Vistazol

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

Composition:

Active substance: zoledronic acid;

1 ml of solution contains 0.8528 mg of zoledronic acid monohydrate, equivalent to 0.8000 mg of zoledronic acid;

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

Pharmaceutical form. Concentrate for solution for infusion.

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

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 target 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 shown 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, resulting in reduced 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 a peak 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 prolonged period 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 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 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 via the kidneys. Total body clearance of the drug is 5.04 ± 2.5 L/h and is independent of dose, gender, age, race, and body weight. Increasing the infusion duration from 5 to 15 minutes reduces the concentration of zoledronic acid at the end of infusion by 30%, but does not affect the area under the plasma concentration-time curve (AUC).

As with other bisphosphonates, inter-patient variability in the pharmacokinetic parameters of zoledronic acid 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 human cytochrome P450 enzymes and is not subject to biotransformation. Experimental animal studies show that less than 3% of the administered dose is excreted in feces, suggesting that hepatic function does not 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% in patients with creatinine clearance of 20 mL/min (severe renal impairment) and 72% in those with 50 mL/min (moderate renal impairment). 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 symptoms related to bone involvement (pathological fractures, spinal cord compression, complications following surgical interventions or radiation therapy, or hypercalcemia due to malignancy) in patients with advanced malignant diseases.
• Treatment of hypercalcemia due to malignancy.

Contraindications.

• Hypersensitivity to the active substance (zoledronic acid), other bisphosphonates, or to any excipient contained in 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.

According to in vitro study data, 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 concomitantly with loop diuretics, as they may have an additive effect, potentially leading to hypocalcemia. Care should be taken when administering zoledronic acid with other potentially nephrotoxic agents. The possibility of developing hypomagnesemia during treatment should 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 medicinal agents (drugs that reduce tumor blood supply).

Special precautions for use.

General

Prior to administration of 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 related to hypercalcaemia, such as calcium, phosphate, and magnesium levels, should be carefully monitored after initiating zoledronic acid therapy. If hypocalcaemia, hypophosphataemia, or hypomagnesaemia occurs, short-term corrective therapy may be necessary.

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

The medicinal product Vistazol contains the active substance zoledronic acid. Patients receiving therapy with Vistazol should not simultaneously take other medicinal products containing zoledronic acid.

Patients receiving therapy with Vistazol should also not use any other bisphosphonates.

Renal impairment

When considering the use of Vistazol in patients with malignancy-related hypercalcaemia and concomitant 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 noted that the therapeutic effect becomes evident after 2–3 months.

Renal dysfunction associated with bisphosphonate use has been reported. Risk factors for renal impairment include dehydration, pre-existing renal impairment, 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 4 mg is administered over at least 15 minutes, renal impairment remains possible. Cases of renal impairment, progression to renal failure, and need for dialysis have been observed in patients after administration of the initial or a single dose of zoledronic acid 4 mg.

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

Serum creatinine levels should be assessed in patients before each dose of zoledronic acid. In 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 to moderate renal impairment (see table in 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, Vistazol should be administered at the same dose as prior to temporary discontinuation.

Due to the potential effect of bisphosphonates, including Vistazol, 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 loss and fractures, respectively), and due to limited pharmacokinetic data in patients with severe renal impairment (creatinine clearance < 30 mL/min), the use of Vistazol 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 exhibited signs of local infection, including osteomyelitis.

Initiation or resumption of therapy should be delayed in patients with open, non-healing 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 versus 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, concomitant medical 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 initiating bisphosphonate therapy, an oral examination should be performed with appropriate dental prophylaxis.

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 to suggest whether discontinuation of bisphosphonate therapy reduces the risk of osteonecrosis of the jaw in patients requiring dental procedures. 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 such cases. 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 include concomitant use of steroids and 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 report symptoms related to hearing, 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 zoledronic acid. The time to onset of symptoms varied from one day to several months after initiation of treatment. In most patients, symptoms improved after discontinuation of therapy. Recurrence of symptoms was observed in some patients upon reinitiation of the same or another bisphosphonate.

Atypical femoral fracture

Atypical subtrochanteric and diaphyseal femoral fractures have been reported during bisphosphonate therapy, particularly 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. Some patients experience thigh or groin pain, often associated with radiological signs of stress fracture, weeks or months before a complete femoral fracture occurs. Fractures are often bilateral; therefore, the contralateral femur should be evaluated 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, discontinuation of bisphosphonate therapy should be considered in patients suspected of having atypical femoral fractures.

Patients receiving bisphosphonate therapy should be advised to report any new thigh, hip, or groin pain to their physician, 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 documented. Cases of severe hypocalcaemia requiring hospitalization have been reported. In some cases, hypocalcaemia may be life-threatening.

Important information about excipients

Sodium

The medicinal product Vistazol contains 24 mg of sodium per dose. Caution should be exercised when administering this product to patients on a controlled sodium diet.

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. Animal reproductive toxicity studies have shown reproductive toxicity. The potential risk to humans is unknown.

Breastfeeding

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

Administration and Dosage

The medicinal product Vistazol must be administered only by physicians experienced in intravenous administration of bisphosphonates.

Prior to administration, 5 mL of Vistazol 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 solution for intravenous infusion should be administered as a single intravenous infusion lasting at least 15 minutes.

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

Prevention of skeletal-related events in patients with advanced malignancies

Adults, including 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 supplements (500 mg) and vitamin D (400 IU) daily.

When making treatment decisions for patients with bone metastases to prevent skeletal-related events, it should be considered that the onset of therapeutic effect occurs after 2–3 months.

Treatment of tumor-induced hypercalcemia

Adults, including elderly patients

For the treatment of hypercalcemia (serum calcium level corrected for albumin ≥ 12.0 mg/dL or ≥ 3.0 mmol/L), a single dose of 4 mg zoledronic acid is recommended.

Renal Impairment

Tumor-induced hypercalcemia

Treatment of tumor-induced hypercalcemia in patients with severe renal impairment may be considered only after careful assessment of the risks and expected benefits of treatment. 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 tumor-induced hypercalcemia and serum creatinine levels < 400 μmol/L or < 4.5 mg/dL.

Prevention of skeletal-related events in patients with advanced malignancies

Prior to initiating zoledronic acid therapy in patients with multiple myeloma or solid tumor bone metastases, serum creatinine levels and creatinine clearance should be assessed. Creatinine clearance should be calculated using the Cockroft-Gault formula based on serum creatine levels. Vistazol is not recommended for patients with severe renal impairment prior to starting therapy (creatinine clearance < 30 mL/min). Clinical studies on the use of the drug 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:

* Doses are calculated assuming a target AUC = 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 comparable to that observed in patients with a creatinine clearance of 75 mL/min.

Serum creatinine levels should be measured before each dose of zoledronic acid is administered. If renal function deteriorates, treatment should be discontinued. In 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 studies, zoledronic acid therapy was resumed once serum creatinine returned to within 10% of baseline. Zoledronic acid therapy should be resumed at the same dose used prior to treatment interruption.

Children

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

Instructions for preparation of zoledronic acid doses

For intravenous use only.

5 mL of the 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 Vistazol are recommended for patients with mild to moderate renal impairment.

Instructions for preparation of reduced doses of the medicinal product

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 should be ensured before and after administration of Vistazol.

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. Cases of accidental administration of up to 48 mg of zoledronic acid have been reported. Patients who receive doses exceeding the recommended amount should be placed under close medical supervision, as renal impairment (including renal failure) and alterations 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

Acute-phase reactions have been reported within three days following administration of zoledronic acid, with symptoms including bone pain, fever, weakness, arthralgia, myalgia, chills, and arthritis with joint swelling. These symptoms typically resolve within a few days.

Important adverse reactions identified with the use of zoledronic acid include renal impairment, osteonephrosis of the jaw, acute-phase reactions, hypocalcemia, visual disturbances, atrial fibrillation, anaphylaxis, and interstitial lung disease.

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

The following adverse reactions were collected from clinical trials, 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 (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), frequency 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, hyposthesia, 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:

Uncommon – pruritus, rash (including erythematous and maculopapular rash), 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).

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 system disorders:

Common – renal impairment;
Uncommon – acute renal failure, hematuria, proteinuria;
Rare – acquired Fanconi syndrome;
Frequency not known – tubulointerstitial nephritis.

Immune system disorders:

Uncommon – hypersensitivity reactions;
Rare – angioneurotic edema.

General disorders and administration site conditions:

Common – fever, influenza-like illness (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, hypocalcemia;
Uncommon – hypomagnesemia, hypokalemia;
Rare – hyperkalemia, hypernatremia.

Renal impairment

Renal function impairment has been reported with the use of zoledronic acid. Based on safety data analysis from registration trials of zoledronic acid for prevention of skeletal-related events in patients with advanced malignancies, the incidence of renal impairment 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 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 need for hemodialysis have been reported after the first or single administration of 4 mg zoledronic acid.

Osteonecrosis of the jaw

Cases of osteonecrosis (predominantly of the jaw) have been reported mainly 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 therapy (e.g., chemotherapy, radiation therapy, corticosteroids), and comorbid conditions (e.g., anemia, coagulopathy, infections, oral cavity diseases). Although a causal relationship has not been 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 drug infusion. These reactions are referred to as "flu-like" syndrome or "post-dose" syndrome.

Atypical femoral fractures

Rarely, during post-marketing use, atypical subtrochanteric and diaphyseal fractures of the femur have been reported (an adverse reaction associated with bisphosphonates).

Adverse reactions due to hypocalcemia

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

No special storage conditions are required for this medicinal product. Keep out of reach of children.

Incompatibilities.

The concentrate of Vistazol must be diluted in sterile 0.9% sodium chloride solution or 5% glucose solution. The concentrate must not be mixed with infusion solutions containing calcium or other divalent cations, such as lactated Ringer's solution. It should 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) showed no incompatibility with the above-mentioned packaging materials.

Packaging. 5 ml (4 mg) in a vial; 1 vial per pack.

Prescription status. Prescription only.

Manufacturer. RAFARM S.A.

Manufacturer's address and location of business activity.
Tesi Pousi Xaths Agio Louka, Paiania, 190 02, Greece.