Proli solution for sc injection 0.06/ml 1 ml n1

Composition

Description of the dosage form

Transparent liquid, from colorless to light yellow color, practically free from visible inclusions.

Pharmacology

Pharmacological action - inhibiting bone resorption.

Pharmacodynamics

Mechanism of action

Denosumab is a fully human monoclonal antibody (IgG2) that has high affinity and specificity for the ligand of the nuclear factor activator receptor κB (RANKL), and thus prevents the activation of a single receptor RANKL - the nuclear factor activator κB (RANK) located on the surface of osteoclasts and predecessors. Thus, preventing the interaction of RANKL / RANK inhibits the 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

The administration of denosumab in a dose of 60 mg resulted in a rapid decrease in serum concentrations of the bone tissue resorption marker 1C-telopeptide (CTX) —about 70% within 6 hours after subcutaneous administration 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 serum CTX concentration partially decreased with a decrease in serum denosumab concentration, 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 bone tissue remodeling, there was a decrease in the content of bone formation markers (for example, bone-specific ALT and serum N-terminal propeptide type I collagen) from the first month after the first dose of denosumab. Bone remodeling markers (markers of bone formation and bone resorption), as a rule, reached concentrations of the period before the start of treatment no later than 9 months after taking the last dose of the drug. After the resumption of treatment with denosumab, the degree of decrease in CTX concentrations was similar to the degree of decrease in the concentration of CTX at the beginning of the course of treatment with denosumab.

It was shown that a switch from treatment with alendronic acid (average duration of use - 3 years) to denosumab leads to an additional decrease in serum CTX concentration compared with a 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) resulted in slower bone growth and impaired teething. Therefore, treatment with denosumab can inhibit the growth of bones with open growth zones in children and lead to impaired teething.

Immunogenicity

Denosumab is a human monoclonal antibody, therefore, as for 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 sensitive electrochemiluminescence method in combination with an immunological analysis. In less than 1% of patients who had taken denosumab for 5 years, antibodies were detected (including preexisting, transient and growing). Seropositive patients were further examined for the formation of neutralizing antibodies using chemiluminescent analysis in cell culture. in vitro, neutralizing antibodies were not detected. There were no changes in pharmacokinetic profile, toxic profile or clinical response due to the formation of antibodies.

Clinical efficacy

Postmenopausal osteoporosis treatment

In women with postmenopausal osteoporosis Prolia^Tm increases bone mineral density, reduces the incidence of hip fractures, 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, compared with placebo, reduces the risk of vertebral and non-vertebral fractures, hip fractures in women with postmenopausal osteoporosis. The study included 7808 women, of whom 23.6% had frequent vertebral fractures. All three efficacy endpoints for fractures reached statistically significant values, assessed by a predetermined sequential test pattern.

Reducing 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. The history of vertebral fractures, nonvertebral fractures, patient age, bone mineral density, bone remodeling, and previous therapy for osteoporosis also did not affect the risk reduction.

In women older than 75, post-menopausal denosumab reduced the incidence of new vertebral fractures, and, according to post hoc analysis, reduced the incidence of hip fractures.

A decrease in the incidence of nonvertebral fractures was observed regardless of the 10-year probability of the occurrence of large osteoporotic fractures.Denosumab significantly, compared to placebo, increased bone mineral density in all anatomical areas. Bone mineral density was determined 1, 2 and 3 years after the start of therapy. A similar effect on bone mineral density is noted in the lumbar spine, regardless of age, race, body mass index (BMI), bone mineral density, and bone remodeling. Histological studies confirmed the normal architectonics of the bone and, as expected, a decrease in bone remodeling compared with placebo. No pathological changes were noted, including fibrosis, osteomalacia and impaired bone marrow architecture.

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

Treatment of bone loss due to androgen deprivation

The efficacy and safety of denosumab in the treatment of bone loss associated with a decrease in the concentration of androgens were proven in a 3-year study that included 1,468 patients with non-metastatic prostate cancer. A significant increase in bone mineral density was determined in the lumbar spine, the entire femur, the femoral neck, and the skew of the femur 1 month after taking the first dose. The increase in bone mineral density in the lumbar spine did not depend on age, race, geographic region, BMI,initial values ​​of bone mineral density, bone remodeling; the duration of hormone therapy and the presence of a vertebral fracture in history.

Denosumab significantly reduced the risk of new vertebral fractures over the course of 3 years of use. Risk reduction was observed after 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 treatment with aromatase inhibitors for breast cancer

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

Pharmacokinetics

At s / c introduction Denosumab is characterized by non-linear pharmacokinetics, dose-dependent in a wide range of doses, and dose-dependent increase in exposure for a dose of 60 mg (or 1 mg / kg) and above.

Suction

After s / c injection of denosumab in a dose of 60 mg bioavailability was 61% and C_max - 6 µg / ml (range 1-17 µg / ml), these parameters were observed after 10 days (range 2-28 days). After reaching C_max serum drug levels decreased with 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 not detected in the serum after 6 months from the last injection.

Distribution

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

Metabolism

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

Removal

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

Selected patient groups

Elderly patients (65 years or older). Age does not have a significant effect on the pharmacokinetics of denosumab, according to a pharmacokinetic analysis in a population of 28 to 87 years.

Children and teenagers (under 18). Pharmacokinetics in children has not been studied.

Race. The pharmacokinetics of denosumab are independent of race.

Patients with renal failure. In a study of 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 was necessary for the dosage of denosumab in chronic renal failure.

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

Indications drug Prolia^Tm

treatment of postmenopausal osteoporosis;

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

Contraindications

hypersensitivity to any of the components of the drug;

hypocalcemia.

Use during pregnancy and lactation

There is no data on the use of the drug during pregnancy. The prolia^Tm not recommended for use in pregnant women.

In toxicological studies on 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 genes turned off showedthat the absence of RANKL can lead to disruption of the development of lymph nodes in the fetus, and in the postnatal period it can be a cause of impaired teething and bone growth; may also affect the maturation of the breast, which may lead to a weakening of lactation.

Patients whose pregnancy occurred during treatment with Prolia^Tm, should register with the company's pregnancy monitoring program Amgen. Patients or doctors with whom they are under observation can call the telephone number listed at the end of this manual for registration in the Monitoring Program.

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

Side effects

Data obtained from controlled use in clinical studies.

Undesirable reactions are given by organ system classes in terms of the Medical Dictionary of Regulatory Activity (MedDRA). The frequency of occurrence is defined as follows: very often -> 1 out of 10; often -> 1 out of 100 and <1 out of 10; infrequently -> 1 out of 1000 and <1 out of 100; rarely> 1 out of 10,000 and <1 out of 1000; very rarely <1 out of 10,000.

In each group of organ systems and message frequencies, adverse reactions are listed in descending order of severity.

¹ See section "Special instructions".

² In men who receive androgen therapy for prostate cancer.

³ Including dermatitis, allergic dermatitis, atopic dermatitis, contact dermatitis.

Dosage and administration

Introduction

Conducting an injection of the drug requires prior training - see recommendations for the introduction of the drug, listed at the end of this section.

Dose

The recommended dose of the drug Proli^Tm - one sc injection of 60 mg every 6 months. During the course of treatment it is recommended to take calcium supplements and vitamin D.

Use in selected patient groups

Children. Drug Prolia^Tm not recommended for use in pediatrics, because the efficacy and safety of this drug has 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 is required for the dosage 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 group of patients, no adjustment of the dosage regimen of the drug is required (see “Pharmacokinetics”, Selected patient groups).

Patients with severe renal insufficiency (Cl creatinine <30 ml / min) or on dialysis have a high risk of hypocalcemia. These patients need to take additional calcium supplements and vitamin D.

Liver failure. Efficiency and safety have not been studied.

Instructions for use

You should evaluate the solution before administration for the presence of inclusions or discoloration. The solution can not be used in turbidity or color change. 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. Dispose of the syringe with the remnants of the drug. Detailed recommendations for self-administered injection of the drug are included in these instructions for medical use.

Any amount of unused drug or unused materials must be disposed of in accordance with local requirements.

Instructions for Administration of Proli^Tmprefilled syringes with needle guard

This section provides information on the proper injection of a pre-filled syringe (PZS) with a needle guard. It is very important that before you proceed to self-injection, your doctor, nurse will give you detailed instructions on the technique of the injection.If you have any questions about the technique of injection, contact your doctor or nurse.

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