Zoledrex® (Zoledrex®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Dosage form: & nbsp

Lyophilizate for solution for infusion.

Composition:

1 bottle contains:

active substance: 4 mg of zoledronic acid (anhydrous), which corresponds to 4.2 mg of zoledronic acid monohydrate;

Excipients: Mannitol 220.0 mg, sodium citrate 24.0 mg.

Description:

Lyophilized mass in the form of a flat cake, individual aggregates or white powder.

Pharmacotherapeutic group:Inhibitor of bone resorption, bisphosphonate.
Pharmacodynamics:

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. Zoledronic acid inhibits the activity of osteoclasts without exerting undesirable effects on the formation, mineralization and mechanical properties of bone tissue.

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.In preclinical studies it was shown that zoledronic acid:

  • In vivo: inhibits bone resorption by osteoclasts, changes the microenvironment of the bone marrow, reduces the growth of tumor cells; exhibits anti-angiogenic activity.
    Suppression of bone resorption is clinically accompanied, including a marked decrease in pain.
  • In vitro: inhibits the proliferation of osteoblasts, exhibits direct cytostatic and pro-apoptotic activity, a synergistic cytotoxic effect with antitumor drugs; anti-adhesive and anti-invasive activity.

In patients with prostate cancer 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.

Pharmacokinetics:

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

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

The connection with plasma proteins is 56%. Not exposed to metabolism. The low affinity of zoledronic acid for blood elements is noted.

It is excreted by the kidneys in unchanged form in 3 stages: 1 and 2 phases - rapid removal of the drug from the systemic blood stream, with half-life (T1) - 0.24 h and 1.87 h respectively, and 3 phase - long, with T1 - 146 h. There was no cumulation of the drug with repeated injections every 28 days.During the first 24 hours in urine, 23-55% are found. 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; 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 the drug, sex, age, race and body weight of the patient. 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).

Kidney clearance is positively correlated with creatinine clearance (CC) and is 42-108% of CC, averaging 55-113%. In patients with severe (CC <20 ml / min) and moderate renal failure (CC 20-50 ml / min), the zoledronic acid clearance is 37% and 72%, respectively, of clearance values ​​in patients with CC> 84 ml / min.

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 myeloma (to reduce the risk of pathological fractures, spinal cord compression, hypercalcemia,associated with a tumor and reducing the need for radiotherapy).

Contraindications:

  • Hypersensitivity to zoledronic acid, other bisphosphonates or any other components that make up the drug;
  • initial severe impairment of renal function (creatinine clearance <30 mL / min);
  • pregnancy and the period of breastfeeding;
  • children and adolescence (safety and efficacy of the application 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 in the appointment of zoledronic acid in patients with bronchial asthma caused by acetylsalicylic acid (with the use of other bisphosphonates, there were cases of bronchospasm).

Dosing and Administration:

Zoledrex® is administered intravenously drip, for at least 15 minutes.

Hypercalcemia in malignant neoplasms

At a concentration of albumin corrected serum calcium> 12 mg / dL or 3 mmol / L, the maximum recommended dose is 4 mg. Before the infusion of Zoledex®, it is necessary to check the concentration of creatinine in the blood serum.

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 serum, 2.7 mmol / L and below) or in the case of refractory ™ to the first administration. Repeatedly Zoledrex® is administered at a 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.

In case of impaired renal function

In patients with mild or moderate renal failure (serum creatinine <400 μmol / L or 4.5 mg / dl), dose adjustment is not required.

Multiple myeloma and metastatic bone damage with solid tumors

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

Initial clearance of creatinine (ml / min)

The recommended dose of Zoledrax®

>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 Zoledex®. 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): increase in creatinine concentration by> 0.5 mg / dl;
  • for patients with a changed baseline serum creatinine concentration (> 1.4 mg / dL): increase in creatinine concentration by> 1.0 mg / dl.

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

Patients should additionally to the therapy of zoledronic acid appoint calcium inwards at a dose of 500 mg per day and vitamin D inside at a dose of 400 IU per day.

Instructions for preparing a solution for infusions

From a concentrate of 4mg / 5ml (contents of 1 bottle), a solution for infusions is prepared in aseptic conditions. Before the introduction of the drug dilute the concentrate (the contents of 1 bottle or a smaller volume if required) 100 ml of 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 + 2-8 ° 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 + 2-8 ° C and the end of the drug administration should not exceed 24 hours.

The solution of Zoledrax® 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:

Undesirable reactions associated with the use of zoledronic acid are usually mild.Criteria for the frequency of adverse reactions: very often (≥1 / 10), often (≥1 / 100, <1/10), sometimes (≥1 / 1000, <1/100), rarely (≥1 / 10,000, <1 / 1000), very rarely (<1/10 000, including individual cases).

On the part of the organs of hematopoiesis: often - anemia, sometimes - thrombocytopenia, leukopenia; rarely - pancytopenia.

From the nervous system: often - headache; sometimes - dizziness, paresthesia, taste disorders, hypoesthesia, hyperesthesia, tremor, anxiety, sleep disturbance; rarely confusion.

From the side of the organ of vision: often - conjunctivitis; sometimes - blurred vision, 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.

From the skin and skin appendages: sometimes - itching, rash (including erythematous and macular), increased sweating.

From the musculoskeletal system: often - pain in the bones, myalgia, arthralgia, generalized pain; sometimes - muscle cramps.

From the cardiovascular system: sometimes - marked increase in blood pressure; rarely - aetiology.

From the urinary system: often - impaired renal function; sometimes - acute renal failure, hematuria, proteinuria.

From the immune system: sometimes - allergic reactions; rarely - angioedema.

Other: often - fever, flu-like condition (including chills, malaise, fever); sometimes - asthenia, peripheral edema, pain in the chest, weight gain.

Local reactions: pain, irritation, swelling, the formation of an infiltrate at the site of administration of the drug.

From the laboratory indicators: very often - hypophosphatemia; often - an increase in the concentration of creatinine and urea in the blood, hypocalcemia; sometimes - hypomagnesemia, rarely - hyperkalemia, hypokalemia; hypernatremia.

On the background of zoledronic acid therapy, the following undesirable phenomena were noted in clinical practice, regardless of the presence of a causal relationship with the drug:

In the treatment of patients with bisphosphonates, including zoledronic acid, sometimes there were cases of osteonecrosis of the jaw (usually after extraction of the tooth or other dental intervention).

In very rare cases, with the use of zoledronic acid, there was a decrease in blood pressure leading to syncope or circulatory collapse, mainly in patients with risk factors, the development of drowsiness, bronchoconstriction, and atrial fibrillation.

Overdose:

Symptoms: In acute overdosage of zoledronic acid (limited data), renal dysfunction, including kidney failure, changes in electrolyte composition, including calcium, phosphate and magnesium concentrations in the blood plasma, were noted. 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:

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 weakly binds to plasma proteins and does not inhibit the isoenzymes of the cytochrome P450 system.

It is advisable to use caution when using bisphosphonates and aminoglycosides at the same time, because simultaneous administration of these drugs causes a longer decrease in the concentration of calcium in the blood plasma.

Caution is needed when using zoledronic acid with drugs potentially having a nephrotoxic effect.

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

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

Special instructions:

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.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, 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 kidney function in this category of patients is necessary.

When deciding on the treatment of patients with bone metastases with zoledronic acid, it should be taken into account that the therapeutic effect occurs 2-3 months after the start of treatment with zoledronic acid.

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.

Since there are limited 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.

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.

Before each administration of zoledronic acid, the serum creatinine concentration should be determined. At the beginning of treatment with a drug of patients with bone metastases that have poor renal and moderate renal function, zoledronic acid is recommended in low doses. In patients whose renal dysfunction occurred during therapy with zoledronic acid, therapy can be continued only after the serum creatinine concentration returns to values ​​that are within 10% of the baseline value. 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.

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.

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:

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:

Lyophilizate for the preparation of a solution for infusions of 4 mg.

Packaging:

4 mg of active ingredient per glass bottle.

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

Storage conditions:

Store at a temperature not exceeding 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-001476
Date of registration:06.02.2012
The owner of the registration certificate:ANSTAR, AG ANSTAR, AG Switzerland
Manufacturer: & nbsp
Representation: & nbspANSTAR AG ANSTAR AG Switzerland
Information update date: & nbsp14.09.2015
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