Table of Contents
1. Name of the medicinal product
2. Qualitative and quantitative composition
3. Pharmaceutical form
4. Clinical particulars
4.1 Therapeutic indications
4.2 Posology and method of administration
4.3 Contraindications
4.4 Special warnings and precautions for use
4.5 Interaction with other medicinal products and other forms of interaction
4.6 Fertility, pregnancy and lactation
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
4.9 Overdose
5. Pharmacological properties
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
5.3 Preclinical safety data
6. Pharmaceutical particulars
6.1 List of excipients
6.2 Incompatibilities
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
6.6 Special precautions for disposal and other handling
7. Marketing authorisation holder
8. Marketing authorisation number(s)
9. Date of first authorisation/renewal of the authorisation
10. Date of revision of the text

1. Name of the medicinal product
 Prolia® 60 mg solution for injection in a pre-filled syringe
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.

Excipient with known effect:

Each ml of solution contains 47 mg sorbitol (E420) (see section 4.4).

For the 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 and men at increased risk of fractures. In postmenopausal women 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 upper 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 ≥ 65)

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 listed in section 6.1.
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

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.

In the post-marketing setting, severe symptomatic hypocalcaemia has been reported (see section 4.8).

Skin Infections

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)

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 eva luation.

Atypical fractures of the femur

Atypical femoral fractures have been reported in patients receiving Prolia (see section 4.8). Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur. Specific radiographic findings characterize these events. Atypical femoral fractures have also been reported in patients with certain comorbid conditions (e.g. vitamin D deficiency, rheumatoid arthiritis, 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 Prolia-treated patients who have sustained a femoral shaft fracture. Discontinuation of Prolia therapy in patients suspected to have an atypical femur fracture should be considered pending eva luation of the patient based on an individual benefit risk assessment. During Prolia treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with such symptoms should be eva luated for an incomplete femoral fracture.

Dry natural rubber

The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions.

Concomitant treatment with other denosumab-containing medicinal products

Patients being treated with Prolia 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).

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
 In an interaction study, Prolia did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4). This indicates that Prolia should not alter the pharmacokinetics of drugs metabolized by CYP3A4.

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 Fertility, pregnancy and lactation
 Pregnancy

There are no adequate data from the use of Prolia in pregnant women. Reproductive toxicity was shown in a study of cynomolgus monkeys, dosed throughout pregnancy with denosumab at AUC exposures 119-fold higher than the human dose (see section 5.3)..

Prolia is not recommended for use in pregnant women.

Women who become pregnant during Prolia treatment are encouraged to enrol in Amgen's Pregnancy Surveillance programme. Contact details are provided in section 6 of the Package Leaflet – Information for the user.

Breast-feeding

It is unknown whether denosumab is excreted in human milk. 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) 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.

Women who are nursing during Prolia treatment are encouraged to enrol in Amgen's Lactation Surveillance Program. Contact details are provided in section 6 of the Package Leaflet – Information for the user.

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
 Summary of the safety profile
The overall safety profile of Prolia was similar in patients with osteoporosis and in breast or prostate cancer patients receiving hormone ablation in five Phase III placebo-controlled clinical trials.
Uncommon cases of cellulitis; rare cases of hypocalcaemia, hypersensitivity, osteonecrosis of the jaw and atypical femoral fractures (see sections 4.4 and section 4.8 - description of selected adverse reactions) have been observed with Prolia.
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) based on crude incidence rates. Within each frequency grouping and system organ class, undesirable effects 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

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 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 Prolia 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 in patients at increased risk of hypocalcaemia receiving Prolia.

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]); in men with osteoporosis (placebo [0.8%, 1 out of 120] versus Prolia [0%, 0 out of 120]) 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 clinical trials in osteoporosis and in breast or prostate cancer patients receiving hormone ablation the (12347 patients, 9912 treated ≥ 1 year), ONJ was reported rarely with Prolia (see section 4.4).

Atypical fractures of the femur

In the osteoporosis clinical trial program, atypical femoral fractures were reported rarely in patients treated with Prolia (see section 4.4).

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 or men 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 or men with osteoporosis and in women undergoing aromatase inhibitor therapy for nonmetastatic 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 Prolia.

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).

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

Tel: Freephone 0808 100 3352

Website: www.mhra.gov.uk/yellowcard

Ireland

Pharmacovigilance Section

Irish Medicines Board

Kevin O'Malley House

Earlsfort Centre

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6767836

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie
4.9 Overdose
 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.
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 ≥ 87% to approximately ≥ 45% (range 45-80%), reflecting the reversibility of Prolia'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 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 preva lent 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

Prolia significantly reduced the risk of new vertebral fractures at 1, 2 and 3 years (p < 0.0001) (see table 2).
Table 2 The effec

*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

+ 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, Prolia 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 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.

Open-label Extension Study in the Treatment of Postmenopausal Osteoporosis

A total of 4550 patients (2343 Prolia & 2207 placebo) who missed no more than one dose of investigational product in the pivotal study described above and completed all study visits agreed to enroll in a 7-year, multinational, multicenter, open label, single-arm extension study to eva luate the long-term safety and efficacy of Prolia. At month 24 of the extension study, after 5 years of denosumab treatment, the long-term group increased BMD by 13.8% at the lumbar spine, 7.0% at the total hip, 6.2% at the femoral neck and 9.7% at the trochanter from the original pivotal study baseline. Fracture incidence was eva luated as a safety endpoint: continued Prolia treatment maintained a low incidence of new vertebral and non-vertebral fractures in years 4 and 5 (annualised rate of new vertebral fracture was 1.4% in both years 4 and 5, while 1.4% and 1.1% of patients had a nonvertebral fracture in years 4 and 5 respectively). Three cases of osteonecrosis of the jaw (ONJ) occurred during the first 25 months in the study, two cases in the de novo treatment group and one case in the long term treatment group, all cases resolved.

Treatment of osteoporosis in men

Efficacy and safety of Prolia 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 eva luated. Prolia 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). Prolia 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

Bone histology was eva luated 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 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: 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 -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 eva luated. 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).

Paediatric population

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 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. See section 4.2 for information on paediatric use.
5.2 Pharmacokinetic properties
 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 μg/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.

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 fertility, or produced specific target organ toxicity.

Standard tests to investigate the genotoxicity potential of denosumab have not been eva luated, 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 eva luated 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 (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. 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.
6. Pharmaceutical particulars
  
6.1 List of excipients
 Acetic acid, glacial*

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
 In the absence of compatibility studies, 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 medicinal 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
0. Date of revision of the text
 June 2014
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu