Pathological fractures, compression of the spinal column; complications after surgery and radiation therapy; hypercalcemia in patients with a malignant tumor.
active substance: zoledronic acid
5 ml of concentrate contains 4 mg of anhydrous zoledronic acid, which corresponds to 4.26 mg of zoledronic acid monohydrate;
excipients: mannitol (E 421), sodium (E 331), water for injection.
Concentrate for preparation of solution for infusion.
BASIC PHYSICAL AND CHEMICAL PROPERTIES:
clear, colorless liquid.
Agents affecting the structure and mineralization of bones. Bisphosphonates. ATX code М05В А08.
Zolendronic acid belongs to the class of bisphosphonates that act in a specific way on bone tissue. It is an inhibitor of osteoclasts of bone resorption.
The selective effect of bisphosphonates on bone is based on their high affinity with mineralized bone tissue; however, the molecular mechanism leading to the inhibition of osteoclast activity has not yet been clarified. Animal studies have shown that Zometa inhibits bone resorption without adversely affecting bone formation, mineralization and mechanical properties.
In addition to inhibiting bone resorption of osteoclasts, Zometa has a direct antitumor effect that may increase overall efficacy in the treatment of metastatic bone disease. The following properties have been demonstrated in preclinical studies:
in vivo – inhibition of osteoclasts of bone resorption, which acts on the structure of the microcrystalline matrix of the bone, reduces tumor growth, antiangiogenic effect (effect on blood vessels, which leads to a decrease in the blood supply to the tumor), anti-pain effect;
in vitro – inhibition of osteoblastic proliferation, direct cytostatic effect, proapoptostatic effect on tumor cells, synergistic cytostatic effect with other anticancer drugs, antiadhesive and anti-invasive action.
Pharmacokinetic data for bone metastases obtained after single and repeated 5- and 15-minute infusions of 2, 4, 8 and 16 mg of zoledronic acid to 64 patients. Pharmacokinetic characteristics do not depend on the dose of the drug.
After the start of the infusion of zoledronic acid, plasma concentrations of the drug rapidly increase, reaching a peak at the end of the infusion, followed by a rapid decrease in concentration to <10% of the peak value after 4:00 and to <1% of the peak value after 24 hours with a consistently prolonged period of low concentrations , do not exceed 0.1% of the peak, before the introduction of the second infusion on the 28th day.
Zometa, injected intravenously, is excreted by the kidneys in 3 stages: rapid two-phase elimination of the drug from the systemic circulation with a half-life of t ½α = 0.24 hours and t ½β = 1.87 hours, then a long elimination phase with a terminal half-life of t ½γ = 146 hours … There was no accumulation of zoledronic acid in plasma with repeated administrations every 28 days. Zoledronic acid is not metabolized and is excreted by the kidneys unchanged. During the first 24 hours, 39 ± 16% of the administered dose is found in urine. The rest of the drug binds to bone tissue. Then, zoledronic acid is slowly released from the bone tissue into the systemic circulation and excreted by the kidneys. The total body clearance is 5.04 ± 2.5 l / h and does not depend on the drug dose, gender, age, race and body weight of the patient. An increase in the duration of infusion 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 the dependence of concentration on time in blood plasma (AUC).
The variability of the pharmacokinetic parameters of zoledronic acid in different patients was high, as in the case of the use of other bisphosphonates.
There are no data on the pharmacokinetics of zoledronic acid in patients with hypercalcemia and hepatic impairment. According to data obtained in in vitro studies, zoledronic acid does not inhibit the human P450 enzyme and does not undergo biotransformation. According to experimental studies carried out on animals, less than 3% of the administered dose is excreted in the feces, 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 75 ± 33% of creatinine clearance, reaching an average of 84 ± 29 ml / min (range 22 – 143 ml / min) in 64 cancer patients who participated in the study. The analysis showed that in patients with creatinine clearance of 20 ml / min (acute renal failure) and 50 ml / min (moderate renal failure), the relative clearance of zoledronic acid was 37% and 72%, respectively. However, data with such in patients with acute renal failure (creatinine clearance <30 ml / min) are limited.
Found a low affinity of zoledronic acid with cellular components of the blood. Plasma protein binding 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 that in adults when used in equivalent doses (mg / kg). Age, body weight, patient sex, and creatinine clearance did not appear to affect systemic exposure to zoledronic acid.
Prevention of symptoms associated with damage to bone tissue (pathological fractures, compression of the spinal column, complications after surgery and radiation therapy, or hypercalcemia caused by a malignant tumor) in patients with advanced malignant tumors.
Treatment of hypercalcemia due to malignant tumor.
Hypersensitivity to the active ingredient (zoledronic acid), other bisphosphonates or any excipients that make up the drug.
Pregnancy or breastfeeding.
INTERACTIONS WITH OTHER DRUGS AND OTHER KINDS OF INTERACTIONS
During clinical studies, Zometa was often prescribed together with other drugs, in particular anticancer drugs, antibiotics, and analgesics. There were no clinically significant interactions.
According to data obtained during in vitro studies, Zometa does not significantly bind to blood plasma proteins and does not inhibit cytochrome P450 enzymes. However, special clinical studies to study drug interactions have not been conducted.
It is recommended to be careful with the simultaneous administration of bisphosphonates and aminoglycosides, as they can exhibit additive effects, as a result of which the level of calcium in the blood serum may remain lowered longer than necessary.
FEATURES OF APPLICATION
Ensure that all patients, including those with mild to moderate renal impairment, are adequately hydrated before administration of this drug.
Overhydration should be avoided in patients at risk of developing heart failure.
Routine metabolic parameters associated with hypercalcemia, such as calcium, phosphate and magnesium levels, should be carefully monitored after initiating zoledronic acid therapy. If hypocalcemia, hypophosphatemia, or hypomagnesemia occurs, short-term corrective therapy may be necessary.
Patients with untreated hypercalcemia usually have some renal impairment, so close monitoring of renal function is necessary.
Patients receiving therapy with zoledronic acid should not simultaneously take other drugs containing Zometa or other bisphosphonate drugs.
Impaired renal function
When deciding on the use of this drug in patients with hypercalcemia caused by a malignant tumor, against the background of impaired renal function, the patient’s condition should be assessed and it should be concluded that the potential benefit of treatment prevails 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 have been reports of renal dysfunction associated with the use of zoledronic acid. Factors that increase the likelihood of renal impairment include dehydration, pre-existing renal impairment, repeated cycles of zoledronic acid or other bisphosphonates, and the use of nephrotoxic drugs or infusion at a shorter time than recommended. Although the risk is reduced with the introduction of zoledronic acid at a dose of 4 mg for at least 15 minutes, deterioration of renal function is still possible.
An increase in serum creatinine levels is also observed in some patients who regularly take the drug at the recommended doses to prevent the onset of symptoms associated with diseases of the spine, although this is quite rare.
Before taking each dose, patients should be monitored for serum creatinine levels. At the beginning of treatment, lower doses of zoledronic acid are recommended for patients with bone metastases and mild to moderate renal insufficiency. Patients who experience deterioration of renal function during treatment, the drug can be restored only when the creatinine level returns to its original value within 10% of the initial value. Treatment with zoledronic acid is restored at the same dose that was administered to interrupt treatment.
Through the possible effect of zoledronic acid on renal function due to the lack of detailed data on clinical safety in patients with severe renal insufficiency (serum creatinine ≥ 400 μmol / L, or ≥ 4.5 mg / dL, for patients with hypercalcemia and creatinine B serum ≥ 265 μmol / L, or ≥ 3 mg / dL, for patients with cancer and bone metastases, respectively) at the beginning of treatment and only limited pharmacokinetic data in patients with severe renal insufficiency at the beginning of treatment (creatinine clearance <30 ml / min ) according to Stosuvannya zoledronic acid in patients with severe renal insufficiency is not recommended.
Patients, especially the elderly and those on diuretic therapy, should be properly hydrated before taking zoledronic acid.
There are no recommendations for patients with severe hepatic impairment as only limited clinical data are available.
Osteonecrosis of the jaw
Osteonecrosis of the jaw has been reported predominantly in cancer patients receiving bone resorption inhibitory drugs, including Zometa. A large number 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.
It is necessary to take into account such risk factors to assess the individual risks of developing osteonecrosis of the jaw.
bisphosphonate activity (greater risk for more active constituents), route of administration (greater risk for parenteral administration) and cumulative dose;
cancer, chemotherapy, radiotherapy, corticosteroid therapy, smoking;
history of dental diseases, inadequate oral hygiene, periodontal disease, invasive dental procedures and failure to fit a denture.
Before starting treatment with bisphosphonates, an oral examination should be performed with appropriate dental prophylaxis.
During therapy, these patients should, if possible, avoid invasive.
ABILITY TO INFLUENCE THE RATE OF REACTION WHEN DRIVING A VEHICLE OR OTHER MECHANISMS
Adverse reactions of the drug, such as dizziness and drowsiness, can affect the ability to drive vehicles or other mechanisms, therefore, caution is required when driving or operating machinery while using zoledronic acid.
DOSAGE AND APPLICATION
Zolt is administered only by doctors who have experience in administering bisphosphonates.
Before the introduction, 4 mg of the concentrate is diluted in 100 ml of 0.9% sodium chloride solution or 5% glucose solution. The ready-made solution for infusion is administered as a single infusion for at least 15 minutes.
The concentrate of this drug should not be mixed with infusion solutions containing calcium or other divalent cations, such as Ringer’s lactate solution, and must be administered as a single infusion using a separate infusion set.
Use only clear, colorless, particle-free solution. Any unused drug or waste must be disposed of in accordance with local regulations.
Prevention of symptoms associated with damage to bone tissue in patients with advanced malignant neoplasms
Adults, including elderly patients
The recommended dose of Zolt for the prevention of symptoms associated with bone damage in patients with malignant neoplasms is 4 mg of zoledronic acid every 3 to 4 weeks. Patients also need daily oral calcium supplementation at a dose of 500 mg and 400 IU of vitamin D per day.
The decision to treat patients with metastatic bone lesions for the prevention of symptoms associated with bone lesions should take into account that the onset of the treatment effect occurs after 2 to 3 months.
Treatment of hypercalcemia caused by a malignant tumor.
Adults, including elderly patients
The recommended dose for hypercalcemia (albumin corrected for serum calcium ≥ 12.0 mg / dL or 3.0 mmol / L) is 4 mg as a single infusion. Before and during administration of the drug, it is necessary to ensure sufficient hydration of the patient.
Impaired renal function
Hypercalcemia due to malignant tumor
Treatment of cancer-related hypercalcemia in patients with severe renal impairment is only possible after assessing the risks and benefits of such treatment. There are no clinical trials for patients with serum creatinine levels> 400 μmol / L, or> 4.5 mg / dL. No dose adjustment is required in patients with cancer-related hypercalcemia with serum creatinine <400 μmol / L, or <4.5 mg / dL.
Prevention of symptoms associated with damage to bone tissue in patients with advanced malignant neoplasms
When starting treatment for patients with multiple myeloma or metastatic bone lesions due to solid tumors, serum creatinine levels and creatinine clearance should be determined. CC is calculated from the serum creatinine level according to the Cockcroft-Gault formula. Zolta is not recommended for patients with existing severe renal impairment (creatinine clearance <30 ml / min). Clinical studies on the use of zoledronic acid in patients with serum creatinine levels> 265 μmol / L, or> 3 mg / dL, have not been conducted.
Recommended doses of the drug for patients with metastatic bone disease with mild or moderate renal impairment (creatinine clearance 30-60 ml / min):
After the start of therapy, the serum creatinine level should be measured before each dose of Zolta is administered, in case of deterioration of renal function, treatment should be canceled. In the course of studies, the deterioration of the degree of renal failure was determined as follows:
for patients with a normal baseline serum creatinine level (<1.4 mg / dL, or <124 μmol / L) – an increase of 0.5 mg / dL, or 44 μmol / L;
for patients with altered baseline serum creatinine levels (> 1.4 mg / dL, or> 124 μmol / L) – an increase of 1 mg / dL, or 88 μmol / L.
During the studies, Zometa therapy was restored after the creatinine level returned to the initial level within 10% of the initial value (see Section “Peculiarities of use”). Zolt therapy should be reinstated in the same dose that was prescribed to interrupt treatment.
Dose preparation instructions
Doses of the concentrate for the preparation of a solution for infusion in milliliters (ml), corresponding to the doses of Zolt:
4.4 ml corresponds to 3.5 mg
4.1 ml corresponds to 3.3 mg
3.8 ml corresponds to 3.0 mg.
The required amount of liquid concentrate should be diluted in 100 ml of sterile 0.9% sodium chloride solution or 5% glucose solution for intravenous infusion. The dose is given as a single infusion over at least 15 minutes.
For children from 1 to 17 years of age, the safety and efficacy of using zoledronic acid has not been established.
Clinical experience in the treatment of acute overdose of Zometa is limited. Misuse of zoledronic acid at a dose of 48 mg has been reported. Patients who received a dose exceeding the recommended dose should be monitored constantly, since renal dysfunction (including renal failure), changes in serum electrolyte composition (including calcium, phosphate and magnesium concentrations) are possible. If hypocalcemia occurs, an infusion of calcium gluconate is indicated according to clinical indications. Treatment is symptomatic.
Within three days after using the drug, gostrophasic reactions were usually reported, the symptoms of which included bone pain, fever, weakness, arthralgia, myalgia, chills, and arthritis with joint edema. These symptoms usually disappear within a few days.
In the case of using zoledronic acid, the following important adverse reactions have been identified:
impaired renal function, jaw necrosis, gostrophasic reactions, hypocalcemia, visual impairment, atrial fibrillation, anaphylaxis.
Information on the frequency of adverse reactions when using zoledronic acid at a dose of 4 mg is based mainly on data obtained during long-term therapy. Adverse reactions associated with the use of the drug, similar to those reported with the use of other bisphosphonates, and can develop in about one third of all patients.
Adverse reactions are classified by frequency of occurrence: very often (≥ 1/10), often (≥ 1/100, <1/10), sometimes (≥ 1/1000, <1/100), rarely (≥ 1/10000, < 1/1000), very rare (<1/10000), unknown (cannot be estimated from the available data).
From the blood and lymphatic system: often – anemia, sometimes – thrombocytopenia, leukopenia, rarely – pancytopenia.
From the nervous system: often – headache; sometimes – paresthesia, dizziness, taste disturbances, hypesthesia, hyperesthesia, tremor, drowsiness very rarely – epileptic seizures, numbness and tetany (secondary to hypocalcemia).
From the side of the psyche: sometimes – concern, sleep disorders; rarely – confusion.
From the side of the organ of vision: often – conjunctivitis; sometimes – blurred vision, scleritis and inflammation of the orbit; very rarely – uveitis, episcleritis.
From the digestive system: often – nausea, vomiting, anorexia; sometimes – diarrhea, constipation, abdominal pain, indigestion, stomatitis, dry mouth.
From the respiratory system: sometimes – shortness of breath, cough, bronchoconstriction, rarely – interstitial lung disease.
On the part of the skin and subcutaneous tissues: sometimes – itching, rash (including erythematous and macular rash), increased sweating.
From the musculoskeletal system, connective tissue: often – bone pain, myalgia, arthralgia, generalized pain, sometimes muscle cramps, osteonecrosis of the jaw *.
From the side of the cardiovascular system: sometimes – arterial hypertension, arterial hypotension, atrial fibrillation arterial hypotension, causes fainting and circulatory collapse; rarely – bradycardia, very rarely – arrhythmia (secondary to hypocalcemia).
From the kidneys and genitourinary system: often – renal disorders; sometimes – acute renal failure, hematuria, proteinuria.
From the immune system: sometimes – hypersensitivity reactions, rarely – angioedema.
General disorders and reactions at the injection site: often – fever, flu-like condition (including fatigue, chills, malaise and hot flashes) sometimes – reactions at the injection site (including pain, irritation, swelling, induration), asthenia, peripheral edema, chest pain , weight gain, anaphylactic reactions / shock, urticaria, rarely – arthritis and swelling of the joints as symptoms of gastrophasic reactions.
Deviation of laboratory parameters: very often – hypophosphatemia; often – an increase in the level of creatinine and urea in the blood, hypocalcemia, sometimes – hypomagnesemia, hypokalemia rarely – hyperkalemia, hypernatremia.
* Based on clinical trials, examination of possible cases of osteonecrosis of the jaw.
Impaired renal function
There is evidence that the use of zoledronic acid may impair renal function. Factors that may increase the potential risk of impaired renal function include dehydration, previous impaired renal function, repeated courses of treatment with zoledronic acid or other bisphosphonates, and concomitant use of other nephrotoxic drugs or shortening the recommended infusion time. Cases of deterioration of renal function, progression of renal failure and the need for hemodialysis have been reported in patients after the first or single use of zoledronic acid at a dose of 4 mg.
Osteonecrosis of the jaw
Cases of osteonecrosis (mainly of the jaw) have been reported predominantly in cancer patients treated with drugs that inhibit bone breakdown, such as Zometa. Many of these patients presented with local infection, including osteomyelitis, and most of the cases were associated with dental procedures such as tooth extraction. Osteonecrosis of the jaw has many established risk factors, in particular, cancer diagnosed, concomitant therapy (eg chemotherapy, radiation therapy, corticosteroids) and comorbidities (eg anemia, coagulopathy, infections, existing oral diseases). Although no causal relationship has been established, it is recommended that invasive dental procedures be avoided.
With zoledronic acid 5 mg once a year for the treatment of postmenopausal osteoporosis (PTO), the overall incidence of atrial fibrillation in patients treated with 5 mg zoledronic acid and placebo was 2.5% (96 out of 3862) and 1, 9 % (75 out of 3852) respectively. The incidence of atrial fibrillation as a serious adverse event in patients treated with 5 mg zoledronic acid and placebo was 1.3% (51 of 3862) and 0.6% (22 of 3852), respectively. This difference in frequency, which was observed in this study, was not noted in other studies of the use of zoledronic acid, including studies of the use of zoledronic acid at a dose of 4 mg every 3-4 weeks in patients with malignant neoplasms. The mechanism underlying the increased incidence of atrial fibrillation in this separate clinical study is not known.
These adverse reactions include the following symptoms: fever, myalgia, headache, limb pain, nausea, vomiting, diarrhea, and arthralgia, which may begin within the first 3 days after zoledronic acid infusion.
Atypical femur fractures
During the period of post-marketing use, the following reactions were rarely reported: acute pidvert-lug and diaphyseal fractures of the femur (adverse reactions to bisphosphonates).
Hypocalcemia has been reported in patients using this drug. There have been reports of arrhythmias and neurologic reactions (including seizures, numbness, and tetany) secondary to severe hypocalcemia. Cases of severe hypocalcemia have been reported requiring hospitalization. Sometimes hypocalcemia can be life threatening.
A sealed bottle is stored for 3 years.
From a microbiological point of view, the diluted infusion solution should be used immediately. If the solution was not used immediately, the user is responsible for the duration and storage conditions when using, usually should not exceed 24 hours at a temperature of 2-8 ° C. The cooled solution must be brought to room temperature before administration.
Store in its original packaging at a temperature not exceeding 25 ° C out of reach of children.
5 ml in a bottle; 1 bottle in a cardboard box.