Omeprazole-vokate

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OMEPRAZOLE-VOCATE (OMEPRAZOLE-VOCATE)

Composition:

Active substance: omeprazole;

One vial contains: sodium omeprazole equivalent to omeprazole 40 mg;

Excipient: sodium hydroxide;

One ampoule of solvent contains: polyethylene glycol 400, citric acid monohydrate, water for injections.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: white or almost white lyophilized powder.

Pharmacotherapeutic group.
Agents for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. ATC code A02BC01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Omeprazole, a racemic mixture of two enantiomers, reduces gastric hydrochloric acid secretion through a targeted mechanism of action. Omeprazole inhibits gastric acid secretion by specifically acting on the proton pump in parietal cells. When administered once daily, the drug acts rapidly and provides control through reversible suppression of gastric juice hydrochloric acid secretion.

Omeprazole is a weak base that accumulates and is converted into its active form in the highly acidic environment of the intracellular canaliculi of parietal cells, where it inhibits the enzyme H⁺, K⁺-ATPase (proton pump). This effect at the final stage of gastric juice hydrochloric acid formation is dose-dependent and provides highly effective inhibition of both basal and stimulated acid secretion, regardless of the type of stimulation.

Pharmacodynamic effects

All pharmacodynamic effects can be explained by the influence of omeprazole on hydrochloric acid secretion.

Effect on gastric acid secretion

Intravenous administration of omeprazole causes dose-dependent inhibition of gastric hydrochloric acid secretion in humans. To achieve an immediate reduction in intragastric acidity equivalent to that obtained with repeated oral doses of 20 mg, an initial intravenous dose of 40 mg is recommended. This results in an immediate reduction in intragastric acidity and sustained maintenance of this reduced level, averaging a 90% decrease over 24 hours, both after intravenous injection and intravenous infusion.

Inhibition of acid secretion correlates with the area under the concentration-time curve (AUC) of omeprazole and does not depend on the actual plasma concentration of omeprazole at any given moment.

No signs of tachyphylaxis have been observed during omeprazole treatment.

Effect on Helicobacter pylori

Helicobacter pylori is associated with the development of peptic ulcer disease, including duodenal and gastric ulcers. Helicobacter pylori is a primary factor in the development of atrophic gastritis, which is associated with an increased risk of gastric cancer.

Eradication of Helicobacter pylori using omeprazole in combination with antimicrobial agents is associated with high healing rates and prolonged remission in peptic ulcer disease.

Other effects related to inhibition of gastric acid secretion

During long-term treatment, an increased frequency of gastric glandular cyst formation has been reported. These changes are a consequence of pronounced inhibition of hydrochloric acid secretion and are benign and reversible in nature.

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Serum chromogranin A levels also increase due to reduced gastric acidity. Elevated chromogranin A levels may interfere with neuroendocrine tumor testing. To avoid this effect, proton pump inhibitor therapy should be discontinued 5 days before chromogranin A measurement. If chromogranin A and gastrin levels have not returned to reference values after initial measurements, testing should be repeated 14 days after discontinuation of PPI therapy.

An increase in ECL-cell numbers, possibly related to elevated serum gastrin levels, has been observed in both children and adults during prolonged omeprazole treatment. These findings are considered to have no clinical significance.

During prolonged treatment courses, a slightly increased frequency of gastric glandular cysts has been reported. These changes are a physiological consequence of pronounced inhibition of hydrochloric acid secretion; the process is benign and likely reversible.

Reduction of gastric juice acidity by any means, including proton pump inhibitors, increases the number of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing agents may lead to a slightly increased risk of gastrointestinal infections caused by Salmonella and Campylobacter.

Pharmacokinetics.

Distribution

The apparent volume of distribution in healthy volunteers is approximately 0.3 L/kg body weight. Omeprazole is approximately 97% bound to plasma proteins.

Metabolism

Omeprazole is completely metabolized by the cytochrome P450 (CYP) system. The majority of its metabolism depends on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the main metabolite in plasma. The remainder depends on another specific isoenzyme (CYP3A4), responsible for the formation of omeprazole sulfone. Due to omeprazole's high affinity for CYP2C19, there is potential for competitive inhibition and metabolic drug-drug interactions with other CYP2C19 substrates. However, due to its low affinity for CYP3A4, omeprazole does not inhibit the metabolism of other CYP3A4 substrates. Furthermore, omeprazole does not inhibit major CYP enzymes.

Approximately 3% of individuals of Caucasian ethnicity and 15–20% of individuals of Mongoloid ethnicity lack functional CYP2C19 enzyme and are considered "poor metabolizers." In these individuals, omeprazole metabolism may be primarily catalyzed by CYP3A4. After repeated administration of omeprazole at a dose of 20 mg once daily, the mean area under the concentration-time curve (AUC) in "poor metabolizers" is 5–10 times higher than in individuals with functional CYP2C19 enzyme ("extensive metabolizers"). Mean peak plasma concentrations were also higher—by 3–5 times. However, these results do not affect omeprazole dosing.

Elimination

Total plasma clearance is approximately 30–40 L/h after a single dose. The elimination half-life of omeprazole in plasma is generally less than 1 hour, both after single and repeated once-daily administration. Omeprazole is completely cleared from plasma between doses, with no tendency toward accumulation when administered once daily. Nearly 80% of the dose is excreted in urine as metabolites, and the remainder is excreted in feces, primarily via biliary secretion.

The AUC of omeprazole increases with repeated administration. This increase is dose-dependent and results in a nonlinear relationship between AUC and dose after repeated dosing. This time- and dose-dependent relationship is due to reduced presystemic metabolism and systemic clearance, possibly caused by inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (e.g., sulfone). No metabolite has been shown to affect gastric juice hydrochloric acid secretion.

Special patient groups

Patients with hepatic impairment

Omeprazole metabolism is slowed in patients with impaired liver function, leading to increased AUC. However, with once-daily administration, no tendency toward drug accumulation has been observed.

Patients with renal impairment

The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are unchanged in patients with impaired renal function.

Elderly patients

The rate of omeprazole metabolism is slightly reduced in elderly patients (75–79 years of age).

Clinical characteristics.

Indications.

Omeprazole-Vokate for intravenous use is indicated as an alternative to oral therapy in the following cases.

Adults

• Treatment of duodenal ulcer.
• Prevention of recurrence of duodenal ulcer.
• Treatment of gastric ulcer.
• Prevention of recurrence of gastric ulcer.
• In combination with appropriate antibiotics for eradication of Helicobacter pylori (H. pylori) in peptic ulcer disease.
• Treatment of gastric and duodenal ulcers associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs).
• Prevention of gastric and duodenal ulcers associated with NSAID use in high-risk patients.
• Treatment of reflux esophagitis.
• Long-term treatment of patients with inactive reflux esophagitis.
• Treatment of symptomatic gastroesophageal reflux disease.
• Treatment of Zollinger-Ellison syndrome.

Contraindications.

Hypersensitivity to omeprazole, substituted benzimidazoles, or to any of the excipients of the medicinal product. Omeprazole, like other proton pump inhibitors, should not be taken concomitantly with nelfinavir and atazanavir.

Special precautions.

Warning about the risk of allergic reactions:

• do not use if you are allergic to omeprazole.
• omeprazole may cause serious skin reactions. Symptoms may include:

• redness of the skin;
• blistering;
• rash.

If an allergic reaction occurs, discontinue use and seek immediate medical attention.

Interaction with other medicinal products and other forms of interaction.

Effect of omeprazole on the pharmacokinetics of other medicinal products.

Medicinal products whose absorption is pH-dependent.

Suppression of gastric acid secretion during treatment with omeprazole and other proton pump inhibitors (PPIs) may reduce or increase the absorption of medicinal products whose absorption depends on gastric pH. As with other medicinal products that reduce intragastric acidity, absorption of drugs such as ketoconazole, itraconazole, and erlotinib may be decreased, whereas absorption of drugs such as digoxin may be increased during omeprazole treatment. Concomitant administration of omeprazole (20 mg once daily) and digoxin in healthy volunteers increased the bioavailability of digoxin by 10% (in two out of ten subjects, by up to 30%).

Nelfinavir, atazanavir.

Plasma levels of nelfinavir and atazanavir are reduced when administered concomitantly with omeprazole.

Concomitant use of omeprazole and nelfinavir is contraindicated. Concomitant administration of omeprazole (40 mg once daily) reduced the average exposure to nelfinavir by approximately 40%, and the average exposure to its pharmacologically active metabolite M8 was reduced by approximately 75–90%. This interaction may also be due to inhibition of CYP2C19 activity.

Concomitant use of omeprazole with atazanavir is not recommended. Concomitant administration of omeprazole (40 mg once daily) and atazanavir 300 mg/ritonavir 100 mg in healthy volunteers resulted in a 75% reduction in atazanavir exposure. Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Concomitant administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg in healthy volunteers resulted in approximately a 30% reduction in atazanavir exposure compared to atazanavir 300 mg/ritonavir 100 mg once daily.

Digoxin.

Concomitant treatment with omeprazole (20 mg/day) and digoxin in healthy volunteers increased digoxin bioavailability by 10%. Rare cases of digoxin toxicity have been reported. However, caution should be exercised when prescribing high doses of omeprazole to elderly patients. Therapeutic drug monitoring of digoxin should be intensified. Patients receiving concomitant digoxin should be closely monitored by a physician.

Clopidogrel.

In a study, clopidogrel (loading dose 300 mg, followed by 75 mg/day) was administered alone and with omeprazole (80 mg given simultaneously with clopidogrel) for 5 days. When clopidogrel and omeprazole were administered together, exposure to the active metabolite of clopidogrel decreased by 46% (day 1) and 42% (day 5). Mean inhibition of platelet aggregation decreased by 47% (at 24 hours) and 30% (day 5) when clopidogrel and omeprazole were co-administered. Another study showed that administering clopidogrel and omeprazole at different times did not prevent their interaction, likely due to the inhibitory effect of omeprazole on CYP2C19. Conflicting data on the clinical significance of this pharmacokinetic/pharmacodynamic interaction regarding major cardiovascular events have been reported in observational and clinical studies. Therefore, concomitant use of omeprazole and clopidogrel should be avoided.

Other medicinal products.

Absorption of posaconazole, erlotinib, ketoconazole, and itraconazole is significantly reduced; therefore, clinical efficacy may be diminished. Concomitant use of the medicinal product with posaconazole and erlotinib should be avoided.

Medicinal products metabolized by CYP2C19.

Omeprazole is a moderate inhibitor of CYP2C19, the main enzyme responsible for omeprazole metabolism. Thus, metabolism of concomitantly administered medicinal products that are also metabolized by CYP2C19 may be reduced, and systemic exposure to these drugs may be increased. Examples include R-warfarin and other vitamin K antagonists, cilostazol, diazepam, and phenytoin.

Pharmacokinetic/pharmacodynamic interaction between clopidogrel (loading dose 300 mg, maintenance dose 75 mg/day) and omeprazole (80 mg/day orally, i.e., a dose four times higher than the standard daily dose) was observed in healthy volunteers, resulting in a mean reduction of 46% in exposure to the active metabolite of clopidogrel and a mean reduction of 16% in maximum inhibition of adenosine diphosphate (ADP)-induced platelet aggregation. The clinical significance of this interaction remains unknown. As a precautionary measure, concomitant use of omeprazole and clopidogrel should be avoided.

Cilostazol.

In healthy volunteers, administration of omeprazole 40 mg increased Cmax and AUC of cilostazol by 18% and 26%, respectively, and of one of its active metabolites by 29% and 69%, respectively.

Phenytoin.

Plasma concentration monitoring of phenytoin is recommended during the first two weeks after initiation of omeprazole treatment. If phenytoin dose adjustment is required, monitoring and further dose adjustments should continue after discontinuation of omeprazole.

Unknown mechanism of interaction.

Saqunavir.

Concomitant administration of omeprazole with saquinavir/ritonavir resulted in an increase in saquinavir plasma levels by approximately 70%, which was associated with acceptable tolerability in HIV-infected patients.

Tacrolimus.

Increased serum levels of tacrolimus have been reported with concomitant use of omeprazole. Enhanced monitoring of tacrolimus concentrations and renal function (creatinine clearance) is required, and dose adjustment of tacrolimus may be necessary.

Metotrexate.

Elevated methotrexate levels have been observed in some patients when administered concomitantly with proton pump inhibitors. In cases where high-dose methotrexate is required, temporary discontinuation of omeprazole should be considered.

Effect of other medicinal products on the pharmacokinetics of omeprazole.

Inhibitors of CYP2C19 and/or CYP3A4.

Since omeprazole is metabolized by CYP2C19 and CYP3A4 enzymes, medicinal products known to inhibit the activity of CYP2C19 or CYP3A4, or both enzymes (e.g., clarithromycin and voriconazole), may lead to increased omeprazole serum levels due to reduced metabolic rate. Concomitant administration of voriconazole resulted in more than a twofold increase in omeprazole exposure. As high doses of omeprazole are generally well tolerated, dose adjustment of omeprazole is usually not required. However, dose adjustment should be considered in patients with severe hepatic impairment and in cases requiring long-term treatment.

Omeprazole is partially metabolized by CYP3A4 as well, but does not inhibit this enzyme. Therefore, omeprazole does not affect the metabolism of medicinal products metabolized by CYP3A4, such as cyclosporine, lidocaine, quinidine, estradiol, erythromycin, and budesonide.

Inducers of CYP2C19 and/or CYP3A4.

Medicinal products known to induce the activity of CYP2C19 or CYP3A4, or both enzymes (e.g., rifampicin and St. John's wort), may lead to decreased omeprazole serum levels due to accelerated metabolism.

Special precautions for use.

In patients with gastric ulcer or suspected gastric ulcer, if alarming symptoms occur such as significant unintentional weight loss, frequent vomiting, dysphagia, hematemesis, or melena, malignancy should be ruled out, since the use of the medicinal product may mask its symptoms and delay diagnosis.

Concomitant use of atazanavir with proton pump inhibitors is not recommended.

If co-administration of atazanavir with a proton pump inhibitor cannot be avoided, careful clinical monitoring (e.g., viral load) is recommended, along with increasing the dose of atazanavir to 400 mg with 100 mg ritonavir. The dose of omeprazole should not exceed 20 mg.

Omeprazole, like other acid-inhibiting agents, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered when treating patients with vitamin B12 deficiency, those at risk of reduced vitamin B12 absorption, or those with cachexia during long-term therapy. In individual cases, monitoring plasma vitamin B12 levels may be advisable.

Omeprazole is an inhibitor of CYP2C19. Potential interactions with drugs metabolized by CYP2C19, such as clopidogrel, should be considered at the beginning or end of omeprazole treatment.

Use of proton pump inhibitors may slightly increase the risk of gastrointestinal infections caused by pathogens such as Salmonella and Campylobacter.

The use of proton pump inhibitors, particularly at high doses and for prolonged periods (>1 year), is associated with a slightly increased risk of fractures of the hip, wrist, and spine, primarily in elderly patients or in the presence of other risk factors. Epidemiological studies indicate that proton pump inhibitors may increase fracture risk by 10–40%. In some cases, this is associated with the presence of other risk factors in the patient. Patients at risk of osteoporosis should receive appropriate treatment and adequate intake of vitamin D and calcium.

During long-term therapy, especially when treatment duration exceeds one year, patients require medical supervision and regular laboratory monitoring of serum magnesium and calcium levels.

In patients taking proton pump inhibitors, including omeprazole, for at least 3 months, significant hypomagnesemia may develop (in most cases, patients had been taking the drug for approximately 1 year).

After discontinuation of the drug, serum magnesium levels returned to normal. Clinical features of hypomagnesemia include increased neuromuscular excitability, manifested as carpopedal spasms, motor agitation; tachycardia, cardiac arrhythmias, elevated blood pressure; and dystrophic disorders such as trophic skin erosions and ulcers. The diagnostic criterion for hypomagnesemia is a serum magnesium concentration below 1 mEq/L. Additionally, cases have been reported where hypomagnesemia led to hypocalcemia due to suppressed parathyroid hormone secretion in conditions of low magnesium levels in the body. In some patients, severe hypocalcemia and hypomagnesemia were observed, with development of seizure syndrome, cardiac arrhythmias, tetany, psychiatric disturbances, and severe vomiting, leading to electrolyte imbalance.

During treatment with antisecretory drugs, plasma gastrin concentration increases as a result of reduced hydrochloric acid secretion. Due to decreased hydrochloric acid secretion, chromogranin A levels increase. Elevated chromogranin A levels may interfere with tests for detecting neuroendocrine tumors. To prevent such interference, proton pump inhibitor therapy should be discontinued at least 5 days before measuring chromogranin A levels. If chromogranin A and gastrin levels do not return to reference values after initial measurements, testing should be repeated 14 days after discontinuation of PPI therapy.

In patients with intolerance to certain sugars, consultation with a physician is recommended before initiating treatment with this medicinal product.

Use during pregnancy or breastfeeding.

Epidemiological studies involving over 1000 pregnant women who had normal deliveries have not shown any adverse effects of omeprazole on pregnancy or on the health of the fetus/newborn. The medicinal product may be used during pregnancy only if, in the physician’s judgment, the expected benefit to the mother outweighs the potential risk to the fetus.

Omeprazole is excreted in small amounts into breast milk, but its effect on the infant is unknown. Therefore, breastfeeding should be discontinued during treatment with this medicinal product.

Ability to affect reaction speed when driving or operating machinery.

The effect of the drug on the ability to drive or operate machinery is unlikely; however, the possibility of adverse reactions such as dizziness and visual disturbances should be considered.

Method of Administration and Dosage

Dosage

Alternative to Oral Therapy

For patients for whom oral administration of the drug is unsuitable, intravenous administration of Omeprazole-Vokate 40 mg once daily is recommended. For patients with Zollinger-Ellison syndrome, the recommended initial intravenous dose of omeprazole is 60 mg per day. Higher daily doses may be required; therefore, the dose should be individually adjusted. If the daily dose exceeds 60 mg, it should be divided equally into two parts and administered twice daily. The drug should be administered intravenously as an infusion over 20–30 minutes.

Reconstitution of the Drug Prior to Administration

Prior to intravenous bolus injection, the lyophilized powder contained in the vial should be reconstituted with 10 mL of solvent (the ampoule with solvent is supplied). The drug solution should be administered slowly over no less than 2 minutes. Omeprazole-Vokate should be reconstituted immediately before use. The reconstituted solution is stable for 4 hours.

Prior to intravenous infusion, the drug should be dissolved in 100 mL of 0.9% sodium chloride solution or 5% glucose solution. Ensure complete dissolution of the drug. The resulting solution should be used for intravenous infusion within 20–30 minutes.

The infusion solution prepared in 0.9% sodium chloride solution should be used within 12 hours.

The infusion solution prepared in 5% glucose solution should be used within 6 hours.

For prevention of gastric content aspiration prior to general anesthesia, Omeprazole-Vokate 40 mg should be administered intravenously 1 hour before surgery.

Any unused product or waste material should be disposed of in accordance with local requirements.

Special Patient Populations

Renal Impairment

Acute tubulointerstitial nephritis (TIN) has been observed in patients taking omeprazole and may occur at any time during omeprazole therapy (see section "Adverse Reactions"). Acute tubulointerstitial nephritis may progress to renal failure.

If TIN is suspected, omeprazole should be discontinued and appropriate treatment initiated immediately.

Dose adjustment is not required in patients with impaired renal function.

Hepatic Impairment

In patients with hepatic impairment, a daily dose of 10–20 mg may be sufficient.

Elderly Patients (>65 years of age)

Dose adjustment is not required in elderly patients.

Children

Experience with intravenous omeprazole in pediatric practice is limited.

Overdose

Human data on the effects of omeprazole overdose are very limited. Cases of doses up to 560 mg of omeprazole have been reported, as well as single oral doses of 2400 mg (120 times higher than the usual recommended clinical dose). Symptoms reported include nausea, vomiting, dizziness, abdominal pain, diarrhea, and headache. In isolated cases, lethargy, depression, and confusion have also been reported.

The described symptoms are transient. Elimination kinetics remain unchanged (first-order kinetics) with increasing dose.

Treatment. There is no specific antidote. Omeprazole is poorly dialyzable. Gastric lavage is indicated, along with symptomatic and supportive therapy.

Side effects.

The most commonly observed adverse effects are headache, abdominal pain, constipation, diarrhea, bloating, and nausea/vomiting.

The following criteria are used to assess the frequency of adverse reactions: 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 due to lack of data).

Eye disorders: rare – blurred vision, visual disturbances.

Ear and labyrinth disorders: uncommon – vertigo.

Respiratory system disorders: rare – bronchospasm.

Gastrointestinal disorders: common – abdominal pain, constipation, diarrhea, flatulence, nausea, vomiting; rare – dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis, abdominal discomfort, fundic gland polyps (benign).

Hepatobiliary disorders: uncommon – increased liver enzyme activity; rare – hepatitis, with or without jaundice; very rare – hepatic failure, encephalopathy in patients with severe hepatic impairment.

Renal and urinary disorders: frequency not known – tubulointerstitial nephritis (with possible progression to renal failure).

Metabolism and nutrition disorders: rare – hyponatremia; frequency not known – hypomagnesemia, hypocalcemia, hypokalemia.

Nervous system disorders: common – headache; uncommon – dizziness, paraesthesia, sleep disturbances, feeling of weakness, somnolence; rare – taste disturbances.

Psychiatric disorders: uncommon – insomnia; rare – anxiety, mild disorientation, depression; very rare – aggression, hallucinations, agitation, confusion.

Blood and lymphatic system disorders: rare – thrombocytopenia, leukopenia; very rare – agranulocytosis, pancytopenia.

Immune system disorders: rare – hypersensitivity reactions such as fever, angioneurotic edema, and anaphylactic reaction/shock.

Skin and subcutaneous tissue disorders: uncommon – dermatitis, hyperemia, pruritus, rash, vesicles, urticaria; rare – alopecia, photosensitivity; very rare – erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: rare – arthralgia, myalgia, fracture of femur, wrist or spine; very rare – muscle weakness.

Reproductive system and breast disorders: very rare – impotence, gynecomastia.

Other: uncommon – malaise, peripheral edema; rare – increased sweating.

The adverse event profile observed in children is consistent with that in adults, both during short-term and long-term therapy.

Reporting suspected adverse reactions after marketing authorization is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are encouraged to 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 in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

The reconstituted solution (with solvent provided in ampoule) should be stored at a temperature not exceeding 25 °C and used within 4 hours.

Incompatibilities.

Do not use solvents other than those specified in the section "Dosage and administration".

Packaging.

Lyophilisate for solution for injection, 40 mg per vial No. 1, supplied with solvent 10 ml in ampoule No. 1, in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

ANFARM HELLAS S.A., Greece / ANFARM HELLAS S.A., Greece.

Manufacturer's address.

Schimatari Viotias, 32009, 61st km Nat. Rd. Athens-Lamia, Greece / Schimatari Viotias, 32009, 61st km Nat. Rd. Athens-Lamia, Greece.

Marketing Authorization Holder.

Pharmaceuticals company «VOCATE S.A.», Greece / Pharmaceuticals company «VOCATE S.A.», Greece.

Address of Marketing Authorization Holder.

150 Gounari str. 16674 Glifada Athens, Greece / 150 Gounari str. 16674 Glifada Athens, Greece.