1. Name Of The Medicinal Product
Prolia®
2. Qualitative And Quantitative Composition
Each pre-filled syringe contains 60 mg of denosumab in 1 ml of solution (60 mg/ml).
Denosumab is a human monoclonal IgG2 antibody produced in a mammalian cell line (CHO) by recombinant DNA technology.
Excipients known to have a recognised action:
Each ml of solution contains 47 mg sorbitol (E420) (see section 4.4).
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Solution for injection (injection).
Clear, colourless to slightly yellow solution.
4. Clinical Particulars
4.1 Therapeutic Indications
Treatment of osteoporosis in postmenopausal women at increased risk of fractures. Prolia 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 (see section 5.1). In men with prostate cancer receiving hormone ablation, Prolia significantly reduces the risk of vertebral fractures.
4.2 Posology And Method Of Administration
Posology
The recommended dose of Prolia is 60 mg administered as a single subcutaneous injection once every 6 months into the thigh, abdomen or back of arm.
Patients must be adequately supplemented with calcium and vitamin D (see section 4.4).
Patients with renal impairment
No dose adjustment is required in patients with renal impairment (see sections 4.4 and 5.2).
Patients with hepatic impairment
The safety and efficacy of denosumab have not been studied in patients with hepatic impairment (see section 5.2).
Elderly Patients (age
No dose adjustment is required in elderly patients.
Paediatric population
Prolia is not recommended in paediatric patients (age < 18) as the safety and efficacy of Prolia 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 (see also section 5.3).
Method of administration
Administration should be performed by an individual who has been adequately trained in injection techniques. For subcutaneous use.
The instructions for use, handling and disposal are given in section 6.6.
4.3 Contraindications
- Hypocalcaemia (see section 4.4).
- Hypersensitivity to the active substance or to any of the excipients.
4.4 Special Warnings And Precautions For Use
Calcium and Vitamin D supplementation
Adequate intake of calcium and vitamin D is important in all patients.
Precautions for use
Hypocalcaemia must be corrected by adequate intake of calcium and vitamin D before initiating therapy. Patients with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis are at greater risk of developing hypocalcaemia. Clinical monitoring of calcium levels is recommended for patients predisposed to hypocalcaemia.
Patients receiving Prolia may develop skin infections (predominantly cellulitis) leading to hospitalisation (see section 4.8). Patients should be advised to seek prompt medical attention if they develop signs or symptoms of cellulitis.
Osteonecrosis of the jaw (ONJ) has been reported in patients treated with denosumab or bisphosphonates, another class of anti-resorptive agents. Most cases have been in cancer patients; however some have occurred in patients with osteoporosis.
ONJ has been reported rarely in clinical studies in patients receiving denosumab at a dose of 60 mg every 6 months for osteoporosis.
There have been reports of ONJ in clinical studies in patients with advanced cancer treated with denosumab at the studied dose of 120 mg administered monthly. Known risk factors for ONJ include a diagnosis of cancer with bone lesions, concomitant therapies (e.g., chemotherapy, antiangiogenic biologics, corticosteroids, radiotherapy to head and neck), poor oral hygiene, dental extractions, and co-morbid disorders (e.g., pre-existing dental disease, anaemia, coagulopathy, infection) and previous treatment with bisphosphonates.
A dental examination with appropriate preventive dentistry should be considered prior to treatment with Prolia in patients with concomitant risk factors. While on treatment, these patients should avoid invasive dental procedures if possible.
Good oral hygiene practices should be maintained during treatment with Prolia. For patients who develop ONJ while on Prolia therapy, dental surgery may exacerbate the condition. If ONJ occurs during treatment with Prolia, use clinical judgment and guide the management plan of each patient based on individual benefit/risk evaluation.
The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions.
Warnings for Excipients
Patients with rare hereditary problems of fructose intolerance should not use Prolia.
This medicinal product contains less than 1 mmol sodium (23 mg) per 60 mg i.e. essentially 'sodium-free'.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
No interaction studies have been performed.
There are no clinical data on the co-administration of denosumab and hormone replacement therapy (oestrogen), however the potential for a pharmacodynamic interaction is considered to be low.
In postmenopausal women with osteoporosis the pharmacokinetics and pharmacodynamics of denosumab were not altered by previous alendronate therapy, based on data from a transition study (alendronate to denosumab).
4.6 Pregnancy And Lactation
Pregnancy
There are no adequate data from the use of Prolia in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). In genetically engineered mice in which RANKL has been turned off by gene removal (a “knockout mouse”), studies suggest absence of RANKL (the target of denosumab – see section 5.1) could interfere with the development of lymph nodes in the foetus and could lead to postnatal impairment of dentition and bone growth (see section 5.3). Prolia is not recommended for use in pregnant women.
Breast-feeding
It is unknown whether denosumab is excreted in human milk. Knockout mouse studies suggest absence of RANKL during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum (see section 5.3). A decision on whether to abstain from breast-feeding or to abstain from therapy with Prolia should be made, taking into account the benefit of breast-feeding to the newborn/infant and the benefit of Prolia therapy to the woman.
Fertility
No data are available on the effect of denosumab on human fertility. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).
4.7 Effects On Ability To Drive And Use Machines
Prolia has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable Effects
Tabulated summary of adverse reactions
The safety of Prolia was evaluated in 10,534 postmenopausal women with osteoporosis (up to 5 years duration) and breast or prostate cancer patients receiving hormone ablation in phase II and III placebo-controlled clinical trials.
The following convention has been used for the classification of the adverse reactions reported in these phase II and III clinical studies (see table 1): very common (
Table 1 Adverse reactions reported in phase II and phase III placebo-controlled clinical studies in women with postmenopausal osteoporosis and breast or prostate cancer patients receiving hormone ablation
MedDRA system organ class
|
Frequency category
|
Undesirable effect
|
Infections and infestations
|
Common
|
Urinary tract infection
|
Common
|
Upper respiratory tract infection
|
|
Uncommon
|
Diverticulitis1
|
|
Uncommon
|
Cellulitis1
|
|
Uncommon
|
Ear infection
|
|
Metabolism and nutrition disorders
|
Very rare
|
Hypocalcaemia1
|
Nervous system disorders
|
Common
|
Sciatica
|
Eye disorders
|
Common
|
Cataracts1
|
Gastrointestinal disorders
|
Common
|
Constipation
|
Skin and subcutaneous tissue disorders
|
Common
|
Rash
|
Uncommon
|
Eczema
|
|
Musculoskeletal and connective tissue disorders
|
Common
|
Pain in extremity
|
1 See section Description of selected adverse reactions
In a pooled analysis of data from all phase II and phase III placebo controlled studies, Influenza-like illness was reported with an event rate of 0.006 per subject year for denosumab and 0.003 per subject year for placebo. Although this imbalance was identified via the pooled analysis, it was not identified via the stratified analysis which was used to calculate the adverse reactions reported in table 1. There were no individual studies in which this imbalance was observed.
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 Prolia administration. Declines of serum calcium levels (less than 1.88 mmol/l) were not reported in the two phase III placebo-controlled clinical trials in patients receiving hormone ablation.
Skin infections
In phase III placebo-controlled clinical trials, the overall incidence of skin infections was similar in the placebo and the Prolia groups in postmenopausal women with osteoporosis (placebo [1.2%, 50 out of 4,041] versus Prolia [1.5%, 59 out of 4,050]) and in breast or prostate cancer patients receiving hormone ablation (placebo [1.7%, 14 out of 845] versus Prolia [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 Prolia. 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 Prolia (0.6%, 5 out of 860) groups in the breast and prostate cancer studies.
Osteonecrosis of the jaw
In the osteoporosis clinical trial program (8710 patients treated
Cataracts
In a single phase III placebo-controlled clinical trial in patients with prostate cancer receiving androgen deprivation therapy (ADT) an imbalance in cataract adverse events was observed (4.7% denosumab, 1.2% placebo). No imbalance was observed in postmenopausal women with osteoporosis or in women undergoing aromatase inhibitor therapy for nonmetastatic breast cancer.
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 with osteoporosis and in women undergoing aromatase inhibitor therapy for nonmetastatic breast cancer.
Other special populations
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 (see section 4.4).
4.9 Overdose
There is no experience with overdose in clinical studies. Prolia 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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Drugs for the treatment of bone diseases – Other drugs affecting bone structure and mineralization, 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
Prolia 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
Immunogenicity
In clinical studies, neutralising antibodies have not been observed for Prolia. 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.
Treatment of osteoporosis in postmenopausal women
Efficacy and safety of Prolia administered once every 6 months for 3 years were investigated in post-menopausal 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
Effect on vertebral fractures
Prolia 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 Prolia 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
|
Prolia
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
Prolia 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 Prolia group at 3 years.
In a post-hoc analysis in women > 75 years, a 62% relative risk reduction was observed with Prolia (1.4% absolute risk reduction, p < 0.01).
Effect on all clinical fractures
Prolia significantly reduced fractures across all fracture types/groups (see table 3).
Table 3 The effect of Prolia 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
|
Prolia
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 (secondary endpoint included in multiplicity adjustment), ***p
+ 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
The reduction in the incidence of new vertebral fractures, hip fractures and non-vertebral fractures by Prolia over 3 years were consistent regardless of the 10-year baseline fracture risk.
Effect on bone mineral density
Prolia significantly increased BMD at all clinical sites measured, versus placebo at 1, 2 and 3 years. Prolia 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 Prolia, 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 Prolia is required to maintain the effect of the medicinal product. Re-initiation of Prolia resulted in gains in BMD similar to those when Prolia was first administered.
Bone histology
Bone histology was evaluated in 62 postmenopausal women with osteoporosis or with low bone mass who had transitioned from previous alendronate therapy following 1-3 years treatment with Prolia. Bone biopsy results from both studies showed bone of normal architecture and quality with no evidence of mineralisation defects, woven bone or marrow fibrosis.
Treatment of bone loss associated with androgen deprivation
Efficacy and safety of Prolia 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.
Prolia 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.
Prolia demonstrated a significant relative risk reduction of new vertebral fractures at 1 year: 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).
Treatment of bone loss associated with adjuvant aromatase inhibitor therapy
Efficacy and safety of Prolia 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
The primary efficacy variable was percent change in lumbar spine BMD, fracture efficacy was not evaluated. Prolia 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).
The European Medicines Agency has waived the obligation to submit the results of studies with Prolia in all subsets of the paediatric population in the treatment of menopausal and other perimenopausal disorders, and in the treatment of bone loss associated with sex hormone ablative therapy. See 4.2 for information on paediatric use.
5.2 Pharmacokinetic Properties
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 μg/ml (range 1-17 μg/ml) occurred in 10 days (range 2max, 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. In dose ranging studies, denosumab exhibited nonlinear, 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.
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.
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.
Special populations
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.
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.
The pharmacokinetic profile in paediatric populations has not been assessed.
5.3 Preclinical Safety Data
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 reproduction, 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.
At exposures up to 100-fold higher than the human exposure, denosumab showed no evidence of impaired female fertility and harm to the foetus in cynomolgus monkeys in development toxicity 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 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 (see section 4.6) 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. The reversibility of the effects of OPG-Fc has not been examined. 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.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Glacial acetic acid*
Sodium hydroxide (for pH adjustment)*
Sorbitol (E420)
Polysorbate 20
Water for injections
* Acetate buffer is formed by mixing acetic acid with sodium hydroxide
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products.
6.3 Shelf Life
3 years
Prolia may be stored at room temperature (up to 25°C) for up to 30 days in the original container. Once removed from the refrigerator, Prolia must be used within this 30 day period.
6.4 Special Precautions For Storage
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Keep the pre-filled syringe in the outer carton in order to protect from light.
Do not shake excessively.
6.5 Nature And Contents Of Container
One ml solution in a single use pre-filled syringe made from type I glass with stainless steel 27 gauge needle, with or without needle guard.
The needle cover of the pre-filled syringe contains dry natural rubber, which is a derivative of latex (see section 4.4).
Pack size of one, presented in blistered (pre-filled syringe with or without a needle guard) or unblistered packaging (pre-filled syringe only).
6.6 Special Precautions For Disposal And Other Handling
Before administration, the Prolia solution should be inspected. Do not inject the solution if it contains particles, or is cloudy or discoloured. Do not shake excessively. 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. Dispose of any medicinal product remaining in the pre-filled syringe.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
Amgen Europe B.V.
Minervum 7061
NL-4817 ZK Breda
The Netherlands
8. Marketing Authorisation Number(S)
EU/1/10/618/001
EU/1/10/618/002
EU/1/10/618/003
9. Date Of First Authorisation/Renewal Of The Authorisation
26 May 2010
10. Date Of Revision Of The Text
20 September 2010
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
