Zoledronic acid
Zoledronic acid: instructions for use and reviews
- 1. Release form and composition
- 2. Pharmacological properties
- 3. Indications for use
- 4. Contraindications
- 5. Method of application and dosage
- 6. Side effects
- 7. Overdose
- 8. Special instructions
- 9. Application during pregnancy and lactation
- 10. Use in childhood
- 11. In case of impaired renal function
- 12. Use in the elderly
- 13. Drug interactions
- 14. Analogs
- 15. Terms and conditions of storage
- 16. Terms of dispensing from pharmacies
- 17. Reviews
- 18. Price in pharmacies
Latin name: Zoledronic acid
ATX code: M05BA08
Active ingredient: zoledronic acid
Producer: Pharmidea LLC (Latvia), Biocad CJSC, Pharm-Sintez CJSC (Russia), Bion LLC (Russia)
Description and photo update: 18.10.2018
Prices in pharmacies: from 2498 rubles.
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Zoledronic acid is a bisphosphonate, an inhibitor of bone resorption.
Release form and composition
Dosage forms of Zoledronic acid:
- concentrate for the preparation of solution for infusion: transparent liquid, colorless or with a slight yellow tint (5 ml in a plastic bottle, in a cardboard box 1 bottle);
- lyophilized powder for the preparation of a sterile solution for infusion (4 mg in a vial, in a cardboard box 1 vial).
Depending on the manufacturer, the substance-powder can have the following packaging: 10 g in a glass bottle of dark color; 5 g, 10 g, 25 g, 50 g or 100 g in a polymer jar; 5 g, 10 g, 25 g, 50 g or 100 g each in a dark glass jar; 100 g, 500 g or 1000 g in a three-layer polyethylene bag, 1 bag each packed in a laminated multilayer aluminum foil bag and container; 5 g, 10 g, 15 g, 20 g, 30 g, 50 g, 100 g in a jar.
1 bottle of concentrate contains:
- active substance: zoledronic acid monohydrate - 4,264 mg, which is equivalent to 4 mg of zoledronic acid;
- auxiliary components: sodium citrate dihydrate, mannitol, water for injection.
1 vial of lyophilized powder contains 4 mg of zoledronic acid.
Pharmacological properties
Pharmacodynamics
Zoledronic acid is a highly effective bisphosphonate that selectively acts on bone tissue. By acting on osteoclasts, the drug inhibits bone resorption.
The inhibition of osteoclast activity provides a precise molecular mechanism that is not fully understood. A high affinity for mineralized bone tissue provides a selective effect of bisphosphonates on bone tissue, while the drug does not have an undesirable effect on mineralization, formation and mechanical properties of bones.
In vivo studies have confirmed the antitumor properties of zoledronic acid, which reduce the growth of tumor cells. The drug changes the microenvironment of the bone marrow, slows down osteoclastic resorption of bone tissue, has antiangiogenic activity, and significantly reduces pain.
The antitumor properties of the drug, ensuring efficacy in bone metastases in vitro - inhibition of osteoblast proliferation, direct pro-apoptotic and cytostatic effect, synergistic cytostatic effect when combined with antitumor agents, invasive or antiadhesive activity.
Due to its ability to suppress proliferation and induce apoptosis, Zoledronic acid has an antitumor effect directly on myeloma and breast cancer cells. The antimetastatic properties of the drug are confirmed by a decrease in the penetration of breast cancer cells through the extracellular matrix. By inhibiting the proliferation of human and animal endothelial cells, it exhibits its anti-angiogenic effect.
In case of metastatic bone lesions against the background of solid malignant neoplasms, the drug prevents compression of the spinal cord, the development of pathological fractures, and reduces tumor hypercalcemia. Antitumor activity reduces the need for radiation therapy and surgery. The drug ensures the containment of the progression of pain syndrome. In patients with osteolytic foci, the therapeutic effect is more pronounced than with osteoblastic ones.
The use of Zoledronic acid at a dose of 4 mg in the treatment of multiple myeloma and breast cancer with at least one bone lesion has a therapeutic effect equivalent to 90 mg of pamidronate.
The effect of the drug in tumor hypercalcemia is manifested by a decrease in the level of calcium in the blood serum and the excretion of calcium by the kidneys. Calcium levels usually return to normal after 4–10 days, with relapse (albumin-corrected serum calcium levels of at least 2.9 mmol / L) occurring within 30–40 days. The effectiveness of zoledronic acid in the treatment of hypercalcemia does not significantly depend on the dose used - 4 mg or 8 mg.
Pharmacokinetics
Pharmacokinetics does not depend on the dose of the drug.
The serum concentration of zoledronic acid increases rapidly from the start of the infusion, reaching its peak by the end of the administration. After 4 hours, the concentration level decreases by 10%, after 24 hours there is a decrease in the concentration level by less than 1% of the peak, followed by a prolonged period of low drug content, not exceeding 0.1% of the maximum level, until the next injection on day 28.
After intravenous administration, zoledronic acid is excreted unchanged by the kidneys in three stages without undergoing metabolism. Rapid excretion from the systemic circulation with half-lives of 0.24 hours and 1.87 hours and the final long stage with a half-life of 146 hours. Repeated injections every 28 days do not cause accumulation of the drug. Its content in urine within 24 hours after infusion is 39 ± 16% of the administered dose, the other part enters into interaction with bone tissue. The process of release of zoledronic acid from bone tissue into the systemic circulation occurs slowly, with its gradual excretion by the kidneys. Total plasma clearance does not depend on the dose of zoledronic acid, age, sex, body weight or race of the patient, and is in the range of 5.04 ± 2.5 L / h.
Pharmacokinetic studies have not been performed for hypercalcemia and liver failure.
The results of in vitro studies of zoledronic acid indicate that it does not inhibit isozymes of the cytochrome P 450 system, does not undergo biotransformation, which means that the state of liver function cannot significantly affect its pharmacokinetics.
Up to 3% of the administered dose is excreted through the intestines.
A low affinity of the drug is shown to the cellular components of the blood, binding to plasma proteins does not depend on the concentration of zoledronic acid and is about 56%.
The clearance of creatine positively correlates with the renal clearance of zoledronic acid, which is 75 ± 33% of 84 ± 29% of the creatinine clearance.
In severe renal failure with a creatinine clearance (CC) of 20 ml / min or moderate renal failure (CC 50 ml / min), the clearance of zoledronic acid will be 37% and 72%, respectively, of the clearance of zoledronate in patients with CC 84 ml / min.
Indications for use
- multiple myeloma - as part of complex therapy;
- bone metastases in prostate cancer, breast cancer and other malignant solid neoplasms;
- hypercalcemia due to malignant tumors.
Contraindications
- severe renal dysfunction (CC less than 30 ml / min);
- period of pregnancy;
- breast-feeding;
- childhood;
- hypersensitivity to bisphosphonates, including zoledronic acid, and auxiliary components of the drug.
Caution should be exercised when prescribing Zoledronic acid for mild and moderate renal dysfunction (CC greater than 30 ml / min), severe liver dysfunction, aspirin bronchial asthma, concomitant use of calcitonin, aminoglycosides, antiangiogenic agents, "loop" diuretics and other causing hypocalcemia of drugs, drugs with nephrotoxic activity.
Instructions for the use of Zoledronic acid: method and dosage
Concentrate for solution for infusion
The finished solution of the drug is intended for intravenous (IV) drip administration for 15 minutes or more.
In aseptic conditions, immediately before use, the contents of 1 bottle of Zoledronic acid concentrate are mixed with 100 ml of 0.9% sodium chloride solution or 5% dextrose solution.
Do not mix with calcium-containing solutions, Ringer's solution and other medicinal products!
Zoledronic acid is administered with a separate infusion system!
If necessary, the prepared solution can be stored in a refrigerator at a temperature of 2 to 8 ° C under aseptic conditions for no more than 24 hours. Before infusion, the solution should be removed from the refrigerator to return to room temperature. It should be borne in mind that the period from the moment of preparation of the solution to the end of the administration should not exceed 24 hours.
Recommended dosage of Zoledronic acid:
- bone metastases against the background of malignant solid tumors and multiple myeloma: 4 mg 1 time in 3-4 weeks, additionally the patient should be prescribed oral intake of calcium in a daily dose of 500 mg and vitamin D - 400 IU (international units) per day;
- hypercalcemia due to malignant tumors: (the concentration of serum calcium corrected for albumin is greater than 12 mg / dl or 3 mmol / l) - 4 mg once. To ensure water balance in the body, the patient should be injected with saline before, during or after the infusion.
Elderly patients do not need to adjust the dosage regimen of Zoledronic acid.
The use of the drug for hypercalcemia caused by malignant neoplasms in patients with severe renal impairment should be prescribed only after careful comparison of the risk and the expected effect of therapy. If the serum creatinine is less than 400 μmol / L or 4.5 mg / dL, no dosage adjustment is required.
Recommended dosage for bone metastases of advanced malignant tumors and multiple myeloma for patients with mild to moderate renal impairment:
- CC 50-60 ml / min: 3.5 mg or 4.4 ml of concentrate;
- CC 40–49 ml / min: 3.3 mg or 4.1 ml of concentrate;
- CC 30–39 ml / min: 3 mg or 3.8 ml of concentrate.
The concentration of serum creatinine should be determined before the introduction of each subsequent dose of the drug; in case of deterioration of renal function, the administration of the next dose should be postponed.
Criteria for assessing renal dysfunction:
- patients with a baseline serum creatinine concentration of less than 1.4 mg / dl: if the creatinine concentration increased by 0.5 mg / dl;
- patients with a baseline serum creatinine concentration of more than 1.4 mg / dl: if the creatinine concentration has increased by 1 mg / dl.
The therapy should be resumed at the initial dose only after the creatinine level is restored to values that are 10% more or less than the initial value.
Lyophilized powder for preparation of solution for infusion
A ready-made solution of Zoledronic acid is used in / in drip and in the form of injections into bone metastases and osteolytic foci with multiple myeloma as part of combination therapy. Immediately before administration, 4 mg of powder is mixed with 5 ml of water for injection and shaken thoroughly until completely dissolved. Then the resulting solution is diluted in 50 ml of 0.9% sodium chloride solution or 5% dextrose solution. The duration of the infusion is 15 minutes.
Do not use infusion solutions containing calcium.
Recommended dosage: 4 mg once every 3-4 weeks.
Patients with hypercalcemia caused by malignant tumor should be provided with adequate hydration during infusion. Repeated administration of the drug at a dose of 8 mg is indicated in case of exacerbation of symptoms after reaching a serum calcium concentration of up to 2.7 mmol / L or in case of resistance to the first administration. To assess the effect, the interval between the first and second infusion should be at least one week.
With mild to moderate renal failure, no dosage adjustment is required. Serum creatinine concentration is required prior to each infusion.
Side effects
- from the lymphatic system and blood: often - anemia; rarely - pancytopenia; sometimes - leukopenia, thrombocytopenia;
- from the nervous system: often - paresthesia, headache; infrequently - dizziness, hypesthesia, dysgeusia, tremor, hyperesthesia; very rarely - convulsions, against the background of hypocalcemia - kinesthesia and tetany; frequency unknown - drowsiness;
- mental disorders: often - sleep disturbance; infrequently - anxiety; rarely - confusion of consciousness;
- on the part of the organ of vision: often - conjunctivitis; sometimes - blurred vision; very rarely - episcleritis, uveitis; frequency unknown - scleritis, inflammatory pathologies of the orbit;
- from the gastrointestinal tract: often - anorexia, nausea, vomiting; sometimes - dry mouth, abdominal pain, diarrhea, constipation, dyspepsia, stomatitis;
- from the respiratory system, chest and mediastinal organs: sometimes - cough, shortness of breath; rarely - interstitial lung disease; frequency unknown - bronchospasm;
- dermatological reactions: sometimes - itching, excessive sweating, rash (including erythematous, macular); frequency unknown - urticaria;
- on the part of the musculoskeletal and connective tissue: often - bone pain, myalgia, arthralgia, generalized pain, joint stiffness; infrequently - jaw necrosis, muscle cramps; frequency unknown - severe sudden impairment of joint mobility, severe pain in joints, muscles and / or bones (including disability), atypical diaphyseal and subtrochanteric fractures of the femur;
- on the part of the heart and blood vessels: sometimes - a pronounced increase or decrease in blood pressure (BP); rarely - bradycardia, against the background of hypocalcemia - arrhythmia; the frequency is unknown - atrial fibrillation, against the background of a decrease in blood pressure in patients with risk factors - fainting or circulatory collapse;
- from the urinary system: often - renal dysfunction; sometimes - hematuria, proteinuria, acute renal failure;
- from the immune system: sometimes - hypersensitivity reactions; rarely - angioedema; frequency unknown - anaphylactic reaction or shock;
- laboratory parameters: very often - hypophosphatemia; often - hypocalcemia, increased concentration of creatinine and urea in the blood serum; sometimes - hypokalemia, hypomagnesemia; rarely - hypernatremia, hyperkalemia;
- general disorders: often - acute phase reaction, fever, flu-like syndrome, general malaise, chills, hot flashes, asthenia, peripheral edema; infrequently - chest pain, weight gain; rarely - arthritis, joint swelling;
- local reactions: infrequently - pain, redness, swelling, irritation, induration at the injection site.
Overdose
Symptoms of an acute overdose of Zoledronic acid: impaired renal function, renal failure, changes in the electrolyte composition, including the level of calcium, magnesium, phosphates in the blood plasma.
Treatment: constant monitoring of the patient's condition; in case of clinical manifestations of hypocalcemia, drip administration of calcium gluconate is indicated.
special instructions
It is impossible to allow the development of hyperhydration of the patient's body during the period of treatment with Zoledronic acid, as this can cause complications from the cardiovascular system.
The use of zoledronic acid should be accompanied by constant monitoring of the concentration of calcium, magnesium, phosphorus and creatinine in the blood serum. In the case of hypocalcemia, hypomagnesemia or hypophosphatemia, the patient is additionally prescribed a short-term administration of the appropriate drugs.
In untreated hypercalcemia, renal function should be closely monitored.
It should be borne in mind that in bone metastases, the therapeutic effect of using zoledronic acid to reduce the risk of spinal cord compression, pathological fractures, tumor-related hypercalcemia, and reduce the need for radiation therapy or bone surgery occurs after 2–3 months of therapy.
Perhaps the development of osteonecrosis of the jaw, the most likely risk group includes patients with oncological pathologies (especially, widespread breast cancer, myeloma) with simultaneous chemotherapy, radiation therapy, taking antiangiogenic drugs, glucocorticosteroids, as well as those with concomitant oral diseases (including history), infections, anemia, coagulopathy.
Since dental diseases (tooth extraction, periodontal disease, poor fixation of dentures) are one of the risk factors, a dental examination and complete oral cavity sanitation must be performed before using the drug. Any invasive dental interventions during the use of Zoledronic acid can worsen the patient's condition.
In rare cases, against the background of bisphosphonate therapy, osteonecrosis of the pelvic or femur, the external auditory canal develops.
With prolonged therapy with bisphosphonates for osteoporosis, subtrochanteric and diaphyseal fractures of the femur (from the lesser trochanter to the supracondylar fossa) may appear. A characteristic feature of these fractures is that they can occur spontaneously or with minimal trauma. If pain in the hip or groin occurs, imaging tests should be done for a stress fracture, which may occur several weeks before a complete hip fracture develops. Patients with a completed femur fracture require examination of the contralateral femur because the fracture can be on both sides. The healing process of these fractures is long. The decision to continue using the drug is made individually after comparing the risks and benefits of therapy.
The possible appearance of muscle pain is transient.
The risk of developing hypocalcemia, including in severe form with cardiac arrhythmia, tetany, numbness, convulsions, should be taken into account. When combined with drugs that cause hypocalcemia, special care should be taken. Before starting therapy, the level of calcium in the blood serum should be determined and hypocalcemia should be corrected, the patient is prescribed calcium and vitamin D preparations.
When treating with Zoledronic acid, the use of other bisphosphonates is contraindicated.
Influence on the ability to drive vehicles and complex mechanisms
Due to the possible development of dizziness, confusion of consciousness during therapy with zoledronic acid, caution should be exercised when driving vehicles and mechanisms.
Application during pregnancy and lactation
The appointment of Zoledronic acid during pregnancy is contraindicated, since there is a potential threat of adverse effects on the fetus.
During treatment, women of reproductive age should use reliable methods of contraception.
Conception during therapy can cause intrauterine fetal malformations (including skeletal anomalies). The time interval after the use of bisphosphonates, safe for the moment of conception, has not been established.
According to the instructions, Zoledronic acid cannot be used while breastfeeding.
The effect on fertility in humans has not been established.
Pediatric use
It is contraindicated to use zoledronic acid for the treatment of children under the age of 18, since the safety of use and the effectiveness of the drug have not been established.
With impaired renal function
In severe renal impairment (CC less than 30 ml / min), the use of Zoledronic acid is contraindicated.
Correction of the dosage regimen is not required in patients with CC more than 60 ml / min or serum creatinine less than 400 μmol / L or 4.5 mg / dL.
Recommended dosage of Zoledronic acid for bone metastases of common malignant tumors and multiple myeloma for patients with mild to moderate renal impairment:
- CC 50-60 ml / min: 3.5 mg;
- CC 40–49 ml / min: 3.3 mg;
- CC 30–39 ml / min: 3 mg.
The concentration of serum creatinine should be determined before the introduction of each subsequent dose of the drug; in case of deterioration of renal function, the administration of the next dose should be postponed.
Criteria for assessing renal dysfunction:
- patients with a baseline serum creatinine concentration of less than 1.4 mg / dl: if the creatinine concentration increased by 0.5 mg / dl;
- patients with a baseline serum creatinine concentration of more than 1.4 mg / dl: if the creatinine concentration has increased by 1 mg / dl.
The therapy should be resumed at the initial dose only after the creatinine level is restored to values that are 10% more or less than the initial value.
Use in the elderly
For elderly patients, correction of the dosage regimen of Zoledronic acid is not required.
Drug interactions
There was no clinically significant interaction with commonly used other anticancer drugs, antibiotics, analgesics, diuretics.
Since the simultaneous administration of aminoglycosides, calcitonin, "loop" diuretics causes a prolonged decrease in the level of calcium in the blood plasma, it is recommended to be careful with these combinations.
Care should be taken to use drugs that have a nephrotoxic effect.
With intravenous administration of thalidomide, the risk of developing functional renal disorders increases.
Zoledronic acid is pharmaceutically incompatible with Ringer's solution and other infusion solutions containing calcium ions.
Analogs
Structural analogues of Zoledronic acid are: Zoledronate-Teva, Zoledrex, Aklasta, Zometa, Blaztera, Veroclast, Zolerix, Zolendronic-Rus 4, Rezoklastin FS, Rezorba.
Terms and conditions of storage
Keep out of the reach of children.
Store at temperatures up to 25 ° C in a dark place.
The shelf life is 3 years.
Terms of dispensing from pharmacies
Dispensed by prescription.
Reviews of Zoledronic acid
According to reviews, Zoledronic Acid is effective but can cause side effects.
Zoledronic acid price in pharmacies
There is no price data available for Zoledronic acid.
Zoledronic acid: prices in online pharmacies
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Drug name Price Pharmacy |
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Zoledronic acid 4 mg / 5 ml concentrate for preparation of solution for infusion 5 ml 1 pc. 2498 RUB Buy |
Maria Kulkes Medical journalist About the author
Education: First Moscow State Medical University named after I. M. Sechenov, specialty "General Medicine".
Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!
