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1 syringe (1 ml) includes 60 mg of a denosumab.
In addition: 47 mg of sorbitol, 0.1 mg of polysorbate 20, 1 of mg of glacial acetic acid, to 1 ml of water for infection, to rn 5.0-5.5 sodium hydroxide.
The Prolia is issued in the form of injection solution for p / to (hypodermic) introduction, in syringes on 1 ml No. 1 in secondary packaging.
Inhibiting (oppressing) a bone resorption.
Pharmacodynamics and pharmacokinetics
Active ingredient of drug of Prolia – denosumab – completely is a monoclone of the person and belongs to an immunoglobin subclass of IgG2. This substance is characterized by high specificity and affinity to a receptor ligand κВ (RANKL) – to the activator of a nuclear factor and, contacting it, blocks activation of the only thing of the RANK receptor which is on a surface of osteoclasts, and also their predecessors – the activator of a nuclear factor κВ (RANK). Thereof, interaction of RANKL/RANK does not happen that leads to suppression of education, activation and duration of functioning of osteoclasts and in turn reduces a bone resorption (destruction), and also increases durability and mass of trabecular and cortical layers of a bone.
At hypodermic (p / to) introduction of 60 mg of a denosumab fast decrease in plasma concentration of a 1C-telopeptid (STH) which is a marker of a resorption of a bone tissue, approximately for 70% for 6 hours after an injection and for 85% within the next 3 days was observed. Steadily lowered STH level remained for half a year. At decrease in plasma concentration of a denosumab the speed of lowering of serumal maintenance of STH somewhat decreased that testifies to reversibility of impact of a denosumab on bone remodeling. Such effects were noted during all therapeutic course.
In the course of remodeling of a bone tissue according to physiological interrelation between its education and a resorption, after the first injection of a denosumab within the first month decrease in quantity of markers of bone education was noted (for example, P1NP and kostnospetsifichesky ShchF). Markers of bone remodeling (formation of a bone and its resorption) usually came to the level observed prior to therapy, after no more than 9 months after introduction of the last dose of a denosumab. When resuming introduction of a denosumab the level of decrease in STH corresponded to that at the beginning of a medical course.
In the conducted researches of replacement of therapy from reception of alendronovy acid (treatment duration on average – 3 years) on introduction of a denosumab, taking place with involvement of women with a small bone weight in a postmenopause proved additional reduction of the STH serumal level at use of a denosumab in comparison with reception of alendronovy acid. At the same time plasma concentration of calcium in both studied groups were similar.
Also when carrying out these researches, suppression of interaction of RANK/RANKL in parallel with binding of a Fc-fragment (OPG-Fc) with osteoprotegeriny led to braking of bone growth and delay of a teething. Thereof use of a denosumab for children can negatively influence a teething and development of the bones possessing open growth zones.
Because denosumab its use, as well as other drugs of the proteinaceous nature is a human monoclone, can theoretically lead to an immunogenicity. Using immunoassay in combination with method of sensitive electrochemiluminescence, inspections more than 13000 patients regarding forming at them the connecting antibodies were made. Less than in 1% of cases use of a denosumab for 5 years led to definition of antibodies (including growing, tranzitorny and existing earlier). Seropositive patients passed further inspections for the purpose of identification of neutralized antibodies. In culture of cells of in vitro by method of the chemiluminescent analysis of such antibodies it was revealed not. Also the changes of the clinical answer, a pharmacokinetic and toxic profile dependent on antibody formation were not observed.
At women with the diagnosed post-menopausal osteoporosis use of Prolia strengthened mineral bone density, thereby reducing the frequency of nevertebralny and vertebralny changes, and also hip neck fractures. Profiles of safety and efficiency of a denosumab at therapy of post-menopausal osteoporosis are completely proved during the researches conducted for 3 years. By results of these researches use of Prolia in comparison with administration of "placebo" significantly reduces risk of any changes arising in a postmenopause at women with osteoporosis. 7808 women took part in research, at 23,6% from them fractures of vertebras were earlier often noted. All three final efficient points concerning changes came to statistically significant indicators which estimated according to previously developed consecutive plan of testing.
Use of Prolia for more than 3 years showed significant and stable reduction of risk of emergence of vertebralny changes. Decrease in such risk was observed in independence of 10-year probability of formation of osteoporotichesky large changes, earlier occurring frequent fractures of vertebras, age of patients, nevertebralny changes, the mineral density of bones, extent of bone remodeling and the previous treatment of osteoporosis.
At patients in a postmenopause at the age of 75 years use of Prolia is also more senior led to decrease in frequency of new episodes of vertebralny changes, and also according to carrying out post hoc of the analysis reduced the frequency of cases of fractures of femoral neck.
Decrease in frequency of emergence of nevertebralny changes also did not depend on 10-year probability of formation of osteoporotichesky large changes. Medicine of Prolia in comparison with use of "placebo" significantly increased the mineral bone density determined every year carrying out 3-year-old treatment in one and all anatomic areas. Similar impact of drug on a mineralization of bones was revealed in the lumbar region of a backbone and did not depend on racial accessory of the patient, his age, BWI (body weight index), values of mineral bone density and remodeling of a bone. The conducted histologic researches proved normal structure of bones and, in comparison with "placebo ", lowering of their remodeling. Pathological changes, including osteomalacy, fibrosis and disturbances of bone structure were not noted.
Safety and efficiency of drug of Prolia appointed for therapy of decrease in bone weight because of reduction of maintenance of androgens were also proved during 3-year-old research with involvement of 1468 patients having not metastatic prostate cancer. Significant increase of bone mineral density was revealed in lumbar department, a femur its spit and a neck 30 days later after the first injection of drug. Increase in mineral bone density in lumbar department arose in independence of racial accessory, age, IMT, the geographical region, initial indicators of mineral bone density and bone remodeling, and also existence of the previous vertebralny changes and duration of gormondeprivatsionny therapy.
Throughout 3-year-old use of Prolia the essential reduction of risk of formation of fresh vertebralny changes estimated in 12 and 24 months after purpose of drug was observed. Also introduction of Prolia reduced risk of emergence over one change of osteoporotichesky nature of any localization.
Safety and efficiency of Prolia at therapy of loss of bone weight, because of carrying out adjuvant therapy with aromatase inhibitor use, decided during 2-year-old research on involvement of 252 women with the diagnosed breast cancer (not metastatic). Use of Prolia, in comparison with administration of "placebo ", considerably increased mineral bone density in all studied anatomic areas for 2 years. In lumbar department accumulation of mineral bone density was noted 30 days later after introduction of the first dose and remained throughout all treatment irrespective of age of the patient, IMT, duration of use of inhibitor of aromatase, the previous chemotherapy and use of SMRE, and also time which passed from approach of a menopause.
Pharmacokinetics of a denosumab at it p / to introduction nonlinear and dozozavisimy with the broad dosing range, characterized by increase of exposure of drug in dosages of 60 mg (or 1 mg/kg) and more. At introduction of 60 mg of drug in 10 days (with variability of 2-28 days) its bioavailability was 61%, plasma Cmax made 6 mkg/ml (with variability of 1-17 mkg/ml). On achievement of Cmax serumal concentration decreased since T1/2 26 days (with variability 6-52 days) and further for 3 months (with variability 1,5-4,5 months). In 6 months after introduction of the last dose of Prolia in plasma it was not found in 53% of patients of a denosumab any more. At repeated introduction of 60 mg of a denosumab in each half a year its cumulation and changes of pharmacokinetics was not noted.
As well as ordinary immunoglobulin, denosumab consists of carbohydrates and amino acids. By results of the conducted preclinical trials it is supposed that its metabolic transformations and further removal will take place on the way of usual clearance and removal of immunoglobulins, with disintegration on separate amino acids and short peptide chains.
The pharmacokinetics of a denosumab at its use by patients at the age of 28-87 is not exposed to significant changes. Racial accessory of patients also does not influence drug pharmacokinetics.
Existence at patients of pathologies of kidneys, according to researches with involvement of 55 patients with varying severity of a renal failure including who are on a hemodialysis did not lead to changes of a pharmacodynamics and pharmacokinetics of a denosumab that speaks about lack of need of correction of the dosing mode.
Influence of hepatic pathologies on pharmacokinetic parameters of a denosumab was not studied.
Indications to use
Purpose of Prolia is shown for therapy of post-menopausal osteoporosis, and also loss of mass of a bone tissue at the women with a breast cancer passing treatment using inhibitors of aromatase and at the men with a prostate cancer who are on gormondeprivatsionny therapy.
Use of Prolia is contraindicated at the present hypocalcemia and personal hypersensitivity to a denosumab and/or the HP other ingredients.
When carrying out controlled clinical trials observed the following negative reactions: often – forming of a cataract at the male patients with a prostate cancer passing androgendeprivatsionny therapy, pain in extremities; infrequently – development of eczemas (including, including allergic, contact and atopic dermatitis), inflammatory processes in hypodermic cellulose; seldom – a maxillary osteonecrosis; incidentally – emergence of a hypocalcemia.
Prolia, application instruction
Carrying out p / to injections by drug of Prolia is recommended to carry out twice a year (1 time in 6 months) in a dose of 60 mg. Throughout all course of treatment advise in parallel to accept vitamin D and drugs of calcium.
It is possible to start independent introduction of Prolia only after preliminary consultation at the attending physician during which he has to explain in detail to the patient all nuances of technology of carrying out injections.
For the purpose of decrease in risk of accidental pricks each already filled syringe is equipped with the protective safety lock for a needle which is activated automatically for its closing right after performance of an injection.
It is not necessary to try to disassemble the syringe or to activate a protective safety lock. It is impossible to use syringes with the absent cap or the activated needle safety lock.
For carrying out an injection by drug of Prolia independently you need the new filled syringe and spirit napkins.
Just before introduction it is necessary to get the syringe from the refrigerator, at the same time, without taking it for a protective cap or the piston as it can lead to damage of the device.
For comfortable introduction it is necessary to leave for some time the syringe at the room temperature, but not under the influence of sunshine (it is not necessary to warm up the syringe in hot water, the microwave oven, etc.). It is not necessary to stir up the syringe and to delete a protective cap prior to the beginning of an injection.
Further it is necessary to be convinced of compliance of a period of validity of drug of Prolia specified on packaging and to visually check injection solution for foreign inclusions and discolorations (administration only of transparent, colourless or light yellow solution is allowed). Administration of solution with small vials of air is authorized.
To choose well lit, comfortable place with close located pure surface on which to place materials, necessary for an injection, and to carefully wash up hands.
It is the best of all for injection to carry out to the upper area of a hip or stomach. In case of carrying out procedure by other person the dorsum of hands can be used. At puffiness or reddening of expected area of introduction it is necessary to choose other place for an injection.
To disinfect the chosen place a spirit napkin.
It is accurate to remove a protective cap, without rotating it, and having just pulled up. It is necessary to avoid a contact to a needle and pressing the piston.
To take the syringe in a convenient hand and, without squeezing, to clamp skin between index and big fingers of other hand. To enter a needle into the skin fold basis at an angle 45 ° on depth about 15 mm.
Holding a skin fold smoothly and slowly, to press on the piston before full administration of solution. The protective safety lock of a needle will be closed only when the syringe completely becomes empty.
Without changing pressure upon the piston, it is necessary to remove a needle from a skin fold then to release the piston and to allow a protective safety lock to close entirely a needle.
In case of failure of a safety lock perhaps incomplete introduction of a dose of drug that will demand additional consultation from the doctor.
At emergence of blood in an injection site it is necessary to remove it with a wadded napkin accurately. It is not necessary to pound skin around an injection. The place of a puncture can be stuck with a plaster.
One syringe is intended for carrying out only one injection. The remained drug repeatedly is forbidden to be used.
The used syringe should not be closed a cap. It is necessary to utilize all its parts according to the rules recommended by the doctor.
During the conducted clinical trials introduction of a monthly dose of Prolia of 180 mg for half a year (in the sum of 1080 mg in 6 months) did not reveal any negative symptoms.
The directed researches of interaction of a denosumab with other HP it was not carried out. You should not mix drug with other solutions.
Terms of sale
It is possible to buy Prolia only according to the recipe.
Long safety of drug demands temperature of 2-8 °C. It is necessary to store syringes in packaging of manufacturing plant, in the refrigerator, without freezing. After withdrawal of Prolia from the refrigerator the term of its storage at a temperature up to 25 °C is limited 30 days.
Period of validity
On condition of observance of temperature of 2-8 °C drug can be used for 3 years.
Elderly patients and patients with pathologies of kidneys do not demand correction of the dosing mode of a denosumab.
Influence of pathologies of a liver on safety and efficiency of Prolia was not studied.
During therapy by drug of Prolia recommend to accept in parallel vitamin D and drugs of calcium, in particular to patients with pathologies of kidneys.
Before an initiation of treatment correction of the present hypocalcemia can be made by reception of adequate doses of vitamin D and drugs of calcium. At patients with the increased risk of forming of a hypocalcemia it is necessary to watch the content of calcium.
In certain cases use of Prolia led to development of skin infections and its appendages (as a rule, inflammatory processes in hypodermic cellulose are observed) which can sometimes demand hospitalization. In the conducted researches emergence of such reactions was more often observed in group of use of a denosumab (0,4%) in comparison with group of introduction "placebo" (0,1%). In case of developing of skin infections patients have to report about it to the doctor immediately.
At patients with widespread cancer who passed treatment with monthly introduction of 120 mg of a denosumab, occasionally observed development of an osteonecrosis of a jaw. Also there are separate messages on forming of the given pathology at use of the scheme of therapy denosumaby – 60 mg twice in 12 months.
In the presence at the patient of an allergy to latex it is necessary to avoid contacts to a needle cap.
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