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%)
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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.
Side effects of the drug Aklasta
Adverse effects have been reported from various clinical program studies. Adverse effects observed in the postmenopausal osteoporosis treatment study were fever (18.1%), myalgia (9.4%), flu-like symptoms (7.8%), arthralgia (6.8%), and headache (6). .5%), most of which occurred within the first 3 days after the administration of Aklasta. Most of these symptoms were mild to moderate in severity; they disappeared within 3 days. The incidence of these symptoms decreased significantly with subsequent administration of Aclasta. The severity of the above symptoms can be reduced by approximately 50% by administering drugs such as paracetamol or ibuprofen immediately after administration of the drug. The following are the adverse reactions that, according to the expert's assessment, are associated with taking the drug and were observed when using the drug for: treatment of osteoporosis in men and postmenopausal women, prevention of clinical fractures after low-traumatic fracture of the femur, treatment and prevention of glucocorticoid-induced osteoporosis and Paget's disease; systematized according to classes of organ systems and frequency, using the following symbols: very often (1/10), often (1/100, ≤1/10), infrequently (1/1,000, ≤1/100), rarely (1/10,000, ≤1/1,000). Infections and infestations : uncommon - flu-like symptoms, nasopharyngitis. From the blood and lymphatic system : infrequently - anemia. Metabolic and nutritional disorders : often - anorexia, loss of appetite. From the side of the central nervous system : often - headache, dizziness; infrequently - lethargy, paresthesia, drowsiness, tremor, fainting (syncope), insomnia. From the side of the organ of vision: infrequently - conjunctivitis, pain in the eyes; rarely - uveitis, episcleritis, inflammation of the iris. From the organ of hearing and labyrinth: infrequently - vertigo. From the vascular system : infrequently - hypertension, flushing of the face. From the respiratory system, chest and mediastinal organs : infrequently - cough, shortness of breath. From the gastrointestinal tract : often - nausea, vomiting, diarrhea; Uncommon: dyspepsia, upper abdominal pain, abdominal pain, gastroesophageal reflux, constipation, dry mouth, esophagitis. From the skin and subcutaneous tissue : uncommon - rash, hyperhidrosis, itching, erythema. From the musculoskeletal system and connective tissue : often – myalgia, arthralgia, bone pain, back pain, pain in the extremities; Uncommon – neck pain, musculoskeletal stiffness, joint swelling, muscle spasms, shoulder pain, musculoskeletal chest pain, musculoskeletal pain, joint stiffness, arthritis, muscle weakness. From the genitourinary system: infrequently – pollakiuria, proteinuria. Laboratory indicators : infrequently - increased creatinine levels in the blood. General disorders and disorders associated with the route of administration : very often - fever; often – flu-like symptoms, chills, fatigue, asthenia, pain, malaise; uncommon – peripheral edema, thirst, acute phase reaction, chest pain of non-cardiac origin. Adverse reactions reported in individual studies and not listed above (due to lower incidence compared with placebo) include: conjunctivitis, increased C-reactive protein, hypocalcemia, dysgeusia, toothache, gastritis, palpitations , reaction at the injection site. During a 3-year study of osteoporosis in postmenopausal women, the overall incidence of atrial fibrillation was 2.5% (96 of 3,862 patients) in the Aclasta group compared with 1.9% (75 of 3,852 patients) in the placebo group. ; the incidence of the serious adverse reaction of atrial fibrillation was 1.3% (51 of 3,862) in patients who received Aclasta compared with 0.6% (22 of 3,852) in patients who received placebo. The mechanism that causes the increased incidence of atrial fibrillation is unknown. Renal dysfunction. With intravenous administration of bisphosphonates, including zoledronic acid, cases of renal dysfunction (for example, increased serum creatinine levels) and rarely, acute renal failure have been observed. Impaired renal function has been observed with the use of zoledronic acid, especially in patients with a history of renal pathology or additional risk factors (for example, cancer patients undergoing chemotherapy, concomitant use of nephrotoxic drugs, severe dehydration); Most of these patients received the drug at a dose of 4 mg every 3-4 weeks, but in some cases, renal dysfunction was observed after a single dose of the drug. In the HORIZON-PFT study, changes in creatinine clearance (determined annually before drug administration) and the incidence of renal failure or renal dysfunction were comparable in the Aklasta and placebo groups over 3 years. There was a transient increase in serum creatinine levels over 10 days in 1.8% of patients assigned to Aklast, compared with 0.8% of patients assigned to placebo. In studies that were conducted to justify the use of the drug for the prevention of clinical fractures after a fracture of the femoral neck (hip bones) in men and women, the treatment of osteoporosis in men, the treatment and prevention of glucocorticoid-induced osteoporosis, changes in creatinine clearance were comparable in the Aklasty group and placebo or comparison drug. Laboratory data. In the HORIZON-PFT study, approximately 0.2% of patients experienced a marked decrease in serum calcium levels (less than 1.87 mmol/L) after using Aclasta. No symptomatic cases of hypocalcemia were observed. In the HORIZON-RFT study for the treatment of osteoporosis in men and the prevention of glucocorticoid-induced osteoporosis, none of the patients had serum calcium levels below 1.87 mmol/L. In a study of Paget's disease, symptomatic hypocalcemia was observed in approximately 1% of patients (all cases resulted in normalization of blood calcium levels). Local reactions. In the HORIZON-PFT study, local infusion site reactions of redness, swelling and/or pain were reported (0.7%) after administration of zoledronic acid. In the same study, the incidence of local reactions was similar for the Aclasta and placebo groups. Osteoporosis in men - the incidence of local reactions was 2.6% in the zoledronic acid group and 1.4% in the alendronate group. During the treatment and prevention of glucocorticoid-induced osteoporosis, the development of local reactions has not been reported. Osteonecrosis of the jaw. Cases of necrosis (most often of the jaw) predominantly occurred in cancer patients who were taking bisphosphonates, including zoledronic acid. Many of these patients had evidence of local infections, including osteomyelitis, and most reports involved patients with cancer who developed osteonecrosis after tooth extraction or other dental surgery. Osteonecrosis of the jaw has many documented risk factors, including cancer diagnosis and concomitant treatments (eg, chemotherapy, radiation therapy, corticosteroids). Although a causal relationship has not been established, it is recommended to avoid dental procedures as the recovery process may be lengthy. In the HORIZON-PFT study, among 7,736 patients, there was only 1 case of osteonecrosis of the jaw in a patient who received Aclasta and 1 case in a patient who took placebo. All cases ended in normalization of the condition. In the same study, no cases of osteonecrosis of the jaw were reported in the treatment of men with osteoporosis, treatment and prevention of glucocorticoid-induced osteoporosis. Post-marketing experience. In the post-marketing period, there were reports of hypersensitivity reactions: rarely - bronchospasm, urticaria and angioedema; very rarely - anaphylactic reaction/shock.
Storage conditions for the drug Aklasta
An unopened bottle does not require any special storage conditions. After opening the bottle, the solution is chemically and physically stable for 24 hours at a temperature of 2–8 °C. From a microbiological point of view, the drug must be used immediately. Otherwise, the medical staff performing the injection is responsible for the period and conditions of storage of the drug until use. The total time from the beginning of dissolution, storage in the refrigerator at a temperature of 2–8 ° C until the end of use should not exceed 24 hours.
List of pharmacies where you can buy Aklast:
- Moscow
- Saint Petersburg
Interactions of the drug Aklasta
No specific drug interaction studies have been conducted with zoledronic acid. Zoledronic acid is not systemically metabolized and does not affect human cytochrome P450 enzymes in vitro . Zoledronic acid is characterized by a low degree of binding to plasma proteins (about 56%); therefore, interactions due to displacement of highly protein-bound drugs from binding sites are unlikely. Zoledronic acid is eliminated from the body by renal excretion. Caution should be exercised when using Aklasta simultaneously with drugs that can have a significant effect on renal function (for example, aminoglycosides or diuretics that cause dehydration). Pharmaceutical interactions: Aklast solution cannot be mixed with infusion solutions containing calcium ions (for example, in the same system for intravenous drip administration).