Prolia^® (Solution) Instructions for Use

Marketing Authorization Holder

Amgen Europe, B.V. (Netherlands)

Manufactured By

Amgen Manufacturing, Limited (Puerto Rico)

Packaging and Quality Control Release

AMGEN EUROPE, B.V. (Netherlands)

Or

AMGEN TECHNOLOGY (Ireland), Unlimited Company (Ireland)

Or

DOBROLEK, LLC (Russia)

ATC Code

M05BX04 (Denosumab)

Active Substance

Denosumab (Rec.INN registered by WHO)

Dosage Form

Prolia®

Solution for subcutaneous administration 60 mg/1 ml: 1 ml syringe 1 pc.

Dosage Form, Packaging, and Composition

Solution for subcutaneous administration in the form of a clear or slightly opalescent liquid from colorless to slightly yellow, practically free from visible inclusions.

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

1 ml – single-use prefilled syringes* (1) – trays (1) – cardboard packs^×.
1 ml – single-use prefilled syringes* (1) – blister packs with thermal label (1) – cardboard packs^×.

* with 27G needle, cap and plunger (with or without needle safety device).
^× each pack has a transparent protective label – first opening control, with a longitudinal colored stripe.
The cardboard pack is supplied with a tear-off reminder card.
The drug Prolia^® is a sterile product and does not contain preservatives.

Clinical-Pharmacological Group

Bone resorption inhibitor. Monoclonal antibody

Pharmacotherapeutic Group

Means for the treatment of bone diseases; agents affecting bone structure and mineralization; other agents affecting bone structure and mineralization

Pharmacological Action

Denosumab is a fully human monoclonal antibody (IgG2) with high affinity and specificity for the receptor activator of nuclear factor kappa-B ligand (RANKL), thereby preventing the activation of the sole receptor for RANKL – receptor activator of nuclear factor kappa-B (RANK), located on the surface of osteoclasts and their precursors. Thus, preventing the RANKL/RANK interaction inhibits the formation, activation, and survival of osteoclasts. As a result, Denosumab reduces bone resorption and increases the mass and strength of cortical and trabecular bone.

Pharmacodynamic effects

Administration of denosumab at a dose of 60 mg led to a rapid decrease in serum concentrations of the bone resorption marker – C-terminal telopeptide (CTX) – by approximately 70% within 6 hours after subcutaneous administration and by approximately 85% over the next 3 days. The decrease in CTX concentration remained stable over the 6-month dosing interval. The rate of decrease in serum CTX concentration partially decreased with the decrease in serum denosumab concentration, reflecting the reversibility of denosumab’s effect on bone remodeling. These effects were observed throughout the course of treatment. In accordance with the physiological relationship between formation and resorption processes in bone remodeling, a decrease in the content of bone formation markers (e.g., bone-specific alkaline phosphatase and serum N-terminal propeptide of type 1 collagen) was observed from the first month after the first dose of denosumab. Bone remodeling markers (bone formation and bone resorption markers) generally reached pre-treatment concentrations no later than 9 months after the last dose of the drug. Upon resumption of denosumab treatment, the degree of CTX reduction was similar to the degree of CTX reduction at the start of the denosumab treatment course.

It was shown that switching from alendronic acid treatment (average duration of use – 3 years) to Denosumab leads to an additional decrease in serum CTX compared to the group of postmenopausal women with low bone mass who continued alendronic acid treatment. At the same time, changes in serum calcium levels were the same in both groups.

In experimental studies, inhibition of RANK/RANKL simultaneously with binding of osteoprotegerin to the Fc fragment (OPG-Fc) led to delayed bone growth and impaired tooth eruption. Therefore, denosumab treatment may inhibit bone growth in children with open growth plates and lead to impaired tooth eruption.

Immunogenicity

Denosumab is a human monoclonal antibody, therefore, as with other protein drugs, there is a theoretical risk of immunogenicity. More than 13,000 patients were tested for the formation of binding antibodies using a sensitive electrochemiluminescence method combined with an immunoassay. Less than 1% of patients taking Denosumab for 5 years had antibodies (including pre-existing, transient, and increasing). Seropositive patients were further tested for the formation of neutralizing antibodies using an in vitro cell culture chemiluminescent assay; no neutralizing antibodies were found. No changes in pharmacokinetic profile, toxicity profile, or clinical response due to antibody formation were identified.

Clinical efficacy

Treatment of postmenopausal osteoporosis

In women with postmenopausal osteoporosis, Prolia^® increases bone mineral density (BMD), reduces the incidence of hip fractures, vertebral and nonvertebral fractures. The efficacy and safety of denosumab in the treatment of postmenopausal osteoporosis was proven in a 3-year study. The study results show that Denosumab significantly, compared to placebo, reduces the risk of vertebral and nonvertebral fractures, hip fractures in women with postmenopausal osteoporosis. The study included 7808 women, of whom 23% had prevalent vertebral fractures. All three efficacy endpoints for fractures reached statistically significant values, assessed according to a pre-specified sequential testing scheme.

The reduction in the risk of new vertebral fractures with denosumab use for more than 3 years remained stable and significant. The risk reduction was independent of the 10-year probability of major osteoporotic fractures. The reduction in risk was also not affected by the presence of a history of prevalent vertebral fractures, nonvertebral fractures, patient age, BMD, bone remodeling level, and prior osteoporosis therapy.

In postmenopausal women over 75 years of age, Denosumab reduced the incidence of new vertebral fractures and, according to a post hoc analysis, reduced the incidence of hip fractures.

The reduction in the incidence of nonvertebral fractures was observed regardless of the 10-year probability of major osteoporotic fractures.

Denosumab significantly, compared to placebo, increased BMD in all anatomical sites. BMD was determined at 1 year, 2 and 3 years after the start of therapy. A similar effect on BMD 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, reduced bone remodeling compared to placebo. No pathological changes, including fibrosis, osteomalacia, and impaired bone architecture, were noted.

Clinical efficacy in the treatment of bone loss caused by hormone deprivation therapy or aromatase inhibitor therapy

Treatment of bone loss caused by androgen deprivation

The efficacy and safety of denosumab in the treatment of bone loss associated with decreased androgen concentrations were proven in a 3-year study including 1,468 patients with non-metastatic prostate cancer.

A significant increase in BMD was determined in the lumbar spine, total hip, femoral neck, and trochanter of the femur 1 month after the first dose. The increase in lumbar spine BMD was independent of age, race, geographic region, BMI, baseline BMD, bone remodeling; duration of hormone deprivation therapy and history of vertebral fracture.

Denosumab significantly reduced the risk of new vertebral fractures over 3 years of use. The risk reduction was observed at 1 year and 2 years after the start of therapy. Denosumab also reduced the risk of more than one osteoporotic fracture of any location.

Treatment of bone loss in women receiving aromatase inhibitor therapy for breast cancer

The efficacy and safety of denosumab in the treatment of bone loss caused by adjuvant aromatase inhibitor therapy was evaluated in a 2-year study including 252 patients with non-metastatic breast cancer. Denosumab significantly increased BMD in all anatomical sites, compared to placebo, over 2 years. An increase in BMD was observed in the lumbar spine one month after the first dose. A positive effect on BMD in the lumbar spine was noted regardless of age, duration of aromatase inhibitor therapy, BMI, prior chemotherapy, prior use of a selective estrogen receptor modulator (SERM) and time since menopause.

Pharmacokinetics

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

Absorption

After subcutaneous administration of denosumab at a dose of 60 mg, the bioavailability was 61% and the C_max of denosumab was 6 µg/ml (range 1-17 µg/ml), these parameters were observed after 10 days (range 2-28 days). After reaching C_max, the drug content in the serum decreased with a T_1/2 of 26 days (range 6-52 days) and further over 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

No changes in the pharmacokinetic parameters of denosumab, nor accumulation over the entire time of taking multiple doses of the drug at 60 mg every 6 months, were observed.

Metabolism

Denosumab consists of amino acids and carbohydrates, like a regular immunoglobulin. Based on preclinical data, denosumab metabolism is expected to occur via the immunoglobulin clearance pathway, resulting in breakdown into small peptide chains and individual amino acids.

Excretion

Based on preclinical data, denosumab excretion will occur via the excretion pathway of all immunoglobulins, resulting in breakdown into small peptide chains and individual amino acids.

Specific patient groups

Age did not have a significant effect on the pharmacokinetics of denosumab according to a population pharmacokinetic analysis in patients from 28 to 87 years old.

Pharmacokinetics in children has not been studied.

The pharmacokinetics of denosumab does not depend on race.

In a study of 55 patients with varying degrees of renal impairment, including patients on dialysis, the degree of renal impairment did not affect the pharmacokinetics and pharmacodynamics of denosumab; therefore, no adjustment of the denosumab dosing regimen is required for chronic renal failure.

No studies have been conducted on the effect of hepatic impairment on the pharmacokinetics of denosumab.

Indications

• Treatment of postmenopausal osteoporosis;
• Treatment of bone loss in women receiving aromatase inhibitor therapy for breast cancer and in men with prostate cancer receiving hormone deprivation therapy.

ICD codes

Dosage Regimen

Administration

Administering the drug injection requires prior training – see the recommendations for drug administration provided at the end of this instruction.

The recommended dose of Prolia^® is one subcutaneous injection of 60 mg every 6 months. During the course of treatment, it is recommended to additionally take calcium and vitamin D supplements.

Children

The drug Prolia^® is not recommended for use in pediatrics, as the efficacy and safety of this drug have not been studied in this age group.

Elderly patients

Based on available data on the efficacy and safety of the drug in this age group, no dose adjustment is required.

Renal impairment

Based on available data on the efficacy and safety of the drug in this patient group, no dose adjustment is required.

In patients with severe renal impairment (creatinine clearance <30 ml/min) or on dialysis, there is a high risk of developing hypocalcemia. Such patients need to additionally take calcium and vitamin D supplements.

Hepatic impairment

Efficacy and safety have not been studied.

Instructions for use

The solution should be inspected before administration for the presence of inclusions or color change. The solution should not be used if cloudy or discolored. Do not shake.

To avoid discomfort at the injection site, the solution should be warmed to room temperature (up to 25°C (77°F)) before injection, and then slowly inject the entire contents of the prefilled syringe. Discard the syringe with any remaining drug.

Any amounts of unused drug or unused materials must be disposed of in accordance with local requirements.

Adverse Reactions

Data obtained from controlled use in clinical studies.

Adverse reactions are presented by system organ classes in terms of the Medical Dictionary for Regulatory Activities (MedDRA).

The frequency of adverse events was classified as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), including isolated cases.

Within each system organ class and frequency group, adverse reactions are presented in descending order of severity.

Contraindications

• Hypocalcemia;
• Hypersensitivity to any of the components of the drug.

Use in 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 in lower primates, it was shown that at doses 100 times higher than those recommended for clinical use, Denosumab had no effect on fertility or fetal development.

Experiments on knockout mice have shown that the absence of RANKL can lead to impaired development of fetal lymph nodes, and in the postnatal period can cause impaired tooth eruption and bone growth; an effect on mammary gland maturation is also possible, which may lead to impaired lactation.

It is not known whether Denosumab is excreted in breast milk. Since it is known that Denosumab may potentially cause adverse reactions in breastfed infants, breastfeeding should either be discontinued or the drug should be discontinued.

Use in Hepatic Impairment

Efficacy and safety have not been studied.

Use in Renal Impairment

Based on available data on the efficacy and safety of the drug in this patient group, no dose adjustment is required.

In patients with severe renal impairment (creatinine clearance <30 ml/min) or on dialysis, there is a high risk of developing hypocalcemia. Such patients need to additionally take calcium and vitamin D supplements.

Pediatric Use

The drug Prolia^® is not recommended for use in pediatrics, as the efficacy and safety of this drug have not been studied in this age group.

Geriatric Use

Based on available data on the efficacy and safety of the drug in this age group, no dose adjustment is required.

Special Precautions

It is recommended to take calcium and vitamin D supplements during the use of Prolia^®.

Hypocalcemia can be corrected by taking adequate doses of calcium and vitamin D supplements before starting denosumab therapy. Monitoring of calcium levels is recommended in patients predisposed to hypocalcemia.

Patients receiving Prolia^® may develop infections of the skin and its appendages (predominantly cellulitis), which in some cases may require hospitalization. Such reactions were reported more frequently in the denosumab group (0.4%) than in the placebo group (0.1%). However, the overall incidence of skin infections was comparable between the denosumab and placebo groups. Patients should be instructed to seek medical attention promptly if they develop symptoms and signs of cellulitis.

Cases of osteonecrosis of the jaw have been reported in patients with advanced cancer receiving 120 mg of denosumab every 4 weeks. There are isolated reports of osteonecrosis of the jaw occurring at the dose of 60 mg every 6 months.

Persons with latex allergy should not touch the needle cap rubber (a latex derivative).

Influence on the Ability to Drive Vehicles and Operate Machinery

Studies on the effect on the ability to drive vehicles and operate machinery have not been conducted.

Overdose

No cases of drug overdose were observed in clinical studies.

In clinical studies, doses of denosumab up to 180 mg every 4 weeks (cumulative dose up to 1080 mg over 6 months) were administered.

Drug Interactions

Drug interaction studies have not been conducted.

The drug should not be mixed with other medicinal products.

Storage Conditions

Store at a temperature of 2-8°C (17.6°F). Do not freeze. Store in the original package to protect from light.
Do not shake. Keep out of reach of children!

After removal from the refrigerator, Prolia^® can be stored at room temperature not exceeding 25°C (77°F) in the original package for no more than 30 days.

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.