There is no experience with overdose in clinical studies. Denosumab has been administered in clinical studies using doses up to 180 mg every 4 weeks (cumulative doses up to 1,080 mg over 6 months), and no additional adverse reactions were observed.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Hypocalcaemia.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Summary of the safety profile
The most common side effects with Пролиа (seen in more than one patient in ten) are musculoskeletal pain and pain in the extremity.8 - description of selected adverse reactions) have been observed in patients taking Пролиа.
Tabulated list of adverse reactions
The data in Table 1 below describe adverse reactions reported from Phase II and III clinical trials in patients with osteoporosis and breast or prostate cancer patients receiving hormone ablation; and/or spontaneous reporting.
The following convention has been used for the classification of the adverse reactions (see table 1): very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000) and very rare (< 1/10,000). Within each frequency grouping and system organ class, adverse reactions are presented in order of decreasing seriousness.
Table 1 Adverse reactions reported in patients with osteoporosis and breast or prostate cancer patients receiving hormone ablation
| MedDRA system organ class | Frequency category | Adverse reactions |
| Infections and infestations | Common Common Uncommon Uncommon Uncommon | Urinary tract infection Upper respiratory tract infection Diverticulitis1 Cellulitis1 Ear infection |
| Immune system disorders | Rare Rare | Drug hypersensitivity1 Anaphylactic reaction1 |
| Metabolism and nutrition disorders | Rare | Hypocalcaemia1 |
| Nervous system disorders | Common | Sciatica |
| Gastrointestinal disorders | Common Common | Constipation Abdominal discomfort |
| Skin and subcutaneous tissue disorders | Common Common | Rash Eczema |
| Musculoskeletal and connective tissue disorders | Very common Very common Rare Rare Not Known | Pain in extremity Musculoskeletal pain1 Osteonecrosis of the jaw1 Atypical femoral fractures1 Osteonecrosis of the external auditory canal2 |
1 See section Description of selected adverse reactions
2
In a pooled analysis of data from all phase II and phase III placebo-controlled studies, Influenza-like illness was reported with a crude incidence rate of 1.2% for denosumab and 0.7% for placebo. Although this imbalance was identified via a pooled analysis, it was not identified via a stratified analysis.
Description of selected adverse reactions
Hypocalcaemia
In two phase III placebo-controlled clinical trials in postmenopausal women with osteoporosis, approximately 0.05% (2 out of 4,050) of patients had declines of serum calcium levels (less than 1.88 mmol/l) following Пролиа administration. Declines of serum calcium levels (less than 1.88 mmol/l) were not reported in either the two phase III placebo-controlled clinical trials in patients receiving hormone ablation or the phase III placebo-controlled clinical trial in men with osteoporosis.
In the post-marketing setting, rare cases of severe symptomatic hypocalcaemia have been reported predominantly in patients at increased risk of hypocalcaemia receiving Пролиа, with most cases occurring in the first weeks of initiating therapy. Examples of the clinical manifestations of severe symptomatic hypocalcaemia have included QT interval prolongation, tetany, seizures and altered mental status. Symptoms of hypocalcaemia in denosumab clinical studies included paraesthesias or muscle stiffness, twitching, spasms and muscle cramps.
Skin infections
In phase III placebo-controlled clinical trials, the overall incidence of skin infections was similar in the placebo and the Пролиа groups: in postmenopausal women with osteoporosis (placebo [1.2%, 50 out of 4,041] versus Пролиа [1.5%, 59 out of 4,050]); in men with osteoporosis (placebo [0.8%, 1 out of 120] versus Пролиа [0%, 0 out of 120]); in breast or prostate cancer patients receiving hormone ablation (placebo [1.7%, 14 out of 845] versus Пролиа [1.4%, 12 out of 860]). Skin infections leading to hospitalisation were reported in 0.1% (3 out of 4,041) of postmenopausal women with osteoporosis receiving placebo versus 0.4% (16 out of 4,050) of women receiving Пролиа. These cases were predominantly cellulitis. Skin infections reported as serious adverse reactions were similar in the placebo (0.6%, 5 out of 845) and the Пролиа (0.6%, 5 out of 860) groups in the breast and prostate cancer studies.
Osteonecrosis of the jaw
ONJ has been reported rarely, in 16 patients, in clinical trials in osteoporosis and in breast or prostate cancer patients receiving hormone ablation including a total of 23,148 patients. Thirteen of these ONJ cases occurred in postmenopausal women with osteoporosis during the phase III clinical trial extension following treatment with Пролиа for up to 10 years. Incidence of ONJ was 0.04% at 3 years, 0.06% at 5 years and 0.44% at 10 years of Пролиа treatment. The risk of ONJ increased with duration of exposure to Пролиа.
Atypical fractures of the femur
In the osteoporosis clinical trial program, atypical femoral fractures were reported rarely in patients treated with Пролиа.
Diverticulitis
In a single phase III placebo-controlled clinical trial in patients with prostate cancer receiving ADT an imbalance in diverticulitis adverse events was observed (1.2% denosumab, 0% placebo). The incidence of diverticulitis was comparable between treatment groups in postmenopausal women or men with osteoporosis and in women undergoing aromatase inhibitor therapy for non-metastatic breast cancer.
Drug-related hypersensitivity reactions
In the post-marketing setting, rare events of drug-related hypersensitivity, including rash, urticaria, facial swelling, erythema, and anaphylactic reactions have been reported in patients receiving Пролиа.
Musculoskeletal pain
Musculoskeletal pain, including severe cases, has been reported in patients receiving Пролиа in the post-marketing setting. In clinical trials, musculoskeletal pain was very common in both denosumab and placebo groups. Musculoskeletal pain leading to discontinuation of study treatment was uncommon.
Other special populations
Renal impairment
In clinical studies, patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis were at greater risk of developing hypocalcaemia in the absence of calcium supplementation. Adequate intake of calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: [email protected]
In single and repeated dose toxicity studies in cynomolgus monkeys, denosumab doses resulting in 100 to 150 times greater systemic exposure than the recommended human dose had no impact on cardiovascular physiology, male or female fertility, or produced specific target organ toxicity.
Standard tests to investigate the genotoxicity potential of denosumab have not been evaluated, since such tests are not relevant for this molecule. However, due to its character it is unlikely that denosumab has any potential for genotoxicity.
The carcinogenic potential of denosumab has not been evaluated in long-term animal studies.
In preclinical studies conducted in knockout mice lacking RANK or RANKL, impairment of lymph node formation was observed in the foetus. An absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy) was also observed in knockout mice lacking RANK or RANKL.
In a study of cynomolgus monkeys dosed with denosumab during the period equivalent to the first trimester at AUC exposures up to 99-fold higher than the human dose (60 mg every 6 months), there was no evidence of maternal or foetal harm. In this study, foetal lymph nodes were not examined.
In another study of cynomolgus monkeys dosed with denosumab throughout pregnancy at AUC exposures 119-fold higher than the human dose (60 mg every 6 months), there were increased stillbirths and postnatal mortality; abnormal bone growth resulting in reduced bone strength, reduced haematopoiesis, and tooth malalignment; absence of peripheral lymph nodes; and decreased neonatal growth. A no observed adverse effect level for reproductive effects was not established. Following a 6 month period after birth, bone related changes showed recovery and there was no effect on tooth eruption. However, the effects on lymph nodes and tooth malalignment persisted, and minimal to moderate mineralisation in multiple tissues was seen in one animal (relation to treatment uncertain). There was no evidence of maternal harm prior to labour; adverse maternal effects occurred infrequently during labour. Maternal mammary gland development was normal.
In preclinical bone quality studies in monkeys on long-term denosumab treatment, decreases in bone turnover were associated with improvement in bone strength and normal bone histology. Calcium levels were transiently decreased and parathyroid hormone levels transiently increased in ovariectomised monkeys treated with denosumab.
In male mice genetically engineered to express huRANKL (knock-in mice), which were subjected to a transcortical fracture, denosumab delayed the removal of cartilage and remodelling of the fracture callus compared to control, but biomechanical strength was not adversely affected.
Knockout mice lacking RANK or RANKL exhibited decreased body weight, reduced bone growth and lack of tooth eruption. In neonatal rats, inhibition of RANKL (target of denosumab therapy) with high doses of a construct of osteoprotegerin bound to Fc (OPG-Fc) was associated with inhibition of bone growth and tooth eruption. These changes were partially reversible in this model when dosing with RANKL inhibitors was discontinued. Adolescent primates dosed with denosumab at 27 and 150 times (10 and 50 mg/kg dose) the clinical exposure had abnormal growth plates. Therefore, treatment with denosumab may impair bone growth in children with open growth plates and may inhibit eruption of dentition.
Treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures. In postmenopausal women Пролиа significantly reduces the risk of vertebral, non-vertebral and hip fractures.
Treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. In men with prostate cancer receiving hormone ablation, Пролиа significantly reduces the risk of vertebral fractures.
Pharmacotherapeutic group: Drugs for the treatment of bone diseases - Other drugs affecting bone structure and mineralisation, ATC code: M05BX04
Mechanism of action
Denosumab is a human monoclonal antibody (IgG2) that targets and binds with high affinity and specificity to RANKL, preventing activation of its receptor, RANK, on the surface of osteoclast precursors and osteoclasts. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function and survival, thereby decreasing bone resorption in cortical and trabecular bone.
Pharmacodynamic effects
Пролиа treatment rapidly reduced the rate of bone turnover, reaching a nadir for the bone resorption marker serum type 1 C-telopeptides (CTX) (85% reduction) by 3 days, with reductions maintained over the dosing interval. At the end of each dosing interval, CTX reductions were partially attenuated from maximal reduction of > 87% to approximately > 45% (range 45-80%), reflecting the reversibility of Пролиа's effects on bone remodelling once serum levels diminish. These effects were sustained with continued treatment. Bone turnover markers generally reached pre-treatment levels within 9 months after the last dose. Upon re-initiation, reductions in CTX by denosumab were similar to those observed in patients initiating primary denosumab treatment.
Immunogenicity
In clinical studies, neutralising antibodies have not been observed for denosumab. Using a sensitive immunoassay < 1% of patients treated with denosumab for up to 5 years tested positive for non neutralising binding antibodies with no evidence of altered pharmacokinetics, toxicity, or clinical response.
Clinical efficacy and safety in postmenopausal women with osteoporosis
Efficacy and safety of Пролиа administered once every 6 months for 3 years were investigated in postmenopausal women (7,808 women aged 60-91 years, of which 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 fracture probability of 18.60% (deciles: 7.9-32.4%) for major osteoporotic fracture and 7.22% (deciles: 1.4-14.9%) for hip fracture. Women with other diseases or on therapies that may affect bone were excluded from this study. Women received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily.
Effect on vertebral fractures
Пролиа significantly reduced the risk of new vertebral fractures at 1, 2 and 3 years (p < 0.0001) (see table 2).
Table 2 The effect of Пролиа on the risk of new vertebral fractures
| Proportion of women with fracture (%) | Absolute risk reduction (%) (95% CI) | Relative risk reduction (%) (95% CI) | ||
| Placebo n = 3,906 | Пролиа n = 3,902 | |||
| 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
Пролиа 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 fracture was 1.2% in the placebo group compared to 0.7% in the Пролиа group at 3 years.
In a post-hoc analysis in women > 75 years, a 62% relative risk reduction was observed with Пролиа (1.4% absolute risk reduction, p < 0.01).
Effect on all clinical fractures
Пролиа significantly reduced fractures across all fracture types/groups (see table 3).
Table 3 The effect of Пролиа on the risk of clinical fractures over 3 years
| Proportion of women with fracture (%)+ | Absolute risk reduction (%) (95% CI) | Relative risk reduction (%) (95% CI) | ||
| Placebo n = 3,906 | Пролиа n = 3,902 | |||
| 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 rates based on Kaplan-Meier estimates at 3 years.
1 Includes clinical vertebral fractures and non-vertebral fractures.
2 Excludes those of the vertebrae, skull, facial, mandible, metacarpus, and finger and toe phalanges.
3 Includes pelvis, distal femur, proximal tibia, ribs, proximal humerus, forearm, and hip.
4 Includes clinical vertebral, hip, forearm, and humerus fractures, as defined by the WHO.
In women with baseline femoral neck BMD ≤ -2.5, Пролиа reduced the risk of non-vertebral fracture (35% relative risk reduction, 4.1% absolute risk reduction, p < 0.001, exploratory analysis).
The reduction in the incidence of new vertebral fractures, hip fractures and non-vertebral fractures by Пролиа over 3 years were consistent regardless of the 10-year baseline fracture risk.
Effect on bone mineral density
Пролиа significantly increased BMD at all clinical sites measured, versus placebo at 1, 2 and 3 years. Пролиа 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 hip 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 examining the effects of discontinuation of Пролиа, BMD returned to approximately pre-treatment levels and remained above placebo within 18 months of the last dose. These data indicate that continued treatment with Пролиа is required to maintain the effect of the medicinal product. Re-initiation of Пролиа resulted in gains in BMD similar to those when Пролиа was first administered.
Open-label extension study in the treatment of postmenopausal osteoporosis
A total of 4,550 women (2,343 Пролиа & 2,207 placebo) who missed no more than one dose of investigational product in the pivotal study described above and completed the month 36 study visit agreed to enrol in a 7-year, multinational, multicentre, open-label, single-arm extension study to evaluate the long-term safety and efficacy of Пролиа. All women in the extension study were to receive Пролиа 60 mg every 6 months, as well as daily calcium (at least 1 g) and vitamin D (at least 400 IU). A total of 2,626 subjects (58% of the women included in the extension study i.e. 34% of the women included in the pivotal study) completed the extension study.
In patients treated with Пролиа for up to 10 years, BMD increased from the pivotal study baseline 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. The mean lumbar spine BMD T-score at the end of the study was -1.3 in patients treated for 10 years.
Fracture incidence was evaluated as a safety endpoint but efficacy in fracture prevention cannot be estimated due to high number of discontinuations and open-label design The cumulative incidence of new vertebral and non-vertebral fractures were approximately 6.8% and 13.1% respectively, in patients who remained on denosumab treatment for 10 years (n = 1,278). Patients who did not complete the study for any reason had higher on-treatment fracture rates.
Thirteen adjudicated cases of osteonecrosis of the jaw (ONJ) and two adjudicated cases of atypical fractures of the femur occurred during the extension study.
Clinical efficacy and safety in men with osteoporosis
Efficacy and safety of Пролиа once every 6 months for 1 year were investigated in 242 men aged 31-84 years. Subjects with an eGFR < 30 mL/min/1.73 m2 were excluded from the study. All men received calcium (at least 1,000 mg) and vitamin D (at least 800 IU) supplementation daily.
The primary efficacy variable was percent change in lumbar spine BMD, fracture efficacy was not evaluated. Пролиа significantly increased BMD at all clinical sites measured, relative to placebo at 12 months: 4.8% at lumbar spine, 2.0% at total hip, 2.2% at femoral neck, 2.3% at hip trochanter, and 0.9% at distal 1/3 radius (all p < 0.05). Пролиа increased lumbar spine BMD from baseline in 94.7% of men at 1 year. Significant increases in BMD at lumbar spine, total hip, femoral neck and hip trochanter were observed by 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 with low bone mass who were either naïve to osteoporosis therapies or had transitioned from previous alendronate therapy following 1-3 years treatment with Пролиа. Fifty nine women participated in the bone biopsy sub-study at month 24 (n = 41) and/or month 84 (n = 22) of the extension study in postmenopausal women with osteoporosis. Bone histology was also evaluated in 17 men with osteoporosis following 1 year treatment with Пролиа. Bone biopsy results showed bone of normal architecture and quality with no evidence of mineralisation defects, woven bone or marrow fibrosis. Histomorphometry findings in the extension study in postmenopausal women with osteoporosis showed that the antiresorptive effects of Пролиа, as measured by activation frequency and bone formation rates, were maintained over time.
Clinical efficacy and safety in patients with bone loss associated with androgen deprivation
Efficacy and safety of Пролиа once every 6 months for 3 years were investigated in men with histologically confirmed non-metastatic prostate cancer receiving ADT (1,468 men aged 48-97 years) who were at increased risk of fracture (defined as > 70 years, or < 70 years with a BMD T-score at the lumbar spine, total hip, or femoral neck < -1.0 or a history of an osteoporotic fracture.) All men received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily.
Пролиа significantly increased BMD at all clinical sites measured, relative to treatment with placebo at 3 years: 7.9% at the lumbar spine, 5.7% at the total hip, 4.9% at the femoral neck, 6.9% at the hip 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 were observed at the lumbar spine, total hip, femoral neck and the hip trochanter 1 month after the initial dose.
Пролиа demonstrated a significant relative risk reduction of new vertebral fractures: 85% (1.6% absolute risk reduction) at 1 year, 69% (2.2% absolute risk reduction) at 2 years and 62% (2.4% absolute risk reduction) at 3 years (all p < 0.01).
Clinical efficacy and safety in patients with bone loss associated with adjuvant aromatase inhibitor therapy
Efficacy and safety of Пролиа once every 6 months for 2 years was investigated in women with non-metastatic breast cancer (252 women aged 35-84 years) and baseline BMD T-scores between -1.0 to -2.5 at the lumbar spine, total hip or femoral neck. All women received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily.
The primary efficacy variable was percent change in lumbar spine BMD, fracture efficacy was not evaluated. Пролиа significantly increased BMD at all clinical sites measured, relative to treatment with placebo at 2 years: 7.6% at lumbar spine, 4.7% at total hip, 3.6% at femoral neck, 5.9% at hip trochanter, 6.1% at distal 1/3 radius and 4.2% at total body (all p < 0.0001).
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Пролиа in all subsets of the paediatric population in the treatment of bone loss associated with sex hormone ablative therapy, and in subsets of the paediatric population below the age of 2 in the treatment of osteoporosis.
Absorption
Following subcutaneous administration of a 1.0 mg/kg dose, which approximates the approved 60 mg dose, exposure based on AUC was 78% as compared to intravenous administration at the same dose level. For a 60 mg subcutaneous dose, maximum serum denosumab concentrations (Cmax) of 6 mcg/mL (range 1-17 μg/mL) occurred in 10 days (range 2-28 days).
Biotransformation
Denosumab is composed solely of amino acids and carbohydrates as native immunoglobulin and is unlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids.
Elimination
After Cmax, serum levels declined with a half-life of 26 days (range 6-52 days) over a period of 3 months (range 1.5-4.5 months). Fifty-three percent (53%) of patients had no measurable amounts of denosumab detected at 6 months post-dose.
No accumulation or change in denosumab pharmacokinetics with time was observed upon subcutaneous multiple-dosing of 60 mg once every 6 months. Denosumab pharmacokinetics was not affected by the formation of binding antibodies to denosumab and was similar in men and women. Age (28-87 years), race and disease state (low bone mass or osteoporosis; prostate or breast cancer) do not appear to significantly affect the pharmacokinetics of denosumab.
A trend was observed between higher body weight and lower exposure based on AUC and Cmax. However, the trend is not considered clinically important, since pharmacodynamic effects based on bone turnover markers and BMD increases were consistent across a wide range of body weight.
Linearity/non-linearity
In dose ranging studies, denosumab exhibited non-linear, dose-dependent pharmacokinetics, with lower clearance at higher doses or concentrations, but approximately dose-proportional increases in exposures for doses of 60 mg and greater.
Renal impairment
In a study of 55 patients with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics of denosumab.
Hepatic impairment
No specific study in patients with hepatic impairment was performed. In general, monoclonal antibodies are not eliminated via hepatic metabolic mechanisms. The pharmacokinetics of denosumab is not expected to be affected by hepatic impairment.
Paediatric population
The pharmacokinetic profile in paediatric populations has not been assessed.
Calcium and Vitamin D supplementation
Adequate intake of calcium and vitamin D is important in all patients.
Precautions for use
Hypocalcaemia
It is important to identify patients at risk for hypocalcaemia. Hypocalcaemia must be corrected by adequate intake of calcium and vitamin D before initiating therapy. Clinical monitoring of calcium levels is recommended before each dose and, in patients predisposed to hypocalcaemia within two weeks after the initial dose. If any patient presents with suspected symptoms of hypocalcaemia during treatment calcium levels should be measured. Patients should be encouraged to report symptoms indicative of hypocalcaemia.
In the post-marketing setting, severe symptomatic hypocalcaemia has been reported , with most cases occurring in the first weeks of initiating therapy, but it can occur later.
Skin infections
Patients receiving Пролиа may develop skin infections (predominantly cellulitis) leading to hospitalisation. Patients should be advised to seek prompt medical attention if they develop signs or symptoms of cellulitis.
Osteonecrosis of the Jaw (ONJ)
ONJ has been reported rarely in patients receiving Пролиа for osteoporosis.
The start of treatment/new treatment course should be delayed in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with denosumab in patients with concomitant risk factors.
The following risk factors should be considered when evaluating a patient's risk of developing ONJ:
- potency of the medicinal product that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy.
- cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.
- concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck.
- poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures e.g. tooth extractions.
All patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling or non-healing of sores or discharge during treatment with denosumab. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to Пролиа administration.
The management plan of the patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.
Osteonecrosis of the external auditory canal
Osteonecrosis of the external auditory canal has been reported with denosumab. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving denosumab who present with ear symptoms including chronic ear infections.
Atypical fractures of the femur
Atypical femoral fractures have been reported in patients receiving denosumab. Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur. Specific radiographic findings characterise these events. Atypical femoral fractures have also been reported in patients with certain co-morbid conditions (e.g. vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and with use of certain pharmaceutical agents (e.g. bisphosphonates, glucocorticoids, proton pump inhibitors). These events have also occurred without antiresorptive therapy. Similar fractures reported in association with bisphosphonates are often bilateral; therefore the contralateral femur should be examined in denosumab-treated patients who have sustained a femoral shaft fracture. Discontinuation of Пролиа therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient based on an individual benefit-risk assessment. During denosumab treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture.
Long-term antiresorptive treatment
Long-term antiresorptive treatment (including both denosumab and bisphosphonates) may contribute to an increased risk for adverse outcomes such as osteonecrosis of the jaw and atypical femur fractures due to significant suppression of bone remodelling.
Concomitant treatment with other denosumab-containing medicinal products
Patients being treated with Пролиа should not be treated concomitantly with other denosumab-containing medicinal products (for prevention of skeletal related events in adults with bone metastases from solid tumours).
Renal impairment
Patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis are at greater risk of developing hypocalcaemia. The risks of developing hypocalcaemia and accompanying parathyroid hormone elevations increase with increasing degree of renal impairment. Adequate intake of calcium, vitamin D and regular monitoring of calcium is especially important in these patients, see above.
Dry natural rubber
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions.
Warnings for excipients
This medicinal product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicinal product.
This medicinal product contains less than 1 mmol sodium (23 mg) per 60 mg i.e. essentially 'sodium-free'.
Пролиа has no or negligible influence on the ability to drive and use machines.
Posology
The recommended dose of Пролиа is 60 mg administered as a single subcutaneous injection once every 6 months into the thigh, abdomen or upper arm.
Patients must be adequately supplemented with calcium and vitamin D.
Patients treated with Пролиа should be given the package leaflet and the patient reminder card.
The optimal total duration of antiresorptive treatment for osteoporosis (including both denosumab and bisphosphonates) has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of denosumab on an individual patient basis, particularly after 5 or more years of use.
Renal impairment
).
Hepatic impairment
The safety and efficacy of denosumab have not been studied in patients with hepatic impairment.
Elderly (age > 65)
No dose adjustment is required in elderly patients.
Paediatric population
Пролиа is not recommended in paediatric patients (age < 18) as the safety and efficacy of Пролиа in these patients have not been established. Inhibition of RANK/RANK ligand (RANKL) in animal studies has been coupled to inhibition of bone growth and lack of tooth eruption.
Method of administration
For subcutaneous use.
Administration should be performed by an individual who has been adequately trained in injection techniques.
- Before administration, the solution should be inspected. Do not inject the solution if it contains particles, or is cloudy or discoloured.
- Do not shake.
- To avoid discomfort at the site of injection, allow the pre-filled syringe to reach room temperature (up to 25°C) before injecting and inject slowly.
- Inject the entire contents of the pre-filled syringe.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
