Prolia

Denosumab.

Each pre-filled syringe contains 60 mg of denosumab in 1.0 mL solution (60 mg/mL).
Excipients/Inactive Ingredients: Acetate, Sodium hydroxide, Sorbitol, Polysorbate 20, Water for injection.

PHARMACOLOGY: Pharmacodynamics: Mechanism of action: Denosumab is a human monoclonal antibody (IgG2) that targets and binds with high affinity and specificity to RANKL preventing RANKL from activating its only receptor, RANK, on the surface of osteoclasts and their precursors, independent of bone surface. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival. Denosumab therefore reduces bone resorption and increases bone mass and strength in both cortical and trabecular bone.
Pharmacodynamic effects: In clinical studies, treatment with 60 mg of denosumab resulted in rapid reduction in the bone resorption marker serum type 1 C-telopeptides (CTX) within 6 hours of subcutaneous administration (by approximately 70%) with reductions of approximately 85% occurring by 3 days. CTX reductions were maintained over the 6-months 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 remodelling once serum levels diminish. These effects were sustained with continued treatment. Consistent with the physiological coupling of bone formation and resorption in skeletal remodelling, reductions in bone formation markers (e.g. bone specific alkaline phosphatase [BSAP] and serum N-terminal propeptide of type I collagen [P1NP]) were observed beginning 1 month after the first dose of denosumab.
Bone turnover markers (bone resorption and formation markers) generally reached pre-treatment levels within 9 months after the last 60 mg subcutaneous dose. Upon re-initiation, the degree of inhibition of CTX by denosumab was similar to that observed in patients initiating denosumab treatment.
In a clinical study of postmenopausal women with low bone mass (N = 504) who were previously treated with alendronate for a median duration of 3 years, those transitioning to receive denosumab experienced additional reductions in serum CTX, compared with women who remained on alendronate. In this study the changes in serum calcium were similar between the two groups.
Immunogenicity: Denosumab is a human monoclonal antibody; as with all therapeutic proteins, there is a theoretical potential for immunogenicity. More than 13,000 patients were screened for binding antibodies using a sensitive electrochemiluminescent bridging immunoassay. Less than 1% of patients treated with denosumab for up to 5 years tested positive (including pre-existing, transient, and developing antibodies). The patients that tested positive for binding antibodies were further evaluated for neutralising antibodies using a chemiluminescent cell-based in vitro biological assay and none of them tested positive. No evidence of altered pharmacokinetic profile, toxicity profile, or clinical response was associated with binding antibody development.
Clinical Studies: OSTEOPOROSIS: Treatment of Postmenopausal Osteoporosis: FREEDOM, a 3-year, randomised, double-blind, placebo-controlled, multinational study that demonstrated that denosumab was effective compared to placebo in reducing new vertebral, non-vertebral and hip fractures in postmenopausal women with osteoporosis. 7,808 women aged 60-91 years were enrolled of which 23.6% had prevalent vertebral fractures.
Women received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily.
Effect on vertebral fractures: Denosumab significantly reduced the risk of new vertebral fractures (primary endpoint) by 68% (risk ratio: 0.32; p <0.0001) over 3 years. The 3-year fracture rates for new vertebral fractures were 7.2% in the placebo group and 2.3% in the PROLIA group (unadjusted absolute risk reduction of 4.8%).
Effect on all clinical fractures: Denosumab significantly decreased the risk of non-vertebral fractures (secondary endpoint) by 20% (hazard ratio: 0.80; p = 0.0106) over 3 years. Three-year non-vertebral fracture rates were 8.0% in the placebo group to 6.5% in the denosumab group (unadjusted absolute risk reduction of 1.5%).
Effect on hip fractures: Denosumab significantly decreased the risk of hip fractures (secondary endpoint) by 40% (hazard ratio: 0.60; p = 0.0362) over 3 years. Three-year hip fracture rates were 1.2% in the placebo group and 0.7% in the denosumab group (unadjusted absolute risk reduction of 0.5%).
Effect on bone mineral density (BMD): Denosumab significantly increased BMD at all clinical sites measured, relative to treatment with placebo at 1, 2 and 3 years. Denosumab 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. Increases in BMD at lumbar spine, total hip and hip trochanter were observed as early as 1 month after the initial dose. Denosumab increased lumbar spine BMD from baseline in 96% of postmenopausal women at 3 years. Consistent effects on BMD were observed at the lumbar spine regardless of baseline age, race, weight/BMI, BMD and bone turnover level.
Open-label extension study in the treatment of postmenopausal osteoporosis: 4,550 patients who completed the study (N = 7,808) enrolled in a 7-year, open-label, single-arm extension study to evaluate the long-term safety and efficacy of denosumab. All patients in the extension study received denosumab every 6 months as a single 60 mg SC dose, as well as daily calcium (at least 1 g) and vitamin D (at least 400 IU).
Denosumab treatment maintained a low incidence of new vertebral and non-vertebral fractures through to year 7 (7% of patients had at least one new vertebral fracture, 9.3% of patients had at least one non-vertebral fracture).
Denosumab treatment increase BMD at the lumbar spine (10.8%), total hip (3.4%), femoral neck (3.8%) and trochanter (5.1%) from the extension baseline through 7 years. Percent increase in BMD from the original FREEDOM study baseline (i.e, after 10 years of treatment) in the long-term group was 21.7% at the lumbar spine, 9.2% at the total hip, 9.0% at the femoral neck and 13% at the trochanter.
Comparative clinical data vs alendronate in the treatment of postmenopausal women with low bone mass: In two randomised, double-blind, active-controlled studies, one in treatment-naïve women and another in women previously treated with alendronate, denosumab showed significantly greater increases in BMD and reductions in bone turnover markers (e.g. serum CTX), compared to alendronate.
Consistently greater increases in BMD were seen at the lumbar spine, total hip, femoral neck, hip trochanter, and distal ¹/₃ radius in women treated with denosumab, compared to those who continued to receive alendronate therapy (all p < 0.05).
Bone histology: Histology assessments showed bone of normal architecture and quality, as well as the expected decrease in bone turnover relative to placebo treatment. There was no evidence of mineralisation defects, woven bone or marrow fibrosis.
Treatment of osteoporosis in men: The efficacy and safety of PROLIA in the treatment of men with osteoporosis was demonstrated in a 1-year, randomised, double-blind, placebo-controlled, multinational study of men with low bone mass, who had a baseline BMD T-score between -2.0 and -3.5 at the lumbar spine or femoral neck. Men with a BMD T-score between -1.0 and -3.5 at the lumbar spine or femoral neck and with history of prior fragility fracture were also enrolled. Men with other diseases (such as rheumatoid arthritis, osteogenesis imperfecta, and Paget's disease) or on therapies that may affect bone were excluded from this study.
The 242 men enrolled in the study ranged in age from 31 to 84 years and were randomised to receive SC injections of either placebo (n = 121) or PROLIA 60 mg (n = 121) once every 6 months. Patients also received at least 1,000 mg calcium and at least 800 IU vitamin D supplementation daily. The primary efficacy variable was percent change in lumbar spine BMD at 1 year. Secondary efficacy variables included percent change in total hip, hip trochanter, femoral neck, and distal ¹/₃ radius BMD at 1 year, and change in CTX at day 15.
Treatment with PROLIA significantly increased BMD from baseline at the lumbar spine and all measured skeletal sites (proximal femur, distal radius) at 1 year. PROLIA increased lumbar spine BMD by 4.8%, total hip BMD by 2.0%, hip trochanter by 2.3%, femoral neck BMD by 2.2%, distal ¹/₃ radius BMD by 0.9%, relative to placebo.
Increases in BMD at lumbar spine, total hip, and hip trochanter were observed as early as 6 months. PROLIA increased lumbar spine BMD from baseline in 94.7% of men at 1 year.
Consistent effects on BMD were observed at the lumbar spine regardless of baseline age, race, weight/body mass index (BMI), BMD, and level of bone turnover.
Bone histology and histomorphometry: A total of 29 transiliac crest bone biopsy specimens were obtained from men with osteoporosis at 12 months (17 specimens in PROLIA group, 12 specimens in placebo group). Qualitative histology assessments showed normal architecture and quality with no evidence of mineralisation defects, woven bone, or marrow fibrosis in patients treated with PROLIA.
TREATMENT OF BONE LOSS ASSOCIATED WITH HORMONE ABLATION: Treatment of bone loss associated with androgen deprivation therapy for prostate cancer: The efficacy and safety of denosumab in the treatment of bone loss associated with androgen deprivation was assessed in a 3-year randomised, double-blind, placebo-controlled, multinational study of 1,468 men with non-metastatic prostate cancer aged 48-97 years. Men less than 70 years of age also had either a BMD T-score at the lumbar spine, total hip, or femoral neck < -1.0 or a history of an osteoporotic fracture. Significant increases in BMD were observed at the lumbar spine, total hip, femoral neck and the hip trochanter as early as 1 month after the initial dose. Denosumab increased lumbar spine BMD by 7.9%, total hip BMD by 5.7%, femoral neck BMD by 4.9%, hip trochanter BMD by 6.9%, distal ¹/₃ radius BMD by 6.9%, and total body BMD by 4.7% over 3 years, relative to placebo (p < 0.0001). Consistent effects on BMD were observed at the lumbar spine regardless of age, race, geographical region, weight/BMI, BMD, bone turnover level; duration of androgen deprivation and presence of vertebral fracture at baseline.
Denosumab significantly decreased the risk of new vertebral fractures by 62% (hazard ratio: 0.38; p < 0.0063) over 3 years. Denosumab also reduced the subject incidence of more than one osteoporotic fracture at any site by 72% relative to placebo over 3 years (placebo 2.5% vs. denosumab 0.7%, p=0.0063).
Treatment of bone loss in women undergoing aromatase inhibitor therapy for breast cancer: The efficacy and safety of denosumab in the treatment of bone loss associated with adjuvant aromatase inhibitor therapy was assessed in a 2-year, randomised, double-blind, placebo-controlled multinational study of 252 women with non-metastatic breast cancer aged 35-84 years. Women had baseline BMD T-scores between -1.0 to -2.5 at the lumbar spine, total hip or femoral neck. Women received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily.
Denosumab significantly increased BMD at all clinical sites measured, relative to treatment with placebo at 2 years: 7.6% at the lumbar spine, 4.7% at the total hip, 3.6% at the femoral neck, 5.9% at the hip trochanter, 6.1% at the distal ¹/₃ radius and 4.2% at the total body. Significant increases in BMD were observed at the lumbar spine as early as 1 month after the initial dose. Consistent effects on BMD were observed at the lumbar spine regardless of baseline age, duration of aromatase inhibitor therapy, weight/BMI, prior chemotherapy, prior selective estrogen receptor modulator (SERM) use, and time since menopause.
Treatment of Glucocorticoid-induced Osteoporosis: The efficacy and safety of PROLIA in the treatment of glucocorticoid-induced osteoporosis were demonstrated in a 1-year, randomized, multicenter, double-blind, double-dummy, parallel-group, active-controlled study of 795 patients (70% women and 30% men) aged 20 to 94 years (mean age of 63.1 years) treated with ≥ 7.5 mg daily oral prednisone (or equivalent).
Two subpopulations were studied: glucocorticoid-continuing (≥ 7.5 mg daily prednisone or its equivalent for ≥ 3 months prior to study enrollment and planning to continue treatment for a total of at least 6 months; n = 505) and glucocorticoid-initiating (≥ 7.5 mg daily prednisone or its equivalent for < 3 months prior to study enrollment and planning to continue treatment for a total of at least 6 months; n = 290). Within each subpopulation, randomization was stratified by gender and patients were randomized (1:1) to receive either PROLIA 60 mg subcutaneously once every 6 months (n = 398) or oral risedronate 5 mg once daily (active-control) (n = 397). All patients were to receive at least 1,000 mg calcium and 800 IU vitamin D supplementation daily.
Enrolled patients < 50 years of age were required to have a history of osteoporotic fracture. Enrolled patients ≥ 50 years of age who were in the glucocorticoid-continuing subpopulation were required to have a baseline BMD T-score of ≤ -2.0 at the lumbar spine, total hip, or femoral neck; or a BMD T-score ≤ -1.0 at the lumbar spine, total hip, or femoral neck and a history of osteoporotic fracture.
Effect on Bone Mineral Density (BMD): In the glucocorticoid-continuing subpopulation, PROLIA demonstrated a significantly greater increase in lumbar spine BMD compared to risedronate at 1 year (PROLIA 4.4%, risedronate 2.3%) with a treatment difference of 2.2% (p < 0.001). In the glucocorticoid-initiating subpopulation, PROLIA demonstrated a significantly greater increase in lumbar spine BMD compared to risedronate at 1 year (PROLIA 3.8%, risedronate 0.8%) with a treatment difference of 2.9% (p < 0.001).
Consistent effects on lumbar spine BMD were observed regardless of gender; race; geographic region; menopausal status; and baseline age, lumbar spine BMD T-score, and glucocorticoid dose within each subpopulation.
In addition, significant differences between treatment groups in the mean percent increase in BMD from baseline at 1 year were also observed at the total hip, femoral neck, and hip trochanter (both subpopulations), and distal ¹/₃ radius (glucocorticoid-continuing subpopulation only).
Bone Histology: Bone biopsy specimens were obtained from 17 patients (6 in the PROLIA treatment group and 11 in the risedronate treatment group). Qualitative histology assessments showed normal architecture and quality with no evidence of mineralization defects, woven bone, or marrow fibrosis in patients treated with PROLIA.
Pharmacokinetics: Following subcutaneous administration, denosumab displayed non-linear pharmacokinetics with dose over a wide dose range, and dose-proportional increases in exposure for doses of 60 mg (or 1 mg/kg) and higher.
Absorption: Following a 60 mg subcutaneous dose of denosumab, bioavailability was 61% and maximum serum denosumab concentrations (C_max) of 6 μg/mL (range 1-17 μg/mL) occurred in 10 days (range 2-28 days). After C_max, 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 of patients had no measurable amounts of denosumab detected at 6 months post-dose.
Distribution: No accumulation or change in denosumab pharmacokinetics with time was observed upon multiple-dosing of 60 mg subcutaneously once every 6 months.
Denosumab pharmacokinetics were not affected by the formation of binding antibodies and were similar in men and women.
Metabolism: Denosumab is composed solely of amino acids and carbohydrates as native immunoglobulin. Based on nonclinical data, denosumab metabolism is expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids.
Elimination: Denosumab is composed solely of amino acids and carbohydrates as native immunoglobulin and is not expected to be eliminated via hepatic metabolic mechanisms (e.g. cytochrome P450 (CYP) enzymes). Based on nonclinical data, its elimination is expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids.
Drug interactions: In a study of 17 postmenopausal women with osteoporosis, midazolam (2 mg oral) was administered two weeks after a single dose of denosumab (60 mg subcutaneously), which corresponds to time of maximal pharmacodynamic effects of denosumab. Denosumab did not affect the pharmacokinetics of midazolam, which is metabolised by cytochrome P450 3A4 (CYP3A4). This indicates that denosumab should not alter the PK of drugs metabolised by CYP3A4.
The pharmacokinetics and pharmacodynamics of denosumab were similar in patients receiving hormone ablation for prostate or breast cancer.
The pharmacokinetics and pharmacodynamics of denosumab were similar in patients with glucocorticoid-induced osteoporosis.
Special patient populations: Elderly (greater than or equal to 65 years of age): Age was not found to be a significant factor on denosumab pharmacokinetics in a population pharmacokinetic analysis of patients ranging in age from 28 to 87 years of age.
Children and adolescents (up to 18 years of age): No pharmacokinetic data are available in paediatric patients.
Race: The pharmacokinetics of denosumab were not affected by race in postmenopausal women or in breast cancer patients undergoing hormone ablation.
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 and pharmacodynamics of denosumab; therefore dose adjustment for renal impairment is not necessary.
Hepatic impairment: No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of denosumab.
Toxicology: Preclinical safety data: Carcinogenicity: The carcinogenic potential of denosumab has not been evaluated in long-term animal studies.
Mutagenicity: The genotoxic potential of denosumab has not been evaluated.
Reproductive toxicology: Fertility: Denosumab had no effect on female fertility or male reproductive organs in monkeys at AUC exposures that were 100- to 150-fold higher than the human exposure at 60 mg administered subcutaneously once every 6 months.
Animal pharmacology: Long-term treatment (16 months) of aged ovariectomized monkeys with denosumab at doses of 25 or 50 mg/kg SC once monthly was associated with significant gains in the mass, density (BMD), and strength of cancellous and cortical bone. Bone tissue was normal with no evidence of mineralisation defects, accumulation of osteoid or woven bone.
Denosumab is a potent inhibitor of bone resorption via inhibition of RANK ligand.
Tissue distribution studies indicated that denosumab does not bind to tissues known for expression of other member of the TNF superfamily, including TNF-related apoptosis-inducing ligand (TRAIL).
Transition from 6-months treatment with alendronate to denosumab did not cause any meaningful decreases of serum calcium or have detrimental effects on bone quality and strength. Bone strength parameters at these sites were maintained or improved with transition relative to continuous treatment with alendronate. Bone strength and reduction in bone resorption at all skeletal sites were maintained or improved in monkeys switched from alendronate to denosumab.
Adolescent primates dosed with denosumab at 150 times (50 mg/kg dose) and 27 times (10 mg/kg dose) the area under the curve (AUC) exposure in adult humans dosed at 60 mg subcutaneously every 6 months had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab.
In neonatal cynomolgus monkeys exposed in utero to denosumab at 50 mg/kg, there was increased postnatal mortality; abnormal bone growth resulting in reduced bone strength, reduced haematopoiesis, and tooth malalignment; absence of peripheral lymph nodes; and decreased neonatal growth. Following a recovery period from birth to 6 months of age, the effects on bone returned to normal. Minimal to moderate mineralisation in multiple tissues was seen in one recovery animal. Maternal mammary gland development was normal.
Since the biological activity of denosumab in animals is specific to nonhuman primates evaluation of genetically engineered (knockout) mice or use of other inhibitors of the RANK/RANKL pathway, namely OPG-Fc provided additional information on the pharmacodynamic properties of denosumab. Knockout mice lacking RANK or RANKL: had an absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy); exhibited impairment of lymph node formation; and exhibited reduced bone growth and lack of tooth eruption. Similar phenotypic changes were seen in a corroborative study in 2-week old rats given OPG-Fc. These changes were partially reversible in this model when dosing with the RANKL inhibitors was discontinued.

Postmenopausal Osteoporosis: PROLIA is indicated for the treatment of osteoporosis in postmenopausal women at increased risk of fractures. In postmenopausal women with osteoporosis, PROLIA increases bone mineral density (BMD) and reduces the incidence of hip, vertebral and non-vertebral fractures.
Bone Loss in Patients Undergoing Hormone Ablation for Cancer: PROLIA is indicated for the treatment of bone loss in patients undergoing hormone ablation for prostate or breast cancer at increased risk of fractures. In patients with prostate cancer, PROLIA reduces the incidence of vertebral fractures.
Male Osteoporosis: PROLIA is indicated for the treatment of osteoporosis in men at the increased risk of fractures.
Glucocorticoid-Induced Osteoporosis: PROLIA is indicated for the treatment of bone loss associated with long-term systemic glucocorticoid therapy in adult patients at increased risk of fracture.

Administration: Administration should be performed by an individual who has been adequately trained in injection techniques.
Dosage: The recommended dose of PROLIA is a single subcutaneous injection of 60 mg administered once every 6 months.
Patients should receive adequate calcium and vitamin D supplements whilst undergoing treatment.
Populations: Children: PROLIA is not recommended in paediatric patients as the safety and efficacy of PROLIA have not been established in the paediatric age group. In animal studies, inhibition of RANK/RANK ligand (RANKL) with a construct of osteoprotegerin bound to Fc (OPG-Fc) has been coupled to inhibition of bone growth and lack of tooth eruption (see PHARMACOLOGY: Toxicology: Preclinical safety data under Actions). Therefore, treatment with denosumab may impair bone growth in children with open growth plates and may inhibit eruption of dentition.
Elderly: Based on the available safety and efficacy data in the elderly, no dosage adjustment is required (see PHARMACOLOGY: Pharmacokinetics: Special patient populations under Actions).
Renal impairment: Based on the available safety and efficacy data in the elderly, no dosage adjustment is required in patients with renal impairment (see PHARMACOLOGY: Pharmacokinetics: Special patient populations under Actions).
Patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis are at greater risk of developing hypocalcaemia. Adequate intake of calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis.
Hepatic impairment: The safety and efficacy of PROLIA have not been studied in patients with hepatic impairment.

No data from clinical trials are available regarding overdosage of PROLIA.
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 effects were observed.

PROLIA is contraindicated in patients who have a history of hypersensitivity reactions to denosumab and/or its excipients. Hypocalcaemia.

Adequate intake of calcium and vitamin D is important in all patients.
Hypocalcaemia must be corrected prior to initiating therapy with denosumab. In patients predisposed to hypocalcaemia, clinical monitoring of calcium levels is recommended during treatment, especially in the first few weeks of initiating therapy (see Adverse Reactions).
In clinical trials in women with postmenopausal osteoporosis, skin infections leading to hospitalisation were reported more frequently in the denosumab (0.4%) versus the placebo (0.1%) groups (see Adverse Reactions). These cases were predominantly cellulitis. The overall incidence of skin infections was similar between the placebo and denosumab groups. Patients should be advised to seek prompt medical attention if they develop signs or symptoms of cellulitis.
Cases of osteonecrosis of the jaw (ONJ) were reported predominantly in patients with advanced cancer receiving 120 mg every 4 weeks. ONJ was reported rarely in patients with osteoporosis receiving 60 mg every 6 months (see Adverse Reactions).
Poor oral hygiene and invasive dental procedures (e.g. tooth extraction) were risk factors for ONJ in patients receiving PROLIA in clinical trials. The risk of ONJ may increase with duration of exposure to PROLIA.
It is important to evaluate patients for risk factors for ONJ before starting treatment. If risk factors are identified, a dental examination with appropriate preventive dentistry is recommended prior to treatment with PROLIA. Good oral hygiene practices should be maintained during treatment with PROLIA.
Avoid invasive dental procedures during treatment with PROLIA. For patients in whom invasive dental procedures cannot be avoided, the clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
Patients who are suspected of having or who develop ONJ while on PROLIA should receive care by a dentist or an oral surgeon. In patients who develop ONJ during treatment with PROLIA, a temporary interruption of treatment should be considered based on individual risk/benefit assessment until the condition resolves.
Atypical femoral fractures have been reported in patients receiving PROLIA. Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur and may be bilateral. Specific radiographic findings characterise these events. Atypical femoral fractures have also been reported in patients with certain comorbid 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. During PROLIA 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 and the contralateral femur should also be examined.
PROLIA contains the same active ingredient (denosumab) found in XGEVA. Patients receiving PROLIA should not receive XGEVA.
Multiple vertebral fractures (MVF) may occur following discontinuation of treatment with PROLIA, particularly in patients with a history of vertebral fracture.
Advise patients not to interrupt PROLIA therapy without their physician's advice. Evaluate the individual benefit/risk before discontinuing treatment with PROLIA.
If PROLIA treatment is discontinued, consider transitioning to an alternative antiresorptive therapy.
Effects on ability to drive and use machine: No studies on the effect on the ability to drive or use heavy machinery have been performed in patients receiving denosumab.
Use in Children: Hypercalcemia in Pediatric Patients with Osteogenesis Imperfecta: Prolia is not indicated for use in pediatric patients. In clinical trials, hypercalcemia has been reported in pediatric patients with osteogenesis imperfecta treated with denosumab. Some cases required hospitalization.
Denosumab is not indicated for use in pediatric patients.
In clinical trials, hypercalcemia has been reported very commonly in pediatric patients with osteogenesis imperfecta treated with denosumab. Some cases required hospitalization and were complicated by acute renal injury.

Pregnancy: There is no adequate data in pregnant women. PROLIA is not recommended for use in pregnant women.
At AUC exposures up to 100-fold higher than the human exposure (60 mg every 6 months), denosumab showed no evidence of impaired fertility in cynomolgus monkeys (see PHARMACOLOGY: Toxicology: Preclinical safety data under Actions).
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. There was no evidence of maternal harm prior to labour; adverse maternal effects occurred infrequently during labour. Maternal mammary gland development was normal.
Studies in knockout mice suggest absence of RANKL could interfere with maturation of the maternal mammary gland leading to impaired lactation post-partum.
Lactation: It is not known if denosumab is excreted in human milk. Because denosumab has the potential to cause adverse reactions in breast-feeding infants, a decision should be made whether to discontinue breast-feeding or discontinue the drug.

Clinical trial data: NOTE: Frequency is provided by CIOMS category [eg, Very common (≥ 10%), Common (≥ 1% and < 10%), Uncommon (≥ 0.1% and < 1%), Rare (≥ 0.01% and < 0.1%), Very rare (< 0.01%), and Not known (cannot be estimated from the available data)]. (See Table 1.)

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Postmarketing data: See Table 2.

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PROLIA (60 mg subcutaneously) did not affect the pharmacokinetics of midazolam, which is metabolised by cytochrome P450 3A4 (CYP3A4), indicating that it should not affect the pharmacokinetics of drugs metabolised by this enzyme (see PHARMACOLOGY: Pharmacokinetics under Actions). Concomitant use with immunosuppressive agents may increase the risk of serious infections. Risks and benefits should be assessed to guide use of PROLIA in patients receiving immunosuppressive agents.

Incompatibilities: This medicinal product must not be mixed with other medicinal products.
Instructions for use/handling: Persons sensitive to latex should not handle the needle cap on the single-use pre-filled syringe, which contains dry natural rubber (a derivative of latex).
Before administration, the PROLIA solution should be inspected for particulate matter and discolouration. The solution should not be used if 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. Dispose of any medicinal product remaining in the pre-filled syringe.
Instruction for self-administration by subcutaneous injection is included in the package leaflet.
Any unused product or waste material should be disposed of in accordance with local requirements.
Not all presentations are available in every country.

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 direct light.
Do not shake.
If removed from the refrigerator, PROLIA should be kept at controlled room temperature (store below 25°C or 30°C) in the original carton and must be used within 30 days.

Drug product with same active ingredient: Advise patient that denosumab is also marketed as XGEVA and if taking PROLIA, they should not receive XGEVA.
Hypersensitivity: Advise patient to seek prompt medical attention if signs or symptoms of hypersensitivity reactions occurs. Advise patient who have had signs or symptoms of systemic hypersensitivity reactions that they should not receive denosumab (PROLIA or XGEVA).
Hypocalcaemia: Adequately supplement patients with calcium and vitamin D and instruct them on the importance of maintaining serum calcium levels while receiving PROLIA. Advise patients to seek prompt medical attention if they develop signs or symptoms of hypocalcaemia.
Osteonecrosis of the jaw: Advise patients to maintain good oral hygiene during treatment with PROLIA and to inform their dentist prior to dental procedures that they are receiving PROLIA. Patients should inform their physician or dentist if they experience persistent pain and/or slow healing of the mouth or jaw after dental surgery.
Atypical subtrochanteric and diaphyseal femoral fractures: Advise patients to report new or unusual thigh, hip or groin pain.
Multiple Vertebral Fractures (MVF) following discontinuation of PROLIA treatment: Advise patients not to interrupt PROLIA therapy without talking to their physician.
Serious infections: Advise patients to seek prompt medical attention if they develop signs or symptoms of infections, including cellulitis.
Dermatologic reactions: Advise patients to seek prompt medical attention if they develop signs or symptoms of dermatological reactions (dermatitis, rashes, and eczema).
Musculoskeletal pain: Inform patients that severe bone, joint, and/or muscle pain have been reported in patients taking PROLIA. Patients should report severe symptoms if they develop.
Embryo-Fetal toxicity: Pregnancy: Advise patients that PROLIA is contraindicated in women who are pregnant and may cause fetal harm.
Nursing mothers: Advise patients that because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from PROLIA, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Schedule of administration: If a dose of PROLIA is missed, administer the injection as soon as convenient. Thereafter, schedule injections every 6 months from the date of the last injection.
INSTRUCTIONS FOR INJECTING WITH THE PROLIA PRE-FILLED SYRINGE WITH A MANUAL NEEDLE GUARD: IMPORTANT: In order to minimize accidental needle sticks, the PROLIA single-use pre-filled syringe will have a green safety guard; manually activate the safety guard after the injection is given.
DO NOT slide the green safety guard forward over the needle before administering the injection; it will lock in place and prevent injection.
Activate the green safety guard (slide over the needle) after the injection.
The grey needle cap on the single-use pre-filled syringe contains dry natural rubber (a derivative of latex); people sensitive to latex should not handle the cap.
Step 1: Remove Grey Needle Cap: Remove needle cap.
Step 2: Administer Subcutaneous Injection: Choose an injection site. The recommended injection sites for PROLIA include: the upper arm OR the upper thigh OR the abdomen.
Insert needle and inject all the liquid subcutaneously. Do not administer into muscle or blood vessel.
DO NOT put grey needle cap back on needle.
Step 3: Immediately Slide Green Safety Guard Over Needle: With the needle pointing away from you.
Hold the pre-filled syringe by the clear plastic finger grip with one hand. Then, with the other hand, grasp the green safety guard by its base and gently slide it towards the needle until the green safety guard locks securely in place and/or you hear a "click". DO NOT grip the green safety guard too firmly - it will move easily if you hold and slide it gently.
Hold clear finger grip.
Gently slide green safety guard over needle and lock securely in place. Do not grip green safety guard too firmly when sliding over needle.
Immediately dispose of the syringe and needle cap in the nearest sharps container. DO NOT put the needle cap back on the used syringe.

Agents Affecting Bone Metabolism

M05BX04 - denosumab ; Belongs to the class of other drugs affecting bone structure and mineralization. Used in the treatment of bone diseases.

D