Zoledronate

Zoledronate is a drug from the group of bisphosphonates that affects the process of bone mineralization and bone structure.

Indications Zoledron

It is used for hypercalcemia, provoked by the effect of a tumor that has a malignant character.

It is also prescribed to prevent the development of signs caused by bone tissue damage in people with malignant tumors (fractures of the pathological type, compression of the spine, hypercalcemia in persons with malignant forms of tumors and complications arising after surgical procedures) in later stages.

Used to prevent loss of bone mass, as well as fractures in women with breast carcinoma (early phase) during postmenopause, in combination with the intake of aromatase inhibitors.

[1]

Release form

Release of the medicine is made in an infusion solution, in flacons with a capacity of 5 ml. The package contains 1 such bottle.

[2], [3]

Pharmacodynamics

Zolendronic acid is a bisphosphonate, which affects mainly the bones. The substance slows the processes of osteolysis.

The selective effect of the substance with respect to bones is based on a high degree of affinity for mineralized bone tissues, but it has not yet been possible to accurately determine the molecular effect that causes the deceleration of osteoclastic processes. With prolonged tests on animals, it was noted that the component slows down osteolysis, at the same time without adversely affecting the processes of mineralization and bone formation or their mechanical parameters.

In addition to slowing osteolysis, the drug has a direct antitumor effect on the cultured cells of the breast carcinoma and myeloma - slowing down the cell proliferation and induction of apoptosis. From this it can be concluded that the active drug component may have antimetastatic properties.

Pre-clinical tests demonstrated the presence of such characteristics:

• in vivo: slowing down the processes of osteolysis, due to which the bone marrow microenvironments change, weakening the susceptibility to tumor cells. An analgesic and anti-angiogenic effect also develops;
• in vitro: slowing down the reproduction of osteoblasts, and in addition direct proapoptotic and cytostatic effects on neoplastic cells, a synergistic cytotoxic effect along with other antitumor agents, and an invasive / anti-adhesion effect.

[4],

Pharmacokinetics

After application of disposable and reusable 5-and also 15-minute infusion procedures with the administration of 2, 4, 8 and 16 mg of the preparation to 64 patients with bone metastases, it was possible to obtain the pharmacokinetic parameters described below independent of the size of serving).

With the beginning of the procedure, the level of medication inside the blood plasma increased rapidly, reaching its maximum at the end of the infusion. Further, the indicators fell rapidly to <10% from Cmax (after 4 hours) and <1% (after 24 hours). After that, there was a long interval with extremely low rates, which did not exceed 0.1% of Cmax, lasting until the second infusion of drugs on the 28th day.

After intravenous infusion, the substance is excreted in 3 phases: first a rapid 2-stage excretion from a large circle of blood flow with a half-life-α of 0.24 hours, and in addition a half-life-β equal to 1.87 hours; After this, a long stage of elimination with a final half-life of γ reaching 146 hours is carried out.

The medication does not cumulate inside the blood plasma for repeated use at intervals of 28 days.

Zolendronic acid is not subjected to metabolic processes, excreted through the kidneys in the unmodified state. During the first 24 hours, approximately 39 ± 16% of the used portion is recorded inside the urine, and most of the remainder of the substance is synthesized with bone tissue, from which the medicine is released at very low speed again into the circulatory system and excreted through the kidneys.

The total values of the LS clearance are 5.04 ± 2.5 l / h, without reference to the dosage size. Also, weight, gender, race and age do not affect this indicator. The extension of the infusion time from 5 to 15 minutes by 30% reduces the level of the substance by the end of the procedure, but does not affect the AUC indices.

The variability of pharmacokinetic characteristics of the drug in different patients was quite high, which corresponds to the properties of other bisphosphonates.

The level of clearance within the kidneys correlates with the QC values. In the kidneys, it reaches 75 ± 33% of the CC level, which shows an average of 84 ± 29 ml / minute (within 22-143 ml / minute) in 64 people with carcinoma participating in the test.

Population analysis demonstrated that in patients with a CC level of 20 ml / minute (severe renal activity disorder) or 50 ml / minute (moderate disease), the predicted drug clearance rate is 37%, respectively 72%.

For people with severe kidney failure (QC level below 30 ml / minute), only limited information exists.

Zoledronic acid has no affinity for cellular blood elements, and affinity for blood plasma proteins is rather low (about 56%) and does not have a binding to the indices of the substance.

[5], [6],

Dosing and administration

The medication is administered intravenously - in the form of a 1-fold infusion, for which a separate infusion intravenous system is used.

Therapy with hypercalcemia, provoked by the action of a malignant tumor.

Adults and elderly people need to administer 4 mg of medication. On the recommendation of the doctor, repetition of the procedure is allowed, but only if the serum calcium values remain unchanged or are not normalized after the initial therapy. Before starting the infusion, it is necessary to assess the patient's water balance, making sure that he does not have symptoms of dehydration.

Prevention of the appearance of signs caused by damage to bone tissue in people with malignant tumors.

It is prescribed the administration of 4 mg of drug substance, with a frequency of 1-fold for 3-4 weeks.

It is also necessary to ingest calcium medicines daily in a dose of 0.5 g, and in addition multivitamins containing calciferol (400 IU each).

Prevention of loss of bone mass and fractures in women with breast carcinoma in the early phase (during postmenopause), using aromatase inhibitors.

Elderly and adult patients are administered 4 mg of medication at a single dose every 0.5 years.

In addition, you need to take oral calcium medicines (0.5 g) and multivitamins containing calciferol (400 IU) every day.

Method of application.

The substance concentrate is required to dissolve in sterile 0.9% NaCl solution or 5% glucose solution (0.1 L). Then it is administered with a 1-fold infusion, lasting at least 15 minutes.

People with kidney failure.

People with this disease have a high likelihood of developing toxic symptoms that affect renal function.

Persons with serum creatinine values <4.5 mg / dL are allowed to use the medicine for hypercalcaemia triggered by cancer, only in situations where the benefits of the therapy are more likely than the possibility of the appearance of toxic signs in the kidney area; you do not need to adjust the dosage.

The use of zoledronic acid is prohibited for people with multiple myeloma or metastases of solid tumors within the bones (with a serum creatinine level of> 3 mg / dL within these tumors or a QC value of <30 ml / minute).

When using zoledronate for the treatment of the above diseases in people with a deficiency of renal function, which has a moderate or mild form (the level of QC is within 30-60 ml / minute), it is necessary to make such adjustment of doses:

• Initial KK> 60 ml / minute - 4 mg of the substance (5 ml). At the same time there is no need to adjust the portion, the patient only needs to ensure optimal hydration;
• the level of SC in the range of 50-60 ml / minute - 3.5 mg (4.4 ml);
• the values of SC within 40-49 ml / minute - 3.3 mg (4.1 ml);
• the level of QA within 30-39 ml / minute - 3 mg (3.8 ml);
• KK <30 ml / minute - the drug is not used.

The required amount of the drug is dissolved with a sterile 0.9% solution of NaCl or 5% glucose solution (0.1 L), and then injected with a 1-time infusion over a minimum of 15 minutes.

The medicament solution stored in the refrigerator should be heated to room indices before the infusion procedure.

[14], [15], [16], [17],

Use Zoledron during pregnancy

The effect of the drug on the body of pregnant women has not been studied before, because of what you can not use it in this period.

Information on the ability of the active substance to penetrate into the mother's milk is not. Therefore, if the patient is using Zoledronate in lactation, she should stop breastfeeding during therapy.

Contraindications

The main contraindications:

• presence of intolerance to zoledronic acid or other bisphosphonates, or to additional elements of drugs;
• failure of renal function in severe degree;
• BA or intolerance to aspirin;
• cardiac pathology.

[7], [8], [9]

Side effects Zoledron

The use of infusions can trigger the development of some side effects:

• problems affecting the circulation of blood: anemia often develops. Sometimes leukemia or thrombocytopenia occurs. Occasionally - pancytopenia;
• violations in the NA area: headaches are often noted. Sometimes there are taste disorders, tremor, hyperesthesia or hypoesthesia, as well as paresthesia, tremors and dizziness;
• the defeat of the psyche: sometimes there is insomnia or a feeling of excitement. Occasionally there are convulsions;
• disorders of the function of the visual organs: often there are conjunctivitis. Sometimes visual turbidity is observed. Epicleritis or uveitis develops singly;
• problems affecting digestive activity: often there is nausea, anorexia or vomiting. Sometimes constipation, stomatitis, abdominal pain, diarrhea, dryness of the oral mucosa and symptoms of dyspepsia are observed;
• signs from the respiratory system: sometimes there is a cough or dyspnea;
• defeat of the epidermis: sometimes there is itching, rashes and hyperhidrosis;
• disruption of the function of connective tissue and musculoskeletal structure: often there are painful sensations in the musculature, bones and joints, osteonecrosis and generalized pain. Sometimes there are cramps in the muscles;
• disorders in the work of the CCC: sometimes there is an increase or decrease in blood pressure. Occasionally bradycardia develops;
• problems affecting the urinary and renal function: often there are violations in the work of the kidneys. Sometimes hematuria develops, renal failure in the acute stage and proteinuria;
• immune disorders: sometimes there are symptoms of intolerance; occasionally - Quincke's edema;
• systemic signs and manifestations on the site of infusion: often developing influenza-like (including dyspnea, chills, a feeling of malaise and fatigue) or febrile state. Sometimes there are peripheral puffiness, asthenia and signs in the injection zone (among them irritation, pain and swelling), and in addition weight gain and pain in the sternum;
• laboratory test data: extremely often reported development of hypophosphatemia. Also often enough note hypocalcemia and an increase in the blood values of urea with creatinine. Sometimes there is hypokalemia or -magnesium. Occasionally, hypernatremia or -coliemia develops;
• other symptoms: progression of cancer, alopecia and increased malignancy.

[10], [11], [12], [13]

Overdose

Cases with drug intoxication to date have not been recorded.

For people who received a dosage in excess of the standard size, a constant observation should be established, and if there are strong symptoms of hypocalcemia, administer calcium gluconate through the infusion.

[18], [19]

Interactions with other drugs

Zoledronate was prescribed for treatment in combination with antitumor and diuretic drugs, as well as with analgesics and antibiotics. At the same time, no therapeutic interaction or reaction was recorded.

Because zoledronic acid does not have an intense ability to synthesize with a plasma protein, and it does not inhibit the hemoprotein P450 system, it is necessary to use the drug with care in parallel with patients with aminoglycosides. This is associated with the risk of developing an additive effect with respect to serum calcium values, because of which they may remain lowered longer than required.

In addition, caution is required when combining the drug with substances that can potentially provoke a nephrotoxic effect.

In people with myeloma, the likelihood of a disorder of kidney activity may increase with the combined use of intravenous bisphosphonates and thalidomide.

[20]

Storage conditions

Zoledronate is required to be kept out of the reach of children. Temperature values are not higher than 30 ° C.

[21]

Shelf life

Zoledronate can be used within 24 months after the release of the drug. The diluted infusion can be stored at a temperature of 2-8 ° C (in the refrigerator) for a maximum of 24 hours. After performing aseptic dissolution, immediately start the injection of the finished product.

[22], [23], [24]

Application for children

There is no data on the safety and drug effectiveness of drugs in children, so it is not used in pediatrics.

[25], [26], [27], [28], [29], [30], [31]

Analogues

Analogues of the medicine are medicines of Aklast, Resorb and Resoclastin with Zometa.

[32], [33], [34], [35], [36]