Composition, form of production and packaging
Concentrate for the preparation of a solution for infusions 1 fl.
zoledronic acid 4 mg
5 ml - bottles (1) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
PHARMACHOLOGIC EFFECT
Zoledronic acid refers to bisphosphonates having a selective effect on bone tissue. Suppresses excessive resorption of bone tissue, affecting osteoclasts. The exact mechanism that provides the inhibition of osteoclast activity is still unexplained. Zoledronic acid does not have undesirable effects on the formation, mineralization and mechanical properties of bone.
In patients with hypercalcemia, induced by malignant tumors, a single infusion of zoledronic acid is accompanied by a decrease in the concentration of calcium and phosphorus in the blood serum and an increase in the excretion of calcium and phosphorus in the urine.
The main pathophysiological mechanism for the development of hypercalcemia in malignant neoplasms and bone metastases is the hyperactivity of osteoclasts, leading to an increase in bone resorption. Excessive release of calcium into the blood due to bone resorption leads to polyuria and gastrointestinal disturbances, accompanied by progressive dehydration and a decrease in the glomerular filtration rate, which in turn leads to an increase in the reverse absorption of calcium in the kidneys, further exacerbates systemic hypercalcemia and creates a "vicious vicious circle ". Suppression of excessive resorption of bone tissue and ensuring adequate fluid intake are necessary conditions in the treatment of hypercalcemia caused by malignant neoplasm.
According to the pathophysiological mechanism of hypercalcemia, patients with hypercalcemia caused by malignant neoplasm can be divided into two groups: patients with humoral hypercalcemia and patients with hypercalcemia due to tumor invasion into bone tissue. In the case of humoral hypercalcemia, the activation of osteoclasts and stimulation of bone resorption is effected by such factors as parathyroid hormone-bound protein produced by tumor cells and entering the systemic circulation. Humoral hypercalcemia, as a rule, develops in squamous cell malignancies of the lungs, head and neck or tumors of the genitourinary system, such as renal cell carcinoma or ovarian cancer. In these patients, bone metastases may be absent or minimal.
With the widespread invasion of tumor cells into bone tissue, they produce locally acting substances that activate osteoclastic bone resorption, which also leads to the development of hypercalcemia. To tumors, accompanied by locally-mediated hypercalcemia, usually include breast cancer and multiple myeloma.
The total serum calcium concentration of patients with hypercalcemia caused by malignant neoplasm may not reflect the severity of hypercalcemia due to the presence of concomitant hypoalbuminemia. Ideally, to diagnose and treat hypercalcemic conditions, it is necessary to determine the concentration of ionized calcium, however, in many clinical situations this study is not available or is not performed quickly enough. In this regard, instead of determining the ionized calcium, a common indicator of serum calcium concentration adjusted for the level of albumin (corrected serum calcium) is often used. To carry out these calculations, there are several nomograms.
PHARMACOKINETICS
Pharmacokinetic parameters do not depend on the dose. After the start of the infusion, the plasma 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.
The connection with plasma proteins is 56%.
Not exposed to metabolism.
It is excreted by the kidneys unchanged in 3 stages: 1 and 2 phases - rapid removal of zoledronic acid from the systemic blood stream with T 1/2 0.24 h and 1.87 h respectively and 3 phase - prolonged excretion with T 1/2 146 h. There was no cumulation of the drug with repeated administration every 28 days. During the first 24 hours in urine, 23-55% is found. The rest of the zoledronic acid binds to the bone tissue, after which it is slowly released back into the systemic circulation and excreted by the kidneys; with feces less than 3% is output. The total plasma clearance is 2.54-7.54 l / h, it does not depend on the dose of zoledronic acid, sex, age, race and body weight of the patient. An increase in the infusion time from 5 to 15 minutes results in a 30% decrease in the concentration of zoledronic acid at the end of the infusion, but does not affect the area under the "concentration-time" curve (AUC). Kidney clearance positively correlates with QC and is 42-108% of CC, averaging 55-113%.
In patients with severe (QC less than 20 ml / min) and moderate renal failure (QC 20 to 50 ml / min), the zoledronic acid clearance is 37% and 72%, respectively, of the zoledronic acid clearance values ​​in patients with CC of 84 ml / min.
INDICATIONS
- hypercalcemia (KSK concentration not less than 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 the form of intravenous (IV) infusion for at least 15 minutes.
Hypercalcemia (KSK concentration not less than 12 mg / dp or 3 mmol / l), induced by malignant tumors
The feasibility of zoledronic acid should be determined taking into account both the severity level and the manifestations of hypercalcemia associated with malignant tumors. For the treatment of mild asymptomatic forms of hypercalcemia, only enhanced hydration by the administration of saline solutions (with or without the use of loop diuretics) can be sufficient.
The maximum recommended dose: 4 mg in the form of a single intravenous infusion for at least 15 minutes. The introduction of a repeat dose is possible if the calcium concentration is not normalized or there is a deterioration after a distinct clinical effect. To realize the full clinical effect of the initial dose, the interval before reintroduction should be at least 7 days.
Throughout the course of treatment, adequate hydration (saline solutions) is necessary, but excessive hydration, especially in patients with heart failure, should be avoided. It is recommended to maintain a diuresis of about 2 liters / day throughout the treatment. Diuretics can only be used after correction of hypovolemia.
Metastatic bone damage in malignant solid tumors and myeloma
The recommended dose in combination with standard antitumor therapy: 4 mg in the form of a single IV infusion for at least 15 minutes every 3-4 weeks.
To prevent hypocalcemia and preserve homeostasis, patients should also take calcium preparations at a dose of 500 mg / day and multivitamins containing vitamin D at a rate of 400 IU / day in combination with standard antitumor therapy.
Patients with renal insufficiency
The introduction of zoledronic acid leads to an increased risk of developing nephrotoxic syndrome. Patients with hypercalcemia with an initial moderate impairment of renal function (creatinine concentration not more than 4.5 mg / dL) dose adjustment is not required. If signs of worsening kidney function appear, an appropriate examination should be performed to determine the relationship between the potential benefit of further treatment and the possible risk. In patients with a creatinine concentration of more than 4.5 mg / dL (400 Ојmol / L), zoledronic acid is used only if the expected benefit prevails over the potential risk of developing renal failure.
In patients with renal insufficiency in the treatment of metastatic bone lesions in malignant solid tumors and myeloma, the dose is adjusted according to the indices of renal dysfunction:
• Zoledronic acid is not recommended for patients with a creatinine concentration greater than 3 mg / dl:
• with SC more than 60 ml / min, the recommended dose of the drug is 4.0 mg (5.0 ml concentrate);
• with SC from 50 to 60 ml / min the recommended dose of the drug is 3.5 mg (4.4 ml of concentrate);
• with SC from 40 to 49 ml / min the recommended dose of the drug is 3.3 mg (4.1 ml of concentrate);
• with QC from 30 to 39 ml / min the recommended dose of the drug is 3.0 mg (3.8 ml of concentrate);
• with QC less than 30 ml / min, zoledronic acid is not used.
Patients who showed progressive renal dysfunction during treatment were resumed after a decrease in serum creatinine levels to within 10% of the baseline.
Patients with hepatic insufficiency
Experience in the use of zoledronic acid in the treatment of hypercalcemia. induced cancer in patients with hepatic insufficiency is limited, and the obtained data do not allow us to recommend a certain dosage regimen or tactics of safe use in such patients.
Application for asthma
Patients with aspirin-sensitive asthma have had cases of bronchial obstruction with other bisphosphonates. Despite the lack of data on such manifestations on the background of treatment with zoledronic acid, care must be taken when prescribing to patients with aspirin-sensitive asthma.
Preparation of a solution for infusion
Before the administration of the preparation, concentrate (the contents of one vial or a smaller volume) is diluted in 100 ml of an infusion solution that does not contain calcium (0.9% sodium chloride solution or 5% dextrose solution).
Do not mix Zoledronate-Teva with other medications, solutions containing calcium or other divalent cations, including Ringer's lactate solution. The prepared zoledronic acid solution must be administered using a separate system for intravenous infusion immediately after preparation.
SIDE EFFECT
Side effects of zoledronic acid are usually minor and transient, similar to side effects noted with the use of other bisphosphonates. In / in infusion is often accompanied by a fever. Often, patients develop an influenza-like syndrome, including fever, chills, fever, bone pain and / or arthralgia, myalgia. After IV introduction, reactions from the digestive tract, such as nausea and vomiting, are noted. Local reactions at the site of administration, such as redness or swelling, are less than in 1% of patients. In most cases, the symptoms disappear within 24-48 hours without specific treatment. It has been reported rare cases of skin rash, itching and chest pain after the administration of zoledronic acid.
Just as with the use of other bisphosphonates, cases of conjunctivitis and hypomaschemia have been reported.
The incidence of adverse reactions is classified according to WHO recommendations: very often - not less than 10%; often - not less than 1%, but less than 10%;infrequently - not less than 0,1%, but less than 1%; rarely - not less than 0.01%, but less than 0.1%; very rarely - less than 0.01% (including single cases or at an unset frequency).
On the part of the intestine: often - nausea, vomiting; infrequently - abdominal pain, constipation, diarrhea; frequency is not established - stomatitis, dryness of the oral mucosa, dyspepsia, inflammation of the gastrointestinal mucosa.
On the part of the blood and lymphatic system: often - anemia; infrequently, thrombocytopenia; rarely - pancytopenia; frequency is not established - granulocytopenia, neutropenia.
From the side of laboratory indicators: very often - hypophosphatemia; often, hypocalcemia; infrequently - hypokalemia, hypomagnesemia.
From the side of metabolism: dehydration, anorexia, increased sweating.
From the musculoskeletal system: arthralgia, muscle cramps, asthenia, bone pain, muscle pain, back pain, pain in the limbs.
From the nervous system: often - headache, confusion; infrequently, golovruzhenie, hypesthesia, hyperesthesia, paresthesia; frequency not established - anxiety, nervousness, anxiety, irritability, sleep disturbance, depression, hallucinations, drowsiness, dizziness, taste perversion, insomnia, tremor, anxiety.
From the cardiovascular system: infrequently - arterial hypotension; rarely a-bradycardia.
On the part of the respiratory system: infrequently - dyspnea, cough; frequency is not established - a pleural effusion, a pain in a thorax.
From the skin: the frequency is not established - alopecia.
Allergic reactions: infrequent - itchy skin; frequency is not established - dermatitis, angioedema.
From the genitourinary system: often - a violation of kidney function; infrequently-hematuria, proteinuria.
On the part of the musculoskeletal system: one hundred - joint pain, pain in the bones of myalgia; frequency is not established - pain in the back area, pain in the chest.
From the side of the eye: often - conjunctivitis; infrequently - blurred vision; very rarely - episcleritis, uveitis.
Benign, malignant and unspecified neoplasms (including cysts and polyps): frequency not established - complication of the course and progression of malignant formation.
Infectious diseases: frequency not established - candidiasis, infectious diseases of the upper respiratory tract, infectious diseases of the urinary tract.
Other: often - influenza-like syndrome; infrequently - asthenia; frequency is not established - peripheral edemas, hyperthermia, fast fatigue.
CONTRAINDICATIONS
- severe renal failure (CC less than 30 mg / min);
- renal failure (creatinine concentration greater than 3 mg / dl or 265 Ојmol / l) in patients with metastatic bone lesions in malignant solid tumors and myeloma;
- renal failure (creatinine concentration greater than 4.5 mg / dL or 400 Ојmol / L);
- liver failure in patients with hypercalcemia, induced by malignant tumors;
- Aspirin-sensitive asthma;
- heart disease accompanied by heart failure;
- hypocalcemia;
- Children's age under 18 years (no data on efficiency and safety);
- Pregnancy;
- lactation period;
- Hypersensitivity to zoledronic acid, other bisphosphonates and other components of the drug.
With caution: when using zoledronic acid in patients with bronchial asthma, sensitive to acetylsalicylic acid (with the use of other bisphosphonates, there have been cases of bronchospasm, see the section "Method of administration and dose").
PREGNANCY AND LACTATION
Contraindicated in pregnancy and lactation.
APPLICATION FOR FUNCTIONS OF THE LIVER
The introduction of zoledronic acid leads to an increased risk of developing nephrotoxic syndrome. Patients with hypercalcemia with an initial moderate impairment of renal function (creatinine concentration not more than 4.5 mg / dL) dose adjustment is not required. If signs of worsening kidney function appear, an appropriate examination should be performed to determine the relationship between the potential benefit of further treatment and the possible risk. In patients with a creatinine concentration of more than 4.5 mg / dL (400 Ојmol / L), zoledronic acid is used only if the expected benefit prevails over the potential risk of developing renal failure.
In patients with renal insufficiency in the treatment of metastatic bone lesions in malignant solid tumors and myeloma, the dose is adjusted according to the indices of renal dysfunction:
• Zoledronic acid is not recommended for patients with a creatinine concentration greater than 3 mg / dl:
• with SC more than 60 ml / min, the recommended dose of the drug is 4.0 mg (5.0 ml concentrate);
• with SC from 50 to 60 ml / min the recommended dose of the drug is 3.5 mg (4.4 ml of concentrate);
• with SC from 40 to 49 ml / min the recommended dose of the drug is 3.3 mg (4.1 ml of concentrate);
• with QC from 30 to 39 ml / min the recommended dose of the drug is 3.0 mg (3.8 ml of concentrate);
• with QC less than 30 ml / min, zoledronic acid is not used.
Patients who showed progressive renal dysfunction during treatment were resumed after a decrease in serum creatinine levels to within 10% of the baseline.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
The experience of using zoledronic acid in the treatment of hypercalcemia induced by malignant tumors in patients with hepatic insufficiency is limited, and the data obtained do not allow us to recommend a certain dosing regimen or tactics of safe use in such patients.
APPLICATION FOR CHILDREN
Contraindicated in children under 18 years.
SPECIAL INSTRUCTIONS
Before the beginning of treatment and throughout the course of treatment, it is necessary to correct the symptoms of dehydration and hypovolemia. It is recommended to maintain a diuresis of about 2 liters / day throughout the course of treatment.
After the start of therapy, careful monitoring of the concentration of calcium, phosphorus and magnesium in blood serum is necessary. Zoledronic acid is not used in patients with initial hypocalcemia. Electrolyte imbalance (hypocalcemia, hypomagnesemia or hypophosphatemia) requires short-term therapy replenishes.
Before each dose necessary to determine the creatinine concentration for determining kidney function.
Patients receiving zoledronic acid for the treatment of hypercalcemia of malignancy with confirmed progressive renal function must be suitably rated to determine the prevalence of the expected benefits of continuous treatment over possible risks. Due to the possibility of clinically significant impairment of renal function until renal failure single dose should not exceed 4 mg and infusion duration should not be less than 15 minutes.
Avoid excessive hydration in patients with heart failure. There are reported cases of osteonecrosis of the jaw in patients with cancer, in the treatment regimen which included bisphosphonates. Many of these patients also received chemotherapy and corticosteroids. Most of the reports concerned patients who underwent dental procedures such as tooth extractions, while there were signs of local infection, including osteomyelitis.
Patients with a history of risk factors such as cancer tumors, chemotherapy, corticosteroids, oral hygiene problems, it is recommended prior to treatment with bisphosphonates sanitation inspection and teeth. During bisphosphonate treatment, these patients, if possible, should avoid traumatic dental procedures, as bisphosphonates allegedly create the conditions for the occurrence of osteonecrosis of the jaw. There are no posts to reduce the risk of osteonecrosis of the jaw in dose reduction or cessation of bisphosphonate therapy with bisphosphonates in patients who need to conduct dental procedures. Clinical treatment regimen of the patient in a given situation is determined by the attending physician and is based on an individual assessment of benefit / risk ratio.
Impact on the ability to drive vehicles and manage mechanisms
The study of the effect of zoledronic acid on the ability to drive vehicles and operating machinery has not been. However, caution should be exercised in the development of side effects in the nervous system (dizziness, somnolence) able to cause a decrease in concentration and psychomotor reactions.
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 the hypocalcemia, hypomagnesemia or hypophosphatemia with clinically significant manifestations shown holding infusion calcium gluconate, sodium or potassium phosphate, magnesium sulfate, respectively.
DRUG INTERACTION
While the use of zoledronic acid other commonly used drugs (antineoplastic agents, 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 cytochrome P450 isozymes. Special not conducted clinical studies of drug interactions.
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. With careful use of the drug with loop diuretics due to increased risk of hypercalcaemia. Caution is also necessary while the use of zoledronic acid 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 when i / v infusion of bisphosphonates, including zoledronic acid, in combination with thalidomide. Pharmaceutical interaction
Diluted solution of zoledronic acid can not be mixed with infusion solutions containing calcium ions (e.g., Ringer-lactate).
When using glass bottles, infusion bags and systems of various types, made of polyvinyl chloride, polyethylene and polypropylene (prefilled 0.9% sodium chloride or 5% dextrose solution, sodium), any signs of incompatibility has been detected with zoledronic acid.
TERMS OF RELEASE FROM PHARMACY
On prescription.
TERMS AND CONDITIONS OF STORAGE
At a temperature of no higher than 30 В° C. Keep out of the reach of children. Shelf life - 2 years.
