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

One bottle contains: active substance: zoledronic acid monohydrate 4.26 mg (corresponding to zoledronic acid anhydrous 4.0 mg). Excipients: D-mannitol 220.0 mg, Sodium citrate two-water 27.34 mg in terms of anhydrous 24.0 mg.

Solvent in ampoule: water for injection 5 ml.

Solvent in a polymer container: Sodium chloride 9.0 g, Water for injection up to 1 liter.

Description:

Lyophilized powder or porous mass of white or almost white color.

Solvent in ampoule: Transparent, colorless, odorless liquid.

Solvent in a polymer container: Transparent, colorless, odorless liquid.

Pharmacotherapeutic group:Bone resorption inhibitor - bisphosphonate.

ATX: & nbsp

M.05.B.A.08 Zoledronic acid

Pharmacodynamics:

Zoledronic acid refers to highly effective bisphosphonates, selectively acting 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 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 with metastases in the bones. In vivo: inhibits the resorption of bone tissue 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, in particular, by 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. 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 human breast cancer cells through the extracellular matrix, 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 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 multiple myeloma and breast cancer with at least one bone focus, the effectiveness of zoledronic acid at a dose of 4 mg is comparable to pamidronic acid at a dose of 90 mg.

In patients with tumor hypercalcemia, the effect of the drug is characterized by a decrease in serum calcium and calcium excretion 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, 8 mg, pamidronic acid at a dose of 90 mg or placebo in both bone metastases and hypercalcemia.

Pharmacokinetics:

Data on the pharmacokinetics for bone metastases were obtained after a 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. After the start of the infusion, the serum concentrations increase 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 re-infusion for 28 days.

Zoledronic acid, administered intravenously, is excreted by the kidneys in three stages: a rapid two-phase elimination of the drug from the systemic circulation with half-life periods of 0.24 h and 1.87 h and a long phase with a terminal elimination half-life of 146 h.There was no cumulation of the drug with repeated administration every 28 days. Zoledronic acid is not metabolized and is excreted by the kidneys in an unchanged form. Zoledronic acid It does not inhibit the isoenzymes of the cytochrome P450 system in humans. 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 30% decrease in zoledronic acid 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 failure 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 liver function state does not significantly affect the pharmacokinetics of zoledronic acid.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 64 patients enrolled in the study. The analysis of the population showed that in patients with severe renal (creatinine clearance <20 ml / min) or moderate renal failure (creatinine clearance 20-50 ml / min) the calculated clearance of zoledronic acid is 37% and 72%, respectively, of the zoledronic acid clearance values in patients with creatinine clearance> 84 ml / min. Limited pharmacokinetic data were obtained for patients with severe renal insufficiency (creatinine clearance less than 30 ml / min).

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

Indications:

Hypercalcemia (concentration of albumin-corrected serum calcium ≥12 mg / dL or Zmmol / L), induced by malignant tumors.

Metastatic bone damage in malignant solid tumors and myeloma (to reduce the risk of pathological fractures, compression of the spinal cord, hypercalcemia caused by the tumor,and reducing the need for radiotherapy).

Contraindications:

Hypersensitivity to zoledronic acid, other bisphosphonates or any other components that make up the drug.
Severe renal insufficiency (creatinine clearance less than 30 ml / min).
Pregnancy and lactation.
Child and adolescence (safety and efficacy not established).

Carefully:

With caution in the violation of renal function, expressed by liver failure (no data on use), in patients with bronchial asthma, sensitive to acetylsalicylic acid.

Pregnancy and lactation:

Contraindicated use during pregnancy and breastfeeding.

Dosing and Administration:

Intravenously drip for at least 15 minutes.

With bone metastases and osteolytic foci with multiple myeloma the recommended dose 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 MB per day.

With hypercalcemia (calcium concentration with an albumin correction of ≥ 12 mg / dL or 3 mmol / L) due to malignant tumors, the recommended dose is 4 mg, once.Infusion is performed under the condition of adequate hydration of the patient.

Precautions for 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.

Bone metastases of common malignant tumors and myeloma

The dose of zoledronic acid depends on the baseline creatinine clearance (CK) calculated by the Cockcroft-Gault formula. With severe renal dysfunction (CK <30 ml / min), zoledronic acid is not recommended.

Recommended doses for mild or moderate renal impairment (creatinine clearance values of 30-60 ml / min) are given below.

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

Determination of 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 baseline creatinine abnormalities (> 1.4 mg / dl), an increase in serum creatinine by 1 mg / dl.

Therapy with zoledronic acid is resumed only after the level of creatinine reaches values that exceed the original value by no more than 10%, in the same dose that was used before the interruption of treatment.

Instructions for preparing a solution for infusions

The solution is prepared in aseptic conditions; 4 mg is dissolved in 5 ml of water for injection, 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. Do not use solutions containing calcium. Prepared solution is preferably used immediately after preparation. The unused solution can be stored in the refrigerator at a temperature of + 2-8 ° C for not more than 24 hours. The solution stored in the refrigerator should be warmed to room temperature before introduction.

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, <1/1000) , very rarely (<1/10000), including individual messages.

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

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

On the part of the organs of vision: often - conjunctivitis; sometimes - blurred vision; very rarely - uveitis, episcleritis.

From the gastrointestinal tract: 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 side of the cardiovascular system: sometimes - marked increase or decrease in blood pressure; rarely - aetiology.

From the excretory system: often violations of kidney function, sometimes acute renal failure, hematuria, proteinuria.

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

Violations of 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, sickness, fever), sometimes - asthenia, peripheral edema, chest pain, weight gain.

When treating 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, a reduction in blood pressure with zoledronic acid therapy resulted in syncope or circulatory collapse.

Overdose:

In acute overdose of zoledronic acid, renal dysfunction, including kidney failure, changes in electrolyte composition, including concentration of calcium, phosphate and magnesium in blood plasma, are possible. In case of an accidental overdose, the patient should be under constant supervision. In the case of hypocalcemia, accompanied by clinical manifestations, an infusion of calcium gluconate is indicated.

Interaction:

Solvents that contain calcium, such as Ringer's solution, can not be used as solvents.

With simultaneous use with antitumor drugs, diuretics, antibiotics, analgesics, clinically significant interactions have not been observed.

Bisphosphonates and aminoglycosides have a unidirectional effect on the concentration of calcium in the blood serum, so when they are concurrently prescribed, the risk of hypocalcemia and hypomagnesemia increases. 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.

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

In patients with multiple myeloma, there may be an increased risk of kidney dysfunction with intravenous bisphosphonate administration in combination with thalidomide.

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.

The drug should not be mixed with other drugs.

Special instructions:

Before the infusion should be convinced of adequate, hydration in the patient. If necessary, the introduction of saline 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 administration of the drug, constant monitoring of the concentration of calcium, magnesium, phosphorus and creatinine in the blood serum is necessary.

On the background of therapy with zoledronic acid should closely monitor the function of the kidneys. Risk factors for the occurrence of renal dysfunction include dehydration preceding renal failure, multiple doses of zoledronic acid or other bisphosphonates, as well as the use of nephrotoxic drugs and too rapid administration of the drug.

It should be borne in mind that in the appointment of other bisphosphonates to patients with bronchial asthma sensitive to acetylsalicylic acid, there have been cases of bronchospasm, but with the use of zoledronic acid, such cases have not yet been documented.

Against the backdrop of treatment with bisphosphonates, including zoledronic acid, cases of osteonecrosis of the jaw are described in cancer patients, so before the treatment with bisphosphonates it is necessary to provide a dental examination and if there are risk factors (anemia, coagulopathies, infections, poor hygiene or oral diseases, concomitant chemo- or radiotherapy, therapy, corticosteroid treatment) to conduct appropriate preventive procedures.

Against the background of treatment with zoledronic acid, patients with risk factors, whenever possible, should avoid dental surgical interventions.

Contraindicated use during pregnancy and breastfeeding. Contraindicated in the use of the drug in childhood and adolescence, as safety and effectiveness of the application are not established.

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

The study of the effect of the drug on the ability to drive vehicles and work with complex mechanisms was not carried out. In the case of side effects from the central nervous system, it is recommended to avoid activities requiring increased attention and speed of mental and motor reactions.

Form release / dosage:Lyophilizate for solution for infusion.

Packaging:

Lyophilizate, containing 4.0 mg of zoledronic acid (in terms of anhydrous substance), in bottles of dark neutral glass with a capacity of 10 ml, hermetically sealed with stoppers made of rubber and covered with aluminum-plastic caps.

For 5 ml of solvent ("Water for Injection") into neutral glass ampoules having a tension ring for dissection, or with a fracture point or without it.

For 100 ml of solvent ("Sodium chloride solution for infusion 0.9%") into PVC containers for single-use infusion solutions of CPIR with two sterile ports. One container is placed in a bag of polyethylene or polyethylene polyamide film.

1 bottle with the drug and 1 ampoule with the solvent ("Water for Injection") in the contour squamous packaging. 1 circuit cell pack together with a knife for opening ampoules or a scarifier ampoule and instructions for use in a cardboard bundle.

1 contour pack with an ampoule opener or ampoule scarifier, 1 container in a solvent bag ("Sodium chloride solution for infusions 0,9%") and instructions for use in a cardboard pack.

When you pack the solvent ("Water for Injection") into import ampoules that have a ring of tension for opening, or in ampoules with a fracture point, the knife or scarifier is not injected into the ampoule.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C. The reconstituted solution is at a temperature of 5 to 25 ° C.

Keep out of the reach of children.

Shelf life:

Lyophilizate - 3 years.

The reconstituted solution is 24 h.

The solvent ("Water for Injection") is 5 years.

Solvent ("Sodium chloride solution for infusion 0.9%") - 3 years.

The shelf life of the kit is set according to the component with the shortest shelf life.

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

Terms of leave from pharmacies:On prescription

Registration number:LS-002724

Date of registration:19.12.2011

The owner of the registration certificate:FARM-SYNTHESIS, CJSC FARM-SYNTHESIS, CJSC Russia

Manufacturer: & nbsp

FARM-SYNTHESIS, CJSC Russia

Information update date: & nbsp18.10.2015

Illustrated instructions

Instructions

Resorba (Resorba)