Blaztere^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Dr. Reddy’s Laboratories Ltd. (India)

ATC Code

M05BA08 (Zoledronic acid)

Active Substance

Zoledronic acid (Swiss Ph.)

Dosage Form

Blaztere®

Lyophilisate for preparation of solution for infusion 4 mg: vial 1 pcs.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for infusion in the form of a cake, separate aggregates or powder, white or almost white in color.

Excipients: mannitol – 220 mg, sodium citrate (for pH adjustment) – 24 mg, water for injections (prior to lyophilization) – up to 2.5 ml.

Colorless glass vials (1) – cardboard packs.

Clinical-Pharmacological Group

Bone resorption inhibitor for bone metastases

Pharmacotherapeutic Group

Bone resorption inhibitor – bisphosphonate

Pharmacological Action

Inhibitor of bone resorption. Zoledronic acid belongs to the highly effective bisphosphonates, which have a selective effect on bone tissue. The drug suppresses bone resorption by acting on osteoclasts.

The selective action of bisphosphonates on bone tissue is based on their 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 efficacy in bone metastases.

Zoledronic acid, by suppressing proliferation and inducing apoptosis, has a direct antitumor effect on human myeloma cells and breast cancer cells, and also reduces the penetration of human breast cancer cells through the extracellular matrix, indicating its antimetastatic properties. Furthermore, Zoledronic acid inhibits the proliferation of human endothelial cells and has demonstrated antiangiogenic effects in animals.

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

Pharmacokinetics

Pharmacokinetic parameters do not depend on the dose of the drug.

Absorption and Distribution

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. 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 AUC.

Plasma protein binding is 56%. Zoledronic acid has low affinity for blood components.

Metabolism and Excretion

It is not metabolized.

It is excreted by the kidneys unchanged in 3 phases: phase 1 and 2 – rapid elimination of the drug from the systemic circulation, with T_1/2 of 0.24 hours and 1.87 hours respectively, and phase 3 – a long phase, 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 the drug 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 feces. Total plasma clearance is 2.54-7.54 L/h. It does not depend on the drug dose, gender, age, race, or body weight of the patient.

Pharmacokinetics in Special Clinical Situations

Renal clearance positively correlates with CrCl and is 42-108% of CrCl, averaging 55-113%. In patients with severe renal impairment (CrCl 20 ml/min) and moderate renal impairment (CrCl 50 ml/min), the clearance of zoledronic acid is 37% and 72%, respectively, of the clearance values in patients with CrCl 84 ml/min.

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, reduce tumor-induced hypercalcemia, and reduce the need for radiation therapy).

ICD codes

Dosage Regimen

The drug is administered intravenously by drip over at least 15 minutes.

For hypercalcemia of malignancy, with an albumin-corrected serum calcium concentration ≥ 12 mg/dl or 3 mmol/l, the maximum recommended dose is 4 mg.

Before infusion, serum creatinine concentration should be checked. Dose adjustment in patients with mild or moderate renal impairment (serum creatinine concentration <400 µmol/l or <4.5 mg/dl) is not required.

The infusion is carried out provided the patient is adequately hydrated (administration of 0.9% sodium chloride solution before, simultaneously with, or after the infusion of zoledronic acid). Re-administration of the drug at a dose of 4 mg is indicated in case of deterioration after a clear effect (i.e., achieving a serum ionized calcium concentration of 2.7 mmol/l and below) or in case of refractoriness to the first administration. The interval between the first and repeated administration should be at least 1 week to assess the effect.

If re-administration of zoledronic acid is necessary, serum creatinine concentration should be determined before each infusion.

For multiple myeloma and metastatic bone lesions from solid tumors, the dose of Blaztere^® depends on the baseline CrCl calculated using the Cockcroft formula.

Recommended doses for patients with mild or moderate renal impairment (CrCl values 30-60 ml/min) are given below.

After initiation of zoledronic acid therapy, serum creatinine concentration should be determined before the administration of each dose of the drug.

If renal impairment is detected, the next administration of the drug should be postponed. Renal impairment is defined by the following parameters:

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

Zoledronic acid therapy is resumed only after the creatinine level reaches values within 10% of the baseline value, at the same dose that was used before treatment interruption.

Patients should be additionally prescribed oral calcium at a dose of 500 mg/day and oral vitamin D at a dose of 400 IU/day along with zoledronic acid therapy.

Instructions for preparation of the infusion solution

The solution is prepared under aseptic conditions. The contents of the vial (4 mg of zoledronic acid) are dissolved in 5 ml of Water for Injections and 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.

The prepared solution is preferably used immediately after preparation. The unused solution can be stored in the refrigerator at a temperature of 2-8°C (17.6°F) for no more than 24 hours. Before administration, the solution should be allowed to reach room temperature.

The total time between dilution of the concentrate, storage of the prepared solution in the refrigerator at 2-8°C (17.6°F), and the end of drug administration should not exceed 24 hours.

The zoledronic acid solution should not be mixed with any other medicinal products or with solutions containing calcium or any other divalent cations, such as Ringer’s solution. A separate infusion system should always be used.

Adverse Reactions

Adverse reactions associated with the use of zoledronic acid are usually mild. Frequency criteria for adverse reactions: 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).

From the hematopoietic system: common – anemia; uncommon – thrombocytopenia, leukopenia; rare – pancytopenia.

From the CNS and peripheral nervous system: common – headache; uncommon – dizziness, paresthesia, taste disturbances, hypoesthesia, hyperesthesia, tremor, anxiety, sleep disorders; rare – confusion.

From the organ of vision: common – conjunctivitis; uncommon – blurred vision; very rare – uveitis, episcleritis.

From the digestive system: common – nausea, vomiting, anorexia; uncommon – diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.

From the respiratory system: uncommon – dyspnea, cough.

Dermatological reactions: uncommon – pruritus, rash (including erythematous and macular), increased sweating.

From the musculoskeletal system: common – bone pain, myalgia, arthralgia, generalized pain; uncommon – muscle cramps.

From the cardiovascular system: uncommon – marked increase in BP; rare – bradycardia.

From the urinary system: common – renal function impairment; uncommon – acute renal failure, hematuria, proteinuria.

Allergic reactions: uncommon – hypersensitivity reactions; rare – angioedema.

From laboratory parameters: very common – hypophosphatemia; common – increased serum creatinine and urea concentrations, hypocalcemia; uncommon – hypomagnesemia, hypokalemia; rare – hyperkalemia, hypernatremia.

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

Other: common – fever, flu-like syndrome (including malaise, chills, feeling of illness, increased body temperature); uncommon – asthenia, peripheral edema; chest pain, weight gain.

In clinical practice, rare cases of osteonecrosis of the jaw have been described in patients treated with bisphosphonates (usually after tooth extraction or other dental procedures). A clear causal relationship for the development of osteonecrosis has not been established.

Contraindications

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

With caution

When deciding on the use of zoledronic acid in patients with hypercalcemia of malignancy against the background of renal impairment, it is necessary to assess the patient’s condition and conclude whether the potential benefit of administering the drug outweighs the possible risk.

Caution should be exercised 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).

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and lactation.

Use in Renal Impairment

Recommended doses for patients with mild or moderate renal impairment (CrCl values 30-60 ml/min) are given below.

After initiation of zoledronic acid therapy, serum creatinine concentration should be determined before the administration of each dose of the drug.

If renal impairment is detected, the next administration of the drug should be postponed. Renal impairment is defined by the following parameters:

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

Zoledronic acid therapy is resumed only after the creatinine level reaches values within 10% of the baseline value, at the same dose that was used before treatment interruption.

Pediatric Use

Contraindication: childhood and adolescence (safety and efficacy have not been studied).

Special Precautions

Treatment with zoledronic acid should be carried out under the supervision of a physician experienced in the use of bisphosphonates.

When deciding on the use of zoledronic acid in patients with hypercalcemia of malignancy against the background of renal impairment, it is necessary to assess the patient’s condition and conclude whether the potential benefit of administering the drug outweighs the possible risk. Before each administration of zoledronic acid, serum creatinine concentration should be determined. At the start of treatment with the drug in patients with bone metastases who have mild to moderate renal impairment, it is recommended to use zoledronic acid in reduced doses. If renal impairment occurs during zoledronic acid therapy, therapy with the drug can be continued only after the creatinine concentration returns to values within 10% of the baseline value.

Before infusion, adequate hydration of the patient should be ensured. If necessary, administration of 0.9% sodium chloride solution before, in parallel with, or after the infusion of zoledronic acid is recommended. Overhydration of the patient should be avoided due to the risk of cardiovascular complications.

After administration of zoledronic acid, constant monitoring of serum calcium, phosphorus, magnesium, and creatinine concentrations is necessary. 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, so careful monitoring of renal function is necessary in this category of patients. When deciding on treatment with zoledronic acid for patients with bone metastases from solid tumors, it should be taken into account that the therapeutic effect occurs 2-3 months after the start of treatment.

There are isolated reports of renal function impairment during the use of bisphosphonates. Risk factors for such complications 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 administration of the drug. Although the risk of the above complications is reduced when zoledronic acid is administered at a dose of 4 mg over at least 15 minutes, the possibility of renal function impairment remains.

Increased serum creatinine concentrations are also observed in some patients with long-term use of zoledronic acid at recommended doses, although less frequently.

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

Cases of osteonecrosis of the jaw have been described in cancer patients during antitumor treatment including bisphosphonates. Many patients had signs of a local infectious-inflammatory process, including osteomyelitis.

Before starting treatment with bisphosphonates, dental examination and appropriate preventive procedures should be planned in patients with risk factors (concomitant therapy – chemotherapy, radiation therapy, corticosteroid treatment; concomitant diseases – anemia, coagulopathies, infection, pre-existing oral disease; poor oral hygiene).

During treatment of these patients, dental surgery should be avoided if possible. There are no data indicating that interrupting bisphosphonate treatment 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.

Overdose

Symptoms: intensification of symptoms of hypocalcemia.

Treatment: administration of calcium gluconate.

Drug Interactions

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

According to data obtained from in vitro studies, Zoledronic acid does not exhibit significant binding to plasma proteins and does not inhibit cytochrome P450 system isoenzymes.

Caution is advised when bisphosphonates and aminoglycosides are used simultaneously, as the combined effect of these drugs may lead to a prolonged decrease in plasma calcium concentration.

Caution is necessary when zoledronic acid is used concomitantly with drugs that have potential nephrotoxic effects.

In patients with multiple myeloma, there may be an increased risk of renal function impairment with intravenous administration of bisphosphonates, such as Zoledronic acid, in combination with thalidomide.

Pharmaceutical Interactions

The diluted solution of zoledronic acid must not be mixed with infusion solutions containing calcium ions, such as Ringer’s solution.

Storage Conditions

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

Shelf Life

The shelf life is 2 years.

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.