Prolia, syringe, 60mg

Composition

Active ingredient:

denosumab 60 mg;

Auxiliary substances:

sorbitol (E 420) — 47 mg;

glacial acetic acid-1 mg;

polysorbate 20-0.1 mg;

sodium hydroxide – up to pH 5.0–5.5;

water for injection – up to 1 ml

Pharmacological action

Prolia – inhibits bone resorption.

Pharmacodynamics

Mechanism of action

Denosumab is a fully human monoclonal antibody (IgG2) that has a high affinity and specificity for the ligand of the nuclear factor kB activator receptor (RANKL), and thus prevents the activation of a single RANKL receptor — the nuclear factor kB activator (RANK) located on the surface of osteoclasts and their precursors. Thus, preventing the RANKL/RANK interaction inhibits the formation, activation, and survival of osteoclasts. As a result, denosumab reduces bone resorption and increases the mass and strength of the cortical and trabecular layers of bone.

Pharmacodynamic effects

use of denosumab at a dose of 60 mg resulted in a rapid decrease in serum concentrations of the bone resorption marker 1 C-telopeptide (CTX) — approximately 70% within 6 hours after subcutaneous use and approximately 85% over the next 3 days. The decrease in CTX concentration remained stable in the 6-month interval between dosing. The rate of decrease in CTX concentration 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 entire course of treatment. According to the physiological relationship between the processes of formation and resorption during bone remodeling, a decrease in the content of markers of bone formation (for example, bone-specific ALP and serum N-terminal collagen type I propeptide) was observed 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 pre-treatment 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 concentrations at the beginning of denosumab treatment.

It was shown that switching from alendronic acid treatment (average duration of use — 3 years) to denosumab leads to an additional decrease in serum CTX concentration compared to the group of postmenopausal women with low bone mass who continued treatment with alendronic acid. At the same time, changes in serum calcium content 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 teething. Therefore, treatment with denosumab may inhibit the growth of bones with open growth zones in children and lead to teething disorders.

Immunogenicity

Denosumab is a human monoclonal antibody, so, as with other drugs of 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 who took denosumab for 5 years had antibodies detected (including pre-existing, transient, and growing ones). Seropositive patients were further examined for the formation of neutralizing antibodies using chemiluminescence analysis in cell culture in vitro, no neutralizing antibodies were detected. There were no changes in the pharmacokinetic profile, toxic profile, or clinical response due to antibody formation.

Clinical efficacy

Postmenopausal Osteoporosis treatment

In women with postmenopausal osteoporosis, Prolia™ increases bone mineral density, reduces the incidence of hip fractures, vertebral and non-vertebral fractures. The efficacy and safety of denosumab in the treatment of postmenopausal osteoporosis was demonstrated in a 3-year study. The results of the study show that denosumab significantly reduces the risk of vertebral and non-vertebral fractures and hip fractures in postmenopausal women with osteoporosis compared to placebo. The study included 7,808 women, of whom 23.6% had frequent vertebral fractures. All three endpoints of effectiveness for fractures achieved statistically significant values, evaluated according to a predefined sequential testing scheme.

The reduction in the risk of new vertebral fractures when using denosumab for more than 3 years remained stable and significant. The risk was reduced regardless of the 10-year probability of major osteoporotic fractures. Risk reduction was also not affected by the presence of a history of frequent vertebral fractures, non-vertebral fractures, patient age, bone mineral density, bone remodeling levels, or previous treatment for osteoporosis.

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

A decrease in the incidence of non-vertebral fractures was observed regardless of the 10-year probability of major osteoporotic fractures. Denosumab significantly increased bone mineral density in all anatomical areas compared to placebo. Bone mineral density was determined 1,2, and 3 years after the start of therapy. Similar effects on bone mineral density were observed in the lumbar spine, regardless of age, race, body mass index( BMI), bone mineral density, and bone remodeling. Histological studies confirmed normal bone architectonics and, as expected, reduced bone remodeling compared to placebo. There were no pathological changes, including fibrosis, osteomalacia, and bone architectonics disorders.

Clinical efficacy in the treatment of bone loss caused by hormone deprivation therapy or aromatase inhibitor therapy

Treatment of bone loss caused by androgen deprivation

The efficacy and safety of denosumab in the treatment of bone loss associated with reduced androgen concentrations were demonstrated in a 3-year study involving 1,468 patients with non-metastatic prostate cancer. A significant increase in bone mineral density was detected in the lumbar spine, the entire femur, the femoral neck, and the femoral trochanter 1 month after the first dose. The increase in bone mineral density in the lumbar spine did not depend on age, race, geographical region, BMI, initial values of bone mineral density, bone remodeling, duration of hormone deprivation therapy, and the presence of a vertebral fracture in the anamnesis.

Denosumab significantly reduced the risk of new vertebral fractures during 3 years of use. A reduction in risk was observed at 1 year and 2 years after the start of therapy. Denosumab also reduced the risk of more than one osteoporotic fracture of 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 bone mineral density in all anatomical areas, compared to placebo, for 2 years. An increase in bone mineral density was observed in the lumbar spine one month after the first dose. A positive effect on bone mineral density in the lumbar spine was observed regardless of age, duration of aromatase inhibitor therapy, BMI, previous chemotherapy, previous use of a selective estrogen receptor modulator (SMRE), and time elapsed from the onset of menopause.

Pharmacokinetics

When administered subcutaneously, denosumab is characterized by non-linear pharmacokinetics, dose-dependent over a wide dose range, and a dose-dependent increase in exposure for a dose of 60 mg (or 1 mg/kg) and higher.

Suction

After subcutaneous use of denosumab at a dose of 60 mg, the bioavailability was 61% and the_cmax was 6 mcg / ml (range 1-17 mcg / ml), these parameters were observed after 10 days (range 2-28 days). After reaching_cmax, the drug content in the blood serum decreased from T_1/2 for 26 days (range 6-52 days) and then for 3 months (range 1.5–4.5 months). In 53% of patients, denosumab was not detected in the blood serum after 6 months from the last use of the drug.

Distribution

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

Metabolism

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

Deduction

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

Individual patient groups

Elderly patients (65 years or older). Age does not significantly affect the pharmacokinetics of denosumab, according to pharmacokinetic analysis in the population of patients aged 28 to 87 years.

Children and teenagers (under 18 years of age). Pharmacokinetics in children have not been studied.

Racial affiliation. The pharmacokinetics of denosumab are independent of race.

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

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

Indications

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.

Use 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 on lower primates, it was shown that at doses 100 times higher than recommended for clinical use, denosumab did not affect fertility or fetal development.

Experiments on mice with the gene turned off have shown that the absence of RANKL can lead to impaired development of lymph nodes in the fetus, and in the postnatal period it can cause impaired teething and bone growth; it can also affect the maturation of the breast, 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 Prolia.

Contraindications

Hypersensitivity to any of the components of the drug; hypocalcemia.

Side effects

Infections and infestations: inflammation of the subcutaneous tissue.

From the side of metabolism and electrolyte metabolism: hypocalcemia.

From the side of the visual organs: cataract.

Skin and subcutaneous fat disorders: eczema.

Musculoskeletal and connective tissue disorders: pain in the extremities; osteonecrosis of the jaw.

Interaction

No drug interaction studies have been conducted.

The drug should not be mixed with other medicines.

How to take, course of use and dosage

Introduction

Injecting the drug requires prior training — see the recommendations for injecting the drug given at the end of this section.

Dosage

The recommended dose of Prolia™ is one subcutaneous injection of 60 mg every 6 months. During the course of treatment, it is recommended to take additional calcium and vitamin D supplements.

Use in selected groups of patients

Children. Prolia™ is not recommended for use in pediatrics, as 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, there is no need to adjust the dosage regimen of the drug (see “Pharmacokinetics”, Individual patient groups).

Kidney failure

Based on the available data on the efficacy and safety of the drug in this group of patients, there is no need to adjust the dosage regimen of the drug (see “Pharmacokinetics”, Individual patient groups).

In patients with severe renal insufficiency (creatinine clearance

Liver failure. Efficacy and safety have not been studied.

Instructions for use

The solution should be evaluated for inclusions or discoloration before use. 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. Discard the syringe containing the remaining drug. Detailed recommendations for self-subcutaneous use of the drug are included in these instructions for medical use.

Any quantities of unused medicine or unused materials must be disposed of in accordance with local regulations.

Overdose

No cases of overdose of Prolia have been reported in clinical trials.

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

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 supplements before starting denosumab therapy. It is recommended to monitor the calcium concentration in patients predisposed to hypocalcemia (see “Side effects”).

Patients receiving Prolia™ may develop infections of the skin and its appendages (mainly inflammation of the subcutaneous tissue), in some cases requiring hospitalization. These reactions were reported more frequently in the denosumab group (0.4%) than in the placebo group (0.1%) (see “Side effects”). 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 tissue 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 separate reports of the development of osteonecrosis of the jaw at a dose of 60 mg every 6 months (see “Side effects”).

Persons allergic to latex should not touch the rubber needle cap (a latex derivative).

Influence on the ability to drive motor vehicles and handle machinery. Studies of the effect on the ability to drive motor vehicles and manage mechanisms have not been conducted.

Product form

solution for subcutaneous use

Storage conditions

At a temperature of 2-8 °C (do not freeze)

Shelf life

3 years

Active ingredient

Denosumab

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection

Purpose

For postmenopausal women, For adults as prescribed by a doctor

Indications

Cancer, Osteoporosis