Zoledronic acid concentrate for infusions 4 mg/5 ml. vial №1


Prevention of symptoms associated with bone damage (pathological fractures, spinal cord compression, complications after surgery and radiation therapy or hypercalcemia due to malignant tumor) in patients with advanced malignant neoplasms. Treatment of hypercalcemia due to malignant tumor.



Concentrate for solution for infusion

colorless or slightly yellowish, transparent.

zoledronic acid monohydrate 4.264 mg,

which corresponds to a zoledronic acid content of 4 mg

Excipients: mannitol – 220 mg, sodium citrate dihydrate – 24 mg, water d / i – up to 5 ml.

Clinical and pharmacological group:

Inhibitor of bone resorption in bone metastases

Pharmacotherapeutic group:

Bone resorption inhibitor bisphosphonate

Pharmacological action

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

The selective action of bisphosphonates on bone tissue is based on a high affinity for mineralized bone tissue. After intravenous administration, zoledronic acid is rapidly redistributed in bone and, like other bisphosphonates, is localized predominantly at bone remodeling sites.

The main molecular target of zoledronic acid in 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 defined by high affinity to the active center of FPS and the expressed affinity to the mineralized bone tissue.

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

In addition to the inhibitory effect on bone resorption, zoledronic acid has antitumor properties that provide therapeutic efficacy in bone metastases.

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

In vitro: inhibition of osteoblast proliferation, direct cytotoxic and proapoptotic activity, synergistic cytostatic effect with antitumor drugs; antiadhesive / invasive activity.

Zoledronic acid, by inhibiting proliferation and inducing apoptosis, has a direct antitumor effect on human myeloma cells and breast cancer, and reduces the penetration of breast cancer cells through the extracellular matrix, indicating the presence of its anti-tumor properties. In addition, zoledronic acid inhibits the proliferation of human endothelial cells and causes antiangiogenic activity in animals.

In patients with tumor-induced hypercalcaemia, zoledronic acid has been shown to decrease serum calcium and decrease urinary excretion.


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

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

Zoledronic acid is not systemically metabolized and is excreted unchanged by the kidneys. During the first 24 hours, 39 ± 16% of the administered dose is detected in the urine. The rest is mainly associated with bone tissue. Then slowly reverse release of zoledronic acid from bone tissue into the systemic bloodstream and its excretion by the kidneys. The total plasma clearance is 5.04 ± 2.5 l / h. Increasing the infusion time from 5 to 15 minutes results in a 30% decrease in zoledronic acid concentration at the end of the infusion, but does not affect 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 is shown. Plasma protein binding is low (on average about 50%) and independent of zoledronic acid concentration.

Indications of active substances of the drug Zoledronic acid

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 corticosteroids; 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.

Dosing mode

The method of application and dosage regimen of a particular drug depend on its form of release and other factors. The optimal dosing regimen is determined by the physician. The compliance of the used dosage form of a particular drug with the indications for use and dosage regimen should be strictly observed.

Injected intravenously

The dose and treatment regimen depend on the indications, the therapeutic regimen used, the therapeutic efficacy.

Side effect

From the hematopoietic system:

infrequently – anemia.

From a metabolism:

infrequently – decrease in appetite; frequency unknown – dehydration (developing due to post-infusion phenomena such as fever, vomiting and diarrhea), hypophosphatemia.

From the nervous system:

often – headache, dizziness; infrequently – inhibition, paresthesias, drowsiness, tremor, fainting, hypoaesthesia, dysgeusia.

Mental disorders:

infrequently – insomnia, anxiety.

From the organ of vision:

infrequently – conjunctivitis, eye pain, vertigo; rarely – uveitis, episcleritis, iritis.

From the hearing organ and labyrinthine disorders:

infrequently – vertigo.

From cardiovascular system:

infrequently – increase in BP, sudden reddening of the face; frequency unknown – marked decrease in blood pressure (in patients with risk factors).

From the respiratory system:

infrequently – cough, shortness of breath.

From the skin and subcutaneous tissues:

infrequently – skin rash, hyperhidrosis, itchy skin, erythema.

From the digestive system: often – nausea, vomiting, diarrhea; uncommon – dyspepsia, upper abdominal pain, abdominal pain, gastroesophageal reflux, constipation, dry mouth, esophagitis.

From the musculoskeletal system and connective tissue:

often – arthralgia, myalgia, bone pain, back and limb pain; uncommon – neck pain, muscle stiffness, swelling in the joints, 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 blood creatinine, pollakiuria, proteinuria.

Infectious and parasitic diseases:

infrequently – influenza, nasopharyngitis.

From the immune system:

hypersensitivity reactions, including anaphylactic reaction, anaphylactic shock, angioneurotic edema, 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, non-cardiogenic chest pain.

Contraindications to use

Severe disorders of mineral metabolism, including hypocalcemia; severe renal impairment (CC <35 ml / min); pregnancy; breastfeeding period; age up to 18 years; hypersensitivity to zoledronic acid or to any bisphosphonates.

Use during pregnancy and breastfeeding

Contraindicated during pregnancy and breastfeeding.

Use in renal impairment

It is not recommended for use in patients with severe renal impairment (serum creatinine concentration ≥400 μmol / l or ≥4.5 mg / dl) unless the expected benefit of therapy outweighs the potential risk.

There have been isolated reports of renal dysfunction with bisphosphonates. Risk factors for the development of such complications include previous renal failure and prolonged use of zoledronic acid in high doses (8 mg), reduced infusion time.

Use in children

Efficacy and safety of 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 concomitantly with drugs that can have a significant effect on renal function (for example, with aminoglycoside antibiotics or diuretics that cause dehydration).

When re-administered, serum creatinine should be determined before each administration. If the data indicate a deterioration in renal function, it is necessary to assess the risks and benefits of therapy.

Dehydration in the patient should be ruled out before infusion. To ensure adequate hydration, saline is recommended before, during, or after zoledronic acid infusion. Hyperhydration of the patient should be avoided due to the risk of complications from the cardiovascular system.

After administration of zoledronic it is necessary to constantly monitor the concentration of calcium, phosphorus, magnesium and creatinine in the serum.

If hypocalcaemia, hypophosphatemia, or hypomagnesemia develops, short-term maintenance therapy is required.

Effects on ability to drive and use machines

Because dizziness is a side effect of zoledronic acid, patients should exercise caution when performing potentially hazardous activities. If dizziness occurs, you should refrain from these activities.

Drug interaction

When bisphosphonates and aminoglycosides are used concomitantly, serum calcium levels may remain lower for longer than required, as an additive effect on serum calcium levels may occur.

Concomitant use with drugs that have potentially nephrotoxic effects increases the risk of deterioration of renal function.