Prolia solution 60mg, 1ml # 1 syringe

• treatment of postmenopausal osteoporosis;

• treatment of bone loss in women receiving aromatase inhibitor therapy for breast cancer and in men with prostate cancer receiving hormone deprivation therapy.

Introduction

The injection of the drug requires prior training - see the recommendations for drug administration given at the end of this manual.

The recommended dose of Prolia is one s / c injection of 60 mg every 6 months. During the course of treatment, it is recommended to additionally take calcium and vitamin D preparations.

Children

The drug Prolia is not recommended for use in pediatrics, since the efficacy and safety of this drug have not been studied in this age group.

Elderly patients

Based on the available data on the efficacy and safety of the drug in this age group, no correction of the drug dosage regimen is required.

Renal failure

Based on the available data on the efficacy and safety of the drug in this group of patients, no correction of the drug dosage regimen is required.

In patients with severe renal impairment (creatinine clearance <30 ml / min) or on dialysis, there is a high risk of developing hypocalcemia. Such patients need to additionally take calcium and vitamin D supplements.

Liver failure

Efficacy and safety have not been studied.

Instructions for use

The solution should be assessed before administration for inclusions or discoloration. The solution should not be used if it becomes cloudy or discolored. Do not shake.

To avoid discomfort at the injection site, warm the solution to room temperature (up to 25 ? C) before injection, and then slowly inject the entire contents of the pre-filled syringe. Throw away the syringe with the remains of the drug.

Any quantities of unused drug or unused materials must be destroyed in accordance with local requirements.

The solution for subcutaneous administration is transparent, from colorless to light yellow, practically free of visible inclusions.

1 syringe 1 ml

denosumab 60 mg 60 mg

Excipients: sorbitol (E420) 47 mg, glacial acetic acid 1 mg, sodium hydroxide to pH 5.0 - 5.5, polysorbate 20 0.1 mg, water d / and up to 1 ml.

• hypocalcemia;

• hypersensitivity to any component of the drug.

pharmachologic effect

Denosumab is a fully human monoclonal antibody (IgG2) with high affinity and specificity for the ligand of the nuclear factor kappa B (RANKL) activator receptor and thereby prevents the activation of the only RANKL receptor, the nuclear factor kB activator (RANK), located on the surface of osteoclasts and their predecessors. Thus, prevention of the RANKL / RANK interaction inhibits osteoclast formation, activation and duration. As a result, denosumab reduces bone resorption and increases the mass and strength of the cortical and trabecular bone layers.

Pharmacodynamic effects

The administration of denosumab at a dose of 60 mg led to a rapid decrease in serum concentrations of the marker of bone resorption - 1C-telopeptide (CTX) - by approximately 70% within 6 hours after s / c administration and by approximately 85% over the next 3 days. The decrease in CTX concentration remained stable over the 6-month dosing interval. The rate of decrease in the concentration of CTX in the blood serum partially decreased with a decrease in the concentration of denosumab in the blood serum, which reflects the reversibility of the effect of denosumab on bone remodeling. These effects were observed throughout the course of treatment. According to the physiological relationship of the processes of formation and resorption during remodeling of bone tissue, a decrease in the content of markers of bone formation was observed (for example,bone-specific alkaline phosphatase and serum N-terminal propeptide of collagen type 1) from the first month after the first dose of denosumab. Markers of bone remodeling (markers of bone formation and bone resorption), as a rule, reached pretreatment concentrations no later than 9 months after the last dose of the drug. After the resumption of denosumab treatment, the degree of decrease in CTX concentrations was similar to the degree of decrease in CTX concentration at the beginning of the course of denosumab treatment.After the resumption of denosumab treatment, the degree of decrease in CTX concentrations was similar to the degree of decrease in CTX concentration at the beginning of the course of denosumab treatment.After the resumption of denosumab treatment, the degree of decrease in CTX concentrations was similar to the degree of decrease in CTX concentration at the beginning of the course of denosumab treatment.

It has been shown that the transfer from treatment with alendronic acid (average duration of use - 3 years) to denosumab leads to an additional decrease in the concentration of CTX in serum compared with the group of postmenopausal women with low bone mass who continued treatment with alendronic acid. At the same time, changes in serum calcium were similar in both groups.

In experimental studies, inhibition of RANK / RANKL, simultaneously with the binding of osteoprotegerin to the Fc-fragment (OPG-Fc), led to a slowdown in bone growth and impaired dentition. Therefore, treatment with denosumab can inhibit the growth of bones with open growth zones in children and lead to teething problems.

Immunogenicity

Denosumab is a human monoclonal antibody, therefore, as with other drugs of a protein nature, there is a theoretical risk of immunogenicity. More than 13,000 patients were examined for the formation of binding antibodies using the method of sensitive electrochemiluminescence in combination with immunological analysis. Less than 1% of patients taking denosumab for 5 years had antibodies (including preexisting, transient, and growing antibodies). Seropositive patients were further examined for the formation of neutralizing antibodies using chemiluminescence assay in an in vitro cell culture; no neutralizing antibodies were detected. There were no changes in the pharmacokinetic profile, toxicity profile, or clinical response due to antibody formation.

Clinical efficacy

Postmenopausal osteoporosis treatment

In women with postmenopausal osteoporosis, Prolia increases bone mineral density (BMD), reduces the incidence of hip fractures, vertebral and non-vertebral fractures. The efficacy and safety of denosumab in the treatment of postmenopausal osteoporosis has been proven in a 3-year study. The results of the study show that denosumab significantly, in comparison with placebo, reduces the risk of vertebral and non-vertebral fractures, hip fractures in postmenopausal women with osteoporosis. The study included 7808 women, of whom 23% had frequent vertebral fractures. All three endpoints for efficacy in fracture ratios achieved statistically significant values ??as measured by a predetermined sequential testing scheme.

The reduction in the risk of new vertebral fractures with the use of denosumab for more than 3 years remained stable and significant. The risk decreased regardless of the 10-year probability of major osteoporotic fractures. Risk reduction was also not affected by a history of frequent vertebral fractures, non-vertebral fractures, age, patients, BMD, level of bone remodeling, and prior therapy for osteoporosis.

In postmenopausal women over 75 years of age, denosumab reduced the incidence of new vertebral fractures and, according to post hoc analysis, decreased the incidence of hip fractures.

A decrease in the incidence of non-vertebral fractures was observed regardless of the 10-year likelihood of major osteoporotic fractures.

Denosumab significantly increased BMD in all anatomical regions compared with placebo. The BMD was determined 1 year, 2 and 3 years after the start of therapy. A similar effect on BMD was noted in the lumbar spine, regardless of age, race, body mass index (BMI), BMD, and bone remodeling.

Histological studies confirmed normal bone architectonics and, as expected, decreased bone remodeling compared to placebo. There were no pathological changes, including fibrosis, osteomalacia, and disruption of the architectonics of bone tissue.

Clinical efficacy in the treatment of bone loss caused by hormone-deprivation therapy or therapy with aromatase inhibitors

Treatment of bone loss caused by androgen deprivation

The efficacy and safety of denosumab in the treatment of bone loss associated with a decrease in androgen concentration was proven in a 3-year study involving 1,468 patients with non-metastatic prostate cancer.

A significant increase in BMD was determined in the lumbar spine, the entire femur, the femoral neck, and the trochanter of the femur 1 month after the first dose. The increase in BMD in the lumbar spine did not depend on age, race, geographic region, BMI, initial BMD values, bone remodeling; the duration of hormone deprivation therapy and the presence of a vertebral fracture in history.

Denosumab significantly reduced the risk of new vertebral fractures over 3 years of use. A decrease in risk was observed after 1 year and 2 years after initiation of therapy. Denosumab also reduced the risk of more than one osteoporotic fracture at any location.

Treatment of bone loss in women receiving aromatase inhibitor therapy for breast cancer

The efficacy and safety of denosumab in the treatment of bone loss caused by adjuvant aromatase inhibitor therapy was evaluated in a 2-year study involving 252 patients with non-metastatic breast cancer. Denosumab significantly increased BMD in all anatomical regions compared with placebo over 2 years. An increase in BMD was observed in the lumbar spine one month after taking the first dose. A positive effect on BMD in the lumbar spine was noted regardless of age, duration of therapy with an aromatase inhibitor, BMI, previous chemotherapy, prior use of a selective estrogen receptor modulator (SERM), and time elapsed from the onset of menopause.

Pharmacokinetics

When administered s / c, denosumab is characterized by nonlinear pharmacokinetics, dose-dependent in a wide dose range, and dose-dependent increase in exposure for a dose of 60 mg (or 1 mg / kg) and above.

Suction

After subcutaneous administration of denosumab at a dose of 60 mg, bioavailability was 61% and Cmax of denosumab was 6 ?g / ml (range 1-17 ?g / ml), these parameters were observed after 10 days (range 2-28 days). After reaching Cmax, the serum concentration of the drug decreased from T1 / 2 26 days (range 6-52 days) and then within 3 months (range 1.5-4.5 months). In 53% of patients, denosumab was not detected in blood serum after 6 months from the last injection of the drug.

Distribution

There were no changes in the pharmacokinetic parameters of denosumab, as well as cumulation during the entire time of taking multiple doses of the drug, 60 mg every 6 months.

Metabolism

Denosumab is composed of amino acids and carbohydrates, just like a normal immunoglobulin. Based on data from preclinical studies, it is expected that the metabolism of denosumab will occur along the pathway of clearance of immunoglobulins, the result of which will be the breakdown into small peptide chains and individual amino acids.

Withdrawal

Based on preclinical data, the elimination of denosumab will occur along the pathway of elimination of all immunoglobulins, the result of which will be the breakdown into small peptide chains and individual amino acids.

Separate patient groups

Age does not significantly affect the pharmacokinetics of denosumab according to pharmacokinetic analysis in a population of patients from 28 to 87 years old.

Pharmacokinetics in children has not been studied.

The pharmacokinetics of denosumab does not depend on race.

In a study on 55 patients with varying degrees of renal failure, including patients on dialysis, the degree of renal failure did not affect the pharmacokinetics and pharmacodynamics of denosumab; therefore, no correction of the denosumab dosage regimen is required in chronic renal failure.

Studies of the effect of liver failure on the pharmacokinetics of denosumab have not been conducted.

Application during pregnancy and lactation

There are no data on the use of the drug during pregnancy Prolia is not recommended for use in pregnant women.

In toxicological studies in lower primates, it was shown that at doses 100-fold higher than those recommended for clinical use, denosumab did not affect fertility or fetal development.

Experiments on mice with the gene turned off showed that the absence of RANKL can lead to a violation of the development of lymph nodes in the fetus, and in the postnatal period it can be the cause of a violation of teething and bone growth; it is also possible to influence the maturation of the mammary gland, which can lead to a weakening of lactation.

It is not known whether denosumab is excreted in breast milk. Since it is known that denosumab can potentially cause adverse reactions in infants, it is necessary to either stop breastfeeding or discontinue the drug.

Application for violations of liver function

Efficacy and safety have not been studied.

Application for impaired renal function

Based on the available data on the efficacy and safety of the drug in this group of patients, no correction of the drug dosage regimen is required.

In patients with severe renal impairment (creatinine clearance <30 ml / min) or on dialysis, there is a high risk of developing hypocalcemia. Such patients need to additionally take calcium and vitamin D supplements.

Application in children

The drug Prolia is not recommended for use in pediatrics, since the efficacy and safety of this drug have not been studied in this age group.

Use in elderly patients

Based on the available data on the efficacy and safety of the drug in this age group, no correction of the drug dosage regimen is required.

special instructions

It is recommended to take calcium and vitamin D supplements while using Prolia.

Hypocalcemia can be corrected by taking adequate doses of calcium and vitamin D before starting denosumab therapy. It is recommended to control the calcium concentration in patients prone to hypocalcemia.

In patients receiving Prolia, infections of the skin and its appendages (mainly inflammation of the subcutaneous tissue) may develop, in some cases requiring hospitalization. Such reactions were more often reported for the denosumab group (0.4%) than for the placebo group (0.1%). However, the overall incidence of skin infections was comparable in the denosumab and placebo groups. Patients should be instructed to seek immediate medical attention if symptoms and signs of subcutaneous inflammation develop.

Cases of osteonecrosis of the jaw have been reported in patients with advanced cancer who received 120 mg of denosumab every 4 weeks. There are isolated reports of the development of osteonecrosis of the jaw at a dose of 60 mg every 6 months.

Individuals with a latex allergy should not touch the rubber needle cap (latex derivative).

Influence on the ability to drive vehicles and use mechanisms

Studies of the effect on the ability to drive vehicles and use mechanisms have not been conducted.

Overdose

In clinical studies, there have been no cases of drug overdose.

In clinical trials, denosumab doses of up to 180> mg have been administered every 4 weeks (cumulative dose up to 1080 mg at 6 months).

Drug interactions

No drug interaction studies have been conducted.

The drug should not be mixed with other medicines.