Zoledronate-Teva, 4 mg 5 ml
ATX: M.05.B.A.08 Zoledronic acid
Zoledronic acid refers to highly effective bisphosphonates that act selectively on bone tissue by inhibiting bone resorption by acting on osteoclasts.
The selective action of bisphosphonates on bone tissue is based on their high affinity for mineralized bone tissue. The exact molecular mechanism providing inhibition of osteoclast activity is still unclear.
Zoledronic acid has no undesirable effects on bone formation, mineralization and mechanical properties.
In addition to its inhibitory effect on bone resorption, zoledronic acid has antitumor properties that make the drug effective against bone metastases. In vitro: inhibits proliferation of osteoblasts, shows direct cytostatic and proapoptotic activity, synergistic cytostatic effect with antitumor drugs, anti-adhesive and anti-invasive activity. Zoledronic acid, by inhibiting proliferation and inducing apoptosis, has a direct antitumor effect against human myeloma cells and breast cancer cells, and also reduces penetration of human breast cancer cells through the extracellular matrix, indicating that it has antimetastatic properties. In addition, zoledronic acid inhibits proliferation of human and animal endothelial cells and has anti-angiogenic effect. In patients with breast cancer, prostate cancer and other solid tumors with metastatic involvement of bone tissue zoledronic acid prevents the development of pathological fractures, spinal cord compression, reduces the need for radiation therapy and surgery, reduces tumor hypercalcemia. The drug is able to inhibit the progression of pain syndrome. The therapeutic effect is less pronounced in patients with osteoblastic foci than in osteolytic ones. In patients with multiple myeloma and breast cancer with at least one bone foci the efficacy of zoledronic acid in a dose of 4 mg is comparable to pamidronic acid in a dose of 90 mg. In patients with tumor hypercalcemia, the action of the drug is characterized by a decrease in serum calcium and renal calcium excretion. The average time to normalization of calcium is about 4 days. By day 10, calcium levels normalize in 87-88% of patients. The average time to relapse (albumin-corrected serum calcium content of at least 2.9 mmol/L) is 30-40 days. There is no significant difference between the effectiveness of zoledronic acid at doses of 4 and 8 mg in the treatment of hypercalcemia. The studies show no significant differences in the frequency and severity of adverse events observed in patients treated with zoledronic acid at doses of 4 mg and 8 mg, pamidronic acid at a dose of 90 mg, or placebo in both the treatment of bone metastases and hypercalcemia.
In vitro: inhibits proliferation of osteoblasts, shows direct cytostatic and proapoptotic activity, synergistic cytostatic effect with antitumor drugs, anti-adhesive and anti-invasive activity.
Zoledronic acid, by inhibiting proliferation and inducing apoptosis, has a direct antitumor effect against human myeloma cells and breast cancer cells, and also reduces penetration of human breast cancer cells through the extracellular matrix, indicating that it has antimetastatic properties. In addition, zoledronic acid inhibits proliferation of human and animal endothelial cells and has anti-angiogenic effect.
In patients with breast cancer, prostate cancer and other solid tumors with metastatic involvement of bone tissue zoledronic acid prevents the development of pathological fractures, spinal cord compression, reduces the need for radiation therapy and surgery, reduces tumor hypercalcemia. The drug is able to inhibit the progression of pain syndrome. The therapeutic effect is less pronounced in patients with osteoblastic foci than in osteolytic ones.
In patients with multiple myeloma and breast cancer with at least one bone foci the efficacy of zoledronic acid in a dose of 4 mg is comparable to pamidronic acid in a dose of 90 mg.
In patients with tumor hypercalcemia, the action of the drug is characterized by a decrease in serum calcium and renal calcium excretion.
The average time to normalization of calcium is about 4 days. By day 10, calcium levels normalize in 87-88% of patients. The average time to relapse (albumin-corrected serum calcium content of at least 2.9 mmol/L) is 30-40 days. There is no significant difference between the effectiveness of zoledronic acid at doses of 4 and 8 mg in the treatment of hypercalcemia.
The studies show no significant differences in the frequency and severity of adverse events observed in patients treated with zoledronic acid at doses of 4 mg and 8 mg, pamidronic acid at a dose of 90 mg, or placebo in both the treatment of bone metastases and hypercalcemia.
Pharmacokinetic data for bone metastases were obtained after single and repeated 5- and 15-minute infusions of 2, 4, 8, and 16 mg of zoledronic acid in 64 patients. Pharmacokinetic parameters were independent of the drug dose.
After infusion initiation, serum zoledronic acid concentrations increase rapidly, peaking at the end of the infusion, followed by a rapid 10% decrease in concentration after 4 hours and a less than 1% peak after 24 hours with a consistently prolonged period of low concentrations not exceeding 0.1% of maximum until repeat infusion at day 28.
The low affinity of zoledronic acid for blood cellular components has been shown, with a mean whole blood to plasma concentration ratio of 0.59 over a concentration range of 30 ng/mL to 5000 ng/mL. Binding to plasma proteins is low, the fraction of unbound fraction is 60-77% and depends slightly on the drug concentration (from 2 to 2000 ng/ml).
Zoledronic acid is not metabolized and is excreted unchanged by the kidneys. According to the data obtained in vitro, zoledronic acid does not inhibit human cytochrome P450 isoenzymes and undergoes no biotransformation, which suggests that the state of liver function does not affect zoledronic acid pharmacokinetics in any significant way.
The zoledronic acid administered intravenously is excreted by the kidneys in three phases: a rapid biphasic elimination of the drug from the systemic circulation with half-lives of 0.24 h and 1.87 h and a prolonged phase with a final half-life of 146 h.
No cumulation of the drug was observed with repeated administrations every 28 days. During the first 24 h, 39±16% of the administered dose is detected in the urine. The remaining amount is mainly bound to the bone tissue. Then there is a slow reverse release of zoledronic acid from the bone tissue into the systemic bloodstream and its excretion by the kidneys.
The total plasma clearance of the drug is 5.04±2.5 L/h and is independent of the drug dose, sex, age, race and body weight of the patient. Increasing the infusion time from 5 to 15 minutes leads to a 30% decrease in zoledronic acid concentration at the end of infusion, but does not affect the area under the concentration-time curve (AUC).
Pharmacokinetic studies have not been performed in patients with hypercalcemia or impaired liver function. Less than 3% of the drug dose is excreted through the intestine.
Pharmacokinetics in special cases
There are no data describing the pharmacokinetics of zoledronic acid in patients with hepatic impairment. According to in vitro data, zoledronic acid does not inhibit human cytochrome P450 isoenzymes and is not biotransformed. In animal studies, less than 3% of the administered dose was detected in the feces. The above suggests that the state of liver function has no significant effect on the pharmacokinetics of zoledronic acid.
Renal clearance of zoledronic acid correlated with creatine clearance (CK) and was 75±33% of CK, a mean of 84±29 ml/min (range 22-143 ml/min) in 64 patients included in the study. A population analysis showed that in patients with moderate renal impairment (CK of 50 mL/min), the calculated zoledronic acid clearance was 72% of the zoledronic acid clearance value in patients with creatinine clearance ≥84 mL/min.
There are limited data on the pharmacokinetics of the drug in patients with severe renal dysfunction (CK less than 30 ml/min).
Gender, age, and race
The data from three pharmacokinetic studies in patients with cancer with bone metastases showed no effect of body weight, age (38 to 84 years), gender, and race on zoledronic acid clearance.
– Bone metastases in malignant solid tumors (prostate cancer, breast cancer and others) and multiple myeloma, including to reduce the risk of pathological fractures, spinal cord compression, tumor-induced hypercalcemia and reduce the need for radiation therapy or surgical bone interventions.
– Hypercalcemia due to malignancies (serum albumin-corrected calcium content > 12.0 mg/dL [3.0 mmol/L]).
In 1 vial contains:
the active substance:
zoledronic acid monohydrate (in terms of anhydrous substance) 4.00 mg;
Mannitol 220.00 mg,
Sodium citrate 24.00 mg,
Injection water to 5.00 ml.
How to take, the dosage
Zoledronate-Teva should only be administered by qualified medical personnel experienced in intravenous bisphosphonates.
The drug Zoledronate-Teva should not be mixed with solutions containing calcium or other divalent ions (e.g. Ringer’s solution). Zoledronate-Teva should be administered intravenously by IV drip for at least 15 minutes without mixing with other drugs.
Patients with dehydration (if present) should be corrected prior to administration of Zoledronate-Teva.
Bone metastases of solid malignancies and multiple myeloma in adults and elderly patients
The recommended dose is 4 mg every 3-4 weeks. Oral calcium at a dose of 500 mg per day and vitamin D at a dose of 400 ME per day should be used in addition.
Hypercalcemia due to malignancies in adults and elderly patients
In hypercalcemia (albumin corrected serum calcium ≥12 mg/dL or 3 mmol/L), the recommended single dose of the drug is 4 mg. The patient should be adequately hydrated before or during the infusion.
Patients with impaired renal function
Hypercalcemia due to malignancies
Patients with serum creatinine concentrations less than 400 µmol/L or < 4.5 mg/dL do not require dosing adjustments.
Bone metastases of solid malignancies and multiple myeloma
Serum creatinine and CK concentrations should be determined in all patients before starting therapy with the drug.
The dose of Zoledronate-Teva depends on the baseline creatinine clearance calculated by the Cockcroft-Gault formula. The drug is contraindicated in patients with severe renal dysfunction (creatinine clearance <30 ml/min) (see section “Contraindications”).
The recommended doses in patients with mild to moderate renal dysfunction (creatinine clearance values 30-60 ml/min) are given below.
Initial creatinine clearance value (ml/min)
Recommended dose of Zoledronate-Teva
4.0 mg (5 ml concentrate)
3.5 mg (4.4 ml concentrate)
3.3 mg (4.1 ml concentrate)
3.0 mg (3.8 ml concentrate)
3.0 mg (3.8 ml concentrate)
After initiation of therapy, serum creatinine concentration should be determined before each subsequent dose of the drug is administered. If renal function abnormalities are detected, the next dose of Zoledronate-Teva should be delayed.
In clinical studies, impaired renal function has been defined as follows:
– in patients with baseline serum creatinine concentration within normal limits (< 1.4 mg/dL), a 0.5 mg/dL increase in serum creatinine concentration;
– in patients with deviations of baseline serum creatinine concentration from normal (> 1.4 mg/dL) – increase in serum creatinine concentration by 1 mg/dL. Therapy with Zoledronate-Teva should be resumed only after serum creatinine concentration reaches values within ±10% of the initial one, at the same dose used before treatment interruption.
Preparation of solution for infusion
Before administering the drug, the concentrate (the contents of one vial or a smaller volume) is diluted in 100 ml of calcium-free solution for infusion (0.9% sodium chloride solution or 5% dextrose solution).
The drug Zoledronate-Teva should not be mixed with other medicinal products, solutions containing calcium or other divalent cations, including Ringer-lactate solution.
Prepared zoledronic acid solution should be administered using a separate IV infusion system immediately after preparation.
Caution is recommended with concomitant use of bisphosphonates with aminoglycosides, calcitonin, and “loop” diuretics because the concomitant effects of these drugs are manifested by an increased duration of plasma calcium reduction.
Caution is necessary when using zoledronic acid concomitantly with drugs with potential nephrotoxic effects.
Caution should be exercised when using concomitantly with angiogenesis inhibitors due to increased incidence of jaw necrosis.
No clinically significant interactions have been noted with other commonly used medications (antineoplastic agents, diuretics [excluding “looping”], antibiotics, analgesics) when used concomitantly with zoledronic acid.
In the combined use of Zoledronate-Teva with thalidomide, no dose adjustment of zoledronic acid is required, except for use in patients with mild to moderate renal impairment.
The combined use of thalidomide (100 mg or 200 mg once daily) and Zoledronate-Teva (4 mg) in patients with multiple myeloma does not significantly affect the pharmacokinetics of zoledronic acid and CK.
Pharmaceutical interactions and compatibility issues
Diluted zoledronic acid solution should not be mixed with infusion solutions containing calcium ions, such as Ringer’s solution.
When using glass vials, infusion systems and bags of different types made of polyvinyl chloride, polyethylene and polypropylene (pre-filled with 0.9% sodium chloride solution or 5% dextrose solution) for administration of zoledronic acid, no evidence of incompatibility with the drug has been found.
Before infusion, ensure that the patient is adequately hydrated. If necessary, it is recommended to administer 0.9% sodium chloride solution before, in parallel or after infusion of Zoledronate-Teva. Hyperhydration should be avoided due to the risk of cardiovascular complications.
After administration of Zoledronate-Teva, continuous monitoring of calcium (corrected for albumin), phosphorus, magnesium and serum creatinine concentration is necessary.
If hypocalcemia, hypophosphatemia or hypomagnesemia develops, short-term additional administration of the appropriate agents may be necessary. Patients with untreated hypercalcemia usually have impaired renal function, so careful monitoring of renal function is necessary in patients in this category.
When considering treatment with Zoledronate-Teva in patients with bone metastases to decrease the risk of pathological fractures, spinal cord compression, and tumor-caused hypercalcemia, and to decrease the need for radiation therapy or bone surgery, it should be considered that therapeutic benefit is seen in 2-3 months after initiation of therapy with the drug.
There have been some reports of renal dysfunction with bisphosphonates. Risk factors for these complications include dehydration, previous renal dysfunction, repeated administration of Zoledronate-Teva or other bisphosphonates, and use of nephrotoxic medications, and overmedication. Although the risk of the above described complications is reduced if the drug is administered at a dose of 4 mg for at least 15 minutes, the possibility of renal dysfunction persists.
There have been cases of worsening of renal function, progression of renal impairment to renal failure and the need for hemodialysis on first or single dose zoledronic acid.
Elevated serum creatinine concentrations have also been seen in some patients with long-term use of the drug at the recommended doses, although with less frequency.
Cases of osteonecrosis of the jaw have been described, mainly in patients with cancer during treatment with bisphosphonates, including zoledronic acid. Many of these patients received concomitant therapy with glucocorticosteroids or chemotherapy. Many patients had signs of local infection, including osteomyelitis.
In clinical practice, the most frequent development of osteonecrosis of the jaw has been seen in patients with advanced breast cancer and myeloma, as well as with dental disease (after tooth extraction, periodontal disease, unsatisfactory fixation of dentures).
Known risk factors for osteonecrosis of the jaw include cancer, concurrent therapy (chemotherapy, radiation therapy, anti-angiogenic drugs, glucocorticosteroids), comorbid conditions (anemia, coagulopathies, infection, prior oral disease).
Bisphosphonates should be preceded by a dental examination and necessary preventive procedures in patients with cancer, and strict oral hygiene should be recommended.
Dental invasive interventions should be avoided if possible during treatment with bisphosphonates. In patients with osteonecrosis of the jaw on bisphosphonates therapy, invasive dental interventions may worsen the condition. There is no evidence that interrupting treatment with bisphosphonates prior to dental intervention reduces the risk of osteonecrosis of the jaw. The treatment plan for an individual patient should be based on an individual risk/benefit assessment.
Osteonecrosis of other localizations, including pelvic bone, femur, and external auditory canal, has been described, mainly in adult patients with cancer receiving bisphosphonate therapy, including zoledronic acid.
Atypical femur fractures
Atypical subjacent and diaphyseal fractures of the femur have been described in patients receiving long-term bisphosphonate therapy for osteoporosis. Transverse or short oblique fractures can occur anywhere along the length of the femur from the fibula to the supramandibular fossa.
The fractures described occur after minimal trauma or spontaneously. Some patients experience pain in the hip or groin, often accompanied by signs of stress fractures on imaging diagnostic examinations, which occur weeks to months before a complete (complete) femoral fracture develops. It is not uncommon for fractures to occur on both sides, so if a femoral fracture occurs in a patient receiving bisphosphonate therapy, the contralateral femur should be evaluated. Slow healing (fusion) of these fractures has also been reported.
Atypical femoral fractures have been reported in patients treated with zoledronic acid, but a causal association of these fractures with zoledronic acid therapy has not been established. The decision to discontinue therapy with Zoledronic-Teva in patients with suspected atypical femur fractures prior to evaluation should be based on an individual assessment of the ratio of expected benefit to possible risk.
Patients treated with Zoledronate-Teva should be cautioned to report any hip or groin pain to medical personnel; any patient complaining of such symptoms should be evaluated for possible incomplete femoral fracture.
In clinical practice, there have been infrequent reports of severe and in some cases disabling pain in bones, joints and muscles during treatment with bisphosphonates, which include zoledronic acid. These symptoms developed over a period of one day to several months after the start of treatment. After discontinuation of treatment, most patients showed resolution of their symptoms. A few patients experienced a recurrence of symptoms when resuming therapy or using another bisphosphonate.
The development of hypocalcemia has been reported in clinical practice in patients treated with zoledronic acid. In case of severe hypocalcemia development adverse events have been observed in nervous system (seizures, tetany and numbness), cardiac arrhythmia. In some cases hypocalcemia can be life threatening.
Cautions must be taken when using Zoledronate-Teva with other drugs which can cause hypocalcaemia, because this can cause synergistic interaction and development of severe hypocalcaemia. Before initiating therapy with Zoledronate-Teva, serum calcium levels should be determined and hypocalcemia should be corrected. Patients should receive adequate supplementation with calcium preparations and vitamin D.
Patients receiving therapy with Zoledronate-Teva should not receive other bisphosphonates at the same time.
The efficacy and safety of Zoledronate-Teva in pediatric practice has not yet been established.
The effect of the drug Zoledronate-Teva on the ability to drive vehicles and mechanisms has not been studied. In case of adverse reactions on the nervous system side, patients are advised to refrain from driving vehicles and operating machinery as well as engaging in activities requiring concentration and strain of psychomotor functions.
– Hypersensitivity to zoledronic acid, other bisphosphonates or any other component of the drug.
– Serious renal dysfunction (CKR less than 30 ml/min).
– Pregnancy and lactation.
– Childhood and adolescence (efficacy and safety not established).
If you have any of the above conditions, be sure to consult your doctor before taking the drug.
Cautiously use the drug in patients with mild to moderate renal dysfunction (CK > 30 ml/min).
Caution should be exercised when using concomitantly with other drugs that may cause hypocalcemia (e.g., aminoglycosides, calcitonin, “loop diuretics”) due to the risk of synergistic effects leading to severe hypocalcemia.
Caution should be used concomitantly with other drugs with nephrotoxic potential.
Precaution should be used concomitantly with antiangiogenic drugs due to an increased risk of osteonecrosis of the jaw.
Perhaps caution should be exercised when used in patients with severe hepatic impairment due to limited data on the use of the drug in this category of patients.
The most serious adverse reactions (HP) in patients receiving zoledronic acid for reported indications were: anaphylactic reaction, ocular adverse events, osteonecrosis of the jaw, atypical femoral fracture, atrial fibrillation, renal dysfunction, acute phase reactions and hypocalcemia.
The information on the incidence of HP with zoledronic acid at a dose of 4 mg is based primarily on data from long-term therapy. HP associated with zoledronic acid use is usually mild and transient, similar to that reported with other bisphosphonates. These HPs can occur in approximately one-third of patients treated with zoledronic acid.
The symptoms of acute phase reactions usually developed 3 days after zoledronic acid administration: general malaise, bone pain, fever, chills, flu-like syndrome, and arthritis followed by joint swelling; symptoms usually resolved within a few days. HP such as arthralgia and myalgia were also frequently reported.
Very often a decrease in renal calcium excretion was accompanied by a sharp decrease in phosphorus, which was asymptomatic and did not require treatment. Often a decrease in serum calcium up to the development of hypocalcemia may be accompanied by a lack of clinical manifestations.
There have been reports of frequent gastrointestinal reactions, such as nausea and vomiting after intravenous infusion of zoledronic acid.
Local reactions at the infusion site, such as redness or swelling and/or pain, have been observed infrequently.
Anorexia was frequently observed in patients receiving zoledronic acid at a dose of 4 mg.
Incidents of rash or pruritus have been infrequent. As with other bisphosphonates, frequent cases of conjunctivitis have been reported.
Anemia of severe anemia (hemoglobin concentration < 8.0 g/dl) has been reported frequently in patients receiving zoledronic acid at a dose of 4 mg, based on a pooled analysis of controlled studies.
The HPs are grouped according to the MedDRA classification of organs and organ systems, listed within each group in decreasing order of frequency of occurrence and within each subgroup in decreasing order of significance.
The criteria for evaluating frequency of occurrence are: very common (≥ 1/10), frequent (≥ 1/100, < 1/10), infrequent (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), including individual reports.
Blood and lymphatic system disorders: frequent – anemia; infrequent – thrombocytopenia, leukopenia; rare – pancytopenia.
Psychiatric disorders: frequently – sleep disturbance; infrequently – anxiety; rarely – mental confusion.
Nervous system disorders: often – headache, paresthesia; infrequent – dizziness, dysgeusia, hypoesthesia, hyperesthesia, tremor; very rare – convulsions, hypoesthesia and tetany (developing due to hypocalcemia).
Visual organ disorders: frequently – conjunctivitis; infrequently – “blurred” vision; rarely – uveitis.
Digestive system disorders: frequently – nausea, vomiting, decreased appetite, constipation; infrequently – diarrhea, abdominal pain, dyspepsia, stomatitis, dry mouth.
Respiratory system disorders, thoracic and mediastinal organs: infrequent – dyspnea, cough; rarely – interstitial lung disease.
Skin and subcutaneous tissue disorders: frequently – increased sweating; infrequently – itching, rash (including erythematous and macular).
Musculoskeletal and connective tissue disorders: frequently – bone pain, myalgia, arthralgia, generalized pain, joint stiffness; infrequently – necrosis of the jaw, muscle cramps.
Chronic disorders: rarely – bradycardia, arrhythmia (due to hypocalcemia).
Vascular disorders: often – increase of blood pressure; infrequently – decrease of blood pressure.
Renal and urinary tract disorders: frequently – renal dysfunction; infrequently – acute renal failure, hematuria, proteinuria.
Intrinsic system disorders: infrequent hypersensitivity reactions; rarely – angioedema.
Laboratory and instrumental data: very frequently – hypophosphatemia; frequently – increased concentration of creatinine and urea in blood serum, hypocalcemia; infrequently – hypomagnesemia, hypokalemia; rarely – hyperkalemia, hypernatriemia.
General disorders and disorders at the site of administration: frequent – acute phase reaction, increased body temperature, flu-like syndrome (including general malaise, chills, malaise, “hot flashes”), peripheral edema, asthenia; infrequent – injection site reaction (pain, irritation, swelling, thickening, redness), chest pain, increased body weight; rare – arthritis and joint swelling as symptom of acute phase reaction.
Please note that when using other bisphosphonates there have been cases of bronchospasm in patients with bronchial asthma sensitive to acetylsalicylic acid, but this has not been observed with zoledronic acid.
Indesirable reactions according to spontaneous reports and literature reports (frequency unknown)
Immune system disorders: anaphylactic reaction/shock.
Nervous system disorders: drowsiness.
Visual system disorders: episcleritis, scleritis and inflammatory diseases of the orbit.
Cardiac disorders: atrial fibrillation.
Vascular disorders: decreased blood pressure leading to syncope or circulatory collapse, mainly in patients with risk factors.
Respiratory system, chest and mediastinum disorders: bronchospasm.
Skin and subcutaneous tissue disorders: urticaria.
Muscular and connective tissue disorders: sudden severe restriction of joint mobility and/or severe and in some cases incapacitating pain in bones, joints and/or muscles, atypical intertrochanteric and diaphyseal fractures of the femur.
Description of individual adverse reactions
The use of zoledronic acid has been associated with the development of renal dysfunction. When the drug was used in clinical trials to prevent skeletal complications in patients with advanced malignancies with bone lesions, the frequency of renal dysfunction associated with the use of the drug was distributed as follows: multiple myeloma (3.2%), prostate cancer (3.1%), breast cancer (4.3%), lung cancer and other solid tumors (3.2%).
Factors that may increase the risk of impaired renal function include: dehydration, prior impairment of renal function, multiple courses of treatment with zoledronic acid or other bisphosphonates, concurrent use of nephrotoxic drugs, or administration of the drug for less than the recommended period of time.
Worsening of renal function and progression of renal impairment to renal failure and the need for hemodialysis after starting or starting a single dose of zoledronic acid have been reported.
Osteonecrosis of the jaw
In treatment with bisphosphonates, including zoledronic acid, cases of osteonecrosis have been reported mainly in patients with cancer (mainly of the jaw, but also in other locations, including the pelvis, femur, and external auditory canal).
Many patients showed signs of local infection, including osteomyelitis; most of these cases were in patients with cancer after tooth extraction or after dental surgery.
There are well-known multiple risk factors predisposing to the development of osteonecrosis of the jaw, such as malignancies, concurrent therapy (e.g., chemotherapy, antiangiogenic drugs, radiation therapy, glucocorticosteroids) and concurrent conditions (e.g., anemia, coagulopathies, infections, prior oral disease). Although a causal relationship has not been established, it is advisable to avoid dental surgery because of the possibility of delayed recovery. Based on available data, the incidence of osteonecrosis of the jaw is related to the nature of the tumor (advanced breast cancer, multiple myeloma).
The acute phase reaction
This adverse reaction is a complex of symptoms: increased body temperature, general weakness, bone pain, chills, flu-like syndrome. It usually begins ≤3 days after infusions of zoledronic acid. The reaction is also referred to using the terms “flu-like” or “post-dose” symptoms. Symptoms usually resolve after a few days.
. In one clinical trial, when zoledronic acid was used for 3 years in patients with postmenopausal osteoporosis (at a dose of 5 mg once a year), the overall incidence of atrial fibrillation was 2.5% (96 of 3,862) compared with 1.9% (75 of 3,852) in the placebo group. The incidence of atrial fibrillation with severe hemodynamic abnormalities was 1.3% (51 of 3862) and 0.6% (22 of 3852) for zoledronic acid and placebo, respectively.
A similar imbalance has not been seen in other clinical trials of zoledronic acid, including the use of zoledronic acid at a dose of 4 mg once every 3-4 weeks in patients with cancer.
The reason for the increased incidence of atrial fibrillation on zoledronic acid therapy in patients with postmenopausal osteoporosis was not established in this study.
If any of the side effects listed in the instructions worsen, or if you notice any other side effects not listed in the instructions, inform your physician.In acute overdose with the drug (limited data), renal dysfunction, including renal failure, changes in electrolyte composition, including decreased plasma calcium, phosphate and magnesium concentrations, have been reported. A patient who has received a dose of the drug in excess of the recommended dose should be kept under constant observation.
In case of hypocalcemia accompanied by clinical manifestations, calcium gluconate infusion is indicated.
In acute drug overdose (limited data) renal dysfunction, including renal failure, changes in electrolyte composition, including decreased concentration of calcium, phosphate and magnesium in blood plasma have been reported. A patient who has received a dose of the drug in excess of the recommended dose should be kept under constant observation.
In case of hypocalcemia accompanied by clinical manifestations, calcium gluconate infusion is indicated.
The use of Zoledronate-Teva during pregnancy is contraindicated.
The drug Zoledronate-Teva may have adverse effects on the fetus. Studies in animals have shown toxic effects on reproductive function. There are no data on the use of the drug during pregnancy in humans.
If pregnancy occurs during therapy with bisphosphonates, there may be a risk of intrauterine fetal malformations (e.g., skeletal and other abnormalities). The dependence of risk on the amount of time between discontinuation of bisphosphonates therapy and the time of conception, the route of administration, and the characteristics of a particular drug is unknown.
Women of reproductive age should be advised to use reliable contraception during treatment with Zoledronate-Teva.
It is not known whether zoledronic acid passes into breast milk. The use of the drug Zoledronate-Teva during breastfeeding is contraindicated.
In studies in animals, zoledronic acid suppressed fertility at a dose of 0.1 mg/kg/day. There are no data on the effect of zoledronic acid on fertility in humans.
2 years. Do not use after the expiration date printed on the package.
|Conditions of storage|
Store at a temperature not exceeding 25 ° C. Store out of the reach of children.
Pliva Hrvatska d.o.o., Croatia
concentrate for preparation of infusion solution
Pliva Hrvatska d.o.o.
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