Proliya - instructions for use, doses, side effects, contraindications

Active substanceDenosumabDenosumab

Similar drugsTo uncover

Prolia®

solution PC

Amgen Europe BV Netherlands

Exjiva®

solution PC

Amgen Europe BV Netherlands

Dosage form: & nbsphypodermic solution

Composition:

Each pre-filled syringe contains:

active substance: 60 mg of denosumab in 1 ml of the solution (60 mg / ml);

Excipients: sorbitol (E420) 47 mg, acetic acid ice 1 mg, polysorbate 20 0.1 mg, sodium hydroxide to pH 5.0-5.5, water for injection up to 1 ml.

Prolia® is a sterile product and does not contain preservatives.

Description:

Transparent liquid, from colorless to light yellow, virtually free of visible inclusions.

Pharmacotherapeutic group:antibodies monoclonal

ATX: & nbsp

M.05.B.X Other drugs affecting the mineralization of bones

Pharmacodynamics:

Mechanism of action

Denosumab is a fully human monoclonal antibody (IgG2), having a high affinity and specificity for the receptor of the nuclear factor Kappa B receptor (RANKL) and thereby prevents the activation of a single receptor RANKL - activator of nuclear factor KV (RANK), located on the surface of osteoclasts and their precursors. Thus, preventing interaction RANKL/RANK 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 bone.

Pharmacodynamic effects

The use of 60 mg of dinosumab led to a rapid decrease in serum concentrations of bone resorption marker-1C-telopeptide (CTX) by approximately 70% within 6 hours after subcutaneous administration and approximately 85% during the next 3 days. The decrease in the CTX concentration remained stable in the 6-month interval between administrations. 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 densomab on bone remodeling. These effects were observed throughout the course of treatment. Correspondingly, the physiological relationship between the processes of formation and resorption in the remodeling of bone tissue showed a decrease in the content of bone formation markers (eg, bone-specific alkaline phosphatase and serum N-terminal propeptide of type I collagen) from the first month after the administration of the first dose of denosumab.

The 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 administration of the last dose of the drug. After the resumption of treatment with denosumab, the degree of reduction in CTX concentrations was similar to the degree of decrease in CTX concentration at the beginning of the course of treatment with denosumab.

It was shown that the transfer from treatment with alendronic acid (average duration of use - 3 years) for 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 RANK/RANKL simultaneously 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 dentition.

Immunogenicity

Denosumab is a human monoclonal antibody, therefore, as with other protein-like drugs, there is a theoretical risk of immunogenicity. More than 13,000 patients were examined for the formation of binding antibodies using the sensitive electrochemiluminescence method in combination with immunoassay. Less than 1% of patients who took denosumab for 5 years, antibodies were determined (including those that existed before transient and growing). Seropositive patients were further examined for the formation of neutralizing antibodies, using chemiluminescent analysis in cell culture in vitro, no neutralizing antibodies were 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 effectiveness 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 23.6% had frequent vertebral fractures. All three endpoints of fracture efficacy reached statistically significant values, estimated from a predefined sequential test 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 history, non-vertebral fractures, patient age, BMD, bone remodeling level and previous therapy for osteoporosis.

In women older than 75 years in postmenopausal women denosumab reduced the frequency the occurrence 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. Effect of treatment with the preparation of Prolia^® in cases of occurrence of new vertebral and non-vertebral fractures during the year were evaluated within the framework of a 5-year extended study with a total duration of 8 years. When treating with Prolia^® there is a low risk of new vertebral and non-vertebral fractures, and also continues to increase BMD compared with the baseline in the lumbar spine, the entire femur, the femoral neck and the thigh bone for 5 years.

Histological studies of 5-year-old Prolia® treatment confirmed normal architectonics 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 therapy with aromatase inhibitors

Treatment of bone loss caused by deprivation of androgens

The effectiveness and safety of denosumab in the treatment of bone loss associated with a decrease in androgen concentration were demonstrated in a 3-year study of 1,468 patients with nonmetastatic prostate cancer.

A significant increase in BMD was determined in the lumbar spine, the entire femur, the femoral neck, and the thigh bone after 1 month after the first dose. The increase in BMD in the lumbar spine did not depend on age, race, geographic region, BMI, initial BMD, 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 during 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 localization.

Treatment of bone loss, in women receiving aromatase inhibitors therapy for breast cancer glands

The effectiveness 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 that included 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 administration of the first dose. A positive effect on the BMD in the lumbar spine was noted regardless of the age, duration of therapy with the aromatase inhibitor, BMI, prior chemotherapy, the prior use of the selective estrogen receptor modulator (CMEF), and the time elapsed since the onset of menopause.

Treatment of osteoporosis in men

Efficiency and Security of the Province^® in the treatment of osteoporosis in men was demonstrated in a 12-month study that included 242 patients with reduced bone mass, with a baseline T-score of MIC between -2.0 and -3.5 in the lumbar spine or femoral neck. Men with a T-score of MIC between -1.0 and -3.5 for the lumbar spine or femoral neck and fractures in the anamnesis were also included. Men with other diseases (such as rheumatoid arthritis, osteogenesis and Paget's disease) or treatment that may have an effect on bone have been excluded from the study.

Treatment with Prolia® within 1 year significantly increased BMD compared with baseline values in the lumbar spine and all parts of the skeleton (proximal femur, distal radius). Prolia® increased the lumbar spine of the lumbar spine to 4.8%, the MIC of the femur to 2.0%, the BMD of the femur spit to 2.3%, the cervical femoral neck to 2.2%, the peripheral 1/3 of the MPC radius to 0, 9%, compared with placebo.

An increase in the BMD of the lumbar spine, femur and trochanter of the femur was observed after 6 months.Stable effects on the BMD of the lumbar spine were observed regardless of age, race, body weight / body mass index (BMI), BMD and bone resorption.

Histology of the bone and histomorphometry

Qualitative histological evaluations showed normal architectonics and bone quality, without any defects in bone mineralization or bone marrow fibrosis in patients treated with Prolia®.

Pharmacokinetics:

When administered subcutaneously denosumab characterized by a nonlinear pharmacokinetics, dose-dependent over a wide range of doses, and a dose-dependent increase in exposure for a dose of 60 mg (or 1 mg / kg) and above.

Suction

After subcutaneous administration of densomab at a dose of 60 mg, the bioavailability was 61% and the maximum concentration of denosumab (C_m_Oh) - 6 μg / ml (range 1-17 μg / ml), these parameters were observed after 10 days (range 2-28 days). After attaining FROM_m_Oh the serum content of the drug decreased with a half-life of 26 days (range 6-52 days) and further within 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 of the drug.

Distribution

There were no changes in pharmacokinetic parameters denosumab, as well as cumulation for the entire time of administration of 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 immunoglobulin clearance pathway, which will result in the breakdown into small peptide chains and individual amino acids. In the study, 17 women with postmenopausal osteoporosis received midazolam (2 mg orally) two weeks after a single injection of densomab (60 mg subcutaneously), which corresponds to the time to reach the maximum pharmacodynamic effects of denosumab. Denosumab did not affect the pharmacokinetics of midazolam metabolized by isoenzyme CYP3A4 cytochrome P450. Consequently, denosumab should not change the pharmacokinetics of drugs metabolized by isoenzyme CYP3A4.

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

Patients of advanced age (age 65 years or older)

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.

Children and adolescents (under 18 years of age)

Pharmacokinetics in children have not been studied.

Race

The pharmacokinetics of denosumab does not depend on race.

Patients with renal insufficiency

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.

Chronic liver 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 mass loss in women receiving aromatase inhibitor therapy for breast cancer, and in men with prostate cancer receiving hormone-deprivation therapy;

- treatment of senile osteoporosis in men.

Contraindications:

- Hypersensitivity to any of the components of the drug;

hypocalcemia.

Pregnancy and lactation:

Pregnancy

There is no data on the use of the drug during pregnancy. Prolia® is not recommended for use in pregnant women.

Denosumab did not cause a decrease in fertility in Javanese macaques when exposed to the drug 100 times higher than human exposure (60 mg every 6 months).

In a study on Javanese macaques, there was no adverse effect on the mother or fetus during the period equivalent to the first trimester of exposure to densumab at doses 99 times higher than the human dose (60 mg every 6 months). In this study, the formation of the fetal lymph nodes was not evaluated.

In another study in Javanese macaques, who received denosumab during pregnancy, at an exposure 119 times greater than that in humans (60 mg every 6 months), there was an increase in the rate of fetal birth and postnatal mortality; abnormal growth bones with reduced bone strength, decreased hematopoiesis and dysplasia; absence of peripheral lymph nodes; and a decrease in the growth of the newborn.There was no negative impact on the mother's body before delivery; rarely had adverse reactions during labor. The development of the mammary gland of the mother was normal.

Experiments on mice with a switched off gene showed that absence RANKL can affect the maturation of the breast, which can lead to a weakening of lactation.

Breast-feeding

It is not known whether denosumab 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.

Dosing and Administration:

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.

Dose

The recommended dose of Prolia® is one subcutaneous injection of 60 mg every 6 months.

During the course of treatment it is recommended to take additional calcium preparations and vitamin D.

Use in selected patient groups

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 for correction of the dosage regimen of the drug, see the section "Pharmacokinetics", subsection "Individual patient groups").

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 adjust the dosage regimen of the drug (see the section "Pharmacokinetics", subsection "Individual patient groups").

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 preparations 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 ° 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.

Detailed recommendations for independent subcutaneous administration of the drug are included in this manual for medical use.

Any quantities of unused product or unused materials must be destroyed in accordance with local requirements.

Side effects:

Conclusion on the safety profile of the drug

Based on the results of four placebo-controlled studies of the third phase, the safety profile of the preparation of Prolia® is similar when used in postmenopausal women and in patients with malignant neoplasms of the mammary glands or prostate gland receiving hormone-deprivation therapy.

When using the preparation, Prolia® was rarely reported on the development of cellulite, rare cases of hypocalcaemia, hypersensitivity and osteonecrosis of the jaw, and rare cases of development of atypical fractures of the femur (see section "Special instructions" and a description of some of the undesirable reactions of this section).

Unwanted reactions recorded in Phase 2 and 3 studies that included postmenopausal patients receiving hormone-deprivation therapy, as well as spontaneous reports received during the post-marketing period, are shown in the table below.

Frequency of occurrence is determined as follows: very often (≥ 1/10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000), based on the overall rate of occurrence. In each group of organ systems and frequency of messages, undesirable reactions are given in descending order of severity.

System class bodies	Frequency	Unwanted reaction
Infections and invasions	Often	Urinary tract infections
	Often	Respiratory infection
	Infrequently	Diverticulitis¹
	Infrequently	Inflammation subcutaneous cellulose¹
	Infrequently	Ear infections
From the immune system	Rarely	Reactions hypersensitivity¹
From the side of metabolism and electrolyte metabolism	Rarely	Hypocalcemia¹
From the nervous system	Often	Ischialgia
From the side of the organ of vision	Often	Cataract¹
From the side of the digestive system	Often	Constipation
From the skin and subcutaneous fat	Often Often	Rash Eczema
From the side of the osteo-muscular system and connective tissue	Highly often	Pain in the extremities
	Rarely	Osteonecrosis jaws¹
	Rarely	Atypical fracture thigh bone¹

¹see the description of individual unwanted reactions.

In a generalized analysis of data from all placebo-controlled studies of Phase II and III on the development of influenza-like syndrome was reported with a total incidence rate of 1.2% for denosumab and 0.7% for placebo. This imbalance was established in a generalized data analysis and was not detected in a stratified analysis.

Description of individual adverse reactions

Hypocalcemia

In two placebo-controlled third-phase studies that included women in the postmenopausal period, approximately 0.05% of patients (2 of 4050) had lower serum calcium concentrations (less than 1.88 mmol / L) after administration of the drug. There was no reported decrease in serum calcium concentrations (below 1.88 mmol / L) in two placebo-controlled studies that included patients receiving a hormone-deprivation therapy.

When used in routine clinical practice, rare cases of severe symptomatic hypocalcemia were reported in patients with an increased risk of hypocalcemia receiving Prolia®.

Skin Infections

The incidence of reports of skin infections was comparable for the Prolia® group (1.5%, 59 of 4050) and placebo [1.2%, 50 of 4041] in controlled trials of the third phase in postmenopausal women with osteoporosis,receiving hormone-deprivation therapy for breast or prostate cancer (placebo [1.7%, 14 of 845] compared with the group of the drug Prolia^® [1.4%, 12 of 860]). Skin infections requiring hospitalization were developed in 0.1% (3 of 4041) of patients with postmenopausal osteoporosis in the placebo group and 0.4% (16 of 4050) of the patients of the Prolia® group. It was mostly cases of cellulite. Serious cases of skin infections have been reported with similar frequency in placebo groups (0.6%, 5 of 845) and the preparation of Prolia^® (0.6%, 5 of 860) in studies with hormone-deprivation therapy.

Osteonecrosis of the jaw

In clinical studies of osteoporosis (treated with 9768 patients for more than one year), rare reports on the development of osteonecrosis of the jaw in the group of the preparation of Prolia® (see section "Special instructions") have been recorded.

Atypical fractures of the femur

In clinical studies of osteoporosis, rare cases of atypical fractures of the femur have been reported in patients in the group receiving the preparation of Prolia® (see section "Special instructions").

Cataract

In one of the placebo-controlled Phase III studies in patients with prostate cancer receiving hormone-derivational therapy, there was an imbalance in reports of cataract development (4.7% in the group of denosumab, 1.2% in the placebo group).This imbalance has not been documented in studies involving postmenopausal women or women receiving aromatase inhibitor therapy for breast cancer.

Diverticulitis

In one of the placebo-controlled Phase III studies in patients with prostate cancer receiving hormone-deprivation therapy, there was an imbalance in reports of diverticulitis (1.2% in the denosumab group, 0% in the placebo group). The incidence of diverticulitis was comparable in the study groups that included postmenopausal women or in women receiving aromatase inhibitor therapy for breast cancer.

Hypersensitivity reactions

In patients receiving the preparation of Prolia^®in the post-marketing period, rarely reported on hypersensitivity reactions associated with the drug, including rash, hives, face swelling, erythema and anaphylactic reactions.

Musculoskeletal pain

Patients receiving Prolya® received reports of musculoskeletal pain, including severe pain.

Other selected patient groups

In clinical studies,patients with severe renal insufficiency (creatinine clearance <30 ml / ml) or dialysis patients, there was a higher risk of developing hypocalcemia in the absence of calcium supplementation.

Patients in this group should take calcium and vitamin preparations D (see section "Special instructions").

Overdose:In clinical studies, no cases of drug overdose have been reported. In clinical studies, doses of denosumab were administered up to 180 mg every 4 weeks (cumulative dose up to 1080 mg in 6 months).

Interaction:

Prolia® (60 mg subcutaneously) does not affect the pharmacokinetics of midazolam metabolized by the cytochrome P450 isoenzyme CYP3A4, which shows that there is no effect on the pharmacokinetics of drugs metabolized along this pathway (see section "Pharmacokinetics").

Pharmaceutical incompatibility

The drug should not be mixed with other drugs.

Special instructions:

It is recommended to take calcium and vitamin preparations D during the application of the preparation Prolia®.

Hypocalcemia can be corrected by taking calcium and vitamin preparations D in adequate doses before the initiation of therapy with denosumab.It is recommended to monitor the concentration of calcium during therapy in patients prone to hypocalcemia, especially in the first weeks after the initiation of therapy (see section "Side effect").

Patients receiving the preparation of Prolia® can 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%) (see the "Side effect" section). In this case, the overall incidence of skin infections is comparable in the groups of densomab and placebo. Patients should be instructed promptly Seek medical attention if symptoms develop and signs of inflammation of the subcutaneous tissue.

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 (see the "Side effect" section).

Inadequate oral hygiene and invasive dental procedures (for example, tooth extraction) were risk factors for VLF in patients receiving Prolya^®in clinical studies.

Before starting therapy, it is important to assess patients with risk factors for VLF development. If risk factors are identified before treatment with Prolia^®it is recommended to conduct an examination of the oral cavity and teeth with the implementation of appropriate preventive dental activities. During treatment with Prolia®, adequate hygiene of the cavity of the company should be maintained.

During treatment with Prolia®, invasive dental procedures should be avoided. If such procedures are necessary, the decision on the treatment plan for each patient should be taken in conjunction with the attending physician on the basis of an individual benefit / risk ratio assessment.

Patients with suspected development of VLF, or whose VLF developed during treatment with Prolia®, should be monitored by a dentist or maxillofacial surgeon. In patients with VLF developed during the use of Prolia®, a decision may be made to temporarily discontinue treatment until the condition is resolved on the basis of an individual evaluation risk / benefit ratio.

Atypical fractures of the femur were noted in patients in the Prolia® group.Atypical fractures of the femur - susceptible or diaphyseal fractures of the proximal femur - may occur with minimal trauma or without trauma and may be bilateral. In the pictures, these fractures usually have a characteristic appearance.

On Atypical femoral fractures have also been reported in patients with concomitant diseases and conditions (e.g., vitamin deficiency, rheumatoid arthritis, hypophosphatasia) and in patients treated with some types of therapy (e.g., bisphosphonates, glucocorticoids, proton pump inhibitors). These cases were also observed in the absence of antiresorptive therapy. Should instruct patients receiving drug Prolia®, the need to report the emergence of a new or unusual pain in the thigh, hip or groin. Patients who develop such symptoms, They should be screened for the presence of femoral fractures and should also be investigated contralateral hip.

Persons who are allergic to latex should not touch the rubber needle cover (a derivative of latex).

Prolia® contains the same active substance (denosumab), as well as Exgiva®. Patients receiving Prolynia^®, should not take Exgiva®.

Instructions for administering Prolia® in a pre-filled syringe with a needle guard

Guide to parts of the syringe

See Fig. 1.

Important: Read this manual carefully before using Prolia® in a pre-filled syringe with a needle guard:

- It is very important that before you start independent injections, your doctor or nurse thoroughly instructed you on the technique of performing the injection.

- Prolia® is administered subcutaneously (subcutaneous injection).

- Inform your doctor if you are allergic to latex (the needle cap of the pre-filled syringe consists of a latex derivative).

- Not remove the gray cap from the needle of the pre-filled syringe until you are ready to be injected.

- Not Use a pre-filled syringe if it has fallen on a hard surface. Use a new pre-filled syringe and inform your doctor or nurse about it.

- Not try to activate the protective device of the pre-filled syringe beforeinjection.

- Not Try to remove the transparent protective device from the pre-filled syringe before injection.

If you have any questions, please contact your doctor or nurse.

Step 1: Preparation

A. Extract the outline package with the prefilled syringe from the package and prepare everything that is needed for the injection.

For a more comfortable injection, leave the pre-filled syringe at room temperature for about 30 minutes before the injection. Wash your hands thoroughly with soap and water. Place the pre-filled syringe on a clean, well-lit surface. Also prepare alcohol-soaked napkins, cotton swabs or bandage and a band-aid (not attached to the syringe).

- Not Try to warm up the syringe in hot water or a microwave.

- Not leave the pre-filled syringe in direct sunlight.

- Not shake pre-filled syringe.

- Store the pre-filled syringe in a place inaccessible to children.

AT. Open the outline package by pulling the label.To remove the pre-filled syringe from the contour pack, hold on to the protective device.

Take the syringe as shown in Figure 2 (see Figure 2).

For security:

- Not grasp the plunger

- Not grasp the gray needle cap

FROM. Check the preparation and pre-filled syringe.

- Not use a pre-filled syringe if:

the preparation is cloudy or contains foreign particles. The solution should be clear, colorless or light yellow;
lThe juba of parts is damaged or broken;
fromThe first needle cap is missing or loosely attached;
andstack the last day of the expiration date indicated on the label of the month.

Tell your doctor or nurse about all of the cases listed.

Step 2: Preparation of injection site

A. Wash your hands thoroughly. Prepare and treat the injection site.

You can use (see Figure 3):

Upper thigh
The abdomen, except for the area around the navel, is about 5 cm
The outer surface of the shoulder (only if someone else does the injection to you).

Treat the injection site with a tampon moistened with alcohol. Allow the skin to dry.

- Not Touch the injection site before injection.

- Not Use for injection areas where the skin is thin, with a hematoma, red or hard. Avoid injections in areas with scars or stretch marks.

AT. Gently pull the gray cap from the needle without twisting, away from the syringe.

FROM. Clamp the injection site to obtain an elastic surface.

It is important to keep the skin clamped during injection (see Figure 4).

Step 3: Introduction

A. Pinch the skin. ENTER the needle into the skin (see Figure 5).

- Not touch the treated area of the injection.

AT. Slowly and smoothly SUCK on the piston until you feel or hear a "click". Press down on the piston until it clicks (see figure 6).

It is important to press the plunger until it clicks to insert the entire dose.

FROM. RELEASE your thumb. Then, remove the syringe from the skin (see Figure 7).

After you release the plunger, the protective device of the pre-filled syringe will cover the needle.

- Not Wear the gray needle cap back onto the pre-filled syringe.

Step 4: Finish

A. Discard the used pre-filled syringe and other related materials in accordance with local regulations.

Discard the used pre-filled syringe and the gray needle cap.Drugs should be disposed of in accordance with local requirements. Ask the doctor or pharmacist how to destroy the drug if it is no longer needed. These measures will help protect the environment. Keep syringes and related materials out of the reach of children.

- Not use the pre-filled syringe again.

AT. Examine the injection site.

- If blood appears at the injection site, press a cotton swab or bandage to it.

Not rub the injection site. If necessary, seal the injection site with a patch.

Instructions for the administration of the drug Prolia^® in a pre-filled syringe

This section provides information on the proper administration of the injection previously filled with a syringe.

It is very important that before you start independent injections, your doctor, nurse, in detail, instructed you on the technique of performing the injection.

Wash hands thoroughly before performing the injection.

If you have any questions about the technique of doing the injection, then contact your doctor or nurse.

Before the injection:

Read all instructions carefully before using the PZS.

DO NOT use PZH if the cap has been removed.

How do I use a pre-filled syringe?

Your doctor has prescribed a Prolia® PZH for subcutaneous injections. You must enter the entire contents of the syringe (1 ml) once and repeat the injection at 6 months, as prescribed by your doctor.

Equipment

For a self-injection you will need:

1. A new preparation of the preparation Prolia®; and

2. alcohol-soaked tampons or similar materials.

What you need to do before self-introduction of Prolia^® subcutaneously?

1. Take the syringe out of the refrigerator. DO NOT take the PZS by the piston or protective cap, this may damage the device.

2. The PZS can be left outside the refrigerator to reach room temperature. it will make the injection more comfortable.

NOT heat the PZS in some other way (for example, in a microwave oven or in hot water).

NOT leave the syringe in direct sunlight.

3. NOT shake the PZS.

4. NOT remove the cap from the PZH until you are ready to be injected.

5. Check the expiration date of the FSP. Shelf life is indicated on the package as "YEAR BEFORE: MMGYYY".

NOT Use PZH if the last day of the expiration date indicated on the label of the month has expired.

6. Check the appearance of the preparation Prolia®. The solution should be clear, colorless or light yellow. If the solution is cloudy or colored differently, the drug should not be used.

7. Choose a comfortable, well-lit place and a clean surface where you can conveniently arrange all the necessary materials.

8. Wash hands thoroughly.

How to choose the right place for injection?

It is best to inject in the upper part of the hip and in the abdomen.

If you are injected to someone else, you can use the outer surface of the shoulder (see Figure 8).

How to make an injection correctly?

1. Disinfect the injection site with an alcohol-soaked tampon.

2. To avoid bending the needle, gently pull the cap off the needle immediately without twisting.

NOT Touch the needle and do not press the plunger.

3. If small air bubbles are visible inside the PZH, there is no need to remove them before injection.

The introduction of a solution with air bubbles is safe.

4. Hold the skin (not squeezing) between the thumb and forefinger. Insert the needle into the skin completely, as the doctor or nurse showed you.

5. Slow and gently push the piston, while holding the skin fold. Push the piston until the syringe is empty.

6. Remove the needle from the skin, and release the skin fold.

7. If blood flows at the site of the injection puncture, gently wipe it with a cotton swab or tissue. Do not rub the injection site. If necessary, seal the injection site with a patch.

8. Use one PZH for only one injection. DO NOT use the drug left in the syringe.

Remember: If you have any problems, ask for help or advice from your doctor or nurse.

Disposal of used syringes

- DO NOT put the cap back on the used syringe.

- Keep the used syringe out of the reach of children.

- The used syringe must be disposed of in accordance with local regulations. Ask the doctor or pharmacist how to destroy the drug if it is no longer needed. These measures will help protect the environment.

Effect on the ability to drive transp. cf. and fur:

Studies of the impact on the ability to drive vehicles and management mechanisms have not been conducted.

Form release / dosage:Solution for subcutaneous administration, 60 mg / ml.

Packaging:

In a disposable pre-filled syringe (PZH) 1 ml of glass I hydrolytic class with a needle 27G stainless steel, elastomeric cap and elastomer plunger, laminated fluoropolymer (with or without needle guard).

The labeled syringe is placed in a cardboard pack, along with the instructions for use.

The PZS can be additionally placed in a contour mesh package with a thermal sticker.

Each contour mesh package is placed in a cardboard box together with an instruction for use and a patient card describing the injection technique (for a PZS with a needle guard). The cardboard box is provided with a tear-off reminder card with two reminding stickers.

For each protective label - control the first opening, having a longitudinal color strip.

Storage conditions:

Store at 2-8 ° C. Do not freeze.

Keep in original packaging to protect from light.

Do not shake.

Keep out of the reach of children.

After removal from the refrigerator, Prolia® can be stored at room temperature not higher than 25 ° C, in the original packaging, no more than 30 days.

Shelf life:

3 years.

Do not use at the end of the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-000850

Date of registration:14.10.2011 / 22.06.2015

Date of cancellation:2016-10-14

The owner of the registration certificate:Amgen Europe BVAmgen Europe BV Netherlands

Manufacturer: & nbsp

AMGEN EUROPE, B.V. Netherlands

DOBROLEK, LLC Russia

Representation: & nbspAMDZHEN LLC AMDZHEN LLC Russia