Zolacid

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOLACID (ZOLACID)

Composition:

Active substance: zoledronic acid;

5 ml of concentrate (1 vial) contains 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 (E 331), 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 inhibitors of osteoclastic 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 osteoblastic bone resorption affecting the microcrystalline matrix structure of bone, resulting in reduced tumor growth; antiangiogenic effect (effect on blood vessels leading to reduced tumor blood supply); and analgesic effect.

In vitro – inhibition of osteoblastic proliferation, cytostatic effect, pro-apoptotic effect on tumor cells, synergistic cytostatic effect 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- to 15-minute infusions of 2, 4, 8, and 16 mg of zoledronic acid administered to 64 patients. Pharmacokinetic parameters were independent of the dose administered.

After the start of zoledronic acid infusion, plasma concentration of the drug 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 period of low concentrations not exceeding 0.1% of peak levels until the next infusion on day 28. Intravenously administered zoledronic acid is eliminated via the kidneys in three phases: rapid biphasic elimination from systemic circulation with half-lives t½α = 0.24 hours and t½β = 1.87 hours, and 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 body clearance of the drug is 5.04±2.5 L/h and is independent of dose, gender, age, race, or body weight of the patient. 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).

The pharmacokinetic parameters of zoledronic acid, as with other bisphosphonates, showed high inter-patient variability.

Pharmacokinetic data for zoledronic acid in patients with hypercalcemia and hepatic insufficiency are lacking. In vitro data indicate that zoledronic acid does not inhibit human cytochrome P450 enzymes 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 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 shows low affinity for blood cellular components. Plasma protein binding is low, with unbound fractions 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 were found not to influence systemic exposure to zoledronic acid.

Clinical characteristics.

Indications.

Prevention of symptoms related to bone damage (pathological fractures, spinal cord compression, complications following surgery or radiotherapy, or hypercalcemia due to malignancy) in patients with advanced-stage malignant tumors.

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.

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 zoledronic acid. No clinically significant interactions were observed.

In vitro data indicate that zoledronic acid does not significantly bind to plasma proteins and does not inhibit cytochrome P450 enzyme system. However, specific clinical interaction studies have not been conducted.

Caution is recommended when administering bisphosphonates together with aminoglycosides, as they may have an additive effect, potentially leading to prolonged reduction in serum calcium levels. Caution is also advised when using bisphosphonates together with loop diuretics, as additive effects may lead to hypocalcemia. Care should be taken when prescribing Zolacid together with other potentially nephrotoxic agents.

Potential development of 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 zoledronic acid and antiangiogenic agents (medicinal products that reduce tumor blood supply).

Special precautions for use

General

Before administering Zoledronic acid, 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 levels of calcium, phosphate, and magnesium, should be carefully monitored after initiation of therapy with Zoledronic acid. 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 therapy with Zoledronic acid should not simultaneously take other medicinal products containing zoledronic acid.

Patients receiving therapy with Zoledronic acid should not also be treated with any other bisphosphonates.

Renal impairment

When considering the use of Zoledronic acid in patients with malignancy-related hypercalcaemia 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 to prevent skeletal-related events, it should be considered that the therapeutic effect becomes evident after 2–3 months.

Renal dysfunction has been reported in association with the use of bisphosphonates. Factors increasing the risk of renal impairment include dehydration, pre-existing renal dysfunction, multiple cycles of zoledronic acid or other bisphosphonates, concomitant use of nephrotoxic agents, or infusion administered over a shorter duration than recommended. Although the risk is reduced when zoledronic acid 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 levels have also been observed in some patients receiving 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 loss and fractures, although this occurs infrequently.

Serum creatinine levels should be assessed in patients before each dose of Zoledronic acid. For patients with bone metastases and postmenopausal women with early-stage breast cancer receiving aromatase inhibitors (AIs) for prevention of bone loss and fractures, lower doses of Zoledronic acid are recommended in cases of mild or moderate renal impairment (see table in the section "Dosage and administration"). In patients who experience deterioration in 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, Zoledronic acid should be administered at the same dose as prior to the temporary interruption.

Due to the potential effect of bisphosphonates, including Zoledronic acid, 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 the limited pharmacokinetic data available in patients with severe renal impairment (creatinine clearance < 30 mL/min), the use of Zoledronic acid is not recommended in patients with severe renal impairment.

Hepatic impairment

No specific recommendations can be made for patients with severe hepatic impairment due to limited clinical data.

Osteonecrosis of the jaw

Osteonecrosis of the jaw has been reported primarily in cancer 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 of treatment or a new course of treatment should be postponed if patients have non-healing open soft tissue lesions in the oral cavity, except in medical emergencies. 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:

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

A dental examination with appropriate preventive dental care should be performed before initiating bisphosphonate therapy. During therapy, invasive dental procedures should be avoided whenever possible. Dental surgery may worsen the condition in patients who develop osteonecrosis of the jaw while on 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.

The treatment regimen for patients who develop osteonecrosis of the jaw should be developed in close collaboration between the treating physician and a dentist or oral surgeon experienced in managing patients with osteonecrosis of the jaw. 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 use of steroids 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 present with symptoms related to the auditory organs, including chronic ear infections.

Musculoskeletal pain

During post-marketing surveillance, severe and occasionally incapacitating bone, joint, and/or muscle pain have been reported in patients taking bisphosphonates. However, such reports have been infrequent. This class of drugs includes Zoledronic acid (zoledronic acid). The time to onset of symptoms varied from one day to several months after initiation of treatment. In most patients, symptoms decreased after discontinuation of the drug. Recurrence of symptoms was observed in this group of patients 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 flare. These fractures occur with minimal or no trauma, and some patients experience thigh or groin pain, often 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 benefit and risk, a decision should be made regarding discontinuation of bisphosphonate therapy in patients suspected of having atypical femoral fractures. Patients undergoing bisphosphonate therapy should be advised to inform their physician about any pelvic, thigh, or groin pain, and any patient presenting with such symptoms should be evaluated for incomplete femoral fracture.

Hypocalcaemia

Hypocalcaemia has been reported in patients treated with Zoledronic acid. Cases of cardiac arrhythmias and neurological reactions (including epileptic seizures, numbness, and tetany) secondary to severe hypocalcaemia have been reported. Cases of severe hypocalcaemia requiring hospitalization have also been reported. In some cases, hypocalcaemia may be life-threatening.

Use during pregnancy or breastfeeding

The medicinal 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.

Effect on ability to drive and use machines

Adverse reactions to medicinal products such as dizziness and somnolence may affect the ability to drive or operate machinery; therefore, caution should be exercised when driving or operating complex machinery during treatment with Zoledronic acid.

Method of Administration and Dosage

Zoledacid must be administered only by a physician experienced in intravenous bisphosphonate administration.

Before administration, 5 ml of Zoledacid concentrate containing 4 mg of zoledronic acid should be diluted in 100 ml of 0.9% sodium chloride solution or 5% glucose solution. The prepared Zoledacid infusion solution should be administered as a single intravenous infusion over not less than 15 minutes.

Zoledacid 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 intravenous infusion using a separate infusion system.

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

Adults and elderly patients

The recommended dose of Zoledacid is 4 mg 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 considered that the onset of therapeutic 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, ≥ 12.0 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 risks and expected benefits of therapy. 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 and serum creatinine levels < 400 μmol/L or < 4.5 mg/dL.

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

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

For patients with metastatic bone disease and mild to moderate renal impairment prior to treatment initiation (creatinine clearance 30–60 mL/min), the following doses of the drug are recommended:

Serum creatinine levels should be measured before administration of each dose of Zoledronic acid. If renal function deteriorates, 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.

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

Paediatric populations

The safety and efficacy of zoledronic acid in children aged 1 to 17 years have not been established. There are no recommendations regarding administration in children.

Preparation of infusion solution

For intravenous infusion only.

5 mL of Zoledronic acid 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 Zoledronic acid.

Instructions for preparing reduced doses of Zoledronic acid:

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 before and after administration of Zoledronic acid.

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 up to 48 mg of zoledronic acid has been reported. Patients who receive doses exceeding the recommended amount must 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 the event of hypocalcemia, calcium gluconate infusion should be administered as clinically indicated. Treatment is symptomatic.

Adverse Reactions

Within three days following the administration of zoledronic acid, acute-phase reactions are usually reported, the symptoms of which include bone pain, fever, fatigue, arthralgia, myalgia, chills, and arthritis with joint swelling. These symptoms typically resolve within a few days.

The following serious adverse reactions have been identified with the use of Zolacide:

renal impairment, osteonecrosis of the jaw, acute-phase reactions, hypocalcemia, visual disturbances, atrial fibrillation, anaphylaxis, interstitial lung disease.

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

The 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 the 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 system disorders:

uncommon – dyspnea, cough, bronchoconstriction;

rare – interstitial lung disease.

Skin and subcutaneous tissue disorders:

common – hyperhidrosis;

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

Musculoskeletal and connective tissue disorders:

common – bone pain, myalgia, arthralgia, generalized pain;

uncommon – muscle spasms, osteonecrosis of the jaw;

very rare – osteonecrosis of the external auditory canal (adverse reactions typical of bisphosphonates).

Cardiovascular system 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 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, 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.

Investigations:

very common – hypophosphatemia;

common – increased blood creatinine and urea levels, hypocalcemia;

uncommon – hypomagnesemia, hypokalemia;

rare – hyperkalemia, hypernatremia.

Renal function impairment

Renal function deterioration has been reported with the use of zoledronic acid. Based on safety data analysis from registration trials of zoledronic acid for the prevention of skeletal-related events in patients with advanced malignancies, the incidence of renal function disorders considered related to zoledronic acid was as follows: multiple myeloma – 3.2%, prostate cancer – 3.1%, breast cancer – 4.3%, lung cancer and other solid tumors – 3.2%. Risk factors that may increase the likelihood 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, and shortening of the recommended infusion duration. Cases of worsening renal function, progression of renal failure, and the 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 zoledronic acid. 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 several established risk factors, including malignancy diagnosis, concomitant therapies (e.g., chemotherapy, radiation therapy, corticosteroids), and comorbid conditions (e.g., anemia, coagulopathies, infections, oral cavity diseases).

Although a causal relationship has not been definitively established, 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, arthralgia, and arthritis associated with joint swelling, which may occur within the first 3 days after Zolacide infusion. These reactions are referred to as "flu-like" syndrome or "post-dose" syndrome.

Atypical femoral fractures

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

Adverse reactions due to hypocalcemia

Hypocalcemia is an important identified risk with the use of Zolacide for approved indications. Clinical and post-marketing data indicate an association between Zolacide therapy, reported cases of hypocalcemia, and the development of secondary cardiac arrhythmias. Additionally, data suggest a link between hypocalcemia and reported 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 when stored at 2–8 °C.

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

Incompatibilities:

Zolacide concentrate must be diluted in sterile 0.9% sodium chloride solution or 5% glucose solution. Zolacide 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.

Compatibility 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) showed no incompatibility with the above-mentioned packaging materials.

Packaging:

5 mL of concentrate for solution for infusion in a colorless plastic vial with a gray rubber stopper and an aluminum flip-off cap.

1, 4, or 10 vials per cardboard box.

Prescription status: Prescription only.

Manufacturer:

LLC "Farmideya", Latvia.

Manufacturer's address:

4 Rupnīcu Street, Olaine, Olaine District, LV-2114, Latvia.

Marketing Authorization Holder:

LLC "ROKET-PHARM", Ukraine.

Address of the Marketing Authorization Holder:

6 Mykhaila Boichuka Street, Office 103, Kyiv, 01103, Ukraine.