Composition, form of production and packaging
Liofilizate for the preparation of a solution for infusions in the form of a powder or a porous mass of white or almost white color; The applied solvents are clear, colorless, odorless liquids.
1 f.
zoledronic acid monohydrate 4.26 mg,
which corresponds to the content of zoledronic acid anhydrous 4 mg
[PRING] D-mannitol - 220 mg, sodium citrate two-water - 27.34 mg (in terms of sodium citrate anhydrous - 24 mg).
Solvent in ampoule: water d / u - 5 ml.
Solvent in container: sodium chloride solution for infusion 0.9% - 100 ml.
Vials of dark glass with a capacity of 10 ml (1) complete with a solvent water d / and (amp 1 pc.) - packings, cellular outline (1) - packs cardboard.
Vials of dark glass with a capacity of 10 ml (1) complete with a solvent water d / and (amp 1 pcs.) - packings of cellular contour (1), containers in bags with sodium chloride solvent infusion solution 0.9% (1) - packs cardboard .
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Zoledronic acid is a highly effective bisphosphonate that acts selectively on bone tissue. 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 bone resorption, zoledronic acid has antitumor properties that ensure the effectiveness of the drug in bone metastases. In vivo: inhibits bone resorption by osteoclasts, changes the microenvironment of the bone marrow, reduces the growth of tumor cells; shows antiangiogenic activity.Suppression of bone resorption is clinically accompanied, in particular, by a marked decrease in pain sensations.
In vitro: inhibits the proliferation of osteoblasts, exhibits direct cytostatic and pro-apoptotic activity, a synergistic cytotoxic effect with antitumor drugs; anti-adhesive and anti-invasive activity. Zoledronic acid, due to a synergistic effect, in combination with hormonal therapy or chemotherapy inhibits proliferation and induces apoptosis, has a direct antitumor effect against human myeloma cells and breast cancer, and also reduces the penetration of human breast cancer cells through the extracellular matrix, indicating its antimetastatic properties. In addition, zoledronic acid inhibits the proliferation of endothelial cells in humans and animals and has an anti-angiogenic effect.
In patients with breast cancer, prostate cancer and other solid tumors with metastatic bone lesions, zoledronic acid 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 zoledronic acid at a dose of 4 mg is comparable to pamidronic acid at a dose of 90 mg.
In patients with tumor hypercalcemia, the effect of the drug is characterized by a decrease in serum calcium and calcium excretion by the kidneys. 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 efficacy of zoledronic acid in doses of 4 and 8 mg in the treatment of hypercalcemia is not observed.
Studies show no significant differences in the incidence and severity of adverse events observed in patients treated with zoledronic acid at doses of 4 mg, 8 mg, pamidronic acid at a dose of 90 mg or placebo in both bone metastases and hypercalcemia.
PHARMACOKINETICS
Data on pharmacokinetics in bone metastases were obtained after a single and repeated 5 and 15 minute infusions of 2, 4, 8 and 16 mg of zoledronic acid in 64 patients.
Suction and distribution
Pharmacokinetic parameters do not depend on the dose. After the start of infusion, serum concentration increases rapidly, reaching Cmax at the end of the infusion, followed by a rapid decrease in concentration by 10% after 4 hours and by less than 1% of C max after 24 hours with a further long period of low concentrations not exceeding 0.1 % of C max , until repeated infusion for 28 days.
Metabolism and excretion
Zoledronic acid is not metabolized and is excreted by the kidneys unchanged. Zoledronic acid is not
inhibits isoenzymes of the cytochrome P450 system in humans.
Zoledronic acid, injected 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 finite T 1/2 of 146 h. No cumulation of the drug with repeated administration every 28 days.
During the first 24 hours, 39 В± 16% of the administered dose is detected in the urine. The rest of the drug is mainly
binds to the bone tissue. Then slowly the reverse release of zoledronic acid from the bone tissue into the systemic blood flow 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. Time extension
infusion from 5 minutes to 15 leads to a decrease in the concentration of zoledronic acid by 30% at the end of the infusion, but not
affects the AUC.
Pharmacokinetics in special clinical cases
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 isoenzymes of the cytochrome P450 system
human and not subjected to biotransformation, which suggests that the state of liver function does not affect anything significantly on the pharmacokinetics of zoledronic acid. Less than 3% of the dose is excreted through the intestine.
Renal clearance of zoledronic acid positively correlates with QC and is 75 В± 33% of CS, averaging 84 В± 29% (range 22-143 ml / min) in 64 patients included in the study. Analysis of the population showed that in patients with severe renal failure (CC <20 ml / min) or moderate renal failure (CC 20-50 ml / min) the calculated clearance of zoledronic acid is 37% and 72%, respectively, of the zoledronate clearance in patients with QC > 84 ml / min. Limited pharmacokinetic data were obtained for patients with severe renal insufficiency (CC less than 30 ml / min).
Low affinity of zoledronic acid for blood components is shown, binding to plasma proteins is low (about 56%) and does not depend on the drug concentration.
INDICATIONS
- hypercalcemia (concentration of albumin corrected serum calcium of 12 mg / dl or 3 mmol / l), induced by malignant tumors;
- Metastatic bone lesions in malignant solid tumors and myeloma (to reduce the risk of pathological fractures, spinal cord compression, tumor-induced hypercalcemia and reduced need for radiotherapy).
DOSING MODE
In / in the drip for at least 15 minutes.
In bone metastases and osteolytic foci with multiple myeloma, the recommended dose is 4 mg every 3-4 weeks.
In addition, it is recommended to prescribe calcium in a dose of 500 mg / day and vitamin D at a dose of 400 IU / day.
With hypercalcemia (calcium concentration with a correction of albumin level of 12 mg / dl or 3 mmol / l) due to malignant tumors, the recommended dose is 4 mg, once. Infusion is performed under the condition of adequate hydration of the patient.
Patients with impaired renal function
Hypercalcemia due to malignant tumors: the decision to treat zoledronic acid in patients with severe renal dysfunction should only be taken after a thorough assessment of the risk / benefit ratio. At a serum creatinine concentration <400 Ојmol / l or <4.5 mg / dl, dosage adjustment is not required.
Bone metastases of common malignant tumors and myeloma: the dose of zoledronic acid depends on the baseline QC level, calculated by the Cockcroft-Gault formula.
In severe disorders of kidney function (KK <30 ml / min) , zoledronic acid is not recommended.
Recommended doses for mild or moderate renal dysfunction (CC values ​​of 30-60 ml / min) are given below.
Initial SC (ml / min) The recommended dose of zoledronic acid
> 60 4.0 mg
50-60 3.5 mg
40-49 3.3 mg
30-39 3.0 mg
Determination of the serum creatinine concentration should be determined before each dose of the drug is administered. In the detection of violations of kidney function, the next administration of zoledronic acid 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.
Therapy with zoledronic acid is resumed only after the creatinine level has reached the values ​​exceeding the baseline by no more than 10%, at the same dose that was used before the interruption of treatment.
Instructions for preparing a solution for infusions
The solution is prepared in aseptic conditions; 4 mg is dissolved in 5 ml of water for injection, gently shaken until completely dissolved. The resulting solution with the required dose is diluted in 100 ml of 0.9% sodium chloride solution or 5% dextrose solution. Do not use solutions containing calcium.
Prepared solution is preferably used immediately after preparation. The unused solution can be stored in the refrigerator at a temperature of + 2 В° to + 8 В° C for a maximum of 24 hours. The solution stored in the refrigerator should be warmed to room temperature before introduction.
SIDE EFFECT
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 nervous system: often - headache; sometimes - dizziness, paresthesia, taste disorders, hypoesthesia, hyperesthesia, tremor, anxiety, sleep disorders; rarely confusion.
From the side of the eye: often - conjunctivitis; sometimes - blurred vision; very rarely - uveitis, episcleritis.
From the digestive tract: 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 osteomuscular 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.
Violations of laboratory indicators: very often - hypophosphatemia; often - increased serum creatinine and urea concentrations, hypocalcemia; sometimes hypomagnesemia, hypokalemia; rarely - hyperkalemia, hypernatremia.
Local reactions: pain, irritation, puffiness, 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. In the treatment of patients with bisphosphonates, including zoledronic acid, cases of osteonecrosis of the jaw (usually after extraction of the tooth or other dental intervention) have been observed. In very rare cases, a decrease in blood pressure on the background of therapy with zoledronic acid led to fainting or circulatory collapse.
CONTRAINDICATIONS
- severe renal failure (CK <30 ml / min);
- Pregnancy;
- the period of lactation (breastfeeding);
- child and adolescence (safety and efficacy not established);
- Hypersensitivity to zoledronic acid, other bisphosphonates or any other components that make up the drug.
With caution: with renal dysfunction, severe hepatic insufficiency (no data on use), in patients with bronchial asthma sensitive to acetylsalicylic acid.
PREGNANCY AND LACTATION
Contraindicated use during pregnancy and during breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution should prescribe the drug in violation of kidney function.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Caution should be given to the drug with severe hepatic insufficiency (no data on use).
APPLICATION FOR CHILDREN
Contraindication: child and adolescence (safety and efficacy not established).
SPECIAL INSTRUCTIONS
Before infusion, you should ensure adequate hydration in the patient. If necessary, the introduction of saline before, parallel or after infusion of zoledronic acid is recommended. It is necessary to avoid hyperhydration of the patient because of the risk of complications from the cardiovascular system.
After the administration of the drug, constant monitoring of the concentration of calcium, magnesium, phosphorus and creatinine in the blood serum is necessary.
On the background of therapy with zoledronic acid should closely monitor the function of the kidneys. The risk factors for renal impairment include dehydration, previous kidney failure, repeated administration of zoledronic acid or other bisphosphonates, as well as the use of nephrotoxic drugs, and too rapid administration of the drug.
It should be borne in mind that in the appointment of other bisphosphonates to patients with bronchial asthma sensitive to acetylsalicylic acid, there have been cases of bronchospasm, but with the use of zoledronic acid, such cases have not yet been documented.
Against the backdrop of treatment with bisphosphonates, including zoledronic acid, cases of osteonecrosis of the jaw are described in cancer patients, so before the treatment with bisphosphonates it is necessary to provide a dental examination and if there are risk factors (anemia, coagulopathies, infections, poor hygiene or oral diseases, concomitant chemo- or radiotherapy, treatment with corticosteroids) to conduct appropriate preventive procedures. Against the background of treatment with zoledronic acid, patients with risk factors, whenever possible, should avoid dental surgical interventions.
Use in Pediatrics
Contraindicated use of the drug in childhood and adolescence, tk. safety and efficacy have not been established.
Impact on the ability to drive vehicles and manage mechanisms
The study of the effect of the drug on the ability to drive vehicles and work with complex mechanisms was not carried out. In the event of side effects from the central nervous system, it is recommended to avoid activities requiring increased attention and speed of mental and motor reactions.
OVERDOSE
Symptoms: acute overdose of zoledronic acid may impair renal function, including kidney failure, changes in electrolyte composition, including the concentration of calcium, phosphate and magnesium in the blood plasma.
Treatment: In case of accidental overdose, the patient should be under constant supervision. In the case of hypocalcemia, accompanied by clinical manifestations, an infusion of calcium gluconate is indicated.
DRUG INTERACTION
Solvents that contain calcium, such as Ringer's solution, can not be used as solvents.
With simultaneous use with antitumor drugs, diuretics, antibiotics, analgesics, clinically significant interaction was not observed.
Bisphosphonates and aminoglycosides have a unidirectional effect on the concentration of calcium in the blood serum, so when they are concurrently prescribed, the risk of hypocalcemia and hypomagnesemia increases. With the development of hypocalcemia, hypophosphatemia, or hypomagnesemia, there may be a need for a short-term additional administration of the relevant substances. In patients with untreated hypercalcemia, as a rule, there is a violation of kidney function, so careful monitoring of kidney function in this category of patients is necessary. When deciding on the treatment of patients with bone metastases with zoledronic acid, it should be taken into account that the therapeutic effect occurs 2-3 months after the start of treatment with zoledronic acid.
Caution is needed when using zoledronic acid with drugs potentially having a nephrotoxic effect.
In patients with multiple myeloma, may increase the risk of renal dysfunction at / in the introduction of bisphosphonates in combination with thalidomide.
Although the risk of complications is reduced above provided administration of zoledronic acid 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 zoledronic acid.
The drug should not be mixed with other drugs.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The preparation should be stored in a dry place, protected from light and the reach of children at a temperature not higher than 25 В° C. Shelf life of the lyophilisate - 3 years, solvent - 5 years.
The reconstituted solution can be stored at a temperature of from 5 В° to 25 В° C for 24 hours.
