patients receiving denosumab (mean exposure 12 months; range: 0.1–40.5) and in 1.3% of patients receiving zoledronic acid. Clinical characteristics of these cases were similar between treatment groups. In most patients with confirmed ONJ (81% in both treatment groups), history included tooth extraction, poor oral hygiene, and/or denture use. Most patients were receiving or had previously received chemotherapy.

A study involving patients with breast or prostate cancer included an extended denosumab treatment phase (mean total exposure 14.9 months; range: 0.1–67.2). ONJ was confirmed in 6.9% of patients with breast or prostate cancer during the extended treatment phase.

The patient-year adjusted incidence rate of confirmed ONJ cases was 1.1 per 100 patient-years during the first year of treatment, 3.7 during the second year, and 4.6 in subsequent years. The median time to onset of ONJ was 20.6 months (range: 4–53).

Data from a non-randomized, retrospective observational study involving 2877 cancer patients treated with denosumab or zoledronic acid in Sweden, Denmark, and Norway showed that the 5-year incidence of confirmed ONJ was 5.7% (95% CI: 4.4, 7.3; median observation time: 20 months [range 0.2–60]) in the cohort receiving denosumab and 1.4% (95% CI: 0.8, 2.3; median observation time: 13 months [range 0.1–60]) in the separate cohort receiving zoledronic acid. The 5-year incidence of ONJ in patients who switched to denosumab after prior zoledronic acid treatment was 6.6% (95% CI: 4.2, 10.0; median observation time: 13 months [range 0.2–60]).

In a phase III clinical trial in patients with non-metastatic prostate cancer (a population for which denosumab is not indicated), with long-term exposure up to 7 years of treatment, the patient-year adjusted incidence rate of confirmed ONJ was 1.1 per 100 patient-years during the first year of treatment, 3.0 during the second year, and 7.1 in subsequent years.

In a long-term open-label phase II clinical trial in patients with giant cell tumor of bone (Study 6, see section "Pharmacodynamics"), ONJ was confirmed in 6.8% of patients, including one child (median number of doses: 34; range: 4–116). At study completion, the median duration of participation, including the follow-up phase, was 60.9 months (range: 0–112.6). The patient-year adjusted overall incidence rate of confirmed ONJ was 1.5 per 100 patient-years (0.2 per 100 patient-years during the first year of treatment, 1.5 during the second year, 1.8 during the third year, 2.1 during the fourth year, 1.4 during the fifth year, and 2.2 in subsequent years). The median time to onset of ONJ was 41 months (range: 11–96).

Study 7 was conducted to continue monitoring patients with giant cell tumor of bone who had been treated in Study 6 for an additional 5 or more years. ONJ was recorded in 6 (11.8%) of 51 treated patients, with a median total number of denosumab doses of 42. Three of these ONJ cases were medically confirmed.

Hypersensitivity reactions related to drug administration. In post-marketing use, hypersensitivity reactions have been reported in patients receiving denosumab, including rare cases of anaphylactic reactions.

Atypical femoral fractures. Overall, in the clinical trial program, atypical femoral fractures were infrequently reported in patients receiving denosumab, with risk increasing with longer duration of treatment. These events occurred during treatment and up to 9 months after discontinuation of treatment (see section "Special instructions for use").

In the clinical trial program for giant cell tumor of bone, atypical femoral fractures were commonly observed in patients receiving denosumab treatment. In Study 6, the incidence of confirmed atypical femoral fractures was 0.95% (5/526) in patients with giant cell tumor of bone. In the subsequent Study 7, the incidence of confirmed atypical femoral fractures was 3.9% (2/51) in patients receiving denosumab.

Musculoskeletal pain. In post-marketing use, musculoskeletal pain, including severe cases, has been reported in patients receiving denosumab. In clinical trials, musculoskeletal pain was very commonly reported in both denosumab and zoledronic acid groups, although it rarely led to discontinuation of the drug.

New primary malignancy. In the primary phases of double-blind treatment in four active-controlled phase III clinical trials involving patients with advanced malignancies involving bone, primary malignancies were observed in 54 of 3691 (1.5%) patients receiving denosumab (median exposure 13.8 months; range: 1.0–51.7) and in 33 of 3688 (0.9%) patients receiving zoledronic acid (median exposure 12.9 months; range: 1.0–50.8).

Cumulative incidence at one year was 1.1% for denosumab and 0.6% for zoledronic acid.

No treatment-related pattern was observed for individual cancer types or cancer distribution across groups.

In patients with giant cell tumor of bone, the incidence of new malignancies, including bone and extraosseous malignancies, was 3.8% (20/526) in Study 6. In the subsequent Study 7, the incidence was 11.8% (6/51) among patients receiving denosumab.

Drug-induced lichenoid eruptions. Drug-induced lichenoid eruptions (e.g., reactions resembling lichen planus) have been observed in patients during the post-marketing period.

Children

Denosumab was studied in an open-label trial involving 28 children with mature skeletal systems who had giant cell tumor of bone. Based on these limited data, the adverse reaction profile was similar to that in adults.

In the post-marketing period, clinically significant hypercalcaemia after discontinuation of treatment has been reported in children (see section "Special instructions for use").

Other special patient groups

Renal impairment

In a clinical trial in patients without advanced cancer and with severe renal impairment (creatinine clearance < 30 mL/min) or patients on dialysis, a higher risk of hypocalcaemia was observed in the absence of calcium supplementation. The risk of hypocalcaemia during denosumab treatment increases with the severity of renal impairment. In a clinical trial involving patients without advanced cancer, hypocalcaemia occurred in 19% of patients with severe renal impairment (creatinine clearance < 30 mL/min) and in 63% of patients on hemodialysis, despite calcium supplementation. The overall incidence of clinically significant hypocalcaemia was 9%.

Concomitant elevations in parathyroid hormone levels were also observed in patients receiving denosumab who had severe renal impairment or were on dialysis. Monitoring of calcium levels and adequate calcium and vitamin D intake are particularly important for patients with renal impairment (see section "Special instructions for use").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

Store at 2–8 °C in the original packaging to protect from light. Do not freeze. Keep out of reach of children.

The medicinal product may be stored at temperatures not exceeding 25 °C for up to 30 days in the original packaging to protect from light.

Incompatibilities

Since compatibility studies with other agents have not been conducted, this medicinal product must not be mixed with other medicinal products.

Packaging

1.7 mL (120 mg) in a vial; 1 vial in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Lek Pharmaceuticals d.d.

Manufacturer's address and location of its business operations

Verovškova 57, 1526 Ljubljana, Slovenia