Zoledronate

Zoledronate is a bisphosphonate drug that affects bone mineralization and bone structure.

Indications Zoledronata

It is used for hypercalcemia caused by the influence of a tumor of a malignant nature.

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

It is used to prevent bone loss and fractures in women with breast carcinoma (early phase) during postmenopause, in combination with aromatase inhibitors.

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Release form

The medicine is released in an infusion solution, in 5 ml vials. The package contains 1 such vial.

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Pharmacodynamics

Zoledronic acid is a bisphosphonate that acts primarily on bones. The substance slows down the process of osteolysis.

The selective effect of the substance on bones is based on a high degree of affinity for mineralized bone tissue, but it has not yet been possible to accurately determine the molecular effect that causes a slowdown in osteoclastic processes. In long-term animal tests, it was noted that the component slows down osteolysis, while not having a negative effect on the processes of mineralization and bone formation or their mechanical parameters.

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

Preclinical tests have demonstrated the presence of the following characteristics:

• in vivo: slowing down of osteolysis processes, due to which bone marrow microenvironments are changed, weakening susceptibility to tumor cells. An analgesic and antiangiogenic effect also develops;
• in vitro: inhibition of osteoblast proliferation, as well as direct proapoptotic and cytostatic effects on neoplastic cells, synergistic cytostatic effect with other antitumor agents, and invasive/anti-adhesive effects.

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Pharmacokinetics

After the use of single and multiple 5- and 15-minute infusion procedures with the introduction of 2, 4, 8 and 16 mg of the drug in 64 patients with bone metastases, it was possible to obtain the pharmacokinetic parameters described below (independent of the portion size).

At the beginning of the procedure, the drug level in the blood plasma increased rapidly, reaching its maximum by the end of the infusion. Then there was a rapid drop in the indicators to <10% of Cmax (after 4 hours) and <1% (after 24 hours). After that, there was a long period with extremely low indicators that did not exceed 0.1% of Cmax, which lasted until the use of the 2nd infusion of the drug on the 28th day.

Following intravenous infusion, the substance is excreted in 3 phases: first, a rapid 2-stage excretion from the systemic circulation with an α-half-life of 0.24 hours and a β-half-life of 1.87 hours; then, a prolonged elimination phase occurs with a final γ-half-life of 146 hours.

The drug does not accumulate in the blood plasma when used multiple times at intervals of 28 days.

Zoledronic acid is not subject to metabolic processes, being excreted unchanged through the kidneys. During the first 24 hours, approximately 39±16% of the used portion is recorded in the urine, and most of the remainder of the substance is synthesized with bone tissue, from which the drug is released again at a very low rate into the circulatory system and excreted through the kidneys.

The overall drug clearance values are 5.04±2.5 l/hour, regardless of the dosage size. This indicator is also not affected by weight, gender, race, and age. Extending the infusion period from 5 to 15 minutes reduces the substance level by 30% by the end of the procedure, but does not affect the AUC values.

The variability of the pharmacokinetic characteristics of the drug in different patients was quite high, which is consistent with the properties of other bisphosphonates.

The clearance rate inside the kidneys correlates with the CK values. In the kidneys it reaches 75±33% of the CK level, which demonstrates a mean value of 84±29 ml/min (in the range of 22-143 ml/min) in 64 people with carcinoma who participated in the test.

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

For people with severe renal failure (CrCl level below 30 ml/min), there is only limited information.

Zoledronic acid has no affinity for cellular blood elements, and its affinity for blood plasma proteins is quite low (about 56%) and is not related to the drug's performance.

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Dosing and administration

The medication is administered intravenously - as a single infusion, for which a separate intravenous infusion system is used.

Therapy for hypercalcemia caused by malignant tumors.

Adults and the elderly should be administered 4 mg of the drug. The procedure may be repeated on the doctor's recommendation, but only if serum calcium levels remain the same or have not returned to normal after the initial therapy. Before starting the infusion, it is necessary to assess the patient's water balance, making sure that he or she has no symptoms of dehydration.

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

The prescribed dose is 4 mg of the drug, once every 3-4 weeks.

It is also necessary to take calcium medications orally every day in a 0.5 g portion, and in addition to this, multivitamins containing calciferol (400 IU).

Prevention of bone loss and fractures in women with early-phase (postmenopausal) breast carcinoma using aromatase inhibitors.

Elderly and adult patients are administered 4 mg of the drug once every 0.5 years.

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

Method of application.

The substance concentrate must be dissolved in a sterile 0.9% NaCl solution or 5% glucose solution (0.1 l). Then it is administered as a single infusion lasting at least 15 minutes.

People with renal insufficiency.

People with this condition are at high risk of developing toxic symptoms affecting kidney function.

Patients with serum creatinine levels <4.5 mg/dL may use the drug for cancer-induced hypercalcemia only when the benefit of therapy is likely to outweigh the risk of renal toxicity; no dosage adjustment is necessary.

The use of zoledronic acid is contraindicated in patients with multiple myeloma or metastatic solid tumors within the bones (with serum creatinine levels within these tumors >3 mg/dL or CrCl <30 mL/min).

When using Zoledronate for the treatment of the above diseases in people with moderate or mild renal impairment (creatinine clearance level is within 30-60 ml/minute), the following dose adjustments should be made:

• initial CC value >60 ml/minute – 4 mg of substance (5 ml). In this case, there is no need to adjust the dose, the patient only needs to be provided with optimal hydration;
• CC level within 50-60 ml/minute – 3.5 mg (4.4 ml);
• CC values within 40-49 ml/minute – 3.3 mg (4.1 ml);
• CC level within 30-39 ml/minute – 3 mg (3.8 ml);
• CC index <30 ml/minute – the drug is not used.

The required amount of the drug is dissolved in a sterile 0.9% NaCl solution or 5% glucose solution (0.1 l), and then administered as a single infusion over a period of at least 15 minutes.

The medicinal solution stored in the refrigerator should be warmed to room temperature before the infusion procedure.

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Use Zoledronata during pregnancy

The effect of the drug on the body of pregnant women has not been previously studied, which is why it cannot be used during this period.

There is no information regarding the ability of the active substance to penetrate into breast milk. Therefore, if the patient uses Zoledronate during lactation, she should stop breastfeeding for the duration of therapy.

Contraindications

Main contraindications:

• the presence of intolerance to zoledronic acid or other bisphosphonates, or to additional components of the drug;
• severe renal failure;
• asthma or aspirin intolerance;
• cardiac pathologies.

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Side effects Zoledronata

The use of infusions may provoke the development of some side effects:

• problems affecting blood circulation: anemia often develops. Sometimes leukopenia or thrombocytopenia appears. Rarely – pancytopenia;
• disorders in the nervous system: headaches are often observed. Sometimes taste disorders, tremor, hyperesthesia or hypoesthesia develop, as well as paresthesia, tremor and dizziness;
• Mental disorders: sometimes insomnia or a feeling of excitement appears. Convulsions occur occasionally;
• visual organ dysfunction: conjunctivitis often appears. Sometimes visual clouding is observed. Episcleritis or uveitis develops sporadically;
• problems affecting digestive activity: nausea, anorexia or vomiting often occur. Sometimes constipation, stomatitis, abdominal pain, diarrhea, dry mouth and dyspeptic symptoms are observed;
• signs from the respiratory system: sometimes cough or dyspnea occurs;
• lesions of the epidermis: sometimes itching, rashes and hyperhidrosis appear;
• dysfunction of connective tissues and musculoskeletal structure: pain in the area of muscles, bones and joints, osteonecrosis and generalized pain are often observed. Sometimes cramps appear in the muscle area;
• disorders in the functioning of the cardiovascular system: sometimes an increase or decrease in blood pressure is observed. Rarely, bradycardia develops;
• problems affecting urinary and renal function: kidney dysfunction often occurs. Sometimes hematuria, acute renal failure and proteinuria develop;
• immune disorders: sometimes symptoms of intolerance occur; rarely – Quincke’s edema;
• Systemic signs and manifestations at the infusion site: a flu-like (including dyspnea, chills, malaise and fatigue) or feverish state often develops. Occasionally, peripheral edema, asthenia and signs at the injection site (including irritation, pain and swelling) appear, as well as weight gain and chest pain;
• laboratory test data: hypophosphatemia is very often reported. Hypocalcemia and increased blood urea and creatinine levels are also quite common. Sometimes hypokalemia or -magnesemia occurs. Rarely, hypernatremia or -kalemia develops;
• other symptoms: progression of cancer, alopecia and enlargement of malignant neoplasms.

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Overdose

There have been no cases of drug intoxication recorded to date.

People who have received a dose larger than the standard should be closely monitored and given calcium gluconate by infusion if symptoms of hypocalcemia are severe.

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Interactions with other drugs

Zoledronate has been used in combination with antineoplastic and diuretic drugs, as well as with analgesics and antibiotics. No therapeutic interactions or reactions have been reported.

Because zoledronic acid does not have a strong plasma protein synthesis capacity and does not suppress the P450 hemoprotein system, extreme caution is required when using the drug concomitantly with aminoglycosides. This is due to the risk of developing an additive effect on serum calcium levels, which may cause them to remain lowered longer than necessary.

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

In people with myeloma, the risk of kidney problems may be increased by the combined use of intravenous bisphosphonates and thalidomide.

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Storage conditions

Zoledronate must be kept in a place closed to children. Temperature values - not higher than 30°C.

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Shelf life

Zoledronate can be used within 24 months from the date of manufacture of the medicinal product. The diluted infusion can be stored at a temperature of 2-8°C (in the refrigerator) for a maximum of 24 hours. After aseptic dilution, the finished product should be administered immediately.

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Application for children

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

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Analogues

Analogues of the drug are the medications Aclasta, Resorba and Rezoklastin with Zometa.

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