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

active substance: zoledronic acid in terms of anhydrous substance - 4.0 mg; Excipients: Mannitol - 220.0 mg, sodium citrate - 24.0 mg. water for injection - up to 5 ml.

Description:

Transparent colorless liquid.

Pharmacotherapeutic group:Bone resorption inhibitor, bisphosphonate

ATX: & nbsp

M.05.B.A.08 Zoledronic acid

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.

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 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; shows antiangiogenic 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 in the urine. 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 average time to relapse (adjusted for albumin serum calcium concentration 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.

Pharmacokinetics:

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

After the onset of infusion of zoledronic acid, serum concentrations increase rapidly, reaching a maximum serum concentration (C_max) 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_max after 24 hours with a further long period of low concentrations not exceeding 0.1% of C_max before re-infusion for 28 days. The connection with plasma proteins is 56%. Not exposed to metabolism. Low affinity of zoledronic acid to blood components is noted.

It 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_1/2) - 0,24 h and 1,87 h respectively, and 3 phase - long, with T_1/2- 146 h. No cumulation of the drug was observed 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; with feces less than 3% is output.The total serum clearance of the drug 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. Increasing the duration of infusion 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). The renal clearance of zolendronic acid positively correlates with creatinine clearance (CC) and is 42-108% of CC, averaging 55-113%. In patients with severe (KK ≤20 ml / min) and moderate renal failure (QC 20 to 50 ml / min), 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, tumor-induced hypercalcemia, and reduced need for radiotherapy).

Contraindications:

Hypersensitivity to zoledronic acid, other bisphosphonates, other components of the drug.
Initial severe impairment of kidney function (creatinine clearance ≤30 ml / min).
Pregnancy and lactation.
Children and adolescence (safety and efficacy 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 using zoledronic acid in patients with bronchial asthma, sensitive to acetylsalicylic acid (with the use of other bisphosphonates, there have been cases of bronchospasm).

Dosing and Administration:

Intravenously drip for at least 15 minutes.

Hypercalcemia due to malignant tumors

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 it is necessary to check the concentration of creatinine in the blood serum. Correction of the dosing regimen in patients with mild or moderate renal failure (serum creatinine concentration <400 μmol / d or <4.5 mg / dl) is not required. Infusion is performed under condition of adequate hydration of the patient (introduction of 0.9% solution of sodium chloride before, simultaneously or after 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., achieving a concentration of calcium ions in the blood serum 2.7 mmol / L and below) or in case of refractoriness to the first administration. The interval between the first and repeated administration should be at least 1 week to assess the effect.

If it is necessary to re-introduce zoledronic acid, the serum creatinine concentration should be determined before each infusion.

Metastatic bone damage in malignant solid tumors and myeloma

The recommended dose of the drug in patients without impaired renal function (CK> 60 ml / min) is 4 mg every 3-4 weeks.

The dose of the drug in patients with impaired renal function depends on the baseline creatinine clearance calculated by the Cockcroft-Gault formula.

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

The initial value of the SC (ml / min)	The recommended dose of VeraClast
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 with VeraClast, the 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 normal baseline creatinine values (<1.4 mg / dL), increase serum creatinine concentration by 0.5 mg / dl.

- for patients with abnormalities of the initial creatinine value (> 1.4 mg / dL), an increase in the serum creatinine concentration by 1 mg / dl.

The drug therapy is resumed only after the creatinine concentration reaches values within 10% of the initial value, the same dose that was used before the interruption of treatment.

Patients should, in addition to therapy with VeraClast, prescribe calcium inwards at a dose of 500 mg per day and vitamin D inside at a dose of 400 IU / day.

Instructions for preparing a solution for infusions

Before administration, a solution for infusion is prepared from the concentrate. The solution is prepared in aseptic conditions. Concentrate (the contents of 1 vial or a smaller volume, if required) are diluted in 100 ml of a solution for calcium-free infusions (0.9% sodium chloride solution or 5% dextrose solution). Prepared solution is preferably used immediately after preparation. Unused immediately 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 kept indoors until reaching room temperature.

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 zoledronic acid solution 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 poorly expressed.Criteria for the frequency of adverse reactions: very often (≥1 / 10), often (≥1 / 100, <1/10), sometimes (≥1 / 1000, <1/100), rarely - (≥1 / 10000, <1 / 1000), very rarely (<1/10000), including individual messages.

From the hematopoiesis: often - anemia, sometimes - thrombocytopenia, leukopenia; rarely - pancytopenia.

From the nervous system: often - headache; sometimes - dizziness, paresthesia, taste disorders, hypoesthesia, hyperesthesia, tremor, anxiety, sleep disorders; 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, dyspepsia, 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 - hypersensitivity reactions; rarely - angioedema.

From the laboratory indicators: very often - hypophosphatemia; often - increased serum creatinine and urea concentrations, hypocalcemia; sometimes hypomagnesemia, hypokalemia; rarely - hyperkalemia, hypernatremia.

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

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

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 drugs (antitumor agents, diuretics, antibiotics, analgesics) with zoledronic acid, no clinically significant interactions were noted.

According to data obtained in in vitro studies, 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 simultaneously, since the simultaneous action of these drugs prolongs the period of decrease in serum calcium concentration.

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 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.

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 worsening of the function of the nights, progression of renal failure and the need for hemodialysis in the first or one-time application 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.

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 a weak and moderate function, it is recommended to use zoledronic acid in reduced 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:

Information on the effect of zoledronic acid on the ability to drive vehicles and other mechanisms are absent.

Form release / dosage:

Concentrate for the preparation of a solution for infusions of 4 mg / 5 ml.

Packaging:

For 5 ml of the drug in colorless plastic bottles, hermetically sealed with rubber stoppers, with caps coated with aluminum or aluminum-plastic caps. 1 bottle with instructions for use in a pack of cardboard. For 50, 80 bottles with an equal number of instructions for use in a box of cardboard (for hospitals).

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-006249/10

Date of registration:01.07.2010 / 12.08.2016

Expiration Date:Unlimited

The owner of the registration certificate:VEROPHARM SA VEROPHARM SA Russia

Manufacturer: & nbsp

VEROPHARM SA Russia

Information update date: & nbsp05.02.2017

Illustrated instructions

Instructions

Veroclast (Veroklast)