Zometa concentrate for infusions 4mg/5ml №1

Indications

- bone metastases of common malignant tumors (prostate cancer, breast cancer) and myeloma, including to reduce the risk of pathological fractures, compression of the spinal cord, hypercalcemia caused by a tumor, and reducing the need for radiotherapy or surgical interventions on the bone;

- hypercalcemia due to a malignant tumor.

Dosage and administration

At bone metastases of common malignant tumors and multiple myeloma adults and elderly patients The recommended dose is 4 mg. Before the introduction of the drug diluted concentrate (the contents of 1 bottle) in 100 ml of solution for infusion, not containing Calcium (0.9% sodium chloride solution or 5% dextrose solution). Zometa is introduced into / into the drip; duration of infusion - not less than 15 minutes. The multiplicity of appointments - every 3-4 weeks.

Patients should also be prescribed calcium orally at a dose of 500 mg / day and vitamin D orally at a dose of 400 IU / day.

At hypercalcemia due to malignant tumor (calcium concentration corrected for albumin ≥12 mg / dL or 3 mmol / l), adults and elderly patients The recommended dose is 4 mg.Before the introduction of the drug diluted concentrate (the contents of 1 bottle) in 100 ml of solution for infusion, not containing calcium (0.9% sodium chloride solution or 5% dextrose solution). Zometa is introduced into / into the drip; duration of infusion - not less than 15 minutes. To ensure adequate hydration of the patient, the introduction of saline is recommended before, in parallel or after infusion of Zometa.

The decision on treatment Zometoy hypercalcemia due to a malignant tumor, at patients with severe renal impairment should be taken only after a thorough assessment of the risk of using the drug and the expected benefits of therapy. Patients whose serum creatinine concentration is <400 mcmol / L or <4.5 mg / dL do not need to adjust the dosage regimen.

At bone metastases of common malignant tumors and multiple myeloma Zometa dose depends on the initial level of QC, calculated by the Cockroft formula. It is not recommended to use Zometa in patients with severe impaired renal function (CC values ​​<30 ml / min).

Recommended doses in patients with mild or moderately impaired renal function (CC values ​​30–60 ml / min) are given below.

After starting Zometa therapy, the concentration of serum creatinine should be determined before the administration of each dose of the drug. If any renal impairment is found, the next injection of Zometa should be postponed.Renal impairment is determined by the following parameters:

- for patients with normal creatinine baseline values ​​(<1.4 mg / dL) - an increase in serum creatinine concentration by 0.5 mg / dL;

- for patients with abnormal creatinine levels (> 1.4 mg / dL) - an increase in serum creatinine concentration by 1 mg / dL.

Zomet's therapy is resumed only after the creatinine level reaches values ​​within the initial value of ± 10% in the same dose that was applied before interrupting treatment.

Terms of preparation of the solution for infusion

Concentrate 4 mg / 5 ml (contents of 1 bottle) to prepare a solution for infusion. The solution should be prepared under aseptic conditions. Before the introduction of the drug diluted concentrate (the contents of 1 bottle or a smaller volume, if required), 100 ml of solution for infusion, not containing calcium (0.9% sodium chloride solution or 5% dextrose). Prepared Zometa solution is preferably used immediately after preparation. The solution that is not used immediately can be stored in a refrigerator at a temperature of 2 ° -8 ° C for no more than 24 hours. Before the introduction, the solution should be kept indoors until it reaches room temperature.

The total time between dilution of the concentrate, storage of the prepared solution in a refrigerator at a temperature of 2 ° -8 ° C and the end of the introduction of the drug should not exceed 24 hours.

Zometa solution should not be mixed with any other drugs.Zomet should not be mixed with any solutions containing calcium or any other divalent cations, such as Ringer's lactate solution. The prepared solution of zoledronic acid must be administered using a separate system for IV infusion.

Adverse effects

Information about the frequency of adverse reactions when using Zometa at a dose of 4 mg is based mainly on data obtained during long-term therapy. Adverse reactions associated with the use of Zometa, usually mild and transient; similar to those reported when using other bisphosphonates.

With on / in the introduction usually observed the development of influenza-like syndrome in almost 9% of patients, while there were bone pains, fever, general malaise, chills.

Occasionally (approximately 3% of patients) reported cases of arthralgia and myalgia.

Often (approximately 20% of patients), a decrease in renal calcium excretion was accompanied by a sharp decrease in the concentration of phosphorus, which was asymptomatic and did not require treatment. In approximately 3% of patients, serum calcium concentration decreased to hypocalcemia (without clinical manifestations).

There are reports of reactions from the gastrointestinal tract, such as nausea (5.8%) and vomiting (2.6%), after IV infusion Zometa.

Local reactions at the site of infusion, such as redness or swelling and / or pain, were observed in less than 1% of patients.

Anorexia was observed in 1.5% of patients who received Zomet at a dose of 4 mg.

There were several cases of rash or itching (less than 1%).

As with the use of other bisphosphonates, cases of conjunctivitis are reported - approximately 1%.

There are reports of impaired renal function (2.3%); however, other risk factors in patients in this group may also be relevant.

Based on a cumulative analysis of controlled studies, severe anemia (hemoglobin <8.0 g / dl) was reported in 5.2% of patients who received Zomet at a dose of 4 mg, compared with 4.2% who received placebo.

Undesirable reactions are listed below by 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 / 10 000, <1/1000 ), very rarely (<1/10 000), including individual messages.

From the side of blood-forming organs: often - anemia, sometimes - thrombocytopenia, leukopenia; rarely pancytopenia.

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

Special senses: often - conjunctivitis; sometimes blurred vision; very rarely - uveitis, episcleritis.

Gastrointestinal: often - nausea, vomiting, anorexia; sometimes - diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.

Respiratory: sometimes - shortness of breath, cough.

Dermatologic: sometimes itching, rash (including erythematous and macular), increased sweating.

Musculoskeletal system: often - bone pain, myalgia, arthralgia, generalized pain; sometimes muscle cramps.

Since the cardiovascular system: sometimes - a marked increase or decrease in blood pressure; rarely bradycardia.

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

On the part of the immune system: sometimes - hypersensitivity reactions; rarely - angioedema.

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

Local reactions: pain, irritation, swelling, formation of infiltration at the injection site.

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

It should be borne in mind that when using other bisphosphonates in patients with bronchial asthma sensitive to Acetylsalicylic acid, there were cases of bronchospasm, however, when using Zometa this phenomenon was not observed.

In one clinical study, when zolendronic acid was administered for 3 years in patients with postmenopausal osteoporosis (at a dose of 5 mg 1 time / year), the overall incidence of atrial fibrillation was 2.5% (96 people out of 3862) compared to 1.9% (75 people out of 3852) in the placebo group.The incidence of atrial fibrillation, accompanied by severe hemodynamic disturbances, was 1.3% (51 people out of 3862) and 0.6% (22 people out of 3852) for zoledronic acid and placebo, respectively. The reason for the increase in the frequency of atrial fibrillation during therapy with zoledronic acid in patients with postmenopausal osteoporosis has not been established.

In clinical studies with the use of zendronic acid (at a dose of 4 mg every 3-4 weeks) in patients with cancer, an increase in the frequency of atrial fibrillation was not observed.

The following adverse events were noted during Zomet therapy in clinical practice, regardless of whether there is a causal relationship with the drug: in treating patients with bisphosphonates (including Zomet), rare cases of osteonecrosis of the jaw (usually after tooth extraction or other dental interventions).

In very rare cases, the use of Zometa resulted in a decrease in blood pressure leading to syncope or circulatory collapse, mainly in patients with risk factors, the development of drowsiness, bronchoconstriction, atrial fibrillation, Anaphylactic reactions / shock and urticaria.

Contraindications

- pregnancy;

- lactation (breastfeeding);

- Hypersensitivity to zoledronic acid, other bisphosphonates and other components of the drug.

Use during pregnancy and lactation

Zometa's drug is contraindicated for use during pregnancy and lactation (breastfeeding).

Application for violations of the liver

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

Application for violations of kidney function

When deciding on the use of Zometa in patients with hypercalcemia caused by a malignant tumor, on the background of renal dysfunction, it is necessary to assess the patient's condition and to conclude whether the potential benefit from the drug predominates over the possible risk.

Before each administration of Zometa, the concentration of serum creatinine should be determined. At the beginning of drug treatment in patients with bone metastases with impaired renal function of weak and moderate severity, it is recommended to use Zomet in low doses. In patients whose renal impairment appears during Zomet's therapy, drug therapy can be continued only after the creatinine concentration returns to values ​​that are within 10% of the initial value.

Considering the possibility of impaired renal function when using bisphosphonates, including Zometa, and also due to the lack of comprehensive data on the clinical safety of the drug in patients with severely impaired renal function (serum creatinine concentration ≥400 μmol / l or ≥4.5 mg / dl in patients with hypercalcemia,due to a malignant tumor and ≥265 mcmol / l or ≥3.0 mg / dl in patients with malignant tumors with bone metastases) and the availability of very limited pharmacokinetic data in patients with initial severe renal impairment (CK≤30 ml / min), the use of Zometa this cohort of patients is not recommended.

Use in children

The efficacy and safety of using Zometa in pediatric practice has not yet been established.

special instructions

When deciding on the use of Zometa in patients with hypercalcemia caused by a malignant tumor, on the background of renal dysfunction, it is necessary to assess the patient's condition and to conclude whether the potential benefit from the drug predominates over the possible risk.

Before each administration of Zometa, the concentration of serum creatinine should be determined. At the beginning of drug treatment in patients with bone metastases with impaired renal function of weak and moderate severity, it is recommended to use Zomet in low doses. In patients whose renal impairment appears during Zomet's therapy, drug therapy can be continued only after the creatinine concentration returns to values ​​that are within the initial value of ± 10%.

Considering the possibility of impaired renal function when using bisphosphonates, including Zometa, and also due to the lack of comprehensive data on the clinical safety of the drug in patients with severely impaired renal function (serum creatinine concentration ≥400 μmol / l or ≥4.5 mg / dl in patients with hypercalcemia,due to a malignant tumor and ≥265 mcmol / l or ≥3.0 mg / dl in patients with malignant tumors with bone metastases) and the availability of very limited pharmacokinetic data in patients with initial severely impaired renal function (CC ≤ 30 ml / min), the use of Zometa this cohort of patients is not recommended.

Before infusion, ensure that the patient is adequately hydrated. If necessary, the introduction of saline is recommended before, in parallel or after infusion of Zometa. Patient overhydration should be avoided due to the risk of cardiovascular complications.

After the introduction of Zometa, constant monitoring of the concentration of calcium, phosphorus, Magnesium and creatinine in serum is necessary. With the development of hypocalcemia, hypophosphatemia, or hypomagnesaemia, it may be necessary to short-term additional administration of the relevant substances. Patients with untreated hypercalcemia, as a rule, have impaired renal function, therefore careful monitoring of renal function in this category of patients is necessary.

When deciding on Zomet treatment of patients with bone metastases in order to reduce the risk of pathological fractures, compression of the spinal cord, hypercalcemia caused by the tumor, and reduce the need for radiotherapy or surgery on the bone, it is necessary to take into account the therapeutic effect 2-3 months after starting Zometa.

There are separate reports of impaired renal function during the use of bisphosphonates.The risk factors for such complications include dehydration, previous renal failure, repeated administration of Zometa 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 is reduced provided that Zometa is administered at a dose of 4 mg for at least 15 minutes, the possibility of impaired renal function remains.

There have been cases of deterioration of renal function, progression of renal failure and the need for hemodialysis with the first or one-time use of Zometa.

Increased serum creatinine concentrations are also observed in some patients with long-term use of Zometa in recommended doses, although less often.

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

Cases of osteonecrosis of the jaw in cancer patients on the background of antitumor treatment, including bisphosphonates (including Zomet) are described. Many patients had signs of local 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 (including after tooth extraction, with periodontal diseases, and unsatisfactory fixation of dental prostheses).The known risk factors for osteonecrosis of the jaw are: cancer, cancer-related treatment (including Chemotherapy, radiation therapy, corticosteroids), comorbidities (including anemia, coagulopathy, infection, previous oral disease).

Before prescribing bisphosphonates to patients with oncological diseases, a dental examination should be carried out and appropriate preventive procedures should be carried out, as well as strict adherence to the rules of oral hygiene should be recommended.

During the treatment of these patients, dental surgery should be avoided whenever possible. There is no evidence that interrupting treatment with bisphosphonates prior to dental interventions reduces the risk of osteonecrosis of the jaw. The treatment plan for a particular patient should be based on an individual assessment of the risk / benefit ratio.

In clinical practice, infrequent cases of severe and in some cases disabling pain in bones, joints and muscles have been reported with the use of bisphosphonates, which include zoledronic acid.

These symptoms developed during the period from 1 day to several months after the start of treatment. After discontinuation of treatment, most patients had symptoms. In several patients, symptoms recurred when therapy was resumed or another bisphosphonate was administered.

Zometa contains the same active ingredient as Aclasta - zoledronic acid.Patients receiving Zomet therapy should not receive Aclasta at the same time.

Use in pediatrics

The efficacy and safety of using Zometa in pediatric practice has not yet been established.

Influence on ability to drive motor transport and control mechanisms

The study of the influence of Zometa on the ability to drive vehicles and operating machinery was not conducted.

Overdose

Symptoms: in acute overdose of the drug (limited data), impaired renal function (including renal failure), changes in the electrolyte composition (including concentrations of calcium, phosphate and magnesium in blood plasma) were noted. The patient who received the drug in a dose higher than the recommended should be under constant supervision.

Treatment: when hypocalcemia occurs with clinically significant manifestations, Calcium gluconate infusion is indicated.

Drug interaction

With the simultaneous use of other commonly used drugs (anti-tumor drugs, diuretics, antibiotics, analgesics) with Zometa, no clinically significant interactions were noted.

According to data obtained in in vitro studies, zoledronic acid does not have significant binding to plasma proteins and does not inhibit the enzymes of the cytochrome P450 system. Nevertheless, special clinical studies on the study of drug interactions were not conducted.

It is recommended that caution be taken with the simultaneous use of bisphosphonates and aminoglycosides, since the simultaneous action of these drugs is manifested by an increase in the duration of the decrease in calcium concentration in the blood plasma.

Caution is needed when simultaneously applying Zometa with drugs that potentially have nephrotoxic effects.

It should also be borne in mind the likelihood of hypomagnesemia.

In patients with multiple myeloma, there may be an increased risk of developing renal dysfunction when IV is administered with bisphosphonates, such as Zometa, in combination with thalidomide.

Pharmaceutical Interaction

Diluted solution Zometa should not be mixed with infusion solutions containing calcium ions (for example, Ringer's solution).

When used for the introduction of Zometa glass bottles, 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), no signs of incompatibility with Zomet were detected.

Terms and conditions of storage

The drug should be stored out of reach of children at a temperature not exceeding 30 ° C.