Instructions and indications for use of Exjiva
Indications
Exjiva medicine is used to prevent the deterioration of bone cells. Similar symptoms occur when:
- frequent fractures;
- exposure to radioactive radiation;
- surgical procedures in patients with serious tumor metastases spreading to the bones.
Pharmacology
Retarder of bone epithelium resorption. Immune cells that produce protective proteins. The drug Denosumab is a human component that has the protective functions of polysaccharides and has the ability to bind the activated centers of molecules with a certain set of antibodies. RANK proteins are found in the body in membrane connections and are capable of dissolution. RANKL is an intermediary at the moment of transformation of the sequence of chemical processes that carry out the resorption of bone epithelium in the presence of huge multinucleated cells. The high energy of the latter causes the breakdown of bones in the presence of tumor foci. Denosumab prevents bone degradation, which is caused by malignant ulcers.
How to use Exjiva
Dose. How to take Exjiva is determined by highly qualified and trained medical personnel. The amount of medication taken is one dose of subcutaneous injection of one hundred and twenty milligrams for 4 weeks. The product is injected into the area of the shoulder, thigh or abdomen. During the therapy period, it is advisable to consume calcium at a rate of at least five hundred milligrams and vitamin D-400 ME.
Before use, Exgiva solution must be checked for the presence of foreign bodies, color changes or turbidity. And for painless administration, it is advisable to heat the drug to ambient temperature. The medication should not be shaken. The needle used for injection must be 27 gauge.
Exjiva instructions for use
Active ingredient Denosumab Dosage form: solution for subcutaneous administration
Composition: Each vial contains: active substance: 120 mg of denosumab in 1.7 ml of solution (70 mg/ml); excipients: sorbitol (E420) 78.2 mg, glacial acetic acid 1.8 mg, sodium hydroxide to pH 5.2, water for injection up to 1.7 ml.
Description: Transparent liquid from colorless to light yellow, practically free of visible inclusions.
Pharmacotherapeutic group: monoclonal antibodies ICD-10: II.C76-C80.C79.5 Secondary malignant neoplasm of bones and bone marrow XIII.M80-M85.M81.0 Postmenopausal osteoporosis XIII.M80-M85.M81.4 Drug-induced osteoporosis ATC: M .05.BX Other drugs affecting bone mineralization
Pharmacodynamics: Mechanism of Action Denosumab is a fully human monoclonal antibody (IgG2) that has high affinity and specificity for receptor activator of nuclear factor kappa B (RANKL) ligand and interferes with the activation of the single RANKL receptor of activator of nuclear factor kB (RANK), located on the surface of osteoclasts and their predecessors. The RANK ligand is a protein present in the body in membrane-bound and soluble forms. RANKL is a major mediator of a metabolic pathway required for the formation, function and survival of osteoclasts, the only cell type responsible for bone resorption. Increased osteoclast activity induced by RANKL is a major cause of bone destruction in bone metastases from solid tumors and multiple myeloma. Prevention of RANKL/RANK interaction inhibits osteoclast formation, activation, and survival. As a result, denosumab reduces bone resorption and bone destruction caused by malignant neoplasms. Giant cell tumors of bone are characterized by RANK ligand expression by stromal cells and RANK-expressing osteoclast-like giant cells. In patients with giant cell tumor of bone, denosumab binds to the RANK ligand, significantly reducing the number or eliminating osteoclast-like giant cells. Consequently, osteolysis is reduced and the proliferative tumor stroma is replaced by non-proliferative, differentiated dense new bone tissue. Pharmacodynamic effects The use of Exgiva® at a dose of 120 mg subcutaneously every 4 weeks led to a rapid decrease in the levels of markers of bone resorption (urinary N-telopeptide corrected for creatinine (uNTX/Cr) and serum 1C-telopeptide) with an average decrease of 82% uNTX/ Cr for a week. Reductions in bone turnover markers remained stable and ranged from 74% to 82% for uNTX/Cr from weeks 2 to 25 of repeated doses of 120 mg every 4 weeks. In 2075 patients with metastatic cancer (breast, prostate, other solid tumors, multiple myeloma) treated with XGIVA®, the average reduction in uNTX/Cr was approximately 80% of baseline values over 3 months of treatment. Repeated subcutaneous administration of 120 mg every 4 weeks or every 12 weeks resulted in a mean decrease in uNTX/Cr from baseline values after 3 to 6 months of treatment in patients with metastatic cancer and bone metastases (including patients with multiple myeloma and bone metastases), previously receiving intravenous bisphosphonates and an initial uNTX/Cr value of less than 50 nmol/mmol at week 25 of treatment. In a phase 2 study in patients with giant cell tumor of bone who received subcutaneous injections of 120 mg of Exjiva® with loading doses of 120 mg on days 8 and 15 after the starting dose in the first month of treatment and then at a dose of 120 mg once every 4 weeks ( Q4W), starting from the second month of treatment, by week 9 there was an average decrease in uNTx/Cr and sCTx by approximately 80%. Reductions in bone turnover markers were maintained, with mean decreases in uNTx/Cr values from 56% to 77% and sCTx values from 79% to 83% from weeks 5 to 25 of continued 120 mg dosing. Immunogenicity Clinical studies have not demonstrated the formation of neutralizing antibodies. In less than 1% of patients treated with denosumab, binding but not neutralizing antibodies were detected by sensitive immunoassay. There were no changes in the pharmacokinetic profile, toxic profile or clinical response due to antibody formation. Clinical efficacy Prevention of skeletal complications (OSCT) in patients with metastatic cancer and bone metastases The efficacy and safety of Exjiva® in the prevention of skeletal complications in patients with metastatic cancer and bone metastases was proven in 3 randomized, double - blinded studies with active control. Exjiva® reduces or prevents the risk of developing OSCT or multiple OSCT (first and subsequent), compared with active control, in patients with malignant tumors that have metastasized to the bone. Effect on Pain Pain analyzes included changes from baseline in the modified Brief Pain Inventory (BPI-SF), time to worsening pain, moderate to severe pain, improvement, and the proportion of patients meeting these criteria. The mean time to worsening (increased pain, greater than 4 scale points or greater than or equal to 2 points increase from baseline) was longer for XGIVA® compared to the active control. Time to improvement (i.e., greater than or equal to 2 points of pain improvement from baseline on the BPI-SF) was similar for denosumab and active control across individual studies and integrated analyses. Overall survival and disease progression Overall survival remained similar between the denosumab and active control groups for all three studies and in the pooled analysis of study data. In each of the three studies, overall survival was balanced between the denosumab and active control groups in patients with malignancies that had metastasized to bone: breast cancer, prostate cancer, other solid tumors, or multiple myeloma. Overall survival was higher in the Exjiva 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 between groups in patients with other solid tumors. In an integrated analysis of data from all three studies, overall survival was similar between the denosumab and active control groups. Treatment of giant cell tumor of bone in skeletally mature adults or adolescents The safety and effectiveness of Exjiva® was studied in two open-label, single-comparative phase 2 studies involving 305 patients with giant cell tumor of bone that was unresectable or in whom surgery was likely to be associated with a severe complication. Patients received 120 mg of Exjiva® subcutaneously every 4 weeks with loading doses of 120 mg on days 8 and 15. Overall, 71.6% of patients responded to Exjiva®. Response rate was defined as at least 90% clearance of giant cells from baseline (or complete clearance of giant cells in cases where giant cells constituted <5% of tumor cells) , or the absence of progression of the target tumor lesion during radiographic studies in cases where pathohistological data were not available. The median time to response was 3.1 months. Median duration of response could not be assessed because several patients experienced disease progression with a median follow-up of 13.4 months. The efficacy results in skeletally mature adolescents were similar to those observed in adult patients.
Pharmacokinetics: After subcutaneous administration, bioavailability is 62%. When administered subcutaneously, denosumab exhibits nonlinear dose-dependent pharmacokinetics over a wide dose range and a dose-dependent increase in exposure for doses of 60 mg (or 1 mg/kg) and above. In patients with advanced malignancy, repeated administration of 120 mg every 4 weeks results in a two-fold increase in denosumab serum concentrations, reaching steady state at approximately 6 months of treatment. In patients with giant cell tumor of bone receiving 120 mg every 4 weeks with loading doses on days 8 and 15, steady-state was achieved during the first month of treatment. Between weeks 9 and 49, median trough concentrations changed by no more than 9%. The mean serum concentration at steady state was 20.6 μg/mL (range, 0.456–56.9 μg/mL). In patients who discontinued treatment, the mean elimination half-life was approximately 28 days (range, 14-55 days). To assess the influence of demographic factors, pharmacokinetics analysis was performed in populations. This analysis showed no significant differences in pharmacokinetics associated with age (18–87 years), race, body weight (36–174 kg), or in patients with solid tumors and giant cell tumor of bone. The pharmacokinetics and pharmacodynamics of denosumab were similar in men and women and in patients switched to denosumab from intravenous bisphosphonate therapy. Denosumab consists of amino acids and carbohydrates, like natural immunoglobulin, and therefore is not metabolized through the hepatic metabolic pathways. Denosumab is metabolized and eliminated presumably by the same mechanisms as immunoglobulins, with degradation to small peptides and amino acids. Selected Patient Populations Elderly Patients (age 65 years or older) Age did not have a significant effect on the pharmacokinetics of denosumab based on pharmacokinetic analysis in the patient population 18 years to 87 years of age. Children and adolescents (under 18 years of age) Pharmacokinetics have not been studied in children. Race: The pharmacokinetics of denosumab are independent of race. Patients with Renal Impairment In studies of denosumab (60 mg, N=55 and 120 mg, N=32), in 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 ; therefore, no adjustment of the denosumab dosage regimen is required for chronic renal failure. Chronic liver failure No studies have been conducted to study the effect of liver failure on the pharmacokinetics of denosumab.
Indications: Bone Complications Prevention of bone complications (pathologic fractures, bone radiation, spinal cord compression, or bone surgery) in adults with solid tumors that have metastasized to bone. Giant cell tumor of bone Treatment of giant cell tumor of bone in adult patients or adolescents with a mature skeleton (see section “Clinical effectiveness”)
Contraindications: Hypersensitivity to any of the components of the drug. Severe untreated hypocalcemia. Pregnancy and lactation period. Children under 18 years of age (according to indications - prevention of complications from bone tissue). Children under 12 years of age and with an immature skeleton (if indicated - treatment of giant cell tumor of the bone). Exjiva® is not recommended for use in pediatric patients, with bone metastases of solid tumors for the prevention of complications from bone tissue, 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 tooth eruption. Thus, the use of denosumab in children with open growth plates may lead to impaired bone growth and open growth plates and impaired tooth eruption.
Pregnancy and lactation: Pregnancy There are no data on the use of the drug during pregnancy. The drug is not recommended for use in pregnant women. While using Exjiva®, and for 5 months after stopping treatment, women are advised to use contraceptive methods to prevent pregnancy. Denosumab did not cause decreased fertility in cynomolgus monkeys at exposures 16 times higher than human exposure (120 mg every 4 weeks). In a study in cynomolgus monkeys, there were no adverse effects on the mother or fetus during a period equivalent to the first trimester of exposure to denosumab at doses 10 times the human dose (120 mg every 4 weeks). This study did not evaluate fetal lymph node formation. In another study in cynomolgus monkeys treated with denosumab during pregnancy, at an exposure 12 times that of humans (120 mg every 4 weeks), an increase in the incidence of stillbirth and postnatal mortality was observed; abnormal bone growth with reduced bone strength, reduced hematopoiesis and impaired tooth formation; absence of peripheral lymph nodes and decreased growth of the newborn. There were no negative effects on the mother’s body before childbirth; Rarely, the mother experienced adverse reactions during childbirth. Maternal breast development was normal. Animal experiments have shown that the absence of RANKL may affect mammary gland maturation, which may lead to decreased lactation. Breastfeeding 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 the drug.
Method of administration and dosage: Introduction Subcutaneous injection. Injecting the drug requires prior training. During the course of treatment, it is recommended to additionally take calcium supplements in a dose of at least 500 mg and vitamin D - 400 IU. Dose Bone complications The recommended dosage is one 120 mg subcutaneous injection every 4 weeks in the thigh, abdomen, or upper arm. Giant cell tumor of bone The recommended dose of the drug is 120 mg with loading doses of 120 mg on days 8 and 15 of treatment after the starting dose in the first month of treatment and then one subcutaneous injection of 120 mg every 4 weeks starting from the second month of treatment.
Use in certain groups of patients Elderly patients Based on the available data on the effectiveness and safety of the drug in this age group, no adjustment of the drug dosage regimen is required (see section “Pharmacokinetics”, subsection “Separate groups of patients”). Children and adolescents (under 18 years of age) The safety and effectiveness of Exjiva® have not been established in children, with the exception of skeletally mature adolescents with giant cell tumor of bone. Exgiva® is not recommended for use in children, with the exception of skeletally mature adolescents with giant cell tumor of bone. Exjiva was studied in an open-label, phase 2 study that included a subgroup of 10 adolescents (ages 12–17 years) with giant cell tumor of bone and skeletal maturity, as defined by at least one mature long bone (eg, epiphyseal plate closure) humeral height) and body weight ≥ 45 kg (see section “Indications for use” and “Clinical effectiveness”). Renal failure Based on the available data on the effectiveness and safety of the drug in this group of patients, no adjustment of the drug dosage regimen is required (see section “Pharmacokinetics”, subsection “Separate groups of patients”). In clinical trials in patients without metastatic cancer with varying degrees of renal function (including patients with severe renal impairment [creatinine clearance <30 mL/min] or on dialysis), there was a greater risk of developing hypocalcemia with increasing degrees of renal impairment and in the absence of medications. calcium. Monitoring calcium concentrations and appropriate administration of calcium and vitamin D supplements is important for patients with severe renal failure or on dialysis (see section "Special Instructions"). Liver failure Efficacy and safety have not been studied.
Instructions for use The solution should be assessed before administration for inclusions or color changes. The solution should not be used if it becomes cloudy or changes color. Do not shake. It is recommended to administer the drug with a 27-gauge single-use needle. To avoid discomfort at the injection site, the solution should be warmed to room temperature before injection. Any unused quantities of the drug or unused materials must be destroyed in accordance with national requirements.
Adverse Effects: Data obtained from controlled use in clinical trials and from use in routine clinical practice are listed by organ system class in Medical Dictionary for Regulatory Activities (MedDRA) terms. The frequency of occurrence is defined as follows: Very common - ≥1/10 Common - ≥1/100 and <1/10 Uncommon - ≥1/1000 and <1/100 Rare - ≥1/10000 and <1/1000 Very rare - < 1/10000 In each group of organ systems and frequency of reports, adverse reactions are listed in descending order of severity. Organ system class Frequency Adverse reaction Infections and infestations UncommonInflammation of the subcutaneous tissue Disorders of the immune system Uncommon Hypersensitivity reactions1 Rarely Anaphylactic reactions1 Metabolic and electrolyte disorders Common Hypocalcemia1 Common Hypophosphatemia Skin and subcutaneous tissues Common Hyperhidrosis Digestive system disorders Very common Diarrhea Very common Nausea Common Tooth loss Respiratory, thoracic and mediastinal disorders Very common Dyspnea Very common Cough Musculoskeletal and connective tissue disorders Common Osteonecrosis of the jaw1 Rare Atypical femoral fracture1 General disorders and changes at the injection site Very common Fatigue Nervous system Very common Headache 1 see section “Special Instructions”. Hypocalcemia In clinical studies in patients with tumors metastasizing to the bone, hypocalcemia was more common in the Exjiva group (9.6%) than in the active comparison group (5.0%). Grade 3 decreases in serum calcium concentrations were observed in 2.5% of patients in the Exjiva group and in 1.2% of patients in the active comparator group. A grade 4 decrease in serum calcium concentrations was observed in 0.6% of patients and in 0.2% of patients in the active control group. Severe symptomatic hypocalcemia (including fatal cases) has been reported when used in routine clinical practice. Osteonecrosis of the jaw (ONJ) In three active-controlled phase 3 clinical trials in patients with advanced bone malignancies, OJV was confirmed in 1.8% of patients in the Exjiva® group (median exposure 12.0 months; range 0.1- 40.5) and in 1.3% of patients in the active control group. Studies in patients with breast or prostate cancer included an open-label continuation phase of treatment with XJIV® (median total exposure, 14.9 months; range, 0.1–67.2) (see Clinical Efficacy section). The patient-year-adjusted incidence of confirmed ONJ was 1.1% during the first year of treatment and 4.1% thereafter. The median time to onset of ONJ was 20.6 months (range: 4-53). Atypical femoral fractures Atypical femoral fractures have been reported with the use of XGIV®. Hypersensitivity reactions Hypersensitivity, including anaphylactic reactions. Musculoskeletal pain Musculoskeletal pain, including severe pain.
Overdose: In clinical studies, there were no cases of drug overdose.
Interaction: No drug interaction studies have been conducted. In clinical studies, the drug was administered simultaneously with standard antineoplastic therapy, including in patients previously treated with bisphosphonates. Concomitant use with chemotherapy or hormonal therapy did not cause changes in the pharmacokinetics/pharmacodynamics of denosumab, nor did previous intravenous administration of bisphosphates. Pharmaceutical incompatibility The drug should not be mixed with other drugs.
Special instructions: Hypocalcemia Existing hypocalcemia should be corrected by taking calcium and vitamin D supplements in adequate doses before starting denosumab therapy. It is recommended to take calcium and vitamin D supplements during use of the drug, in the absence of hypocalcemia. Hypocalcemia may occur during treatment with XGIVA®. Monitoring calcium concentrations is recommended throughout treatment with Exjiva®, especially in the first weeks after starting therapy. Patients with severe renal impairment (creatinine clearance less than 30 ml/min) or 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 supplementation is recommended as needed (see Dosage and Administration - Use in Selected Patient Populations). Infections of the skin and appendages In patients receiving denosumab, infections of the skin and its appendages (mainly inflammation of the subcutaneous tissue) were more often observed, in some cases requiring hospitalization. Such reactions were more often reported for the denosumab group (0.9%) than for the comparison group (0.7%) (see section "Side effects"). Patients should be instructed to immediately seek medical attention if symptoms and signs of subcutaneous tissue inflammation develop. Osteonecrosis of the jaw (ONJ) OJJ has been observed in patients treated with denosumab. In clinical studies, the incidence of ONJ was higher with longer exposure durations (see section "Side effects"). Poor oral hygiene, invasive dental procedures (eg, tooth extraction), antiangiogenic treatments, and gum or oral infections were risk factors for the development of ONJ in patients receiving XGIVA in clinical studies. An examination of the oral cavity and a preventive examination by a dentist is recommended before starting Exjiva® 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 Exjiva®. During treatment, invasive dental procedures should be avoided. 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 ONJ that develops while using Exjiva® should receive adequate dental treatment. In patients with ONJ that develops while using XGIVA®, 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 assessment of the benefit/risk ratio is required before prescribing Exjiva® to patients with irreparable risk factors for the development of osteonecrosis of the jaw and for patients in whom osteonecrosis of the jaw developed while using the drug. Exgiva® contains the same active ingredient (denosumab) as Prolia. Patients receiving Prolia should not take XGIVA®. Atypical femoral fractures Atypical femoral fractures have been reported with the use of XGIV®. Atypical femoral fractures—subtrochanteric or diaphyseal fractures of the proximal femur—may occur with minimal or no trauma and may be bilateral. On imaging, these fractures usually have a characteristic appearance. Atypical femoral fractures have also been reported in patients with underlying diseases and conditions (eg, vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and in patients receiving certain therapies (eg, bisphosphonates, corticosteroids, proton pump inhibitors). These cases have also been observed in the absence of antiresorptive therapy. Patients receiving XJIVA® should be instructed to report any new or unusual pain in the thigh, hip, or groin. Patients who experience these symptoms should be evaluated for a femoral fracture and the contralateral hip should also be examined. Patients with hepatic impairment No clinical studies have been conducted in patients with hepatic impairment. Excipient Warning: Patients with rare hereditary fructose intolerance should not use Exjiva®. Calcium supplements Additional short-term calcium supplementation may be necessary (see Dosage and Administration). Patients with multiple myeloma Exjiva® is not used to prevent bone complications in patients with multiple myeloma.
Impact on the ability to drive vehicles. Wed and mech.: No studies have been conducted on the effect on the ability to drive vehicles and operate machinery.
Release form/dosage: Solution for subcutaneous administration 70 mg/ml.
Packaging: 1.7 ml of the drug in a 3 ml glass bottle of hydrolytic class I with a 13 mm elastomeric stopper, an aluminum cap and a break-off polypropylene cap. 1 or 4 bottles are placed in a cardboard pack, equipped with a cardboard retainer, along with instructions for use. A transparent protective label is affixed to each pack - first-opening control, which has a longitudinal colored stripe.
Storage conditions: Store at a temperature of 2-8 °C. Do not freeze. Store in original packaging to protect from light. Do not shake. Keep out of the reach of children. After removal from the refrigerator, the drug can be stored at room temperature no higher than 25 ° C, in the original packaging for no more than 30 days.
Shelf life: 3 years. Do not use after the expiration date stated on the package.
Conditions for dispensing from pharmacies: By prescription
Manufacturer: AMGEN EUROPE, BV Netherlands
Special Cautions
Exjiva should be taken with extreme caution if:
- hypocalcemia;
- renal failure;
- skin infections;
- osteonecrosis of the jaw.
For complications associated with a low amount of calcium in the blood (hypocalcemia), Exjiva is recommended to be used after a preliminary course of taking medicinal calcium and vitamin D.
Ability to manage transport and perform responsible functions. The effects of the drug on the ability to drive cars and other equipment have not been studied.
Use in old age. There is no need to change the dosage of the medication for older people.
