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 syringe 1 ml
densomab 60 mg 60 mg
Excipients: sorbitol (E420) 47 mg, acetic acid ice 1 mg, sodium hydroxide to pH 5.0-5.5, polysorbate 20 0.1 mg, water q / and up to 1 ml.
1 ml - disposable syringes (1) pre-filled - cardboard packs.
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 (RANKL) receptor and thus inhibits the activation of a single RANKL activator of the nuclear factor KB (RANK) located on the surface of osteoclasts and their predecessors. Thus, the prevention of RANKL / RANK interaction inhibits the formation, activation, and duration of osteoclasts. As a result, denosumab reduces bone resorption and increases the mass and strength of the cortical and trabecular layers of the bone.
Pharmacodynamic effects
The administration of 60mg of denosumab resulted in a rapid decrease in serum concentrations of bone resorption marker-1C-telopeptide (CTX) by approximately 70% within 6 hours after SC administration and by 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 the concentration of CTX in the serum partially decreased with a decrease in the concentration of denosumab in the blood serum, which reflects the reversibility of the effect of denosumab on bone remodeling. These effects were observed throughout the course of treatment.Accordingly, the physiological relationship between the processes of formation and resorption in the remodeling of bone tissue, a decrease in the content of bone formation markers (for example, bone-specific alkaline phosphatase and serum N-terminal propeptide
type 1 collagen) from the first month after the administration of the first dose of denosumab. Markers of bone remodeling (markers of bone formation and bone resorption), as a rule, reached the concentrations of the period before the start of treatment no later than 9 months after the last dose of the drug. After resumption of treatment with denosumab, the degree
decrease in CTX concentrations was similar to the degree of decrease in CTX concentration at the beginning of the course of treatment with denosumab.
It has been shown that the transfer from treatment with alendronic acid (average duration of use - 3 years) to denosumab leads to an additional decrease in the concentration of CTX in the serum compared with the group of postmenopausal women with low bone mass who continued treatment with alendronic acid. At the same time, changes in the serum calcium content were the same in both groups.
In experimental studies, inhibition of RANK / RANKL concomitantly with the binding of osteoprotegerin to the Fc fragment (OPG-Fc), led to a slowing of bone growth and impaired dentition. Therefore, treatment with denosumab may inhibit the growth of bones with open growth zones in children and lead to impaired eruptions
teeth.
Immunogenicity
Denosumab is a human monoclonal antibody, therefore, as with other protein-based drugs, there is a theoretical risk of immunogenicity. More than 13,000 patients have been examined for antibody binding by using sensitive electrochemiluminescence in combination with immunoassay. Less than 1% of patients who took denosumab for 5 years, determined antibodies (including those that existed before, transient and growing). Seropositive patients were further examined for the formation of neutralizing antibodies, using chemiluminescent analysis in in vitro cell culture, neutralizing antibodies was not detected. There were no changes in the pharmacokinetic profile, toxic profile, or clinical response due to the formation of antibodies.
Clinical efficacy
Treatment of osteoporosis in postmenopausal women
In women with postmenopausal osteoporosis, prolia increases bone mineral density (BMD), reduces the incidence of hip fractures, vertebral and non-vertebral fractures. The efficacy and safety of denosumab in the treatment of postmenopausal osteoporosis was demonstrated in a study lasting 3 years. The results of the study show that denosumab significantly, in comparison with placebo, reduces the risk of vertebral and non-vertebral fractures, hip fractures in women with osteoporosis in postmenopausal women. The study included 7,808 women, of whom 23% had frequent vertebral fractures. All three endpoints of efficacy in fracture relationships reached statistically significant values, estimated from a pre-determined sequential testing pattern.
The reduction in the risk of new vertebral fractures with the use of denosumab for more than 3 years remained stable and significant. The risk decreased regardless of the 10-year probability of major osteoporotic fractures. The risk reduction was also not affected by the presence of frequent vertebral fractures in the history, non-vertebral fractures, age, patients, BMD, bone remodeling level and previous therapy for osteoporosis.
In women older than 75 years in postmenopause, denosumab reduced the incidence of new vertebral fractures, and, according to post hoc analysis, reduced the incidence of hip fractures.
A decrease in the frequency of occurrence of non-vertebral fractures was observed regardless of the 10-year probability of major osteoporotic fractures.
Denosumab significantly, compared with placebo, increased BMD in all anatomical areas. IPC was determined after 1 year, 2 and 3 years after initiation of therapy. A similar effect on the MIC was noted in the lumbar spine, regardless of age, race, body mass index (BMI), BMD and bone remodeling.
Histological studies confirmed normal bone architecture and, as expected, decreased bone remodeling compared with placebo. No pathological changes were noted, including fibrosis, osteomalacia, and a violation of bone tissue architectonics.
Clinical efficacy in the treatment of bone loss caused by hormone-deprivation therapy or aromatase inhibitor therapy
Treatment of bone loss caused by deprivation of androgens
The effectiveness and safety of denosumab in the treatment of bone loss associated with a reduction in androgen concentration were demonstrated in a 3-year study involving 1,468 patients with nonmetastatic prostate cancer.
A significant increase in BMD was determined in the lumbar spine, the entire femur, the femoral neck, the thigh bone spine 1 month after the first dose. The increase in BMD in the lumbar spine did not depend on age, race, geographic region, BMI, initial values
IPC, bone remodeling; the duration of hormone-deprivation therapy and the presence of a vertebral fracture in the anamnesis.
Denosumab significantly reduced the risk of new vertebral fractures over 3 years of use. The risk reduction was observed after 1 year and 2 years after the initiation of therapy. Denosumab also reduced the risk of more than one osteoporotic fracture of any location.
Treatment of bone loss, in women receiving aromatase inhibitors therapy 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 involving 252 patients with nonmetastatic breast cancer. Denosumab significantly increased BMD in all anatomical areas, compared with placebo, for 2 years. An increase in BMD was observed in the lumbar spine a month after the first dose. A positive effect on the BMD in the lumbar spine was noted regardless of the age, duration of aromatase inhibitor therapy, BMI, previous chemotherapy, prior use of the selective estrogen receptor modulator (SMRE), and the time elapsed since the onset of menopause.
PHARMACOKINETICS
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.
Suction
After sc administration of 60mg of denosumab, the bioavailability was 61% and Cmax of denosumab was 6 Ојg / ml (range 1-17 Ојg / ml), these parameters were observed after 10 days (range 2-28 days). After reaching C max , the serum content of the drug 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 not detected in the serum after 6 months from the last administration
preparation.
Distribution
There were no changes in the pharmacokinetic parameters of denosumab, as well as cumulation for the entire time of taking multiple doses of the drug at 60 mg every 6 months
Metabolism
Denosumab consists of amino acids and carbohydrates, like regular immunoglobulin. Based on preclinical studies, it is expected that the metabolism of denosumab will occur along the pathway of immunoglobulin clearance, which will result in the breakdown into small peptide chains and individual amino acids.
Excretion
Based on preclinical data, excretion of denosumab will occur along the path of elimination of all immunoglobulins, the result of which will be the breakdown into small peptide chains and individual 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 28 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
- treatment of postmenopausal osteoporosis;
- treatment of bone loss in women receiving aromatase inhibitors therapy for breast cancer and men with prostate cancer receiving hormone-deprivation therapy.
DOSING MODE
Introduction
Carrying out the injection of the drug requires preliminary training - see the recommendations for the administration of the drug listed at the end of this manual.
The recommended dose of the drug is Prolia - one SC injection of 60 mg every 6 months. During the course of treatment it is recommended to take additional calcium and vitamin D.
Children
The preparation of Prolia is not recommended for use in pediatrics, since the efficacy and safety of this drug have 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, 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.
To avoid discomfort at the injection site, the solution should be warmed to room temperature (up to 25 В° C) before injection, and then slowly enter the entire contents of the pre-filled syringe. Dispose of the syringe with the remnants of the drug.
Any quantities of unused product or unused materials must be destroyed in accordance with local requirements
SIDE EFFECT
Data acquired through controlled use in clinical trials.
Undesirable reactions are given by the classes of organ systems in terms of the Medical Regulatory Dictionary (MedDRA).
The incidence of adverse events was classified as follows: very often (? 1/10), often (? 1/100, <1/10), sometimes (? 1/1000, <1/100), rarely (? 1 / 10,000 , <1/1000), very rarely (<1/10 000), including individual cases.
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 metabolism and electrolyte metabolism Very rarely hypocalcemia
From the side of the vision organ Often cataracts in men receiving androgen deprivation therapy for prostate cancer
On the part of the skin and subcutaneous fat. Infrequent eczema, including dermatitis, allergic dermatitis, atopic dermatitis, contact dermatitis
From the musculoskeletal system and connective tissue Often Seldom Pain in the limbs Osteonecrosis of the jaw
CONTRAINDICATIONS
- hypocalcemia;
- Hypersensitivity to any of the components of the drug.
PREGNANCY AND LACTATION
There are no data on the use of the drug during pregnancy. Prolia is not recommended for use in pregnant women.
In toxicological studies on lower primates, it was shown that in doses 100 times greater than those recommended for clinical use, denosumab had no effect on fertility or fetal development.
Experiments on mice with the genome turned off showed that the absence of RANKL can lead to a disruption in the development of the lymph nodes in the fetus, and in the postnatal period may be a cause of impaired 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
The preparation of Prolia is not recommended for use in pediatrics, since the efficacy and safety of this drug have not been studied in this age group.
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
It is recommended to take calcium and vitamin D preparations during the use of the preparation.
Hypocalcemia can be corrected by taking calcium and vitamin D preparations in adequate doses before starting therapy with denosumab. It is recommended that calcium concentration be monitored in patients prone to hypocalcemia.
Patients receiving the preparation of Prolia may develop infections of the skin and its appendages (mainly inflammation of the subcutaneous tissue), in some cases requiring hospitalization. Such reactions were more often reported for the group of denosumab (0.4%) than placebo groups (0.1%). In this case, the overall incidence of skin infections is comparable in the groups of densomab and placebo. Patients should be instructed to seek medical help immediately if symptoms and signs of inflammation of the subcutaneous tissue develop.
Patients with advanced cancer who received 120 mg of denosumab every 4 weeks were reported to develop cases of osteonecrosis of the jaw. There are some reports of the development of osteonecrosis of the jaw at a dose of 60 mg every 6 months.
Persons with an allergy to latex should not touch the rubber cap of the needle (latex derivative).
Impact on the ability to drive vehicles and manage mechanisms
Studies of the impact on the ability to drive vehicles and management mechanisms have not been conducted.
OVERDOSE
In clinical studies, no cases of drug overdose have been reported.
In clinical studies, doses of densumab up to 180 mg were administered every 4 weeks (cumulative dose up to 1080 mg in 6 months).
DRUG INTERACTION
No drug interactions were studied.
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 at 2-8 В° C. Do not freeze. Store in the original package to protect from light.
Do not shake. Keep out of the reach of children!
After removal from the refrigerator shed can be stored at room temperature of not higher than 25 В° C in original package is not more than 30 days.
Shelf life - 3 years.
