2010/09/17

Aclasta



Composition, structure and packing

Solution for infusion transparent, colorless. 100 ml of zoledronic acid monohydrate 5.33 mg, which corresponds to the content of zoledronic acid anhydrous 5 mg.

Excipients: mannitol, sodium citrate, water d / and.

Clinico-pharmacological group: an inhibitor of resorption of bone tissue. Bisphosphonates.

Pharmacological action

Inhibitor of bone resorption, bisphosphonates. Zoledronic acid belongs to a class aminobisfosfonatov, operates mainly in bone, suppresses the activity of osteoclasts and resorption of bone tissue. The selective action of bisphosphonates on bone is based on a high affinity for mineralized bone tissue.

Following in / introduction of zoledronic acid rapidly redistributed to bone and, like other bisphosphonates, is localized mainly in the field of remodeling of bone tissue.

The main molecular target of zoledronic acid in the osteoclast is the enzyme farnezilpirofosfatsintetaza (FBS), while not excluding the possibility of other mechanisms of action of the drug. An extended period of drug action is determined by the high affinity to the active center of the FBS and marked affinity for mineralized bone tissue.

In applying Aklasty patients with postmenopauznym osteoporosis (T-test values of bone mineral density of the femoral neck less than - 2.5) indicated a statistically significant reduction in the risk of vertebral fractures by 70% by the end of 3 years of treatment, as well as reduced risk of developing one or more new / repeat fractures and moderate / severe vertebral fractures by 60-70%. In patients with osteoporosis at age 75 and older in the treatment of Aklastoy achieved to reduce the risk of vertebral fractures by 61%. When treating Aklastoy relative risk of fractures nevertebralnyh any location (including fractures of the phalanges and facial bones of the skull) was reduced by 33%, respectively. In applying Aklasty for 3 years in patients with osteoporosis postmenopauznym showed an increase in bone mineral density of lumbar vertebrae and femur in general, femoral neck and distal radius by an average of 6.9%, 6%, 5% and 3.2% respectively .

The therapy Aklastoy within 1 year in patients with osteoporosis observed decrease in bone isoenzyme of alkaline phosphatase, N-terminal propeptide of type I collagen (PINP) and β-C-terminal telopeptide blood to premenopauznogo level. Repeated administration of the drug for 3 years, there has been further reduction in blood levels of markers of bone remodeling.

Application Aklasty for 3 years significantly reduced the rate of loss of growth in patients, as well as helped to improve physical activity in postmenopausal women with osteoporosis and fractures of the vertebrae.

When treating Aklastoy patients with Paget's disease of bone with statistically accurate, rapid and sustained therapeutic response, normalization of bone metabolism and the concentration of alkaline phosphatase in blood plasma. The drug is also highly effective in patients who previously received treatment with oral bisphosphonates. Found that the majority of patients in the application of zoledronic acid therapeutic response persists throughout the treatment period (about 2 years).

A marked decrease in pain at 6 months after a single injection Aklasty 5 mg is comparable to the analgesic effect rizedronata a dose of 30 mg / day.

Patients with postmenopauznym osteoporosis and bone disease Paget zoledronic acid does not affect the qualitative state of the normal bone does not violate the process of bone remodeling and mineralization and helps maintain normal trabecular bone architectonics.

In experimental models of accelerated osteorezorbtsii shown that zoledronic acid significantly inhibits bone resorption without undesirable effects on the formation, mineralization and mechanical properties of bone, dose-dependent manner reduces the activity of osteoclasts and the frequency of activation of new foci of remodeling in trabecular as well as in cortical (Haversian) bone, no causing the formation of fibrous bone and aberrant accumulation of osteoid. Except for high antiresorptive action, the effect of zoledronic acid on bone similar to that for other bisphosphonates.

Pharmacokinetics

Data on the pharmacokinetics obtained after single and repeated 5 - and 15-minute infusions of 2, 4, 8 and 16 mg zoledronic acid 64 patients.

Pharmacokinetic parameters do not depend on the dose. After the start of infusion Aklasty concentration of zoledronic acid in plasma increased rapidly, reaching a peak at the end of infusion, followed by a rapid decrease in concentration by 10% from the peak after 4 h and less than 1% of the peak after 24 h consistently prolonged period of low concentrations, not exceeding 0.1% of the Cmax. Zolendronovaya acid introduced I / O and displays the kidneys in 3 phases: a rapid biphasic elimination of the drug from the systemic circulation with a T1 / 2 0.24 h (α-phase) and 1.87 h (β-phase) and a long phase with a finite T1 / 2, is 146 h (γ-phase). The rapid decline in drug concentration (α-and β-phase) in the blood plasma may be due to the rapid distribution of zoledronic acid in bone tissue and its excretion by the kidneys. There was no accumulation of the drug after repeated administration every 28 days.

Zoledronic acid is not subject to metabolism, elimination by the kidneys unchanged. During the first 24 h in urine detected 39 ± 16% of the administered dose. The rest of the drug is associated exclusively with bone tissue. Then slowly, the reverse was the release of zoledronic acid back out of the bone tissue in the systemic circulation and excretion by the kidneys. Total plasma clearance of the drug was 5.04 ± 2.5 L / h and is not dependent on dose, sex, age, race and body weight. It is shown that the variability of the plasma clearance of zoledronic acid in the same patient and in different patients was respectively 36% and 34%. Increasing infusion time from 5 to 15 min leads to a decrease in the concentration of zoledronic acid to 30% at the end of infusion, but does not affect bioavailability.

Zoledronic acid binding to plasma proteins is low (43-55%) and does not depend on its concentration.

Pharmacokinetics in special clinical situations

Renal clearance of zoledronic acid is positively correlated with CC and 75 ± 33% of the creatinine clearance, averaging 84 ± 29 ml / min (range 22-143 ml / min) in 64 patients included in the study.

The small increase observed in the bioavailability (30-40%) in violation of renal function from mild to moderate degree, compared with patients with normal renal function, and lack of cumulation of the drug after repeated administration, regardless of renal function suggest that there is no need to adjust the dose of zoledronic acid at the light (CC 50-80 ml / min) and moderate (CC 30-50 ml / min) renal events.

Statement
postmenopauzny osteoporosis (to reduce the risk of fractures of the femur, vertebrae and nevertebralnyh fractures, to increase bone mineral density);
Paget's disease of bone.

Dosage regimen

The drug is introduced in the form of in / infusions. Before the introduction of Aklasty should ensure adequate hydration of the body. This is especially important for patients receiving treatment with diuretics. For the treatment of osteoporosis postmenopauznogo Aklasty recommended dose is 5 mg (1 bottle - 100 ml) in / 1 per year. If the intake of calcium and vitamin D from food is not enough, patients with osteoporosis should be further appoint agents of calcium and vitamin D. Long-term use is determined by a physician individually depending on the condition of the patient with postmenopauznym osteoporosis.

For the treatment of Paget's disease of bone is recommended once in / introduction of the drug in a dose of 5 mg. Since Paget's disease of bone is characterized by high bone turnover, all patients with this disease are advised to take daily rate of calcium and vitamin D during the first 10 days after the introduction Aklasty.

Repeated treatment of Paget's disease of bone Aklastoy. After the first introduction Aklasty observed a long period of remission. Currently the special data for the re-treatment of bone disease Paget is not available. However, the potential reintroduction of Aklasty can be considered in the case of patients with recurrent disease based on the following criteria: no normalization of serum alkaline phosphatase, increasing its level in the dynamics, as well as the presence of clinical signs of Paget's disease, detected during a medical examination 12 months after introduction of the first dose Aklasty.

Patients with impaired renal function in QA> 30 ml / min does not require correction dose. Aklastu not recommended in patients with severely impaired renal function (CC <30 ml / min) due to lack of sufficient clinical experience using the product in this category of patients.

Patients with impaired liver function does not require correction dose. Since the bioavailability, distribution and excretion are similar in nature in elderly patients and younger patients, elderly patients aged 65 years and older do not need to correct dose.

Rules infusion

In the preparation and conduct of infusion should observe the rules of asepsis.

Solution Aklasty should not be confused or administered simultaneously with any other drugs. To implement the solution Aklasty should always use a separate system for infusion.

The introduction of the drug should be conducted with a valve infusion system that provides continuous infusion rate for at least 15 minutes. After opening the bottle of solution is chemically and physically stable for 24 hours at a temperature of 2 ° to 8 ° C.

Solution Aklasty preferably used immediately after opening the vial. Unused right solution can be stored in a refrigerator at a temperature of 2 ° to 8 ° C not more than 24 h. If the solution is cooled before its introduction should stand in a room until they reach room temperature.

Side effect

The most frequently reported adverse reactions following a duration of usually not more than 3 days after drug administration: fever (18.1%), myalgia (9.4%), flu-like syndrome (7.8%), arthralgia (6.8%), headache (6.5%). Most of these reactions were mild to moderate. Repeated administration of the drug to female patients with osteoporosis postmenopauznym severity adverse reactions is significantly reduced.

Evaluation of the incidence of adverse reactions possibly related to use of the drug: very often (> 1 / 10), frequently (> 1 / 100, <1> 1 / 1000, <1> 1 / 10 000, <1 / 1000).
From the central nervous system and peripheral nervous systems: common - headache, dizziness, and sometimes - lethargy (often - with Paget's disease of bone), paresthesia, drowsiness, dizziness, tremor, Syncope, taste disorders.
From the senses: sometimes - conjunctivitis, eye pain, uveitis, vertigo, rarely - episcleritis, iritis.
On the part of the respiratory system: often - shortness of breath (only when the bone disease Paget).
On the part of the digestive system: frequent - nausea, vomiting, diarrhea, and sometimes - dyspepsia (often - with Paget's bone disease), abdominal pain, dry mouth, esophagitis. Dermatological reactions: sometimes - a rash.
On the part of the musculoskeletal system: often - arthralgia, myalgia, bone pain, pain in the back and limbs.
From the urinary system: sometimes - increase the level of serum creatinine.

When i / in the introduction of bisphosphonates, including zoledronic acid, there were cases of renal dysfunction, manifested by increased serum creatinine and in rare cases - acute renal failure.

Impaired kidney function during treatment with zoledronic acid was observed in patients with renal disease or a history of any additional risk factors (eg, cancer, concomitant chemotherapy, the use of nephrotoxic drugs or severe dehydration). Most of these patients received therapy zoledronic acid 4 mg every 3-4 weeks, but in some cases, renal dysfunction was noted after a single application of zoledronic acid.

In therapy Aklastoy for 3 years in patients with osteoporosis postmenopauznym rate increase in serum creatinine and blood of renal failure did not differ from that in the application of placebo in patients receiving placebo. Patients who received Aklastu somewhat more common in a transient increase in serum creatinine in the blood within 10 days after infusion compared with placebo (1.8% and 0.8% respectively).

On the part of the body as a whole: very often - a fever, and sometimes - hypocalcemia, flu-like syndrome (very often - with Paget's disease), chills, fatigue, asthenia, pain, malaise, tremor, and sometimes - anorexia, peripheral edema, thirst.

From the laboratory tests: patients with osteoporosis during treatment with Aklasty in 0.2% of cases has decreased calcium concentration (<1.87 mmol / l) in serum, clinical signs of hypocalcemia in this case was not observed. In patients with Paget's disease of approximately 1% of cases detected transient hypocalcemia was accompanied by clinical manifestations. Local reactions: 0.7% - redness, swelling and / or tenderness at the injection site.

Other: Cases of osteonecrosis (most often - jaw) occurred mostly in cancer patients treated by bisphosphonates, after tooth extraction or other dental procedures. The majority of these patients have marked symptoms of local infectious-inflammatory process, including osteomyelitis.

In clinical studies in patients with osteoporosis case of jaw osteonecrosis occurred in 1 patient with Aklastu, and 2 patients who received placebo.

In all 3 cases mentioned authorization process. In a three-year clinical study in patients with osteoporosis postmenopauznym overall incidence of atrial fibrillation was low and amounted to: 2.5% (96 of 3862) in patients receiving Aklastu, and 1.9% (75 of 3852 patients) in the group receiving placebo. Increased frequency of atrial fibrillation compared with placebo, as described in this study were not found in other clinical studies, zoledronic acid.

Contraindications
severe disorders of mineral metabolism, including hypocalcaemia;
Pregnancy
Lactation (breastfeeding);
childhood and adolescence to 18 years (since the safety and efficacy of Aklasty this category of patients not studied);
Hypersensitivity to zoledronic acid, other bisphosphonates and other components of the drug. Aklastu not recommended in patients with severely impaired renal function (CC <30 ml / min), because sufficient clinical experience using the product in this category of patients there.

Pregnancy and lactation

Aklasta drug is contraindicated during pregnancy and lactation (breastfeeding). Data on the use of zoledronic acid in pregnant women are absent. In experimental studies have shown the presence of teratogenicity in one of the experimental rodents. The potential risk for human use is unknown.

Application for violations of liver function

Patients with impaired liver function does not require correction dose.

Application for violations of renal function

Patients with impaired renal function in QA> 30 ml / min does not require correction dose. Aklastu not recommended in patients with severely impaired renal function (CC <30 ml / min) due to lack of sufficient clinical experience using the product in this category of patients.

Cautions

A physician should inform patients of the main manifestations of hypocalcemia and ensure regular monitoring of patients at risk.

Before the appointment of the drug should determine the level of creatinine in serum. In the presence of hypocalcemia before application Aklasty need to be treated with adequate doses of calcium and vitamin D. You should also be treated with other existing disorders of mineral metabolism (eg, gipoparatireoza, reduce calcium absorption in the intestine) and ensure regular monitoring of patients with hypocalcaemia.

To reduce the frequency of adverse reactions recorded in 3 days after drug administration, you can assign paracetamol or ibuprofen immediately after infusion Aklasty.

Despite the fact that zoledronic acid is the active ingredient as Aklasty and Zomety (a drug used to treat cancer patients), these drugs are not interchangeable.

Effects on ability to drive vehicles and management mechanisms

Data on the negative effect of the drug's ability to control the motor and working with machines or not.

Overdose

So far, cases of overdose Aklasty not reported. In case of overdosing leading to hypocalcemia and accompanied by clinical symptoms (numbness, tingling, muscle cramps and spasms), is shown taking medication of calcium inside and / or infusion of calcium gluconate.

Drug Interactions

Specific studies on the interaction of zoledronic acid with other drugs was conducted. Zoledronic acid is not metabolised systemically and does not affect the isoenzymes of cytochrome P450 in vitro. Zoledronic acid is characterized by a low degree of binding to plasma proteins (43-55%) due to the interaction of displacement of drugs with a high degree of protein binding of the binding sites is unlikely. Zoledronic acid is derived by the kidneys. Caution must be exercised while applying Aklasty with drugs that can have significant impact on renal function (eg aminoglycosides or diuretics, which cause dehydration).

Pharmaceutical interactions

Solution Aklasty not be mixed with infusion solutions containing calcium ions (for example, in one system for the in / drip).

Terms and Conditions of storage

List B. The drug should be stored away from children at or above 25 ° C.

After opening the bottle of solution is stable at a temperature of 2 ° -8 ° C for 24 hours Shelf life - 3 years.