Prolia, 60 mg/ml 1 ml

Prolia is an inhibitor of bone resorption.

Pharmacodynamics

The mechanism of action

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

Pharmacodynamic effects

Administration of denosumab at a dose of 60 mg resulted in a rapid decrease in serum concentrations of the bone resorption marker, 1C-telopeptide (STX), by approximately 70% within 6 h after subcutaneous administration and by approximately 85% over the following 3 days. The decrease in CTC concentration remained stable at the 6-month inter-dosing interval. The rate of decrease in serum CTC concentration partially decreased with decreasing serum denosumab concentration, reflecting the reversible effect of denosumab on bone remodeling. These effects were observed throughout the entire course of treatment. Consistent with the physiological relationship between formation and resorption in bone remodeling, a decrease in bone formation markers (e.g., bone-specific ALP and serum type I collagen N-terminal propeptide) was observed from the first month after the first dose of denosumab. Bone remodeling markers (markers of bone formation and bone resorption) generally reached pre-treatment period concentrations no later than 9 months after the last drug dose. After resumption of treatment with denosumab, the degree of decline in CTC concentrations was similar to the degree of decline in CTC concentrations at the start of treatment with denosumab.

The switch from alendronic acid treatment (mean duration of 3 years) to denosumab was shown to result in additional reductions in serum CTC concentrations compared to the group of postmenopausal women with low bone mass who continued alendronic acid treatment. At the same time, changes in serum calcium content were similar in both groups.

In experimental studies, inhibition of RANK/RANKL simultaneously with binding of osteoprotegerin to the Fc-fragment (OPG-Fc) resulted in stunted bone growth and impaired tooth eruption. Therefore, treatment with denosumab may inhibit bone growth with open growth zones in children and lead to dental eruption disorders.

Denosumab is a human monoclonal antibody, so like other drugs of protein nature, there is a theoretical risk of immunogenicity. More than 13,000 patients were screened for binding antibodies using sensitive electrochemiluminescence combined with immunoassays. Less than 1% of patients taking denosumab for 5 years were determined to have antibodies (including pre-existing, transient, and growing antibodies). Seropositive patients were further screened for neutralizing antibodies using an in vitro chemiluminescence assay in cell culture; no neutralizing antibodies were detected. No changes in pharmacokinetic profile, toxic profile or clinical response due to antibody formation were detected.

Clinical efficacy

The treatment of postmenopausal osteoporosis

In women with postmenopausal osteoporosis, Prolia™ increases bone mineral density and reduces the incidence of femoral neck fractures and vertebral and nonvertebral 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 reduces the risk of vertebral and nonvertebral fractures and femoral neck 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 efficacy endpoints for fractures achieved statistically significant values as assessed by a pre-specified sequential testing regimen.

The reduction in risk of new vertebral fractures with denosumab over 3 years remained stable and significant. The risk was reduced regardless of the 10-year probability of major osteoporotic fractures. A history of frequent vertebral fractures, nonvertebral fractures, patient age, bone mineral density, level of bone remodeling, and prior therapy for osteoporosis also had no effect on risk reduction.

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

The reduction in the incidence of nonvertebral fractures was independent 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. No pathological changes, including fibrosis, osteomalacia and disruption of bone architectonics, were observed.

Clinical efficacy in the treatment of loss of bone mass caused by hormondeprivation therapy or aromatase inhibitor therapy

The treatment of loss of bone mass caused by androgen deprivation

The efficacy and safety of denosumab in the treatment of bone mass loss associated with androgen deprivation was proven in a 3-year study including 1,468 patients with nonmetastatic prostate cancer. Significant increases in bone mineral density were determined in the lumbar spine, entire femur, femoral neck, and femoral trochanter 1 month after the first dose. The increase in lumbar spine bone mineral density was independent of age, race, geographic region, BMI, initial bone mineral density values, bone remodeling; duration of hormondeprivation therapy and history of vertebral fracture.

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

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

The efficacy and safety of denosumab in treating bone loss caused by adjuvant aromatase inhibitor therapy was evaluated in a 2-year study including 252 patients with nonmetastatic breast cancer. Denosumab significantly increased bone mineral density in all anatomic regions, compared with placebo, over 2 years. Increased bone mineral density was observed in the lumbar spine one month after the first dose. Positive effects on bone mineral density in the lumbar spine were observed regardless of age, duration of aromatase inhibitor therapy, BMI, prior chemotherapy, prior use of a selective estrogen receptor modulator (SERM) and time since the onset of menopause.

Pharmacokinetics

In p/q administration, denosumab is characterized by nonlinear, dose-dependent pharmacokinetics over a wide dose range and dose-dependent increases in exposure for doses of 60 mg (or 1 mg/kg) and higher.

Introduction

After a 60-mg dose of denosumab administered b/w, bioavailability was 61% and C_max was 6 µg/mL (range 1-17 µg/mL), these parameters were observed after 10 days (range 2-28 days). After C_max was reached, serum drug content decreased from T_1/2 26 days (range 6-52 days) and then for 3 months (range 1.5-4.5 months). In 53% of patients, denosumab was undetectable in serum after 6 months from the last drug administration.

Distribution

There were no changes in the pharmacokinetic parameters of denosumab and no changes in cumulation over the course of multiple doses of 60 mg every 6 months.

Metabolism

Denosumab is composed of amino acids and carbohydrates like conventional immunoglobulin. Based on preclinical data, the metabolism of denosumab is expected to follow an immunoglobulin clearance pathway that results in the breakdown into small peptide chains and individual amino acids.

Elevation

Based on preclinical data, excretion of denosumab will follow the clearance pathway of all immunoglobulins, which will result in the breakdown into small peptide chains and individual amino acids.

Patients who are elderly (65 years or older). Age has no significant effect on the pharmacokinetics of denosumab, according to pharmacokinetic analysis in a patient population of 28 to 87 years.

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

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

Patients with renal impairment. In a study of data from 55 patients with varying degrees of renal impairment, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics and pharmacodynamics of denosumab, so no dosing adjustments for denosumab in chronic renal impairment are required.

Chronic hepatic insufficiency. No studies have been conducted on the effect of hepatic insufficiency on the pharmacokinetics of denosumab.

Indications

Treatment of postmenopausal osteoporosis;

The treatment of loss of bone mass in women receiving aromatase inhibitors therapy for breast cancer and in men with prostate cancer receiving hormondeprivation therapy.

Active ingredient

Composition

Active substance:

denosumab 60 mg;

Supplementary substances:

sorbitol (E420) – 47 mg;

glacial acetic acid – 1 mg;

Polysorbate 20 – 0.1 mg;

sodium hydroxide – to pH 5.0-5.5;

water for injection – up to 1 ml

How to take, the dosage

Injection

Injection of the drug requires prior training – see administration guidelines at the end of this section.

Dose

The recommended dose of Prolia™ is one oral injection of 60 mg every 6 months. Calcium and vitamin D supplementation is recommended during the course of treatment.

Performance in Selected Patient Groups

Children. Prolia™ is not recommended for pediatric use because the efficacy and safety of the product have not been studied in this age group.

Patients in the elderly. Based on the available data on the efficacy and safety of the drug in this age group, there is no need to adjust the dosing regimen of the drug (see “Pharmacokinetics”, Selected Patient Groups).

Renal failure

Based on the available data on the efficacy and safety of the drug in this patient group, no adjustment of the drug dosing regimen is required (see Pharmacokinetics, Selected Patient Groups).

In patients with severe renal impairment (Cl creatinine

Hepatic impairment. Efficacy and safety have not been studied.

Instructions for use

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

In order to avoid discomfort at the injection site, warm the solution to room temperature (up to 25°C) before injection, then slowly inject the entire contents of the pre-filled syringe. The syringe with the rest of the medicine should be thrown away. Detailed recommendations for self-administration of the drug by injection are included in these instructions for medical use.

Any amount of unused medication or unused materials must be disposed of according to local regulations.

Interaction

There have been no studies of drug interactions.

The drug should not be mixed with other medicinal products.

Special Instructions

Calcium and vitamin D supplementation is recommended during administration of Prolia™.

Hypocalcemia can be corrected by taking calcium and vitamin D in adequate doses before initiating therapy with denosumab. Monitoring of calcium concentrations in patients predisposed to hypocalcemia is recommended (see “Side effects”).

Patients receiving Prolia™ may develop infections of the skin and its appendages (primarily subcutaneous inflammation), in some cases requiring hospitalization. These reactions have been reported more frequently for the denosumab group (0.4%) than for the placebo group (0.1%) (see “Adverse Events”). The overall incidence of skin infections was comparable in the denosumab and placebo groups. Patients should be instructed to seek immediate medical attention if they develop symptoms and signs of subcutaneous inflammation.

In patients with advanced cancer who received 120 mg of denosumab every 4 weeks, the development of osteonecrosis of the jaw has been reported. There have been isolated reports of the development of osteonecrosis of the jaw at a dose of 60 mg every 6 months (see side effects).

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

Impact on ability to drive vehicles and handle machinery. There have been no studies of the effect on the ability to drive vehicles and operate machinery.

Contraindications

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

Side effects

Infections and invasions: inflammation of the subcutaneous tissue.

Metabolism and electrolyte metabolism: hypocalcemia.

Visual organs: cataract.

Skin and subcutaneous fatty tissue: eczema.

Skeletal and muscular system and connective tissue: pain in the extremities; osteonecrosis of the jaw.

Overdose

There have been no cases of overdose of Prolia in clinical trials.

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

Pregnancy use

There are no data on the use of the drug during pregnancy. Prolia is not recommended for use in pregnant women.
In toxicology studies in lower primates, denosumab was shown to have no effect on fertility or fetal development at doses 100 times greater than those recommended for clinical use.

The experiments in mice with the gene turned off showed that absence of RANKL can lead to impaired fetal lymph node development, and in the postnatal period can cause impaired teething, and bone growth; it can also affect mammary maturation, which can lead to impaired lactation.

It is not known whether denosumab is excreted in breast milk. Because denosumab is known to potentially cause adverse reactions in infants, it is necessary to either stop breastfeeding or discontinue Prolia.