Aklasta solution for inf. 5mg / 100ml, # 1

• Postmenopausal osteoporosis (to reduce the risk of fractures of the femur, vertebrae and extravertebral fractures, to increase bone mineral density); prevention of subsequent (new) osteoporotic fractures in men and women with fractures of the proximal femur; osteoporosis in men; prevention and treatment of osteoporosis caused by the use of GCS; prevention of postmenopausal osteoporosis (in patients with osteopenia); Paget's bone disease.

• Osteolytic, osteoblastic and mixed bone metastases of solid tumors and osteolytic foci in multiple myeloma, as part of combination therapy; hypercalcemia caused by a malignant tumor.

AklastaЃ, a solution for infusion, is administered intravenously by infusion. The introduction of the drug should be carried out using a valve infusion system that provides a constant infusion rate for at least 15 minutes.

Before the administration of AklastaЃ, an adequate

For the treatment of postmenopausal osteoporosis in women and osteoporosis in men, the recommended dose of AklastЃ is 5 mg (the contents of one bottle of the drug are 100 ml of solution) intravenously 1 time per year. In case of insufficient intake of calcium and vitamin D with food, calcium and vitamin D preparations should be additionally used.

For the prevention of subsequent fractures in patients with fractures of the proximal femur, the recommended dose of AklastЃ is 5 mg (the contents of one bottle of the drug are 100 ml of solution) intravenously 1 time per year. Patients with a recent (up to 90 days) fracture of the proximal femur are recommended to take a single dose of vitamin D in a high dose (from 50,000 to 125,000 IU orally or intramuscularly) 2 weeks before the first infusion of AklastaЃ. With a single use of AklastaЃ, patients are advised to take calcium supplements daily (1000 mg per day and vitamin D (800 IU per day) for 14 days prior to infusion). After infusion of AklastaЃ for a year, patients should also take calcium and vitamin supplements D.

To prevent subsequent fractures in patients with fractures of the proximal femur, the first infusion of AklastaЃ should be carried out 2 or more weeks after surgery.

For the treatment of osteoporosis caused by the use of glucocorticosteroids, the recommended dose of AklastЃ is 5 mg (the contents of one bottle of the drug are 100 ml of solution) intravenously 1 time per year. In case of insufficient intake of calcium and vitamin D with food in patients with osteoporosis, calcium and vitamin D preparations should be additionally used.

For the prevention of postmenopausal osteoporosis, the recommended dose of AklastЃ is 5 mg (the content of one bottle of the drug is 100 ml of solution) intravenously 1 time in 2 years.

In order to decide whether to re-infuse, the risk of fractures and the clinical response to therapy should be re-assessed annually.

For the prevention of postmenopausal osteoporosis, it is very important to have sufficient intake of calcium and vitamin D. In case of insufficient intake of them with food, additional intake of calcium and vitamin D preparations is recommended.

For the treatment of Paget's bone disease, a single administration of 5 mg of AklastЃ intravenously is recommended.

Paget's bone disease is characterized by high activity of bone tissue metabolism. Due to the rapid onset of the effect on bone metabolism after the use of AklastaЃ, transient hypocalcemia may develop during the first 10 days after infusion. While using AklastaЃ, you should ensure a sufficient intake of vitamin D. In addition to this, it is strictly recommended to take an adequate dose of calcium (at least 500 mg of elemental calcium 2 times a day) for at least the first 10 days after the administration of AklastaЃ.

Retreatment with AklastaЃ in patients with Paget's bone disease
After a single use of AklastaЃ for Paget's bone disease, patients experienced a prolonged (about 7.7 years on average) remission. Since Paget's bone disease is a chronic disease, repeated use of the drug is recommended. Re-use of the drug for Paget's disease consists in its intravenous administration at a dose of 5 mg one year or more from the start of treatment. The interval between injections of AklastЃ should be determined individually based on the effectiveness of treatment and the results of determining the concentration of alkaline phosphatase, which should be carried out every 6-12 months. In the absence of clinical signs of worsening, such as bone pain and compression symptoms. and / or radiological signs of disease progression,the next infusion of AklastЃ can be carried out no earlier than 12 months after the first.

Duration of therapy The
optimal duration of drug therapy for long-term use has not been determined. In all patients receiving the drug, the response to therapy and the need for further continuation of treatment should be periodically assessed, taking into account the therapeutic effect, the risk of fractures and concomitant diseases.

In patients with a low risk of fractures, the possibility of discontinuing the drug after the first three years of its use should be considered, while in patients at high risk, the possibility of continuing regular therapy should be considered. In patients who discontinue treatment, the risk of fractures should be re-assessed every 2-3 years and, if necessary, treatment should be resumed.

Patients with impaired renal function
The use of the drug in patients with creatinine clearance <35 ml / min is contraindicated.
In patients with creatinine clearance ?35 ml / min, dose adjustment is not required.

Patients with impaired liver function
Patients with impaired liver function do not require dose adjustment of the drug.

Elderly patients (?65 years)
No dose adjustment is required, since bioavailability, distribution and excretion in patients of different ages are similar.

Directions for use of the drug
When preparing and carrying out the infusion, you should follow the rules of asepsis.

Before the administration of AklastaЃ, the quality and color of the solution should be visually assessed. The drug should not be used if the color changes or the appearance of undissolved visible particles.

AklastЃ drug should not be mixed or administered together with any other drugs. Do not allow AklastЃ preparation to come into contact with any solutions containing calcium or any other divalent cations. A separate infusion system should always be used to administer the drug.

The unused solution of AklastЃ, which remains in the vial, cannot be used.

It is advisable to use AklastaЃ solution immediately after opening the bottle. The solution unused immediately can be stored in the refrigerator at a temperature from +2 to +8 ? — for no more than 24 hours. If the solution is cooled, it should be kept indoors until it reaches room temperature before administration.

The solution for infusion is transparent, colorless.

100 ml

zoledronic acid monohydrate 5.33 mg,

which corresponds to the content of zoledronic acid (anhydrous) 5 mg

Excipients: mannitol - 4950 mg, sodium citrate dihydrate - 30 mg, water d / i - up to 100 ml.

• Severe disorders of mineral metabolism, including hypocalcemia;

• severe renal dysfunction (CC <35 ml / min);

• pregnancy;

• breastfeeding period;

• age under 18;

• hypersensitivity to zoledronic acid or to any bisphosphonates.

pharmachologic effect

Bone resorption inhibitor, nitrogen-containing bisphosphonate. Acts primarily on bone, inhibits osteoclast activity and bone resorption.

The selective effect of bisphosphonates on bone tissue is based on a high affinity for mineralized bone tissue. After intravenous administration, zoledronic acid is rapidly redistributed to the bones and, like other bisphosphonates, is localized mainly in the sites of bone tissue remodeling.

The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthetase (FPS), while the possibility of other mechanisms of action is not excluded. The long period of action is determined by a high affinity for the active center of FPS and a pronounced affinity for mineralized bone tissue.

With the exception of the high antiresorptive effect, the effect of zoledronic acid on bone tissue is similar to that for other bisphosphonates.

In addition to inhibiting bone resorption, zoledronic acid has antitumor properties that provide therapeutic efficacy in bone metastases.

In vivo: inhibition of osteoclastic resorption of bone tissue, altering the microenvironment of the bone marrow, leading to a decrease in the growth of tumor cells; antiangiogenic activity. Suppression of bone resorption is clinically accompanied by a marked reduction in pain.

In vitro: inhibition of osteoblast proliferation, direct cytotoxic and pro-apoptotic activity, synergistic cytostatic effect with anticancer drugs; antiadhesive / invasive activity.

Zoledronic acid, suppressing proliferation and inducing apoptosis, has a direct antitumor effect on human myeloma cells and breast cancer, and also reduces the penetration of breast cancer cells through the extracellular matrix, which indicates that it has antimetastatic properties. In addition, zoledronic acid inhibits the proliferation of human endothelial cells and induces anti-angiogenic effects in animals.

In patients with tumor-induced hypercalcemia, it has been shown that the action of zoledronic acid is characterized by a decrease in serum calcium concentration and a decrease in its excretion in the urine.

Pharmacokinetics

After the start of the infusion, the concentration of zoledronic acid in the plasma rapidly increases, reaching Cmax at the end of the infusion, followed by a rapid decrease in concentration by 10% after 4 hours and by less than 1% after 24 hours with a consistently prolonged period of low concentrations not exceeding 0.1% of Cmax before repeated infusion on the 28th day.

Zoledronic acid, administered intravenously, is excreted by the kidneys in 3 stages: rapid two-phase excretion from the systemic circulation with T1 / 2 of 0.24 h and 1.87 h and a prolonged phase with a final T1 / 2 of 146 h. No cumulation was observed with repeated injections every 28 days.

Zoledronic acid does not undergo systemic metabolism and is excreted by the kidneys unchanged. During the first 24 hours, 39 ± 16% of the administered dose is found in the urine. The rest is mainly associated with bone tissue. Then, the reverse release of zoledronic acid from the bone tissue into the systemic circulation and its excretion by the kidneys occurs slowly. The total plasma clearance is 5.04 ± 2.5 L / h. An increase in the infusion time from 5 to 15 minutes leads to a decrease in the concentration of zoledronic acid by 30% at the end of the infusion, but does not affect the AUC.

Less than 3% is excreted in the feces.

Renal clearance of zoledronic acid is positively correlated with CC.

Low affinity of zoledronic acid for blood components has been shown. Plasma protein binding is low (on average about 50%) and does not depend on the concentration of zoledronic acid.

Side effect

From the hematopoietic system: infrequently - anemia.

From the side of metabolism: infrequently - decreased appetite; the frequency is unknown - dehydration (developing as a result of post-infusion events such as fever, vomiting and diarrhea), hypophosphatemia.

From the nervous system: often - headache, dizziness; infrequently - lethargy, paresthesia, drowsiness, tremor, fainting, hypesthesia, dysgeusia.

Mental disorders: infrequently - insomnia, anxiety.

From the side of the organ of vision: infrequently - conjunctivitis, pain in the eyes, vertigo; rarely - uveitis, episcleritis, iritis.

On the part of the organ of hearing and labyrinthine disorders: infrequently - vertigo.

From the side of the cardiovascular system: infrequently - increased blood pressure, sudden facial flushing; the frequency is unknown - a pronounced decrease in blood pressure (in patients with risk factors).

From the respiratory system: infrequently - cough, shortness of breath.

Skin and subcutaneous tissue disorders: infrequently - skin rash, hyperhidrosis, pruritus, erythema.

From the digestive system: often - nausea, vomiting, diarrhea; infrequently - dyspepsia, pain in the upper abdomen, abdominal pain, gastroesophageal reflux, constipation, dry mouth, esophagitis.

From the musculoskeletal system and connective tissue: often - arthralgia, myalgia, bone pain, pain in the back and limbs; infrequently - neck pain, muscle stiffness, joint swelling, muscle spasms, chest pain of musculoskeletal origin, musculoskeletal pain, joint stiffness, arthritis, muscle weakness; frequency unknown - osteonecrosis of the jaw.

From the urinary system: infrequently - an increase in the concentration of blood creatinine, pollakiuria, proteinuria.

Infectious and parasitic diseases: infrequently - influenza, nasopharyngitis.

From the immune system: hypersensitivity reactions, including anaphylactic reaction, anaphylactic shock, angioedema, bronchospasm, urticaria.

General reactions and disorders at the injection site: very often - fever; often - flu-like syndrome, chills, fatigue, asthenia, pain, general malaise; infrequently - peripheral edema, thirst, acute phase reactions, noncardiogenic chest pain.

Application during pregnancy and lactation

Use during pregnancy and breastfeeding is contraindicated.

Application for impaired renal function

It is not recommended for use in patients with severely impaired renal function (serum creatinine concentration? 400 ?mol / L or? 4.5 mg / dL), except in cases where the expected benefit of therapy outweighs the potential risk.

There are isolated reports of impaired renal function with the use of bisphosphonates. Risk factors for the development of such complications include previous renal failure and long-term use of zoledronic acid in high doses (8 mg), and a reduction in infusion time.

Application in children

The efficacy and safety of using zoledronic acid in pediatric practice have not been established.

special instructions

The drug containing zoledronic acid should be used strictly according to the indications for the corresponding dosage form.

Use with caution in patients with mild to moderate renal impairment; in patients with complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses, and intolerance to acetylsalicylic acid or other NSAIDs (including a history); when used simultaneously with drugs that can have a significant effect on renal function (for example, with antibiotics-aminoglycosides or diuretics that cause dehydration).

With repeated use, the concentration of creatinine in the blood serum should be determined before each administration. If the data obtained indicate a deterioration in renal function, it is necessary to assess the risks and benefits of the therapy.

Dehydration in the patient should be excluded before infusion. To ensure adequate hydration, it is recommended that saline be administered before, during, or after the infusion of zoledronic acid. Overhydration of the patient should be avoided due to the risk of complications from the cardiovascular system.

After the introduction of zoledronic, constant monitoring of the concentration of calcium, phosphorus, magnesium and creatinine in the blood serum is necessary.

If hypocalcemia, hypophosphatemia, or hypomagnesemia develops, short-term supportive therapy is necessary.

Influence on the ability to drive vehicles and mechanisms

Due to the fact that dizziness is one of the side effects of zoledronic acid, patients should be careful when performing potentially hazardous activities. If dizziness occurs, you should refrain from these activities.

Drug interactions

With the simultaneous use of bisphosphonates and aminoglycosides, the serum calcium level may remain reduced for a longer time than is required, since an additive effect on the serum calcium concentration is possible.

With simultaneous use with drugs that have a potentially nephrotoxic effect, the risk of deterioration of renal function increases.