Prolia solution for injection 60 mg/ml syringe 1 ml No. 1

Instructions Prolia solution for injection 60 mg/ml syringe 1 ml No. 1

Composition

active ingredient: denosumab;

1 ml of solution contains 60 mg of denosumab;

Excipients: glacial acetic acid, sodium hydroxide, sorbitol (E 420), polysorbate 20, water for injections.

Dosage form

Solution for injection.

Main physicochemical properties: almost transparent, colorless or yellowish solution, practically free of foreign particles.

Pharmacotherapeutic group

Medicines for the treatment of bone diseases, other medicines that affect the structure and mineralization of bones.

ATX code M05B X04.

Pharmacological properties

Pharmacodynamics

Mechanism of action

Denosumab is a human monoclonal antibody (IgG2) produced in a mammalian cell line (Chinese hamster ovary cells) using recombinant DNA technology, targeting RANKL, to which the drug binds with high affinity and specificity, preventing the activation of its receptor RANK on the surface of osteoclast precursors and osteoclasts. Prevention of RANKL/RANK interaction inhibits osteoclast formation, function and viability, thereby reducing the resorption of both tubular and cancellous bones.

Pharmacodynamic effects

Treatment with Prolia® rapidly reduces bone remodeling, reaching nadirs in serum levels of the bone resorption marker type 1 collagen C-telopeptides (CTX) (85% reduction) within 3 days. The reduction was maintained throughout the dosing interval. At the end of each post-dose period, the CTX-lowering effect was partially attenuated, from a maximum reduction of more than 87% to a reduction of approximately more than 45% (range 45 to 80%), reflecting the reversibility of the effects of Prolia® on bone remodeling after serum levels had declined. These effects were maintained with continued therapy.

Bone remodeling markers generally returned to pre-treatment levels within 9 months of the last dose. After rechallenge, the level of CTX inhibition by denosumab was similar to that observed in patients who first started treatment with the drug.

Immunogenicity

No neutralizing antibodies to denosumab were observed in clinical studies. Less than 1% of patients treated with denosumab for up to 5 years tested positive (by sensitive immunoassay) for non-neutralizing binding antibodies without evidence of altered pharmacokinetics, toxicity, or clinical effect.

Clinical efficacy and safety in postmenopausal women with osteoporosis

The efficacy and safety of denosumab administered once every 6 months for 3 years was studied in postmenopausal women (7808 women aged 60-91 years, of whom 23.6% had prevalent vertebral fractures) with baseline lumbar spine or hip bone mineral density (BMD) T-scores 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 fractures and 7.22% (deciles: 1.4-14.9%) for hip fractures. Women with other medical conditions or those treated with medications that may affect bone were excluded from the study. The women received calcium supplements (at least 1,000 mg) and vitamin D (at least 400 IU) daily.

Impact on vertebral fractures

Prolia® significantly reduces the risk of new vertebral fractures at years 1, 2, and 3 (p < 0.0001) (see Table 1).

Table 1. Effect of Prolia® on the risk of new vertebral fractures

*p < 0.0001, **p < 0.0001 – exploratory analysis

Impact on femoral neck 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 with 0.7% in the Prolia® group at 3 years.

In a post hoc analysis in women >75 years of age, a 62% relative risk reduction was observed with Prolia® (1.4% absolute risk reduction, p <0.01).

Impact on all clinical fractures

Prolia® significantly reduced the incidence of fractures of all types/groups (see Table 2).

Table 2. Effect of Prolia® on the risk of clinical fractures over 3 years

*p ≤ 0.05, ** p = 0.0106 (secondary endpoint included in multiplicity adjustment), *** p ≤ 0.0001

+ Event rates are based on Kaplan–Meier estimates over 3 years.

1 Includes clinical vertebral and non-vertebral fractures.

2 Excludes fractures of the vertebrae, skull, face, lower jaw, metacarpus, phalanges of the fingers and toes.

3 Includes pelvis, distal femur, proximal tibia, ribs, proximal humerus, forearm, and thigh.

4 Includes clinical vertebral fractures, fractures of the femoral neck, forearm and humerus as defined by WHO.

In women with a baseline femoral neck BMD ≤ -2.5, Prolia® reduced the risk of non-vertebral fractures (35% relative risk reduction, 4.1% absolute risk reduction, p < 0.001, exploratory analysis).

The reductions in the incidence of new vertebral fractures, hip fractures, and non-vertebral fractures with Prolia® over 3 years were consistent regardless of 10-year baseline fracture risk.

Effect on bone mineral density

Compared with placebo at years 1, 2, and 3, Prolia® significantly increased BMD at all anatomical regions. Prolia® increased BMD by 9.2% at the lumbar spine, 6.0% at the hip, 4.8% at the femoral neck, 7.9% at the femoral trochanter, 3.5% at the distal 1/3 of the radius, and 4.1% at the total body over 3 years (all p < 0.0001).

In clinical studies of the effects of discontinuation of Prolia®, BMD returned to approximately pretreatment levels and remained higher than in the placebo group for 18 months after the last dose. These data indicate that continued treatment with Prolia® is necessary to maintain the drug's effect. Re-administration of Prolia® resulted in increases in BMD similar to those seen with the first dose of Prolia®.

Open-label extension study of postmenopausal osteoporosis treatment

A total of 4,550 women (2,343 on Prolia® and 2,207 on placebo) who missed no more than one dose in the pivotal study described above and completed the 36-month follow-up visit participated in a 7-year, multinational, multicenter, open-label, noncomparative extension study of the long-term safety and efficacy of Prolia®. All women in the extension study were required to receive 60 mg of Prolia® every 6 months, along with daily calcium (at least 1 g) and vitamin D (at least 400 IU). A total of 2,626 patients (58% of women enrolled in the extension study, i.e. 34% of women enrolled in the pivotal study) completed the extension study.

In patients treated with Prolia® for up to 10 years, BMD increased from baseline in the pivotal study by 21.7% at the lumbar spine, 9.2% at the hip, 9.0% at the femoral neck, 13.0% at the trochanter, and 2.8% at the distal 1/3 of the radius. At the end of the study, the mean lumbar spine BMD T-score in patients treated for 10 years was -1.3.

Fracture incidence was assessed as a safety endpoint, but the efficacy of fracture prevention could not be assessed due to the high number of discontinuations and the open-label design of the study. In patients who received denosumab for 10 years (n = 1278), the cumulative incidence of new vertebral and non-vertebral fractures was approximately 6.8% and 13.1%, respectively. In patients who did not complete the study for any reason, the incidence of fractures during the treatment period was higher.

Thirteen reported cases of osteonecrosis of the jaw (ONJ) and two reported cases of atypical femoral fractures were observed during the extended study.

Clinical efficacy and safety in men with osteoporosis

The efficacy and safety of Prolia® administered once every 6 months for 1 year was studied in 242 men aged 31–84 years. Subjects with eGFR < 30 mL/min/1.73 m2 were excluded from the study. All men received calcium (at least 1000 mg) and vitamin D (at least 800 IU) supplements daily.

The primary efficacy endpoint was the percent change in lumbar spine BMD; efficacy against fractures was not assessed. Compared with placebo, Prolia® significantly increased BMD in all anatomical regions over 12 months: 4.8% at the lumbar spine, 2.0% at the hip, 2.2% at the femoral neck, 2.3% at the femoral trochanter, and 0.9% at the distal 1/3 of the 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 the lumbar spine, hip joint, femoral neck, and femoral trochanter were observed after 6 months (p < 0.0001).

Bone histology was evaluated in 62 postmenopausal women with osteoporosis or low bone mass who were previously untreated for osteoporosis or who had switched from prior alendronate therapy and after 1 to 3 years of treatment with Prolia®. Fifty-nine women participated in the 24-month (n = 41) and/or 84-month (n = 22) bone biopsy substudy of the postmenopausal osteoporosis extension study. Bone histology was also evaluated in 17 men with osteoporosis after 1 year of treatment with Prolia®. Bone biopsy results showed bone of normal shape and quality with no evidence of mineralization defects, immature bone, or bone marrow fibrosis. Histomorphometry results in an extended study showed that in postmenopausal women with osteoporosis, the antiresorptive effects of Prolia®, as measured by activation frequency and bone formation rate, were maintained over time.

Clinical efficacy and safety in patients with bone loss associated with androgen deprivation

The efficacy and safety of Prolia® administered once every 6 months for 3 years was studied in men with histologically confirmed non-metastatic prostate cancer receiving androgen deprivation therapy (ADT) (1468 men aged 48–97 years). These patients were at increased risk of fracture (defined as age > 70 years or age < 70 years and a BMD T-score at the lumbar spine, hip, or femoral neck < -1.0 or a history of osteoporotic fracture). All men received calcium (at least 1000 mg) and vitamin D (at least 400 IU) supplements daily.

Compared with placebo, Prolia® significantly increased BMD at all anatomical sites over 3 years: 7.9% at the lumbar spine, 5.7% at the hip, 4.9% at the femoral neck, 6.9% at the femoral acetabular joint, 6.9% at the distal 1/3 of the 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, hip, femoral neck, and femoral acetabular joint 1 month after the initial dose.

Prolia® demonstrated a significant reduction in the relative risk 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).

Clinical efficacy and safety in patients with bone loss associated with adjuvant aromatase inhibitor therapy

The efficacy and safety of Prolia®, administered once every 6 months for 2 years, was studied in women with non-metastatic breast cancer (252 women aged 35–84 years) and a baseline BMD T-score between -1.0 and -2.5 at the lumbar spine, hip, or femoral neck. All women received calcium (at least 1000 mg) and vitamin D (at least 400 IU) supplements daily.

The primary efficacy endpoint was the percent change in lumbar spine BMD; efficacy against fractures was not assessed. Compared with placebo, Prolia® significantly increased BMD over 2 years: 7.6% at the lumbar spine, 4.7% at the hip, 3.6% at the femoral neck, 5.9% at the femoral trochanter, 6.1% at the distal 1/3 of the radius, and 4.2% at the total body (all p < 0.0001).

Treatment of bone loss associated with systemic glucocorticoid therapy

The efficacy and safety of Prolia® were studied in 795 patients (70% women and 30% men) aged 20 to 94 years who received ≥ 7.5 mg of oral prednisone daily (or equivalent).

Two subpopulations were studied: patients continuing to take glucocorticoids (≥ 7.5 mg prednisone per day or equivalent for ≥ 3 months prior to study entry; n = 505) and patients newly initiated on glucocorticoids (≥ 7.5 mg prednisone per day or equivalent for < 3 months prior to study entry; n = 290). Patients were randomized (1:1) to receive either Prolia® 60 mg subcutaneously once every 6 months or risedronate 5 mg orally once daily (active control) for 2 years. Patients received daily calcium (at least 1000 mg) and vitamin D (at least 800 IU).

Effect on bone mineral density

In the subpopulation that continued glucocorticoids, Prolia® demonstrated a greater increase in lumbar spine BMD than risedronate at 1 year (Prolia® 3.6%, risedronate 2.0%; p < 0.001) and 2 years (Prolia® 4.5%, risedronate 2.2%; p < 0.001). In the subpopulation that initiated glucocorticoids, Prolia® demonstrated a greater increase in lumbar spine BMD than risedronate at 1 year (Prolia® 3.1%, risedronate 0.8%; p < 0.001) and 2 years (Prolia® 4.6%, risedronate 1.5%; p < 0.001).

The study was not designed to demonstrate a difference in fractures. At 1 year, the incidence of new radiographic vertebral fractures was 2.7% (denosumab) versus 3.2% (risedronate). The incidence of nonvertebral fractures was 4.3% (denosumab) versus 2.5% (risedronate). At 2 years, the corresponding figures were 4.1% versus 5.8% for new radiographic vertebral fractures and 5.3% versus 3.8% for nonvertebral fractures. The majority of fractures occurred in the subpopulation that continued to receive glucocorticoids.

Pediatric 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 2 years of age in the treatment of osteoporosis. See section 4.2 for information on paediatric use.

Pharmacokinetics

Absorption

Following subcutaneous administration of 1.0 mg/kg, which approximately corresponds to the approved dose of 60 mg based on AUC, exposure was 78% of that obtained with intravenous administration of the same dose. Following subcutaneous administration of 60 mg denosumab, the maximum serum concentration (Cmax) of denosumab is 6 μg/mL (range 1–17 μg/mL) and is reached within 10 days (range 2–28 days).

Biotransformation

Denosumab is composed exclusively of amino acids and carbohydrates, like natural immunoglobulin. Therefore, it is unlikely to be eliminated by hepatic metabolism. It is believed that its metabolism and elimination occur through the same pathways as immunoglobulin clearance, after the drug is broken down into small peptides and individual amino acids.

Breeding

After reaching Cmax, serum levels decline over a period of 3 months (range 1.5–4.5 months) due to a half-life of 26 days (range 6–52 days). Denosumab was undetectable in 53% of patients 6 months after administration.

With multiple administration of denosumab at a dose of 60 mg subcutaneously once every 6 months, neither accumulation of the drug nor changes in its pharmacokinetics over time were observed. The pharmacokinetics of denosumab were not affected by the formation of antibodies to denosumab, and the pharmacokinetics of the drug were the same in women and men. Age (28–87 years), race, and disease status (bone loss or osteoporosis, prostate cancer, or breast cancer) had no significant effect on the pharmacokinetics of denosumab.

There was a trend towards increased body weight and decreased exposure as measured by AUC and Cmax. However, this trend is not considered clinically relevant as the pharmacodynamic effect is assessed by markers of bone remodeling and BMD increases, which were consistent across weight groups.

Linearity/nonlinearity

Dose-response studies revealed a nonlinear relationship between denosumab pharmacokinetics and dose, with drug clearance decreasing with increasing dose or concentration, but an approximately dose-proportional increase in drug exposure was observed at doses of 60 mg and above.

Kidney failure

In a study of 55 patients with varying degrees of renal impairment, including patients requiring dialysis, the level of renal impairment did not affect the pharmacokinetics of denosumab.

Liver failure

No specific studies have been conducted in patients with hepatic impairment. In general, monoclonal antibodies are not eliminated by hepatic metabolism, and therefore hepatic impairment is not expected to have an effect on the pharmacokinetics of denosumab.

Pediatric population

The pharmacokinetic profile in the pediatric population has not been evaluated.

Preclinical data

In single- and multiple-dose toxicity studies in cynomolgus monkeys, doses of denosumab that produced systemic responses 100–150 times higher than the recommended human dose did not affect cardiovascular physiology, male or female reproductive function, or specific target organ toxicity.

Standard tests to determine the genotoxic potential of denosumab were not performed because such tests are not relevant for this molecule. However, it is unlikely that denosumab has any genotoxic potential.

The carcinogenic potential of denosumab has not been evaluated in long-term animal studies.

In preclinical studies, mice with a blocked RANK or RANKL gene demonstrated impaired fetal lymph node formation and failed to lactate due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy).

Another study in cynomolgus monkeys administered denosumab during pregnancy at AUC levels 119 times the human dose (60 mg every 6 months) showed: increased rates of stillbirth and postnatal mortality; impaired bone growth, manifested by decreased bone strength, decreased hematopoiesis, and delayed teething; absence of peripheral lymph nodes, and reduced neonatal fetal growth. The highest dose that did not result in observable adverse effects was not established. At 6 months postpartum, bone-related changes showed a return to normal, and there was no effect on teething. However, effects on lymph nodes and occlusion persisted, and one animal had minimal to moderate mineralization of multiple tissues (relationship to treatment not apparent). There was no evidence of harm to the mother before delivery; adverse maternal reactions occurred infrequently during delivery. The development of the macaques' mammary glands was no different from normal.

In preclinical bone quality studies in monkeys, long-term treatment with denosumab resulted in decreased bone remodeling associated with improved bone strength and normal bone histology. Calcium levels were transiently decreased and parathyroid hormone levels were transiently increased in ovariectomized monkeys treated with denosumab.

In male mice genetically engineered to express huRANKL (knock-in mice) and subjected to transcortical fracture, denosumab delayed cartilage organization and bone callus remodeling compared to controls, but biochemical strength was not adversely affected.

Knockout mice (see section “Use during pregnancy or lactation”) with a blocked RANK or RANKL gene exhibited reduced body weight, impaired bone growth, growth zone abnormalities, and absence of teething. Impaired bone growth, growth zone abnormalities, and absence of teething were also observed in studies of neonatal rats treated with RANKL inhibitors, and these changes were partially reversible upon withdrawal of the RANKL inhibitor.

In neonatal mice, inhibition of RANKL (targeted therapy with denosumab) with high doses of an osteoprotegerin Fc-linked construct (OPG Fc) was associated with suppression of bone growth and teething. These changes were partially reversible in this model when dosing with RANKL inhibitors was discontinued. In adolescent primates treated with denosumab at doses 27 and 150 times (10 and 50 mg/kg) higher than the clinical dose, growth zones were pathologically altered. Thus, denosumab treatment may impair bone growth in children with open growth zones and may suppress teething.

Indication

Treatment of osteoporosis in postmenopausal women and men at increased risk of fractures. In postmenopausal women, Prolia® significantly reduces the risk of vertebral fractures, non-vertebral fractures, and hip fractures.

Treatment of bone loss in men at increased risk of fracture receiving hormone-suppressive therapy for prostate cancer (see section 5.1). In men with prostate cancer receiving hormone-suppressive therapy, Prolia® 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 (see section 5.1).

Contraindication

Hypersensitivity to the active substance or to any of the excipients of the drug.

Hypocalcemia (see section "Special warnings and precautions for use").

Interaction with other medicinal products and other types of interactions

An interaction study found that denosumab did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4). This suggests that denosumab has no effect on the pharmacokinetics of drugs metabolized by CYP3A4.

There are no clinical data on the interaction of denosumab and hormone replacement therapy (estrogens), however, the potential for pharmacodynamic interaction is considered low.

According to the study (when switching from previous alendronate therapy to denosumab treatment), in postmenopausal women with osteoporosis, the pharmacokinetics and pharmacodynamics of denosumab did not change after previous alendronate use.

Application features

Traceability

In order to improve the traceability of biological medicinal products, the name and batch number of the medicinal product used should be clearly recorded.

Calcium and vitamin D supplementation

Adequate calcium and vitamin D intake is very important for all patients.

Precautions for use

It is important to identify patients at risk of hypocalcemia. Correct hypocalcemia with adequate calcium and vitamin D intake before initiating treatment with the drug. Clinical monitoring of blood calcium levels is recommended in patients prone to hypocalcemia for the first two weeks after the initial dose. If any patient is suspected of developing symptoms of hypocalcemia during treatment with the drug (see section "Adverse reactions" for symptoms), calcium levels should be determined. Patients should be advised to report symptoms suggestive of hypocalcemia.

In post-marketing experience, severe symptomatic hypocalcemia, including fatal cases (see section 4.8), has been reported, most of which occurred within the first weeks of treatment but may also occur later.

Concomitant treatment with glucocorticoids is an additional risk factor for hypocalcemia.

Kidney failure

Patients with severe renal impairment (creatinine clearance < 30 ml/min) or those on dialysis are at increased risk of developing hypocalcemia. The risk of developing hypocalcemia and concomitant elevations in parathyroid hormone levels increases with increasing degree of renal impairment. Adequate calcium and vitamin D intake and regular monitoring of calcium levels are particularly important for these patients (see above).

Skin infections

Skin infections (predominantly cellulitis) leading to hospitalization may occur in patients taking denosumab (see Adverse Reactions section). Patients should seek immediate medical attention if they develop symptoms of cellulitis.

Osteonecrosis of the jaw (ONJ)

Rare reports of ONJ have been received in patients treated for osteoporosis with Prolia® (see section “Adverse reactions”).

Patients with non-healing oral soft tissue lesions should delay the start/new course of treatment for one month.

Before treatment with denosumab, patients with concomitant risk factors should consult a dentist for appropriate preventive measures and an individual assessment of the benefit/risk ratio.

Factors to consider when assessing a patient's risk of developing ONJ:

the potency of the drug that inhibits bone resorption (greater risk for more potent compounds), the route of administration (greater risk for parenteral administration), and the cumulative dose of the drug to treat bone resorption;

cancer, comorbid conditions (e.g. anemia, coagulopathy, infections), smoking;

concomitant therapy: corticosteroids, chemotherapy, angiogenesis inhibitors, head and neck radiotherapy;

poor oral hygiene, periodontal disease, inappropriate dentures, history of dental disease, invasive dental procedures (e.g. tooth extractions).

All patients should maintain appropriate oral hygiene, have regular dental check-ups, and promptly report any oral symptoms, including tooth mobility, pain or swelling, non-healing wounds, or wound discharge during treatment with denosumab.

If, after careful consideration, a decision is made to perform invasive dental procedures, they should not be performed in the days immediately before or immediately after denosumab administration.

The occurrence of ONJ requires a clinical evaluation and treatment plan by the patient's physician, together with a dentist or surgeon experienced in the treatment of ONJ. Consideration should be given to temporarily stopping treatment until the osteonecrosis of the jaw has resolved and risk factors have been mitigated.

Osteonecrosis of the external auditory canal

Cases of osteonecrosis of the external auditory canal have been reported with denosumab treatment. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered when treating patients with ear disorders, including chronic ear infections, with denosumab.

Atypical hip fractures

Withdrawal of denosumab should be considered for patients with suspected atypical hip fracture during patient assessment based on individual benefit/risk.

During treatment with denosumab, patients should be advised to report any new or unusual hip, thigh, or groin pain. Patients presenting with these symptoms should be evaluated for incomplete hip fractures.

Long-term treatment with antiresorptive drugs

Long-term treatment with antiresorptive drugs (including both denosumab and bisphosphonates) may lead to an increased risk of side effects such as osteonecrosis of the jaw and atypical hip fractures due to significant inhibition of bone remodeling (see section 4.2).

Concomitant treatment with other medicinal products containing denosumab

Patients treated with denosumab should not take other medicines containing denosumab (for the prevention of bone lesions in adult patients with bone metastases from solid tumors) at the same time.

Hypercalcemia in pediatric patients

Prolia® should not be used in pediatric patients (under 18 years of age). Severe cases of hypercalcemia have been reported. In clinical trials, complications such as acute renal failure occurred in some patients.

Excipients precautions

This medicine contains 47 mg of sorbitol in each ml of solution.

It is necessary to take into account the additive effect of concomitantly used drugs containing sorbitol (or fructose) and the intake of sorbitol (or fructose) taken with food.

This medicine contains less than 1 mmol sodium (23 mg) per 60 mg, i.e. essentially sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

There are limited data from the use of denosumab in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3).

Prolia® is not recommended for use in pregnant women and women of childbearing potential not using contraception. Women should be advised to avoid pregnancy during treatment with Prolia® and for at least 5 months thereafter. Any effects of Prolia® are likely to be greater in the second and third trimesters of pregnancy because monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the greatest amount transferred during the third trimester.

Breast-feeding

It is not known whether denosumab is excreted in human milk. Studies in genetically modified mice in which RANKL is inactivated by gene deletion (knockout mice) suggest that the absence of RANKL (a target for denosumab, see section 5.1) affects mammary gland maturation, leading to impaired lactation after delivery (see section 5.2). A decision to discontinue breast-feeding or to discontinue Prolia® therapy should be made taking into account the benefit of breast-feeding for the infant and the benefit of Prolia® therapy for the mother.

Fertility

There are no data on the effect of denosumab on human fertility. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section “Preclinical safety data”).

Ability to influence reaction speed when driving vehicles or other mechanisms

Prolia® has no or very little effect on the reaction speed when driving or operating other mechanisms.

Method of administration and doses

Dosage

Recommended dose of denos