Zolerix - instructions for use, dose, side effects, contraindications

Zoledronic acid refers to highly effective bisphosphonates having a selective effect on bone tissue. The drug suppresses the resorption of bone tissue, affecting the osteoclasts.

The selective effect of bisphosphonates on the bone is due to their high affinity for the mineralized bone, but their exact molecular mechanism of action is still unclear. After intravenous administration zoledronic acid is rapidly redistributed into bones and, like other bisphosphonates, is localized primarily in places of bone tissue remodeling. The main molecular target of zoledronic acid in osteoclast is the enzyme farnesyl pyrophosphate synthetase (FPS); while the possibility of other mechanisms of action of the drug is not excluded. The long period of action of the drug is determined by a high affinity for the active center of FBS and a pronounced affinity for the mineralized bone tissue. On experimental models of accelerated resorption with prolonged use of zoledronic acid, it is shown that zoledronic acid significantly inhibits bone resorption without adversely affecting the formation, mineralization and mechanical properties of bone tissue, dose-dependently decreases the activity of osteoclasts and the frequency of activation of new foci of remodeling in both trabecular (spongy) and cortical (compact) bone tissue without causing the formation of fibrous bone tissue and aberrant accumulation of osteoid, as well as bone mineralization defects. Except for a high antiresorptive effect, the effect of zoledronic acid on bone is similar to that of other bisphosphonates.

In addition to the inhibitory effect on bone resorption zoledronic acid possesses various antitumoral properties, which can contribute to the achievement of the overall effect in the therapy of metastatic process in bones. 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 breast cancer cells through the extracellular matrix, which indicates that it has antimetastatic properties. Besides, zoledronic acid inhibits the proliferation of endothelial cells in humans and animals and has an anti-angiogenic effect.

In patients with breast cancer, prostate and other solid tumors with metastatic bone damage zoledronic acid prevents the development of pathological fractures, compression of the spinal cord, reduces the need for radiotherapy and surgical interventions, 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 tumor hypercalcemia, the action of zoledronic acid is characterized by a decrease in the concentration of calcium in the blood serum and the excretion of calcium by the kidneys. The average time to normalize the calcium concentration is about 4 days. By the 10th day, the concentration of calcium is normalized in 87-88% of patients.The mean time to relapse (adjusted for albumin concentration of serum calcium at least 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.

When zoledronic acid is used in postmenopausal osteoporosis, there is a rapid decrease in bone turnover from elevated postmenopausal values to the lowest acceptable level (by day 7 for bone resorption rates and by 11 weeks for bone formation indices). Subsequently, bone exchange rates stabilize within pre-menopausal values. The use of zoledronic acid in postmenopausal osteoporosis reliably reduces the relative risk of any fractures and leads to an increase in bone mineral density (BMD).

When administered to patients with recent (within 90 days) fractures of the proximal femur, the drug reduces the frequency of subsequent osteoporotic fractures of any location and reduces the risk of death.

When used in patients with other types of osteoporosis (senile osteoporosis,osteoporosis in hypogonadism, osteoporosis caused by the use of glucocorticosteroids), and for the prevention of postmenopausal osteoporosis in women with different menopause lengths, there is also a clinically significant increase in MCP and a decrease in bone metabolism in blood plasma.

In the treatment of zoledronic acid in patients with Paget's bone disease, there is a rapid and long-lasting normalization of bone metabolism and alkaline phosphatase activity in blood plasma.

The drug is highly effective in patients who received previous treatment with oral bisphosphonates. The analgesic effect of zoledronic acid is comparable to the effect of risedronic acid.

In patients with postmenopausal osteoporosis and bone disease Paget zoledronic acid does not affect the quality of normal bone tissue, does not interfere with bone remodeling and mineralization processes and contributes to the preservation of normal architectonics of the trabecular bone.

Pharmacokinetics:

Data on pharmacokinetics were obtained after single and repeated 5- and 15-minute infusions of 2, 4, 8 and 16 mg of zoledronic acid in 64 patients.Pharmacokinetic parameters do not depend on the dose of the drug.

Distribution: the drug is administered intravenously, after the start of infusion, the serum concentration increases rapidly, reaching a maximum concentration (C_m_Oh) at the end of the infusion, followed by a rapid decrease in concentration by 10% after 4 hours and at less than 1% of C_m_Oh after 24 hours with a further long period of low concentrations not exceeding 0.1% of C_m_Oh, until repeated infusion for 28 days.

Low affinity of zoledronic acid for blood components is shown, binding to plasma proteins is low (60-77%) and weakly depends on the drug concentration.

Metabolism: not subject to metabolism. Zoledronic acid does not inhibit cytochrome P450 isoenzymes.

Excretion: is excreted by the kidneys unchanged in 3 stages: 1 and 2 phases - rapid removal of the drug from the systemic blood flow, with a half-life (T_½) 0,24 h and 1,87 h, respectively, and 3 phase - long, with a finite T_1/2146 h. There was no cumulation of the drug with repeated injections every 28 days. During the first 24 hours in urine, 23-55% of the administered dose is detected. The rest of the drug binds to the bone tissue, after which a slow reverse release of it into the systemic circulation and excretion by the kidneys occurs; less than 3% is excreted through the intestine.The total plasma clearance is 2.54-7.54 l / h and does not depend on the dose of the drug, sex, age, race and body weight of the patient. It was found that the variability of plasma clearance in the same patient and in different patients is 36% and 34%, respectively. An increase in the infusion time from 5 to 15 min leads to a 30% decrease in zoledronic acid at the end of the infusion, but does not affect the area under the concentration-time curve (AUC).

Pharmacokinetics in special patient groups:

Patients with impaired hepatic function: pharmacokinetic studies in patients with hypercalcemia and liver dysfunction were not performed. According to the data obtained in vitro, zoledronic acid does not inhibit the isoenzymes of the human cytochrome P450 system and does not undergo biotransformation, which suggests that the state of liver function does not significantly affect the pharmacokinetics of zoledronic acid. Correction of the dose is not required.

Patients with impaired renal function: renal clearance positively correlates with creatinine clearance (CC) and is 75 ± 33% of the CK, averaging 84 ± 29 ml / min.(range 22-143 ml / min) in 64 patients included in the study. A slight increase in AUC0-24, by 30-40%, with mild and moderate renal dysfunction, compared with the norm, and the absence of cumulation of the drug with repeated administration regardless of renal function, allow us to believe that there is no need to correct the dose of zoledronic acid at renal dysfunction is mild (creatinine clearance = 50-80 ml / min.) and moderate (creatinine clearance = 30-50 ml / min). In patients with severe and moderate renal dysfunction, the zoledronic acid clearance is 37% and 72%, respectively, of the zoledronate clearance value in patients with creatinine clearance> 84 ml / min. The use of the drug in patients with impaired renal function of severe degree (creatinine clearance <35 ml / min.) Is contraindicated because of the increased risk of kidney failure.

Indications:

Hypercalcemia (concentration of albumin corrected serum calcium> 12 mg / dl or 3 mmol / l), induced by malignant tumors.
Metastatic bone damage in malignant solid tumors and multiple myeloma (to reduce the risk of pathological fractures, spinal cord compression, hypercalcemia caused by the tumor,and reducing the need for radiotherapy).
Postmenopausal form of primary osteoporosis (to reduce the risk of fracture of the femur, vertebrae and extravertebral fractures, to increase bone mineral density);
Senile form of primary osteoporosis;
Secondary osteoporosis;
Bone disease of Paget.

Contraindications:

Hypersensitivity to zoledronic acid, other bisphosphonates or any other components that make up the drug;
Severe disorders of mineral metabolism, including hypocalcemia;
Violation of the function of the kidneys of severe degree (creatinine clearance <35 ml / min);
Pregnancy and the period of breastfeeding;
Age to 18 years (because safety and effectiveness of zoledronic acid in childhood and adolescence have not been studied).

Carefully:

When deciding on the use of zoledronic acid 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.Caution should be observed when prescribing zoledronic acid:

patients with impaired renal function of mild to moderate severity,
patients in a state of severe dehydration,
patients with concomitant oncological diseases and chemotherapy in the anamnesis,
patients with hepatic insufficiency,
patients with bronchial asthma caused by acetylsalicylic acid,
while the use of zoledronic acid with drugs able to exert a significant influence on renal function (e.g., aminoglycoside antibiotics-or diuretic causing dehydration).

Pregnancy and lactation:

Data on the use of zoledronic acid in pregnant women are absent. Experimental studies have shown the presence of toxic effects on the part of the reproductive system. Potential risk when used in humans is unknown. It is not known whether zoledronic acid with breast milk. The drug Zolerix® is contraindicated in pregnancy and during breastfeeding.

Dosing and Administration:

Zolerix® is used intravenously drip, for at least 15 minutes.

It is necessary to correct the dehydration in patients (if any) before the administration of zoledronic acid (this is especially important for patients aged> 65 years, as well as for patients receiving diuretic therapy).

With hypercalcemia due to malignant tumors

At a concentration of albumin corrected serum calcium> 12 mg / dL or 3 mmol / L, the maximum recommended single dose is 4 mg. Before the infusion of Zolerix®, it is necessary to check the concentration of serum creatinine. To ensure adequate hydration of the patient, it is recommended to administer the physiological solution before, at the same time or after the infusion of the drug. Repeated administration of the drug at a dose of 4 mg is indicated in case of deterioration after a distinct effect (i.e., achievement of Ca concentration²⁺ in the blood serum 2.7 mmol / l and below) or in case of refractoriness to the first injection. Repeated Zolerix® can be administered at a maximum dose of 8 mg for 15 minutes. If repeated administration is necessary, the concentration of serum creatinine should be determined before each infusion.The interval before reintroduction should be at least 7 days, this is necessary to realize the full clinical effect of the initial dose.

With metastatic bone damage in malignant solid tumors and multiple myeloma the recommended dose of the drug is 4 mg, every 3-4 weeks. In addition, it is recommended to prescribe calcium in a dose of 500 mg per day and vitamin D at a dose of 400 IU per day.

In the postmenopausal and senile form of primary osteoporosis with the aim of increasing the mineral density of bone tissue, preventing fractures of vertebral bodies and other bones of the skeleton, the recommended dose of Zolerix® is 5 mg, once a year.

With secondary osteoporosis the recommended dose of Zolerix® is 5 mg, once a year. If the intake of calcium and vitamin D in the body is not enough, patients with osteoporosis should additionally be prescribed calcium and vitamin D. Duration of the drug is determined by the doctor individually depending on the patient's condition.

For the treatment of Paget's bone disease it is recommended a single intravenous administration of the drug in a dose of 5 mg.Since, Paget's bone disease is characterized by a high level of bone metabolism, it is recommended that all patients with this disease take a daily intake of calcium and vitamin D within the first 10 days after the administration of zoledronic acid.

Repeated treatment with zoledronic acid of Paget's bone disease. After the first administration of the drug, a long period of remission is observed. Currently, there is no specific data on re-treatment of Paget's bone disease. However, the possibility of re-introduction of the drug can be considered in case of detection of relapse of the disease in patients based on the following criteria: the lack of normalization of serum alkaline phosphatase activity, the increase in its activity in dynamics, and the presence of clinical signs of Paget's bone disease detected after a medical examination after 12 months after the administration of the first dose of zoledronic acid.

Use in patients with impaired renal function

Hypercalcemia due to malignant tumors:

The decision to treat zoledronic acid patients with severe renal dysfunction should only be taken after a thorough assessment of the risk / benefit ratio.When the serum creatinine concentration is <400 μmol / L or <4.5 mg / dl, correction of the dosing regimen is not required.

Metastatic bone damage in malignant solid tumors and multiple myeloma:

The dose of Zolerix® in patients with impaired renal function depends on the initial clearance of creatinine, calculated by the Cockcroft-Gault formula. Recommended doses in patients with impaired renal function of mild or moderate degree (creatinine clearance values of 30-60 ml / min) are given below.

Initial clearance of creatinine (ml / min)	The recommended dose of Zolerix®
>60	4.0 mg (5.0 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 initiation of therapy, the serum creatinine concentration should be measured before each dose of Zolericx®. If the kidney function worsens, the next administration of the drug should be postponed. Impairment of kidney function is defined as follows:

for patients with a normal baseline serum creatinine concentration (<1.4 mg / dl): an increase in creatinine concentration> 0.5 mg / dL;
for patients with a changed baseline serum creatinine concentration (> 1.4 mg / dL): an increase in creatinine concentration of> 1.0 mg / dl.

Therapy with Zolerix® is resumed at the same dose as before the interruption of treatment, when the creatinine concentration returns to its original value or deviates no more than 10% from it.

Primary and secondary osteoporosis therapy

In patients with creatinine clearance> 35 ml / min. no dose adjustment is required. Use in patients with clearance of creatinine <35 ml / min. it is contraindicated.

Patients with impaired hepatic function

Correction of the dose is not required.

Patients of advanced age (> 65 years)

Correction of the dose of the drug is not required, since the bioavailability, distribution and excretion of the drug in patients of different ages have a similar nature.

Instructions for preparing a solution for infusions

When preparing and carrying out infusion, you should follow the rules of asepsis. Before the introduction of zoledronic acid, the quality and color of the solution should be visually assessed. The drug can not be used for discoloration or the appearance of non-dissolved visible particles.

From concentrate 4mg / 5ml, 5 mg / 6.25 ml (contents of 1 bottle) solution for infusion. Before the introduction of the drug dilute the concentrate (the contents of 1 bottle or a smaller volume if required) 100 ml of a 0.9% solution of sodium chloride or 5% solution of dextrose.Prepared solution is preferably 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. Before administration, the solution should be left in the room until the room temperature is reached.

The total time between the dilution of the concentrate, storage of the prepared solution in the refrigerator at a temperature of 2 to 8 ° C and the end of the drug administration should not exceed 24 hours.

The solution of Zolerix® should not be mixed with any other medicinal products or with solutions containing calcium or any other divalent cations such as Ringer's lactate solution. Always use a separate system for infusion.

Side effects:

The following are undesirable events (AEs) in organs and systems, with frequency of occurrence according to WHO recommendations: very often (≥ 10%), often (from ≥ 1% to <10%), infrequently (from ≥ 0.1% to <1 ), rarely (≥ 0.01% and <0.1%), very rarely (<0.01%) and the frequency is unknown (according to the reports in the literature).

When used in patients with metastatic bone lesions in malignant solid tumors and multiple myeloma, hypercalcemia:

Violations from the blood and lymphatic system: often - anemia, infrequently - thrombocytopenia, leukopenia; rarely - pancytopenia.

Immune system disorders: infrequently - reactions increased sensitivity; rarely - angioedema, frequency unknown - anaphylactic reaction / shock.

Disorders of the psyche: often - sleep disturbance; infrequently - anxiety

Impaired nervous system: often - headache; paresthesia; infrequently - dizziness, taste disorders, hypoesthesia, hyperesthesia, tremor; rarely - confusion, the frequency is unknown - drowsiness.

Disorders from the side of the organ of vision: often - conjunctivitis; infrequent - blurred vision, frequency unknown - uveitis, episcleritis, scleritis and inflammatory diseases of the orbit.

Heart Disease: rarely - bradycardia, frequency unknown - atrial fibrillation.

Vascular disorders often - increased blood pressure; infrequently - lowering blood pressure, frequency unknown - lowering blood pressure, leading to syncope or circulatory collapse, mainly in patients with risk factors.

Disturbances from the respiratory system, chest and mediastinal organs: infrequently - shortness of breath, cough, frequency unknown - bronchospasm, interstitial lung disease.

Disorders from the gastrointestinal tract: often - nausea, vomiting, anorexia, constipation; infrequently - diarrhea, abdominal pain, dyspepsia, stomatitis, dry mouth.

Disturbances from the skin and subcutaneous tissues: often - increased sweating; infrequently - itching, rash (including erythematous and macular), frequency unknown - hives.

Disturbances from musculoskeletal and connective tissue: often - pain in the bones, myalgia, arthralgia, generalized pain, stiff joints; infrequently - necrosis of the lower jaw, muscle cramps, frequency unknown - sudden pronounced restriction of mobility of bones, joints and / or pain, atypical susceptible and diaphyseal fractures of the femur.

Disorders from the kidneys and urinary tract: often - impaired renal function; infrequently - acute renal failure, hematuria, proteinuria.

General disorders and disorders at the site of administration: often acute phase reaction, fever, influenza-like state (including general malaise, chills, painful condition, fever), peripheral edema, asthenia; infrequently - the reaction at the injection site (pain, irritation, swelling, tightness, redness), chest pain, weight gain.

Laboratory and instrumental data: very often - hypophosphatemia; often - an increase in the concentration of creatinine and urea in the blood, hypocalcemia; infrequently - hypomagnesemia, hypokalemia; rarely - hyperkalemia, hypernatremia. The above-mentioned AEs associated with the use of zoledronic acid for these indications are usually mild and transitory in nature, they can be observed in a third of patients receiving treatment with the drug.

In the treatment and prevention of various types of osteoporosis, treatment of Paget's bone disease and for the prevention of new fractures in men and women with fractures of the proximal femur

Impaired nervous system: often - headache *, dizziness; infrequent - retardation *, paresthesia, decreased sensitivity (met only in patients who received the drug for the prevention of postmenopausal osteoporosis), drowsiness, tremor *, fainting, dysgeusia.

Disorders of the side of the organ of vision: often - sclera hyperemia; infrequently - conjunctivitis, pain in the eyes, vertigo, fuzzy vision (only seen in patients who received the drug for the prevention of postmenopausal osteoporosis); rarely - uveitis *, episcleritis, iritis *; frequency unknown - inflammation of the sclera and orbit.

Disturbances from the respiratory system, chest and mediastinal organs: infrequently - shortness of breath *, cough.

Disorders from the digestive system: often - nausea *, vomiting, diarrhea; infrequent anorexia *, decreased appetite, indigestion *, abdominal pain *, dry mouth, esophagitis *, gastroesophageal reflux, upper abdominal pain *, constipation *, gastritis (in patients receiving glucocorticosteroids), toothache.

Disturbances from the skin and subcutaneous tissue: infrequently - rash, hyperhidrosis *, itching, erythema.

Disturbances from the musculoskeletal system and connective tissue: often - arthralgia *, myalgia *; pain in the bones, pain in the back and extremities, pain in the jaw and pain in the neck (met only in patients who received the drug for the prevention of postmenopausal osteoporosis); infrequent pain in the neck, joint swelling *, muscle spasms *, shoulder pain, chest pain * musculoskeletal origin, muscle weakness, stiffness in the muscles * and joints *, arthritis, musculoskeletal pain , pain in the side (only seen in patients who received the drug for the prevention of postmenopausal osteoporosis); frequency unknown - osteonecrosis of the jaw.

Disorders from the kidneys and urinary tract: infrequently - increased levels of creatinine, pollakiuria, proteinuria. The frequency is unknown - renal failure.

Violations of the blood and lymphatic system: infrequently anemia.

Heart Disease: atrial fibrillation; infrequent - a feeling of palpitations.

Vascular disorders: infrequently - increased blood pressure, sudden redness of the face; frequency unknown - marked reduction in blood pressure (in patients with risk factors).

Mental disturbance: infrequently - insomnia, anxiety (only seen in patients who received the drug for the prevention of postmenopausal osteoporosis). Infections and infestations: infrequently - flu, nasopharyngitis.

General disorders and disorders at the site of administration: very often - a rise in temperature; often - influenza-like syndrome, chills *, increased fatigue *, asthenia, pain *, general malaise, reactions at the site of infusion; infrequent - peripheral edema, thirst, * acute reactions *, chest pain * (not associated with heart disease); frequency is unknown - dehydration (develops secondary to post-infusion symptoms, such as fever, vomiting, diarrhea).

* - In some studies, including the use of zoledronic acid preparations for the prevention of postmenopausal osteoporosis, the frequency of these adverse events was an order of magnitude higher.

The above AEs associated with the use of zoledronic acid for these indications are usually easy or moderately expressed and occur within three days after the onset. With repeated administration of the drug, the severity of AE data decreased.

In individual studies of zoledronic acid, AEs were recorded whose incidence was lower in the drug group than in the untreated group: redness of the eyes, increased C-reactive protein in the blood, hypocalcemia, dysgeusia, toothache, gastritis, palpitation, reactions at the injection site.

On the background of zoledronic acid therapy, the following adverse events were noted in clinical practice, regardless of the presence of a causal relationship with the use of the drug (frequency not established): hypersensitivity reactions, including in rare cases bronchial obstruction, hives, angioedema and separate reports on the development of anaphylactic reactions, in t.ch. anaphylactic shock.In rare cases, renal dysfunction, including renal insufficiency, requiring hemodialysis, or deaths, especially in patients with a history of having a kidney disease, or additional risk factors (for example, elderly age, concomitant therapy with nephrotoxic drugs, diuretics, or severe dehydration).

Overdose:

Symptoms: In acute overdose of zoledronic acid (limited data), renal dysfunction, including renal insufficiency, changes in electrolyte composition, including a decrease in the concentration of calcium, phosphate and magnesium in the blood plasma.

Treatment: The patient who received a dose of the drug that exceeds the recommended dose should be under constant supervision. In the case of hypocalcemia, accompanied by clinical manifestations, an infusion of calcium gluconate is indicated.

Interaction:

According to the data obtained in the studies in vitro, zoledronic acid weakly binds to plasma proteins and does not inhibit the isoenzymes of the cytochrome P450 system. It is advisable to use caution while using bisphosphonates, aminoglycosides and loop diuretics,since the simultaneous action of these drugs causes a longer-term decrease in the concentration of calcium in the blood plasma.

Zoledronic acid is excreted by the kidneys, so caution is needed when using zoledronic acid with drugs potentially having a nephrotoxic effect. In patients with impaired renal function when zoledronic acid is used together with drugs that are excreted mainly by the kidneys, it is possible to increase the systemic effect of these drugs.

Caution should be exercised in the joint use of zoledronic acid with angiogenesis inhibitors because of the incidence of osteonecrosis of the lower jaw.

With the simultaneous use of other commonly used drugs with zoledronic acid (antitumor agents, diuretics (excluding loop), antibacterial drugs, analgesics), no clinically significant interactions have been observed.

In patients with multiple myeloma combined use of thalidomide (100 or 200 mg once a day) and zoledronic acid does not significantly affect the pharmacokinetics of the drug and creatinine clearance and does not require correction of the dose of drugs,with the exception of the use in patients with impaired renal function of mild and moderate severity, which may require dosage adjustment of zoledronic acid.

Pharmaceutical interaction

The diluted zoledronic acid solution should not be mixed with infusion solutions containing calcium ions (eg, Ringer's solution).

When using glass vials, infusion systems and bags of various types made of polyvinyl chloride, polyethylene and polypropylene (previously filled with 0.9% sodium chloride solution or 5% glucose solution) for the introduction of zoledronic acid, no incompatibility was found.

Special instructions:

Infusion of the drug should be carried out by qualified medical personnel who have experience in the administration of bisphosphonates.

The physician should inform patients about the main manifestations of hypocalcemia and ensure regular monitoring of patients at risk.

To reduce the frequency of some AEs observed within 3 days after the administration of the drug, you can assign paracetamol or ibuprofen immediately after zoledronic acid infusion.

Before zoledronic acid infusion, it should be ensured that the patient is adequately hydrated. If necessary, the introduction of a 0.9% solution of sodium chloride before, in parallel or after the infusion of zoledronic acid is recommended. Avoid hyperhydration of the patient due to the risk of complications from the cardiovascular system.

After the introduction of zoledronic acid, a constant control of the concentration of calcium, phosphorus, magnesium and creatinine in the blood serum is necessary. 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 renal 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.

Hypocalcemia

In the presence of hypocalcemia, before starting zoledronic acid, adequate treatment with adequate doses of calcium and vitamin D.Also, if possible, other existing disorders of mineral metabolism should be treated (for example, arising after operations on the thyroid and parathyroid glands, with hypoparathyroidism or a decrease in calcium absorption in the intestine) and ensure regular monitoring of patients with hypocalcemia.

Clinical practice reported the development of hypocalcemia in patients receiving zoledronic acid. In the case of severe hypocalcemia, undesirable phenomena from the side of the nervous system (convulsions, tetany and numbness), cardiac arrhythmia can be noted. In some cases, hypocalcemia may pose a threat to life.

Impaired renal function

There are some reports of a violation of kidney function against the background of bisphosphonates. The risk factors for such complications include dehydration, previous renal failure, repeated administration of zoledronic acid or other bisphosphonates, as well as the use of nephrotoxic drugs, and too rapid administration of the drug. Despite the fact that the risk of the complications described above decreases with the introduction of zoledronic acid at a dose of 4 mg for at least 15 minutes, the possibility of renal dysfunction persists.There have been cases of impaired renal function, progression of renal failure and the need for hemodialysis in the first or one-time use of zoledronic acid. An increase in serum creatinine concentrations is also observed in some patients with prolonged use of zoledronic acid at recommended doses, although less frequently. When deciding on the use of zoledronic acid 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.

Osteonecrosis of the jaw

Cases of osteonecrosis of the jaw in cancer patients on the background of treatment with bisphosphonates, including zoledronic acid, are described. Many patients had signs of a local infectious inflammatory process, including osteomyelitis.

In clinical practice, the most common development of osteonecrosis of the jaw was observed in patients with advanced breast cancer and myeloma, and in the presence of dental diseases (after tooth extraction, periodontal disease, unsatisfactory fixation of dentures).Known risk factors for osteonecrosis of the jaw are cancer, concomitant treatment (chemotherapy, radiation therapy, glucocorticosteroid treatment), concomitant diseases (anemia, coagulopathy, infection, previous oral disease).

Before prescribing bisphosphonates, patients should conduct a dental examination and perform the necessary preventive procedures, as well as recommend strict adherence to oral hygiene. When treating these patients, dental operations should be avoided whenever possible. There is no evidence that discontinuing bisphosphonate treatment before dental interventions reduces the risk of developing osteonecrosis of the jaw. The treatment plan for a particular patient should be based on an individual risk / benefit ratio.

Atypical fractures of the femur.

Cases of occurrence of atypical susceptible and diaphyseal fractures of the femur are described in patients who have been receiving bisphosphonates for a long time for osteoporosis. Transverse or short oblique fractures can be localized anywhere along the femur from a small spit tosupracondylar fossa. The described fractures appear after minimal trauma or spontaneously. Some patients experience pain in the thigh or groin, often accompanied by visual signs of stress fractures that occur weeks and months before the development of a full (completed) fracture of the femur. Fractures often occur on both sides, therefore, contralateral femur should be examined in patients receiving bisphosphonates who have a fracture of one femur. There was also reported a slow healing of these fractures. The cause-and-effect relationship of such fractures with zoledronic acid therapy has not been established. The decision to discontinue zoledronic acid therapy in patients who are expected to have an atypical femur fracture should be based on an individual risk / benefit ratio.

Patients receiving zoledronic acid therapy should be warned about the need to inform medical personnel of any pain in the thigh or inguinal area. Each patient who complains of such symptoms should be examined to identify possible incomplete fracture of the femur.

Pain in the bones

In clinical practice, infrequent cases of development of strong and in some cases disabling pain in bones, joints and muscles against the background of the use of bisphosphonates, including zoledronic acid. These symptoms developed during the period from one day to several months after the start of treatment. After discontinuation of treatment in most patients, the symptoms passed. In several patients, the symptoms recurred when the therapy was resumed or another bisphosphonate was administered.

Other instructions

There were isolated cases of bronchoconstriction in patients with aspirin bronchial asthma with bisphosphonates. Although there have been no such cases in clinical studies using zoledronic acid, it is recommended to use the drug with caution in patients with "aspirin" bronchial asthma.

Since clinical data on the use of the drug in patients with severe hepatic insufficiency is limited, it is not possible to give specific recommendations for this category of patients.

Patients receiving Zolerix® should not simultaneously receive other bisphosphonate preparations.

The effectiveness and safety of zoledronic acid in pediatric practice has not been established to date.

Effect on the ability to drive transp. cf. and fur:

Studies of the effect of zoledronic acid on the ability to drive vehicles and work with mechanisms have not been carried out. In case of adverse reactions from the nervous system, patients are advised to refrain from managing vehicles and other mechanisms, as well as activities that require concentration of attention, stress of psychomotor functions.

Form release / dosage:

Concentrate for solution for infusion, 0.8 mg / ml.

Packaging:

5 ml (4 mg), 6.25 ml (5 mg) into the bottles of colorless neutral glass I of hydrolytic class or in plastic bottles, hermetically sealed with rubber stoppers, with aluminum caps.

For 1 or 5 bottles together with the instructions for use are placed in a pack of cardboard.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Do not freeze.

Keep out of the reach of children.

Shelf life:

2 years.

The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-002263/10

Date of registration:18.03.2010

The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia

Manufacturer: & nbsp

BIOCAD, CJSC Russia

Information update date: & nbsp14.09.2015

Illustrated instructions

Instructions

Zolerix (Zolerix)