Zoltero

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOLTERO (ZOLTERO)

Composition:

Active substance: zoledronic acid;

5 ml of concentrate contain zoledronic acid monohydrate equivalent to 4 mg of zoledronic acid;

1 ml of concentrate contains 0.8 mg of anhydrous zoledronic acid;

Excipients: mannitol (E 421), sodium citrate, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, almost colorless solution free from visible particles.

Pharmacotherapeutic group. Drugs affecting bone structure and mineralization. Bisphosphonates. ATC code M05B A08.

Pharmacological Properties

Pharmacodynamics

Zoledronic acid belongs to a new class of bisphosphonates that specifically target bone tissue. It is one of the most potent inhibitors of osteoclast-mediated bone resorption known to date.

The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone tissue; however, the molecular mechanism leading to inhibition of osteoclast activity has not yet been fully elucidated. Animal studies have shown that zoledronic acid inhibits bone resorption without negatively affecting bone formation, mineralization, or mechanical bone properties.

In addition to inhibiting osteoclast-mediated bone resorption, zoledronic acid exerts direct antitumor effects on cultured human myeloma and breast cancer cells by inhibiting cell proliferation and inducing apoptosis. This suggests that zoledronic acid may possess antimetastatic properties.

In vivo – inhibition of osteoclast-mediated bone resorption affects the bone marrow microenvironment, making it less favorable for tumor cell growth, resulting in antiangiogenic and analgesic effects.

In vitro – inhibition of osteoblast proliferation, direct cytostatic and pro-apoptotic effects on tumor cells, synergistic cytostatic effects with other antineoplastic agents, anti-adhesive/anti-invasive effects.

Pharmacokinetics

Pharmacokinetic data in patients with bone metastases were obtained after single and repeated 5- and 15-minute infusions of 2, 4, 8, and 16 mg of zoledronic acid administered to 64 patients. Pharmacokinetic parameters are independent of the dose of the drug.

Following the initiation of zoledronic acid infusion, plasma concentration of the drug rapidly increases, reaching a peak at the end of the infusion, followed by a rapid decline to <10% of peak levels within 4 hours and <1% of peak levels within 24 hours. This is followed by a prolonged period of low concentrations, not exceeding 0.1% of peak levels, until the second infusion on day 28. Intravenously administered zoledronic acid is eliminated from the body via the kidneys in three phases: rapid biphasic elimination from systemic circulation with half-lives of t½α = 0.24 hours and t½β = 1.87 hours, followed by a prolonged terminal phase with t½γ = 146 hours. No drug accumulation in plasma was observed with repeated dosing every 28 days. Zoledronic acid is not metabolized and is excreted unchanged by the kidneys. Within the first 24 hours, 39±16% of the administered dose is recovered in urine. The remainder is primarily bound to bone tissue. Subsequently, zoledronic acid is slowly released from bone back into systemic circulation and eliminated renally. Total systemic clearance of the drug is 5.04±2.5 L/h and is independent of dose, sex, age, race, and body weight of the patient. Increasing the infusion duration from 5 to 15 minutes results in a 30% reduction in zoledronic acid concentration at the end of infusion but does not affect the plasma concentration-time curve (AUC).

Pharmacokinetic parameters of zoledronic acid showed high inter-patient variability, consistent with other bisphosphonates.

Pharmacokinetic data for zoledronic acid in patients with hypercalcemia or hepatic insufficiency are lacking. In vitro data indicate that zoledronic acid does not inhibit the human CYP450 enzyme and is not subject to biotransformation. Animal experimental studies show that less than 3% of the administered dose is excreted in feces, suggesting that hepatic function is unlikely to influence the pharmacokinetics of zoledronic acid.

Renal clearance of zoledronic acid correlates with creatinine clearance, with renal clearance of zoledronic acid averaging 75±33% of creatinine clearance. In 64 oncology patients included in the study, creatinine clearance averaged 84±29 mL/min (range 22–143 mL/min). Analysis showed that in patients with creatinine clearance of 20 mL/min (severe renal impairment) and 50 mL/min (moderate renal impairment), relative zoledronic acid clearance was 37% and 72%, respectively. However, pharmacokinetic data in patients with severe renal impairment (creatinine clearance <30 mL/min) are limited.

Zoledronic acid has been shown to have low affinity for blood cellular components. Plasma protein binding is low, with unbound fraction ranging from 60% at 2 ng/mL to 77% at 2000 ng/mL of zoledronic acid.

Special Populations

Children

Limited pharmacokinetic data in children with severe forms of osteogenesis imperfecta suggest that the pharmacokinetics of zoledronic acid in children aged 3 to 17 years is similar to that in adults when administered at equivalent doses (mg/kg). Age, body weight, sex, and creatinine clearance have been shown not to influence systemic exposure to zoledronic acid.

Clinical characteristics.

Indications.

• Prevention of symptoms related to bone involvement (pathological fractures, spinal cord compression, complications following surgery or radiation therapy, or hypercalcemia due to malignancy) in patients with advanced malignant disease.
• Treatment of hypercalcemia due to malignancy.

Contraindications.

Hypersensitivity to the active substance (zoledronic acid), other bisphosphonates, or to any of the excipients of the medicinal product.

Pregnancy or breastfeeding. Pediatric age.

Interaction with other medicinal products and other forms of interaction.

During clinical studies, zoledronic acid was frequently administered concomitantly with other medicinal products such as anticancer agents, antibiotics, and analgesics. No clinically significant interactions were observed.

According to in vitro studies, zoledronic acid does not significantly bind to plasma proteins and does not inhibit cytochrome P450 enzyme system. However, specific clinical drug interaction studies have not been conducted.

Caution is recommended when bisphosphonates are used concomitantly with aminoglycosides, as they may have an additive effect, potentially leading to prolonged reduction in serum calcium levels. Caution is also advised when bisphosphonates are used together with loop diuretics, as their additive effect may lead to hypocalcemia. Care should be taken when prescribing Zoltero together with other potentially nephrotoxic medicinal products. Additionally, the possibility of developing hypomagnesemia during treatment should be considered.

In patients with multiple myeloma, intravenous administration of bisphosphonates in combination with thalidomide increases the risk of renal impairment.

Osteonecrosis of the jaw has been reported in patients receiving concomitant treatment with zoledronic acid and antiangiogenic medicinal products (agents that reduce tumor blood supply).

Special precautions for use.

General

Before administration of the medicinal product Zoltero, adequate hydration should be ensured in all patients, including those with mild to moderate renal impairment.

Hyperhydration should be avoided in patients at risk of developing heart failure.

Standard metabolic parameters associated with hypercalcaemia, such as calcium, phosphate, and magnesium levels, should be carefully monitored after initiation of Zoltero therapy. If hypocalcaemia, hypophosphataemia, or hypomagnesaemia occurs, short-term corrective therapy may be necessary.

Untreated patients with hypercalcaemia usually have some degree of renal impairment; therefore, careful monitoring of renal function parameters is required.

Patients receiving Zoltero therapy should not concurrently receive other medicinal products containing zoledronic acid.

Patients receiving Zoltero therapy should also not concurrently use any other bisphosphonates.

Renal impairment

When considering the use of Zoltero in patients with malignancy-associated hypercalcaemia and impaired renal function, the patient's condition should be evaluated and a decision made as to whether the potential benefit of treatment outweighs the possible risk.

When deciding on treatment of patients with bone metastases to prevent skeletal-related events, it should be noted that the effect of the drug becomes evident after 2–3 months.

Renal dysfunction has been reported with the use of bisphosphonates. Factors increasing the risk of renal impairment include dehydration, pre-existing renal impairment, multiple cycles of Zoltero or other bisphosphonates, concomitant use of nephrotoxic agents, or infusion over a shorter duration than recommended. Although the risk is reduced when Zoltero is administered at a dose of 4 mg over no less than 15 minutes, renal impairment is still possible. Cases of worsening renal function, progression to renal failure, and need for dialysis have been observed in patients after administration of an initial or single 4 mg dose of zoledronic acid.

Elevated serum creatinine levels have also been observed in some patients receiving the drug continuously at recommended doses for prevention of skeletal-related events, although this occurs infrequently.

Prior to each dose of Zoltero, serum creatinine levels should be assessed in patients. After initiation of treatment, lower doses of Zoltero are recommended in patients with bone metastases and in postmenopausal women with early-stage breast cancer receiving aromatase inhibitors (AIs) for prevention of bone loss and fractures, in cases of mild to moderate renal impairment (see table in the section "Dosage and administration"). In patients who develop renal impairment during treatment, the drug may be resumed only when serum creatinine returns to within 10% of baseline. Upon resumption of therapy, Zoltero should be administered at the same dose as prior to temporary discontinuation.

Due to the potential effect of bisphosphonates, including Zoltero, on renal function, and due to the lack of comprehensive clinical safety data in patients with severe renal impairment (serum creatinine >400 µmol/L or >4.5 mg/dL for patients with tumour-induced hypercalcaemia, and serum creatinine >265 µmol/L or >3 mg/dL for patients with bone metastases and postmenopausal women with early-stage breast cancer receiving aromatase inhibitors (AIs) for prevention of bone loss and fractures, respectively), and due to limited pharmacokinetic data in patients with severe renal impairment (creatinine clearance <30 mL/min), the use of Zoltero in patients with severe renal impairment is not recommended.

Hepatic impairment

Specific recommendations for patients with severe hepatic impairment are lacking, as only limited clinical data are available.

Osteonecrosis of the jaw

Osteonecrosis of the jaw has been reported primarily in oncology patients receiving treatment regimens that include bisphosphonates, including zoledronic acid. Many of these patients were also receiving chemotherapy and corticosteroids. Most reported cases were associated with dental procedures, such as tooth extraction. Many patients had signs of local infection, including osteomyelitis.

Initiation or re-initiation of treatment should be delayed if patients have unhealed open soft tissue lesions in the oral cavity, unless medically necessary. Prior to starting bisphosphonate therapy, patients with concomitant risk factors should undergo a dental examination with appropriate preventive dental treatment and individual assessment of benefit and risk.

The following risk factors should be considered when evaluating individual risk of developing osteonecrosis of the jaw:

• bisphosphonate potency (higher risk with more potent agents), route of administration (higher risk with parenteral administration), and cumulative dose;
• cancer, concomitant conditions (e.g., anaemia, coagulopathy, infection), smoking;
• history of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures, and ill-fitting dentures.

Prior to starting bisphosphonate therapy, an oral examination with appropriate dental preventive measures should be performed.

During therapy, invasive dental procedures should be avoided whenever possible. Dental surgery may worsen the condition in patients who develop osteonecrosis of the jaw during bisphosphonate therapy. There are no data in patients requiring dental procedures to suggest whether discontinuation of bisphosphonate therapy reduces the risk of osteonecrosis of the jaw. Management of patients who develop osteonecrosis of the jaw should be planned in close collaboration between the treating physician and a dentist or oral surgeon experienced in managing such patients. Temporary discontinuation of zoledronic acid should be considered until the condition normalizes and risk factors are minimized.

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been observed with bisphosphonate use, primarily during long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use, chemotherapy, and/or local risk factors such as infection or trauma. Osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with otologic symptoms, including chronic ear infections.

Spontaneous reports of osteonecrosis of other bones, including the femur and pelvic bones, have been received in adult oncology patients receiving bisphosphonate therapy.

Musculoskeletal pain

During post-marketing surveillance, severe and sometimes incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. However, such reports have been infrequent. This drug class includes Zoltero. The time to onset of symptoms varied from one day to several months after starting treatment. In most patients, symptoms improved after discontinuation of therapy. Recurrence of symptoms has been observed in this patient group when treatment was resumed with the same or another bisphosphonate.

Atypical femoral fracture

Atypical subtrochanteric and diaphyseal femoral fractures have been reported during bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures may occur anywhere along the femur from slightly below the lesser trochanter to slightly above the condyles. These fractures occur with minimal or no trauma, and some patients experience thigh or groin pain, often associated with radiological signs of stress fracture, several weeks or months before a complete femoral fracture occurs. Fractures are often bilateral; therefore, the contralateral femur should be examined in patients receiving bisphosphonate therapy who have sustained a femoral fracture. Delayed healing of such fractures has also been reported. Based on individual assessment of risk and benefit, the decision to discontinue bisphosphonate therapy should be considered in patients suspected of atypical femoral fractures.

During bisphosphonate therapy, patients should be advised to inform their physician of any thigh, hip, or groin pain, and any patient presenting with such symptoms should be evaluated for incomplete femoral fracture.

Hypocalcaemia

Hypocalcaemia has been reported in patients receiving zoledronic acid. Cases of cardiac arrhythmias and neurological reactions (including seizures, numbness, and tetany) secondary to severe hypocalcaemia have been reported. Cases of severe hypocalcaemia requiring hospitalization have been reported. In some cases, hypocalcaemia may be life-threatening. Caution should be exercised when zoledronic acid is used concomitantly with medicinal products that may cause hypocalcaemia, as they may have a synergistic effect leading to severe hypocalcaemia (see section "Interaction with other medicinal products and other forms of interaction"). Serum calcium levels should be checked before starting therapy and corrected if necessary. Treatment of such patients should be adequately supplemented with calcium and vitamin D.

Sodium

This medicinal product contains less than 1 mmol (23 mg) of sodium per 5 mL dose, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

The product is contraindicated during pregnancy and breastfeeding.

Pregnancy

There are insufficient data on the use of zoledronic acid in pregnant women. Reproductive toxicity has been observed in animal studies. The potential risk to humans is unknown.

Breastfeeding

It is unknown whether zoledronic acid is excreted in human milk.

Fertility

Zoledronic acid has been evaluated for potential adverse effects on fertility in rats. The results of these studies do not allow conclusions to be drawn regarding the effect of zoledronic acid on human fertility.

Ability to influence reaction speed when driving or operating machinery.

Studies on the effect of the medicinal product on the ability to drive or operate machinery have not been conducted. However, due to adverse reactions (dizziness, somnolence), patients should refrain from driving or operating complex machinery during treatment.

Administration and dosage

Zoltero must be administered only by physicians experienced in intravenous administration of bisphosphonates.

Prior to administration, 5 ml of Zoltero concentrate containing 4 mg of zoledronic acid should be diluted in 100 ml of 0.9% sodium chloride solution or 5% glucose solution. The resulting Zoltero infusion solution should be administered as a single intravenous infusion over at least 15 minutes.

Zoltero concentrate must not be mixed with infusion solutions containing calcium or other divalent cations, such as Ringer's lactate solution, and must be administered using a separate infusion system as a single intravenous infusion.

Prevention of skeletal-related events in patients with advanced malignancies

Adults and elderly patients

The recommended dose of Zoltero is 4 mg administered as an infusion every 3–4 weeks.

Patients should also receive daily oral calcium supplements (500 mg) and vitamin D (400 IU) per day.

When deciding to initiate treatment in patients with bone metastases for prevention of skeletal-related events, it should be noted that the onset of treatment effect occurs after 2–3 months.

Treatment of hypercalcemia of malignancy

Adults and elderly patients

For the treatment of hypercalcemia (serum calcium level corrected for albumin ≥ 12 mg/dL or ≥ 3 mmol/L), a single dose of 4 mg zoledronic acid is recommended.

Renal impairment

Hypercalcemia of malignancy

Treatment of hypercalcemia of malignancy in patients with severe renal impairment may be considered only after careful assessment of the risks and expected benefits of the drug. There is no clinical experience with the use of the drug in patients with serum creatinine levels > 400 µmol/L or > 4.5 mg/dL. Dose adjustment is not required in patients with hypercalcemia of malignancy who have serum creatinine levels < 400 µmol/L or < 4.5 mg/dL.

Prevention of skeletal-related events in patients with advanced malignancies

Prior to initiating therapy with the drug in patients with multiple myeloma or bone metastases from solid tumors, serum creatinine and creatinine clearance should be determined. Creatinine clearance should be calculated using the Cockroft-Gault formula based on serum creatinine levels. Zoltero is not recommended for patients with severe renal impairment prior to starting therapy (creatinine clearance < 30 mL/min). Clinical studies on the use of zoledronic acid in patients with serum creatinine levels ≥ 265 µmol/L or ≥ 3 mg/dL have not been conducted.

For patients with bone metastases and mild to moderate renal impairment prior to starting therapy (creatinine clearance 30–60 mL/min), the following dosage recommendations apply:

Initial creatinine clearance level (ml/min)	Recommended dose of zoledronic acid* (mg)
> 60	4
50-60	3.5
40-49	3.3
30-39	3

*Doses are calculated assuming an AUC value of 0.66 mg•h/L (creatinine clearance of 75 mL/min). For patients with impaired renal function, the dose should be reduced to achieve an AUC equivalent to that observed in patients with a creatinine clearance of 75 mL/min.

Serum creatinine levels should be measured before administration of each dose of Zometa, and if renal impairment occurs, treatment should be discontinued. During clinical studies, renal impairment was defined as follows:

• for patients with normal baseline serum creatinine (<1.4 mg/dL or <124 µmol/L) – an increase of 0.5 mg/dL or 44 µmol/L;
• for patients with elevated baseline serum creatinine (>1.4 mg/dL or >124 µmol/L) – an increase of 1 mg/dL or 88 µmol/L.

During clinical trials, therapy with zoledronic acid was resumed after serum creatinine returned to within 10% of the baseline value. Zometa therapy should be resumed at the same dose as prior to treatment interruption.

Instructions for preparation of Zometa doses

For intravenous infusion.

5 mL of Zometa concentrate containing 4 mg of zoledronic acid should be diluted in 100 mL of sterile 0.9% sodium chloride solution or 5% glucose solution for intravenous infusion.

Patients with mild to moderate renal impairment should receive reduced doses of Zometa.

Instructions for preparation of reduced doses of Zometa

Withdraw the appropriate volume of concentrate as indicated below:

• 4.4 mL corresponds to 3.5 mg;
• 4.1 mL corresponds to 3.3 mg;
• 3.8 mL corresponds to 3 mg.

Adequate hydration of the patient should be ensured both before and after administration of Zometa.

Children.

The safety and efficacy of zoledronic acid in children have not been established.

Overdose.

Clinical experience with acute overdose of zoledronic acid is limited. Accidental administration of zoledronic acid at doses up to 48 mg has been reported. Patients who receive doses exceeding the recommended dose should be kept under close medical supervision, as renal impairment (including renal failure) and changes in serum electrolyte levels (including calcium, phosphate, and magnesium concentrations) may occur. In case of hypocalcemia, calcium gluconate infusion should be administered as clinically indicated. Treatment is symptomatic.

Side effects

Within three days following administration of Zoltero, acute-phase reactions have been commonly reported. Symptoms of these reactions include bone pain, fever, weakness, arthralgia, myalgia, chills, and arthritis with joint swelling. These symptoms usually resolve within a few days.

The most clinically significant adverse reactions reported with Zoltero use include: renal impairment, osteonecrosis of the jaw, acute-phase reactions, hypocalcemia, visual disturbances, atrial fibrillation, anaphylaxis, and interstitial lung disease.

Information on the frequency of adverse reactions with Zoltero at a dose of 4 mg is primarily based on data obtained during long-term therapy. Adverse reactions associated with Zoltero are similar to those reported with other bisphosphonates and may occur in approximately one-third of all patients.

Information on the adverse reactions listed below was collected during clinical studies, predominantly after prolonged treatment with zoledronic acid.

Adverse reactions are classified by frequency of occurrence: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), including isolated reports; and not known (cannot be estimated from available data).

Blood and lymphatic system disorders:
Common: anemia;
Uncommon: thrombocytopenia, leukopenia;
Rare: pancytopenia.

Nervous system disorders:
Common: headache;
Uncommon: paresthesia, dizziness, taste disturbances, hypoesthesia, hyperesthesia, tremor, somnolence;
Very rare: epileptic seizures, numbness, and tetany (secondary to hypocalcemia).

Psychiatric disorders:
Uncommon: anxiety, sleep disorders;
Rare: confusion.

Eye disorders:
Common: conjunctivitis;
Uncommon: blurred vision, scleritis, and orbital inflammation;
Rare: uveitis;
Very rare: episcleritis.

Gastrointestinal disorders:
Common: nausea, vomiting, anorexia;
Uncommon: diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.

Respiratory, thoracic and mediastinal disorders:
Uncommon: dyspnea, cough, bronchoconstriction;
Rare: interstitial lung disease.

Skin and subcutaneous tissue disorders:
Uncommon: pruritus, rash (including erythematous and macular rashes), increased sweating.

Musculoskeletal and connective tissue disorders:
Common: bone pain, myalgia, arthralgia, generalized pain;
Uncommon: muscle cramps, osteonecrosis of the jaw;
Very rare: osteonecrosis of the external auditory canal (adverse reactions typical of bisphosphonates).

Cardiac disorders:
Uncommon: arterial hypertension, arterial hypotension, atrial fibrillation; arterial hypotension leading to syncope and circulatory collapse;
Rare: bradycardia;
Very rare: cardiac arrhythmia (secondary to hypocalcemia).

Renal and urinary disorders:
Common: renal function impairment;
Uncommon: acute renal failure, hematuria, proteinuria;
Rare: acquired Fanconi syndrome;
Not known: tubulointerstitial nephritis.

Immune system disorders:
Uncommon: hypersensitivity reactions;
Rare: angioedema.

General disorders and administration site conditions:
Common: fever, influenza-like illness (including fatigue, chills, malaise, and flushing);
Uncommon: injection site reactions (including pain, irritation, swelling, induration), asthenia, peripheral edema, chest pain, weight gain, anaphylactic reactions/shock, urticaria;
Rare: arthritis and joint swelling as symptoms of acute-phase reaction.

Laboratory abnormalities:
Very common: hypophosphatemia;
Common: increased blood creatinine and urea levels, hypocalcemia;
Uncommon: hypomagnesemia, hypokalemia;
Rare: hyperkalemia, hypernatremia.

Renal function impairment

Renal function impairment has been reported during treatment with zoledronic acid. Factors that may increase the risk of renal impairment include dehydration, pre-existing renal dysfunction, multiple courses of treatment with zoledronic acid or other bisphosphonates, concomitant use of other nephrotoxic agents, or shortening of the recommended infusion time. Cases of renal impairment, progression of renal failure, and the need for hemodialysis have been reported following the first or single administration of 4 mg zoledronic acid. In patients with advanced malignancies, the incidence of renal function disorders considered related to zoledronic acid use was as follows: multiple myeloma – 3.2%, prostate cancer – 3.1%, breast cancer – 4.3%, lung cancer and other solid tumors – 3.2%.

Osteonecrosis of the jaw

Cases of osteonecrosis (predominantly of the jaw) have been reported primarily in cancer patients receiving zoledronic acid. Many of these patients exhibited signs of local infection, including osteomyelitis. Most cases were associated with dental procedures such as tooth extraction. Osteonecrosis of the jaw has several established risk factors, including diagnosed cancer, concomitant therapies (e.g., chemotherapy, radiotherapy, corticosteroids), and comorbid conditions (e.g., anemia, coagulopathy, infections, pre-existing oral diseases).

Although a causal relationship has not been established, patients are advised to avoid invasive dental procedures.

Atrial fibrillation

In a study evaluating the efficacy and safety of zoledronic acid in postmenopausal women with osteoporosis, the overall incidence of atrial fibrillation was 2.5% in the group receiving 5 mg zoledronic acid and 1.9% in the placebo group. The reason for the increased incidence of atrial fibrillation is unknown.

Acute-phase reactions

These adverse reactions include fever, myalgia, headache, limb pain, nausea, vomiting, diarrhea, and arthralgia, as well as arthritis associated with joint swelling, which may occur within the first 3 days after zoledronic acid infusion. These reactions are commonly referred to as "flu-like" syndrome or "post-dose" syndrome.

Atypical femoral fractures

During the post-marketing period, rare reports of subtrochanteric and diaphyseal femoral fractures have been received (an adverse reaction associated with bisphosphonates).

Adverse reactions due to hypocalcemia

Hypocalcemia is an important identified risk associated with the use of Zoltero for approved indications. Clinical and post-marketing data indicate an association between zoledronic acid therapy, reports of hypocalcemia, and the development of secondary cardiac arrhythmias. Additionally, data suggest a link between hypocalcemia and secondary neurological reactions, including epileptic seizures, numbness, and tetany.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C, out of reach of children.

After dilution in sterile 0.9% sodium chloride solution or 5% glucose solution, the preparation is stable for 24 hours at a storage temperature of 2–8 °C.

After aseptic dilution, the ready-to-use solution should be administered immediately.

Incompatibilities.

Zoltero concentrate must be diluted in sterile 0.9% sodium chloride solution or 5% glucose solution. Zoltero concentrate must not be mixed with infusion solutions containing calcium or other divalent cations, such as lactated Ringer's solution, and must be administered as a single infusion using a separate infusion system.

Studies with glass vials and various types of infusion bags and infusion systems made of polyvinyl chloride, polyethylene, and polypropylene (pre-filled with 0.9% sodium chloride solution or 5% glucose solution) have shown no incompatibility with the above-mentioned packaging materials.

Packaging. 5 ml of concentrate in a vial, 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Hetero Labs Limited / Hetero Labs Limited.

Manufacturer's address and location of operations.

Unit-VI, TSIIC, Formulation SEZ, Sy No. 410 & 411, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India / Unit-VI, TSIIC, Formulation SEZ, Sy No. 410 & 411, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India.