Zometa concentrate for solution for infusion 4 mg bottle 5 ml No. 1

Instructions for use Zometa concentrate for solution for infusion 4 mg bottle 5 ml No. 1

Composition

active ingredient: zoledronic acid;

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

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

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

Dosage form

Concentrate for solution for infusion.

Main physicochemical properties: transparent 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 target 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, but the molecular mechanism leading to the inhibition of osteoclast activity is not yet understood. Animal studies have shown that zoledronic acid inhibits bone resorption without adversely affecting bone formation, mineralization, or mechanical properties.

In addition to inhibiting osteoclastic bone resorption, zoledronic acid has direct antitumor effects on cultured human myeloma and breast cancer cells by inhibiting cell proliferation and inducing apoptosis. This suggests that zoledronic acid may have antimetastatic properties. In preclinical studies, the following properties have been demonstrated:

In vivo – inhibition of osteoclastic bone resorption, which acts on the structure of the microcrystalline bone matrix, which reduces tumor growth; antiangiogenic (action on blood vessels, which leads to a decrease in the blood supply to the tumor) and analgesic effects.

In vitro – inhibition of osteoblast proliferation, cytostatic effect, pro-apoptotic effect on tumor cells, synergistic cytostatic effect with other antitumor drugs, anti-adhesive and anti-invasive effect.

Pharmacokinetics.

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

After the start of the zoledronic acid infusion, the plasma concentration of the drug increases rapidly, reaching a peak at the end of the infusion. This is followed by a rapid decrease in concentration to < 10% of the peak value after 4 hours and < 1% of the peak value after 24 hours with a successively prolonged period of low concentrations not exceeding 0.1% of the peak until the second infusion on day 28. Zoledronic acid administered intravenously is excreted by the kidneys in 3 phases: a rapid biphasic elimination of the drug from the systemic circulation with a half-life of t½α = 0.24 hours and t½β = 1.87 hours and a prolonged phase with a terminal half-life of t½γ = 146 hours. No accumulation of the drug in plasma was observed with repeated administration every 28 days. Zoledronic acid is not metabolized and is excreted unchanged by the kidneys. During the first 24 hours, 39±16% of the administered dose is detected in the urine. The rest of the drug is mainly bound to bone tissue. Then, zoledronic acid is slowly released back from bone tissue into the systemic circulation and excreted by the kidneys. The total clearance of the drug in the body is 5.04±2.5 l/h and does not depend on the dose of the drug, gender, age, race and body weight of the patient. Increasing the infusion time from 5 to 15 minutes leads to a 30% decrease in the concentration of zoledronic acid at the end of the infusion, but does not affect the plasma concentration-time curve (AUC).

The variability of pharmacokinetic parameters of zoledronic acid, as with other bisphosphonates, was high in different patients.

There are no data on the pharmacokinetics of zoledronic acid in patients with hypercalcemia and hepatic insufficiency. According to in vitro data, zoledronic acid does not inhibit human P450 enzymes and is not biotransformed; according to experimental studies in animals, less than 3% of the administered dose is excreted in the feces, which suggests that the state of liver function does not affect the pharmacokinetics of zoledronic acid.

Renal clearance of zoledronic acid correlates with creatinine clearance, with renal clearance accounting for 75±33% of creatinine clearance, reaching a mean of 84±29 mL/min (range 22–143 mL/min) in 64 cancer patients enrolled in the study. Analysis of the patient population showed that patients with creatinine clearance of 20 mL/min (acute renal failure) and 50 mL/min (moderate renal failure) had relative clearances of 37% and 72%, respectively. However, pharmacokinetic data in patients with acute renal failure (creatinine clearance < 30 mL/min) are limited.

Zoledronic acid has been shown to have low affinity for cellular components of blood.

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

Limited pharmacokinetic data in children with severe osteogenesis imperfecta suggest that the pharmacokinetics of zoledronic acid in children aged 3 to 17 years are similar to those in adults when administered at equivalent doses (mg/kg). Age, weight, gender and creatinine clearance of the patient did not appear to affect the systemic exposure to zoledronic acid.

Indication

Prevention of symptoms associated with bone damage (pathological fractures, spinal cord compression, complications after surgery and radiotherapy or hypercalcemia due to a malignant tumor) in patients with advanced malignant tumors.

Treatment of hypercalcemia caused by a malignant tumor.

Contraindication

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

Pregnancy or breastfeeding.

Interaction with other medicinal products and other types of interactions

During clinical trials, other drugs were often prescribed concomitantly with Zometa®: antineoplastic agents, diuretics, antibiotics, analgesics. No clinically significant interactions were observed.

Zoledronic acid does not bind significantly to plasma proteins and does not inhibit cytochrome P450 enzymes based on in vitro data. However, no specific clinical drug interaction studies have been conducted.

Caution is advised when bisphosphonates and aminoglycosides are used concomitantly, as they may have an additive effect, resulting in serum calcium levels remaining lower than necessary. Caution is advised when bisphosphonates and loop diuretics are used concomitantly, as they may have an additive effect, resulting in hypocalcemia. Caution should be exercised when prescribing Zometa® with other potentially nephrotoxic drugs. The possibility of hypomagnesemia during treatment should also be considered.

No clinically significant interactions have been observed in patients with multiple myeloma when intravenous bisphosphonates are administered in combination with thalidomide.

Osteonecrosis of the jaw has been reported in patients receiving concomitant treatment with Zometa® and antiangiogenic (reducing blood supply to tumors) drugs.

Application features

General

Before administering Zometa®, ensure that all patients, including those with mild to moderate renal impairment, are adequately hydrated.

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

Standard metabolic parameters associated with hypercalcemia, such as calcium, phosphate, and magnesium levels, should be carefully monitored after initiating Zometa® therapy. If hypocalcemia, hypophosphatemia, or hypomagnesemia occurs, short-term corrective therapy may be necessary.

Untreated patients with hypercalcemia usually have some renal dysfunction, so careful monitoring of renal function is necessary.

Zometa® contains the active substance zoledronic acid. Patients receiving Zometa® therapy should not take other medicines containing zoledronic acid at the same time.

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

Kidney dysfunction

When deciding whether to use Zometa® in patients with hypercalcemia due to a malignant tumor and impaired renal function, the patient's condition should be assessed and a conclusion should be drawn as to whether the potential benefit of treatment outweighs the possible risk.

When deciding to treat patients with bone metastases to prevent symptoms associated with spinal diseases, it should be taken into account that the effect of the drug begins to appear after 2 to 3 months.

Renal dysfunction has been reported in association with bisphosphonate use. Factors that increase the risk of renal dysfunction include dehydration, pre-existing renal dysfunction, multiple courses of Zometa® or other bisphosphonates, and use of nephrotoxic agents or infusions shorter than recommended. Although the risk is reduced when Zometa® is administered over at least 15 minutes at a dose of 4 mg, worsening of renal function is possible. Cases of worsening renal function, progression to renal failure, and the need for dialysis have been observed in patients after the initial dose or a single dose of zoledronic acid 4 mg.

Patients should have their serum creatinine levels measured before each dose of Zometa®. After initiation of treatment, lower doses of Zometa® are recommended for patients with bone metastases and postmenopausal women with early breast cancer receiving aromatase inhibitors (AIs) to prevent bone loss and fractures in the presence of mild to moderate renal impairment (see table in the Dosage and Administration section). Patients who experience worsening renal function during treatment should only resume treatment when creatinine levels return to within 10% of baseline. When Zometa® is restarted, the dose should be the same as before discontinuation.

Due to the potential effects of bisphosphonates, including Zometa®, on renal function and the lack of extensive 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 in postmenopausal women with early breast cancer receiving aromatase inhibitors (AIs) to prevent 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 Zometa® in patients with severe renal impairment is not recommended.

Liver dysfunction

There are no specific recommendations for patients with severe hepatic impairment as only limited clinical data are available.

Osteonecrosis of the jaw

Osteonecrosis of the jaw has been reported primarily in cancer patients receiving treatment regimens containing bisphosphonates, including Zometa®.

Many of these patients were also receiving chemotherapy and corticosteroids. Most of the reported cases were associated with dental procedures, such as tooth extractions. Many of the patients had evidence of local infection, including osteomyelitis.

The initiation of treatment or a new course of treatment should be postponed if patients have unhealed open soft tissue lesions in the oral cavity, except in medical emergencies. Before initiating bisphosphonate treatment, patients with concomitant risk factors are recommended to undergo a dental examination with appropriate preventive dental treatment and an individual benefit-risk assessment.

The following risk factors should be considered to assess individual risks of developing osteonecrosis of the jaw:

Bisphosphonate potency (higher risk for more active compounds), route of administration (higher risk for parenteral administration), and cumulative dose.

Cancer, comorbidities (e.g. anemia, coagulopathy, infection), smoking.

History of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures, and ill-fitting dentures.

Before starting treatment with bisphosphonates, an oral examination with appropriate dental prophylaxis should be performed.

During therapy, invasive dental procedures should be avoided in these patients if possible. Dental surgery may worsen the condition of patients who develop osteonecrosis of the jaw while receiving 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. 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 dental surgeon experienced in the management of patients with osteonecrosis of the jaw. Temporary discontinuation of zoledronic acid should be considered until the condition has resolved and risk factors have been minimized.

Osteonecrosis of the external auditory canal

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

Musculoskeletal pain

During postmarketing experience, severe, sometimes disabling bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. However, such reports have been isolated. This category of drugs includes Zometa® (zoledronic acid). The time to onset of symptoms ranged from one day to several months after initiation of treatment. In most patients, symptoms resolved after discontinuation of treatment. In this category of patients, symptoms have recurred when treatment was resumed with the same drug or another bisphosphonate.

Atypical subtrochanteric and diaphyseal fractures of the femur have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the epicondyles. These fractures occur with or without minimal trauma, and some patients experience hip or groin pain, often associated with radiographic evidence of a stress fracture, weeks or months before a complete hip fracture occurs. The fractures are often bilateral, so the other femur should be examined in patients receiving bisphosphonate therapy who have sustained a femoral fracture. Poor healing of these fractures has also been reported. Based on an individual risk-benefit assessment, the decision to discontinue bisphosphonate therapy for patients with suspected atypical hip fractures should be made.

During bisphosphonate treatment, patients should report any pelvic, hip, or groin pain to their physician, and any patient with such symptoms should be evaluated for an incomplete femur fracture.

Hypocalcemia

Hypocalcemia has been reported in patients taking Zometa®. Cases of cardiac arrhythmias and neurological reactions (including seizures, numbness, and tetany) secondary to severe hypocalcemia have been reported. Cases of severe hypocalcemia requiring hospitalization have been reported. In some cases, hypocalcemia can be life-threatening.

Use during pregnancy or breastfeeding

The drug is contraindicated during pregnancy and breastfeeding.

Pregnancy period

There are no adequate data from the use of zoledronic acid in pregnant women. Animal reproduction studies have shown reproductive toxicity. The potential risk for humans is unknown.

Breast-feeding

It is not known whether zoledronic acid passes into breast milk.

Ability to influence reaction speed when driving vehicles or other mechanisms

Adverse drug reactions, such as dizziness and drowsiness, may affect the ability to drive or operate machinery, so caution is required when driving or operating complex machinery while taking Zometa®.

Method of administration and doses

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

Before administration, 5 ml of Zometa® concentrate containing 4 mg zoledronic acid is diluted in 100 ml of 0.9% sodium chloride solution or 5% glucose solution. The prepared Zometa® solution for infusion is administered as a single intravenous infusion over at least 15 minutes.

Zometa® 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 intravenous infusion using a separate infusion set.

Prevention of symptoms associated with bone damage in patients with advanced malignant neoplasms

Adults and elderly patients

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

Patients also need daily oral calcium supplements at a dose of 500 mg and 400 IU of vitamin D per day.

When deciding to treat patients with metastatic bone disease to prevent symptoms associated with bone disease, it should be considered that the onset of the effect of treatment occurs after 2 to 3 months.

Treatment of hypercalcemia due to malignant tumor

Adults and elderly patients

When using the drug in connection with hypercalcemia (albumin-corrected serum calcium ≥ 12.0 mg/dL, or 3.0 mmol/L), a single administration of 4 mg zoledronic acid is recommended.

Kidney dysfunction

Hypercalcemia due to malignant tumor

Treatment of hypercalcemia due to malignancy in patients with severe renal impairment is possible after careful assessment of the risk of using the drug and the expected benefit. There is no clinical experience with the drug in patients with serum creatinine levels > 400 μmol/l or > 4.5 mg/dl. No dose adjustment is required for patients with hypercalcemia due to malignancy with serum creatinine levels < 400 μmol/l or < 4.5 mg/dl.

Prevention of symptoms associated with bone damage in patients with advanced malignant neoplasms

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

*Doses are calculated assuming AUC=0.66 mg•h/L (creatinine clearance 75 mL/min). For patients with renal impairment, dose reduction is expected to achieve AUC similar to that achieved in patients with creatinine clearance 75 mL/min.

After initiation of therapy, serum creatinine levels should be measured before each dose of Zometa®. Treatment should be discontinued if renal function is impaired. In clinical trials, renal function impairment was defined as:

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 altered 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, Zometa® therapy was resumed after creatinine levels returned to baseline within 10% of baseline. Zometa® therapy should be resumed at the same dose as before treatment was interrupted.

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 children.

Instructions for preparing doses of Zometa®

For intravenous administration.

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

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

Instructions for preparing 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 before and after administration of Zometa®.

Children.

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

Overdose

Clinical experience in the treatment of acute overdose with Zometa® is limited. There have been reports of the erroneous use of zoledronic acid in doses up to 48 mg. Patients who have received a dose of the drug exceeding the recommended dose should be under constant medical supervision, as renal function disorders (including renal failure) and changes in serum electrolytes (including calcium, phosphate and magnesium concentrations) are possible. In case of hypocalcemia, calcium gluconate infusion is indicated according to clinical indications. Treatment is symptomatic.

Side effects

Acute phase reactions, which included bone pain, fever, malaise, arthralgia, myalgia, chills, and arthritis with joint swelling, have been reported commonly within three days of Zometa administration. These symptoms usually resolve within a few days.

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

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

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

Information on the following adverse reactions has been collected during clinical trials mainly after long-term treatment with zoledronic acid.

Adverse reactions are classified according to their frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), unknown (cannot be estimated from the available data).

From the blood and lymphatic system:

often - anemia;

sometimes - thrombocytopenia, leukopenia;

rarely - pancytopenia.

From the nervous system:

often - headache;

sometimes - paresthesias, dizziness, taste disturbances, hypoesthesia, hyperesthesia, tremor, drowsiness; very rarely - epileptic seizures, numbness and tetany (secondary to hypocalcemia).

From the psyche:

sometimes - anxiety, sleep disorders;

rarely - confusion.

On the part of the organs of vision:

often – conjunctivitis;

sometimes - blurred vision, scleritis and inflammation of the eye socket;

rarely – uveitis;

very rarely - episcleritis.

From the gastrointestinal tract:

often - nausea, vomiting, anorexia;

sometimes - diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.

On the part of the respiratory system:

sometimes - dyspnea, cough, bronchoconstriction;

rarely - interstitial lung disease.

Skin and subcutaneous tissue disorders:

From the musculoskeletal system, connective tissue:

often - bone pain, myalgia, arthralgia, generalized pain;

sometimes - muscle cramps, osteonecrosis of the jaw;

very rarely - osteonecrosis of the external auditory canal (adverse reactions typical of bisphosphonates).

From the cardiovascular system:

sometimes - arterial hypertension, arterial hypotension, atrial fibrillation, arterial hypotension causing syncope and circulatory collapse;

rarely - bradycardia, very rarely - cardiac arrhythmia (secondary to hypocalcemia).

From the kidneys and genitourinary system:

often - renal disorders;

sometimes - acute renal failure, hematuria, proteinuria;

rarely – acquired Fanconi syndrome.

On the part of the immune system:

sometimes - hypersensitivity reactions;

rarely - angioedema.

General disorders and administration site reactions:

often - fever, influenza-like illness (including fatigue, chills, malaise and hot flashes); sometimes - injection site reactions (including pain, irritation, swelling, induration), asthenia, peripheral edema, chest pain, weight gain, anaphylactic reactions/shock, urticaria;

rarely - arthritis and joint swelling as symptoms of an acute phase reaction.

Laboratory abnormalities:

very often – hypophosphatemia;

often - increased levels of creatinine and urea in the blood, hypocalcemia;

sometimes – hypomagnesemia, hypokalemia;

rarely - hyperkalemia, hypernatremia.

Kidney dysfunction

Renal impairment has been reported with Zometa®. Based on safety data from the post-marketing surveillance studies of Zometa® for the prevention of bone-related adverse events, the incidence of renal impairment considered to be related to Zometa® in patients with advanced malignancies 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 impairment, multiple courses of Zometa® or other bisphosphonates, and concomitant use of other nephrotoxic agents or reduction of the recommended infusion time. Cases of worsening renal function, progression of renal failure and the need for hemodialysis have been reported with the first or single use of zoledronic acid at a dose of 4 mg.

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 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 established cancer, concomitant therapy (e.g. chemotherapy, radiotherapy, corticosteroids) and comorbidities (e.g. anaemia, coagulopathies, infections, oral disease). Although a causal relationship has not been established, these patients are advised to avoid invasive dental procedures.

Atrial fibrillation

In a randomized, double-blind, controlled clinical trial evaluating the efficacy and safety of zoledronic acid in patients with postmenopausal osteoporosis, the overall incidence of atrial fibrillation was 2.5% in the zoledronic acid 5 mg group 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, pain in the extremities, 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” or “post-drug” syndrome.

Atypical femur fractures

During post-marketing use, reactions such as acute subtrochanteric and diaphyseal fractures of the femur (an adverse reaction to bisphosphonates) have been reported rarely.

Adverse reactions due to hypocalcemia

Hypocalcemia is an important identified risk with Zometa® in the approved indications. Clinical and post-marketing data suggest an association between Zometa® therapy, reports of hypocalcemia, and the development of secondary cardiac arrhythmias. In addition, there is evidence of an association between hypocalcemia and reports of secondary neurological reactions, including seizures, numbness, and tetany.

Expiration date

3 years.

Storage conditions

Store at a temperature not exceeding 30 ºС in a place inaccessible to children.

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

After aseptic dilution, the finished product must be used immediately.

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 lactated Ringer's solution, and must be administered as a single infusion using a separate infusion system.

Studies with glass vials, as well as several 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

Concentrate for solution for infusion 5 ml in a colorless plastic bottle with a gray rubber stopper and an aluminum cap with a flip-off component. 1 bottle is packed in a cardboard box.

Vacation category

According to the recipe.

Producer

1. Novartis Pharma Stein AG, Switzerland.

2. Lek Pharmaceuticals d.d./ Lek Pharmaceuticals d.d

Location of the manufacturer and its business address.

1. Schaffhauserstrasse, 4332 Stein, Switzerland.

2. Verovskova Ulica 57, Ljubljana, 1526, Slovenia.