Rezorba (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Pharma-Sintez, JSC (Russia)

Manufactured By

Pharma-Sintez, JSC (Russia)

Or

Diamed, LLC (Russia)

Or

Deko Company, LLC (Russia)

Or

Medsintez Plant, LLC (Russia)

Solvent Manufacturer

Deko Company, LLC (Russia)

Or

Altair, LLC (Russia)

Or

Pharma-Sintez, JSC (Russia)

Labeled By

Deko Company, LLC (Russia)

Or

Diamed, LLC (Russia)

Contact Information

Pharma-Sintez, JSC (Russia)

ATC Code

M05BA08 (Zoledronic acid)

Active Substance

Zoledronic acid (Swiss Ph. Swiss Pharmacopoeia)

Dosage Form

Rezorba

Lyophilisate for preparation of solution for infusion 4 mg: fl. 1 pc. in a kit with solvent

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for infusion in the form of a powder or porous mass of white or almost white color; supplied solvents are transparent colorless liquids without odor.

Excipients: D-mannitol – 220 mg, sodium citrate dihydrate – 27.34 mg (recalculated to anhydrous sodium citrate – 24 mg).

Solvent in ampoule water for injections – 5 ml.
Solvent in container sodium chloride solution for infusion 0.9% – 100 ml.

Dark glass vials with a capacity of 10 ml (1) in a kit with solvent water for injections (amp. 1 pc.) – contour cell packaging (1) – cardboard packs.
Dark glass vials with a capacity of 10 ml (1) in a kit with solvent water for injections (amp. 1 pc.) – contour cell packaging (1), containers in bags with solvent sodium chloride solution for infusion 0.9% (1) – cardboard packs.

Clinical-Pharmacological Group

Bone resorption inhibitor. Bisphosphonate

Pharmacotherapeutic Group

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

Pharmacological Action

Zoledronic acid belongs to the highly effective bisphosphonates that selectively act on bone tissue. The drug suppresses bone resorption by acting on osteoclasts. The selective action of bisphosphonates on bone tissue is based on high affinity for mineralized bone tissue. The exact molecular mechanism providing inhibition of osteoclast activity remains unclear.

Zoledronic acid does not have an undesirable effect on bone formation, mineralization, and mechanical properties.

In addition to the inhibitory effect on bone resorption, Zoledronic acid has antitumor properties that ensure the drug’s effectiveness in bone metastases. In vivo: it inhibits bone resorption by osteoclasts, alters the bone marrow microenvironment, leading to a decrease in tumor cell growth; exhibits antiangiogenic activity. Suppression of bone resorption is clinically accompanied, among other things, by a pronounced reduction in pain sensations.

In vitro: it inhibits the proliferation of osteoblasts, exhibits direct cytostatic and pro-apoptotic activity, synergistic cytostatic effect with antitumor drugs; anti-adhesive and anti-invasive activity. Zoledronic acid, due to a synergistic effect, in combination with hormonal therapy or chemotherapy, suppresses proliferation and induces apoptosis, exerts 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 its antimetastatic properties. Furthermore, Zoledronic acid inhibits the proliferation of human and animal endothelial cells and exerts an antiangiogenic effect.

In patients with breast cancer, prostate cancer, and other solid tumors with metastatic bone lesions, Zoledronic acid prevents the development of pathological fractures, spinal cord compression, reduces the need for radiation therapy and surgical interventions, and reduces tumor-induced hypercalcemia. The drug is able to restrain the progression of pain syndrome. The therapeutic effect is less pronounced in patients with osteoblastic lesions than with osteolytic ones.

In patients with multiple myeloma and breast cancer with at least one bone lesion, the efficacy of zoledronic acid at a dose of 4 mg is comparable to pamidronic acid at a dose of 90 mg.

In patients with tumor-induced hypercalcemia, the drug’s action is characterized by a decrease in serum calcium levels and renal calcium excretion. The average time to normalization of calcium levels is about 4 days. By day 10, calcium concentration normalizes in 87-88% of patients. The average time to relapse (albumin-corrected serum calcium level not less than 2.9 mmol/l) is 30-40 days. No significant differences are observed between the efficacy of zoledronic acid at doses of 4 and 8 mg in the treatment of hypercalcemia.

Studies do not reveal significant differences regarding the frequency and severity of adverse events observed in patients receiving zoledronic acid at doses of 4 mg, 8 mg, pamidronic acid at a dose of 90 mg, or placebo, both in the treatment of bone metastases and hypercalcemia.

Pharmacokinetics

Pharmacokinetic data for bone metastases were obtained after single and repeated 5- and 15-minute infusions of 2, 4, 8, and 16 mg of zoledronic acid in 64 patients.

Absorption and Distribution

Pharmacokinetic parameters are dose-independent. After the start of the infusion, the serum 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.

Metabolism and Excretion

Zoledronic acid is not metabolized and is excreted by the kidneys unchanged. Zoledronic acid does not inhibit human cytochrome P450 isoenzymes.

Intravenously administered Zoledronic acid is excreted by the kidneys in 3 phases: rapid biphasic elimination of the drug from the systemic circulation with T_1/2 – 0.24 h and 1.87 h and a long phase with a terminal T_1/2 of 146 h. No accumulation of the drug was noted with repeated administrations every 28 days.

Within the first 24 hours, 39±16% of the administered dose is detected in the urine. The remaining amount of the drug is mainly bound to bone tissue. Then, a slow reverse release of zoledronic acid from bone tissue into the systemic circulation and its excretion by the kidneys occurs. The total plasma clearance of the drug is 5.04±2.5 L/h and does not depend on the drug dose, gender, age, race, or body weight of the patient. Increasing the infusion time from 5 minutes to 15 minutes leads to a 30% decrease in the concentration of zoledronic acid at the end of the infusion but does not affect the AUC.

Pharmacokinetics in Special Clinical Cases

Pharmacokinetic studies in patients with hypercalcemia or impaired liver function have not been conducted. According to data obtained in vitro, Zoledronic acid does not inhibit human cytochrome P450 isoenzymes and does not undergo biotransformation, suggesting that liver function status does not significantly affect the pharmacokinetics of zoledronic acid. Less than 3% of the drug dose is excreted through the intestines.

The renal clearance of zoledronic acid positively correlates with CrCl and amounts to 75±33% of the CrCl, which averages 84±29% (range 22-143 ml/min) in the 64 patients included in the study. Population analysis showed that in patients with severe renal impairment (CrCl <20 ml/min) or moderate renal impairment (CrCl 20-50 ml/min), the calculated clearance of zoledronic acid is 37% and 72%, respectively, of the zoledronate clearance values in patients with CrCl > 84 ml/min. Limited pharmacokinetic data are available for patients with severe renal impairment (CrCl less than 30 ml/min).

Zoledronic acid has low affinity for blood components, plasma protein binding is low (about 56%) and does not depend on the drug concentration.

Indications

• Hypercalcemia (albumin-corrected serum calcium concentration ≥ 12 mg/dl or 3 mmol/l), induced by malignant tumors;
• Metastatic bone lesions in malignant solid tumors and multiple 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

IV drip over at least 15 min.

For bone metastases and osteolytic lesions in multiple myeloma the recommended dose is 4 mg every 3-4 weeks.

Additionally, it is recommended to prescribe oral calcium at a dose of 500 mg/day and vitamin D at a dose of 400 IU/day.

For hypercalcemia (calcium concentration corrected for albumin level ≥12 mg/dl or 3 mmol/l), induced by malignant tumors, the recommended dose is 4 mg, single administration. The infusion is carried out provided the patient is adequately hydrated.

Patients with impaired renal function

Hypercalcemia induced by malignant tumors: the decision to treat with zoledronic acid in patients with severe renal impairment should be made only after careful assessment of the risk/benefit ratio. For serum creatinine concentration < 400 µmol/l or < 4.5 mg/dl no dosage adjustment is required.

Bone metastases of common malignant tumors and multiple myeloma the dose of zoledronic acid depends on the baseline CrCl calculated using the Cockcroft-Gault formula.
For severe renal impairment (CrCl < 30 ml/min) the use of zoledronic acid is not recommended.
Recommended doses for mild or moderate renal impairment (CrCl values 30-60 ml/min) are given below.

Serum creatinine concentration should be determined before each administration of the drug. If renal impairment is detected, the next administration of zoledronic acid should be postponed.

Renal impairment is defined by the following parameters

• For patients with normal baseline creatinine values (<1.4 mg/dl) – an increase in serum creatinine concentration by 0.5 mg/dl;
• For patients with abnormal baseline creatinine levels (>1.4 mg/dl) – an increase in serum creatinine concentration by 1 mg/dl.

Zoledronic acid therapy is resumed only after the creatinine level reaches values exceeding the baseline by no more than 10%, at the same dose that was used before treatment interruption.

Instructions for preparation of infusion solution

The solution is prepared under aseptic conditions; 4 mg is dissolved in 5 ml of water for injections, gently shaken until completely dissolved. The resulting solution with the required dose is diluted in 100 ml of 0.9% sodium chloride solution or 5% dextrose solution. Do not use solutions containing calcium.

The prepared solution is preferably used immediately after preparation. The unused solution can be stored in the refrigerator at a temperature from +2°C (35.6°F) to + 8°C (46.4°F) for no more than 24 hours. The solution stored in the refrigerator should be warmed to room temperature before administration.

Adverse Reactions

Adverse reactions are listed below by organ systems with an indication of their frequency. Frequency criteria: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), including isolated reports.

Blood and lymphatic system disorders common – anemia, uncommon – thrombocytopenia, leukopenia; rare – pancytopenia.

Nervous system disorders common – headache; uncommon – dizziness, paresthesia, taste disturbances, hypoesthesia, hyperesthesia, tremor, anxiety, sleep disorders; rare – confusion.

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

Gastrointestinal disorders common – nausea, vomiting, anorexia; uncommon – diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.

Respiratory, thoracic and mediastinal disorders uncommon – dyspnea, cough.

Skin and subcutaneous tissue disorders uncommon – pruritus, rash (including erythematous and maculopapular), increased sweating.

Musculoskeletal and connective tissue disorders common – bone pain, myalgia, arthralgia, generalized pain; uncommon – muscle cramps.

Cardiac disorders uncommon – marked increase or decrease in BP; rare – bradycardia.

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

Immune system disorders uncommon – hypersensitivity reactions; rare – angioedema.

Investigations very common – hypophosphatemia; common – increased serum creatinine and urea levels, hypocalcemia; uncommon – hypomagnesemia, hypokalemia; rare – hyperkalemia, hypernatremia.

Administration site conditions pain, irritation, swelling, infiltration at the injection site.

General disorders and administration site conditions common – fever, flu-like syndrome (including malaise, chills, feeling unwell, pyrexia); uncommon – asthenia, peripheral edema; chest pain, weight increase. During treatment with bisphosphonates, including zoledronic acid, cases of osteonecrosis of the jaw have been reported (usually after tooth extraction or other dental procedures). In very rare cases, a decrease in BP during therapy with zoledronic acid led to fainting or circulatory collapse.

Contraindications

• Severe renal failure (CrCl < 30 ml/min);
• Pregnancy;
• Lactation period (breastfeeding);
• Childhood and adolescence (safety and efficacy of use have not been established);
• Hypersensitivity to zoledronic acid, other bisphosphonates, or any other components of the drug.

With caution in renal impairment, severe hepatic insufficiency (no data on use), in patients with bronchial asthma, sensitive to acetylsalicylic acid.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

With caution, the drug should be prescribed for severe hepatic insufficiency (no data on use).

Use in Renal Impairment

With caution, the drug should be prescribed for renal impairment.

Pediatric Use

Contraindication: childhood and adolescence (safety and efficacy of use have not been established).

Special Precautions

Before infusion, ensure adequate patient hydration. If necessary, administration of saline before, during, or after the zoledronic acid infusion is recommended. Overhydration of the patient should be avoided due to the risk of cardiovascular complications.

After drug administration, constant monitoring of serum calcium, magnesium, phosphorus, and creatinine levels is necessary.

During therapy with zoledronic acid, renal function should be carefully monitored. Risk factors for renal impairment include dehydration, pre-existing renal failure, multiple administrations of zoledronic acid or other bisphosphonates, as well as the use of nephrotoxic drugs, and too rapid drug administration.

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

During treatment with bisphosphonates, including zoledronic acid, cases of osteonecrosis of the jaw have been described in cancer patients; therefore, before starting treatment with bisphosphonates, a dental examination should be provided and, in the presence of risk factors (anemia, coagulopathies, infections, poor oral hygiene or oral diseases, concomitant chemotherapy or radiation therapy, treatment with corticosteroids), appropriate preventive procedures should be performed. During treatment with zoledronic acid, patients with risk factors should, if possible, avoid dental surgical interventions.

Use in Pediatrics

The use of the drug in children and adolescents is contraindicated, as safety and efficacy have not been established.

Effect on ability to drive vehicles and operate machinery

Studies of the drug’s effect on the ability to drive vehicles and operate complex machinery have not been conducted. In case of CNS side effects, it is recommended to avoid activities requiring increased attention and speed of mental and motor reactions.

Overdose

Symptoms in case of acute overdose of zoledronic acid, impaired renal function, including renal failure, changes in electrolyte composition, including plasma concentrations of calcium, phosphates, and magnesium, are possible.

Treatment in case of accidental overdose the patient should be under constant observation. In the event of hypocalcemia with clinical manifestations, infusion of calcium gluconate is indicated.

Drug Interactions

Solutions containing calcium, in particular Ringer’s solution, must not be used as solvents.

No clinically significant interaction has been observed with concurrent use with antitumor drugs, diuretics, antibiotics, and analgesics.

Bisphosphonates and aminoglycosides have a unidirectional effect on serum calcium concentration, so their simultaneous use increases the risk of hypocalcemia and hypomagnesemia. If hypocalcemia, hypophosphatemia, or hypomagnesemia develops, short-term additional administration of the corresponding substances may be necessary. Patients with untreated hypercalcemia usually have impaired renal function, therefore careful monitoring of renal function is necessary in this category of patients. When deciding on treatment with zoledronic acid in patients with bone metastases, it should be taken into account that the therapeutic effect occurs 2-3 months after the start of treatment with zoledronic acid.

Caution is required when using zoledronic acid concomitantly with drugs that are potentially nephrotoxic.

In patients with multiple myeloma, the risk of renal function impairment may be increased with intravenous administration of bisphosphonates in combination with thalidomide.

Although the risk of the above complications is reduced provided that zoledronic acid is administered at a dose of 4 mg over at least 15 minutes, the possibility of renal impairment remains. Cases of worsening renal function, progression of renal failure, and the need for hemodialysis have been reported upon first or single use of zoledronic acid.

The drug should not be mixed with other medicinal products.

Storage Conditions

The drug should be stored in a dry place, protected from light and out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life of the lyophilisate is 3 years, the solvent is 5 years.

The reconstituted solution can be stored at a temperature from 5°C (41°F) to 25°C (77°F) for 24 hours.

Dispensing Status

The drug is dispensed 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.