Composition, form of production and packaging
Solution for n / to the introduction is transparent, from colorless to light yellow color, practically free from visible inclusions.
1 f. 1 ml
denzomab 120 mg 70 mg
Excipients: sorbitol (E420) 78.2 mg, acetic acid ice 1.8 mg, sodium hydroxide to pH 5.2, water q / and up to 1.7 ml.
1.7 ml - Glass bottles 3 ml (1) - packs of cardboard with the control of the first opening.
1.7 ml - Glass bottles in volume 3 ml (4) - packs cardboard with the control of the first opening.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
PHARMACHOLOGIC EFFECT
Denosumab is a fully human monoclonal antibody (IgG2) having high affinity and specificity for the receptor of the nuclear factor Kappa B activator receptor (RANKL) and interfering with the activation of a single RANKL activator of the nuclear factor KB (RANK) located on the surface of osteoclasts and their precursors. The RANK ligand is a protein present in the body in the form of a membrane-bound and soluble form. RANKL is the main mediator of the metabolic pathway necessary for the formation, functioning and survival of osteoclasts - the only type of cells responsible for bone resorption. The increased activity of osteoclasts induced by RANKL is the main cause of bone destruction during metastases of solid tumors in bone tissue and in multiple myeloma. Prevention of RANKL / RANK interaction inhibits the formation, activation, and survival of osteoclasts. AT
the result of denosumab reduces bone resorption and destruction of bone tissue caused by malignant neoplasms.
Pharmacodynamic effects
Assignment of densumab at a dose of 120 mg SC every 4 weeks resulted in a rapid decrease in bone resorption markers (N-telopeptide urine adjusted for creatinine (uNTX / Cr) and serum 1C-telopeptide) with an average decrease of 82% uNTX / Cr in a week. The decrease in the content of bone metabolism markers remained stable and ranged from 74% to 82% for uNTX / Cr from the second to 25th week of repeated doses of 120 mg every 4 weeks. In 2075 patients with metastatic cancer (breast, prostate, other solid tumors, multiple myeloma) who received the Exjeeva medication, the mean decrease in uNTX / Cr was approximately 80% of the baseline values ​​for 3 months of treatment. Repeated administration of 120 mg of the drug every 4 weeks or every 12 weeks resulted in an average decrease of uNTX / Cr from baseline after 3-6 months of treatment for patients with metastatic cancer and metastases to bone (including patients with multiple myeloma and metastases to bone ) who had previously received IV bisphosphonates and an initial value of uNTX / Cr of less than 50 nmol / mmol at week 25 of treatment.
Immunogenicity
In clinical studies, the formation of neutralizing antibodies was not shown. Less than 1% of patients receiving denosumab, a sensitive immunological test method was used to identify binding but not neutralizing antibodies. There were no changes in the pharmacokinetic profile, toxic profile, or clinical response due to the formation of antibodies.
Clinical efficacy
Prevention of development of complications from the bone tissue (OCST) in patients with metastatic cancer and metastases to the bone.
The efficacy and safety of Exidgiva in preventing skeletal complications in patients with metastatic cancer and bone metastases was demonstrated in 3 randomized, double-blind studies with active control. Exgiva reduces or prevents the risk of developing a COPD or multiple MCS (first and subsequent), in comparison with active control, in patients with malignant tumors metastasizing to bone.
Effect on pain
Pain analysis included changes from initial values ​​on the scale of the modified short pain questionnaire (BPI-SF), time to pain enhancement, moderate or severe pain, improvement in condition, and the proportion of patients meeting the criteria listed. The average time to deterioration (pain enhancement, more than 4 points on a scale or greater or equal to 2 points of increase from the initial values) was longer for Exgiva than for active control. Time to improvement (i.e., greater than or equal to 2 points of pain reduction from baseline values ​​on the BPI-SF scale) was similar for densomab and active monitoring of individual studies and integrated analysis.
Overall survival and progression of the disease
Overall survival remained similar in the groups of denosumab and active control for all three studies and in the combined analysis of the study data. In each of the three studies, overall survival was balanced in the groups of densomab and active control in patients with malignant tumors metastasizing to bone: breast cancer, prostate cancer, other solid tumors or multiple myeloma.
Overall survival was higher in the Exjeeva 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 groups in patients with other solid tumors. Based on the results of an integrated analysis of the data of all three studies, overall survival is similar between the groups of denosumab and active control.
PHARMACOKINETICS
After sc administration, bioavailability is 62%. With n / to the introduction of 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 higher.
Repeated administration of 120 mg every 4 weeks leads to a two-fold increase in serum concentrations of densumab with an equilibrium state of approximately 6 months of treatment. The mean serum concentration in the equilibrium state was 20.6 Ојg / ml (range 0.456-56.9 Ојg / ml). In patients who stopped treatment, the mean T 1/2 was about 28 days (range 14-55 days).
To assess the impact of demographic factors, pharmacokinetics in populations were analyzed. According to the results of the analysis, it was shown that the age (18-87 years), race, body weight (36-174 kg), type of tumor, there were no significant differences in pharmacokinetic parameters. The pharmacokinetics and pharmacodynamics of denosumab were similar in men and women and in patients switched to densomab with IV bisphosphonate therapy.
Denosumab consists of amino acids and carbohydrates, like natural immunoglobulin, therefore it is not metabolized through hepatic metabolic pathways. Metabolism and deducing of dinosumab are presumably due to the same mechanisms as for immunoglobulins, with degradation to peptides of small size and amino acids.
Individual patient groups
Age does not have a significant effect on the pharmacokinetics of densomab according to pharmacokinetic analysis in the patient population from 18 years to 87 years.
Pharmacokinetics in children have not been studied
The pharmacokinetics of denosumab does not depend on race.
In a study of 55 patients with varying degrees of renal failure, including patients on dialysis, the extent of renal failure did not affect the pharmacokinetics and pharmacodynamics of denosumab; therefore, there is no need to correct the dosage regimen of denosumab for chronic renal failure.
Studies of the effect of liver failure on the pharmacokinetics of denosumab have not been conducted.
INDICATIONS
- Prevention of complications from the bone tissue (pathological fractures, bone irradiation, spinal cord compression or bone surgery) in adults with solid tumors metastasizing to the bone.
DOSING MODE
Introduction
The injection of the drug requires preliminary training.
Dose
The recommended dose of the drug is one SC injection of 120 mg every 4 weeks into the thigh, shoulder or abdominal region.
During the course of treatment it is recommended to take additional calcium preparations in a dose of at least 500 mg and vitamin D-400 ME.
Elderly patients
Based on the available data on the efficacy and safety of the drug in this age group, there is no need to correct the dosage regimen of the drug.
Renal insufficiency
Based on the available data on the efficacy and safety of the drug in this group of patients, there is no need to correct the dosage regimen of the drug.
In patients with severe renal failure (creatinine clearance <30 ml / min) or those on dialysis, there is a high risk of developing hypocalcemia. Such patients must additionally take calcium and vitamin D.
Liver failure
Efficiency 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 in case of turbidity or discoloration. Do not shake.
The drug is recommended to be injected with a needle for a single application of the 27th caliber.
To avoid discomfort at the injection site, the solution should be warmed to room temperature before injection.
Any quantities of unused product or unused materials must be destroyed in accordance with national requirements.
SIDE EFFECT
Data obtained from controlled use in clinical trials are listed by the class of organ systems in terms of the Medical Registry Dictionary (MedDRA). The frequency of occurrence is defined as follows:
Often ? 1 of 10
Often ? 1 out of 100 and <1 of 10
Infrequently ? 1 of 1000 and <1 of 100
Rarely ? 1 out of 10 000 and <1 of 1000
Very rarely <1 out of 10 000
In each group of organ systems and the frequency of messages, unwanted reactions are given in descending order of severity.
Organ system class Frequency Undesirable reaction
Infections and infestations infrequently Inflammation of subcutaneous tissue
From the side of the immune system Infrequent Reactions of hypersensitivity
From the side of metabolism and electrolyte metabolism Often Hypocalcemia
Often Hypophosphatemia
From the skin and subcutaneous tissues Often Hyperhidrosis
From the digestive system Often Diarrhea, tooth loss
From the respiratory system Very often Shortness of breath
From the osteomuscular system and connective tissue Osteonecrosis of the jaw Often
Hypocalcemia
In clinical studies in patients with tumors metastasizing to bone, hypocalcemia was more common in the Exgiva group (9.6%) than in the active comparison group (5.0%). A decrease in serum calcium concentrations of grade 3 was observed in 2.5% of patients in the Exjee group and in 1.2% of patients in the active reference group. A decrease in serum calcium concentrations of grade 4 was noted 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 - 1.8% in the group of densomab and 1.3% in the active control group were reported. Clinical symptoms did not differ in subgroups. Among patients with confirmed osteonecrosis of the jaw, the majority (81% in both subgroups) had a history of tooth extraction, unsatisfactory oral hygiene and / or dental sanitation. Most patients received chemotherapy.
CONTRAINDICATIONS
- severe untreated hypocalcemia;
- Pregnancy;
- lactation period;
- age under 18 years (not recommended for use in pediatrics, since the efficacy 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 dentition. , the use of densomab in children with open growth plates can lead to disruption of bone growth and open growth plates and impaired teething);
- Hypersensitivity to the components of the drug.
PREGNANCY AND LACTATION
There is no data on the use of the drug during pregnancy. The drug is not recommended for use in pregnant women.
In toxicological studies on animals exposed to a drug 9.1 times the exposure recommended for clinical use in humans (120 mg every 4 weeks), denosumab had no effect on fertility or fetal development.
Experiments on animals have shown that the absence of RANKL can lead to a disruption in the development of lymph nodes in the fetus, and in the postnatal period may be a cause of dysfunction, teething and bone growth; It is also possible to influence 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 potentially denosumab can cause unwanted reactions in infants, it is necessary either to stop breastfeeding or to cancel the drug.
APPLICATION FOR FUNCTIONS OF THE LIVER
Based on the available data on the efficacy and safety of the drug in this group of patients, there is no need to correct the dosage regimen of the drug.
In patients with severe renal failure (creatinine clearance <30 ml / min) or those on dialysis, there is a high risk of developing hypocalcemia. Such patients must additionally take calcium and vitamin D.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Efficiency and safety have not been studied.
APPLICATION FOR CHILDREN
Contraindicated:
- age under 18 years (not recommended for use in pediatrics, since the efficacy 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 dentition. , the use of densomab in children with open growth plates can lead to disruption of bone growth and open growth plates and impaired dentition).
APPLICATION IN ELDERLY PATIENTS
Based on the available data on the efficacy and safety of the drug in this age group, there is no need to correct the dosage regimen of the drug.
SPECIAL INSTRUCTIONS
Hypocalcemia
Pre-hypocalcemia should be corrected by taking calcium and vitamin D preparations in adequate doses before initiating therapy with denosumab. It is recommended to take calcium and vitamin D preparations during the application of the drug, in the absence of hypercalcemia.
Patients with severe renal insufficiency (creatinine clearance less than 30 ml / min) or those on dialysis are at greater risk of developing hypocalcemia. It is necessary to monitor the concentration of calcium in this subgroup of patients. If hypocalcemia occurs during treatment, additional short-term calcium supplements are recommended if necessary.
Infections of the skin and appendages
In patients receiving densomusum, skin and epididymal infections (mostly inflammation of the subcutaneous tissue) were more common, and in some cases required hospitalization. Such reactions were more often reported for the group of denosumab (0.9%) than for the comparison group (0.7%). Patients should be instructed to seek medical help immediately if symptoms and signs of inflammation of the subcutaneous tissue develop.
Osteonecrosis of the jaw
It is recommended to examine the oral cavity and preventive examination at the dentist before starting therapy in patients at risk of developing osteonecrosis of the jaw. Adequate oral hygiene should be maintained throughout the treatment period with Exidgiva. During treatment, whenever possible, avoid invasive dental procedures. If such procedures are necessary, the decision must be taken in conjunction with the attending physician. Patients with developed osteonecrosis of the jaw during the use of Exidgiva should receive adequate dental treatment. Individual assessment of the benefit / risk ratio prior to prescribing Exgiva to patients with unremovable risk factors for osteonecrosis of the jaw and patients whose osteonecrosis of the jaw developed during the administration of the drug is necessary.
Impact on the ability to drive vehicles and manage mechanisms
Studies on the ability to drive vehicles and manage mechanisms have not been conducted.
OVERDOSE
In clinical studies, no cases of drug overdose have been reported.
DRUG INTERACTION
No drug interactions were studied.
In clinical trials, the drug was administered simultaneously with standard antineoplastic therapy, incl. patients who had previously received bisphosphonates.
Combined use with chemotherapy or hormone therapy did not involve changes in the pharmacokinetics / pharmacodynamics of denosumab, as well as previous intravenous administration of bisphosphonates.
Pharmaceutical incompatibility
The drug should not be mixed with other drugs.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
Store the drug at a temperature of 2 В° -8 В° 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 not higher than 25 В° C in the original packaging for not more than 30 days.
Shelf life - 3 years. Do not use at the end of the expiration date printed on the package.
