Aklasty

Active material: Zoledronic Acid
When ATH: M05BA08
CCF: Bone resorption inhibitor. Bisfosfonat
ICD-10 codes (testimony): M80, M81.0, M81.1, M81.4, M88
Manufacturer: NOVARTIS PHARMA AG (Switzerland)

Pharmaceutical form, composition and packaging

Solution for infusion clear, colorless.

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

100 ml – plastic bottles (1) – packs cardboard.

Pharmacological action

Bone resorption inhibitor, the representative of the bisphosphonate.

Zoledronic acid belongs to the class of aminobisfosfonatov, acts primarily on bone, inhibits the activity of osteoclasts and bone resorption.

Selective effect of bisphosphonates on bone health is based on the high affinity for mineralized osseous tissue. After the on/in the introduction of zoledronic acid quickly redistributed in bones and, like other bisfosfontam, localized predominantly in the field of bone remodeling.

The main molecular target of zoledronovoj acid in osteoklaste is an enzyme farnezilpirofosfatsintetaza (FPS), This does not prevent other mechanisms of drug actions. Long period of action of the preparation is determined by the high affinity to the active Centre of the FPS and a pronounced affinity for mineralized osseous tissue.

In experimental models of accelerated osteorezorbcii shows, that zoledronic acid significantly inhibits bone resorption without undesirable effects on the formation of, mineralization and mechanical properties of bone, dozozawisimo reduces activity osteoclastov and activation frequency of new hotbeds of remodeling as in trabecular, and the BGS (Gaversovoj) bones, without causing education fibrous bones and accumulation of aberrant osteoida.

Except for high antirezorbtivnogo activity, effect of zoledronovoj acid on the bone is similar to that of other bisphosphonate.

In applying Aklasty in patients with postmenopauznym osteoporosis (t-test values for bone mineral density hip less – 2.5) noted statistically reliable reduction in the risk of vertebral fractures in 70% by the end of 3 year of treatment, as well as reducing the risk of one or more subsequent (new) fractures and moderate/heavy vertebrae fractures 60-70%. Patients with osteoporosis in aged 75 years and older in the treatment of Aklastoj achieved decreased risk of vertebral fractures in 61%.

When treating Aklastoj relative risk of fracture nevertebralnyh of any localization, (including the phalanges fractures of fingers and facial bones of the skull) declined on 33% respectively. In the application of Aklasty during 3 years in patients with postmenopauznym osteoporosis increased bone mineral density (IGC) lumbar vertebrae, femur in General, femur and distal radial bones at an average annual rate of 6.9%, 6% , 5% and 3.2%, respectively.

While therapy for Aklastoj 1 year in patients with postmenopauznym osteoporosis bone level fell izofermenta ALP, N-Terminal propeptida of collagen type I (PINP) and β-c-Terminal telopeptidov blood premenopauznogo level. When re-introductions medication for 3 years there had been a further reduction in blood levels of markers of bone remodeling.

The application of Aklasty during 3 significantly reduced the rate of loss years growth in patients, as well as to contribute to the improvement of physical activity in postmenopausal women with osteoporosis and fractures of the vertebrae.

With the introduction of the drug to patients (men and women) with fractures of the proximal part of the femur (caused by minimal injury and requiring surgical intervention) decreased incidence of subsequent osteoporoticheskih fractures any localization 35% compared to placebo (of them clinically significant fractures of vertebrae are on 46%, vnepozvonochnyh fractures-on 27%).

In patients with fractures of the femur application Aklasty within 2 years resulted in an increase in the IPC of the proximal part of the femur in General and the femur to 5.4% and 4.3%, respectively.

Using drugs 1 Once a year for men with primary (senilnym) or secondary (When gipogonadizme) osteoporosis during 2 years noted expressed increasing IASC lumbar vertebrae, comparable with the effect of alendronova acid in the dose 70 mg a week inside.

In patients with osteoporosis, caused by the application of GKS, therapy Aklastoj also significantly increased the IPC, not rendering negative influence on bone structure and mineralization.

In the treatment of Aklastoj in patients with Paget's disease of the bone was observed statistically reliable, quick and long lasting therapeutic response, bone level normalization of Exchange and concentrations of ALP in blood plasma.

The drug is also highly effective in patients, receiving earlier treatment of oral bisfosfonatami. Established, that in the majority of patients with the use of zoledronovoj acid therapeutic response persists throughout the treatment period (about 2 years).

Decrease of pain syndrome 6 month after a single injection dose Aklasty 5 mg is comparable to the analgesic effect of rizedronova acid in the dose 30 mg / day.

In patients with postmenopauznym osteoporosis and bone disease Pejeta zoledronic acid did not affect the quality of normal bone, does not violate the processes of bone remodeling and mineralization and promotes the preservation of normal Trabecular Bone architectonics.

Pharmacokinetics

Pharmacokinetic data were obtained after single and repeated 5- and a 15-minute infusion 2 mg, 4 mg, 8 mg 16 mg zoledronovoj acid 64 patients. Pharmacokinetic parameters do not depend on the dose.

After the start of infusions of Aklasty zoledronovoj acid concentration in plasma is increasing rapidly, reaching a peak at the end of infusions. After the end of the infusion rapidly decrease the concentration of zolendronovoj acid in plasma (up to the level <10% from the peak through 4 h and to < 1% from the peak through 24 no), then for a long period in the blood plasma concentration of the drug remains low (not to exceed 0.1% from C_max).

Zolendronovaja acid, introduced in/in, report the news in 3 Phase: rapid drug excretion of two-phase systemic blood flow with T_1/2 0.24 no (α-phase) and 1.87 no (b-фаза) and the long end phase T_1/2, component 146 no (γ-phase). The rapid decline of drug concentration (a- and β-phases) in the blood plasma is possible due to the rapid distribution of zoledronovoj acid in bone tissue and breeding her kidneys. No cumulation of the drug with the re-introductions every 28 days.

Zoledronic acid is not metabolizmu, excreted by the kidneys in unchanged form. For the first 24 h in the urine detected 39 ± 16% imposed dose. The rest of the drug is associated exclusively with bone tissue. Then slowly release the opposite occurs zoledronovoj acid back from the bone into the bloodstream and kidneys. Total plasma clearance of the drug is 5.04 ± 2.5 l/h and does not depend on the dose, gender, age, race and body mass index patient. Displaying, variability of plasma clearance of zoledronovoj acid in the same patient and in different patients, respectively, 36% and 34%. Infusion time with 5 to 15 min leads to a decrease in the concentration of zoledronovoj acid 30% at the end of infusions, but does not affect the bioavailability.

Zoledronovoj acid binding protein with the plasma low (43-55%) and does not depend on its concentration.

Pharmacokinetics in special clinical situations

Kidney klirens zoledronovoj acid positively correlated with KK and is 75 ± 33% of creatinine clearance, amounting to an average of 84 ± 29 ml/min (range 22-143 ml / min) in 64 patients, included in the study.

The small observed increases bioavailability (30-40%) If any of the kidneys from mild to moderate degree, compared to patients with normal renal function, and the absence of cumulation of the drug with repeated introduction regardless of the kidneys suggest, that there is no need to adjust doses zoledronovoj acid in light (CC 50-80 ml / min) and moderate (CC 30-50 ml / min) impaired renal function.

Testimony

is post-menopausal osteoporosis (to reduce the risk of fractures of the femur, vertebrae and vnepozvonochnyh fractures, for increasing bone mineral density);

-Prevention of subsequent (new) osteoporoticheskih fractures in men and women with fractures of the proximal part of the femur;

-osteoporosis in men;

-Prevention and treatment of osteoporosis, caused by SCS;

-Paget's disease of bone.

Dosage regimen

The drug is injected in the form of infusions. The introduction of the preparation must be performed using infuzionna system valve, providing continuous infusion speed, for not less than 15 m.

Before the introduction of the Aklasty should ensure that adequate hydratation of organism. This is especially important for patients over the age of 65 years, as well as for patients, receiving therapy dioretikami.

To postmenopauznogo treatment of osteoporosis and osteoporosis in men the recommended dose is Aklasty 5 mg (1 bottle – 100 ml) I / 1 once a year. If the intake of calcium and vitamin D dietary intake is insufficient, patients with osteoporosis should appoint drugs calcium and vitamin D.

To prevent subsequent fractures in patients with fractures of the proximal part of the femur the recommended dose is Aklasty 5 mg (1 bottle – 100 ml) I / 1 once a year. Additionally, such patients are encouraged to take drugs calcium and vitamin D. To prevent subsequent fractures in patients with fractures of the proximal part of the femur first infusion preparation should be carried out through 2 and more weeks after surgery.

To treatment of osteoporosis, caused by the use of GCS, the recommended dose is Aklasty 5 mg (1 bottle – 100 ml) I / 1 once a year. If the intake of calcium and vitamin D dietary intake is insufficient, patients with osteoporosis should appoint drugs calcium and vitamin D.

To treatment of Paget's disease of bone It is recommended that a single on/in the introduction of the drug in a dose 5 mg. Unnecessarily. Paget's disease of bone is characterized by high Exchange bone, all patients with the disease are encouraged to take daily requirement of calcium (at least 500 mg elemental calcium 2 times / day) and vitamin D during the first 10 days after the introduction of the Aklasty.

Re-treatment Aklastojkostnoj Paget's disease. Currently, special recommendations for the treatment of Paget's disease of bone re not available. Patients, responding to therapy Aklastoj, Since its a single injection there was a long period of remission. The possibility of re-introduction of Aklasty can be considered in case of a detection of patients with recurrence of the disease based on the following criteria: lack of normalization of the level of serum ALP, enhancing its level of Dynamics, as well as the availability of clinical signs of Paget's disease, medical examination discovers later 12 months after the introduction of the first dose of Aklasty.

Patients with the human kidney with QC ≥ 35 ml / min It does not require correction dose. Aklastu is not recommended in patients with severely impaired renal function (CC< 35 ml / min).

Patients with impaired hepatic function It does not require correction dose.

Since the bioavailability, distribution and excretion were similar in patients of different ages, older patients aged 65 and older It does not require correction dose.

Rules of infusion

During the preparation and holding of the infusions should observe the rules of asepsis.

Prior to the introduction of Aklasty should visually assess the quality and color solution. The drug cannot be used to change the color or appearance of the nerastvorivshihsja visible particles.

Aklastu should not be confused or in conjunction with any other drugs. Aklasty should not be allowed contact with any solutions, containing calcium or any other bivalent cations.

For the introduction of the drug you should always use a separate system for infusions.

At the end of infusions Aklasty unused solution, the remaining vial, You cannot apply.

After opening bottle solution is chemically and physically stable during 24 h at temperatures from +2° to +8° c.

Aklasty solution, preferably directly after opening bottle. Unused right solution can be stored in the refrigerator at a temperature from 2° to 8° c for no more 24 no.

If the solution has cooled down, before the introduction of it should be kept in the room until the ambient temperature.

Side effect

When applying in postmenopauzne osteoporosis and Paget's disease of bone

After the on/in the Aklasty the most frequently observed undesirable phenomenon lasting usually no more 3 days after injection: fever (18.1%), mialgii (9.4%), flu-like symptoms (7.8%), artralgii (6.8%), headache (6.5%). The majority of these reactions were weakly or moderately expressed. With the re-introduction of the drug patients with osteoporosis postmenopauznym severity of adverse events decreased significantly.

Evaluation of the incidence of adverse events, possibly associated with the use of the drug: Often (≥ 1/10); often (≥ 1/100, < 1/10); sometimes (≥ 1/1 000, < 1/100); rarely (≥ 1/10 000, < 1/1 000).

From the central and peripheral nervous system: often – headache, dizziness; sometimes – lethargy (often – When Paget's disease of bone), paresthesia, drowsiness, tremor, syncope, flavor violation, vertigo.

From the senses: sometimes – conjunctivitis, sore eyes, uveitis; rarely – episcleritis, Irit.

The respiratory system: often – breathlessness (only when Paget's disease).

From the digestive system: often – nausea, vomiting, diarrhea; sometimes – dyspepsia (often – When Paget's disease), stomach ache, dry mouth, esophagitis.

Dermatological reactions: sometimes – rash.

On the part of the musculoskeletal system: often – artralgii, mialgii, ostealgias, pain in the back and limbs; sometimes – swelling of joints, shoulder pain, muscle spasms, muscle weakness, joint stiffness.

From the urinary system: sometimes – increase in serum creatinine.

From the body as a whole: Often – temperature rise; sometimes – hypocalcemia, flu-like symptoms (Often – When Paget's disease), chills, fatigue, asthenia, pain, general malaise, tremor; sometimes – anorexia, peripheral edema, Feeling thirsty.

In one three-year clinical study in patients with postmenopauznym osteoporosis overall incidence of atrial fibrillation was low and amounted to: 2.5% (96 people from 3862) in the Group of patients, receiving Aklastu, and 1.9% (75 from 3852 patients) in Group, placebo. In 1.3% patients (51the patient from 3862), receiving Aklastu, and 0.6% (22 a person from 3852) in the placebo group this unwelcome phenomenon was seen as a serious. The reason for increasing frequency of atrial fibrillation on Aklastoj therapy in this study is not installed.

Increased frequency of atrial fibrillation when compared with placebo, in this study,, was not found in other clinical studies zoledronovoj acid.

When applied to prevent subsequent fractures in patients with fractures of the femur

The majority of adverse events were moderately pronounced and do not require the preparation. The incidence of serious adverse events in the Group amounted to Aklasty 38%, In placebo- 41%.

The incidence of adverse events, possibly associated with the use of the drug, is evaluated as follows:: Often (≥ 1/10); often (≥ 1/100, < 1/10); sometimes (≥ 1/1000, < 1/100); rarely (≥ 1/10 000, < 1/1000).

CNS: often – headache; sometimes – insomnia.

The respiratory system: sometimes – breathlessness.

From the digestive system: often – nausea; sometimes – vomiting, diarrhea, dry mouth, toothache.

On the part of the musculoskeletal system: often – artralgii, mialgii, ostealgias; sometimes – backache, swelling of joints, Musculoskeletal pain.

From the body as a whole: often – temperature rise, chills, asthenia; sometimes – fatigue, pain, general malaise, flu-like symptoms, peripheral edema.

When applying Aklasty for 3 years in patients with fractures of the femur, the frequency of detection of changes (QC) (based on the results of the annual identification to drug administration) and development of the kidney were similar to those in the placebo group.

Use in osteoporosis in men

In applying Aklasty in men with osteoporosis incidence of serious adverse reactions, as well as the proportion of patients, with reported at least one adverse reaction, were similar to those in the Group of alendronova acid (except for symptoms, occur within the first 3 days after injection: fever, myalgia, flu-like symptoms, arthralgia, headache). The overall safety profile of the drug in men with osteoporosis was similar to that of postmenopauzalnym in patients with osteoporosis.

The incidence of adverse reactions, possibly associated with the use of the drug, is evaluated as follows:: Often (≥ 1/10); often (≥ 1/100, < 1/10); sometimes (≥1/1000, < 1/100); rarely (≥ 1/10 000, < 1/1000).

On the part of the organ of vision: often – red eyes.

From the nervous system: often – lethargy; sometimes – sleep disorders.

From the digestive system: often – dyspepsia, esophagitis, abdominal pain.

Dermatological reactions: often – hyperhidrosis.

On the part of the musculoskeletal system: Often – artralgii, mialgii; often – Musculoskeletal pain in
the thorax, stiffness, stiffness and swelling of joints, pain in the muscles and bones.

By the body as a whole and reactions at the site of application: Often – fatigue, pain
(various localization); often – anorexia, fever, flu-like symptoms, headache (occurring within 3 days after injection), reactions at the injection drug, thirst.

Changes in laboratory parameters: often – elevated levels of C-reactive protein.

Use in osteoporosis, caused by the intake of CORTICOSTEROIDS

In applying Aklasty in patients with osteoporosis, caused by the intake of CORTICOSTEROIDS, the incidence of serious adverse reactions, and the overall frequency of adverse reactions, were similar to those in the Group of rizedronova acid (with the exception of
symptoms, occur within the first 3 days after injection: fever, myalgia, flu-like symptoms, arthralgia, headache). The overall safety profile of the drug in patients with osteoporosis, caused by the application of GKS, was similar to those of patients with postmenopauznym osteoporosis.

The incidence of adverse reactions, possibly associated with the use of the drug, is evaluated as follows:: Often (≥ 1/10); often (≥ 1/100, < 1/10); sometimes (≥1/1000, < 1/100); rarely (≥ 1/10 000, < 1/1000).

From the hematopoietic system: sometimes – anemia.

Cardio-vascular system: sometimes – heartbeat, increased blood pressure.

From the digestive system: often – dyspepsia, abdominal pain; sometimes – gastritis, hastroэzofahealnыy reflux, constipation.

On the part of the musculoskeletal system: sometimes – Musculoskeletal pain in chest area, stiffness.

From the laboratory parameters: patients with osteoporosis on a background of application of the Aklasty in 0.2% cases declining concentration of calcium (<1.87 mmol / l) serum, clinical signs gipocalziemii while not observed.

In applying the drug in patients with fractures of the femur, in osteoporosis in men and osteoporosis, caused by the intake of CORTICOSTEROIDS, There has been no decrease in the concentration of calcium in the blood plasma <1.87 mmol / l.

In patients with Paget's disease of bone in approximately 1% cases detected transient hypocalcemia, accompanied by clinical manifestations.

From the urinary system: When in/with the introduction of bisphosphonates, including zoledronovuju acid, There have been cases of kidney function, attributed the increase of the level of serum creatinine and in rare cases – acute renal failure.

Violation of kidney function on a background of application of zoledronovoj acid was observed in patients with the presence of either renal pathology in history, additional risk factors (eg, oncological diseases, concomitant chemotherapy, the use of nefrotoksicskih drugs or severe dehydration). The majority of these patients were receiving therapy zoledronovoj acid at a dose 4 mg every 3-4 of the week, However, in some cases, the violation of the kidney was noted after a single application of zoledronovoj acid. Aklastoj therapy for 3 years in patients with postmenopauznym osteoporosis frequency increase creatinine blood and development of renal failure did not differ from that in applying the placebo in patients, placebo. Patients, receiving Aklastu, more often observed transient increased creatinine blood during 10 days after infusion versus placebo (1.8% and 0.8% respectively).

When applying Aklasty for 2 years in men with osteoporosis and creatinine clearance rate of development of the kidney was similar to that in the Group of alendronova acid. In patients with osteoporosis, caused by the application of GKS, While therapy Aklastoj creatinine clearance rate and development of kidney function was similar to that in the Group of rizedronova acid.

Local reactions: in applying Aklasty in patients with postmenopauznym osteoporosis in 0.7% There have been cases of redness, swelling and/or soreness at the injection. In patients with fractures of the femur incidence of local reactions at the injection drug was comparable with that in the placebo group. In the treatment of osteoporosis in men, the incidence of reactions at the site of Aklasty was 2.6% (compared with 1.4% in the Group of alendronova acid). In patients with osteoporosis, caused by the application of GKS, There was no reaction at the site of application.

Other: cases of osteonekroza (common – jaw) took place mainly in cancer patients, receiving treatment bisfosfonatami, After tooth extraction or other dental manipulations. The majority of these patients noted symptoms of local infectious-inflammatory process, including osteomyelitis. In clinical studies in patients with osteoporosis case osteonekroza Jaw took place at 1 patient, host Aklastu, and 2 patients, placebo. In all 3 cases mentioned permission process.

In applying Aklasty in patients with fractures of the femur, in osteoporosis in men and osteoporosis, caused by the intake of CORTICOSTEROIDS, There have been no cases of jaw osteonekroza.

Against the backdrop of Aklastoj therapy in clinical practice, the following adverse events were reported without indication of a causal relationship to drug (frequency is not installed): hypersensitivity reactions, including rare cases of bronchial obstruction, krapivnicы, angioneuroticeski pain and sporadic reports of anaphylactic reactions development/shock.

Contraindications

- Severe disorders of mineral metabolism, including gipocalziemia;

- Pregnancy;

- Lactation (breast-feeding);

- Childhood and adolescence up 18 years (tk. safety and efficacy of Aklasty in this category of patients have not been studied);

-hypersensitivity to zoledronovoj acid, or to any other component of the drug, or to any bisfosfontam.

As experience with the drug in patients with severely impaired renal function (CC < 35 ml / min) limited, Aklastu is not recommended in this category of patients.

Pregnancy and lactation

Product Aklasta contraindicated in pregnancy and lactation (breast-feeding).

Data on the application of zoledronovoj acid in pregnant women.

IN experimental research shows availability tertogennogo action from one of the experimental rodent species. The potential risk in the application from a person unknown, the product Aklasta is contraindicated in pregnancy and breastfeeding.

Cautions

The physician should inform the patient about the basic manifestations of hypocalcemia and ensure regular monitoring of patients, risk group.

Aklastoj therapy in patients with Paget's disease of bone should be done only by qualified doctors, with experience treating this disease.

To reduce the frequency of adverse reactions, recorded within 3 days after injection, You can assign paracetamol or ibuprofen immediately after infusions Aklasty.

Before prescribing the drug should determine the level of creatinine in the serum.

In the presence of hypocalcemia is necessary before using Aklasty treatment with adequate doses of calcium and vitamin D. Therapy should also conduct other mineral metabolism violations violations of mineral metabolism (eg, emerging after operations on the thyroid and parathyroid glands, When gipoparatireoze or decrease calcium absorption in the gut) and to ensure regular monitoring of patients with c3h5o3.

Risk factors for cancer are osteonekroza, soputstvuyushtaya therapy (eg, chemotherapy, radiation therapy, treatment of the SCS) and the presence of other opportunistic diseases (eg, anemia, coagulopathies, Infections, teeth diseases in history).

Although a causal link osteonekroza JAWS with bisphosphonates is not installed, You should avoid dental operations, because the recovery time after these operations can increase. Before the start of the bisphosphonates should hold a dental examination and complete the necessary preventive procedures in patients, with risk factors (oncological diseases, chemotherapy, treatment with glucocorticosteroids it; non-compliance with oral hygiene).

With the development of osteonekroza jaw while therapy bisfosfonatami holding dental operations may worsen the condition of patients. There is no information about how, that interruption of bisphosphonates to dental intervention reduces the risk of jaw osteonekroza. Tactics of treatment of a particular patient should be based on an individual assessment of the risk/benefit ratio.

Zoledronic acid is the active ingredient as Aklasty, and Zomety (medication for the treatment of cancer patients), However, these drugs are not interchangeable and should not be applied simultaneously.

Effects on ability to drive vehicles and management mechanisms

Data on negative influence of Aklasty on the ability to drive vehicles and operate moving mechanisms no.

Overdose

So far, cases of drug overdose Aklasty were reported.

In the case of drug overdose, leading to hypocalcemia and accompanied by clinical symptoms (numbness, prickle, muscle cramps and twitching), calcium supplementation is shown inside and/or solution infusion of Calcium Gluconate.

Drug Interactions

Special studies on the interaction of zoledronovoj acid with other drugs have been conducted. Zoledronic acid is not subject to systemic metabolism and does not affect the isozyme cytochrome P450 in vitro.

Zoledronic acid is characterized by a low degree of binding to plasma proteins (43-55%); interaction as a result of displacement of drugs with a high degree of binding to proteins from bonding it is unlikely.

Zoledronic acid news. Caution must be exercised while applying Aklasty drugs, that can have a significant effect on renal function (eg, with aminoglikozidami or dioretikami, causing dehydration).

Pharmaceutical interaction

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

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

List B. The drug should be stored out of reach of children at or above 25 ° C. After opening bottle solution is stable at a temperature from 2° to 8° c for 24 no. Shelf life – 3 year.