Omeprazole astra

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OMEPRAZOLE ASTRA

Composition:

Active substance: omeprazole;

1 vial contains omeprazole sodium equivalent to omeprazole 40 mg;

Excipients: mannitol, disodium edetate, meglumine, sodium bisulfite, sodium hydroxide.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or practically white lyophilized mass or powder.

Pharmacotherapeutic group.

Drugs 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 acid secretion through a mechanism of specific targeted 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 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 H⁺, K⁺-ATPase enzyme (proton pump). This effect on the final step of gastric acid production is dose-dependent and results in 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 omeprazole's effect on gastric acid secretion.

Effect on Gastric Acid Secretion

Intravenous administration of omeprazole causes dose-dependent inhibition of gastric acid secretion in humans. To achieve an immediate reduction in intragastric acidity comparable to that achieved 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, with maintenance of this reduced level by approximately 90% over 24 hours, both after intravenous injection and intravenous infusion.

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

No signs of tachyphylaxis have been observed during omeprazole treatment.

Effect on H. pylori

H. pylori is associated with the development of peptic ulcer disease, including duodenal and gastric ulcers. H. pylori is a primary factor in the development of gastritis.

H. pylori, together with gastric acid, is a major factor in the development of peptic ulcer disease. H. pylori is also a primary factor in the development of atrophic gastritis, which is associated with an increased risk of gastric cancer.

Eradication of H. pylori using omeprazole in combination with antimicrobial agents leads to a high rate of ulcer healing and prolonged remission of peptic ulcer disease.

Other Effects Related to Inhibition of Gastric Acid Secretion

During treatment with antisecretory agents, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may interfere with diagnostic testing for neuroendocrine tumors. It has been reported that treatment with proton pump inhibitors should be discontinued 5–14 days before measuring CgA. Testing should be repeated if levels have not normalized by that time.

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

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

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

Pharmacokinetics

Distribution

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

Metabolism and Elimination

Omeprazole is completely metabolized by the cytochrome P450 (CYP) system. Its metabolism is primarily dependent on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the main metabolite in plasma. The remainder is metabolized by another specific isoform (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 have the ability to 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 AUC value in "poor metabolizers" is 5–10 times higher than in individuals with functional CYP2C19 ("extensive metabolizers"). The mean peak plasma concentration is also 3–5 times higher. However, these findings 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 typically less than one hour, both after single and repeated once-daily administration. Omeprazole is completely cleared from plasma between doses, with no tendency for accumulation when administered once daily. Approximately 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 non-linear relationship between AUC and dose after repeated dosing. This time- and dose-dependent relationship is attributed to reduced presystemic metabolism and systemic clearance, possibly due to inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (e.g., sulfone). No metabolite has been shown to affect gastric acid secretion.

Special Patient Populations

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 for drug accumulation has been observed.

Patients with Renal Impairment. The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are not altered 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 Astra for intravenous use is indicated in adults as an alternative to oral therapy:

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

Contraindications.

Hypersensitivity to omeprazole, substituted benzimidazoles, or to any of the excipients.

Omeprazole, like other proton pump inhibitors (PPIs), should not be used concomitantly with nelfinavir and atazanavir (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Effect of omeprazole on the pharmacokinetics of other medicinal products

Medicinal products whose absorption depends on gastric pH

Suppression of gastric secretion during treatment with omeprazole and other PPIs may reduce or increase the absorption of medicinal products whose absorption is pH-dependent. Absorption of drugs such as ketoconazole, itraconazole, erlotinib may be decreased, while absorption of drugs such as digoxin may be increased during omeprazole treatment. It has been reported that concomitant administration of omeprazole (20 mg once daily) and digoxin increased digoxin bioavailability by 10%.

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) reduces the average exposure to nelfinavir by approximately 40%, and the average exposure to the pharmacologically active metabolite M8 is reduced by approximately 75–90%. The interaction may also be due to inhibition of CYP2C19 activity.

Concomitant use of omeprazole and atazanavir is contraindicated.

Concomitant administration of omeprazole (40 mg once daily) with atazanavir 300 mg or ritonavir 100 mg resulted in a 75% reduction in atazanavir exposure. Increasing the atazanavir dose to 400 mg does not compensate for the effect of omeprazole on atazanavir exposure. Concomitant administration of omeprazole (20 mg once daily) with atazanavir 400 mg or ritonavir 100 mg results in approximately a 30% reduction in atazanavir exposure compared to atazanavir 300 mg or ritonavir 100 mg once daily.

Digoxin

Concomitant treatment with omeprazole (20 mg daily) and digoxin increases digoxin bioavailability by 10%. Rare cases of digoxin-induced 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.

Clopidogrel

When clopidogrel and omeprazole are used concomitantly, exposure to the active metabolite of clopidogrel decreases from day 1 to day 5 from 46% to 42%. The mean inhibition of platelet aggregation decreases from 47% to 30% from day 1 to day 5 when clopidogrel and omeprazole are administered together. Administration of clopidogrel and omeprazole at different times does not prevent their interaction, likely due to the inhibitory effect of omeprazole on CYP2C19. Data on the clinical significance of this pharmacokinetic/pharmacodynamic interaction regarding major cardiovascular events are conflicting.

Other medicinal products

Absorption of posaconazole, erlotinib, ketoconazole, and itraconazole is significantly reduced; therefore, clinical efficacy may be diminished. Concomitant use 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 agents may be increased. Examples include R-warfarin and other vitamin K antagonists, cilostazol, diazepam, and phenytoin.

Studies in healthy volunteers have demonstrated a pharmacokinetic/pharmacodynamic interaction between clopidogrel (loading dose 300 mg / maintenance dose 75 mg daily) and omeprazole (80 mg daily orally, i.e., a dose four times higher than the standard daily dose), resulting in a mean reduction of 46% in exposure to the active metabolite of clopidogrel and a mean reduction of 16% in maximum inhibitory effect on adenosine diphosphate (ADP)-induced platelet aggregation. As a precautionary measure, concomitant use of omeprazole and clopidogrel should be avoided.

However, the clinical significance of this interaction remains unclear. There is no evidence of increased risk of adverse cardiovascular outcomes with concomitant use of clopidogrel and PPIs, including esomeprazole.

Several observational studies have shown conflicting results regarding whether the risk of cardiovascular thromboembolic events increases when patients receive clopidogrel together with PPIs.

When clopidogrel is used in combination with acetylsalicylic acid and esomeprazole, compared to clopidogrel monotherapy, a reduction of nearly 40% in exposure to the active metabolite of clopidogrel has been observed. However, maximum inhibitory activity against adenosine triphosphate (ATP)-induced platelet aggregation was similar in groups receiving clopidogrel alone and in combination with acetylsalicylic acid and esomeprazole, likely due to the concomitant administration of low-dose acetylsalicylic acid.

Cilostazol

Administration of omeprazole 40 mg increases the 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; and if the phenytoin dose has been adjusted, monitoring and further dose adjustments should be performed after discontinuation of omeprazole treatment.

Unknown mechanism

Saquinavir

Concomitant use of omeprazole with saquinavir/ritonavir led to 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. Close monitoring of tacrolimus concentrations and renal function (creatinine clearance) is required, and dose adjustment of tacrolimus may be necessary.

Methotrexate

Elevated methotrexate levels have been reported in some patients receiving concomitant PPIs. When 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 that inhibit CYP2C19 or CYP3A4 activity (such as clarithromycin and voriconazole) may cause an increase in omeprazole serum levels due to slowed metabolism. Concomitant use of voriconazole resulted in more than a twofold increase in omeprazole exposure. Since 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 during 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 drugs metabolized by CYP3A4, such as cyclosporine, lidocaine, quinidine, estradiol, erythromycin, and budesonide.

Inducers of CYP2C19 and/or CYP3A4

Medicinal products that induce CYP2C19 or CYP3A4 activity (such as rifampicin and St. John’s wort) may cause decreased omeprazole serum levels due to accelerated metabolism.

Special precautions for use.

In the presence of any alarming symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena), as well as in the presence of gastric ulcer or suspicion of gastric ulcer, malignancy must be excluded, since treatment may reduce symptom severity and delay diagnosis.

Concomitant use of omeprazole and atazanavir is contraindicated.

Concomitant use of atazanavir with proton pump inhibitors is not recommended. If a combination of atazanavir with a proton pump inhibitor cannot be avoided, careful clinical monitoring (e.g. viral load) in combination with increased atazanavir dose to 400 mg with 100 mg ritonavir is recommended; the omeprazole dose should not exceed 20 mg.

Omeprazole Astra, like all medicinal products that suppress gastric acid secretion, may reduce absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with cachexia or risk factors for reduced vitamin B12 absorption during long-term therapy.

Omeprazole is an inhibitor of CYP2C19. At the beginning or end of omeprazole treatment, potential interactions with medicinal products metabolized via CYP2C19 should be considered. An interaction has been observed between clopidogrel and omeprazole. The clinical significance of this interaction remains unclear. As a precautionary measure, concomitant use of omeprazole and clopidogrel should be avoided.

Treatment with proton pump inhibitors slightly increases the risk of gastrointestinal infections, such as Salmonella and Campylobacter.

Do not use if you are allergic to omeprazole. Omeprazole may cause serious skin reactions. Symptoms may include: skin redness; blisters; rash. If you experience an allergic reaction, stop using the medicine and seek immediate medical attention.

In patients who have taken PPIs, including omeprazole, for at least 3 months, severe hypomagnesemia has occurred (in most cases, patients had been taking the drug for approximately 1 year). Hypomagnesemia may manifest with serious symptoms such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. Hypomagnesemia may also be asymptomatic and may not be diagnosed in time. In most patients, symptoms of hypomagnesemia resolve and condition normalizes after administration of magnesium supplements and discontinuation of PPI.

In patients planned for long-term PPI therapy or concomitant use of digoxin or other medicinal products that may cause decreased magnesium levels (e.g. diuretics), serum magnesium concentration should be measured before initiation of PPI therapy and periodically during treatment.

PPIs, particularly when used at high doses and for prolonged periods (>1 year), slightly increase the risk of fractures of the spine, wrist, and hip, especially in elderly patients and in the presence of risk factors. According to observational studies, PPIs may increase the overall risk of fractures by 10–40%. This may partly be related to other risk factors. Patients at risk of developing osteoporosis should receive assistance according to current clinical guidelines and should take vitamin D and calcium at recommended doses.

Subacute cutaneous lupus erythematosus (SCLE)

PPI use has occasionally been associated with the development of SCLE. If skin manifestations occur, particularly in sun-exposed areas and accompanied by arthralgia, patients should seek immediate medical advice and discontinuation of omeprazole should be considered. A history of SCLE following drug use increases the risk of developing SCLE when using other PPIs.

Renal function impairment

Acute tubulointerstitial nephritis (ATIN) 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 ATIN is suspected, omeprazole should be discontinued and appropriate treatment initiated immediately.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels may interfere with tests for detecting neuroendocrine tumours. To avoid this interference, omeprazole should be temporarily discontinued 5 days before CgA measurement. If CgA and gastrin levels have not returned to reference ranges after initial measurements, these parameters should be re-measured 14 days after discontinuation of the drug.

Patients who are taking omeprazole for a prolonged period (especially if treatment lasts longer than 1 year) should be under regular medical supervision.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e. essentially "sodium-free".

Use during pregnancy or breastfeeding.

Studies indicate no adverse effect of omeprazole on pregnancy or the health of the fetus/newborn child. Omeprazole Astra may be used during pregnancy.

Omeprazole passes into breast milk, but the risk of effects on the infant is unlikely if the mother uses the medicinal product at therapeutic doses.

Ability to affect reaction speed when driving or operating machinery.

It is unlikely that Omeprazole Astra affects the ability to drive or operate machinery. Adverse reactions such as dizziness and visual disturbances may occur. If such disorders occur, patients should not drive or operate machinery.

Method of Administration and Dosage

Dosage

Alternative to Oral Therapy

For patients for whom oral administration of the drug is unsuitable, Omeprazole Astra 40 mg is recommended to be administered intravenously once daily. For patients with Zollinger-Ellison syndrome, the recommended initial intravenous dose is 60 mg daily. Higher daily doses may be required; therefore, the dose should be individually adjusted. If the daily dose exceeds 60 mg, it should be divided into two equal doses and administered twice daily.

The medicinal product should be administered only intravenously and must not be given by any other route.

The solution must be used immediately after preparation, but no later than within 4 hours. The diluted solution of Omeprazole Astra must not be stored in a refrigerator. Any unused solution should be discarded.

Reconstitution of the Medicinal Product Prior to Administration

For Intravenous Injections: Reconstitute the contents of each vial of Omeprazole Astra containing 40 mg of omeprazole with 10 mL of sterile water for injection. The intravenous injection solution should be administered slowly over 5 minutes.

For Intravenous Infusions: Reconstitute the contents of each vial of Omeprazole Astra containing 40 mg of omeprazole with 10 mL and then dilute to a total volume of 100 mL with 0.9% sodium chloride solution or 5% glucose solution. The stability of omeprazole depends on the pH of the infusion solution; therefore, other solvents or volumes should not be used for dilution.

The intravenous infusion should be administered over 20–30 minutes.

The solution must be used immediately after preparation, but no later than within 4 hours. The diluted omeprazole solution must not be stored in a refrigerator.

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

Special Patient Populations

Renal Impairment

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

Hepatic Impairment

In patients with impaired liver function, a daily dose of 10–20 mg of the medicinal product 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; therefore, the drug should not be prescribed to this patient group.

Overdose

Information on the consequences of omeprazole overdose in humans is limited. Cases of administration up to 560 mg have been reported. There have also been isolated reports of single oral doses of omeprazole reaching 2400 mg (120 times higher than the usual recommended clinical dose). Reported symptoms include nausea, vomiting, dizziness, abdominal pain, diarrhea, and headache. In isolated cases, lethargy, depression, and confusion have also been reported.

The described symptoms were transient, and no reports of serious outcomes have been received. Elimination rate was unchanged (first-order kinetics) with increasing doses.

If necessary, symptomatic treatment should be administered.

In clinical studies, intravenous administration of up to 270 mg in a single day and up to 650 mg over three days did not result in any dose-dependent adverse reactions.

Side effects.

The most common adverse reactions (1–10% of patients) are headache, abdominal pain, constipation, diarrhoea, flatulence, and nausea/vomiting.

Undesirable effects listed below have been identified during clinical trials with omeprazole and in the post-marketing period. None of these events were considered dose-dependent. The adverse reactions listed below are classified by frequency and by organ system. Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

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

Immune system disorders:
Rare: hypersensitivity reactions, e.g. fever, angioedema, and anaphylactic reactions/shock.

Metabolism and nutrition disorders:
Rare: hyponatremia; very rare: hypomagnesemia, severe hypomagnesemia which may lead to hypocalcemia; hypomagnesemia may also cause hypokalemia.

Psychiatric disorders:
Uncommon: insomnia; rare: restlessness, confusion, depression; very rare: aggression, hallucinations.

Nervous system disorders:
Common: headache; uncommon: dizziness, paraesthesia, somnolence; rare: taste disturbance.

Eye disorders:
Rare: blurred vision.

Ear and labyrinth disorders:
Uncommon: vertigo.

Respiratory, thoracic and mediastinal disorders:
Rare: bronchospasm.

Gastrointestinal disorders:
Common: abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting, fundic gland polyps (benign); rare: dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis.

Hepatobiliary disorders:
Uncommon: increased liver enzymes; rare: hepatitis with or without jaundice; very rare: hepatic failure, encephalopathy in patients with pre-existing liver disease.

Skin and subcutaneous tissue disorders:
Uncommon: dermatitis, pruritus, rash, urticaria; rare: alopecia, photosensitivity; very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN); frequency not known: subacute cutaneous lupus erythematosus.

Musculoskeletal and connective tissue disorders:
Uncommon: fractures of the hip, wrist, or spine; rare: arthralgia, myalgia; very rare: muscle weakness.

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

Reproductive system and breast disorders:
Very rare: gynaecomastia.

General disorders and administration site conditions:
Uncommon: malaise, peripheral oedema; rare: increased sweating.

In isolated cases, irreversible visual disturbances have been reported in critically ill patients receiving omeprazole intravenously, particularly at high doses, but a causal relationship has not been established.

Reporting suspected adverse reactions.

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

Shelf life. 2 years (from the date of manufacture of the in bulk form).

Storage conditions.

Store in the original packaging, out of reach of children, at a temperature not exceeding 25 °C.

Shelf life of reconstituted solution: up to 4 hours at a temperature not exceeding 25 °C.

Storage period of powder after opening: up to 24 hours.

From a microbiological standpoint, the medicinal product should be used immediately unless reconstitution has been carried out under controlled and aseptic conditions validated by appropriate methods.

Incompatibilities.

This medicinal product must not be mixed with other medicinal products except those mentioned in the section "Instructions for use and dosage".

Packaging.

1 or 10 vials per cardboard box.

Prescription status. Prescription only.

Manufacturer.

LLC "ASTRAFARM" (packaging of in bulk form: Shandong Yuxing Pharmaceutical Co., Ltd., People's Republic of China).

Manufacturer's address and place of business.

6, Kyivska Street, Vyshneve, Kyiv-Sviatoshyn District, Kyiv Oblast, 08132, Ukraine.