Zulbex

INSTRUCTION for medical use of the medicinal product Zulbex® (Zulbex®)

Composition:

Active substance: rabeprazole;

1 enteric-coated tablet contains 10 mg of rabeprazole sodium, equivalent to 9.42 mg of rabeprazole;

1 enteric-coated tablet contains 20 mg of rabeprazole sodium, equivalent to 18.85 mg of rabeprazole;

Excipients: mannite (E 421), light magnesium oxide, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, magnesium stearate, ethylcellulose, light magnesium oxide, hypromellose phthalate, diacetylated monoglycerides, talc, titanium dioxide (E 171), red iron oxide (E 172) – for 10 mg only; yellow iron oxide (E 172) – for 20 mg only.

Medicinal form. Enteric-coated tablets.

Main physicochemical properties:

10 mg enteric-coated tablets: orange-pink or pink, round, biconvex tablets with film coating and bevelled edges;

20 mg enteric-coated tablets: light brown-yellow or light yellow, round, biconvex tablets with film coating.

Pharmacotherapeutic group. Proton pump inhibitors.

ATC code A02B C04.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action: Rabeprozole sodium belongs to the class of antisecretory agents substituted benzimidazoles, has no anticholinergic activity or antagonistic activity against histamine H2-receptors, but inhibits gastric acid secretion by specifically inhibiting the H+/K+-ATPase enzyme (acid or proton pump). The effect is dose-dependent and results in suppression of both basal and stimulated acid secretion, regardless of the stimulus. Animal studies indicate that after administration, rabeprozole sodium rapidly disappears from both blood plasma and gastric mucosa. As a weak base, rabeprozole is rapidly absorbed after all doses and accumulates in the acidic environment of parietal cells. Rabeprozole is converted to its active sulfenamide form via protonation, after which it reacts with accessible cysteines on the proton pump.

Antisecretory activity. After oral administration of 20 mg of sodium rabeprozole, the antisecretory effect is observed within 1 hour and reaches maximum within 2–4 hours. The inhibitory effect on basal function and food-stimulated acid secretion 23 hours after the first dose of sodium rabeprozole was 69% and 82%, respectively, and the duration of this effect lasted up to 48 hours. The efficacy of sodium rabeprozole in suppressing acid secretion slightly increases during daily administration of 1 tablet, but steady suppression of secretion is achieved within 3 days after initiation of treatment. After discontinuation of sodium rabeprozole, secretory activity returns to normal within 2–3 days.

Reduction of gastric acidity, regardless of the cause, including proton pump inhibitors such as rabeprozole, increases the number of bacteria in the gastrointestinal tract. Treatment with proton pump inhibitors may increase the risk of gastrointestinal infections such as Salmonella, Campylobacter, and Clostridium difficile.

Effect on serum gastrin concentration. In clinical trials, patients received 10 or 20 mg of sodium rabeprozole once daily for 4–3 months. During the first 2–8 weeks of therapy, serum gastrin concentration increased, reflecting acid secretion inhibition. Gastrin concentrations generally returned to baseline levels within 1–2 weeks after discontinuation of treatment.

Biopsy studies of the gastric fundus and antrum in more than 500 patients who received rabeprozole or a comparator drug for 8 weeks revealed no histological changes in ECL cells, no marked gastritis, no increased incidence of atrophic gastritis, intestinal metaplasia, or spread of H. pylori infection. During long-term treatment of more than 250 patients for 36 months, no significant changes were observed in the results of these analyses.

Other effects. There are currently no data on systemic effects of sodium rabeprozole on the CNS, cardiovascular, or respiratory systems. Oral administration of 20 mg of sodium rabeprozole daily for 2 weeks had no effect on thyroid function, carbohydrate metabolism, or blood concentrations of parathyroid hormone, cortisol, estrogen, testosterone, prolactin, cholecystokinin, secretin, glucagon, follicle-stimulating hormone (FSH), luteinizing hormone (LH), renin, aldosterone, or growth hormone.

In a study involving healthy volunteers, no clinically significant interactions were observed between rabeprozole and amoxicillin.

Rabeprozole has no negative effect on plasma levels of amoxicillin and clarithromycin when used concomitantly for eradication of H. pylori infection in the upper gastrointestinal tract.

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Also, due to decreased gastric acidity, levels of chromogranin A increase. Elevated chromogranin A levels may affect test results for detection of neuroendocrine tumors.

Available published data indicate that proton pump inhibitors (PPIs) should be discontinued 2 weeks to 5 days before measuring chromogranin A levels to allow levels to return to reference values if elevated during PPI therapy.

Pharmacokinetics.

Absorption. Zulbeks® is a tablet coated with an enteric coating, with the active ingredient being sodium rabeprozole. This dosage form is necessary because sodium rabeprozole is susceptible to gastric acid. Absorption of sodium rabeprozole begins only after the tablet passes through the stomach. Sodium rabeprozole is rapidly absorbed from the intestine. Peak plasma concentration of rabeprozole is reached approximately 3.5 hours after a 20 mg dose. Peak plasma concentration (Cmax) and area under the concentration–time curve (AUC) of rabeprozole are linear within the dose range of 10 to 40 mg. Absolute bioavailability after oral administration of 20 mg (compared to intravenous administration) is approximately 52%, primarily due to first-pass metabolism. Furthermore, bioavailability does not increase with repeated administration of sodium rabeprozole. In healthy volunteers, the plasma elimination half-life was approximately 1 hour (ranging from 0.7 to 1.5 hours), and total clearance was estimated at 283±98 mL/min.

No clinically significant interactions with food have been observed. Food and the time of day of administration do not affect the absorption of sodium rabeprozole.

Distribution. In humans, the extent of plasma protein binding of sodium rabeprozole is approximately 97%.

Metabolism and excretion. Like other members of the proton pump inhibitor class, rabeprozole is metabolized by the cytochrome P450 (CYP450) hepatic drug metabolism system. In vitro studies with human liver microsomes showed that sodium rabeprozole is metabolized by CYP450 isoenzymes (CYP2C19 and CYP3A4). At expected human plasma concentrations, rabeprozole does not induce or inhibit CYP3A4. However, in vitro findings cannot always be extrapolated to in vivo situations; these results suggest that interactions between rabeprozole and cyclosporine are not expected. In humans, the main metabolites present in plasma are thioether (M1) and carboxylic acid (M6), while minor metabolites present at low concentrations include sulfone (M2), dimethylthioether (M4), and mercapturic acid conjugate (M5). Only the dimethyl metabolite (M3) has minor antisecretory activity, but it is not present in plasma.

After a single 20 mg dose of 14C-labeled sodium rabeprozole, unchanged drug was not observed in urine. Approximately 90% of the administered dose was eliminated in urine, primarily as two metabolites: mercapturic acid conjugate (M5) and carboxylic acid (M6), along with two unknown metabolites. The remaining portion of the dose was found in feces.

Gender differences. Since the single 20 mg dose of sodium rabeprozole is adjusted for body weight and height, gender differences do not affect pharmacokinetic parameters.

Renal impairment. In patients with end-stage chronic renal failure undergoing maintenance hemodialysis (creatinine clearance ≤5 mL/min/1.73 m²), the disposition of sodium rabeprozole was very similar to that in healthy volunteers. AUC and Cmax of sodium rabeprozole were approximately 35% lower compared to healthy volunteers. Mean elimination half-life values were 0.82 hours in healthy volunteers, 0.95 hours in hemodialysis patients, and 3.6 hours in post-dialysis patients. Drug clearance in dialysis patients with renal impairment was approximately twice that in healthy volunteers.

Hepatic impairment. After a single 20 mg dose of sodium rabeprozole in patients with mild to moderate chronic liver disease, AUC increased twofold and elimination half-life increased 2–3 times compared to healthy volunteers. Although after 7 days of daily 20 mg dosing, AUC increased only 1.5-fold and Cmax increased 1.2-fold. The elimination half-life of sodium rabeprozole in patients with liver disease was 12.3 hours compared to 2.1 hours in healthy volunteers. Pharmacodynamic response (gastric pH-metry) was similar between the two patient groups in terms of therapeutic parameters.

Elderly patients. Elimination of sodium rabeprozole is somewhat reduced in elderly patients. After 7 days of 20 mg daily dosing in elderly subjects, AUC was approximately twice higher, Cmax increased by 60%, and T1/2 increased by 30% compared to younger healthy volunteers. However, there were no signs of sodium rabeprozole accumulation.

Polymorphism of CYP2C19. After 7 days of 20 mg daily dosing of sodium rabeprozole in patients with slow CYP2C19 metabolism, AUC and T1/2 (elimination half-life) were approximately 1.9 and 1.6 times higher, respectively, compared to patients with rapid metabolism; meanwhile, Cmax increased by only 40%.

Clinical characteristics.

Indications.

• Active duodenal ulcer;
• active benign gastric ulcer;
• erosive or ulcerative gastroesophageal reflux disease (GERD);
• long-term treatment of gastroesophageal reflux disease (maintenance therapy for GERD);
• symptomatic treatment of moderate to severe gastroesophageal reflux (symptomatic treatment of GERD);
• Zollinger-Ellison syndrome;

– in combination with appropriate antibacterial therapy regimens for eradication of Helicobacter pylori in patients with gastric and duodenal peptic ulcers.

Contraindications.

Zulbeks® is contraindicated in patients with hypersensitivity to sodium rabeprazole, substituted benzimidazoles, or to any other ingredient of the drug.

Zulbeks® is contraindicated in women during pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interactions.

CYP450 system

Sodium rabeprazole is metabolized by the hepatic enzyme system CYP450, specifically CYP2C19 and CYP3A4.

Studies have shown that sodium rabeprazole has no pharmacokinetic or clinically significant interactions with warfarin, phenytoin, theophylline, or diazepam, each of which is metabolized by CYP450.

Interactions caused by inhibition of gastric acid secretion

Sodium rabeprazole causes a strong and prolonged reduction in gastric acid production. Therefore, rabeprazole may theoretically interact with drugs whose absorption is pH-dependent. Concomitant administration of sodium rabeprazole with ketoconazole or itraconazole may lead to decreased plasma concentrations of the latter, while administration with digoxin may lead to increased digoxin concentrations. Thus, individual patients receiving these medications concomitantly with Zulbeks® should be monitored by a physician to determine the need for dose adjustment.

Antacids

During clinical trials, patients took antacids as needed concomitantly with Zulbeks®; no interaction between sodium rabeprazole and liquid formulations of antacids was observed in a dedicated study.

Atazanavir

Concomitant administration of atazanavir 300 mg/ritonavir 100 mg with omeprazole (40 mg once daily) or atazanavir 400 mg with lansoprazole (60 mg once daily) in healthy volunteers resulted in a significant reduction in atazanavir exposure. Atazanavir absorption is pH-dependent. Although no studies have been conducted, similar results are expected with other proton pump inhibitors. Proton pump inhibitors, including rabeprazole, should not be used in combination with atazanavir (see section "Special precautions for use").

Clopidogrel

Concomitant administration of clopidogrel and rabeprazole to healthy volunteers had no clinically significant effect on concentrations of the active metabolite of clopidogrel. Dose adjustment is not required.

Methotrexate

Case reports of adverse reactions, published data from population pharmacokinetic studies, and retrospective analyses suggest that concomitant use of methotrexate and proton pump inhibitors (particularly at high doses) may lead to increased serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal studies have been conducted.

Food

Studies have shown that ingestion of low-fat food does not affect the absorption of sodium rabeprazole. Administration of sodium rabeprazole with fatty food may delay absorption by

4 hours or more; however, maximum concentration and extent of absorption remain unchanged.

Cyclosporine

In vitro studies have shown that sodium rabeprazole inhibits the metabolism of cyclosporine. This level of inhibition is comparable to that of omeprazole.

Medicinal products contraindicated for concomitant use with Zulbeks®

Medicinal products that should be prescribed with caution

Special precautions for use.

Caution should be exercised when prescribing rabeprozole to patients with known hypersensitivity to drugs. The risk of cross-hypersensitivity to other proton pump inhibitors or substituted benzimidazoles cannot be excluded.

Use in elderly patients.

Zulbeks® is metabolized exclusively in the liver. Since hepatic physiological function may decline with age, adverse reactions may occur in elderly patients. Therefore, elderly patients should be monitored closely and dosing recommendations and treatment duration guidelines should be strictly followed. Symptomatic improvement in response to rabeprozole therapy may occur even in the presence of malignant gastric or esophageal tumors; therefore, malignancy must be ruled out before initiating Zulbeks® therapy.

Patients undergoing long-term treatment (especially those treated for more than 1 year) should be regularly monitored.

The risk of developing cross-hypersensitivity reactions when used with other proton pump inhibitors or substituted benzimidazoles cannot be excluded.

Patients should be advised that Zulbeks® tablets must not be chewed or crushed, but should be swallowed whole.

Zulbeks® is not recommended for use in children, as there is no experience with use in this patient population.

Post-marketing reports have described blood abnormalities (thrombocytopenia and neutropenia). In most cases, no other etiology was identified; blood changes were uncomplicated and resolved after discontinuation of rabeprozole.

Abnormal liver enzyme levels have been reported both during clinical trials and in the post-marketing period. In most cases, no other etiology was identified; abnormalities were uncomplicated and resolved after discontinuation of rabeprozole.

In a specific study in patients with mild or moderate hepatic impairment, no significant difference in the frequency of adverse effects was observed with Zulbeks® compared to the control group matched for gender and age. Physicians should exercise caution when prescribing Zulbeks® at the beginning of therapy in patients with severe hepatic impairment, as there are no clinical data on the use of the drug in this patient group.

Concomitant use of atazanavir and Zulbeks® is not recommended (see section "Interaction with medicinal products and other types of interactions").

Treatment with proton pump inhibitors, including Zulbeks®, may increase the risk of gastrointestinal infections such as Salmonella, Campylobacter, and Clostridium difficile (see section "Pharmacodynamics").

Metotrexate.

Literature data suggest that concomitant use of proton pump inhibitors and methotrexate (particularly at high doses) may increase serum levels of methotrexate and/or its metabolites, potentially leading to methotrexate-related toxicity. If high-dose methotrexate is required, discontinuation of proton pump inhibitor therapy should be considered.

Hypomagnesemia.

Cases of severe hypomagnesemia have been reported in patients taking proton pump inhibitors such as Zulbeks® for at least 3 months, in most cases after a year of treatment. Possible serious manifestations of hypomagnesemia include weakness, tetany, delirium, seizures, dizziness, and ventricular arrhythmia, although these may occur unexpectedly and remain undetected. In most patients, hypomagnesemia resolved after discontinuation of proton pump inhibitors and magnesium replacement therapy.

For long-term treatment or when proton pump inhibitors are used concomitantly with digoxin or other drugs that may lead to hypomagnesemia (e.g., diuretics), physicians should monitor serum magnesium levels before starting treatment and periodically during therapy.

Fracture risk.

Proton pump inhibitors, particularly when used at high doses and for prolonged periods (more than 1 year), may increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other existing risk factors. Observational studies suggest that proton pump inhibitors may increase the overall fracture risk by 10–40%. Risk may also be increased due to other factors. Patients with osteoporosis risk should receive appropriate treatment and take vitamin D and calcium supplements.

Effect on vitamin B12 absorption.

Sodium rabeprozole, like all agents that suppress gastric acid secretion, may reduce absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with low body weight or risk factors for reduced vitamin B12 absorption during long-term treatment or in the presence of relevant clinical symptoms.

Subacute cutaneous lupus erythematosus (SCLE).

The use of proton pump inhibitors has been associated with very rare cases of SCLE. If skin lesions develop, particularly in sun-exposed areas and accompanied by arthralgia, patients should seek immediate medical attention, and physicians should consider discontinuing Zulbeks® therapy. Previous treatment with a proton pump inhibitor may increase the risk of SCLE when other PPIs are used.

Effect on laboratory test results.

Elevated chromogranin A (CgA) levels may interfere with the detection of neuroendocrine tumors. To avoid this effect, treatment with Zulbeks® should be discontinued at least 5 days before measuring chromogranin A levels. If chromogranin A and gastrin levels have not returned to the reference range after the initial measurement, testing should be repeated 14 days after discontinuation of PPI therapy.

Renal function impairment.

Acute tubulointerstitial nephritis (TIN) has been observed in patients taking rabeprozole and may occur at any time during rabeprozole therapy (see section "Adverse reactions"). Acute tubulointerstitial nephritis may progress to renal failure. If TIN is suspected, rabeprozole should be discontinued and appropriate treatment initiated immediately.

Use during pregnancy or breastfeeding.

Pregnancy

There are no data on the safety of rabeprozole use during pregnancy.

Reproductive studies in animals have shown no evidence of impaired fertility or fetal harm associated with sodium rabeprozole; however, minimal placental transfer was observed in rats. Zulbeks® is contraindicated during pregnancy.

Breastfeeding

It is unknown whether sodium rabeprozole passes into human breast milk. Adequate studies have not been conducted. Sodium rabeprozole passes into the milk of rats. Therefore, Zulbeks® should not be administered to women who are breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Based on pharmacodynamic properties and the adverse effect profile, it is unlikely that Zulbeks® intake will impair the ability to drive a vehicle or operate machinery. However, if alertness is impaired due to drowsiness, driving and operating complex machinery should be avoided.

Dosage and Administration

Adults, including elderly patients.

Active duodenal ulcer and active benign gastric ulcer: the recommended dose for these conditions is 20 mg once daily in the morning.

In most patients with active duodenal ulcer, healing occurs within 4 weeks. However, some patients may require additional treatment with Zulbeks® for another 4 weeks to achieve healing. In most patients with active benign gastric ulcer, healing occurs within 6 weeks, but some treatment-resistant patients may require additional treatment with Zulbeks® for up to another 6 weeks.

Erosive or ulcerative gastroesophageal reflux disease (GERD): the recommended dose for these conditions is 20 mg once daily for 4–8 weeks.

Long-term treatment of gastroesophageal reflux disease (maintenance therapy for GERD): for long-term treatment, maintenance doses of Zulbeks® 10 mg or 20 mg once daily may be used (the dose depends on treatment efficacy).

Symptomatic treatment of moderate to very severe GERD: patients without esophagitis should be prescribed Zulbeks® 10 mg once daily. If symptoms do not resolve after 4 weeks of treatment, further patient evaluation is recommended. Once symptoms have resolved, symptom control can be maintained using an "on-demand" regimen: take 10 mg once daily as needed.

Zollinger-Ellison syndrome: dosage should be individually adjusted.

Initial dose is 60 mg daily. The dose may be gradually increased up to 120 mg daily if clinically necessary. A single daily dose of up to 00 mg may be used. If a daily dose of 120 mg is required, the dose should be divided into two administrations of 60 mg each. Treatment should continue as long as clinically indicated.

H. pylori eradication: patients with H. pylori should receive appropriate combination therapy including Zulbeks®. A 7-day regimen is recommended: Zulbeks® 20 mg twice daily + clarithromycin 500 mg twice daily and amoxicillin 1 g twice daily.

Renal and hepatic impairment: patients with renal or hepatic impairment do not require dose adjustment of Zulbeks®. The use of Zulbeks® in patients with severe hepatic impairment is discussed in detail in the section "Special precautions".

Administration method

For indications requiring once-daily dosing, Zulbeks® tablets should be taken in the morning, before meals. Although administration in the morning or food intake has not been shown to affect the action of sodium rabeprazole, this regimen is more favorable for treatment.

Zulbeks® tablets must not be chewed or crushed; they should be swallowed whole.

Children

Zulbeks® is not recommended for use in children due to lack of experience with the drug in this patient population.

Overdose

Experience with intentional or accidental overdose is limited. The maximum studied doses did not exceed 60 mg of sodium rabeprazole twice daily or 160 mg of sodium rabeprazole once daily. Symptoms associated with overdose are generally minimal, consistent with the known adverse event profile, and resolve without requiring further medical intervention. There is no specific antidote for Zulbeks®. Sodium rabeprazole is highly protein-bound and is not dialyzable. In case of overdose, symptomatic and supportive treatment should be administered.

Adverse Reactions

The most commonly reported adverse reactions to rabeprazole during controlled clinical trials were: headache, diarrhea, abdominal pain, asthenia, flatulence, rash, and dry mouth. Most of the adverse events observed during clinical trials were mild to moderate in severity and resolved quickly.

The following adverse reactions have been reported during clinical trials and in the post-marketing period.

Frequency is defined as follows: 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).

Within each group, adverse effects are listed in order of decreasing frequency.

Infections and infestations

Common: infections.

Blood and lymphatic system disorders

Rare: neutropenia, leukopenia, thrombocytopenia, leukocytosis.

Immune system disorders

Rare: hypersensitivity^1,2.

Metabolism and nutrition disorders

Rare: anorexia.

Frequency not known: hyponatremia, hypomagnesemia⁴.

Psychiatric disorders

Common: insomnia.

Uncommon: nervousness.

Rare: depression.

Frequency not known: confusion.

Nervous system disorders

Common: headache, dizziness.

Uncommon: somnolence.

Eye disorders

Rare: visual disturbances.

Vascular disorders

Frequency not known: peripheral edema.

Respiratory system disorders

Common: cough, pharyngitis, rhinitis.

Uncommon: bronchitis, sinusitis.

Gastrointestinal disorders

Common: diarrhea, vomiting, nausea, abdominal pain, constipation, flatulence, benign fundic gland polyp.

Uncommon: dyspepsia, dry mouth, belching.

Rare: gastritis, stomatitis, taste disturbance.

Frequency not known: microscopic colitis.

Hepatobiliary disorders

Rare: hepatitis, jaundice, hepatic encephalopathy³.

Skin and subcutaneous tissue disorders

Uncommon: rash, erythema².

Rare: pruritus, sweating, bullous reactions².

Very rare: erythema multiforme, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome.

Not known: subacute cutaneous lupus erythematosus⁴.

Musculoskeletal and connective tissue disorders

Common: nonspecific pain, back pain.

Uncommon: myalgia, leg cramps, arthralgia, fracture of the femoral neck, wrist or spine⁴.

Renal and urinary disorders

Uncommon: urinary tract infections.

Rare: tubulointerstitial nephritis (TIN) (with possible progression to renal failure).

Reproductive system and breast disorders

Frequency not known: gynecomastia.

General disorders and administration site conditions

Common: asthenia, influenza-like syndrome.

Uncommon: chest pain, chills, pyrexia.

Investigations

Uncommon: increased levels of liver enzymes³.

Rare: weight gain.

¹ Including facial swelling, hypotension, and dyspnea.

² Erythema, bullous reactions, and hypersensitivity reactions usually resolved after discontinuation of treatment.

³ Hepatic encephalopathy has been observed in isolated cases in patients with cirrhosis. Caution is advised when prescribing Zulbeks® to patients with severe hepatic impairment (see section "Special precautions").

⁴ See section "Special precautions".

Adverse reactions of clinical significance:

• Shock and anaphylactic reactions;
• Pancytopenia, leukopenia, agranulocytosis, and hemolytic anemia;
• Fulminant hepatitis, hepatic dysfunction, jaundice;
• Interstitial pneumonia;
• Toxic epidermal necrolysis, confusion, erythema multiforme;
• Acute renal failure, interstitial nephritis;
• Hyponatremia;
• Rhabdomyolysis.

Adverse reactions of clinical significance and typical for proton pump inhibitors:

• Visual disturbances;
• Angioneurotic edema, bronchospasm;
• Confusion.

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, pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life: 2 years.

Storage conditions

Store at temperatures not exceeding 30 °C in the original packaging to protect from light. Keep out of reach of children.

Packaging

14 tablets in a blister; 1, 2, or 4 blisters in a cardboard box.

Prescription status: Prescription only.

Manufacturer

KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.