Xgeva solution for subcutaneous injection, 120mg (70mg/ml) 1.7ml vial, 1pc

Composition

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1 ml. solution for subcutaneous use contains: Active ingredient:

• denosumab 70 mg,

excipients:

• sorbitol (E 420) 78.2 mg,
• glacial acetic acid 1.8 mg,
• sodium hydroxide up to pH 5.2,
• water d/i up to 1.7 ml

Pharmacological action

Pharmacotherapeutic grouppreparations for the treatment of bone diseases – other drugs that affect the structure and mineralization of bone. Monoclonal antibodies. ATX code: M05BX04 Pharmacological Propertiespharmacodynamicmechanism of action Enosumab is a fully human monoclonal antibody (IgG2) that has a high affinity and specificity for the kappa B nuclear factor activator receptor (RANKL) ligand and prevents the activation of a single RANKL receptor – the nuclear factor kB activator (RANK) located on the surface of osteoclasts and their precursors. The RANK ligand is a protein present in the body in both membrane-bound and soluble forms. RANKL is the main mediator of the metabolic pathway necessary for the formation, functioning, and survival of osteoclasts, the only cell type responsible for bone resorption. Increased osteoclast activity induced by RANKL is the main cause of bone destruction in solid tumor metastases to bone and in multiple myeloma. Preventing RANKL/RANK interactions inhibits osteoclast formation, activation, and survival. As a result, denosumab reduces bone resorption, bone calcium loss, and bone destruction caused by malignancies. Giant cell bone tumors are characterized by RANK ligand expression by stromal cells and osteoclast-like giant cells expressing RANK. In patients with a giant cell bone tumor, denosumab binds to the RANK ligand, significantly reducing the number or destroying osteoclast-like giant cells. Consequently, osteolysis decreases, and the proliferative stroma of the tumor is replaced by non-proliferative differentiated dense tissue of the new bone. Pharmacodynamic effectsthe use of Xgeva® at a dose of 120 mg subcutaneously every 4 weeks led to a rapid decrease in the content of bone resorption markers (urine N-telopeptide adjusted for creatinine (uNTX/Cr) and serum 1 C-telopeptide) with an average 82% decline in uNTX / Cr over the course of a week. The decrease in bone metabolism markers remained stable and ranged from 74% to 82% by uNTX/Cr from the second to the 25th week of repeated doses of 120 mg every 4 weeks. In 2,075 patients with metastatic cancer (breast, prostate, other solid tumors, multiple myeloma) treated with Xgeva®, the average uNTX/Cr reduction was approximately 80% of baseline values over 3 months of treatment. Repeated subcutaneous use of 120 mg of the drug every 4 weeks or every 12 weeks resulted in an average decrease in uNTX/Cr from baseline values after 3-6 months of treatment in patients with metastatic cancer and bone metastases (including patients with multiple myeloma and bone metastases) who had previously received intravenous bisphosphonates and an initial uNTX/Cr value of less than 50 nmol / mmol at week 25 of treatment. In a phase 2 study, patients with a giant cell bone tumor who received subcutaneous injections of 120 mg Exjiv® with loading doses of 120 mg on days 8 and 15 after the initial dose in the first month of treatment and, further, at a dose of 120 mg once every 4 weeks (Q4W), starting from the second month of treatment, an average decrease in uNTx/Cr and sCTx indicators by about 80% was observed by week 9. A decrease in bone metabolism markers was maintained, with average reductions in uNTx/Cr values from 56% to 77% and sCTx values from 79% to 83% from week 5 to week 25 of continued 120 mg use. Immunogenicity No neutralizing antibody formation has been shown in clinical studies. In less than 1% of patients treated with denosumab, a sensitive immunological method was used to detect binding, but not neutralizing antibodies. There were no changes in the pharmacokinetic profile, toxic profile, or clinical response due to antibody formation. Clinical efficacy to prevent the development of bone tissue complications (BSCT) in patients with metastatic cancer and bone metastases. The efficacy and safety of Xgeva® in preventing skeletal complications in patients with metastatic cancer and bone metastases was demonstrated in 3 randomized, double – blind, active-control trials. Xgeva ® reduces or prevents the risk of developing OSCT or multiple OSCT (first and subsequent), compared to the active control, in patients with malignant tumors that metastasize to bone. Effects on pain The pain analysis included changes from initial values on the modified Short Pain Assessment Questionnaire (BPI-SF) scale, estimates of time to increased pain, moderate or severe pain, improvement in the condition, and the proportion of patients meeting these criteria. The mean time to deterioration (increased pain, greater than 4 points on the scale, or greater than or equal to 2 points increase from baseline) was longer for Xgeva® compared to the active control. The time to improvement (i. e., greater than or equal to 2 points of pain reduction from initial values on the BPI-SF scale) was similar for denosumab and active control based on the results of separate studies and integrated analysis. Overall survival and disease progression Overall survival remained similar in the denosumab and active control groups for all three studies and in the cumulative analysis of these studies. In each of the three studies, overall survival was balanced in the denosumab and active control groups in patients with malignant tumors that metastasize to bone: breast cancer, prostate cancer, other solid tumors, or multiple myeloma. Overall survival was higher in the Xgeva group in patients with non-small cell lung cancer and higher in the active control group in patients with multiple myeloma. Overall survival was similar in the groups of patients with other solid tumors. Based on the results of an integrated analysis of data from all three studies, overall survival was similar between the denosumab and active control groups. Treatment of giant cell bone tumor in adult patients or adolescents with a developed skeleton. The safety and efficacy of Xgeva® were studied in two open-label, non-comparable phase 2 trials involving 305 patients with unresectable giant cell bone tumors, or in whom surgery may have been associated with a severe complication. Patients received 120 mg of Xgeva subcutaneously every 4 weeks with loading doses of 120 mg on days 8 and 15. Overall,71.6% of patients responded to the use of Xgeva®. The response rate was determined by at least 90% giant cell elimination compared to baseline (or complete giant cell elimination in cases where giant cells accounted for the majority of hypercalcemia in malignant tumors. The safety and efficacy of Xgeva® was studied in an open-label, non-comparative phase 2 trial involving 33 adult patients with hypercalcemia in malignant tumors (with or without bone metastases) resistant to treatment with intravenous bisphosphonates. Patients were given 120 mg of Xgeva subcutaneously every 4 weeks with additional doses of 120 mg on the 8th and 15th days of the first month of treatment. Refractory hypercalcemia in malignant tumors was defined as an albumin-adjusted calcium concentration >12.5 mg/dl (3.1 mmol/L), despite treatment with intravenous bisphosphonates in the last 7-30 days. The primary endpoint was the number of patients who achieved a response, defined as serum calcium concentration adjusted for albumin (CSC) ≤ 11.5 mg/dl (2.9 mmol/L), within 10 days of Xgeva use. Xgeva caused a rapid and prolonged decrease in albumin-adjusted serum calcium concentrations in most patients, including those with or without bone metastases. Pharmacokineticsafter subcutaneous use, the bioavailability is 62%. 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. In patients with advanced malignancy, repeated use of 120 mg every 4 weeks leads to a twofold increase in serum denosumab concentrations, reaching an equilibrium state by approximately 6 months of treatment. In patients with a giant cell bone tumor who received 120 mg every 4 weeks with loading doses on days 8 and 15, the equilibrium state was reached during the first month of treatment. Between 9 and 49 weeks, the median minimum concentrations changed by no more than 9%. The mean serum concentration at steady state was 20.6 mcg / ml (range 0.456-56.9 mcg / ml). In patients who stopped treatment, the average elimination half-life was about 28 days (range 14-55 days). To assess the influence of demographic factors, pharmacokinetics in populations were analyzed. This analysis showed no significant differences in pharmacokinetics related to age (18-87 years), race, body weight (36-174 kg) or in patients with solid tumors and giant cell bone tumors. The pharmacokinetics and pharmacodynamics of denosumab were similar in men and women and in patients transferred to denosumab from intravenous bisphosphonate therapy.Denosumab consists of amino acids and carbohydrates, like natural immunoglobulin, so it is not metabolized through the hepatic metabolic pathways. Denosumab metabolism and elimination presumably follow the same mechanisms as for immunoglobulins, with degradation to small peptides and amino acids. Selected patient groups Elderly patients (age 65 years or older)Age did not significantly affect the pharmacokinetics of denosumab according to pharmacokinetic analysis in the population of patients aged 18 to 87 years. Children and teenagers (under 18 years of age)Pharmacokinetics in children have not been studied. The pharmacokinetics of denosumab are independent of race. Patients with impaired renal function In the denosumab trials (60 mg, N=55 and 120 mg, N=32), in 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; therefore, no adjustment of the dosage regimen of denosumab in chronic renal failure is required. Chronic hepatic insufficiency No studies have been conducted on the effect of hepatic insufficiency on the pharmacokinetics of denosumab.

Indications

Prevention of bone complications (pathological fractures, bone irradiation, spinal cord compression, or bone surgery) in adults with solid tumors that metastasize to bone.

Use during pregnancy and lactation

There are no data on the use of the drug during pregnancy.

The drug is not recommended for use in pregnant women.

In animal toxicological studies, denosumab did not affect fertility or fetal development when exposed to the drug 9.1 times higher than the recommended exposure for clinical use in humans (120 mg every 4 weeks).

Animal experiments 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 disorders, 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.

Contraindications

• Hypersensitivity to any of the components of the drug.
• Severe untreated hypocalcemia.
• Pregnancy and lactation.
• Children under 18 years of age (if indicated-prevention of bone complications).
• Children under 12 years of age and with an unformed skeleton (according to the indication – treatment of a giant cell bone tumor).
• Xgeva®is not recommended for use in pediatrics, with bone metastases of solid tumors for the prevention of bone complications, since the effectiveness and safety of this drug have not been studied in this age group.
• In experimental animal studies, inhibition of RANK/RANKL resulted in inhibition of bone growth and impaired teething. Thus, the use of denosumab in children with open growth plates can lead to impaired bone growth and open growth plates and impaired teething.

Side effects

Data obtained from controlled use in clinical trials are listed by class of organ systems in terms of the Medical Dictionary of Regulatory Activity (MedDRA).

The frequency of occurrence is defined as follows:

• Very often ≥ 1 in 10
• Often ≥ 1 in 100 and < 1 in 10
• Infrequently ≥ 1 in 1000 and < 1 in 100
• Rarely ≥ 1 in 10,000 and < 1 in 1,000
• Very rare < 1 in 10,000

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

Hypocalcemia In clinical studies in patients with bone metastatic tumors, hypocalcemia was more often observed in the Xgeva group (9.6%) than in the active comparison group (5.0%).

A decrease in serum calcium concentrations of the 3rd degree was observed in 2.5% of patients in the Xgeva group and in 1.2% of patients in the active comparison group. A decrease in grade 4 serum calcium concentrations was observed in 0.6% of patients and in 0.2% of patients in the active control group.

Osteonecrosis of the jaw In patients with metastatic cancer, cases of osteonecrosis of the jaw were reported-1.8% in the denosumab group and 1.3% in the active control group. Clinical symptoms did not differ in the subgroups.

Among patients with confirmed osteonecrosis of the jaw, the majority (81% in both subgroups) had a history of tooth extraction, poor oral hygiene, and/or dental sanitation. Most of the patients received chemotherapy.

Interaction

No drug interaction studies have been conducted. In clinical trials, the drug was administered simultaneously with standard antineoplastic therapy, including patients previously treated with bisphosphonates. Concomitant use with chemotherapy or hormone therapy did not alter the pharmacokinetics/pharmacodynamics of denosumab, nor did previous intravenous use of bisphosphonates. Pharmaceutical Incompatibility The product should not be mixed with other medicinal products.

How to take, course of use and dosage

Injectionincutaneous injection. Injecting the drug requires prior training. During the course of treatment, it is recommended to additionally take calcium supplements at a dose of at least 500 mg and vitamin D-400 IU. Dose of bone tissue complicationthe recommended dose of the drug is one subcutaneous injection of 120 mg every 4 weeks in the thigh, abdomen or shoulder. Giant cell bone tumour The recommended dose of the drug is 120 mg with loading doses of 120 mg on days 8 and 15 of treatment after the initial dose is administered in the first month of treatment and, further, one subcutaneous injection of 120 mg every 4 weeks, starting from the second month of treatment. Hypercalcemia in malignant tumors 120 mg every 4 weeks with additional doses of 120 mg on the 8th and 15th days of the first month of treatment. Use in selected patient groups Elderly patients Based on the available data on the efficacy and safety of the drug in this age group, no adjustment of the dosage regimen of the drug is required (see the section “Pharmacokinetics”, subsection “Individual patient groups”). Children and adolescents (under 18 years of age)The safety and efficacy of Xgeva® in children have not been established, with the exception of adolescents with a developed skeleton with a giant cell bone tumor. Xgeva®is not recommended for use in children, with the exception of adolescents with a developed skeleton with a giant cell bone tumor. Xgeva®was studied in an open-label phase 2 study that included a subgroup of 10 adolescents (aged 12-17 years) with a giant cell bone tumor and a developed skeleton, which was determined by at least one mature long tubular bone (for example, by closing the epiphyseal growth plate of the humerus) and a body weight of ≥ 45 kg (see the section “Indications for use” and “Clinical efficacy”). Renal insufficiency 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 the section “Pharmacokinetics”, subsection “Individual patient groups”). In clinical trials in patients without metastatic cancer with varying degrees of renal function (including patients with severe renal insufficiency [creatinine clearance Monitoring of calcium concentrations and appropriate use of calcium and vitamin D supplements is important for patients with severe renal insufficiency, or who are on dialysis.section “Special instructions”). Hepatic insufficiency 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. The drug is recommended to be administered with a single 27-gauge needle. To avoid discomfort at the injection site, warm the solution to room temperature before injection. Any quantities of unused medicine or unused materials must be disposed of in accordance with national requirements.

Overdose

In clinical studies, there were no cases of overdose of the drug.

Special instructions

Hypocalcemia Existing hypocalcemia should be corrected by taking adequate doses of calcium and vitamin D supplements before starting denosumab therapy. It is recommended to take calcium and vitamin D supplements during the use of the drug, in the absence of hypocalcemia. Hypocalcemia may occur during treatment with Xgeva. Monitoring of calcium concentrations is recommended throughout treatment with Xgeva®, especially in the first weeks after the start of therapy. Patients with severe renal insufficiency (creatinine clearance less than 30 ml / min) or who are on dialysis are at greater risk of developing hypocalcemia. When used in routine clinical practice, severe symptomatic hypocalcemia has been reported (see section “Side effects”). If hypocalcemia occurs during treatment, additional short-term calcium supplements are recommended if necessary (see the section “Dosage and use-Use in selected patient groups”). Skin and appendage infections patients receiving denosumab were more likely to have skin and appendage infections (mainly inflammation of the subcutaneous tissue), in some cases requiring hospitalization. These reactions were reported more frequently in the denosumab group (0.9%) than in the comparison group (0.7%) (see section “Side effects”). Patients should be instructed to seek immediate medical attention if symptoms and signs of subcutaneous tissue inflammation develop. Osteonecrosis of the jaw (ULF)ONP was observed in patients treated with denosumab. In clinical studies, the incidence of VLF was higher with a longer duration of exposure (see section “Side effects”). Inadequate oral hygiene, invasive dental procedures (such as tooth extraction), anti-angiogenic treatment, and gum or oral infections were all risk factors for developing HPV in patients receiving Xgeva® in clinical trials. It is recommended to have an oral examination and a preventive dental checkup before starting Xgeva® therapy, especially in patients at risk of developing osteonecrosis of the jaw. Adequate oral hygiene should be maintained throughout the entire period of treatment with Xgeva®. Invasive dental procedures should be avoided during treatment. If such procedures are necessary, the decision on the treatment plan for each patient should be made jointly with the attending physician based on an individual assessment of the benefit / risk ratio. Patients with HPV who develop during the use of Xgeva® should receive adequate dental treatment. In patients with HPV who develop during the use of Xgeva®, a decision may be made to temporarily discontinue treatment until the condition resolves, based on an individual assessment of the risk / benefit ratio. An individual benefit / risk assessment is required before prescribing Xgeva® to patients with unavoidable risk factors for developing osteonecrosis of the jaw and for patients who have developed osteonecrosis of the jaw during the use of the drug. Xgeva® contains the same Active ingredient (denosumab) as Prolia. Patients receiving Prolia should not take Xgeva®. Atypical femoral fractures Atypical femoral fractures have been reported with Xgeva®. Atypical femoral fractures – subtrochanteric or diaphyseal fractures of the proximal femur – may occur with minimal or no trauma and may be bilateral. In the pictures, these fractures usually have a characteristic appearance. Atypical femoral fractures have also been reported in patients with concomitant diseases and conditions (e. g. vitamin D deficiency, rheumatoid arthritis, hypophosphatasia), and in patients receiving certain therapies (e. g. bisphosphonates, glucocorticosteroids, proton pump inhibitors). These cases were also observed in the absence of antiresorptive therapy. Patients receiving Xgeva should be instructed to report any new or unusual pain in the hip, hip joint, or groin area. Patients who experience such symptoms should be examined for a femoral fracture and the contralateral femur should also be examined. Patients with hepatic insufficiency No clinical studies have been conducted in patients with hepatic insufficiency. Excipient warnings Patients with rare hereditary problems of fructose intolerance should not use Xgeva®. Calcium supplementation You may need an additional short-term intake of calcium supplements (see section “Dosage and use”). Patients with multiple myeloma Xgeva® is not used for the prevention of bone complications in patients with multiple myeloma. Influence on the ability to drive vehicles, mechanisms Studies of the effect on the ability to drive vehicles and manage mechanisms have not been conducted.

Product form

solution for subcutaneous use

Storage conditions

Store the preparation at a temperature of 2°-8°C. Do not freeze it. Store in the original packaging to protect from light. Do not shake. Keep out of reach of children. After removal from the refrigerator, the drug can be stored at room temperature.

Shelf

life is 3 years.

Active ingredient

Denosumab

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection