Index of drugs

Prevention of bone complications (pathological fractures, vertebral compression fractures, irradiation or bone surgeries, or tumor-induced hypercalcaemia) in patients with advanced cancer with bone involvement. Treatment of tumor-induced hypercalcaemia (TIH) in adult patients.

1 vial (5 ml) of concentrate contains 4 mg of zoledronic acid (as a monohydrate).

A drug from the class of bisphosphonates, an inhibitor of bone resorption by osteoclasts. Zoledronic acid inhibits bone resorption without adversely affecting the formation, mineralization and mechanical properties of bone tissue. Zoledronic acid also has anticancer properties that can affect its overall effectiveness in the treatment of bone metastases -in vivo: inhibition of bone resorption by osteoclasts, which changes the bone marrow microenvironment, resulting in decreased marrow susceptibility to tumor cell growth, anti-angiogenic activity and analgesia;in vitro: inhibition of osteoblast proliferation, direct cytostatic and pro-apoptotic effects on tumor cells, synergism of cytostatic action with other anticancer drugs, anti-adhesion and anti-invasive effects. After the infusion has started, the plasma concentration increases sharply, reaching the maximum concentration at the end of the infusion. Thereafter a rapid decrease in the drug concentration to <10% of the maximum value after 4 h <1% of the maximum value after 24 h is observed. Then, for a very long time, until the second infusion of zoledronic acid on day 28, very low concentrations, not exceeding 0.1, were observed. % of the maximum value. Elimination of the drug takes place in three phases: in the form of a rapid, two-phase removal of the drug from the general circulation of T_0,5α 0.24 h and T_0,5β 1.87 hours, followed by a long elimination phase with T_0,5γ in the final phase of elimination of 146 h. No accumulation of zoledronic acid in plasma after repeated administration every 28 days. Zoledronic acid is not metabolised and excreted unchanged through the kidneys. During the first 24 h, 39 ± 16% of the administered dose of the drug appears in the urine, while the remainder is primarily associated with the bone tissue. The drug is released very slowly from the bones into the systemic circulation and is excreted through the kidneys. The interindividual variability of the pharmacokinetic parameters of zoledronic acid is high. Zoledronic acid does not show any affinity for the morphotic components of the blood, plasma protein binding is small (about 56%) and does not depend on the concentration of zoledronic acid.

Hypersensitivity to the active substance, to other bisphosphonates or to any of the excipients. Breastfeeding period.

Patients must be examined before drug administration to ensure they are adequately hydrated. Conduction should be avoided in patients at risk of heart failure. After the initiation of therapy, the metabolic parameters, such as the Calcium, phosphate and Magnesium levels tested for hypercalcemia, should be carefully monitored. In case of hypocalcaemia, hypophosphatemia or hypomagnesaemia, short-term adjuvant therapy may be necessary. Patients with untreated hypercalcemia tend to have some degree of impaired renal function; in such patients, careful monitoring of renal function should be considered. Patients using the drug should not simultaneously receive other preparations containing zoledronic acid or other bisphosphonates, because the combined effects of these drugs are unknown. The condition of patients with tumor-induced hypercalcemia (TIH) and symptoms of deterioration of renal function should be appropriately assessed when deciding whether the expected benefit of administering the drug outweighs the possible risk. When deciding to treat patients with bone metastases and to prevent bone complications, it should be remembered that the onset of treatment occurs after 2-3 months. There have been reports of deterioration of renal function following the use of zoledronic acid.Factors that may increase the risk of worsening of renal function include dehydration, renal dysfunction before starting treatment, administration of multiple cycles of zoledronic acid and other bisphosphonates, and the use of other preparations with renal toxicity. The risk of deterioration of renal function is lower, but still possible, after administration of zoledronic acid 4 mg in 15 minutes. Deterioration of renal function up to renal failure and the need for dialysis was reported in patients after the initial dose or a single dose of 4 mg zoledronic acid. Rarely, some patients receiving zoledronic acid for a prolonged period at the recommended doses to prevent bone complications also have an increase in serum creatinine. The serum creatinine should be determined before each subsequent dose. When starting therapy in patients with bone metastases and mild to moderate renal impairment, lower doses of zoledronic acid are recommended. In patients with signs of deterioration of renal function during treatment, the drug should be discontinued. Therapy should be resumed only if serum creatinine levels return to baseline with a 10% deviation. Treatment should be resumed at the same dose as before discontinuation of treatment. There are no specific clinical data on the safety of its use in patients with existing severe renal failure (serum creatinine ≥400 μmol / l or ≥ 4.5 mg / dl for patients with TIH and ≥265 μmol / l or ≥3.0 mg / for patients with tumors and bone metastases) and only limited pharmacokinetic data for patients with existing severe renal impairment (creatinine clearance <30 ml / min), zoledronic acid is not recommended in patients with severe renal impairment. Due to limited clinical data in patients with severe hepatic impairment, no special recommendations for this group of patients can be given. During the treatment with zoledronic acid, the occurrence of osteonecrosis of the jaw was observed - in most cases this was associated with a previously performed dental procedure, e.g. tooth extraction. In patients with risk factors (eg cancer diagnosis, chemotherapy, corticosteroids, improper oral hygiene), a dental examination and appropriate preventive measures should be considered before starting bisphosphonate therapy. Patients in this group should avoid invasive dental procedures as far as possible during treatment. If osteonecrosis of the jaw occurs during bisphosphonate therapy, surgery in the field of maxillofacial surgery may exacerbate this condition. There are no data that would confirm that discontinuation of bisphosphonate therapy reduces the risk of osteonecrosis of the jaw in patients requiring dental procedures. In any case, the physician must assess the patient's clinical condition and consider the risk / benefit ratio. There have been reports of atypical subtrochanteric fractures and femoral shaft in patients using bisphosphonates, mainly in patients who have been on long-term treatment for osteoporosis. This type of fracture occurs after minor injury or without injury, and some patients experience thigh pain or pain in the groin. Fractures often occur on both sides, so patients with bisphosphonates who have had a fracture of the femoral shaft should be examined for the femur in the other limb. In patients suspected of an abnormal hip fracture, discontinuation of bisphosphonates should be considered based on an individual benefit-risk assessment. Patients should be advised to report any pain in the thigh, hip or groin area during treatment with bisphosphonates, and any patient reporting such symptoms should be examined for partial fracture of the thigh bone. The safety and efficacy of zoledronic acid in children aged 1 to 17 years has not yet been established. It contains less than 1 mmol sodium (23 mg) per 5 ml concentrate, which means that the medicine is practically free of sodium.

The drug should not be used during pregnancy - there are no adequate data on the use of zoledronic acid in pregnant women. It is not determined whether zoledronic acid is excreted in human milk. The drug is contraindicated in women who are breastfeeding.

Very often: hypophosphatemia. Common: anemia, headache, conjunctivitis, nausea, vomiting, lack of appetite, bone pain, muscle pain, joint pain, generalized pain, renal dysfunction, fever, flu-like symptoms (including fatigue, chills, malaise and redness), increase in creatinine and urea in the blood, hypocalcaemia. Uncommon: thrombocytopenia, leukopenia, hypersensitivity reactions, anxiety, sleep disturbances, dizziness, paresthesia, disturbed taste, decreased sensation, hyperaesthesia, tremor, drowsiness, blurred vision, scleritis and orbital inflammation, hypertension, hypotension, atrial fibrillation, hypotension manifested by syncope or cardiac collapse, dyspnoea, cough, bronchospasm, diarrhea, constipation, abdominal pain, dyspepsia, oral mucositis, dry mouth, pruritus, rash (including erythematous and lumpy rash), increased sweating, muscle cramps, osteonecrosis of the jaw, acute renal failure, haematuria, proteinuria, weakness, peripheral edema, injection site reactions (including pain, irritation, swelling, induration), chest pain, weight gain, anaphylactic reaction / anaphylactic shock, urticaria, hypomania gnezemia, hypokalemia. Rare: pancytopenia, angioneurotic edema, confusion, bradycardia, hyperkalemia, hypernatremia. Very rare: uveitis, episcleritis. After the introduction of zoledronic acid, abnormal subtrochanteric fracture and femoral shaft fracture have been reported rarely.

It can only be prescribed and given to patients by physicians who have experience in the intravenous administration of bisphosphonate medicines. Intravenously.Prevention of bone complications in patients with advanced cancer with bone involvement. Adults and elderly patients: the recommended dose is 4 mg zoledronic acid every 3 to 4 weeks. Patients should also receive oral supplementation with 500 mg / day Calcium supplements and 400 IU / day of vitamin D. When deciding to treat patients with bone metastases to prevent bone complications, it should be taken into account that the onset of action occurs after 2-3 months.Treatment of hypercalcaemia caused by cancer. Adults and elderly patients: a single dose of 4 mg zoledronic acid.Patients with impaired renal function. Prevention of bone complications in patients with advanced cancer with bone involvement. When initiating therapy in patients with multiple myeloma or with metastases of solid tumors to the bone, serum creatinine and creatinine clearance (CL_cr). Creatinine clearance is calculated based on serum creatinine using the Cockcroft-Gault formula. The drug is not indicated for use in patients with severe renal impairment prior to initiation of therapy (CL_cr<30 ml / min). In clinical trials with zoledronic acid, patients in whom serum creatinine exceeded 265 μmol / l or 3.0 mg / dl were excluded from treatment. In patients with mild to moderate renal impairment prior to initiation of therapy (CL_cr 30-60 ml / min), the following dosage is recommended: Creatinine clearance before treatment> 60 ml / min - the recommended dose of zoledronic acid is 4 mg; 50-60 ml / min - 3.5 mg zoledronic acid; 40-49 ml / min - 3.3 mg zoledronic acid; 30-39 ml / min - 3 mg zoledronic acid. After initiating dosing, serum creatinine should be measured before each dose, and treatment should be discontinued if renal function deteriorates. In clinical trials, deterioration of renal function was defined as follows: for patients with normal serum creatinine before treatment (<1.4 mg / dl or <124 μmol / l), an increase of 0.5 mg / dl or 44 μmol / l; for patients with elevated serum creatinine before treatment (> 1.4 mg / dl or> 124 μmol / l), an increase of 1.0 mg / dl or 88 μmol / l. In clinical trials, zoledronic acid was resumed only when the creatinine concentration returned to the baseline range with a 10% deviation. Treatment should be resumed with the same dose as when treatment was discontinued.Treatment of hypercalcaemia caused by cancer. The use of the drug in patients with TIH and severe renal impairment can only be considered after a risk assessment of the benefits of treatment. In clinical trials, patients with serum creatinine greater than 400 μmol / l or 4.5 mg / dl were excluded from treatment. No dosage adjustment is necessary for patients with TIH whose serum creatinine is less than 400 μmol / l or 4.5 mg / dl. The drug administered in an intravenous infusion, lasting no less than 15 minutes.