Blaztera - instructions for use, doses, side effects, contraindications

Zoledronic acid refers to highly effective bisphosphonates that have a selective effect on bone tissue. The drug inhibits the resorption of bone tissue, acting on 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 have undesirable effects on the formation, mineralization and mechanical properties of 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.

Zoledronic acid, suppressing proliferation and inducing apoptosis, has a direct antitumor effect against 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 demonstrated an anti-angiogenic effect in animals.

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 mean time to relapse (albumin adjusted serum calcium concentration 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, serum concentration increases rapidly, reaching a maximum (C_mOh) 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_mOh after 24 hours with a further long period of low concentrations not exceeding 0.1% of C_mOh, until repeated 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 elimination of the drug from the systemic blood flow, with a half-life (T_1/2) - 0,24 h and 1,87 h accordingly, 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% is found. The remaining amount 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, pop, 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 (KK = 20 ml / min) and moderate renal failure (CK = 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, tumor-induced hypercalcemia, and reduced need for radiotherapy).

Contraindications:

Hypersensitivity to zoledronic acid, other bisphosphonates or any other components that make up the drug.
Initial severe impairment of kidney function (creatinine clearance 530 ml / min).
Pregnancy for the period of breastfeeding.
Children and adolescence (safety and efficacy have not been studied).

Carefully:

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 / L or <4.5 mg / dl) is not required. Infusion is performed under condition of adequate hydration of the patient (introduction of 0.9% sodium chloride solution before, simultaneously or after infusion of eiodernic acid).Repeated administration of the drug in 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 serum 2.7 mmol / L below) or in the 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.

Multiple myeloma and metastatic bone damage with solid tumors

The dose of Blastery ® depends on the initial clearance of creatinine (CK), 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.

The initial value of the SC (ml / min)	The recommended dose of Blazter®
>60	4.0 mg
50-60	3.5 mg
40-49	3.3 mg
30-39	3.0 mg

After initiation of zoledronic acid therapy, serum creatinine should be determined before each dose of the drug is administered. If there are violations of kidney function, the next administration of the drug should be postponed.Impaired renal function is determined by the following parameters:

- for patients with normal baseline creatinine values (<1.4 mg / dL), an increase of 0.5 mg / dl.

- for patients with abnormalities of baseline creatinine level (> 1.4 mg / dl) - an increase of 1 mg / dl.

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.

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

The solution is prepared in aseptic conditions. The contents of the vial (4 mg of zoledronic acid) are dissolved in 5 ml of water for injection and gently shaken until completely dissolved. The resulting solution with the required dose is diluted in 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 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 mild. Criteria for the frequency of adverse reactions: very often (≥1 / 10), often (≥1 / 100, <1/10), sometimes (≥ / 1000, <1/100), rarely (≥ / 10000, <1/1000) , very rarely (<1/10000), including individual messages.

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

From the peripheral nervous system and the central 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.

On the part of 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 osteomuscular system: often - pain in the bones, myalgia, arthralgia generalized pain; sometimes - muscle cramps.

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

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

From the immune system: sometimes - reactions of increased sensitivity; rarely - angioedema.

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

Local reactions: pain, irritation, puffiness, the formation of infiltration 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.

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.

Overdose:

Symptoms: exacerbation, symptoms of hypocalcemia.

Treatment: administration of calcium gluconate.

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 data obtained in in vitro studies, zoledronic acid has no significant binding 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, since the simultaneous action of these drugs is manifested by an increase in the duration of the 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, for example Ringer's solution.

Special instructions:

Treatment with zoledronic acid should be performed under the supervision of a physician with experience in the use of bisphosphonates.

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 creatinine concentration has returned to values that are within 10% of the baseline value.

Before infusion, ensure adequate hydration of the patient. 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, there is usually 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 of solid tumors with zoledronic acid, it should be taken into account that the therapeutic effect occurs 2-3 months after the start of treatment.

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 above complications decreases with the introduction of zoledronic acid at a dose of 4 mg for at least 15 minutes, the possibility of renal dysfunction persists.

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.

Cases of osteonecrosis of the jaw in cancer patients have been described against the backdrop of antitumor treatment, including bisphosphonates. Many patients had signs of a local infectious inflammatory process, including osteomyelitis. Prior to treatment with bisphosphonates is necessary to provide dental examination and appropriate preventive treatments in patients with risk factors (concomitant therapy - chemotherapy, radiation therapy, corticosteroids, concomitant diseases - anemia, coagulopathy, infection with diseases of the oral cavity, poor oral hygiene).

During the treatment of these patients should, if possible, avoid dental operations. There is no evidence that discontinuing bisphosphonate treatment before dental interventions reduces the risk of osteonecrosis of the jaw. The treatment plan for a particular patient should be based on an individual risk / benefit ratio.

Form release / dosage:

Lyophilizate for the preparation of a solution for infusions of 4 mg in bottles of colorless glass.

Packaging:

Liofilizate for the preparation of a solution for infusions of 4 mg in bottles of colorless glass, ukuporennyh brombutilovoy stopper and crimped aluminum cap with a protective plastic cover orange. 1 bottle with instructions for use in a cardboard pack.

Storage conditions:

In a dry, protected from light place at a temperature of no higher than 25 ° C.

Keep out of the reach of children!

Shelf life:

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-002101/10

Date of registration:16.03.2010 / 14.01.2013

Expiration Date:Unlimited

The owner of the registration certificate:Dr. Reddy's Laboratories Ltd.Dr. Reddy's Laboratories Ltd. India

Manufacturer: & nbsp

DR. REDDY`S LABORATORIES, LTD. India

Representation: & nbspDR REDDY'S LABORATORIS LTD. DR REDDY'S LABORATORIS LTD. India

Information update date: & nbsp18.02.2017

Illustrated instructions

Instructions

Blazter® (Blaztere)