Composition, form of production and packaging
Concentrate for the preparation of a solution for infusions in the form of a transparent colorless liquid.
5 ml (1 fl.)
zoledronic acid monohydrate 4.264 mg,
which corresponds to the content of zoledronic acid anhydrous 4 mg
Excipients: mannitol, sodium citrate, water d / a, nitrogen.
5 ml - plastic colorless bottles (1) - cardboard packs.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2010.
PHARMACHOLOGIC EFFECT
Inhibitor of bone resorption. Bisphosphonate.
Zoledronic acid is a highly effective bisphosphonate, which has a selective effect on the bone. The drug suppresses the resorption of bone tissue, affecting the osteoclasts.
The selective effect of bisphosphonates on bone tissue is based on a high affinity for mineralized bone tissue. The exact molecular mechanism providing inhibition of osteoclast activity is still unclear. Zoledronic acid does not have undesirable effects on the formation, mineralization and mechanical properties of bone.
In addition to the inhibitory effect on the resorption of bone tissue, zolendronic acid has antitumor properties that ensure the effectiveness of the drug in bone metastases:
In vivo: inhibition of osteoclastic bone resorption, altering the microenvironment of the bone marrow, leading to a decrease in the growth of tumor cells;antiangiogenic activity. Suppression of bone resorption is clinically accompanied by a marked decrease in pain.
In vitro: inhibition of osteoblast proliferation, direct cytotoxic and pro-apoptotic activity, synergistic cytotoxic effect with antitumor drugs; anti-adhesive / invasive activity.
Zoledronic acid, suppressing proliferation and inducing apoptosis, has a direct antitumor effect against human myeloma cells and breast cancer, and also reduces the penetration of breast cancer cells through the extracellular matrix, which indicates that it has antimetastatic properties. In addition, zoledronic acid inhibits the proliferation of human endothelial cells and has an anti-angiogenic effect in animals.
In patients with breast cancer, prostate cancer and other solid tumors with metastatic bone damage, Zometa prevents the development of pathological fractures, compression of the spinal cord, reduces the need for radiotherapy and surgical interventions, and reduces tumor hypercalcemia. The drug is able to restrain the progression of the pain syndrome. The therapeutic effect is less pronounced in patients with osteoblastic foci than with osteolytic foci. In patients with multiple myeloma and breast cancer with at least one bone focus, the effectiveness of Zometa at a dose of 4 mg is comparable to pamidronate in a dose of 90 mg.
In patients with tumor hypercalcemia, the action of Zometa is characterized by a decrease in the level of calcium in the serum and the excretion of calcium in the urine. The average time to normalize the calcium level is about 4 days. By the 10th day, the concentration of calcium is normalized in 87-88% of patients. The average time to relapse (adjusted for albumin serum calcium level is not less than 2.9 mmol / l) is 30-40 days. Significant differences between the effectiveness of Zometa at doses of 4 and 8 mg in the treatment of hypercalcemia are not observed.
The studies do not reveal significant differences in the incidence and severity of adverse events observed in patients treated with Zomet at doses of 4 mg, 8 mg, pamidronate at a dose of 90 mg, or placebo in both bone metastases and hypercalcemia.
PHARMACOKINETICS
Data on the pharmacokinetics for bone metastases were obtained after single and repeated 5- and 15-minute infusions of 2, 4, 8 and 16 mg of zoledronic acid to 64 patients. Pharmacokinetic parameters do not depend on the dose of the drug.
After the start of the Zometa infusion, the serum concentrations increase rapidly, reaching a peak at the end of the infusion, followed by a rapid decrease in concentration by 10% after 4 hours and by less than 1% after 24 hours with a successively prolonged period of low concentrations not exceeding 0.1% of the maximum repeated infusion for 28 days.
Zolendronic acid, administered IV, is excreted by the kidneys in 3 stages: a rapid two-phase elimination of the drug from the system circulation with T 1/2 0.24 h and 1.87 h and a long phase with a final T 1/2 of 146 h. No cumulation of the drug was observed repeated administration every 28 days.
Zoledronic acid is not subject to systemic metabolism and is excreted by the kidneys unchanged. During the first 24 hours, 39 В± 16% of the administered dose is detected in the urine. The rest of the drug is mainly associated with bone tissue. Then, slowly reverse the release of zolendronic acid from the bone tissue into the systemic circulation and its excretion by the kidneys. The total plasma clearance of the drug is 5.04 В± 2.5 l / h and does not depend on the dose of the drug, sex, age, race and body weight of the patient. Increasing the infusion time from 5 to 15 min leads to a decrease in the concentration of zoledronic acid by 30% at the end of the infusion, but does not affect the AUC.
Pharmacokinetic studies in patients with hypercalcemia or liver failure were not performed. According to the data obtained in vitro, zoledronic acid does not inhibit the human P 450 enzyme and does not undergo biotransformation, which suggests that the state of liver function does not affect the pharmacokinetics of zolendronic acid in any significant way. With feces less than 3% of the dose is withdrawn.
Renal clearance of zolendronic acid positively correlates with creatinine clearance and is 75 В± 33% of CC, reaching an average of 84 В± 29% (range 22-143 ml / min) in 64 patients included in the study. The analysis of the population showed that the calculated zoledronic acid clearance was 37% and 72%, respectively, in patients with SC of 20 ml / min (renal failure of severe degree) or 50 ml / min (renal failure of moderate severity), respectively, from the zoledronate clearance value in patients with CC 84 ml / min. Limited pharmacokinetic data were obtained for patients with severe renal insufficiency (CC less than 30 ml / min).
The low affinity of zolendronic acid for blood components is shown. Binding to plasma proteins is low (about 50%) and does not depend on the concentration of Zometa.
INDICATIONS
- metastasis in the bone of common malignant tumors (prostate cancer, breast cancer) and myeloma, incl. to reduce the risk of pathological fractures, spinal cord compression, tumor-induced hypercalcemia, and reduce the need for radiotherapy or bone surgery;
- hypercalcemia caused by a malignant tumor.
DOSING MODE
With metastases in the bone of common malignant tumors and myeloma, adults and elderly patients receive a recommended dose of 4 mg. Before the introduction of the drug, dilute the concentrate (the contents of 1 bottle) in 100 ml of a solution for calcium-free infusions (0.9% sodium chloride solution or 5% dextrose solution). The zomet is injected intravenously into the drip; duration of infusion - at least 15 minutes. Multiplicity of appointment - every 3-4 weeks.
Patients should also be prescribed calcium inwards at a dose of 500 mg / day and vitamin D inside at a dose of 400 IU / day.
For hypercalcemia caused by a malignant tumor (calcium concentration with a correction for albumin level of 12 mg / dL or 3 mmol / L), for adults and elderly patients, the recommended dose is 4 mg. Before the introduction of the drug, dilute the concentrate (the contents of 1 bottle) in 100 ml of a solution for calcium-free infusions (0.9% sodium chloride solution or 5% dextrose solution). The zomet is injected intravenously into the drip; duration of infusion - at least 15 minutes. To ensure adequate hydration of the patient, it is recommended to inject the physiological solution before, in parallel or after the infusion of Zometa.
The decision to treat Zometa with hypercalcemia caused by a malignant tumor in patients with severe renal dysfunction should be taken only after a thorough assessment of the risk of the drug and the expected benefit of therapy. Patients who have a creatinine serum concentration of <400 Ојmol / L or <4.5 mg / dl do not need a dosage adjustment.
With metastases in the bone of common malignant tumors and myeloma, the dose of Zometa depends on the baseline QC level, calculated by the Cockcroft formula. It is not recommended to use Zometa in patients with severe renal dysfunction (CC values ​​<30 ml / min).
Recommended doses in patients with mild to moderate renal impairment (CC values ​​of 30-60 ml / min) are given below.
Initial KK value (ml / min) Recommended dose of Zometa
> 60 4 mg (5 ml of concentrate)
50 - 60 3.5 mg (4.4 ml of concentrate)
40 - 49 3.3 mg (4.1 ml of concentrate)
30 - 39 3.0 mg (3.8 ml of concentrate)
After starting the therapy with Zometa, a serum creatinine concentration should be determined before each dose of the drug is administered. If there are violations of kidney function, the next introduction of Zometa should be postponed. Impaired renal function is determined by the following parameters:
- for patients with normal baseline creatinine values ​​(<1.4 mg / dl) - an increase in serum creatinine concentration by 0.5 mg / dl;
- for patients with abnormalities of the baseline creatinine level (> 1.4 mg / dl), an increase in the serum creatinine concentration by 1 mg / dl.
Zometa therapy is resumed only after the level of creatinine reaches values ​​within the initial value of ± 10% at the same dose that was used before the interruption of treatment.
Rules for the preparation of a solution for infusions
From a concentrate of 4 mg / 5 ml (contents of 1 bottle), a solution for infusion is prepared. The solution should be prepared under aseptic conditions. Before the introduction of the drug dilute the concentrate (the contents of 1 bottle or a smaller volume, if required) 100 ml of a solution for calcium-free infusions (0.9% sodium chloride solution or 5% dextrose solution). Prepared Zometa solution is preferably used immediately after preparation. Unused immediately solution can be stored in the refrigerator at a temperature of 2 В° -8 В° C for no more than 24 hours. Before administration, the solution should be kept indoors until reaching room temperature.
The total time between the dilution of the concentrate, storage of the prepared solution in the refrigerator at a temperature of 2 В° -8 В° C and the end of the drug administration should not exceed 24 hours.
The solution of Zometa should not be confused with any other medicinal products. Zometh should not be mixed with any solutions containing calcium or any other divalent cations, such as Ringer's lactate solution. The prepared zoledronic acid solution must be administered using a separate system for intravenous infusion.
SIDE EFFECT
Information on the incidence of adverse reactions in the application of Zometa at a dose of 4 mg is based mainly on data obtained during long-term therapy.Undesirable reactions associated with the use of Zometa, usually mild and transient; are similar to those reported in the use of other bisphosphonates.
With iv introduction, the development of influenza-like syndrome was usually observed in almost 9% of patients, with bone pain, fever, general malaise, and chills.
Sometimes (approximately 3% of patients) reported cases of arthralgia and myalgia.
Often (approximately 20% of patients), the decrease in renal calcium excretion was accompanied by a sharp decrease in phosphorus concentration, which was asymptomatic and did not require treatment. In approximately 3% of patients, serum calcium concentration decreased to hypocalcemia (without clinical manifestations).
There are reports of reactions from the digestive tract, such as nausea (5.8%) and vomiting (2.6%), after intravenous infusion of Zometa.
Local reactions at the site of infusion, such as redness or swelling and / or pain, were observed in less than 1% of patients.
Anorexia was observed in 1.5% of patients who received Zometa at a dose of 4 mg.
There were several cases of rash or itching (less than 1%).
As with the use of other bisphosphonates, cases of conjunctivitis are reported - approximately 1%.
There are reports of impaired renal function (2.3%); However, other risk factors in patients in this group may also be important.
Based on a summary analysis of controlled trials, severe anemia (hemoglobin <8.0 g / dL) was reported in 5.2% of patients receiving Zometa at a dose of 4 mg compared with 4.2% receiving placebo.
Undesirable reactions are listed below for organs and systems, indicating the frequency of their occurrence. Frequency criteria: very often (? 1/10), often (? 1/100, <1/10), sometimes (? 1/1000, <1/100), rarely (? 1/10 000, <1/1000 ), very rarely (<1/10 000), including individual messages.
On the part of the organs of hematopoiesis: often - anemia, sometimes - thrombocytopenia, leukopenia; rarely - pancytopenia.
From the peripheral nervous system and the central nervous system: often - headache; sometimes - dizziness, paresthesia, taste disorders, hyposthenia, hyperesthesia, tremor, anxiety, sleep disorders; rarely confusion.
From the side of the organ of vision: often - conjunctivitis; sometimes - blurred vision; very rarely - uveitis, episcleritis.
From the side of the digestive system: often - nausea, vomiting, anorexia; sometimes - diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.
From the respiratory system: sometimes - shortness of breath, cough.
Dermatological reactions: sometimes - itching, rash (including erythematous and macular), increased sweating.
From the musculoskeletal system: often - pain in the bones, myalgia, arthralgia, generalized pain; sometimes - muscle cramps.
From the cardiovascular system: sometimes - a marked increase or decrease in blood pressure; rarely - aetiology.
On the part of the urinary system: often - impaired renal function; sometimes - acute renal failure, hematuria, proteinuria.
From the immune system: sometimes - reactions of increased sensitivity; rarely - angioedema.
From the side of laboratory indicators: very often - hypophosphatemia; often - increased serum creatinine and urea concentrations, hypocalcemia; sometimes hypomagnesemia, hypokalemia; rarely - hyperkalemia, hypernatremia.
Local reactions: pain, irritation, edema, the formation of an infiltrate at the injection site.
Other: often - fever, flu-like syndrome (including general malaise, chills, sickness, fever), sometimes - asthenia, peripheral edema; pain in the chest, weight gain.
It should be borne in mind that when using other bisphosphonates in patients with bronchial asthma sensitive to acetylsalicylic acid, there were cases of bronchospasm, but this phenomenon was not observed when using Zometa.
In one clinical trial with zoledronic acid 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 persons out of 3862) compared with 1.9% (75 of 3852) in the placebo group. The incidence of atrial fibrillation accompanied by severe hemodynamic disturbances was 1.3% (51 persons out of 3862) and 0.6% (22 of 3852) for zoledronic acid and placebo, respectively. The reason for the increased incidence of atrial fibrillation with zolendronic acid therapy in patients with postmenopausal osteoporosis has not been established.
In clinical studies using zolendronic acid (at a dose of 4 mg every 3-4 weeks) in patients with oncological diseases, an increase in the frequency of atrial fibrillation was not observed.
On the background of Zometa's therapy, the following undesirable phenomena were noted in clinical practice, regardless of the presence of a causal relationship with the use of the drug: in the treatment of patients with bisphosphonates (including Zometa), rare cases of osteonecrosis of the jaw (usually after extraction of the tooth or other dental interventions).
In very rare cases, with the use of Zometa, a decrease in blood pressure was observed, leading to fainting or circulatory collapse, mainly in patients with risk factors, development of drowsiness, bronchoconstriction, atrial fibrillation, anaphylactic reactions / shock and urticaria.
CONTRAINDICATIONS
- Pregnancy;
- lactation (breastfeeding);
- Hypersensitivity to zoledronic acid, other bisphosphonates and other components of the drug.
PREGNANCY AND LACTATION
The drug Zometa is contraindicated for use in pregnancy and lactation (breastfeeding).
APPLICATION FOR FUNCTIONS OF THE LIVER
When deciding on the use of Zometa in patients with hypercalcemia due to a malignant tumor, against a background of impaired renal function, it is necessary to assess the patient's condition and to conclude whether the potential benefit from the drug's administration is greater than the possible risk.
Before each introduction of Zometa should determine the concentration of creatinine in the serum. At the beginning of treatment with a drug of patients with bone metastases that have poor renal and moderate renal function, Zometa should be used in reduced doses. In patients whose renal dysfunction occurred during Zometa's therapy, it is possible to continue therapy with the drug only after the creatinine concentration returns to values ​​that are within 10% of the baseline value.
Given the possibility of impaired renal function when using bisphosphonates, incl. Zometas, as well as in the absence of comprehensive data on the clinical safety of the drug in patients with severe renal dysfunction (serum creatinine concentration is 400 μmol / L or ≤ 4.5 mg / dl in patients with hypercalcemia due to malignant tumor and ≥265 μmol / L or ?3.0 мг/дл у больных со злокачественными опухолями с метастазами в кости) и наличия весьма ограниченных фармакокинетических данных у больных с исходными тяжелыми нарушениями функции почек (КК?30 мл/мин), применение Зометы у этого контингента больных не реком nduetsya.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Since there are limited clinical data on the use of the drug in patients with severe hepatic insufficiency, it is not possible to give specific guidance for this category of patients.
APPLICATION FOR CHILDREN
Efficacy and safety of Zometa in pediatric patients has not yet been established.
SPECIAL INSTRUCTIONS
When deciding on the use of Zometa in patients with hypercalcemia due to malignancy, against the background of impaired renal function, it is necessary to evaluate the patient's condition and concluded that prevails if the potential benefit from the administration of the possible risk.
Before each administration of Zometa should determine the concentration of creatinine in serum. At the start of treatment of patients with bone metastases, kidney dysfunction having mild to moderate severity, recommended Zometa in low doses. In patients who have impaired renal function appeared during Zometa therapy, drug therapy can be continued only after the return to the creatinine concentration values which lie within the original value В± 10%.
Given the possibility of renal function in the application of bisphosphonates, including Zometa and also because of the lack of comprehensive data on the clinical safety of the drug in patients with severe renal impairment (serum creatinine? 400 pmol / L or? 4.5 mg / dl in patients with hypercalcemia due to malignancy and? 265 mmol / l, or ? 3.0 mg / dl in patients with malignant tumors with metastasis in the bone) and the presence of very limited pharmacokinetic data from patients with baseline severe renal impairment (creatinine clearance? 30 ml / min), the use of Zometa in this cohort of patients not recom enduetsya.
Before infusion should ensure adequate hydration of the patient. If necessary, it is recommended before the administration of saline, in parallel or after infusion of Zometa. It is necessary to avoid hyperhydration of the patient because of the risk of complications from the cardiovascular system.
After introduction of Zometa requires constant monitoring of concentration of calcium, phosphorus, magnesium and creatinine in the blood serum. With the development of the hypocalcemia, hypomagnesemia or hypophosphatemia may be necessary to short the additional administration of the substances. Patients with untreated hypercalcemia, as a rule, there is impaired renal function, therefore, require careful monitoring of renal function in these patients.
When deciding on the treatment of Zometa in patients with bone metastases to reduce the risk of pathological fractures, spinal cord compression, hypercalcemia due to tumor and reduce the need for radiotherapy or surgical interventions on the bone, it will be appreciated that the therapeutic effect occurs 2-3 months after initiation of treatment Zometa.
There are some reports of a violation of kidney function against the background of bisphosphonates. Risk factors for the occurrence of such complications include dehydration preceding renal failure, multiple introduction Zometa or other bisphosphonates, as well as the use of nephrotoxic drugs, and too rapid administration of the drug. Although the risk of complications is reduced above provided administration Zometa 4 mg for at least 15 min, the ability of renal function is maintained.
Cases of deterioration of renal function, progression of renal failure and the need arises to hemodialysis in the first or single application of Zometa.
Elevated serum creatinine concentration is also observed in some patients during long-term use of Zometa at recommended doses, although less frequently.
Since there are limited clinical data on the use of the drug in patients with severe hepatic insufficiency, it is not possible to give specific guidance for this category of patients.
There are cases of osteonecrosis of the jaw in cancer patients against cancer treatment comprising bisphosphonates (including Zometa). Many patients had signs of local infection-inflammation, including osteomyelitis.
In clinical practice, the most often mentioned jaw osteonecrosis development in patients with breast cancer and rasprostranennnym multiple myeloma, as well as the presence of dental diseases (including after tooth extraction, in periodontal diseases, unsatisfactory fixation of dental prostheses). Known risk factors for osteonecrosis of the jaw are: cancer, cancer concomitant treatment (including chemotherapy, radiation therapy, corticosteroids), concomitant diseases (including anemia, coagulopathy, infection preceding disease of the oral cavity).
Before bisphosphonate therapy for patients with cancer should be performed dental examination and make the appropriate preventive treatments, as well as to recommend strict adherence to the rules of oral hygiene.
During treatment, these patients should be avoided whenever possible dental operations. There is no evidence that the interruption of treatment with bisphosphonates before dental surgery reduces the risk of osteonecrosis of the jaw. The treatment plan specific patient should be based on an individual assessment of risk / benefit ratio.
In clinical practice, it reported the infrequent cases of severe and sometimes disabling pain in the bones, joints and muscles during treatment with bisphosphonates, which include zolendronovaya acid.
These symptoms develop over a period of from 1 day to several months after starting treatment. After discontinuation of treatment in most patients the symptoms were. In some patients, symptoms recurred when resuming therapy or appoint another bisphosphonate.
Zometa contains the same active ingredient as the Aklasta - zolendronovuyu acid. Patients treated with Zometa should not receive both Aklastu.
Use in Pediatrics
Efficacy and safety of Zometa in pediatric patients has not yet been established.
Impact on the ability to drive vehicles and manage mechanisms
The study of the effect of Zometa on the ability to drive vehicles and operating machinery has not been.
OVERDOSE
Symptoms for acute drug overdose (limited data) had renal dysfunction (including renal failure), the change in electrolyte composition (including the concentrations of calcium, phosphate and magnesium in the blood plasma). Patients who received the drug in doses exceeding recommended, should be under constant supervision.
Treatment: at occurrence of hypocalcaemia with clinically significant manifestations shown holding calcium gluconate infusion.
DRUG INTERACTION
With simultaneous use of Zometa with other commonly used drugs (anticancer agents, diuretics, antibiotics, analgesics) any clinically significant interactions were observed.
According to data obtained in in vitro studies, zoledronic acid has no significant binding to plasma proteins and did not inhibit the enzyme cytochrome system P450. Nevertheless special clinical studies of drug interactions have not been conducted.
Caution is recommended with simultaneous application of bisphosphonates and aminoglycosides, since the simultaneous action of these drugs manifests an increase in the duration of reducing calcium concentration in blood plasma.
Caution is needed while applying Zometa with drugs having potentially nephrotoxic effect.
One should also bear in mind the probability of hypomagnesemia.
In patients with multiple myeloma, may increase the risk of renal dysfunction at / in the introduction of bisphosphonates such as Zometa, in combination with thalidomide.
Pharmaceutical interaction
Diluted solution Zometa not be mixed with infusion solutions containing calcium ions (such as Ringer's solution).
When used for administration Zometa glass vials, infusion systems and different types of bags made of polyvinyl chloride, polyethylene and polypropylene (prefilled 0.9% sodium chloride or 5% dextrose solution, sodium), any signs of incompatibility with Zometa detected.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 30 В° C. Shelf life - 3 years. The drug should not be used after the expiration date.
