Jubonti
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DJUBONTI (JUBBONTI®)
Composition:
active substance: denosumab;
1 ml of solution contains 60 mg of denosumab;
excipients: glacial acetic acid, sorbitol (E 420), polysorbate 20, sodium hydroxide, hydrochloric acid diluted, water for injections.
Pharmaceutical form. Solution for injection.
Main physicochemical characteristics: transparent or slightly opalescent, colorless or slightly yellowish, or slightly brown solution with pH from 4.9 to 5.5 and osmolality from 245 to 345 mOsmol/kg.
Pharmacotherapeutic group. Medicinal products for the treatment of bone diseases. Medicinal products affecting bone structure and mineralization. Other medicinal products affecting bone structure and mineralization.
ATC code M05B X04.
Pharmacological Properties
Pharmacodynamics
Mechanism of action
Denosumab is a human monoclonal antibody (IgG2) produced by a mammalian cell line (Chinese hamster ovary cells) using recombinant DNA technology. It specifically targets RANKL, binding to it with high affinity and specificity, thereby preventing the activation of its receptor RANK on the surface of osteoclast precursors and mature osteoclasts. By inhibiting the RANKL/RANK interaction, denosumab suppresses the formation, function, and survival of osteoclasts, thus reducing bone resorption in both cortical and trabecular bone.
Pharmacodynamic effects
Treatment with denosumab rapidly reduces bone turnover, achieving the lowest level of the serum bone resorption marker, type 1 collagen C-telopeptides (CTX), within 3 days (an 85% reduction). This reduced level is maintained throughout the dosing interval. At the end of each dosing period, the CTX-lowering effect was partially attenuated: from a maximum reduction of more than 87% to a reduction of approximately more than 45% (ranging from 45% to 80%), reflecting the reversibility of denosumab's effects on bone remodeling as serum drug levels decline. With continued therapy, these effects were sustained.
Bone remodeling markers generally returned to levels observed before starting treatment within 9 months after the last dose. Upon re-initiation of treatment, the degree of CTX inhibition by denosumab was similar to that observed in patients who were newly starting denosumab therapy.
Immunogenicity
During clinical studies, no neutralizing antibodies against denosumab were detected. Less than 1% of patients treated with denosumab for up to 5 years tested positive (by a sensitive immunoassay method) for non-neutralizing binding antibodies, with no evidence of altered pharmacokinetics, toxicity, or clinical effects.
Clinical efficacy and safety in postmenopausal women with osteoporosis
The efficacy and safety of denosumab administered once every 6 months for 3 years were evaluated in postmenopausal women (7,808 women aged 60–91 years, of whom 23.6% had prevalent vertebral fractures) with baseline bone mineral density (BMD) T-scores at the lumbar spine or total hip between -2.5 and -4.0, and a mean absolute 10-year probability of major osteoporotic fracture of 18.60% (deciles: 7.9–32.4%) and of hip fracture of 7.22% (deciles: 1.4–14.9%). Women with other diseases or those receiving treatments that could affect bone were excluded from the study. All women received daily supplementation with calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Effect on vertebral fractures
Denosumab significantly reduced the risk of new vertebral fractures at years 1, 2, and 3 of treatment (p < 0.0001) (see Table 1).
Table 1. Effect of denosumab on the risk of new vertebral fractures
| Period of use |
Proportion of women with fracture (%) |
Absolute risk reduction (%) (95 % CI) |
Relative risk reduction (%) (95 % CI) |
|
| Placebo n = 3906 |
Denosumab n = 3902 |
|||
| 0–1 year |
2.2 |
0.9 |
1.4 (0.8; 1.9) |
61 (42; 74)** |
| 0–2 years |
5.0 |
1.4 |
3.5 (2.7; 4.3) |
71 (61; 79)** |
| 0–3 years |
7.2 |
2.3 |
4.8 (3.9; 5.8) |
68 (59; 74)* |
*p < 0.0001, **p < 0.0001 – exploratory analysis
Effect on hip fractures
Denosumab demonstrated a 40% relative reduction (0.5% absolute risk reduction) in the risk of hip fracture over 3 years (p < 0.05). The incidence of hip fractures was 1.2% in the placebo group compared to 0.7% in the denosumab group after 3 years.
In a post hoc analysis in women > 75 years of age, a 62% relative risk reduction was observed with denosumab (1.4% absolute risk reduction, p < 0.01).
Effect on all clinical fractures
Denosumab significantly reduced the occurrence of fractures of all types/groups (see Table 2).
Table 2. Effect of denosumab on the risk of clinical fractures over 3 years
| Types of fractures |
Proportion of women with fracture (%) + |
Absolute risk reduction (%) (95 % CI) |
Relative risk reduction (%) (95 % CI) |
|
| Placebo n = 3906 |
Denosumab n = 3902 |
|||
| Any clinical fracture1 |
10.2 |
7.2 |
2.9 (1.6; 4.2) |
30 (19; 41)*** |
| Clinical vertebral fracture |
2.6 |
0.8 |
1.8 (1.2; 2.4) |
69 (53; 80)*** |
| Non-vertebral fracture2 |
8.0 |
6.5 |
1.5 (0.3; 2.7) |
20 (5; 33)** |
| Major non-vertebral fracture3 |
6.4 |
5.2 |
1.2 (0.1; 2.2) |
20 (3; 34)* |
| Major osteoporotic fracture4 |
8.0 |
5.3 |
2.7 (1.6; 3.9) |
35 (22; 45)*** |
* p ≤ 0.05, ** p = 0.0106 (secondary endpoint, included in multiplicity adjustment), *** p ≤ 0.0001
- Event rate is based on Kaplan-Meier estimate over 3 years.
1 Includes clinical vertebral and non-vertebral fractures.
2 Excludes fractures of vertebrae, skull, face, mandible, metacarpals, and phalanges of hands and feet.
3 Includes pelvis, distal femur, proximal tibia, ribs, proximal humerus, forearm, and femur.
4 Includes clinical vertebral fractures, hip, forearm, and humeral fractures as defined by WHO.
In women with baseline femoral neck BMD ≤ ‑2.5, denosumab reduces the risk of non-vertebral fractures (35% reduction in relative risk, 4.1% reduction in absolute risk, p < 0.001, exploratory analysis).
Reductions in the incidence of new vertebral fractures, hip fractures, and non-vertebral fractures with denosumab over 3 years were consistent regardless of baseline 10-year fracture risk.
Effect on bone mineral density (BMD)
Compared with placebo at Years 1, 2, and 3, denosumab significantly increased BMD at all anatomical sites. Denosumab increased BMD by 9.2% at the lumbar spine, 6.0% at the total hip, 4.8% at the femoral neck, 7.9% at the femoral trochanter, 3.5% at the distal 1/3 radius, and 4.1% at the total body over 3 years (all p < 0.0001).
In clinical studies evaluating the effects of denosumab discontinuation, BMD returned to approximately pre-treatment levels and remained higher than in the placebo group for up to 18 months after the last dose. These data indicate that continued treatment with denosumab is necessary to maintain the drug's effect. Re-initiation of denosumab led to BMD increases similar to those observed with initial denosumab treatment.
Open-label extension study in postmenopausal osteoporosis
Overall, 4550 women (2343 of whom received denosumab and 2207 placebo), who missed no more than one dose in the preceding study described above and completed the 36-month study visit, participated in a 7-year, multinational, multicenter, open-label, non-comparative extension study evaluating long-term safety and efficacy of denosumab. All women in the extension study were required to receive 60 mg denosumab every 6 months, as well as daily calcium (at least 1 g) and vitamin D (at least 400 IU). A total of 2626 patients (58% of women enrolled in the extension study, i.e., 34% of women enrolled in the core study) completed the extension study.
In patients receiving denosumab for up to 10 years, BMD increased from baseline of the core study by 21.7% at the lumbar spine, 9.2% at the total hip, 9.0% at the femoral neck, 13.0% at the trochanter, and 2.8% at the distal 1/3 radius. At the end of the study, the mean lumbar spine BMD T-score in patients treated for 10 years was -1.3.
Fracture incidence was evaluated as a safety endpoint; however, fracture prevention efficacy could not be assessed due to a high number of treatment discontinuations and the open-label study design. In patients who received denosumab for 10 years (n = 1278), the cumulative incidence of new vertebral and non-vertebral fractures was approximately 6.8% and 13.1%, respectively. In patients who did not complete the study for any reason, fracture incidence during treatment was higher.
Thirteen confirmed cases of osteonecrosis of the jaw (ONJ) and two confirmed cases of atypical femoral fractures were observed during the extension study.
Clinical efficacy and safety in men with osteoporosis
The efficacy and safety of denosumab administered once every 6 months for 1 year were evaluated in 242 men aged 31–84 years. Subjects with eGFR < 30 mL/min/1.73 m² were excluded from the study. All men received daily calcium (at least 1000 mg) and vitamin D (at least 800 IU) supplements.
The primary efficacy endpoint was the percentage change in lumbar spine BMD; fracture efficacy was not evaluated. Compared with placebo, denosumab significantly increased BMD at all anatomical sites over 12 months: by 4.8% at the lumbar spine, 2.0% at the total hip, 2.2% at the femoral neck, 2.3% at the femoral trochanter, and 0.9% at the distal 1/3 radius (all p < 0.05). Denosumab increased lumbar spine BMD from baseline in 94.7% of men at the end of Year 1. Significant increases in BMD at the lumbar spine, total hip, femoral neck, and femoral trochanter were observed at 6 months (p < 0.0001).
Bone histology in postmenopausal women and men with osteoporosis
Bone histology was evaluated in 62 postmenopausal women with osteoporosis or low bone mass who had either not previously received osteoporosis therapy or had switched from prior alendronate therapy, after 1–3 years of treatment with denosumab. Fifty-nine women participated in the bone biopsy sub-study at 24 months (n = 41) and/or 84 months (n = 22) of the extension study in postmenopausal women with osteoporosis. Bone histology was also evaluated in 17 men with osteoporosis after 1 year of denosumab treatment. Bone biopsy results showed bone of normal morphology and quality without evidence of mineralization defects, immature bone, or bone marrow fibrosis. Histomorphometric results from the extension study showed that in postmenopausal women with osteoporosis, the antiresorptive effects of denosumab, measured by bone activation frequency and bone formation rate, were maintained over the long term.
Clinical efficacy and safety in patients with bone loss associated with androgen deprivation therapy
The efficacy and safety of denosumab administered once every 6 months for 3 years were evaluated in men with histologically confirmed non-metastatic prostate cancer receiving androgen deprivation therapy (ADT) (1468 men aged 48–97 years). These patients were at increased risk of fracture (defined as age > 70 years or age < 70 years with a lumbar spine, total hip, or femoral neck BMD T-score < ‑1.0, or a history of osteoporotic fracture). All men received daily calcium (at least 1000 mg) and vitamin D (at least 400 IU) supplements.
Compared with placebo, denosumab significantly increased BMD at all anatomical sites over 3 years: by 7.9% at the lumbar spine, 5.7% at the total hip, 4.9% at the femoral neck, 6.9% at the femoral trochanter, 6.9% at the distal 1/3 radius, and 4.7% at the total body (all p < 0.0001). In a prospectively planned exploratory analysis, significant increases in BMD at the lumbar spine, total hip, femoral neck, and femoral trochanter were observed 1 month after the initial dose.
Denosumab demonstrated significant reductions in the relative risk of new vertebral fractures: 85% (1.6% absolute risk reduction) at Year 1, 69% (2.2% absolute risk reduction) at Year 2, and 62% (2.4% absolute risk reduction) at Year 3 (all p < 0.01).
Clinical efficacy and safety in patients with bone loss associated with adjuvant aromatase inhibitor therapy
The efficacy and safety of denosumab administered once every 6 months for 2 years were evaluated in women with non-metastatic breast cancer (252 women aged 35–84 years) and baseline BMD T-score between ‑1.0 and ‑2.5 at the lumbar spine, total hip, or femoral neck. All women received daily calcium (at least 1000 mg) and vitamin D (at least 400 IU) supplements.
The primary efficacy endpoint was the percentage change in lumbar spine BMD; fracture efficacy was not evaluated. Compared with placebo, denosumab significantly increased BMD over 2 years: by 7.6% at the lumbar spine, 4.7% at the total hip, 3.6% at the femoral neck, 5.9% at the femoral trochanter, 6.1% at the distal 1/3 radius, and 4.2% at the total body (all p < 0.0001).
Treatment of bone loss associated with systemic glucocorticoid therapy
The efficacy and safety of denosumab were evaluated in 795 patients (70% women and 30% men) aged 20 to 94 years receiving ≥ 7.5 mg of oral prednisone daily (or equivalent).
Two subpopulations were studied: patients continuing glucocorticoid therapy (≥ 7.5 mg prednisone daily or equivalent for ≥ 3 months prior to study entry; n = 505), and patients newly initiating glucocorticoid therapy (≥ 7.5 mg prednisone daily or equivalent for < 3 months prior to study entry; n = 290). Patients were randomized (1:1) to receive either subcutaneous denosumab 60 mg every 6 months or oral risedronate 5 mg once daily (active control) for 2 years. Patients received daily calcium (at least 1000 mg) and vitamin D (at least 800 IU).
Effect on bone mineral density
In the subpopulation continuing glucocorticoid therapy, denosumab demonstrated greater increases in lumbar spine BMD compared to risedronate at Year 1 (denosumab: 3.6%, risedronate: 2.0%; p < 0.001) and Year 2 (denosumab: 4.5%, risedronate: 2.2%; p < 0.001). In the subpopulation newly initiating glucocorticoid therapy, denosumab demonstrated greater increases in lumbar spine BMD compared to risedronate at Year 1 (denosumab: 3.1%, risedronate: 0.8%; p < 0.001) and Year 2 (denosumab: 4.6%, risedronate: 1.5%; p < 0.001).
Additionally, denosumab demonstrated significantly greater mean percentage increases in BMD from baseline compared to risedronate at the total hip, femoral neck, and femoral trochanter.
The study was not designed to demonstrate differences in fractures. At Year 1, the incidence of new radiographic vertebral fractures was 2.7% (denosumab) vs. 3.2% (risedronate). The incidence of non-vertebral fractures was 4.3% (denosumab) vs. 2.5% (risedronate). At Year 2, corresponding rates were 4.1% vs. 5.8% for new radiographic vertebral fractures and 5.3% vs. 3.8% for non-vertebral fractures. Most fractures occurred in the subpopulation continuing glucocorticoid therapy.
Paediatric population
In a non-comparative Phase III clinical study, the safety, efficacy, and pharmacokinetics of denosumab were evaluated in children with osteogenesis imperfecta aged 2 to 17 years, of whom 52.3% were male and 88.2% were Caucasian. A total of 153 patients received subcutaneous denosumab injections at a dose of 1 mg/kg body weight up to a maximum of 60 mg every 6 months for 36 months. Sixty patients switched to a dosing regimen every 3 months.
At Month 12, in the group receiving denosumab every 3 months, the least squares (LS) mean change (standard error – SE) in lumbar spine BMD Z-score from baseline was 1.01 (0.12).
The most common adverse reactions reported in the group receiving denosumab every 6 months were: arthralgia (45.8%), limb pain (37.9%), back pain (32.7%), and hypercalciuria (32.0%). Hypercalcemia was reported in both the group receiving denosumab every 6 months (19%) and the group receiving every 3 months (36.7%). Serious adverse events of hypercalcemia were observed in the group receiving denosumab every 3 months (13.3%).
In the extension study (N = 75), serious adverse events of hypercalcemia (18.5%) were observed in the group receiving denosumab every 3 months.
The studies were terminated early due to life-threatening adverse events and hospitalizations resulting from hypercalcemia (see section "Posology and method of administration").
In one multicenter, randomized, double-blind, placebo-controlled parallel-group study involving 24 paediatric patients with glucocorticoid-induced osteoporosis aged 5 to 17 years evaluating change in lumbar spine BMD Z-score from baseline, safety and efficacy were not established; therefore, denosumab should not be used for this indication.
The European Medicines Agency has waived the obligation to submit results of denosumab studies in all subsets of the paediatric population for the treatment of bone loss associated with ablation therapy with sex hormones, and in subsets of the paediatric population under 2 years of age for the treatment of osteoporosis. See section "Posology and method of administration" for information on paediatric use.
Pharmacokinetics
Absorption
Following subcutaneous administration at a dose of 1.0 mg/kg, which approximately corresponds to the approved dose of 60 mg based on AUC, exposure was 78% of that achieved with intravenous administration of the same denosumab dose. After subcutaneous administration of 60 mg denosumab, the maximum serum concentration (Cmax) of denosumab is 6 µg/mL (range 1–17 µg/mL) and is reached at 10 days (range 2–28 days).
Metabolism
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, following breakdown of the drug into small peptides and individual amino acids.
Elimination
After reaching Cmax, serum levels decline over 3 months (range 1.5–4.5 months) due to a half-life of 26 days (range 6–52 days). In 53% of patients, denosumab was undetectable 6 months after administration.
With repeated administration of denosumab at 60 mg subcutaneously every 6 months, no accumulation or changes in pharmacokinetics over time were observed. The formation of anti-denousmab antibody binding did not affect the pharmacokinetics of denosumab, and denosumab pharmacokinetics were similar in women and men. Patient age (28–87 years), race, disease state (bone loss or osteoporosis, prostate cancer or breast cancer) had no significant effect on denosumab pharmacokinetics.
A trend towards increased body weight and decreased denosumab exposure based on AUC and Cmax was observed. However, this trend is not considered clinically significant, as the pharmacodynamic effect is assessed by bone remodeling markers and BMD increases, which were consistent across different weight categories of patients.
Linearity/Non-linearity
In dose-ranging studies, a non-linear relationship between denosumab pharmacokinetics and dose was observed, with decreasing drug clearance as dose or concentration increases, but approximately dose-proportional increases in exposure are observed with doses starting from 60 mg.
Renal impairment
In a study involving 55 patients with various stages of renal impairment, including patients requiring dialysis, the degree of renal impairment did not affect the pharmacokinetics of denosumab.
Hepatic impairment
No specific studies were conducted in patients with hepatic impairment. Generally, monoclonal antibodies are not eliminated via hepatic metabolism; therefore, hepatic impairment is not expected to affect the pharmacokinetics of denosumab.
Paediatric population
The medicinal product Jubonti must not be administered to paediatric patients (see sections "Posology and method of administration" and "Pharmacological properties").
In a Phase III study in children with osteogenesis imperfecta (N = 153), maximum serum concentrations of denosumab were observed on Day 10 in patients across all age groups. In the groups receiving denosumab every 3 months and every 6 months, average minimum residual serum concentrations of denosumab were higher in children aged 11 to 17 years; the lowest average residual concentrations were recorded in children aged 2 to 6 years.
Preclinical data
In single- and repeat-dose toxicity studies in cynomolgus monkeys, doses of denosumab leading to systemic exposure 100–150 times higher than recommended for humans did not affect cardiovascular physiology, male or female reproductive function, or cause specific target organ toxicity.
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 preclinical studies, mice with blocked RANK or RANKL genes demonstrated impaired lymph node formation in fetuses and lack of lactation due to inhibition of mammary gland maturation (lobulo-alveolar development during pregnancy).
In a study in cynomolgus monkeys administered denosumab during a period equivalent to the first trimester of human pregnancy, at AUC levels up to 99 times higher than the human dose (60 mg every 6 months), no adverse effects on maternal or fetal organisms were observed. Lymph nodes of the fetus were not examined in this study.
In another study in cynomolgus monkeys administered denosumab throughout pregnancy at AUC levels 119 times higher than the human dose (60 mg every 6 months), the following were observed: increased stillbirth and postnatal mortality rates; impaired bone growth manifested as reduced bone strength, decreased hematopoiesis, and delayed tooth eruption; absence of peripheral lymph nodes and reduced fetal 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 dentition persisted, and in one animal, minimal to moderate mineralization of multiple tissues was observed (relationship to treatment not clear). There was no evidence of harm to the mother before delivery; adverse reactions in the mother occurred infrequently during delivery. Mammary gland development in monkeys was normal.
In preclinical bone quality studies in monkeys with long-term denosumab treatment, slowed remodeling was associated with improved bone strength and normal bone histological parameters. Serum calcium levels temporarily decreased, and parathyroid hormone levels temporarily increased in ovariectomized monkeys receiving denosumab.
In male mice genetically modified to express huRANKL (knock-in mice) subjected to trans-cortical fracture, denosumab delayed cartilage tissue organization and callus remodeling compared to control, but biomechanical strength was not adversely affected.
Knockout mice (see section "Use in pregnancy or breastfeeding") with blocked RANK or RANKL genes demonstrated reduced body weight, impaired bone growth, growth plate disturbances, and absence of tooth eruption. Impaired bone growth, growth plate disturbances, and absence of tooth eruption were also observed in newborn rats administered RANKL inhibitors, and these changes were partially reversible after discontinuation of RANKL inhibitor.
In newborn mice, high-dose inhibition of RANKL (the target of denosumab) using an osteoprotegerin-Fc fusion protein (OPG Fc) was associated with suppressed bone growth and tooth eruption. These changes were partially reversible in this model when RANKL inhibitor dosing was discontinued. In adolescent primates receiving denosumab at doses 27 and 150 times (10 and 50 mg/kg) higher 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
Jubonti medicinal product is indicated for:
- Treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures. In postmenopausal women, Jubonti medicinal product significantly reduces the risk of vertebral, non-vertebral, and hip fractures.
- Treatment of bone mass loss in men at increased risk of fractures who are receiving hormonal suppression therapy due to prostate cancer (see section "Pharmacodynamics"). In men with prostate cancer receiving hormonal suppression therapy, Jubonti medicinal product significantly reduces the risk of vertebral fractures.
- Treatment of bone mass loss associated with long-term systemic glucocorticoid therapy in adult patients at increased risk of fractures (see section "Pharmacodynamics").
Contraindications
Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Hypocalcemia (see section "Special Warnings and Precautions for Use").
Interaction with Other Medicinal Products and Other Forms of Interaction
An interaction study has shown that denosumab does not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4). This indicates that denosumab has no influence on the pharmacokinetics of medicinal products metabolized by CYP3A4.
There are no clinical data regarding the interaction between denosumab and hormone replacement therapy (estrogens); however, the potential for pharmacodynamic interaction is considered low.
According to study data (in postmenopausal women with osteoporosis transitioning from prior alendronate therapy to denosumab treatment), the pharmacokinetics and pharmacodynamics of denosumab were not altered by prior alendronate use.
Special precautions for use
Traceability
To improve the traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded.
Calcium and vitamin D supplementation
Adequate intake of calcium and vitamin D is essential for all patients.
Precautions for use
Hypocalcemia
It is important to identify patients at risk of developing hypocalcemia. Hypocalcemia should be corrected with adequate calcium and vitamin D supplementation prior to initiating treatment with the medicinal product. Clinical monitoring of serum calcium levels is recommended in patients at risk of developing hypocalcemia during the first two weeks following the initial dose. If symptoms suggestive of hypocalcemia occur in any patient during treatment (see section "Adverse reactions" for symptoms), serum calcium levels should be measured. Patients should be advised to report symptoms indicative of hypocalcemia.
Post-marketing surveillance has reported cases of severe symptomatic hypocalcemia (resulting in hospitalization, life-threatening events, and fatal outcomes), which mostly occurred within the first weeks after initiating treatment, but may also occur later.
Concomitant glucocorticoid therapy is an additional risk factor for hypocalcemia.
Renal impairment
Patients with severe renal impairment (creatinine clearance < 30 mL/min) or those on dialysis have an increased risk of developing hypocalcemia. The risk of hypocalcemia and associated increase in parathyroid hormone levels rises with the severity of renal impairment. Severe and fatal cases have been reported. Adequate calcium and vitamin D intake, along with regular monitoring of serum calcium levels, is particularly important for these patients (see above).
Skin infections
Skin infections (predominantly cellulitis) requiring hospitalization may occur in patients receiving denosumab (see section "Adverse reactions"). Patients should seek immediate medical attention if symptoms of cellulitis develop.
Osteonecrosis of the jaw (ONJ)
Rare cases of ONJ have been reported in patients receiving denosumab for osteoporosis (see section "Adverse reactions").
Patients with non-healing soft tissue lesions in the oral cavity should delay initiation or resumption of treatment for one month.
Prior to denosumab treatment, patients with concomitant risk factors should undergo a dental consultation with appropriate preventive measures and individual benefit-risk assessment.
Factors to consider when evaluating a patient's risk of developing 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 the agent used for treating bone resorption;
- Cancer, concomitant conditions (e.g., anemia, coagulopathies, infections), smoking;
- Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, head and neck radiotherapy;
- Poor oral hygiene, periodontal disease, ill-fitting dentures, dental disease history, invasive dental procedures (e.g., tooth extractions).
All patients should maintain appropriate oral hygiene, undergo regular preventive dental examinations, and promptly report any oral symptoms during denosumab treatment, including tooth mobility, pain or swelling, non-healing wounds, or discharge from lesions.
If invasive dental procedures are deemed necessary after careful consideration, they should not be performed immediately before or right after denosumab administration.
The occurrence of ONJ requires management by a physician in collaboration with a dentist or surgeon experienced in treating ONJ, including clinical evaluation and development of a treatment plan. Temporary discontinuation of treatment should be considered until the jaw osteonecrosis is resolved and risk factors are mitigated.
Osteonecrosis of the external auditory canal
Cases of osteonecrosis of the external auditory canal have been reported during denosumab treatment. Potential risk factors include steroid and chemotherapy use and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered when treating patients with ear conditions, including chronic ear infections, with denosumab.
Atypical femoral fractures
Cases of atypical femoral fractures have been reported in patients treated with denosumab (see section "Adverse reactions"). Atypical femoral fractures may occur with minimal or no trauma in the subtrochanteric or diaphyseal region of the femur. These events are characterized by specific radiographic features. Atypical femoral fractures have also been reported in patients with certain comorbidities (e.g., vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and with certain medications (e.g., bisphosphonates, glucocorticoids, proton pump inhibitors). Such fractures have also occurred without anti-resorptive therapy. Similar fractures reported with bisphosphonate use are often bilateral; therefore, during denosumab therapy, the contralateral femur should be evaluated in patients with confirmed femoral shaft fractures.
Denosumab discontinuation should be considered for patients suspected of having an atypical femoral fracture, based on individual benefit-risk assessment.
Patients receiving denosumab should be informed of the need to report new or unusual pain in the hip, thigh, or groin. Patients with such symptoms should be evaluated for incomplete femoral fractures.
Long-term treatment with anti-resorptive agents
Long-term treatment with anti-resorptive agents (including both denosumab and bisphosphonates) may increase the risk of adverse effects such as osteonecrosis of the jaw and atypical femoral fractures due to substantial suppression of bone remodeling (see section "Dosage and administration").
Discontinuation of treatment
After discontinuation of denosumab, a decrease in bone mineral density is expected (see section "Pharmacological properties"), leading to an increased risk of fractures. Monitoring of bone mineral density is recommended, and alternative treatment should be considered according to clinical guidelines.
Concomitant use with other medicinal products containing denosumab
Patients receiving Jubbonti should not simultaneously receive other medicinal products containing denosumab (for prevention of skeletal-related events in adult patients with bone metastases from solid tumors).
Hypercalcemia in pediatric patients
Jubbonti should not be administered to pediatric patients (under 18 years of age). Severe cases of hypercalcemia have been reported. During clinical trials, complications such as acute renal failure occurred in some pediatric patients.
Precautions regarding excipients
This medicinal product contains 47 mg of sorbitol in 1 mL of solution.
The additive effect of concomitantly 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 of sodium (23 mg) per 60 mg, i.e., essentially sodium-free.
Use during pregnancy or breastfeeding
Pregnancy
Data on the use of denosumab in pregnant women are limited. Animal studies indicate reproductive toxicity (see section "Preclinical data").
Jubbonti is not recommended for use in pregnant women or women of reproductive potential who are not using contraception. Women should be advised to avoid pregnancy during treatment with Jubbonti and for at least 5 months thereafter. Any effects of Jubbonti are likely to be stronger in the second and third trimesters of pregnancy, as monoclonal antibodies are transferred across the placenta in a linear fashion with advancing gestation, with the greatest transfer occurring during the third trimester.
Breastfeeding
It is unknown whether denosumab is excreted in human breast milk. Studies in genetically modified mice with RANKL inactivated by gene knockout (knockout mice) suggest that the absence of RANKL (the target of denosumab, see section "Pharmacodynamics") affects mammary gland development, leading to impaired breastfeeding after delivery (see section "Preclinical data"). The decision to discontinue breastfeeding or to discontinue/abstain from Jubbonti therapy should be made by considering the benefits of breastfeeding for the infant and the benefits of Jubbonti therapy for the mother.
Fertility
There are no data on the effect of denosumab on human fertility. Animal studies do not indicate direct or indirect adverse effects on fertility (see section "Preclinical data").
Ability to influence reaction speed when driving or operating machinery
Jubbonti has no or negligible influence on the ability to drive or operate machinery.
Dosage and Administration
Dosage
The recommended dose is one subcutaneous injection of 60 mg denosumab every 6 months, administered in the thigh, abdomen, or outer aspect of the upper arm.
Patients should receive calcium-containing medications and dietary supplements, as well as vitamin D (see section "Special Instructions").
The optimal total duration of anti-resorptive therapy for osteoporosis (including both denosumab and bisphosphonates) has not been established. The need for continued treatment should be periodically re-evaluated, taking into account the benefits and potential risks of denosumab use for each individual patient, especially after 5 or more years of treatment (see section "Special Instructions").
Elderly patients (aged ≥ 65 years)
No dosage adjustment is required for elderly patients.
Renal impairment
No dosage adjustment is required for patients with renal impairment (see section "Special Instructions" regarding recommendations for monitoring calcium levels).
There are no data available for patients receiving long-term systemic glucocorticoid therapy and with severe renal impairment (GFR < 30 mL/min).
Hepatic impairment
The safety and efficacy of denosumab in patients with hepatic impairment have not been studied (see subsection "Pharmacokinetics").
Administration method
For subcutaneous administration.
Administration of the medicinal product should be performed by a person who has received appropriate training in injection techniques. Instructions for use, handling, and disposal are provided below.
Special precautions for handling and disposal:
- Inspect the solution before administration. Do not use if the solution is cloudy or contains visible particles.
- Do not shake.
- To minimize injection site discomfort, allow the prefilled syringe to warm to room temperature (up to 25 °C) prior to injection, and administer the medicinal product slowly.
- The entire contents of the prefilled syringe must be administered.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Instructions for using Jubonti and administering the injection
Please read and understand this information carefully before administering injections using the prefilled syringe.
The syringe diagram is shown below (Fig. 1).
Fig. 1
| Important information you need to know before administering the Jubonti medicine.
|
| Storage of the Jubonti medicine. |
Preparation for administering Jubonti medicine Step 1. Bring to room temperature Remove the box containing the prefilled syringe from the refrigerator and leave it unopened for approximately 15–30 minutes to reach room temperature (Fig. 2). Fig. 2 Step 2. Prepare supplies Ensure you have the following supplies (Fig. 3), which are not included in the package.
Fig. 3 Step 3. Unpack Open the blister by peeling off the lid (Fig. 4). Remove the prefilled syringe, holding it in the middle as shown. Do not remove the needle cap until you are ready to administer the injection. Fig. 4 Step 4. Perform safety check Look through the viewing window of the prefilled syringe (Fig. 5). The liquid inside should be a clear or slightly opalescent, colorless or slightly yellowish or slightly brown solution. You may see air bubbles in the liquid, which is normal. Do not attempt to remove the air.
In all these cases, contact your doctor, nurse, or pharmacist. Fig. 5 Step 5. Choose the injection site The injection should be given in the front of the thigh or the lower part of the abdomen (Fig. 6), but not within 5 cm around the navel. Do not administer the injection into tender, red, peeling, hard, bruised skin or areas with scars or stretch marks. If your caregiver, doctor, or nurse is administering the injection, they may also give it in the shoulder. Fig. 6 Administering Jubonti medicine Step 6. Clean the injection site Wash your hands with soap and water. Clean the selected injection site with an alcohol swab (Fig. 7). Wait for it to dry before injecting. Do not touch the cleaned area before injection and do not blow air on it. Fig. 7 Step 7. Remove the needle cap Firmly pull straight off to remove the needle cap from the prefilled syringe (Fig. 8). You may see a drop of liquid at the tip of the needle. This is normal. Do not put the needle cap back on. Discard the needle cap. Fig. 8 Step 8. Insert the needle Gently pinch the skin at the injection site and hold it throughout the injection. With the other hand, insert the needle into the skin at an angle of approximately 45 degrees, as shown (Fig. 9). Do not press on the plunger while inserting the needle. Fig. 9 Step 9. Begin the injection Continue holding the skin pinched. Slowly press the plunger fully down. This ensures the full dose is administered (Fig. 10). Fig. 10 Step 10. Complete the injection Ensure the plunger head is between the wings of the safety guard, as shown (Fig. 11). This will ensure the safety guard has been activated and the needle will be covered after the injection is complete. Fig. 11 Step 11. Release the plunger Holding the prefilled syringe at the injection site, slowly release the plunger until the needle is covered by the safety guard (Fig. 12). Remove the prefilled syringe from the injection site and release the pinched skin. Bleeding may occur at the injection site. You may apply a cotton ball or gauze pad to the injection site until bleeding stops. Do not rub the injection site. If needed, cover the injection site with a small adhesive bandage. Fig. 12 After the injection Step 12. Dispose of the prefilled syringe Place the prefilled syringe into a sharps disposal container immediately after use (Fig. 13). Do not throw the prefilled syringe into household waste. Ask your doctor or pharmacist about proper disposal of the sharps container. Local disposal regulations may apply. Fig. 13 |
Children
The medicinal product Jubonti must not be administered to children (under 18 years of age) due to the risk of developing severe hypercalcemia, potential inhibition of bone growth, and delayed tooth eruption (see section "Special precautions" and subsection "Non-clinical findings"). Current data in children aged 2 to 17 years are presented in the subsections "Pharmacodynamics" and "Pharmacokinetics".
Overdose
Data regarding overdose were not obtained during clinical trials. In clinical studies, denosumab was administered at doses up to 180 mg every 4 weeks (cumulative dose of up to 1080 mg over 6 months), and no adverse effects other than those already reported were observed.
Side effects
Summary of safety profile
The most commonly observed side effects with denosumab (reported in more than 1 in 10 patients) are musculoskeletal pain and pain in extremities. Rare cases of cellulitis; uncommon cases of hypocalcemia, hypersensitivity, osteonecrosis of the jaw, and atypical femoral fractures (see sections "Special precautions" and "Side effects": Description of selected adverse reactions) have been observed in patients receiving denosumab.
Tabulated list of adverse reactions
Table 3 describes adverse reactions reported during phase II and III clinical trials in patients with osteoporosis and patients with breast or prostate cancer receiving hormonal therapy, as well as spontaneous reports.
Adverse reactions are classified into frequency categories as follows (see Table 3): very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are listed by MedDRA system organ class in decreasing order of frequency.
Table 3. Adverse reactions in patients with osteoporosis and patients with breast or prostate cancer receiving hormone suppression therapy
| MedDRA System Organ Class |
Frequency Category |
Adverse Reaction |
| Infections and infestations |
Common |
Urinary tract infections |
| Common |
Upper respiratory tract infections |
|
| Uncommon |
Diverticulitis1 |
|
| Uncommon |
Cellulitis1 |
|
| Uncommon |
Ear infections |
|
| Immune system disorders |
Rare |
Drug hypersensitivity1 |
| Rare |
Anaphylactic reaction1 |
|
| Metabolism and nutrition disorders |
Rare |
Hypocalcemia1 |
| Nervous system disorders |
Common |
Sciatica |
| Gastrointestinal disorders |
Common |
Constipation |
| Common |
Abdominal discomfort |
|
| Skin and subcutaneous tissue disorders |
Common |
Rash |
| Common |
Exanthema |
|
| Common |
Exanthema |
|
| Common |
Alopecia |
|
| Uncommon |
Drug-induced exanthema1 |
|
| Very rare |
Allergic vasculitis |
|
| Musculoskeletal and connective tissue disorders |
Very common |
Limb pain |
| Very common |
Musculoskeletal and bone pain1 |
|
| Rare |
Osteonecrosis of the jaw1 |
|
| Rare |
Atypical femoral fractures1 |
|
| Frequency not known |
Osteonecrosis of the external auditory canal2 |
1 See section "Description of selected adverse reactions".
2 See section "Special warnings and precautions for use".
In a pooled analysis of data from all phase II and III placebo-controlled studies, influenza was reported at a rate of 1.2% with denosumab and 0.7% with placebo. However, this imbalance was observed in the pooled analysis of data and was not identified in the stratified analysis.
Description of selected adverse reactions
Hypocalcaemia
In two phase III placebo-controlled clinical studies in postmenopausal women with osteoporosis, approximately 0.05% (2 out of 4050) of patients experienced a reduction in serum calcium levels (less than 1.88 mmol/L) after administration of denosumab. Reduction in serum calcium levels (less than 1.88 mmol/L) was not reported in either of the two phase III placebo-controlled clinical studies in patients receiving hormonal therapy, or in the phase III placebo-controlled clinical study in men with osteoporosis.
Post-marketing surveillance data have reported rare cases of severe symptomatic hypocalcaemia leading to hospitalization, life-threatening events, and fatal outcomes, primarily in patients at increased risk of hypocalcaemia who were receiving denosumab, and predominantly within the first weeks after initiation of therapy.
Cases of clinical manifestations of severe symptomatic hypocalcaemia included QT interval prolongation, tetany, seizures, and mental status changes (see section "Special warnings and precautions for use"). Symptoms of hypocalcaemia observed during clinical studies with denosumab included paresthesia or muscle stiffness, twitching, spasms, and muscle cramps.
Skin infections
In phase III placebo-controlled clinical studies, the overall frequency of skin infections was similar in the placebo and denosumab groups: in postmenopausal women with osteoporosis (placebo [1.2%, 50 out of 4041] vs. denosumab [1.5%, 59 out of 4050]); in men with osteoporosis (placebo [0.8%, 1 out of 120] vs. denosumab [0%, 0 out of 120]); in patients with breast or prostate cancer receiving hormonal therapy (placebo [1.7%, 14 out of 845] vs. denosumab [1.4%, 12 out of 860]). Skin infections leading to hospitalization occurred in 0.1% (3 out of 4041) of postmenopausal women with osteoporosis receiving placebo compared to 0.4% (16 out of 4050) in those receiving denosumab. In most cases, these were cellulitis. Skin infections reported as serious adverse reactions were similar in the placebo group (0.6%, 5 out of 845) and the denosumab group (0.6%, 5 out of 860) in the breast and prostate cancer studies.
Osteonecrosis of the jaw (ONJ)
Cases of ONJ were reported rarely in 16 patients during clinical studies involving patients with osteoporosis and patients with breast or prostate cancer receiving hormonal therapy, totaling 23,148 patients (see section "Special warnings and precautions for use"). Thirteen of these cases occurred in postmenopausal women with osteoporosis during a phase III clinical trial with continued denosumab treatment up to 10 years. The incidence of ONJ was 0.04% at 3 years, 0.06% at 5 years, and 0.44% at 10 years of denosumab treatment. The risk of ONJ increased with longer duration of denosumab treatment.
The risk of ONJ was assessed in a retrospective cohort study involving 76,192 postmenopausal women who newly initiated denosumab treatment. The incidence of ONJ was 0.32% (95% confidence interval [CI]: 0.26; 0.39) in patients treated with denosumab for up to 3 years and 0.51% (95% CI: 0.39; 0.65) in patients treated with denosumab for up to 5 years of follow-up.
Atypical femoral fractures
In patients treated with denosumab as part of clinical trials for osteoporosis treatment, atypical femoral fractures were rarely reported (see section "Special warnings and precautions for use").
Diverticulitis
In phase III of a placebo-controlled clinical study in patients with prostate cancer receiving androgen deprivation therapy, an imbalance was observed regarding diverticulitis as an adverse reaction (1.2% in the denosumab group vs. 0% in the placebo group). The incidence of diverticulitis was comparable between treatment groups in postmenopausal women or men with osteoporosis and in women receiving aromatase inhibitor treatment for non-metastatic breast cancer.
Drug hypersensitivity
Rare cases of drug hypersensitivity, including rash, urticaria, facial swelling, erythema, and anaphylactic reactions, have been observed in patients receiving denosumab during post-marketing surveillance.
Musculoskeletal pain
Post-marketing surveillance reports have described musculoskeletal pain, including severe cases, in patients receiving denosumab. In clinical trials, musculoskeletal pain was observed very commonly in both study groups: denosumab and placebo. Musculoskeletal pain leading to discontinuation of treatment was reported infrequently in the clinical study.
Drug-induced lichenoid eruptions
Drug-induced lichenoid eruptions (e.g., reactions resembling lichen planus) have been observed in patients during the post-marketing period.
Other special patient populations
Paediatric population
Jubonti must not be administered to paediatric patients (under 18 years of age). Severe cases of hypercalcaemia have been reported (see section "Pharmacological properties"). During clinical studies, some patients experienced complications such as acute renal failure.
Renal impairment
In clinical studies, patients with severe renal impairment (creatinine clearance < 30 mL/min) or patients undergoing dialysis are at increased risk of hypocalcaemia in the absence of calcium supplementation. Adequate intake of calcium and vitamin D is important for patients with severe renal impairment or those undergoing dialysis (see section "Special warnings and precautions for use").
Reporting of 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 professionals, pharmacists, as well as patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: 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 the reach of children.
The medicinal product may be stored at a temperature not exceeding 25 °C for up to 30 days, in the original packaging to protect from light.
Incompatibilities
Due to lack of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Packaging
1 mL (60 mg) in a pre-filled syringe with a safety device; 1 syringe per blister pack in a cardboard box.
Prescription status
Prescription only.
Manufacturer
Novartis Pharmaceuticals Manufacturing GmbH.
Manufacturer's address and location of operations
Biochemistrasse 10, Unterlangkampfen, Langkampfen, 6336, Austria.