Zoledronic acid - instructions for use, dose, side effects, contraindications

Active substance:
Zoledronic acid monohydrate	4,264 mg
in terms of zoledronic acid	4,000 mg
Excipients:
Mannitol	220,000 mg
Sodium citrate dihydrate	24,000 mg
Water for injections	up to 5 ml

Description:Transparent, colorless or slightly yellowish liquid.

Pharmacotherapeutic group:Bone resorption inhibitor-bisphosphonate

ATX: & nbsp

M.05.B.A.08 Zoledronic acid

Pharmacodynamics:

Zoledronic acid refers to highly effective bisphosphonates that selectively act on the bone. The drug suppresses the resorption of bone tissue, affecting the osteoclasts.

Selective action 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 adversely affect the formation, mineralization and mechanical properties of the 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: inhibition of osteoclastic bone resorption, which changes the microenvironment of the bone marrow, leading to a decrease in the growth of tumor cells; anti-angiogenic activity. Suppression of bone resorption is clinically accompanied, including a marked decrease in pain.
In vitro: inhibition of osteoblast proliferation,direct cytotoxic and pro-apoptotic activity, synergistic cytotoxic effect with antitumor drugs; anti-adhesive / invasive activity.

Zoledronic acid, suppressing proliferation and inducing apoptosis, has a direct antitumor effect on human myeloma cells and breast cancer, and also reduces the penetration of human breast cancer cells through the extracellular matrix, which indicates that it has antimetastatic properties. Besides, zoledronic acid inhibits the proliferation of human endothelial cells and has an anti-angiogenic effect in animals.

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 multiple myeloma and breast cancer in the presence of at least one bone focus, the effectiveness of zoledronic acid in a dose of 4 mg is comparable to pamidronate in a dose of 90 mg.

In patients with tumor hypercalcemia, the action of zoledronic acid is characterized by a decrease in the level of calcium in the blood serum and the release of calcium 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.

The studies do not reveal significant differences in the incidence and severity of adverse events observed in patients treated with zoledronic acid at doses of 4 mg and 8 mg, pamidronate at a dose of 90 mg, or placebo in both bone metastases and hypercalcemia.

Pharmacokinetics:

Pharmacokinetic parameters do not depend on the dose of the drug.

After the onset of infusion of zoledronic acid, the serum concentration increases rapidly, reaching a peak at the end of the infusion,followed by a rapid decrease in concentration by 10% after 4 hours and by less than 1% of the peak after 24 hours with a successively prolonged period of low concentrations not exceeding 0.1% of maximal to repeated infusion at day 28. Zoledronic acid, administered intravenously, is excreted by the kidneys in three stages: a rapid two-phase excretion of the drug from the system circulation with half-lives of 0.24 hours and 1.87 hours and a long phase with a terminal elimination half-life of 146 hours. No cumulation of the drug was observed with repeated injections every 28 days. Zoledronic acid is not metabolized and is excreted by the kidneys in an unchanged form. During the first 24 hours, 39 ± 16% of the administered dose is detected in the urine. The rest of the drug is mainly associated with 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 ± 2.5 l / h and does not depend on the dose of the drug, sex, age, race and body weight of the patient. Increasing the infusion time from 5 minutes to 15 leads to a decrease in the concentration of zoledronic acid by 30% at the end of the infusion,but does not affect the area under the concentration-time curve (AUC).

Pharmacokinetic studies in patients with hypercalcemia or liver damage were not performed. According to the data received in vitro, zoledronic acid does not inhibit the isoenzymes of the cytochrome P450 system and does not undergo biotransformation, which suggests that the state of liver function does not affect the pharmacokinetics of zoledronic acid in any significant way. Less than 3% of the dose is excreted through the intestine.

Renal clearance of zoledronic acid positively correlates with creatinine clearance and is 75 ± 33% of creatinine clearance, averaging 84 ± 29% (range 22-143 ml / min). In patients with creatinine clearance of 20 ml / min (severe renal failure) or 50 ml / min (moderate renal failure), the calculated zoledronic acid clearance is 37% and 72%, respectively, of the zoledronate clearance value in patients with creatinine clearance of 84 ml / min. Pharmacokinetic data in patients with severe renal insufficiency (creatinine clearance (CK) less than 30 ml / min) are limited.

The low affinity of zoledronic acid for the cellular components of blood is shown,the binding to plasma proteins is low (about 56%) and does not depend on the concentration of zoledronic acid.

Indications:

Metastases in the bone with malignant solid tumors (prostate cancer, breast cancer and others) and multiple myeloma, including to reduce the risk of pathological fractures, spinal cord compression.

Hypercalcemia (concentration of albumin-corrected serum calcium ≥ 12 mg / dL or 3 mmol / L) due to malignant tumors.

Contraindications:

Hypersensitivity to zoledronic acid, other bisphosphonates or any other components that make up the drug.

Violations of the function of the kidneys of severe severity (QC less than 30 ml / min).

Pregnancy and lactation.

Child age (effectiveness and safety not established).

Carefully:

With caution apply the drug in patients with impaired renal function of mild and moderate severity (CK> 30 ml / min).

Caution should be exercised with simultaneous use with other drugs that can cause hypocalcemia (eg, aminoglycosides, calcitonin, "loop" diuretics) in connection with the risk of developing a synergistic effect leading to severe severity of hypocalcemia.

With caution, the drug should be used concurrently with other drugs that have a nephrotoxic potential.

With caution should be used simultaneously with anti-angiogenic drugs in connection with an increased risk of osteonecrosis of the jaw.

Be cautious when used in patients with impaired liver function of severe severity due to the limited data on the use of the drug in patients in this category.

Pregnancy and lactation:

Application of the drug Zoledronic acid during pregnancy is contraindicated.

A drug Zoledronic acid may have an adverse effect on the fetus. In studies in animals, toxic effects on reproductive function have been identified. There is no data on the use of the drug during pregnancy in humans.

When pregnancy occurs during therapy with bisphosphonates, there may be a risk of intrauterine malformations of the fetus (for example, skeletal anomalies and other anomalies).The dependence of risk on the magnitude of the time interval between cessation of bisphosphonate therapy and the moment of conception, the route of administration and the specific features of the particular drug is unknown.

Women of reproductive age should be warned about the need to apply reliable contraceptive methods during drug treatment Zoledronic acid.

It is not known whether the zoledronic acid in breast milk. Application of the drug Zoledronic acid during the period of breastfeeding is contraindicated.

In studies in animals zoledronic acid suppressed fertility in a dose 0.1 mg / kg per day. There is no evidence of the effect of zoledronic acid on fertility in rights.

Dosing and Administration:

Metastases in the bone with malignant solid tumors and multiple myeloma:

Adults and patients of advanced age

The recommended dose is 4 mg intravenously drip, for at least 15 minutes every 3-4 weeks. Before the introduction of the drug dilute the concentrate (the contents of 1 bottle) 100 ml solution for infusions that do not contain calcium (0.9% solution of sodium chloride or 5% solution of dextrose).

Patients should also be prescribed calcium inwards at a dose of 500 mg per day and vitamin D inside at a dose of 400 ME per day.

Hypercalcemia, caused by malignant tumors:

Adults and patients of advanced age

With hypercalcemia (the concentration of albumin-corrected serum calcium ≥12 mg / dL or 3 mmol / L), the recommended single dose of the drug is 4 mg. To ensure the adequacy of hydration, it is recommended that the physiological solution be administered before, simultaneously, or after the infusion of zoledronic acid.

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 of the drug and the expected benefit of therapy. Patients in whom the serum creatinine concentration is <400 μmol / L or <4.5 mg / dL, dosage adjustment is not required.

Bone metastases of common malignant tumors and multiple myeloma:

The dose of zoledronic acid depends on the baseline creatinine clearance level calculated by formula Cockcroft-Gault. It is not recommended to take zoledronic acid in patients with severe renal dysfunction (creatinine clearance <30 mL / min).

Recommended doses in patients with mild to moderate impairment of renal function (creatinine clearance values of 30-60 ml / min) are given below.

The baseline creatinine clearance (ml / min)	The recommended dose of Zoledronic acid
>60	4.0 mg (5 ml of concentrate)
50-60	3.5 mg (4.4 ml of concentrate)
40-49	3.3 mg (4.1 ml of concentrate)
30-39	3.0 mg (3.8 ml of concentrate)

After initiation of therapy, 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 a normal baseline serum creatinine concentration (<1.4 mg / dl), increase creatinine concentration by 0.5 mg / dL;
For patients with a changed baseline serum creatinine concentration (> 1.4 mg / dL), an increase in creatinine concentration by 1 mg / dl was noted.

Therapy with zoledronic acid is resumed only after the level of creatinine reaches values within ± 10% of the baseline, at the same dose that was used before the interruption of treatment.

Preparation of a solution for infusions

From a concentrate of 4 mg / 5 ml (contents of 1 vial), a solution for infusions is prepared under aseptic conditions. Before the introduction of the drug, dilute the concentrate (the contents of 1 vial or a smaller volume, if required) 100 ml of solution for calcium-free infusions (0.9% sodium chloride solution or 5% dextrose solution). Prepared zoledronic acid solution is preferably used immediately after preparation. Unused immediately solution can be stored in aseptic conditions in the refrigerator at a temperature of + 2-8 ° C not more than 24 hours. Before administration, the solution should be left in the room until the room temperature is reached.

The total time between diluting the concentrate, storing the preparation of the solution in aseptic conditions in the refrigerator at a temperature of + 2-8 ° C and the end of the drug administration should not exceed 24 hours.

The solution of zoledronic acid should not be mixed with any other medicinal products.The preparation should not be mixed with any solutions containing calcium and any other divalent cations, such as Ringer's solution. For the introduction of zoledronic acid solution, you should always use a separate system for infusions.

Side effects:

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 / 10000, <1 / 1,000) , very rarely (<1/10000), including individual messages.

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

Disturbances from the nervous system: often - headache, paresthesia; infrequently - dizziness, dysgeusia, hypoesthesia, hyperesthesia, tremor; very rarely - convulsions, kinesisia and tetany (developing due to hypocalcemia).

Disorders of the psyche: often - sleep disturbance; infrequently - a sense of anxiety; rarely confusion.

Disturbances on the part of the organ of sight: often - conjunctivitis; sometimes blurred vision; very rarely - uveitis, episcleritis.

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

Disturbances from the respiratory system, chest and mediastinal organs: sometimes - shortness of breath, cough; rarely - interstitial lung disease.

Disturbances from the skin and subcutaneous tissues: sometimes - itching, rash (including erythematous and macular), increased sweating.

Disturbances of musculoskeletal and connective tissue: often - pain in the bones, myalgia, arthralgia, generalized pain, stiff joints; infrequently - necrosis of the jaw, muscle cramps.

Violations from the heart and blood vessels: sometimes - marked increase or decrease in blood pressure; rarely - bradycardia; arrhythmia (developing due to hypocalcemia).

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

Immune system disorders: sometimes - hypersensitivity reactions; rarely - angioedema.

Laboratory and instrumental data: very often - hypophosphatemia; often - increased serum creatinine and urea concentrations, hypocalcemia; sometimes - hypomagnesemia,hypokalemia; rarely - hyperkalemia, hypernatremia.

General disorders and disorders at the site of administration: often - the reaction of the acute phase, fever, flu-like syndrome (including general malaise, chills, a feeling of malaise, "hot flashes"), peripheral edema, asthenia; infrequently - reactions at the injection site (pain, irritation, swelling, tightness, redness), chest pain, weight gain; rarely arthritis and swelling of the joints as a symptom of the reaction of the acute phase.

It should be borne in mind that when using other bisphosphonates in patients with bronchial asthma sensitive to acetylsalicylic acid, there have been cases of bronchospasm, but this phenomenon has not been observed with zoledronic acid.

In the treatment of patients with bisphosphonates in clinical practice, rare cases of osteonecrosis of the jaw (usually after extraction of the tooth or other dental intervention) are described. A clear causal relationship between the development of osteonecrosis is not established.

Adverse events according to spontaneous reports and literary reports (frequency unknown)

Immune system disorders: anaphylactic reaction / shock.

Disturbances from the nervous system: drowsiness.

Disorders from the side of the organ of vision: episcleritis, scleritis and inflammatory orbital diseases.

Heart Disease: atrial fibrillation.

Vascular disorders: decrease in blood pressure, leading to syncope or circulatory collapse, mainly in patients with risk factors.

Disturbances from the respiratory system, chest and mediastinal organs: bronchospasm.

Disturbances from the skin and subcutaneous tissues: hives.

Disturbances from the musculoskeletal and connective tissue: sudden severe limitation of joint mobility and / or severe and in some cases limiting the ability to work pain in the bones, joints and / or muscles, atypical susceptible and diaphyseal fractures of the femur.

Overdose:

In acute overdose of the drug (limited data), renal dysfunction, including kidney failure, changes in electrolyte composition, including concentration of calcium, phosphate and magnesium in blood plasma were noted.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:

With the simultaneous use of other commonly used medications (antineoplastic agents, diuretics, antibiotics, analgesics) with zoledronic acid, no clinically significant interactions have been observed.

According to the data obtained in the studies in vitro, zoledronic acid has no significant binding to plasma proteins and does not inhibit the isoenzymes of the cytochrome P450 system. Nevertheless, special clinical studies on the study of drug interactions were not conducted.

It is advisable to use caution when using bisphosphonates with aminoglycosides, calcitonin, loop diuretics, because simultaneous administration of these drugs causes a longer decrease in the concentration of calcium in the blood plasma.

Caution is necessary when using Zoledronic acid with drugs,potentially having a nephrotoxic effect. It should also be borne in mind the likelihood of hypomagnesemia.

In patients with multiple myeloma, an increased risk of developing renal dysfunction with intravenous administration of bisphosphonates, such as zoledronic acid, in combination with thalidomide.

Pharmaceutical interaction and compatibility issues

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

When using glass vials, infusion systems and bags of different types made of polyvinyl chloride, polyethylene and polypropylene (pre-filled with 0.9% sodium chloride solution or 5% dextrose solution) for the introduction of zoledronic acid, no signs of incompatibility with zoledronic acid were found.

Special instructions:

Before the infusion, you should ensure that the patient is adequately hydrated. If necessary, the introduction of 0.9% sodium chloride solution 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 introduction of zoledronic acid, continuous monitoring 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. Patients with untreated hypercalcemia usually have impaired renal 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 in order to reduce the risk of pathological fractures, spinal cord compression, tumor-induced hypercalcemia and reduce the need for radiotherapy or bone surgery, it should be taken into account that the therapeutic effect occurs through 2-3 months after the start of treatment with zoledronic acid.

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 dihydration, 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 above complications decreases with the introduction of zoledronic acid in a dose of 4 mg for at least 15 minutes, the possibility of renal dysfunction is preserved. There have been cases of impaired renal function, progression of kidney failure and the need for hemodialysis in the first or one-time use of the drug.

An increase in serum creatinine concentration is also observed in some patients with prolonged use of Zoledronic acid in recommended doses, although less often.

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

Osteonecrosis

Cases of osteonecrosis of the jaw are described, mainly in patients with oncological diseases against the background of treatment with bisphosphonates, including zoledronic acid. Many of these patients received simultaneous therapy with glucocorticosteroids or chemotherapy. 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, as well as 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, simultaneous therapy (chemotherapy, radiation therapy, anti-angiogenic drugs, glucocorticosteroids), concomitant conditions (anemia, coagulopathy, infection, previous oral disease). Before using bisphosphonates in patients with cancer, you should conduct a dental examination and perform the necessary preventive procedures, as well as recommend strict observance of oral hygiene.

During treatment with bisphosphonates, dental invasive interventions should be avoided whenever possible. In patients with osteonecrosis of the jaw that has arisen against the background of bisphosphonate therapy, conducting an invasive dental intervention can contribute to a worsening of the condition. There is no evidence that interruption of bisphosphonate treatment before dental surgery reduces the risk of osteonecrosis of the jaw. The treatment plan for a particular patient should be based on an individual risk / benefit ratio.

Cases of osteonecrosis of other localization, including, pelvic bone, femur, external auditory canal are described, mainly in adult patients with oncological diseases receiving bisphosphonate therapy, incl. zoledronic acid.

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 to the supracondylar fossa.The described fractures appear after minimal trauma or spontaneously. Some patients experience pain in the thigh or groin, often accompanied by signs of stress fractures based on the results of visualized diagnostic studies that occur weeks and months before the development of a full (completed) fracture of the femur. Fractures often occur on both sides, therefore, if a femoral fracture occurs in a patient receiving bisphosphonate therapy, a contralateral femur examination should be performed. It was also reported about the slow healing (fusion) of these fractures. Reports of atypical hip fractures in patients treated with zoledronic acid have been reported, but the causal relationship of these fractures to zoledronic acid therapy has not been established. The decision to discontinue drug therapy in patients with suspected atypical femur fracture before the survey should be based on an individual assessment of the relationship between expected benefit and possible risk.

Patients receiving drug therapy Zoledronic acid, should be warned about the need to inform medical personnel of any pain in the hip or groin; Each patient who complains of such symptoms should be examined before identifying a possible incomplete (incomplete) fracture of the femur.

Muscle pain

In clinical practice, there have been reports of infrequent cases of development of pain in bones, joints, and muscles that are severe and, in some cases, limiting the ability to work, against the background of bisphosphonate treatment, zoledronic acid. These symptoms developed during the period from one day to several months after the start of treatment. After discontinuation of treatment, the resolution of symptoms is noted in most patients. In several patients, the symptoms recurred when the therapy was resumed or another bisphosphonate was used.

Hypocalcemia

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

Care should be taken when using the drug Zoledronic acid simultaneously with other drugs that can cause hypocalcemia, as this can lead to synergistic interaction and the development of severe hypocalcemia. Before starting therapy with the drug Zoledronic acid should determine the level of calcium in the serum and correct hypocalcemia. Patients should receive adequate calcium and vitamin supplementation D.

Patients receiving drug therapy Zoledronic acid, should not simultaneously receive the drug Aklasta, as well as other bisphosphonates. Efficacy and safety of the drug Zoledronic acid in pediatric practice to date not established.

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

Data on the effect of zoledronic acid on the ability to drive vehicles are absent. However, one should remember about the possible occurrence of dizziness and confusion during therapy with zoledronic acid.

Form release / dosage:Concentrate for solution for infusion, 4 mg / 5 ml.

Packaging:

To 5 ml of the drug in a colorless plastic bottle, corked with a rubber stopper, coated with an aluminum cap with a plastic snap-off lid.

1 bottle with instructions for use in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-003688

Date of registration:20.06.2016 / 27.04.2017

Expiration Date:20.06.2021

The owner of the registration certificate:MIR-FARM, LLC MIR-FARM, LLC Russia

Manufacturer: & nbsp

Pharmidea Latvia

Representation: & nbspMIR-FARM LLC MIR-FARM LLC Russia

Information update date: & nbsp15.10.2017

Illustrated instructions

Instructions

Zoledronic acid (Zoledronic acid)