ZOMETA

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOMETA® (ZOMETA®)

Composition:

Active substance: zoledronic acid;

5 ml of concentrate contain 4 mg of anhydrous zoledronic acid, equivalent to 4.264 mg of zoledronic acid monohydrate;

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, colorless solution.

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

Pharmacological properties.

Pharmacodynamics.

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

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 demonstrated that zoledronic acid inhibits bone resorption without adversely affecting bone formation, mineralization, or mechanical properties of bone.

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. Preclinical studies have demonstrated the following effects:

In vivo – inhibition of osteoclast-mediated bone resorption, acting on the microcrystalline matrix structure of bone, thereby reducing tumor growth; antiangiogenic effects (action on blood vessels leading to reduced tumor blood supply); and analgesic effects.

In vitro – inhibition of osteoblast proliferation, cytostatic effects, pro-apoptotic effects on tumor cells, synergistic cytostatic effects with other antineoplastic agents, anti-adhesive, and 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 zoledronic acid administered to 64 patients. Pharmacokinetic parameters were independent of dose.

After initiation of zoledronic acid infusion, plasma concentration rapidly increases, reaching peak levels at the end of the infusion. This is followed by a rapid decline in concentration to less than 10% of peak levels within 4 hours and less than 1% of peak levels within 24 hours, with a subsequent prolonged phase of low concentrations not exceeding 0.1% of peak levels until the next infusion on day 28. Zoledronic acid administered intravenously is eliminated via the kidneys in three phases: a rapid biphasic elimination from systemic circulation with half-lives 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 administration 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 by the kidneys. Total systemic clearance of the drug is 5.04±2.5 L/h and is independent of dose, gender, age, race, or body weight. Increasing the infusion duration from 5 to 15 minutes reduces the zoledronic acid concentration at the end of infusion by 30%, but does not affect the plasma concentration-time curve (AUC).

Inter-patient variability in the pharmacokinetic parameters of zoledronic acid, as with other bisphosphonates, was high.

Pharmacokinetic data for zoledronic acid in patients with hypercalcemia and hepatic insufficiency are lacking. In vitro data indicate that zoledronic acid does not inhibit the human CYP450 enzyme system and is not subject to biotransformation. Animal experimental studies showed 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 zoledronic acid renal clearance averaging 75±33% of creatinine clearance. In 64 oncology patients included in the study, mean creatinine clearance was 84±29 mL/min (range 22–143 mL/min). Analysis of patient subgroups showed that relative zoledronic acid clearance was 37% and 72% of normal in patients with creatinine clearance of 20 mL/min (severe renal impairment) and 50 mL/min (moderate renal impairment), 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 the 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, gender, and creatinine clearance do not appear to influence systemic exposure to zoledronic acid.

Clinical characteristics.

Indications.

• Prevention of skeletal-related events (pathological fractures, spinal cord compression, complications following surgical intervention or radiation therapy, or hypercalcemia due to malignancy) in patients with advanced malignant disease.
• Treatment of hypercalcemia of malignancy.

Contraindications.

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

Pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

During clinical studies, other medicinal products such as anticancer agents, diuretics, antibiotics, and analgesics were frequently administered concomitantly with Zometa®. 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 systems. 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 concomitantly with loop diuretics, as they may have an additive effect, increasing the risk of hypocalcemia. Care should be taken when prescribing Zometa® together with other potentially nephrotoxic agents. The possibility of developing hypomagnesemia during treatment should also be considered.

In patients with multiple myeloma, no clinically significant interactions were observed when bisphosphonates were administered intravenously in combination with thalidomide.

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

Special precautions for use.

General

Prior to administration of Zometa®, all patients, including those with mild to moderate renal impairment, should be adequately hydrated.

Overhydration 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 Zometa® 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.

Zometa® contains the active substance zoledronic acid. Patients receiving Zometa® therapy should not simultaneously receive other medicinal products containing zoledronic acid.

Patients receiving Zometa® therapy should also not use any other bisphosphonates.

Renal impairment

When considering the use of Zometa® in patients with hypercalcaemia due to malignancy and underlying renal impairment, 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 for prevention of skeletal-related events, it should be considered 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 Zometa® or other bisphosphonates, concomitant use of nephrotoxic agents, or infusion over a shorter duration than recommended. Although the risk is reduced when Zometa® is administered at a dose of 4 mg over no less than 15 minutes, deterioration in renal function is still possible. Cases of worsening renal function, progression to renal failure, and need for dialysis have been observed in patients after administration of the initial or a single 4 mg dose of zoledronic acid.

Elevations in serum creatinine have also been observed in some patients receiving the drug continuously at the recommended doses for prevention of skeletal-related events in patients with bone metastases and in postmenopausal women with early-stage breast cancer receiving aromatase inhibitors (AIs) for prevention of bone mass loss and fractures, although this occurs infrequently.

Serum creatinine levels should be assessed in patients prior to each dose of Zometa®. For patients with bone metastases and postmenopausal women with early-stage breast cancer receiving aromatase inhibitors (AIs) for prevention of bone mass loss and fractures, lower doses of Zometa® are recommended in cases of mild or moderate renal impairment (see table in the section "Dosage and administration"). In patients who experience worsening renal function during treatment, administration of the drug may be resumed only when serum creatinine returns to within 10% of the baseline value. When resuming therapy, Zometa® should be administered at the same dose as before the temporary interruption.

Due to the potential effect of bisphosphonates, including Zometa®, on renal function and in the absence 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 mass loss and fractures, respectively), and due to limited pharmacokinetic data in patients with severe renal impairment (creatinine clearance < 30 mL/min), the use of Zometa® is not recommended in patients with severe renal impairment.

Hepatic impairment

No specific recommendations are available for patients with severe hepatic impairment due to limited clinical data.

Osteonecrosis of the jaw

Osteonecrosis of the jaw has been reported primarily in oncology patients receiving treatment regimens that include bisphosphonates, including Zometa®.

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 of treatment or a new treatment course should be delayed in patients with 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 for developing osteonecrosis of the jaw:

• Potency of bisphosphonates (higher risk with more potent agents), route of administration (higher risk with parenteral administration), and cumulative dose.
• Cancer, comorbid 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 should be performed with appropriate dental prophylaxis.

During therapy, invasive dental procedures should be avoided whenever possible in these patients. Dental surgery may worsen the condition in patients who develop osteonecrosis of the jaw during bisphosphonate therapy. There are no data available on patients requiring dental procedures to determine whether discontinuation of bisphosphonate therapy reduces the risk of developing 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 as much as possible.

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 concomitant steroid use and chemotherapy and/or local risk factors such as infections or trauma. Osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who report symptoms related to the ear, including chronic ear infections.

Musculoskeletal pain

In post-marketing surveillance, severe, sometimes incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. However, such reports have been infrequent. This class of drugs includes Zometa® (zoledronic acid). The time to onset of symptoms ranged from one day to several months after starting treatment. In most patients, symptoms improved after discontinuation of therapy. In this patient group, recurrence of symptoms was observed 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 supracondylar region. These fractures occur with minimal or no trauma, and some patients experience pain in the thigh or groin, often associated with radiological signs of a 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. Poor healing of such fractures has also been reported. Based on individual assessment of benefit and risk, the decision to discontinue bisphosphonate therapy should be considered in patients suspected of having atypical femoral fractures.

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

Hypocalcaemia

Hypocalcaemia has been reported in patients receiving Zometa®. 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.

Use during pregnancy or breastfeeding.

The drug 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 reproductive studies. The potential risk to humans is unknown.

Breastfeeding

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

Ability to affect reaction speed when driving or operating machinery.

Adverse reactions to the drug, such as dizziness and somnolence, may affect the ability to drive or operate machinery; therefore, caution is required when driving or operating complex machinery during treatment with Zometa®.

Administration and Dosage

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

Prior to administration, 5 mL of Zometa® 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 Zometa® infusion solution should be administered as a single intravenous infusion over no less than 15 minutes.

Zometa® 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 involving bone

Adults and elderly patients

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

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

When making treatment decisions for patients with bone metastases for the prevention of skeletal-related events, it should be noted that the therapeutic effect begins after 2–3 months.

Treatment of hypercalcemia of malignancy

Adults and elderly patients

For the treatment of hypercalcemia (serum calcium level corrected for albumin ≥ 12.0 mg/dL or ≥ 3.0 mmol/L), a single 4 mg dose of 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 potential 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 (> 4.5 mg/dL). Dose adjustment is not required for patients with hypercalcemia of malignancy and serum creatinine levels < 400 µmol/L (< 4.5 mg/dL).

Prevention of skeletal-related events in patients with advanced malignancies involving bone

Serum creatinine and creatinine clearance should be determined before initiating therapy with Zometa® in patients with multiple myeloma or solid tumor bone metastases. Creatinine clearance should be calculated using the Cockcroft-Gault formula. Zometa® is not recommended for patients with severe renal impairment prior to treatment initiation (creatinine clearance < 30 mL/min). Clinical studies of Zometa® administration in patients with serum creatinine levels > 265 µmol/L (≥ 3.0 mg/dL) have not been conducted.

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

*Doses were 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 each dose of Zometa® is administered after initiating therapy. If renal impairment occurs, treatment should be discontinued. In clinical studies, renal impairment was defined by the following criteria:

• For patients with normal baseline serum creatinine levels (<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 levels (>1.4 mg/dL or >124 µmol/L) – an increase of 1 mg/dL or 88 µmol/L.

During clinical studies, Zometa® therapy was resumed once serum creatinine levels returned to within 10% of the baseline value. Zometa® therapy should be resumed at the same dose as prior to treatment interruption.

Pediatric populations

The safety and efficacy of zoledronic acid in children aged 1 to 17 years have not been established. There are no recommendations for use in pediatric patients.

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.

Reduced doses of Zometa® are recommended for patients with mild to moderate renal impairment.

Instructions for preparation of reduced doses of Zometa®:

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

Adverse Reactions

Within three days following administration of Zometa®, acute-phase reactions have usually been reported, with symptoms including bone pain, fever, weakness, arthralgia, myalgia, chills, and arthritis with joint swelling. These symptoms usually resolve within several days.

The following important adverse reactions have been identified with the use of Zometa®:

renal impairment, jaw necrosis, acute-phase reactions, hypocalcemia, visual disturbances, atrial fibrillation, anaphylaxis, and interstitial lung disease.

Information on the frequency of adverse reactions with Zometa® at a dose of 4 mg is primarily based on data obtained during long-term therapy. Adverse reactions associated with Zometa® 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 trials, primarily 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), and not known (cannot be estimated from available data).

From the blood and lymphatic system:

common – anemia;

uncommon – thrombocytopenia, leukopenia;

rare – pancytopenia.

From the nervous system:

common – headache;

uncommon – paresthesia, dizziness, taste disturbances, hypoesthesia, hyperesthesia, tremor, somnolence;

very rare – epileptic seizures, numbness, and tetany (secondary to hypocalcemia).

From the psyche:

uncommon – restlessness, sleep disorders;

rare – confusion.

From the visual organs:

common – conjunctivitis;

uncommon – blurred vision, scleritis, and orbital inflammation;

rare – uveitis;

very rare – episcleritis.

From the gastrointestinal tract:

common – nausea, vomiting, anorexia;

uncommon – diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.

From the respiratory system:

uncommon – dyspnea, cough, bronchoconstriction;

rare – interstitial lung disease.

From the skin and subcutaneous tissues:

uncommon – pruritus, rash (including erythematous and macular rashes), increased sweating.

From the musculoskeletal system and connective tissue:

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).

From the cardiovascular system:

uncommon – arterial hypertension, arterial hypotension, atrial fibrillation, arterial hypotension leading to syncope and circulatory collapse;

rare – bradycardia; very rare – cardiac arrhythmia (secondary to hypocalcemia).

From the renal and urinary system:

common – renal impairment;

uncommon – acute renal failure, hematuria, proteinuria;

rare – acquired Fanconi syndrome.

From the immune system:

uncommon – hypersensitivity reactions;

rare – angioedema.

General disorders and administration site reactions:

common – fever, flu-like symptoms (including fatigue, chills, malaise, and hot flushes);

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 test abnormalities:

very common – hypophosphatemia;

common – increased blood creatinine and urea levels, hypocalcemia;

uncommon – hypomagnesemia, hypokalemia;

rare – hyperkalemia, hypernatremia.

Renal function impairment

Worsening of renal function has been reported with the use of Zometa®. Based on safety data analysis from registration trials of Zometa® for prevention of skeletal-related events in patients with advanced malignancies, the incidence of renal function disorders considered related to Zometa® was 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 renal impairment include dehydration, pre-existing renal dysfunction, multiple courses of treatment with Zometa® or other bisphosphonates, concomitant use of other nephrotoxic agents, or shortening of the recommended infusion duration. Cases of worsening renal function, progression of renal failure, and need for hemodialysis have been reported after the first or single administration of 4 mg zoledronic acid.

Osteonecrosis of the jaw

Cases of osteonecrosis (mainly of the jaw) have been reported primarily in cancer patients receiving Zometa®. Many of these patients had signs of local infection, including osteomyelitis. Most cases were associated with dental procedures such as tooth extraction. Osteonecrosis of the jaw has many established risk factors, including diagnosed cancer, concomitant therapy (e.g., chemotherapy, radiation therapy, corticosteroids), and comorbid conditions (e.g., anemia, coagulopathies, infections, oral diseases). Although a causal relationship has not been proven, these patients are advised to avoid invasive dental procedures.

Atrial fibrillation

In a randomized, double-blind, placebo-controlled clinical trial 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 Zometa® infusion. These reactions are referred to as "flu-like" syndrome or "post-dose" syndrome.

Atypical femoral fractures

Rarely reported during post-marketing use are subtrochanteric and diaphyseal femoral fractures (an adverse reaction associated with bisphosphonates).

Adverse reactions due to hypocalcemia

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

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C, in a place inaccessible to children.

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

After aseptic dilution, the prepared solution should be used immediately.

Incompatibility.

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

Studies with glass vials and several types of infusion bags and infusion sets made of polyvinyl chloride, polyethylene, and polypropylene (pre-filled with 0.9% sodium chloride solution or 5% glucose solution) showed no incompatibility with the aforementioned packaging materials.

Packaging.

Concentrate for infusion solution, 5 mL, in a colorless plastic vial with a grey rubber stopper and aluminum cap with flip-off component. One vial is packed in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

1. Novartis Pharma Stein AG, Switzerland / Novartis Pharma Stein AG, Switzerland.
2. Lek Pharmaceuticals d.d. / Lek Pharmaceuticals d.d.

Manufacturer's address and place of business.

1. Schaffhauserstrasse, 4332 Stein, Switzerland / Schaffhauserstrasse, 4332 Stein, Switzerland.
2. Verovskova Ulica 57, Ljubljana, 1526, Slovenia / Verovskova Ulica 57, Ljubljana, 1526, Slovenia.