Aklasta solution for infusion 5 mg/100 ml bottle 100 ml 1 pc. in Moscow

Aklasta solution for infusion 5 mg/100 ml bottle 100 ml 1 pc. in Moscow

Treatment of various types of osteoporosis, Paget's disease of bone and prevention of new fractures in men and women with fractures of the proximal femur.

With intravenous administration of 5 mg of Aklasta once a year for the treatment of postmenopausal osteoporosis in women, osteoporosis in men, for the prevention of new fractures in men and women with fractures of the proximal femur, for the prevention and treatment of osteoporosis caused by the use of GCS and for treatment of Paget's disease of bone, most adverse events (AEs) were mild or moderate. After intravenous administration of the drug Aklasta, the following AEs were most often observed in these patients: usually lasting no more than 3 days (“post-dose” symptoms) - fever (18.1%), myalgia (9.4%), influenza-like syndrome (7. 8%), arthralgia (6.8%), headache (6.5%). Most of the above-mentioned AEs observed within 3 days after drug administration were mild or moderate. With repeated administration of the drug, the severity of these AEs decreased significantly. Below are AEs that may be associated (in the opinion of the treating physicians) with the use of the drug for the treatment of various types of osteoporosis, Paget's disease of bone and for the prevention of new fractures in men and women with fractures of the proximal femur.

The incidence of these AEs was assessed as follows: very often (≥1/10); often (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000), very rare (<1/10000), including isolated reports.

From the nervous system:

often - headache, dizziness; sometimes - lethargy*, paresthesia, drowsiness, tremor, fainting.

From the senses:

sometimes - conjunctivitis, eye pain, vertigo; rarely - uveitis*, episcleritis, iritis.

From the respiratory system:

sometimes - shortness of breath*, cough.

From the digestive system:

often - nausea, vomiting, diarrhea; sometimes - anorexia*, loss of appetite, dyspepsia*, abdominal pain*, dry mouth, esophagitis*, gastroesophageal reflux, pain in the upper abdomen, constipation.

From the skin and subcutaneous tissue:

sometimes - rash, hyperhidrosis*, itching, erythema.

From the musculoskeletal system and connective tissue:

often - arthralgia*, myalgia*; bone pain, pain in the back and limbs; sometimes - pain in the neck, swelling in the joints*, muscle spasms, pain in the shoulder girdle, pain in the chest* of musculoskeletal origin, muscle weakness, stiffness in the muscles* and joints*, arthritis, musculoskeletal pain.

From the urinary system:

sometimes - increased blood creatinine levels, pollakiuria, proteinuria.

From the hematopoietic system:

sometimes - anemia.

From the cardiovascular system:

sometimes - increased blood pressure, sudden redness of the face.

Infections and infestations:

sometimes - flu, nasopharyngitis.

From the body as a whole:

very often - increased temperature; often - flu-like syndrome, chills, increased fatigue*, asthenia, pain*, general malaise; Uncommon: peripheral edema, thirst*, increased excitability*, chest pain (not associated with heart disease).

*Note:

in some studies, the frequency of these AEs increased as follows: very often - myalgia, arthralgia, fatigue, pain; often - lethargy, shortness of breath, dyspepsia, esophagitis, abdominal pain, hyperhidrosis, muscle stiffness, swelling in the joints, pain in the chest area of ​​musculoskeletal origin, stiffness in the joints, anorexia, thirst, increased excitability; infrequently - uveitis.

In separate studies, the following AEs were recorded, the incidence of which in the Aklasta group was lower than in patients who did not receive the drug: redness of the eyes, increased levels of C-reactive protein, hypocalcemia, taste disturbances, toothache, gastritis, palpitations , reactions at the injection site.

When using Aklasta in patients with postmenopausal osteoporosis, the overall incidence of atrial fibrillation during treatment with Aklasta was 2.5% (96 out of 3862 people) compared to 1.9% (75 out of 3852 patients) in patients not treated with the drug (placebo group). In 1.3% of patients (51 out of 3862 patients) receiving Aklasta, and in 0.6% (22 out of 3852) in the placebo group, this adverse event was assessed as serious. The reason for the increased incidence of atrial fibrillation during therapy with Aclasta was not established in this study. The increased incidence of atrial fibrillation compared with placebo observed in this study was not found in other clinical studies of zoledronic acid.

Prevention of postmenopausal osteoporosis

When using Aklasta for the prevention of postmenopausal osteoporosis (PMO), the overall safety profile of the drug was comparable to that in the treatment of PMO, with the exception of AEs that occurred within 3 days after infusion: pain, fever, chills, myalgia, nausea, headache, fatigue , arthralgia, the frequency of which was higher in women receiving the drug to prevent PMO. Most of these AEs were mild or moderate and resolved within 3 days of onset. With repeated administration of the drug, the severity of these AEs decreased significantly.

The following are AEs possibly associated with the use of the drug for the prevention of PMO (according to the attending physicians):

1) AEs that were observed more than once during the administration of Aklasta for the prevention of PMO and were not registered when using the drug for the treatment of various types of osteoporosis, Paget's bone disease and for the prevention of new fractures in men and women with fractures of the proximal femur;

2) AEs, the frequency of which was higher in women receiving the drug to prevent PMO (compared to other categories of patients).

The incidence of these AEs was assessed as follows: very common (≥1/10); often (≥1/100,<1/10); uncommon (≥1/1000, <1/100).

Mental disorders:

sometimes - anxiety.

From the nervous system:

very often - headache; often - tremor, lethargy; infrequently - decreased sensitivity, taste disturbances.

From the side of the organ of vision:

often - conjunctivitis, eye pain, iritis; infrequently - blurred vision.

From the digestive system:

very often - nausea; often - anorexia, abdominal pain, pain in the upper abdomen, constipation.

From the skin and subcutaneous tissue:

often - increased sweating at night.

From the musculoskeletal system and connective tissue:

very often - myalgia; often - musculoskeletal pain, muscle spasm, pain in the chest area of ​​musculoskeletal origin, pain in the jaw area, pain in the neck area; infrequently - pain in the side.

From the body as a whole and reactions at the site of drug administration:

very often - pain, chills; often - peripheral edema, reactions at the injection site, non-cardiac pain in the chest area.

Changes in laboratory results

In patients with postmenopausal osteoporosis, while using Aklasta, a decrease in calcium concentration (<1.87 mmol/l) in the blood serum was observed in 0.2% of cases; clinical signs of hypocalcemia were not observed.

When using the drug in patients with femoral fractures, osteoporosis in men and osteoporosis caused by taking corticosteroids, there was no decrease in the concentration of calcium in the blood plasma <1.87 mmol/l.

When using the drug in patients for the prevention of postmenopausal osteoporosis, there was no decrease in the concentration of calcium in the blood plasma <1.87 mmol/l. In patients with Paget's disease, transient hypocalcemia accompanied by clinical manifestations was found in approximately 1% of cases.

Renal dysfunction.

With intravenous administration of bisphosphonates, including zoledronic acid, there have been cases of renal dysfunction, manifested by an increase in blood creatinine concentrations and, in rare cases, acute renal failure. Impaired renal function with the use of zoledronic acid has been observed in patients with either a history of renal pathology or additional risk factors (for example, cancer requiring chemotherapy, use of nephrotoxic drugs, diuretics or severe dehydration). Most of these patients were treated with zoledronic acid at a dose of 4 mg every 3-4 weeks, but in some cases, renal dysfunction was observed after a single dose of zoledronic acid. When treated with Aklasta for 3 years in patients with postmenopausal osteoporosis, the incidence of increased plasma creatinine and the development of renal failure did not differ from that when using placebo. Patients receiving Aklasta were slightly more likely to experience a transient increase in blood creatinine concentrations within 10 days after infusion compared to placebo (1.8 and 0.8%, respectively).

When using Aklasta for 2 years in men with osteoporosis, the frequency of changes in creatinine clearance and the development of renal dysfunction was similar to that in the alendronic acid group.

In patients with osteoporosis caused by the use of corticosteroids, during therapy with Aklasta, the frequency of changes in creatinine clearance and the development of renal dysfunction was similar to that in the risedronic acid group.

Reactions at the injection site.

When using Aklasta in patients with postmenopausal osteoporosis, redness, swelling and/or pain at the injection site were noted in 0.7% of cases.

In patients with femoral fractures, the incidence of reactions at the injection site was comparable to that in the placebo group. In the treatment of osteoporosis in men, the incidence of reactions at the injection site of Aclasta was 2.6% (compared to 1.4% in the alendronic acid group). In patients with osteoporosis caused by the use of corticosteroids, no reactions were observed at the injection site. When using the drug for the prevention of postmenopausal osteoporosis, the incidence of reactions at the injection site of Aklasta was 1.1% (compared to 2.0% in the placebo group).

Osteonecrosis of the jaw.

Cases of osteonecrosis (most often of the jaw) occurred mainly in cancer patients receiving bisphosphonate treatment after tooth extraction or other dental procedures. Most patients had symptoms of a local infectious and inflammatory process, including osteomyelitis. In clinical studies in patients with osteoporosis, a case of osteonecrosis of the jaw occurred in 1 patient taking Aklasta and in 2 patients taking placebo. In all three cases, resolution of the process was noted. When using the drug Aklasta in patients with femoral fractures, with osteoporosis in men and osteoporosis caused by taking corticosteroids, as well as when using the drug for the prevention of postmenopausal osteoporosis, there were no cases of osteonecrosis of the jaw.

Isolated reports of adverse events

During therapy with Aklasta, the following AEs were observed in clinical practice without indication of a cause-and-effect relationship with the use of the drug (the frequency of AEs has not been established): hypersensitivity reactions, including in rare cases broncho-obstruction, urticaria, angioedema and isolated reports of the development of anaphylactic reactions, in incl. anaphylactic shock. In rare cases, when using Aklasta in clinical practice, patients have experienced renal dysfunction, including renal failure requiring hemodialysis, especially in patients with a history of either renal pathology or additional risk factors (for example, with concomitant therapy with nephrotoxic drugs, diuretics or with severe dehydration).

In very rare cases, the following AEs have been reported:

dehydration due to fever, vomiting and diarrhea occurring after administration of the drug; a pronounced decrease in blood pressure in patients with risk factors, osteonecrosis of the jaw, scleritis and inflammation in the orbital area.

Instructions for use of ACLASTA®

A bone resorption inhibitor belongs to the class of nitrogen-containing bisphosphonates that have a selective effect on bone tissue. Suppresses osteoclast-mediated bone resorption.

The selective effect of bisphosphonates on bone tissue is based on their high affinity for mineralized bone tissue.

After IV administration, zoledronic acid is rapidly redistributed into the bones and, like other bisphosphonates, is localized primarily in areas of intense bone turnover.

The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthetase (FPS), although the possibility of other mechanisms of action of the drug cannot be excluded. The relatively long duration of action of zoledronic acid is determined by the high affinity of its binding to the active site of farnesyl pyrophosphate synthase and its affinity for binding to bone minerals.

Osteoporosis

Treatment with Aklasta quickly reduces the intensity of metabolism in bone tissue:

• from levels increased in the postmenopausal period with the lowest point for resorption markers at 7 days and to formation markers at 12 weeks. After this, the level of bone tissue markers was established within the range that was observed at menopause. There was no progressive decline in bone metabolic markers with repeated annual dosing.

Clinical effectiveness of treatment of postmenopausal osteoporosis

The effectiveness and safety of Aklasta was confirmed in the HORIZON-PFT study; the drug was administered once a year for three consecutive years at a dose of 5 mg in 100 ml of solution for at least 15 minutes, a total of 3 times. The two main outcome measures were the incidence of morphometrically documented vertebral fractures over 3 years and the incidence of femoral fractures over a median period of 3 years. Aklasta significantly reduced the incidence of one or more new vertebral fractures over 3 years, starting in the first year of treatment.

The reduction in vertebral fracture incidence over 3 years was consistent and independent of age, geographic region, race, baseline body mass index, number of baseline vertebral fractures, femoral neck bone mineral density (BMD) T-score, or previous bisphosphonate use.

Effect on the incidence of hip fracture:

When taking Aklasta, there is a 40% reduction in the risk of hip fractures over 3 years.

Effect on the incidence of all clinical fractures:

When taking Aclasta, there was an absolute reduction in the incidence of all clinical fractures (by 4.5%), clinical vertebral fractures (by 2%) and non-vertebral fractures (by 2.8%)
.
Effect on bone mineral density:

Aklasta increases the BMD of the lumbar spine by 6.9%
,
the femur by 6.0%, the femoral neck by 5.0% and the distal radius by 3.2% over 3 years.

Histology of bone tissue:

When performing dynamic histomorphometry in patients with postmenopausal osteoporosis, bone tissue of normal quality was observed without signs of impaired remodeling and impaired mineralization. A study using microcomputed tomography showed preservation of trabecular bone architecture in patients treated with Aclasta compared to placebo.

Bone turnover markers:

Bone-specific alkaline phosphatase (BSALP), collagen type I N-terminal propeptide (B1NP), and serum beta-C-telopeptide were assessed periodically during the study. Treatment with Aklasta at annual doses of 5 mg reduced bone turnover markers to premenopausal ranges. Repeated administration of the drug did not lead to a subsequent decrease in the level of bone turnover markers.

Impact on growth

During the three-year osteoporosis study, height (standing) was measured annually. Patients who received Aclasta experienced a reduction in the rate of height loss compared with placebo (4.2 mm versus 6.7 mm, respectively (p < 0.0001).

Number of days of incapacity for work

Aklasta significantly reduced both the number of days with limited activity and the number of days in bed due to back pain and fractures compared to placebo (all p < 0.01).

Clinical effectiveness of clinical fracture prevention after hip fracture

The effectiveness and safety of Aklasta for preventing the occurrence of clinical fractures in patients with low-traumatic femoral neck fractures was confirmed in the HORIZON-RFT study. The incidence of clinical fractures, including vertebral, nonvertebral, and hip fractures, was assessed in 2127 patients with a recent (within 90 days) low-trauma femoral fracture over a 2-year period. All study participants received 1000 to 1500 mg of elemental calcium and 800 to 1200 IU of vitamin D per day. The primary outcome measure was the number of clinical fractures during the study period.

Effect on all clinical fractures:

There was a 35% reduction in the incidence of any clinical fractures.
Reducing the incidence of clinical spinal fractures by 46%, non-vertebral fractures by 27%, and hip fractures by 30% .
Effect on bone mineral density:

in the HORIZON-RFT study, when treated with Aklasta, there was an increase in BMD in all bones of the hip joint by 5.4% and by 4.3% in the femoral neck over 24 months.

Treatment of osteoporosis in men

The effectiveness and safety of Aklasta in men with osteoporosis was assessed in a two-year study based on changes (in percentage terms) in BMD of the lumbar spine.

Effect on mineral density

bones:

• the effect according to the percentage change in BMD in the lumbar vertebrae at month 24 (compared to baseline values) when Aklasta was administered once a year was not less than in the case of weekly administration of alendronate (Aclasta 6.1% compared to alendronate 6.2%). The percentage increase in lumbar spine BMD at 12 months was also similar in the groups of patients receiving these drugs.

Treatment and prevention of GCS-induced osteoporosis

The efficacy and safety of Aklasta in the treatment and prevention of GCS-induced osteoporosis was assessed in a one-year study involving patients receiving oral prednisolone ≥7.5 mg/day (or equivalent).

Effect on bone mineral density:

There was an increase in BMD of the lumbar spine, femoral neck, femur as a whole, acetabulum and distal radius (in all cases p<0.03).

Histology of bone tissue:

Qualitative and quantitative analysis showed normal architecture and quality of bone tissue, without mineralization disorders.

Paget's disease

Clinical effectiveness of treatment of Paget's disease

The effectiveness of Aklasta was assessed in 2 six-month comparative studies. In both studies, zoledronic acid showed superiority and a faster therapeutic effect compared to risedronate, as evidenced by biochemical markers of bone formation (BFS), N-terminal propeptide type I collagen (P1NP) in blood serum and resorption (CTx in blood and α -CTx in urine). In almost all patients of the Aklasty group, the therapeutic effect persisted for 18 months. Histological examination of the bone tissue showed that the bone tissue was of normal quality without signs of impaired bone remodeling and without signs of impaired mineralization.

Bone safety study:
dose-response and duration of action of single IV administration of zoledronic acid (0.8 to 500 mg/kg) were studied in animals. The results provide fundamental evidence for the efficacy and bone safety of zoledronic acid at clinically acceptable doses. There were no signs of any abnormalities in bone or bone marrow tissue, no signs of abnormal mineralization, no accumulation of osteoid, or membranous reticulofibrous bone tissue.