Rabezol

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

Composition:

Active substance: rabeprozole sodium;

One tablet contains 20 mg of sodium rabeprozole, equivalent to 18.85 mg of rabeprozole;

Excipients: mannite (E 421); heavy magnesium oxide; low-substituted hydroxypropylcellulose; hydroxypropylcellulose; magnesium stearate; ethylcellulose; hypromellose phthalate (HP55); dibutyl sebacate; yellow iron oxide (E 172); titanium dioxide (E 171); talc.

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties: yellow, film-coated, round-shaped tablets with a diameter of 7.3 mm ± 1 mm.

Pharmacotherapeutic group. Drugs affecting the digestive tract and metabolism. Drugs for the treatment of diseases associated with acid imbalance. Anti-ulcer drugs and drugs for the treatment of gastroesophageal reflux. Proton pump inhibitors. Rabeprozole. ATC code A02BC04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Sodium rabeprazole belongs to the class of antisecretory compounds substituted benzimidazoles, has no anticholinergic properties and is not a histamine H2-receptor antagonist, but inhibits gastric acid secretion by specifically inhibiting the H+/K+-ATPase enzyme at the secretory surface of gastric parietal cells (acid, or proton pump). The effect is dose-dependent and results in inhibition of both basal and stimulated acid secretion, regardless of the stimulus. Animal studies have shown that after administration, sodium rabeprazole rapidly disappears from both blood plasma and gastric mucosa. Sodium rabeprazole has weakly basic properties, is rapidly absorbed at all doses and accumulates in parietal cells. Sodium rabeprazole is converted into its active sulfonamide form via protonation and thereby reacts with accessible cysteine residues of the proton pump.

Antisecretory activity. After oral administration of 20 mg of sodium rabeprazole, the antisecretory effect is observed within 1 hour and reaches maximum within 2–4 hours. Inhibition of basal acid secretion and food-stimulated acid secretion 23 hours after the first dose of sodium rabeprazole was 69% and 82%, respectively, with the duration of inhibition lasting up to 48 hours. The inhibitory effect of sodium rabeprazole slightly increases after repeated once-daily administration, with stable suppression of secretion achieved within 3 days. After discontinuation of sodium rabeprazole, secretory activity returns to normal within 2–3 days.

Reduction of gastric acidity, regardless of the agent used, including proton pump inhibitors (PPIs) such as rabeprazole, increases the number of bacteria in the gastrointestinal tract. PPI therapy 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 rabeprazole once daily for up to 43 months. During the first 2–8 weeks of therapy, serum gastrin concentration increased, reflecting acid secretion inhibition. Gastrin concentration typically returned to baseline levels within 1–2 weeks after treatment discontinuation.

Biopsy studies of the gastric fundus and antrum in over 500 patients who received rabeprazole or a comparator drug for 8 weeks revealed no histological changes in ECL cells, degree of gastritis, increased frequency of atrophic gastritis, intestinal metaplasia, or spread of H. pylori infection. In long-term treatment of over 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 on the central nervous system (CNS), cardiovascular or respiratory systems caused by sodium rabeprazole. Oral administration of 20 mg of sodium rabeprazole daily for 2 weeks did not affect 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.

Studies in healthy volunteers showed no clinically significant interactions between rabeprazole and amoxicillin. Rabeprazole has no negative effect on plasma levels of amoxicillin and clarithromycin when co-administered for H. pylori eradication in the upper gastrointestinal tract (GI tract).

During antisecretory therapy, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to decreased gastric acidity, levels of chromogranin A increase. Elevated chromogranin A levels may affect test results for neuroendocrine tumor detection.

Available published data indicate that 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. Rabezol is a medicinal product containing sodium rabeprazole as the active substance, formulated as enteric-coated tablets. This dosage form is necessary because sodium rabeprazole is susceptible to gastric acid. Absorption of sodium rabeprazole begins only after the tablet passes through the stomach. Sodium rabeprazole is rapidly absorbed from the intestine. Maximum plasma concentration (Cmax) of rabeprazole is reached approximately 3.5 hours after a 20 mg dose. Cmax and area under the curve (AUC) of rabeprazole are linear within the dose range of 10–40 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 rabeprazole. In healthy volunteers, the elimination half-life (T1/2) from plasma 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 interaction with food was observed. Neither food type nor time of day affects the absorption of sodium rabeprazole.

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

Metabolism and excretion. Like other PPIs, rabeprazole is metabolized by the cytochrome P450 (CYP450) hepatic drug metabolism system. In vitro studies with human liver microsomes showed that sodium rabeprazole is metabolized by CYP450 isoenzymes (CYP2C19 and CYP3A4). At expected human plasma concentrations, rabeprazole does not induce or inhibit CYP3A4. However, as in vitro findings cannot always be extrapolated to in vivo situations, these results suggest that interactions between rabeprazole and cyclosporine are unlikely. 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 slight antisecretory activity, but it is not present in plasma.

After a single 20 mg dose of 14C-labeled sodium rabeprazole, unchanged rabeprazole was not detected 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 unidentified metabolites. The remainder of the dose was found in feces.

Gender. After adjusting for body weight and height, there are no significant differences in rabeprazole pharmacokinetics based on gender.

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 rabeprazole was very similar to that in healthy volunteers. AUC and Cmax of sodium rabeprazole were approximately 35% lower compared to healthy volunteers. Mean T1/2 values were 0.82 hours in healthy volunteers, 0.95 hours in hemodialysis patients, and 3.6 hours post-dialysis. Drug clearance in hemodialysis patients was approximately twice that in healthy volunteers.

Hepatic impairment. After a single 20 mg dose of sodium rabeprazole in patients with moderate chronic liver disease, AUC was doubled and T1/2 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, T1/2 in patients with impaired liver function was 12.3 hours compared to 2.1 hours in healthy volunteers. Pharmacodynamic response (gastric juice pH-metry) was comparable between the two patient groups.

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

Polymorphism of CYP2C19. After 7 days of 20 mg daily sodium rabeprazole administration, patients with slow CYP2C19 metabolism had AUC and T1/2 levels approximately 1.9 and 1.6 times higher, respectively, compared to those with rapid metabolism; meanwhile, Cmax increased only by 40%.

Clinical characteristics.

Indications.

• Active duodenal ulcer;
• active benign gastric ulcer;
• erosive or ulcerative gastroesophageal reflux disease (GERD);
• long-term treatment of GERD (maintenance therapy for GERD);
• symptomatic treatment of moderate to very severe GERD (symptomatic treatment of GERD);
• Zollinger–Ellison syndrome;
• eradication of Helicobacter pylori (H. pylori) in patients with gastric or duodenal peptic ulcer, in combination with appropriate antibacterial treatment regimens.

Contraindications.

Hypersensitivity to sodium rabeprazole or to any other component of the medicinal product.

Pregnancy and breastfeeding (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

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 due to inhibition of gastric acid secretion

Sodium rabeprazole causes strong and prolonged inhibition of gastric acid secretion. Therefore, rabeprazole may interact with medicinal products whose absorption is pH-dependent. Concomitant administration of sodium rabeprazole and ketoconazole or itraconazole may lead to reduced plasma concentrations of the latter. Thus, individual patients receiving these medicinal products together with rabeprazole should be monitored by a physician to determine the need for dose adjustment.

Antacids

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

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 PPIs. PPIs, including rabeprazole, should not be used in combination with atazanavir (see section "Special precautions for use").

Methotrexate

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

Clopidogrel

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

Food

Studies have shown that consuming a low-fat meal does not affect the absorption of sodium rabeprazole. Taking sodium rabeprazole with a fatty meal may delay absorption by 4 hours or more, but maximum concentration and overall absorption levels 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 not recommended for concomitant use with rabeprazole

Medicinal product	Signs of interaction	Mechanism and risk factors
Atazanavir sulfate	The therapeutic effect of atazanavir may be reduced	Due to its antisecretory effect, rabeprazole increases gastric pH, reduces the solubility of atazanavir sulfate, and thereby decreases its plasma concentration

Medicinal products that should be prescribed with caution

Medicinal product	Signs of interaction	Mechanism and risk factors
Digoxin, methyldigoxin	Blood concentration of digoxin and methyldigoxin may increase	Due to its antisecretory effect, rabeprazole may increase gastric pH, leading to enhanced absorption of digoxin and methyldigoxin
Itraconazole, gefitinib	Blood concentration of itraconazole and gefitinib may decrease	Due to its antisecretory effect, rabeprazole may increase gastric pH, resulting in inhibited absorption of itraconazole and gefitinib
Antacids containing aluminium hydroxide / magnesium hydroxide	Concentration of rabeprazole may decrease when used concomitantly with antacids

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 (PPIs) or substituted benzimidazoles cannot be excluded.

Use in elderly patients

Rabeprozole 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 should be strictly followed.

Symptomatic improvement with sodium rabeprozole therapy does not exclude the presence of a malignant tumor of the stomach or esophagus. Therefore, malignancy should be ruled out before initiating treatment with Rabezol.

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

Patients should be informed that Rabezol tablets must not be chewed or crushed but should be swallowed whole.

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

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

Abnormalities in liver enzymes have been observed both during clinical trials and in the post-marketing period. In most cases, no other etiology was identified, the abnormalities were uncomplicated, and they 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 reactions was observed with rabeprozole tablets compared to the control group of similar age and gender. Physicians should exercise caution when prescribing Rabezol in the early stages of therapy to patients with severe hepatic impairment, as there are no clinical data on the use of rabeprozole in this patient group.

Concomitant use of atazanavir and rabeprozole is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Treatment with PPIs, including rabeprozole, may increase the risk of gastrointestinal infections such as Salmonella, Campylobacter, and Clostridium difficile (see section "Pharmacodynamics").

PPIs, 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 patients with other existing risk factors. Observational studies suggest that PPIs may increase the overall risk of fractures by 10–40%. The risk may also be elevated due to other factors. Patients at risk of osteoporosis should receive appropriate treatment and take vitamin D and calcium supplements.

Cases of severe hypomagnesemia have been reported in patients taking PPIs, such as rabeprozole, for at least 3 months, in most cases for 1 year. Possible serious manifestations of hypomagnesemia include weakness, tetany, delirium, seizures, dizziness, and ventricular arrhythmia, although they may occur unexpectedly and remain undetected. In most patients, hypomagnesemia resolved after discontinuation of PPI therapy and with magnesium replacement therapy.

In patients undergoing long-term treatment or receiving concomitant PPIs with digoxin or other agents that may lead to hypomagnesemia (e.g., diuretics), physicians should monitor serum magnesium levels before starting treatment and periodically during therapy.

Concomitant use of rabeprozole with methotrexate

Published data suggest that concomitant use of PPIs and methotrexate (particularly at high doses) may increase serum levels of methotrexate and/or its metabolites, potentially leading to methotrexate-related toxicity. When high-dose methotrexate is required, discontinuation of PPI therapy should be considered.

Effect on vitamin B12 absorption

Sodium rabeprozole, like all medicinal products that inhibit 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

PPI use has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions develop, particularly in sun-exposed areas and accompanied by arthralgia, patients should seek immediate medical attention, and physicians should consider discontinuing treatment with Rabezol. Previous treatment with PPIs may increase the risk of developing subacute cutaneous lupus erythematosus upon subsequent use of other PPIs.

Renal function impairment

Acute tubulointerstitial nephritis (ATIN) 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 ATIN is suspected, rabeprozole should be discontinued immediately, and appropriate treatment should be initiated without delay.

Effect on laboratory test results

Elevated levels of chromogranin A (CgA) may interfere with the detection of neuroendocrine tumors. To avoid this interference, treatment with Rabezol 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 initial measurement, the test should be repeated 14 days after discontinuation of PPI therapy.

Use during pregnancy or breastfeeding

Pregnancy

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

Reproductive toxicity studies in animals did not reveal evidence of impaired fertility or fetal harm associated with rabeprozole administration, although slight placental transfer was observed in rats.

The use of Rabezol during pregnancy is contraindicated.

Breastfeeding period

It is unknown whether sodium rabeprozole passes into human breast milk. Sodium rabeprozole is excreted in the milk of rats. Adequate studies in breastfeeding women have not been conducted.

Rabebzol should not be administered to women who are breastfeeding.

Ability to affect reaction speed when driving or operating machinery

Based on the pharmacodynamics of sodium rabeprozole and its known adverse effect profile, Rabezol is not expected to negatively affect the ability to drive a car or operate potentially hazardous machinery. However, if drowsiness occurs, patients are advised to avoid driving and operating machinery.

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 peptic duodenal ulcer, healing occurs within 4 weeks. However, some patients may require additional treatment with Rabezol for up to 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 Rabezol for up to another 6 weeks.

Erosive or ulcerative GERD: The recommended dose for these conditions is 20 mg once daily for 4–8 weeks.

Long-term treatment of GERD (maintenance therapy for GERD): For long-term treatment, maintenance doses of rabeprazole 10 mg* or 20 mg once daily may be used, depending on the patient's clinical response.

Symptomatic treatment of moderate to very severe GERD: For patients without esophagitis, rabeprazole should be administered at a dose of 10 mg* once daily. If symptoms persist after 4 weeks of treatment, further patient evaluation is recommended. Once symptoms resolve, ongoing symptom control can be achieved using an "on-demand" regimen: administer 10 mg* once daily as needed.

Zollinger–Ellison syndrome:

The recommended initial dose is 60 mg once daily. The dose may be gradually increased up to 120 mg daily if clinically necessary. A single daily dose of up to 100 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. The duration of treatment depends on clinical necessity.

H. pylori eradication: For patients with H. pylori, the drug should be used in combination with eradication therapy. A 7-day regimen is recommended: rabeprazole 20 mg twice daily + clarithromycin 500 mg twice daily and amoxicillin 1 g twice daily.

For indications requiring once-daily dosing, Rabezol tablets should be taken in the morning before meals. Although administration in the morning or food intake has not demonstrated any impact on the effect of sodium rabeprazole, this dosing schedule is considered more favorable for treatment.

Renal and hepatic impairment. Patients with renal or hepatic impairment do not require dose adjustment of the medicinal product Rabezol. For information on use in patients with severe hepatic impairment, see section "Special precautions for use."

Administration method.

Patients should be instructed not to chew or crush Rabezol tablets; they should be swallowed whole.

* Use rabeprazole preparations at the appropriate dosage strength.

Children.

Rabezol is not recommended for use in children, as there is currently no experience with its use in this age group.

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 effect profile, and resolve without requiring further medical intervention. There is no specific antidote for rabeprazole. Sodium rabeprazole is highly protein-bound and is not removed by dialysis. In case of overdose, symptomatic and supportive treatment should be administered.

Adverse Reactions

The most commonly reported adverse reactions during controlled clinical studies were headache, diarrhoea, abdominal pain, asthenia, flatulence, rash, and dry mouth. Adverse reactions observed during clinical studies were mostly mild, moderate and transient.

The following adverse reactions have been reported during clinical studies 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).

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 oedema.

Respiratory, thoracic and mediastinal disorders:

common – cough, pharyngitis, rhinitis;

uncommon – bronchitis, sinusitis.

Gastrointestinal disorders:

common – diarrhoea, vomiting, nausea, abdominal pain, constipation, flatulence, benign fundic gland polyp;

uncommon – dyspepsia, dry mouth, eructation;

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, increased sweating, bullous reactions²;

very rare – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme;

frequency not known – subacute cutaneous lupus erythematosus⁴.

Musculoskeletal and connective tissue disorders:

common – non-specific 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 (with possible progression to renal failure).

Reproductive system disorders:

frequency not known – gynaecomastia.

General disorders and administration site conditions:

common – asthenia, influenza-like syndrome;

uncommon – chest pain, chills, pyrexia.

Investigations:

uncommon – increased liver enzymes³;

rare – weight gain.

¹ Including facial swelling, hypotension and dyspnoea.

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 liver cirrhosis. Caution is advised when prescribing Rabesol to patients with severe hepatic impairment (see section "Special Warnings and Precautions for Use").

⁴ See section "Special Warnings and Precautions for Use".

Adverse reactions of clinical significance:

• shock and anaphylactic reactions;
• pancytopenia, leukopenia, agranulocytosis, and haemolytic anaemia;
• fulminant hepatitis, hepatic dysfunction, jaundice;
• interstitial pneumonia;
• toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme;
• acute renal failure, interstitial nephritis;
• hyponatremia;
• rhabdomyolysis.

Adverse reactions of clinical significance associated with PPIs:

• visual disturbances;
• angioneurotic oedema, bronchospasm;
• confusion.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in a place protected from light and moisture at a temperature not exceeding 30 °C. Keep out of the reach and sight of children.

Packaging.

14 tablets per blister, 2 blisters per carton.

Prescription category. Prescription only.

Manufacturer.

Laboratorios Liconsa, S.A.

Manufacturer's address and place of business.

Avda. Miralcampo, 7, Pol. Ind. Miralcampo, Azuqueca de Henares, Guadalajara, 19200, Spain.