Prolia 60 mg Solution for subcutaneous injection.

Treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures. In postmenopausal women PROLIA u00ae significantly reduces the risk of vertebral, non-vertebral and hip fractures. Treatment of bone loss 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 u00ae significantly reduces the incidence of vertebral fractures. Treatment of bone loss associated with long-term systemic glucocorticoid therapy in adult patients at increased risk of fracture (see section 5.1).

Posology
The recommended dose is 60 mg denosumab 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). 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 (see section 4.4).
Elderly (age u2265 65)
No dose adjustment is required in elderly patients.
Renal impairment
No dose adjustment is required in patients with renal impairment (see section 4.4 for recommendations relating to monitoring of calcium). No data is available in patients with long-term systemic glucocorticoid therapy and severe renal impairment (GFR < 30 ml/min).
Hepatic impairment
The safety and efficacy of denosumab have not been studied in patients with hepatic impairment (see section 5.2).
Paediatric population
PROLIA u00ae should not be used in children aged < 18 years because of safety concerns of serious hypercalcaemia, and potential inhibition of bone growth and lack of tooth eruption (see sections 4.4 and 5.3). Currently available data for children aged 2 to 17 years are described in sections 5.1 and 5.2.
Method of administration
For subcutaneous use. Administration should be performed by an individual who has been adequately trained in injection techniques. The instructions for use, handling and disposal are given in section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Hypocalcaemia (see section 4.4).

Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
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 (see section 4.8 for symptoms) calcium levels should be measured. Patients should be encouraged to report symptoms indicative of hypocalcaemia. In the post-marketing setting, severe symptomatic hypocalcaemia (resulting in hospitalisation, life-threatening events, and fatal cases) have been reported. While most cases occurred in the first few weeks initiating therapy, it has also occurred later. Concomitant glucocorticoid treatment is an additional risk factor for hypocalcaemia.
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. Severe and fatal cases have been reported. Adequate intake of calcium, vitamin D and regular monitoring of calcium is especially important in these patients, see above.
Skin infections
Patients receiving denosumab 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)
ONJ has been reported rarely in patients receiving PROLIA u00ae for osteoporosis (see section 4.8). 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 patientu2019s 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).

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

Pregnancy
There are no or limited amount of data from the use of denosumab in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). PROLIA u00ae is not recommended for use in pregnant women and women of child-bearing potential not using contraception. Women should be advised not to become pregnant during and for at least 5 months after treatment with PROLIA u00ae. Any effects of PROLIA u00ae are likely to be greater during the second and third trimesters of pregnancy since monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester.
Breastfeeding
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 u201cknockout mouseu201d), 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 breastfeeding or to abstain from therapy with PROLIA u00ae should be made, taking into account the benefit of breastfeeding to the newborn/infant and the benefit of PROLIA u00ae 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).

PROLIA u00ae has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile
The most common side effects with denosumab (seen in more than one patient in ten) are musculoskeletal pain and pain in the extremity. Uncommon cases of cellulitis, rare cases of hypocalcaemia, hypersensitivity, osteonecrosis of the jaw and atypical femoral fractures (see sections 4.4 and 4.8 - description of selected adverse reactions) have been observed in patients taking PROLIA u00ae.
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 (u2265 1/10), common (u2265 1/100 to < 1/10), uncommon (u2265 1/1 000 to < 1/100), rare (u2265 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.

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.