active ingredient : zoledronic acid;
1 ml of concentrate contains 0.8 mg of zoledronic acid
auxiliary substances: mannitol (E 421), sodium, water for injection.
Concentrate for preparation of solution for infusions.
Basic physico-chemical properties: transparent colorless liquid.
Means affecting the structure and mineralization of the bones. Bisphosphonates. Code ATH M05V A08.
Alendronova acid belongs to a new class of bisphosphonates specifically act on bone tissue. It is one of the most potent bone resorption inhibitors known to date.
The selective effect of bisphosphonates on bone is based on their high affinity with mineralized bone tissue, but the molecular mechanism leading to inhibition of osteoclasts of activity, today is not clarified. Animal studies have found that Zometa inhibits bone resorption without adversely affecting bone formation, mineralization and mechanical properties.
In addition to inhibiting bone resorption osteoclasts, Zometa has a direct antitumor effect on cultured myeloma cells and human breast cancer by inhibiting cell proliferation and apoptosis induction. This indicates that Zometa may have anti-metastatic properties.
In vivo - inhibition osteoblast bone resorption, which acts on the structure of the microcrystalline matrix of bone, reduces tumor growth, antiangiogenic effects (effects on blood vessels, which reduces blood supply to tumors), analgesic effect.
In vitro inhibition osteoblast proliferation, a cytostatic effect, proapoptotic effect on tumour cells, synergistic cytostatic effect with other anti-tumor drugs, anti-adhesive and antiinvasive action.
Data on pharmacokinetics in bone metastases obtained after a single and repeated 5-and
15-minute infusion of 2, 4, 8 and 16 mg of zoledronic acid in 64 patients. Pharmacokinetic characteristics do not depend on the dose.
After the onset of the infusion of zoledronic acid plasma concentrations of the drug increase rapidly, reaching a peak at the end of the infusion, then there is a rapid decrease in the concentration of 10% of the peak value after 4: 00 and<1% of the peak value after 24 hours with a sequentially prolonged period of low concentrations not exceeding 0, 1% peak , to the second infusion on the 28th day. Alendronova acid is introduced intravenously and excreted by the kidneys in 3 phases: rapid biphasic elimination of the drug from the systemic circulation with half-lives of t ?? = 0.24 hours and t ?? = 1.87 hours and a long phase with a finite half-life t ?? =
146 hours. There was no cumulation of the drug in plasma with repeated injections every 28 days. Alendronova acid is not metabolized and is excreted by the kidneys unchanged. During the first 24 hours 39 ± 16% of the administered dose is detected in the urine. The rest of the drug is associated with bone tissue. Then slowly there is the reverse release of zoledronic acid from bone tissue into the systemic bloodstream and its excretion by the kidneys. The total clearance in the body is 5,04 ± 2,5 l/h and does not depend on the dose, sex, age, race and body weight of the patient. An increase in infusion time from 5 to 15 minutes leads to a decrease in the concentration of zoledronic acid by 30% at the end of the infusion, but does not affect the curve of concentration versus time in blood plasma (AUC).
Variability of pharmacokinetic parameters of zoledronic acid, as well as other bisphosphonates, was high in different patients.
Data on the pharmacokinetics of zoledronic acid in patients with hypercalcemia and liver failure are not available. According to data obtained in vitro , zolendronovaya acid does not inhibit human enzyme R450 and is not subjected to biotransformation; according to experimental studies conducted in animals, with feces derived less than 3% of the dose, which suggests that the state of liver function does not affect the pharmacokinetics of zoledronic acid.
Renal clearance of zoledronic acid correlates with creatinine clearance, renal clearance is 5 ± 33% creatinine clearance, reaching an average of 84 ± 29 ml/min (range
22-143 ml/min) in 64 cancer patients included in the study. Analysis of the group of patients showed that patients with creatinine clearance 20 ml/min (acute renal failure) and
50 ml/min (average renal failure) relative clearance of zoledronic acid-37% and
72% respectively. However, data from such in patients with acute renal insufficiency
Discovered low affinity of zoledronic acid for the cellular components of blood. Binding to plasma proteins is low (about 56%) and does not depend on the concentration of zoledronic acid.
Limited pharmacokinetic data for children with severe osteogenesis disorders suggest that the pharmacokinetics of zoledronic acid in children aged 3 to 17 years is similar to those in adults when used in equivalent doses (mg/kg). Age, body weight, gender of the patient and creatinine clearance, as it turned out, do not affect the systemic exposure of zoledronic acid.
Prevention of symptoms associated with bone lesions (pathological fractures, compression of the vertebral trunk, complications after surgery and radiation therapy or hypercalcemia due to a malignant tumor) in patients with malignant neoplasms at late stages.
Treatment of hypercalcemia caused by a malignant tumor.
Hypersensitivity to the active substance (zoledronic acid), other bisphosphonates or any auxiliary substances that are part of the drug.
Pregnancy or breast-feeding.
Interaction with other medicinal products and other forms of interaction
There was no clinically significant interaction in the application of zoledronic acid simultaneously with frequently used drugs: antitumor drugs, antibiotics, analgesics.
Zometa does not bind significantly with blood plasma proteins and does not inhibit the enzymes of the human cytochrome P450 system, according to data obtained during in vitro studies, but no special clinical studies have been conducted to study drug interaction.
It is recommended to exercise caution while using bisphosphonates and aminoglycosides, as they may exhibit an additive effect, whereby the level of calcium in the serum may remain reduced for longer than necessary. We recommend caution when concomitant use of bisphosphonates and loop diuretics, since they may show an additive effect, resulting in can occur hypocalcemia. Caution should be exercised in the appointment of zoledronic acid and other potentially nephrotoxic drugs. It should also be borne in mind the possibility of the development of hypomagnesemia treatment time.
In patients with multiple myeloma with intravenous administration of bisphosphonates in combination with talidomide, no clinically significant interactions were observed.
There is evidence of osteonecrosis of the jaw in patients receiving concomitant treatment with Zometa and anti-angiogenic (reduce the blood supply of a tumor) drugs.
Before administration of Zometa-Farmeks it is necessary to be convinced of sufficient hydration of all patients, including patients with easy and moderate renal impairment.
You should avoid fluid overload in patients with risk of development of heart failure.
Standard metabolic parameters associated with hypercalcemia, such as calcium, phosphate and magnesium levels, should be carefully checked after starting Zometa-Farmex therapy. If there is hypocalcemia, hypophosphatemia or hypomagnesemia, short-term corrective therapy may be necessary.
Untreated patients with hypercalcemia usually have some renal impairment, so it is necessary to carefully monitor kidney function.
Zometa-Pharmex contains the active substance of Zometa. Patients receiving treatment with Zometa-Pharmex, should not simultaneously take other medications containing the Zometa.
Patients receiving therapy Zometa-Farmeks, also should not simultaneously apply any other bisphosphonates.
Violation of kidney function
When deciding on the use of Zometa-Farmeks patients with hypercalcemia, due to a malignant tumor, against the background of renal impairment should assess the patient's condition and conclude that the predominant potential benefits of treatment over the possible risk.
When deciding on the treatment of patients with bone metastases in order to prevent symptoms associated with diseases of the spine, it should be borne in mind that the effect of the drug appears after 2-3 months.
There were reports of renal dysfunction associated with the use of bisphosphonates. Factors that increase the possibility of renal impairment include dehydration, pre-existing renal impairment, multiple cycles of zoledronic acid or other bisphosphonates, as well as the use of nephrotoxic agents or infusion in a shorter time than recommended. Although with the introduction of zoledronic acid at a dose of 4 mg for at least 15 minutes the risk decreases, renal impairment is possible.
An increase in serum creatinine levels is also observed in some patients who constantly take the drug in recommended doses to prevent the occurrence of symptoms associated with spinal diseases, although this is quite rare.
Before taking each dose of Zometa-Farmeks in patients, it is necessary to assess the level of serum creatinine. After the start of treatment patients with bone metastases and women with early stages of breast cancer in the postmenopausal period in the treatment of aromatase inhibitors (AIs) to prevent loss of bone mass and bone fractures with minor or moderate renal impairment recommended lower doses Zometa-Farmeks (see the table in the section "Method of application and dose"). Patients who have a deterioration in renal function during treatment, the drug can be restored only when the level of creatinine returns to its original value in the range of
10% of the initial value.
For the possible effect of bisphosphonates, including Zometa-Farmex, on kidney function, due to the lack of detailed data on clinical safety in patients with severe renal insufficiency (creatinine serum> 400 µmol/l, or> 4.5 mg/DL, for patients with hypercalcemia, that induced tumor, and creatinine serum> 265 µmol/l, or> 3 mg/DL, for patients with bone metastases and in women with early stage breast cancer in the postmenopausal period in the treatment of aromatase inhibitors (AIs) to prevent loss of bone mass and bone fractures, respectively) and only limited pharmacokinetic data for patients with severe renal failure (creatinine clearance
Impaired liver function
There are no specific recommendations for patients with severe hepatic insufficiency, as only limited clinical data are available.
the osteonecrosis of the jaw
The osteonecrosis of the jaw was observed predominantly in patients with cancer receiving treatment regimens including bisphosphonates, including Zometa. Many of these patients also received chemotherapy and corticosteroids. Most of the reported cases were related to dental procedures such as tooth extraction. Many of the patients showed signs of local infection, including osteomyelitis.
The following risk factors should be considered to assess the individual risks of jaw osteonecrosis
bisphosphonate activity (greater risk for more active constituents), administration method (greater risk for parenteral administration) and cumulative dose;
cancer, chemotherapy, radiotherapy, corticosteroid therapy, Smoking;
dental diseases in history, insufficient oral hygiene, periodontal disease, invasive dental procedures but not tightly adjacent denture.
Prior to treatment with bisphosphonates, it is necessary to examine the oral cavity with appropriate dental prevention.
During therapy, these patients should avoid invasive dental procedures if possible. Dental surgery can worsen the condition of patients who have developed jaw osteonecrosis during therapy with bisphosphonates. There is no evidence of patients requiring dental procedures to determine whether the risk of jaw osteonecrosis is reduced or not. The physician, in making a clinical assessment, should be guided by each patient's management plan, based on an individual assessment of benefit/risk.
There is evidence of severe, sometimes crippling pain in bones, joints and/or muscles in patients using bisphosphonates. This category of drugs includes Zometa. However, such reports were isolated. The time before the onset of symptoms varied from one day to several months from the start of treatment. In most patients, the severity of symptoms decreased after the termination of treatment. In this category, patients noted a relapse of symptoms if treatment was resumed with the same drug or other bisphosphonates.
Atypical femoral fracture
Edwardlucas and atypical diaphyseal femur fractures were registered during therapy, bisphosphonates, primarily in patients receiving long-term treatment of osteoporosis. These transverse or short oblique fractures occur anywhere along the femur from just below the small trochanter to just above the epicondyle. These fractures occur after or without minimal injury, and some patients experience hip or groin pain, often associated with x-ray signs of a stress fracture, a few weeks or months before a complete hip fracture occurs. Fractures are often bilateral, therefore, the second thigh should be evaluated in patients receiving bisphosphonate therapy and have suffered a femur fracture. Long-term healing of these fractures has also been reported. On the basis of an individual assessment of risks and benefits should decide the issue of termination bisphosphonate the treatment of patients with suspected atypical fractures of the femur.
During treatment with bisphosphonates, patients should inform the doctor about any pain in the pelvis, hip or groin, and each patient with such symptoms should be examined for incomplete fracture of the femur.
Hypocalcemia was reported in patients who used Zometa. Cases of cardiac arrhythmias and neurological reactions (including epileptic seizures, numbness and tetany), secondary to severe hypocalcemia, were reported. Cases of severe hypocalcemia requiring hospitalization were reported. In some cases, hypocalcemia may be life-threatening.
Use during pregnancy or breast-feeding.
The drug is contraindicated during pregnancy and lactation.
There is insufficient data on the use of zoledronic acid in pregnant women. The reproduction studies in animals have shown reproductive toxicity. The potential risk to humans is unknown.
Unknown Zometa gets into breast milk.
The ability to influence the reaction rate when driving motor transport or operating other mechanisms.
Side effects of the drug such as dizziness and drowsiness, can affect the ability to drive vehicles and operate machinery, so care is needed when driving vehicles or work with machinery during the period of use of zoledronic acid.
Method of application and doses
Zometa-Farmex is administered only by doctors with experience in administration of bisphosphonates.
Before the introduction of 4 mg concentrate Zometa-Farmeks diluted in 100 ml 0.9% sodium chloride solution or 5% glucose solution. Ready Zometa-Farmeks solution for infusion is administered as a single infusion for at least 15 minutes.
Zometa concentrate-Pharmex cannot be mixed with solutions for infusion containing calcium or other divalent cations, such as lactate ringer solution and must be administered in a single infusion through the separate infusion systems.
Prevention of symptoms associated with bone lesions in patients with malignant neoplasms at late stages
Adults, including elderly patients
The recommended dose of Zometa-Farmex is 4 mg in the form of infusion each
Patients also need daily administration of calcium products inside at a dose of 500 mg and 400 IU of vitamin d per day.
The decision to treat patients with metastatic bone lesions to prevent symptoms associated with bone lesions should take into account that the beginning of the effect of treatment occurs after 2-3 months.
Treatment of hypercalcemia caused by a malignant tumor
Adults, including elderly patients
The recommended dose of Zometa-Farmex is 4 mg in the form of a single infusion. Before the introduction and with the introduction of Zometa-Farmeks it is necessary to provide sufficient hydration of the patient.
Violation of kidney function
Hypercalcemia caused by a malignant tumor
Treatment of hypercalcemia caused by a malignant tumor in patients with severe renal impairment is possible after a thorough assessment of the risk of the drug and the expected benefits. Clinical experience of the drug in patients with serum creatinine levels> 400 µmol/l, or> 4,5 mg/DL, is absent. Patients with hypercalcemia due to malignant tumor, with the creatinine level in blood serum
<4.5 mg/DL, dose adjustment is not required.
Prevention of symptoms associated with bone lesions in patients with malignant neoplasms at late stages
At the beginning of treatment of patients with multiple myeloma or metastatic bone damage due to a solid tumor should determine the level of serum creatinine and creatinine clearance. KK is calculated by the formula Cockroft-Gault creatinine in the blood serum. Zometa-Farmex is not recommended for patients with severe renal impairment before therapy (creatinine clearance
Patients with metastatic bone damage in violation of kidney function mild to moderate severity prior to therapy (creatinine clearance 30-60 ml/min) are recommended the following doses:
The initial creatinine clearance level (ml/min)recommended dose of Zometa-FARMEKS (mg) *
> 604 mg *
50-603, 5 mg *
40-493, 3 mg *
30-393 mg *
* Doses calculated with a given assumption AUC = 0,66 mg/h/l (creatinine clearance 75 ml/min). For patients with impaired renal function, a dose reduction to a level at which the same AUC is achieved, as in patients with creatinine clearance of 75 ml/min.
After starting therapy, serum creatinine should be measured before administration of each dose of Zometa-Farmex, if kidney function is impaired treatment should be abolished. There is evidence that in clinical trials, the impaired renal function was defined as follows:
for patients with normal baseline creatinine level in the serum (<1.4 mg/DL, or
for patients with altered baseline levels of creatinine in the serum (> 1.4 mg/DL, or
> 124 µmol/l) - increase by 1 mg/DL, or 88 µmol/L.
It was reported that during the studies Zometa therapy was restored after the return of creatinine to the initial level within 10% of the initial value. Zometa-Farmex therapy should be restored in the same dose, as before the interruption of treatment.
The safety and efficacy of zoledronic acid in children from 1 year to 17 years have not been established. There are no recommendations on how to use in children.
Instructions for the preparation of doses of Zometa-Pharmex
Doses of concentrate for the preparation of infusion solution in milliliters, which correspond to Zometa-Farmeks doses in milligrams:
4.4 ml corresponds to 3.5 mg
4.1 ml corresponds to 3.3 mg
3.8 ml corresponds to 3 mg.
The required amount of liquid concentrate should be diluted in 100 ml sterile 0.9% sodium chloride solution or 5% glucose for intravenous infusion.
The content of 1 bottle of the drug (4 mg of zoledronic acid) is dissolved in 100 ml of sodium chloride solution 9 mg/ml of glucose solution 50 mg/ml.the Prepared solution should be used immediately after preparation. Unused solution can be stored in the refrigerator at a temperature of 2 to 8 ° C for no more than 24 hours.
Patients with impaired renal function mild or moderate severity recommended reduced doses of zoledronic acid.
Before the introduction of zoledronic acid and then need to ensure sufficient hydration of the patient.
Safety and efficacy of zoledronic acid in children have not been established.
Clinical experience in the treatment of acute overdose Zometa limited. It was reported that the erroneous use of zoledronic acid at a dose of 48 mg .Patients who used a dose that exceeds the recommended dose should be under constant control, since it is possible to disrupt kidney function (including renal failure), changes in the electrolyte composition of serum (including calcium, phosphate and magnesium concentrations). When hypocalcemia occurs, calcium gluconate infusion is shown to be performed according to clinical indications. Treatment is symptomatic.
Within three days after the application of zoledronic acid, gostrophase reactions were usually reported, symptoms of which included bone pain, fever, weakness, arthralgia, myalgia and chills, arthritis with swelling of the joints. These symptoms usually disappear within a few days.
The most important identified adverse reactions with the use of zoledronic acid were violations of the kidney, necrosis of the jaw, acute phase reaction, hypocalcemia, blurred vision, atrial fibrillation, anaphylaxis.
Adverse reactions associated with the use of zoledronic acid, such as those reported in the application of other bisphosphonates, and can develop in about one third of all patients.
From the blood and lymphatic systems: anemia, thrombocytopenia, leukopenia, pancytopenia.
From the nervous system: headache, paresthesia, dizziness, taste disorders, hypesthesia, hyperesthesia, tremor, drowsiness, epileptic seizures, numbness and tetany (secondary to hypocalcemia).
Psychiatric disorders: insomnia, anxiety, confusion.
From the organs of vision: conjunctivitis, blurred vision, scleritis and inflammation of the orbit, uveitis, episcleritis.
The gastro-intestinal tract: nausea, vomiting, anorexia, diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.
From the respiratory system: shortness of breath, cough, Bronchoconstriction interstitial lung disease.
From the skin and subcutaneous tissues: itching, rash (including erythematous and macular rash), increased sweating.
From the side of musculoskeletal system and connective tissue: bone pain, myalgia, arthralgia, generalised pain muscle cramps, osteonecrosis of the jaw.
From the side of cardiovascular system: hypertension, hypotension, atrial fibrillation, hypotension, causing syncope and circulatory collapse, bradycardia, arrhythmia (secondary to hypocalcaemia).
The part of the kidney and urogenital system : kidney failure, acute renal failure, hematuria, proteinuria.
From the immune system: hypersensitivity reactions, angioedema.
General disorders and reactions at the application site of the drug: fever, flu-like condition (including fatigue, chills, malaise and flushing), reactions at the injection site (including pain, irritation, swelling, induration), asthenia, peripheral edema, chest pain, body mass increase, anaphylactic reaction/shock, urticaria, arthritis and swollen joints as the symptoms gastropathy reaction.
Deviation of laboratory parameters: hypophosphatemia, increased creatinine and blood urea, hypocalcemia, hypomagnesemia, hypokalemia, hyperkalemia, hypernatremia.
Violation of kidney function
There is evidence that the use of zoledronic acid may experience deterioration in kidney function. Factors that may increase the risk of renal impairment include dehydration, previous renal impairment, multiple treatments with zoledronic acid or other bisphosphonates, and the simultaneous use of other nephrotoxic agents or reduction of the recommended infusion time. There is evidence of cases of renal impairment, progression of renal failure and the need for hemodialysis in the first or single application of zoledronic acid at a dose of 4 mg.
the osteonecrosis of the jaw
Cases of osteonecrosis (primarily of the jaw) has been reported predominantly in patients with cancer treated with Zometa. Many of these patients had manifestations of local infection, including osteomyelitis. Most cases were associated with dental procedures such as tooth extraction. Jaw osteonecrosis has many established risk factors, in particular cancer, concomitant therapy (e.g. chemotherapy, radiation therapy, corticosteroids) and concomitant diseases (e.g. anemia, coagulopathy, infections, existing diseases of the oral cavity) are diagnosed.
Although a causal relationship has not been confirmed, these patients are advised to avoid invasive dental procedures.
It was reported that in the study when using zoledronic acid in patients with postmenopausal osteoporosis, the total incidence of atrial fibrillation was 2.5% in the group of patients receiving Zometa at a dose of 5 mg, and 1.9% in the placebo group. The cause of the increased frequency of atrial fibrillation is unknown.
These adverse reactions include fever, myalgia, headache, limb pain, nausea, vomiting, diarrhea and arthralgia, which can begin in the first 3 days after the infusion of zoledronic acid.
Atypical fractures of the femur
There are data on both acute and edwardlucas diotisalvi fractures of the femur (the undesirable reaction to bisphosphonates).
Adverse reactions due to hypocalcemia
Hypocalcemia is an important identified risk in the application of zoledronic acid according to the recorded indications. There are data from clinical trials and post-marketing studies indicating the relationship between therapy with Zometa, reports of hypocalcemia and secondary development of cardiac arrhythmias. In addition, there is evidence of a link between hypocalcemia and reports of secondary neurological reactions, including epileptic seizures, numbness and tetany.
Store in the original packaging at a temperature not exceeding 25 ° C. Keep out of reach of children.
The concentrate of the preparation Zoledronic acid-Farmeks is subject to cultivation in sterile 0,9% sodium chloride solution or 5% glucose solution. Zometa-Farmex concentrate should not be mixed with infusion solutions containing calcium or other bivalent cations, such as ringer lactate solution, and should be administered as a single infusion using a separate infusion system.
A study with glass vials, as well as several types of infusion bags and infusion systems made of polyvinyl chloride, polyethylene and polypropylene (pre-filled with 0.9% sodium chloride solution or 5% glucose solution), showed no incompatibility with the above packaging materials.
5 ml of concentrate in a bottle. 1 or 4 bottle in a blister, for 1 blister in a cardboard pack. 5 bottles in a contour cell pack, 2 contour packs in a carton pack.
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Mistral Kepital Management Ltd.
VISTA ZOLEDRONIC ACID CONCENTRATE 0.8 MG/ML
Alendronova acid in the form of a concentrate for preparation of solution for intravenous infusion is a modern drug that affect mineralization and bone structure.
The drug belongs to the category of bisphosphonate substances. Medication among similar compounds is considered to be the most potent inhibitor of bone osteoclastic resorption.
At the heart of the drug – zoledronic acid, the active effect of which is aimed at preventing the development of tumors, myelomas, breast cancer.
Indications for appointment
The medication is prescribed for:
Prevention of symptoms, which is associated with lesions of varying severity of bone tissue.
Treatment of hypercalcemia in the background of the formation of a malignant tumor.
Improvement of the patient's condition after surgery, fracture, compression of the spinal column.
Method of use, dosage
The drug is administered intravenously only by experienced doctors who know how to work with bisphosphonates. Before using the solution, the contents of the bottle is diluted with glucose and sodium chloride. The resulting composition is introduced for 15 minutes.
The concentrated substance is not mixed with calcium-based infusion solutions.