Zoledronate-Teva, 4 mg 5 ml

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Indications

– Bone metastases in malignant solid tumors (prostate cancer, breast cancer and others) and multiple myeloma, including to reduce the risk of pathological fractures, spinal cord compression, tumor-induced hypercalcemia and reduce the need for radiation therapy or surgical bone interventions.

– Hypercalcemia due to malignancies (serum albumin-corrected calcium content > 12.0 mg/dL [3.0 mmol/L]).

Active ingredient

Composition

In 1 vial contains:

the active substance:

zoledronic acid monohydrate (in terms of anhydrous substance) 4.00 mg;

excipients:

Mannitol 220.00 mg,

Sodium citrate 24.00 mg,

Injection water to 5.00 ml.

How to take, the dosage

Zoledronate-Teva should only be administered by qualified medical personnel experienced in intravenous bisphosphonates.

The drug Zoledronate-Teva should not be mixed with solutions containing calcium or other divalent ions (e.g. Ringer’s solution). Zoledronate-Teva should be administered intravenously by IV drip for at least 15 minutes without mixing with other drugs.

Patients with dehydration (if present) should be corrected prior to administration of Zoledronate-Teva.

Bone metastases of solid malignancies and multiple myeloma in adults and elderly patients

The recommended dose is 4 mg every 3-4 weeks. Oral calcium at a dose of 500 mg per day and vitamin D at a dose of 400 ME per day should be used in addition.

Hypercalcemia due to malignancies in adults and elderly patients

In hypercalcemia (albumin corrected serum calcium ≥12 mg/dL or 3 mmol/L), the recommended single dose of the drug is 4 mg. The patient should be adequately hydrated before or during the infusion.

Patients with impaired renal function

Hypercalcemia due to malignancies

Patients with serum creatinine concentrations less than 400 µmol/L or < 4.5 mg/dL do not require dosing adjustments.

Bone metastases of solid malignancies and multiple myeloma

Serum creatinine and CK concentrations should be determined in all patients before starting therapy with the drug.

The dose of Zoledronate-Teva depends on the baseline creatinine clearance calculated by the Cockcroft-Gault formula. The drug is contraindicated in patients with severe renal dysfunction (creatinine clearance <30 ml/min) (see section “Contraindications”).

The recommended doses in patients with mild to moderate renal dysfunction (creatinine clearance values 30-60 ml/min) are given below.

Initial creatinine clearance value (ml/min)

Recommended dose of Zoledronate-Teva

>60

4.0 mg (5 ml concentrate)

50-60

3.5 mg (4.4 ml concentrate)

40-49

3.3 mg (4.1 ml concentrate)

30-39

3.0 mg (3.8 ml concentrate)

3.0 mg (3.8 ml concentrate)

After initiation of therapy, serum creatinine concentration should be determined before each subsequent dose of the drug is administered. If renal function abnormalities are detected, the next dose of Zoledronate-Teva should be delayed.

In clinical studies, impaired renal function has been defined as follows:

– in patients with baseline serum creatinine concentration within normal limits (< 1.4 mg/dL), a 0.5 mg/dL increase in serum creatinine concentration;

– in patients with deviations of baseline serum creatinine concentration from normal (> 1.4 mg/dL) – increase in serum creatinine concentration by 1 mg/dL. Therapy with Zoledronate-Teva should be resumed only after serum creatinine concentration reaches values within ±10% of the initial one, at the same dose used before treatment interruption.

Preparation of solution for infusion

Before administering the drug, the concentrate (the contents of one vial or a smaller volume) is diluted in 100 ml of calcium-free solution for infusion (0.9% sodium chloride solution or 5% dextrose solution).

The drug Zoledronate-Teva should not be mixed with other medicinal products, solutions containing calcium or other divalent cations, including Ringer-lactate solution.

Prepared zoledronic acid solution should be administered using a separate IV infusion system immediately after preparation.

Interaction

Caution is recommended with concomitant use of bisphosphonates with aminoglycosides, calcitonin, and “loop” diuretics because the concomitant effects of these drugs are manifested by an increased duration of plasma calcium reduction.

Caution is necessary when using zoledronic acid concomitantly with drugs with potential nephrotoxic effects.

Caution should be exercised when using concomitantly with angiogenesis inhibitors due to increased incidence of jaw necrosis.

No clinically significant interactions have been noted with other commonly used medications (antineoplastic agents, diuretics [excluding “looping”], antibiotics, analgesics) when used concomitantly with zoledronic acid.

In the combined use of Zoledronate-Teva with thalidomide, no dose adjustment of zoledronic acid is required, except for use in patients with mild to moderate renal impairment.

The combined use of thalidomide (100 mg or 200 mg once daily) and Zoledronate-Teva (4 mg) in patients with multiple myeloma does not significantly affect the pharmacokinetics of zoledronic acid and CK.

Pharmaceutical interactions and compatibility issues

Diluted zoledronic acid solution should not be mixed with infusion solutions containing calcium ions, such as Ringer’s solution.

When using glass vials, 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 solution) for administration of zoledronic acid, no evidence of incompatibility with the drug has been found.

Special Instructions

Before infusion, ensure that the patient is adequately hydrated. If necessary, it is recommended to administer 0.9% sodium chloride solution before, in parallel or after infusion of Zoledronate-Teva. Hyperhydration should be avoided due to the risk of cardiovascular complications.

After administration of Zoledronate-Teva, continuous monitoring of calcium (corrected for albumin), phosphorus, magnesium and serum creatinine concentration is necessary.

If hypocalcemia, hypophosphatemia or hypomagnesemia develops, short-term additional administration of the appropriate agents may be necessary. Patients with untreated hypercalcemia usually have impaired renal function, so careful monitoring of renal function is necessary in patients in this category.

When considering treatment with Zoledronate-Teva in patients with bone metastases to decrease the risk of pathological fractures, spinal cord compression, and tumor-caused hypercalcemia, and to decrease the need for radiation therapy or bone surgery, it should be considered that therapeutic benefit is seen in 2-3 months after initiation of therapy with the drug.

Renal dysfunction

There have been some reports of renal dysfunction with bisphosphonates. Risk factors for these complications include dehydration, previous renal dysfunction, repeated administration of Zoledronate-Teva or other bisphosphonates, and use of nephrotoxic medications, and overmedication. Although the risk of the above described complications is reduced if the drug is administered at a dose of 4 mg for at least 15 minutes, the possibility of renal dysfunction persists.

There have been cases of worsening of renal function, progression of renal impairment to renal failure and the need for hemodialysis on first or single dose zoledronic acid.

Elevated serum creatinine concentrations have also been seen in some patients with long-term use of the drug at the recommended doses, although with less frequency.

Contraindications

– Hypersensitivity to zoledronic acid, other bisphosphonates or any other component of the drug.

– Serious renal dysfunction (CKR less than 30 ml/min).

– Pregnancy and lactation.

– Childhood and adolescence (efficacy and safety not established).

If you have any of the above conditions, be sure to consult your doctor before taking the drug.

Cautiously use the drug in patients with mild to moderate renal dysfunction (CK > 30 ml/min).

Caution should be used concomitantly with other drugs with nephrotoxic potential.

Precaution should be used concomitantly with antiangiogenic drugs due to an increased risk of osteonecrosis of the jaw.

Perhaps caution should be exercised when used in patients with severe hepatic impairment due to limited data on the use of the drug in this category of patients.

Side effects

The most serious adverse reactions (HP) in patients receiving zoledronic acid for reported indications were: anaphylactic reaction, ocular adverse events, osteonecrosis of the jaw, atypical femoral fracture, atrial fibrillation, renal dysfunction, acute phase reactions and hypocalcemia.

The information on the incidence of HP with zoledronic acid at a dose of 4 mg is based primarily on data from long-term therapy. HP associated with zoledronic acid use is usually mild and transient, similar to that reported with other bisphosphonates. These HPs can occur in approximately one-third of patients treated with zoledronic acid.

The symptoms of acute phase reactions usually developed 3 days after zoledronic acid administration: general malaise, bone pain, fever, chills, flu-like syndrome, and arthritis followed by joint swelling; symptoms usually resolved within a few days. HP such as arthralgia and myalgia were also frequently reported.

Very often a decrease in renal calcium excretion was accompanied by a sharp decrease in phosphorus, which was asymptomatic and did not require treatment. Often a decrease in serum calcium up to the development of hypocalcemia may be accompanied by a lack of clinical manifestations.

There have been reports of frequent gastrointestinal reactions, such as nausea and vomiting after intravenous infusion of zoledronic acid.

Local reactions at the infusion site, such as redness or swelling and/or pain, have been observed infrequently.

Anorexia was frequently observed in patients receiving zoledronic acid at a dose of 4 mg.

Incidents of rash or pruritus have been infrequent. As with other bisphosphonates, frequent cases of conjunctivitis have been reported.

Anemia of severe anemia (hemoglobin concentration < 8.0 g/dl) has been reported frequently in patients receiving zoledronic acid at a dose of 4 mg, based on a pooled analysis of controlled studies.

The HPs are grouped according to the MedDRA classification of organs and organ systems, listed within each group in decreasing order of frequency of occurrence and within each subgroup in decreasing order of significance.

The criteria for evaluating frequency of occurrence are: very common (≥ 1/10), frequent (≥ 1/100, < 1/10), infrequent (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), including individual reports.

Blood and lymphatic system disorders: frequent – anemia; infrequent – thrombocytopenia, leukopenia; rare – pancytopenia.

Psychiatric disorders: frequently – sleep disturbance; infrequently – anxiety; rarely – mental confusion.

Nervous system disorders: often – headache, paresthesia; infrequent – dizziness, dysgeusia, hypoesthesia, hyperesthesia, tremor; very rare – convulsions, hypoesthesia and tetany (developing due to hypocalcemia).

Visual organ disorders: frequently – conjunctivitis; infrequently – “blurred” vision; rarely – uveitis.

Digestive system disorders: frequently – nausea, vomiting, decreased appetite, constipation; infrequently – diarrhea, abdominal pain, dyspepsia, stomatitis, dry mouth.

Respiratory system disorders, thoracic and mediastinal organs: infrequent – dyspnea, cough; rarely – interstitial lung disease.

Skin and subcutaneous tissue disorders: frequently – increased sweating; infrequently – itching, rash (including erythematous and macular).

Musculoskeletal and connective tissue disorders: frequently – bone pain, myalgia, arthralgia, generalized pain, joint stiffness; infrequently – necrosis of the jaw, muscle cramps.

Chronic disorders: rarely – bradycardia, arrhythmia (due to hypocalcemia).

Vascular disorders: often – increase of blood pressure; infrequently – decrease of blood pressure.

Renal and urinary tract disorders: frequently – renal dysfunction; infrequently – acute renal failure, hematuria, proteinuria.

Intrinsic system disorders: infrequent hypersensitivity reactions; rarely – angioedema.

Laboratory and instrumental data: very frequently – hypophosphatemia; frequently – increased concentration of creatinine and urea in blood serum, hypocalcemia; infrequently – hypomagnesemia, hypokalemia; rarely – hyperkalemia, hypernatriemia.

General disorders and disorders at the site of administration: frequent – acute phase reaction, increased body temperature, flu-like syndrome (including general malaise, chills, malaise, “hot flashes”), peripheral edema, asthenia; infrequent – injection site reaction (pain, irritation, swelling, thickening, redness), chest pain, increased body weight; rare – arthritis and joint swelling as symptom of acute phase reaction.

Please note that when using other bisphosphonates there have been cases of bronchospasm in patients with bronchial asthma sensitive to acetylsalicylic acid, but this has not been observed with zoledronic acid.

Indesirable reactions according to spontaneous reports and literature reports (frequency unknown)

Immune system disorders: anaphylactic reaction/shock.

Nervous system disorders: drowsiness.

Visual system disorders: episcleritis, scleritis and inflammatory diseases of the orbit.

Cardiac disorders: atrial fibrillation.

Vascular disorders: decreased blood pressure leading to syncope or circulatory collapse, mainly in patients with risk factors.

Respiratory system, chest and mediastinum disorders: bronchospasm.

Skin and subcutaneous tissue disorders: urticaria.

Muscular and connective tissue disorders: sudden severe restriction of joint mobility and/or severe and in some cases incapacitating pain in bones, joints and/or muscles, atypical intertrochanteric and diaphyseal fractures of the femur.

Description of individual adverse reactions

Renal dysfunction

The use of zoledronic acid has been associated with the development of renal dysfunction. When the drug was used in clinical trials to prevent skeletal complications in patients with advanced malignancies with bone lesions, the frequency of renal dysfunction associated with the use of the drug was distributed as follows: multiple myeloma (3.2%), prostate cancer (3.1%), breast cancer (4.3%), lung cancer and other solid tumors (3.2%).

Factors that may increase the risk of impaired renal function include: dehydration, prior impairment of renal function, multiple courses of treatment with zoledronic acid or other bisphosphonates, concurrent use of nephrotoxic drugs, or administration of the drug for less than the recommended period of time.

Worsening of renal function and progression of renal impairment to renal failure and the need for hemodialysis after starting or starting a single dose of zoledronic acid have been reported.

Osteonecrosis of the jaw

In treatment with bisphosphonates, including zoledronic acid, cases of osteonecrosis have been reported mainly in patients with cancer (mainly of the jaw, but also in other locations, including the pelvis, femur, and external auditory canal).

Many patients showed signs of local infection, including osteomyelitis; most of these cases were in patients with cancer after tooth extraction or after dental surgery.

There are well-known multiple risk factors predisposing to the development of osteonecrosis of the jaw, such as malignancies, concurrent therapy (e.g., chemotherapy, antiangiogenic drugs, radiation therapy, glucocorticosteroids) and concurrent conditions (e.g., anemia, coagulopathies, infections, prior oral disease). Although a causal relationship has not been established, it is advisable to avoid dental surgery because of the possibility of delayed recovery. Based on available data, the incidence of osteonecrosis of the jaw is related to the nature of the tumor (advanced breast cancer, multiple myeloma).

The acute phase reaction

This adverse reaction is a complex of symptoms: increased body temperature, general weakness, bone pain, chills, flu-like syndrome. It usually begins ≤3 days after infusions of zoledronic acid. The reaction is also referred to using the terms “flu-like” or “post-dose” symptoms. Symptoms usually resolve after a few days.

Atrial fibrillation

. In one clinical trial, when zoledronic acid was used for 3 years in patients with postmenopausal osteoporosis (at a dose of 5 mg once a year), the overall incidence of atrial fibrillation was 2.5% (96 of 3,862) compared with 1.9% (75 of 3,852) in the placebo group. The incidence of atrial fibrillation with severe hemodynamic abnormalities was 1.3% (51 of 3862) and 0.6% (22 of 3852) for zoledronic acid and placebo, respectively.

A similar imbalance has not been seen in other clinical trials of zoledronic acid, including the use of zoledronic acid at a dose of 4 mg once every 3-4 weeks in patients with cancer.

The reason for the increased incidence of atrial fibrillation on zoledronic acid therapy in patients with postmenopausal osteoporosis was not established in this study.

If any of the side effects listed in the instructions worsen, or if you notice any other side effects not listed in the instructions, inform your physician.In acute overdose with the drug (limited data), renal dysfunction, including renal failure, changes in electrolyte composition, including decreased plasma calcium, phosphate and magnesium concentrations, have been reported. A patient who has received a dose of the drug in excess of the recommended dose should be kept under constant observation.

In case of hypocalcemia accompanied by clinical manifestations, calcium gluconate infusion is indicated.

Overdose

In acute drug overdose (limited data) renal dysfunction, including renal failure, changes in electrolyte composition, including decreased concentration of calcium, phosphate and magnesium in blood plasma have been reported. A patient who has received a dose of the drug in excess of the recommended dose should be kept under constant observation.

In case of hypocalcemia accompanied by clinical manifestations, calcium gluconate infusion is indicated.

Pregnancy use

The use of Zoledronate-Teva during pregnancy is contraindicated.

The drug Zoledronate-Teva may have adverse effects on the fetus. Studies in animals have shown toxic effects on reproductive function. There are no data on the use of the drug during pregnancy in humans.

If pregnancy occurs during therapy with bisphosphonates, there may be a risk of intrauterine fetal malformations (e.g., skeletal and other abnormalities). The dependence of risk on the amount of time between discontinuation of bisphosphonates therapy and the time of conception, the route of administration, and the characteristics of a particular drug is unknown.

Women of reproductive age should be advised to use reliable contraception during treatment with Zoledronate-Teva.

It is not known whether zoledronic acid passes into breast milk. The use of the drug Zoledronate-Teva during breastfeeding is contraindicated.

In studies in animals, zoledronic acid suppressed fertility at a dose of 0.1 mg/kg/day. There are no data on the effect of zoledronic acid on fertility in humans.