Method of administration
or subcutaneous use. Administration should be performed by an individual who has been adequately trained in injection techniques.
Healthcare Professionals
Summary Product Information
| Route of Administration | Dosage Form / Strength | Composition |
|---|---|---|
| S.C. | 60mg/ml pre-filled syringe |
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 (Chinese hamster ovary cells) by recombinant DNA technology |
Indications And Clinical Use
Treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures.
In postmenopausal women denosumab 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, Denosumab significantly reduces the risk of vertebral fractures.
Treatment of bone loss associated with long-term systemic glucocorticoid therapy in adult patients at increased risk of fracture.
Dosage And Administration
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.
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.
| Use in the elderly (>65years): | No dosage adjustment is necessary for the elderly. |
|---|---|
| Use in renal impairment: |
No dose adjustment is required in patients with renal impairment. No data is available in patients with long-term systemic glucocorticoid therapy and severe renal impairment (GFR < 30 mL/min). |
| Use in Hepatic impairment: | The safety and efficacy of denosumab have not been studied in patients with hepatic impairment |
| Pediatric population | Denosumab is not recommended in paediatric patients (age < 18) as the safety and efficacy of denosumab 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 |
Action and Clinical Pharmacology
Pharmacodynamics
Mechanism of Action
Denosumab binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone
Pharmacodynamics Effect
Denosumab 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 Denosumab’s effects on bone remodeling 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 and Antibody Formation
Denosumab-binding antibodies reported in <1% of patients receiving denosumab for periods of up to 5 years. Denosumab-neutralizing antibodies not reported to date, and antibody formation does not appear to affect denosumab pharmacokinetics, toxicity, or efficacy.
Pharmacokinetics
Bioavailability
Approximately 61–62% following sub-Q administration.
Prolonged absorption phase; median time to peak serum concentrations after single 60-mg sub-Q dose is 10 days (range 3–21 days).
No accumulation observed at dosage of 60 mg every 6 months. At dosage of 120 mg every 4 weeks, accumulation is up to 2.8-fold and steady-state concentrations achieved by 6 months. At dosage of 120 mg every 4 weeks, with additional 120-mg dose on day 8 and day 15 during first month of therapy, steady state achieved in 3 months.
Characterization of other monoclonal antibodies indicates that absorption is probably mediated by the lymphatic system.
Onset
Studies in postmenopausal women with osteoporosis indicate reduction in bone resorption biomarkers observed within 3 days after a 60-mg dose; maximal reductions observed by 1 month.
Duration
Studies in postmenopausal women with osteoporosis indicate effect on bone resorption markers partially attenuated at the end of each 6-month dosing interval. Bone mineral density (BMD) and levels of bone resorption markers return to baseline within 12 months after discontinuing denosumab.
Distribution (Extent)
Not known whether distributed into human milk. Distributed into milk in monkeys (concentrations up to 0.5% of serum concentrations at up to 1 month after the last dose).
Contraindications
- Hypocalcemia (correct pre-existing hypocalcemia prior to initiating denosumab).
- History of clinically important hypersensitivity (e.g., systemic hypersensitivity) to denosumab or any component in the formulation.
- Denosumab also contraindicated in pregnant women.
Warnings and Precautions
Hypocalcemia and Mineral Metabolism
Hypocalcemia may be exacerbated by the use of Prolia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Prolia
Serious Infections
In a clinical trial of over 7800 women with postmenopausal osteoporosis, serious infections leading to hospitalization were reported more frequently in the Prolia group than in the placebo group
Dermatologic Adverse Reactions
In a large clinical trial of over 7800 women with postmenopausal osteoporosis, epidermal and dermal adverse events such as dermatitis, eczema, and rashes occurred at a significantly higher rate in the Prolia group compared to the placebo group
Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing. ONJ has been reported in patients receiving denosumab
Suppression of Bone Turnover
In clinical trials in women with postmenopausal osteoporosis, treatment with Prolia resulted in significant suppression of bone remodeling as evidenced by markers of bone turnover and bone histomorphometry.
Special Populations
Pregnancy & Lactation
Based on animal findings and mechanism of action, denosumab may cause fetal harm if administered to pregnant women. Confirm pregnancy status prior to initiation of therapy in women with reproductive potential. Not known whether denosumab distributes into human milk or affects breast-fed infants or milk production. Distributes into milk in monkeys in concentrations up to 0.5% of serum concentrations at up to one month after the last dose.
Adverse Reactions
Patients with osteoporosis: Back pain, extremity pain, musculoskeletal pain, hypercholesterolemia, cystitis (postmenopausal women) or back pain, arthralgia, nasopharyngitis (men).
Patients with glucocorticoid-induced osteoporosis: Back pain, hypertension, bronchitis and headache.
Patients with bone loss associated with androgen deprivation or aromatase inhibitor therapy: Arthralgia, back pain.
Patients with bone metastases: Fatigue/asthenia, hypophosphatemia, nausea, dyspnea, diarrhea, hypocalcemia, cough, headache.
Patients with multiple myeloma: Diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory infection, rash, headache, severe hypophosphatemia.
Patients with giant cell tumor of bone: Arthralgia, headache, nausea, back pain, fatigue, extremity pain, severe hypophosphatemia.
Drug Interactions
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).
Overdosage
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.
Storage and Stability
Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the container in the outer carton in order to protect from light.
