Pariet®

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

Composition:

Active substance: sodium rabeprazole;

1 tablet contains 10 or 20 mg of sodium rabeprazole, equivalent to 9.42 or 18.85 mg of rabeprazole;

Excipients: mannite (E 421); magnesium oxide; low-substituted hydroxypropylcellulose; hydroxypropylcellulose; magnesium stearate; ethylcellulose; hypromellose phthalate; diacetylated monoglyceride; talc; titanium dioxide (E 171); yellow iron oxide (E 172) (for 20 mg tablets); red iron oxide (E 172) (for 10 mg tablets); carnauba wax; Edible Ink Gray F6 (for 10 mg tablets); Edible Ink Red A1 (for 20 mg tablets).

Medicinal form: Enteric-coated tablets.

Main physicochemical properties:

10 mg tablets: pink, biconvex, film-coated tablets, marked with "E" and "241" in black color on one side;

20 mg tablets: light-yellow, biconvex, film-coated tablets, marked with "E" and "243" in red color on one side.

Pharmacotherapeutic group: Drugs affecting the digestive tract and metabolism. Drugs used in disorders related to acid secretion. Anti-ulcer agents and drugs for treatment of gastroesophageal reflux disease. Proton pump inhibitors. Rabeprazole. ATC code A02BC04.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action.
Sodium rabeprozole belongs to the class of antisecretory compounds substituted benzimidazoles. It has no anticholinergic properties and is not a histamine H₂-receptor antagonist. However, it inhibits gastric acid secretion by specifically inhibiting the H⁺/K⁺-ATPase enzyme located on the secretory surface of gastric parietal cells (the 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 rabeprozole rapidly disappears from both plasma and gastric mucosa. Sodium rabeprozole has weakly basic properties, is rapidly absorbed in all doses, and accumulates in parietal cells. Sodium rabeprozole 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 sodium rabeprozole, antisecretory effects are observed within 1 hour and reach maximum within 2–4 hours. Inhibition of basal acid secretion and food-stimulated acid secretion 23 hours after the first dose was 69% and 82%, respectively, with suppression lasting up to 48 hours. The inhibitory effect of sodium rabeprozole slightly increases with repeated once-daily administration, with stable suppression of acid secretion achieved within 3 days. After discontinuation of sodium rabeprozole, secretory activity returns to normal within 2–3 days.

Reduction of gastric acidity, independent of any factors, 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 fundus and antral regions of the stomach in more than 500 patients who received rabeprozole 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 more than 250 patients for 36 months, no significant changes were observed in the results of these analyses.

Other Effects.
Currently, there are no data on systemic effects on the central nervous system (CNS), cardiovascular, or respiratory systems caused by sodium rabeprozole. Oral administration of 20 mg sodium rabeprozole 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 rabeprozole and amoxicillin. Rabeprozole has no negative effect on plasma levels of amoxicillin and clarithromycin when co-administered for H. pylori eradication in the upper gastrointestinal tract.

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to decreased gastric acidity, chlorogenic acid levels rise. Elevated chlorogenic acid levels may affect test results for detecting neuroendocrine tumors.

Available published data indicate that proton pump inhibitors should be discontinued 2 weeks to 5 days before measuring chlorogenic acid levels to allow levels to return to reference values if elevated during proton pump inhibitor therapy.

Pharmacokinetics

Absorption.
Pariet® is a drug containing sodium rabeprozole as the active ingredient, formulated as enteric-coated tablets. This dosage form is necessary because sodium rabeprozole is susceptible to degradation by 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 AUC of rabeprozole 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 rabeprozole. In healthy volunteers, the plasma half-life is approximately 1 hour (ranging from 0.7 to 1.5 hours), and total clearance is estimated at 283 ± 98 mL/min. No clinically significant interaction with food was observed. Neither type of food nor time of day of administration affects the absorption of sodium rabeprozole.

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

Metabolism and Excretion.
Like other proton pump inhibitors, rabeprozole is metabolized by the cytochrome P450 (CYP450) hepatic drug metabolism system. In vitro studies with human liver microsomes have shown that sodium rabeprozole is metabolized by CYP450 isoenzymes (CYP2C19 and CYP3A4). At expected human plasma concentrations, rabeprozole does not induce or inhibit CYP3A4. However, since 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). 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 rabeprozole, unchanged rabeprozole 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 recovered in feces.

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

Renal Impairment.
In patients with end-stage chronic renal failure on 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 in these patients were approximately 35% lower compared to healthy volunteers. Mean 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 hemodialysis 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 moderate chronic liver disease, AUC was doubled, and a 2–3-fold increase in half-life was observed 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 half-life 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 rabeprozole 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, it should be noted that there are no signs of sodium rabeprozole accumulation.

CYP2C19 Polymorphism.
After 7 days of 20 mg daily sodium rabeprozole administration, patients with slow CYP2C19 metabolism had AUC and t₁/₂ values 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);
• for long-term treatment of gastroesophageal reflux disease (maintenance therapy for GERD);
• for symptomatic treatment of moderate to very severe gastroesophageal reflux disease (symptomatic therapy for GERD);
• Zollinger–Ellison syndrome;
• in combination with appropriate antibacterial therapeutic regimens for eradication of Helicobacter pylori (H. pylori) in patients with gastric and duodenal peptic ulcers.

Contraindications.

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

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

Interaction with other medicinal products and other types 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 due to inhibition of gastric acid secretion

Sodium rabeprazole causes strong and prolonged inhibition of gastric acid secretion. Therefore, rabeprazole may interact with drugs 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 drugs together with the medicinal product Pariet® should be under medical supervision to determine the need for dose adjustment.

Antacids

During clinical trials, patients took antacids as needed concomitantly with Pariet®; in a specific study, no interaction between Pariet® 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 studies have not 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").

Methotrexate

Case reports, 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.

Clopidogrel

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

Food

Studies have shown that consumption 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, but 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 not recommended for concomitant use with Pariet®

Medicinal products that should be prescribed with caution

Special precautions.

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

Use in elderly patients

Pariet® is metabolized exclusively in the liver. Since physiological liver 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 with sodium rabeprazole therapy does not exclude the presence of a malignant tumor of the stomach or esophagus; therefore, the presence of a malignant tumor should be ruled out before initiating treatment with Pariet®.

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 concomitantly with other proton pump inhibitors or substituted benzimidazoles cannot be excluded.

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

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

During the post-marketing period, blood pathology (thrombocytopenia and neutropenia) has been reported. In most cases, no other etiology was identified; hematological changes were uncomplicated and resolved after discontinuation of rabeprazole.

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; abnormalities were uncomplicated and resolved after discontinuation of rabeprazole.

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

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

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

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 risk of fractures by 10–40%. Risk may also be increased 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 proton pump inhibitors such as Pariet® 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 they 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 concomitant use of proton pump inhibitors with digoxin or agents that may lead to hypomagnesemia (e.g., diuretics), physicians should monitor serum magnesium levels in patients before starting treatment and periodically during therapy.

Concomitant use of rabeprazole with methotrexate

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

Effect on vitamin B12 absorption

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

Subacute cutaneous lupus erythematosus

The use of proton pump inhibitors 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 Pariet® therapy. Previous treatment with a proton pump inhibitor may increase the risk of developing subacute cutaneous lupus erythematosus upon subsequent use of other PPIs.

Effect on laboratory test results

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

Use during pregnancy or breastfeeding.

Pregnancy.

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

Reproductive toxicity studies in rats and rabbits did not show evidence of impaired fertility or fetal harm associated with sodium rabeprazole administration, although slight placental transfer was observed in rats.

The use of Pariet® during pregnancy is contraindicated.

Breastfeeding.

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

Pariet® 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 rabeprazole and its known adverse effect profile, Pariet® is not expected to negatively affect the ability to drive a car or operate potentially hazardous machinery. However, if drowsiness occurs, patients should avoid driving and operating machinery.

Method of Administration and Dosage

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 Pariet® 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 therapy with Pariet® 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 management, maintenance doses of Pariet® 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: patients without esophagitis should be treated with Pariet® 10 mg once daily. If symptoms do not resolve after 4 weeks of treatment, further patient evaluation is recommended. Once symptoms resolve, further symptom control can be achieved using an "on-demand" regimen: 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: in patients with H. pylori, the drug should be used in combination with eradication therapy. A 7-day regimen is recommended:

Pariet® 20 mg twice daily + clarithromycin 500 mg twice daily and amoxicillin 1 g twice daily.

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

Renal and hepatic impairment. Patients with renal or hepatic impairment do not require dose adjustment of Pariet®. For information on the use of Pariet® in patients with severe hepatic impairment, see section "Special Warnings and Precautions for Use".

Method of administration.

Patients should be instructed that Pariet® tablets must not be chewed or crushed and should be swallowed whole.

Children.

Pariet® 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 highest 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, typical of the known adverse effect profile, and resolve without the need for further medical intervention. There is no specific antidote for Pariet®. Sodium rabeprazole is highly protein-bound and is not dialyzable. In case of overdose, symptomatic and supportive treatment should be administered.

Adverse Reactions

During controlled clinical studies, the most commonly reported adverse reactions were headache, diarrhea, abdominal pain, asthenia, flatulence, rash, and dry mouth. Adverse effects observed during clinical studies were generally mild, moderate, and transient.

The adverse reactions listed below have been reported during clinical studies and in the post-marketing period.

Frequency is defined as: common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (< 1/10000), 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;

not known – hyponatremia, hypomagnesemia⁴.

Psychiatric disorders:

common – insomnia;

uncommon – nervousness;

rare – depression;

not known – confusion.

Nervous system disorders:

common – headache, dizziness;

uncommon – somnolence.

Eye disorders:

rare – visual disturbances.

Vascular disorders:

not known – peripheral edema.

Respiratory, thoracic and mediastinal 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;

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 – non-specific pain, back pain;

uncommon – myalgia, leg cramps, arthralgia, fracture of hip, wrist or spine⁴.

Renal and urinary disorders:

uncommon – urinary tract infections;

rare – interstitial nephritis.

Reproductive system and breast disorders:

not known – gynecomastia.

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 Includes 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 liver cirrhosis. Caution is advised when prescribing Pariet® 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 hemolytic anemia;
• 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 proton pump inhibitors:

• Visual disturbances;
• Angioedema, bronchospasm;
• Confusion.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product 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: 2 years.

Storage conditions:

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

Packaging:

10 mg tablets: 7 or 14 tablets in a blister pack, 1 blister pack in a cardboard box.

20 mg tablets: 7 tablets in a blister pack, 1 blister pack in a cardboard box;

14 tablets in a blister pack, 1 or 2 blister packs in a cardboard box.

Prescription status: Prescription only.

Manufacturer

Responsible for batch release:

Siegfried AG / Cilag AG

Lusomedicamenta Sociedade Técnica Farmacêutica, S.A. / Lusomedicamenta Sociedade Tecnica Farmaceutica, S.A.

Manufacturer's address and place of business:

Hochstrasse 201, 8200 Schaffhausen, Switzerland

Estrada Consiglieri Pedroso, 66, 69 - B, Queluz de Baixo, 2730-055 Barcarena, Portugal