Zoledronat-Teva (Concentrate) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Pliva Hrvatska, d.o.o. (Croatia)

ATC Code

M05BA08 (Zoledronic acid)

Active Substance

Zoledronic acid (Swiss Ph. Swiss Pharmacopoeia)

Dosage Form

Zoledronat-Teva

Concentrate for solution for infusion 4 mg/5 ml: fl. 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion in the form of a clear, colorless solution.

Excipients: mannitol – 220 mg, sodium citrate dihydrate – 24 mg, water for injections – up to 5 ml.

5 ml – glass bottles (1) – cardboard boxes^×.

^× protective stickers may be additionally applied.

Clinical-Pharmacological Group

Bone resorption inhibitor for bone metastases

Pharmacotherapeutic Group

Means for the treatment of bone diseases; agents affecting bone structure and mineralization; bisphosphonates

Pharmacological Action

Zoledronic acid belongs to bisphosphonates that have a selective effect on bone tissue. It suppresses excessive bone resorption by acting on osteoclasts. The exact mechanism that ensures the inhibition of osteoclast activity has not yet been elucidated. Zoledronic acid does not have an undesirable effect on bone formation, mineralization, and mechanical properties.

In patients with hypercalcemia induced by malignant tumors, a single infusion of zoledronic acid is accompanied by a decrease in the concentration of calcium and phosphorus in the blood serum and an increase in the excretion of calcium and phosphorus in the urine.

The main pathophysiological mechanism for the development of hypercalcemia in malignant neoplasms and bone metastases is the hyperactivity of osteoclasts, leading to increased bone resorption. Excessive release of calcium into the blood due to bone resorption leads to polyuria and gastrointestinal disorders, accompanied by progressive dehydration and a decrease in the glomerular filtration rate, which in turn leads to increased reabsorption of calcium in the kidneys, further aggravating systemic hypercalcemia and creating a “vicious circle”. Suppression of excessive bone resorption and provision of adequate fluid intake are necessary conditions in the treatment of hypercalcemia caused by a malignant neoplasm.

According to the pathophysiological mechanism of hypercalcemia development, patients with hypercalcemia caused by a malignant neoplasm can be divided into two groups: patients with humoral hypercalcemia and patients with hypercalcemia due to tumor invasion into bone tissue. In humoral hypercalcemia, the activation of osteoclasts and stimulation of bone resorption is carried out by factors such as parathyroid hormone-related protein, produced by tumor cells and entering the systemic circulation. Humoral hypercalcemia usually develops with squamous cell malignant neoplasms of the lungs, head and neck, or tumors of the genitourinary system, such as renal cell carcinoma or ovarian cancer. These patients may have no or minimal bone metastases.

With widespread invasion of tumor cells into bone tissue, they produce locally acting substances that activate osteoclastic bone resorption, which also leads to the development of hypercalcemia. Neoplasms accompanied by locally mediated hypercalcemia usually include breast cancer and multiple myeloma.

The total serum calcium concentration in patients with hypercalcemia caused by a malignant neoplasm may not reflect the severity of hypercalcemia due to the presence of concomitant hypoalbuminemia. Ideally, for the diagnosis and treatment of hypercalcemic conditions, it is necessary to determine the concentration of ionized calcium; however, in many clinical situations, this study is not available or is not performed quickly enough. In this regard, instead of determining ionized calcium, the total serum calcium concentration adjusted for albumin level (corrected serum calcium (CSC)) is often used. There are several nomograms for these calculations.

Pharmacokinetics

Pharmacokinetic parameters are dose-independent. After the start of the infusion, the plasma concentration increases rapidly, reaching C_max at the end of the infusion, followed by a rapid decrease in concentration by 10% after 4 hours and to less than 1% of C_max after 24 hours, with a subsequent long period of low concentrations not exceeding 0.1% of C_max, until the next infusion on day 28.

Plasma protein binding – 56%.

Not metabolized.

It is excreted by the kidneys unchanged in 3 stages: phase 1 and 2 – rapid elimination of zoledronic acid from the systemic circulation with T_1/2 of 0.24 hours and 1.87 hours, respectively, and phase 3 – prolonged elimination with T_1/2 of 146 hours. No accumulation of the drug was noted with repeated administrations every 28 days. Within the first 24 hours, 23-55% is found in the urine. The remaining amount of zoledronic acid binds to bone tissue, after which it is slowly released back into the systemic circulation and excreted by the kidneys; less than 3% is excreted in the feces. Total plasma clearance is 2.54-7.54 L/h, does not depend on the dose of zoledronic acid, gender, age, race, or body weight of the patient. Increasing the infusion duration from 5 to 15 minutes results in a 30% decrease in zoledronic acid concentration at the end of the infusion but does not affect the area under the concentration-time curve (AUC). Renal clearance positively correlates with CC and is 42-108% of CC, averaging 55-113%.

In patients with severe (CC less than 20 ml/min) and moderate renal failure (CC from 20 to 50 ml/min), the clearance of zoledronic acid is 37% and 72%, respectively, of the zoledronic acid clearance values in patients with CC of 84 ml/min.

Indications

• Hypercalcemia (CSC concentration of at least 12 mg/dl or 3 mmol/L), induced by malignant tumors;
• Metastatic bone lesion in malignant solid tumors and myeloma (to reduce the risk of pathological fractures, spinal cord compression, tumor-induced hypercalcemia, and to reduce the need for radiation therapy).

ICD codes

Dosage Regimen

As an intravenous (IV) infusion over at least 15 minutes.

Hypercalcemia (CSC concentration of at least 12 mg/dl or 3 mmol/L), induced by malignant tumors

The advisability of using zoledronic acid should be determined taking into account both the severity and manifestations of hypercalcemia associated with malignant tumors. For the treatment of mild asymptomatic forms of hypercalcemia, enhanced hydration by the administration of saline solutions (with or without the use of loop diuretics) may be sufficient.

Maximum recommended dose: 4 mg as a single IV infusion over at least 15 minutes. Administration of a repeated dose is possible if the calcium concentration does not normalize or if deterioration occurs after a distinct clinical effect. To realize the full clinical effect of the initial dose, the interval before re-administration should be at least 7 days.

Throughout the course of treatment, adequate hydration (with saline solutions) must be ensured; however, overhydration should be avoided, especially in patients with heart failure. It is recommended to maintain diuresis of about 2 L/day throughout the treatment. Diuretics can be used only after hypovolemia has been corrected.

Metastatic bone lesion in malignant solid tumors and myeloma

Recommended dose in combination with standard antitumor therapy: 4 mg as a single IV infusion over at least 15 minutes every 3-4 weeks.

To prevent hypocalcemia and maintain homeostasis, patients should also take oral calcium supplements at a dose of 500 mg/day and multivitamins containing vitamin D at a rate of 400 IU/day in combination with standard antitumor therapy.

Patients with renal impairment

Administration of zoledronic acid leads to an increased risk of nephrotoxic syndrome. In patients with hypercalcemia with initial moderate renal impairment (creatinine concentration not more than 4.5 mg/dl), dose adjustment is not required. If signs of worsening renal function appear, an appropriate examination should be performed to determine the ratio of the potential benefit of further treatment and the possible risk. In patients with a creatinine concentration of more than 4.5 mg/dl (400 µmol/L), Zoledronic acid is used only if the expected benefit outweighs the possible risk of renal failure.

In patients with renal impairment when treating metastatic bone lesions in malignant solid tumors and myeloma, the dose is adjusted according to the indicators of impaired renal function

• administration of zoledronic acid is not recommended for patients with a creatinine concentration of more than 3 mg/dl

• with CC more than 60 ml/min, the recommended dose of the drug is 4.0 mg (5.0 ml of concentrate);

• with CC from 50 to 60 ml/min, the recommended dose of the drug is 3.5 mg (4.4 ml of concentrate);

• with CC from 40 to 49 ml/min, the recommended dose of the drug is 3.3 mg (4.1 ml of concentrate);

• with CC from 30 to 39 ml/min, the recommended dose of the drug is 3.0 mg (3.8 ml of concentrate);

• with CC less than 30 ml/min, zoledronic acid is not used.

For patients in whom progressive impairment of renal function was documented during treatment, treatment is resumed after the serum creatinine concentration decreases to levels within 10% of the baseline.

Patients with hepatic impairment

Experience with the use of zoledronic acid in the therapy of hypercalcemia induced by malignant tumors in patients with hepatic impairment is limited, and the data obtained do not allow recommending a specific dosage regimen or tactics for safe use in such patients.

Use in asthma

Cases of bronchial obstruction have been observed with the use of other bisphosphonates in patients with aspirin-sensitive asthma. Although there are no data on such manifestations during treatment with zoledronic acid, caution should be exercised when prescribing to patients with aspirin-sensitive asthma.

Preparation of infusion solution

Before administration, the concentrate (contents of one vial or a smaller volume) is diluted in 100 ml of infusion solution that does not contain calcium (0.9% sodium chloride solution or 5% dextrose solution).

Zoledronat-Teva should not be mixed with other medicinal products, solutions containing calcium or other divalent cations, including Ringer’s lactate solution. The prepared solution of zoledronic acid must be administered using a separate system for IV infusion immediately after preparation.

Adverse Reactions

The side effects of zoledronic acid are usually minor and transient, similar to the side effects noted with the use of other bisphosphonates. IV infusions are most often accompanied by fever. Patients often develop a flu-like syndrome, including fever, chills, flushing, bone pain and/or arthralgia, myalgia. After IV administration, gastrointestinal reactions such as nausea and vomiting have been noted. Local reactions at the injection site, such as redness or swelling, are observed in less than 1% of patients. In most cases, the symptoms disappear within 24-48 hours without specific treatment. Rare cases of skin rash, skin itching, and chest pain after administration of zoledronic acid have been reported.

Also, as with the use of other bisphosphonates, cases of conjunctivitis and hypomagnesemia have been reported.

The frequency of adverse reactions is classified according to WHO recommendations: very common – at least 10%; common – at least 1%, but less than 10%; uncommon – at least 0.1%, but less than 1%; rare – at least 0.01%, but less than 0.1%; very rare – less than 0.01% (including isolated cases or with an unknown frequency).

Gastrointestinal disorders common – nausea, vomiting; uncommon – abdominal pain, constipation, diarrhea; frequency not established – stomatitis, dry mouth, dyspepsia, inflammation of the gastrointestinal mucosa.

Blood and lymphatic system disorders common – anemia; uncommon – thrombocytopenia; rare – pancytopenia; frequency not established – granulocytopenia, neutropenia.

Laboratory parameters very common – hypophosphatemia; common – hypocalcemia; uncommon – hypokalemia, hypomagnesemia.

Metabolism and nutrition disorders dehydration, anorexia, increased sweating.

Musculoskeletal and connective tissue disorders arthralgias, muscle cramps, asthenia, bone pain, muscle pain, back pain, limb pain.

Nervous system disorders common – headache, confusion; uncommon – dizziness, hypoesthesia, hyperesthesia, paresthesia; frequency not established – anxiety, nervousness, restlessness, irritability, sleep disturbance, depression, hallucinations, drowsiness, dizziness, taste perversion, insomnia, tremor, anxiety.

Cardiac disorders uncommon – arterial hypotension; rare – bradycardia.

Respiratory, thoracic and mediastinal disorders uncommon – dyspnea, cough; frequency not established – pleural effusion, chest pain.

Skin and subcutaneous tissue disorders frequency not established – alopecia.

Allergic reactions uncommon – skin itching; frequency not established – dermatitis, angioedema.

Renal and urinary disorders common – renal function impairment; uncommon – hematuria, proteinuria.

Musculoskeletal and connective tissue disorders common – joint pain, bone pain myalgia; frequency not established – back pain, chest pain.

Eye disorders common – conjunctivitis; uncommon – blurred vision; very rare – episcleritis, uveitis.

Benign, malignant and unspecified neoplasms (including cysts and polyps) frequency not established – complication of the course and progression of malignant neoplasm.

Infections and infestations frequency not established – candidiasis, upper respiratory tract infections, urinary tract infections.

General disorders and administration site conditions common – flu-like syndrome; uncommon – asthenia; frequency not established – peripheral edema, hyperthermia, rapid fatigue.

Contraindications

• Severe renal failure (CC less than 30 ml/min);
• Renal failure (creatinine concentration more than 3 mg/dl or 265 µmol/L) in patients with metastatic bone lesions in malignant solid tumors and myeloma;
• Renal failure (creatinine concentration more than 4.5 mg/dl or 400 µmol/L);
• Hepatic failure in patients with hypercalcemia induced by malignant tumors;
• Aspirin-sensitive asthma;
• Heart diseases accompanied by heart failure;
• Hypocalcemia;
• Children under 18 years of age (no data on efficacy and safety);
• Pregnancy;
• Lactation period;
• Hypersensitivity to zoledronic acid, other bisphosphonates, and other components of the drug.

With caution when using zoledronic acid in patients with bronchial asthma sensitive to acetylsalicylic acid (cases of bronchospasm have been noted with the use of other bisphosphonates, see the “Dosage Regimen” section).

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Experience with the use of zoledronic acid in the therapy of hypercalcemia induced by malignant tumors in patients with hepatic impairment is limited, and the data obtained do not allow recommending a specific dosage regimen or tactics for safe use in such patients.

Use in Renal Impairment

Administration of zoledronic acid leads to an increased risk of nephrotoxic syndrome. In patients with hypercalcemia with initial moderate renal impairment (creatinine concentration not more than 4.5 mg/dl), dose adjustment is not required. If signs of worsening renal function appear, an appropriate examination should be performed to determine the ratio of the potential benefit of further treatment and the possible risk. In patients with a creatinine concentration of more than 4.5 mg/dl (400 µmol/L), Zoledronic acid is used only if the expected benefit outweighs the possible risk of renal failure.

In patients with renal impairment when treating metastatic bone lesions in malignant solid tumors and myeloma, the dose is adjusted according to the indicators of impaired renal function

• administration of zoledronic acid is not recommended for patients with a creatinine concentration of more than 3 mg/dl

• with CC more than 60 ml/min, the recommended dose of the drug is 4.0 mg (5.0 ml of concentrate);

• with CC from 50 to 60 ml/min, the recommended dose of the drug is 3.5 mg (4.4 ml of concentrate);

• with CC from 40 to 49 ml/min, the recommended dose of the drug is 3.3 mg (4.1 ml of concentrate);

• with CC from 30 to 39 ml/min, the recommended dose of the drug is 3.0 mg (3.8 ml of concentrate);

• with CC less than 30 ml/min, zoledronic acid is not used.

For patients in whom progressive impairment of renal function was documented during treatment, treatment is resumed after the serum creatinine concentration decreases to levels within 10% of the baseline.

Pediatric Use

Contraindicated in children under 18 years of age.

Special Precautions

Before starting treatment and throughout the course of treatment, it is necessary to correct symptoms of dehydration and hypovolemia. It is recommended to maintain diuresis of about 2 L/day throughout the course of treatment.

After initiation of therapy, careful monitoring of serum calcium, phosphorus, and magnesium concentrations is necessary. Zoledronic acid is not used in patients with pre-existing hypocalcemia. Electrolyte imbalance (hypocalcemia, hypomagnesemia, or hypophosphatemia) requires short-term replacement therapy.

Before each dose administration, serum creatinine concentration should be determined to assess renal function.

The condition of patients receiving zoledronic acid for the treatment of hypercalcemia of malignancy with confirmed progressive renal impairment should be appropriately evaluated to determine whether the anticipated benefit of continued treatment outweighs the potential risk. Due to the possibility of clinically significant deterioration of renal function up to renal failure, a single dose should not exceed 4 mg and the infusion duration should be at least 15 minutes.

Excessive hydration should be avoided in patients with heart failure. There have been reports of osteonecrosis of the jaw in patients with cancer whose treatment regimen included bisphosphonates. Many of these patients also received chemotherapy and corticosteroids. Most reports concerned patients who underwent dental procedures, such as tooth extraction, and who had signs of local infection, including osteomyelitis.

Patients with a history of risk factors such as cancer, chemotherapy, corticosteroid use, and poor oral hygiene are recommended to undergo dental examination and sanitation before starting treatment with bisphosphonates. During treatment with bisphosphonates, these patients should, if possible, avoid traumatic dental procedures, as bisphosphonates are presumed to create conditions for the occurrence of osteonecrosis of the jaw. There are no reports of a reduced risk of developing osteonecrosis of the jaw by reducing the dose of bisphosphonates or discontinuing bisphosphonate therapy in patients who need to undergo dental procedures. The clinical management of the patient in this situation is determined by the attending physician and is based on an individual benefit/risk assessment.

Effect on ability to drive vehicles and operate machinery

Studies on the effect of zoledronic acid on the ability to drive vehicles and operate machinery have not been conducted. However, caution should be exercised if adverse reactions from the nervous system (dizziness, drowsiness) occur, which may cause decreased concentration and psychomotor reactions.

Overdose

Symptoms of acute drug overdose (limited data) included impaired renal function (including renal failure), changes in electrolyte composition (including plasma calcium, phosphate, and magnesium concentrations). A patient who has received the drug at a dose exceeding the recommended one should be under constant observation.

Treatment in case of clinically significant hypocalcemia, hypophosphatemia, or hypomagnesemia, infusion of calcium gluconate, sodium or potassium phosphate, magnesium sulfate, respectively, is indicated.

Drug Interactions

No clinically significant interactions were observed with the simultaneous use of zoledronic acid and other commonly used medicinal products (anticancer agents, antibiotics, analgesics).

According to data obtained from in vitro studies, Zoledronic acid does not have significant binding to plasma proteins and does not inhibit cytochrome P450 isoenzymes. Special clinical studies on drug interactions have not been conducted.

Caution is recommended when using bisphosphonates and aminoglycosides concomitantly, as the simultaneous action of these drugs results in a prolonged reduction in plasma calcium concentration. The drug should be used with caution with loop diuretics due to an increased risk of hypocalcemia. Caution is also necessary when zoledronic acid is used concomitantly with drugs that have potential nephrotoxic effects. The possibility of developing hypomagnesemia should also be considered.

In patients with multiple myeloma, there may be an increased risk of renal function impairment during intravenous infusion of bisphosphonates, including zoledronic acid, in combination with thalidomide. Pharmaceutical interaction

The diluted solution of zoledronic acid should not be mixed with infusion solutions containing calcium ions (for example, Ringer’s lactate solution).

When using glass vials, infusion systems, and bags of various types made of polyvinyl chloride, polyethylene, and polypropylene (pre-filled with 0.9% sodium chloride solution or 5% dextrose solution), no signs of incompatibility with zoledronic acid were found.

Storage Conditions

At a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

The shelf life is 2 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.