Pariet enteric-coated tablets 20 mg No. 14

Instructions for Pariet enteric-coated tablets 20 mg No. 14

Composition

active ingredient: rabeprazole sodium;

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

excipients: mannitol (E 421); magnesium oxide; low-substituted hydroxypropyl cellulose; hydroxypropyl cellulose; magnesium stearate; ethyl cellulose; 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).

Dosage form

Enteric-coated tablets.

Main physicochemical properties:

10 mg tablets: pink biconvex, film-coated tablets, marked with “Е” and “241” in black on one side;

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

Pharmacotherapeutic group

Drugs affecting the digestive tract and metabolism. Drugs for the treatment of diseases associated with acidity disorders. Antiulcer drugs and drugs for the treatment of gastroesophageal reflux. Proton pump inhibitors. Rabeprazole. ATC code A02B C04.

Pharmacological properties

Pharmacodynamics.

Mechanism of action. Rabeprazole sodium belongs to the class of antisecretory compounds, substituted benzimidazoles, does not have anticholinergic properties and is not an antagonist of histamine H2 receptors, but inhibits gastric acid secretion by specific inhibition of the enzyme H+/K+-ATPase on the secretory surface of the gastric parietal cells (acid or proton pump). The effect is dose-dependent and leads to inhibition of both basal and stimulated acid secretion, regardless of the stimulus. Animal studies have shown that after administration, rabeprazole sodium rapidly disappears from both plasma and gastric mucosa. Rabeprazole sodium has weak alkaline properties, is rapidly absorbed and concentrated in parietal cells at all dosages. Rabeprazole sodium is converted to the active sulfonamide form by protonation and, thus, reacts with available cysteine residues of the proton pump.

Antisecretory activity. After oral administration of 20 mg of rabeprazole sodium, the antisecretory effect is observed after 1 hour and reaches a maximum after 2-4 hours. Inhibition of basal secretion and food-stimulated acid secretion 23 hours after the first dose of rabeprazole sodium was 69 and 82%, respectively, and the duration of inhibition reached 48 hours. The inhibitory effect of rabeprazole sodium is somewhat enhanced after repeated administration once a day, stable inhibition of secretion is achieved after 3 days. After discontinuation of rabeprazole sodium, secretory activity normalizes within 2-3 days.

Reducing stomach acidity, regardless of any factors, including proton pump inhibitors such as rabeprazole, 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 concentrations. In clinical trials, patients received 10 or 20 mg of rabeprazole sodium once daily for up to 43 months. Serum gastrin concentrations increased during the first 2 to 8 weeks of therapy, reflecting inhibition of acid secretion. Gastrin concentrations returned to baseline levels, usually within 1 to 2 weeks after discontinuation of treatment.

Examination of gastric fundus and antrum biopsies from over 500 patients treated with rabeprazole or comparator for 8 weeks revealed no histological changes in ECL cells, degree of gastritis, increased incidence of atrophic gastritis, intestinal metaplasia or spread of H. pylori infection. Long-term treatment in over 250 patients for 36 months revealed no significant changes in the results of these tests.

Other effects. To date, there are no data on systemic effects on the central nervous system (CNS), cardiovascular and respiratory systems caused by the use of rabeprazole sodium. Oral administration of 20 mg of rabeprazole sodium per day for 2 weeks had no effect on thyroid function, carbohydrate metabolism, or blood concentrations of parathyroid hormone, cortisol, estrogen, testosterone, prolactin, cholecystokinin, secretin, glucagon, follicle-stimulating hormone (FSH), luteinizing hormone (LH), renin, aldosterone and somatotropic hormone.

During treatment with antisecretory drugs, serum gastrin levels increase in response to decreased acid secretion. Chlorogenic acid levels also increase due to decreased gastric acidity. Elevated chlorogenic acid levels may interfere with the results of studies to detect neuroendocrine tumors.

Available published data suggest that proton pump inhibitors should be discontinued two weeks to 5 days before measuring chlorogenic acid levels to allow time for them to return to reference values if they increase during proton pump inhibitor treatment.

Pharmacokinetics.

Absorption. Pariet® is a drug whose active ingredient is rabeprazole sodium, which is available in enteric-coated tablets. This dosage form is necessary because rabeprazole sodium is exposed to gastric acid. Absorption of rabeprazole sodium begins only after the tablet has passed the stomach. Rabeprazole sodium is rapidly absorbed from the intestine. Peak plasma concentrations of rabeprazole are reached approximately 3.5 hours after a 20 mg dose. Peak plasma concentrations (Cmax) and AUC of rabeprazole are linear in the dose range from 10 to 40 mg. Absolute bioavailability after oral administration of 20 mg (compared to intravenous administration) is about 52%, mainly due to first-pass metabolism. In addition, bioavailability does not increase with repeated administration of rabeprazole sodium. In healthy volunteers, the plasma elimination half-life was approximately 1 hour (range 0.7 to 1.5 hours) and the total clearance was estimated to be 283±98 ml/min. No clinically significant food interaction was observed. Neither the type of food nor the time of day of administration affected the absorption of rabeprazole sodium.

Distribution: In humans, the degree of binding of rabeprazole sodium to blood plasma proteins is approximately 97%.

Metabolism and excretion. Like other proton pump inhibitors, rabeprazole is metabolised by the cytochrome P450 (CYP450) hepatic drug metabolism system. In vitro studies with human liver microsomes have shown that rabeprazole sodium is metabolised by CYP450 isoenzymes (CYP2C19 and CYP3A4). At the expected levels in human plasma, rabeprazole neither induces nor inhibits CYP3A4. However, in vitro studies cannot always be extrapolated to in vivo situations; these results indicate that interactions between rabeprazole and cyclosporine are not expected. In humans, the major metabolites present in plasma are the thioester (M1) and the carboxylic acid (M6), while minor metabolites present at low concentrations are the sulfone (M2), the dimethylthioester (M4) and the mercapturic acid conjugate (M5). Only the dimethyl metabolite (M3) has minor antisecretory activity, but it is not present in blood plasma.

After a single dose of 20 mg of 14C-labeled rabeprazole sodium, no unchanged rabeprazole was detected in the urine. Approximately 90% of the dose was eliminated in the urine, mainly as two metabolites: a mercapturic acid conjugate (M5) and a carboxylic acid (M6), as well as two unknown metabolites. The remainder of the dose was recovered in the feces.

Gender: When adjusted for body weight and height, there are no significant differences in the pharmacokinetics of rabeprazole depending on gender.

Renal impairment. In patients with end-stage renal disease undergoing maintenance haemodialysis (creatinine clearance ≤ 5 ml/min/1.73 m2), the disposition of rabeprazole sodium was very similar to that in healthy volunteers. Rabeprazole sodium AUC and Cmax in these patients were approximately 35% lower than in healthy volunteers. The mean half-life was 0.82 hours in healthy volunteers, 0.95 hours in haemodialysis patients and 3.6 hours in post-dialysis patients. The clearance of the drug in patients with renal failure undergoing haemodialysis was approximately twice that in healthy volunteers.

Hepatic impairment. After a single dose of 20 mg rabeprazole sodium in patients with moderate chronic liver disease, the AUC was doubled and the half-life of rabeprazole was 2-3 times longer than in healthy volunteers. However, after daily administration of 20 mg for 7 days, the AUC increased only 1.5-fold and the Cmax value increased 1.2-fold. The half-life in patients with impaired liver function was 12.3 hours, compared with 2.1 hours in healthy volunteers. The pharmacodynamic response (gastric pH measurement) in the two groups of patients was comparable.

Elderly patients. The elimination of rabeprazole sodium is somewhat reduced in elderly patients. After 7 days of rabeprazole sodium at a dose of 20 mg per day in elderly subjects, AUC was approximately twice as high, Cmax increased by 60%, and t1/2 increased by 30% compared to those in young healthy volunteers. However, it should be noted that there is no evidence of accumulation of rabeprazole sodium.

CYP2C19 polymorphism: After 7 days of rabeprazole sodium 20 mg daily, AUC (area under the curve) and T1/2 (half-life) were approximately 1.9 and 1.6 times higher, respectively, in patients who are CYP2C19 poor metabolisers compared to those in extensive metabolisers, while Cmax was only increased by 40%.

Indication

Active peptic ulcer of the duodenum;

erosive or ulcerative gastroesophageal reflux disease (GERD);

for long-term treatment of gastroesophageal reflux disease (maintenance therapy of GERD);

for the symptomatic treatment of moderate to very severe gastroesophageal reflux disease (symptomatic treatment of GERD);

Zollinger-Ellison syndrome;

in combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori (H. pylori) in patients with peptic ulcer of the stomach and duodenum.

Contraindication

Hypersensitivity to rabeprazole sodium or any other ingredient of the drug.

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

Interaction with other medicinal products and other types of interactions

CYP450 system

Rabeprazole sodium is metabolized by the hepatic CYP450 enzyme system, namely CYP2C19 and CYP3A4.

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

Interactions caused by inhibition of gastric acid secretion

Rabeprazole sodium causes a strong and prolonged inhibition of gastric acid secretion. Thus, rabeprazole may interact with drugs whose absorption depends on gastric pH. Concomitant use of rabeprazole sodium and ketoconazole or itraconazole may lead to a decrease in the concentration of the latter in the blood plasma. Therefore, individual patients who use these drugs together with the drug Pariet® should be under the supervision of a physician to determine the need for dose adjustment.

Antacids

During clinical studies, patients simultaneously with Pariet® took antacids as needed; in a special study, no interaction of Pariet® with antacids in liquid dosage forms was observed.

Atazanavir

Co-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 decrease in atazanavir exposure. Absorption of atazanavir is pH dependent. Although not studied, similar results are expected with other proton pump inhibitors. Proton pump inhibitors, including rabeprazole, should not be used in combination with atazanavir (see section 4.4).

Methotrexate

Adverse reaction reports, published data from population pharmacokinetic studies and retrospective analyses suggest that concomitant use of methotrexate and proton pump inhibitors (mainly at high doses) may lead to increased serum levels of methotrexate and/or its metabolite hydroxymethotrexate. Although no formal studies have been performed.

Clopidogrel

Concomitant administration of clopidogrel and rabeprazole in healthy volunteers had no clinically significant effect on the concentrations of the active metabolite of clopidogrel. No dose adjustment is required.

Food

Studies have shown that the consumption of a low-fat meal does not affect the absorption of rabeprazole sodium. Taking rabeprazole sodium with a fatty meal may delay absorption by 4 hours or more, but the maximum concentration and extent of absorption remain unchanged.

Cyclosporine

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

Medicinal products not recommended for concomitant use with Pariet®

Medications that should be prescribed with caution

Application features

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

Pariet® is metabolized exclusively in the liver. Since physiological liver function may decline with age, elderly patients may experience adverse reactions. Therefore, elderly patients should be monitored and recommendations regarding dosage and duration of treatment should be followed.

Symptomatic improvement from treatment with rabeprazole sodium does not exclude the presence of a malignant tumor of the stomach or esophagus, therefore, before prescribing the drug Pariet®, the presence of a malignant tumor should be excluded.

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

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

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

Pariet® is not recommended for use in children, as there is no experience with its use in this category of patients.

Blood abnormalities (thrombocytopenia and neutropenia) have been reported in the post-marketing period. In most cases, no other etiology was found; the blood abnormalities were uncomplicated and resolved after discontinuation of rabeprazole.

Liver enzyme abnormalities have been observed both in clinical trials and in the post-marketing setting. In most cases, no other etiology was found; the abnormalities were uncomplicated and resolved after discontinuation of rabeprazole.

In a special study in patients with mild or moderate hepatic impairment, no significant difference in the frequency of side effects was observed when taking Pariet® tablets compared to that in the control group of the corresponding gender and age. The physician should exercise caution when prescribing Pariet® in the early stages of therapy to patients with severe hepatic impairment, since there are no clinical data on the use of the drug in this group of patients.

The concomitant use of atazanavir and Pariet® is not recommended (see section “Interaction with other medicinal products and other types of interactions”).

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, especially when used at high doses and for long periods (more than 1 year), may increase the risk of hip, wrist, and vertebral fractures, especially in elderly patients or in patients with other risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fractures by 10-40%. The risk may also be increased by other factors. Patients at risk of osteoporosis should receive appropriate treatment and take vitamin D and calcium.

Cases of severe hypomagnesemia have been reported in patients taking proton pump inhibitors such as Pariet® for at least 3 months, in most cases for a year. Serious manifestations of hypomagnesemia, such as weakness, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, are possible, but they may occur unexpectedly and go undetected. In most patients, hypomagnesemia resolved after discontinuation of the proton pump inhibitor and magnesium replacement therapy.

With prolonged treatment or when proton pump inhibitors are used concomitantly with digoxin or drugs that can lead to hypomagnesemia (e.g., diuretics), physicians should monitor patients' blood magnesium levels before initiating and periodically during treatment.

Concomitant use of rabeprazole with methotrexate

Published data suggest that concomitant use of proton pump inhibitors and methotrexate (mainly at high doses) may increase serum levels of methotrexate and/or its metabolite, which may lead to methotrexate-related toxicity. If high doses of methotrexate are required, discontinuation of proton pump inhibitor treatment should be considered.

Effect on vitamin B12 absorption

Rabeprazole sodium, like all drugs that inhibit gastric acid secretion, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be taken into account in patients with reduced body weight or in the presence of risk factors for reduced absorption of vitamin B12 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, especially in sun-exposed areas, occur, accompanied by arthralgia, the patient should seek medical advice immediately and the physician should consider discontinuing Pariet®. Subacute cutaneous lupus erythematosus after previous treatment with a proton pump inhibitor may increase the risk of subacute cutaneous lupus erythematosus with other PPIs.

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

Use during pregnancy or breastfeeding

Pregnancy.

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

Reproductive toxicity studies in rats and rabbits revealed no evidence of impaired fertility or harm to the fetus associated with the use of rabeprazole sodium, although slight placental penetration was observed in rats.

The use of the drug Pariet® during pregnancy is contraindicated.

Breast-feeding.

It is not known whether rabeprazole sodium is excreted in human milk. No adequate studies have been conducted in lactating women. However, rabeprazole sodium is excreted in the milk of rats.

Pariet® should not be prescribed to women during breastfeeding.

Ability to influence reaction speed when driving vehicles or other mechanisms

Given the pharmacodynamics of rabeprazole sodium and its inherent side effect profile, it can be assumed that Pariet® should not adversely affect driving or operating potentially dangerous machinery. However, in case of drowsiness, it is recommended to avoid driving or operating other machinery.

Method of administration and doses

Adults, including elderly patients.

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

In most patients with active duodenal peptic ulcer, the time required for ulcer healing is up to 4 weeks. However, some patients may require an additional 4 weeks of Pariet® to heal. In most patients with active benign gastric ulcer, healing occurs within 6 weeks, but some patients who are refractory to treatment may require an additional 6 weeks of Pariet® to heal their ulcers.

Erosive or ulcerative gastroesophageal reflux disease: the recommended dose for these diseases is 20 mg once daily for 4-8 weeks.

Long-term treatment of gastroesophageal reflux disease (GERD maintenance therapy): For long-term treatment, 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: in patients without esophagitis, Pariet® should be prescribed at a dose of 10 mg once daily. If symptoms persist after 4 weeks of treatment, the patient should be re-evaluated. Once symptoms have resolved, further control of symptoms 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 to 120 mg daily, if clinically necessary. A single dose of up to 100 mg daily may be used. If 120 mg daily is required, the dose should be divided into two doses of 60 mg. The duration of treatment depends on clinical need.

Eradication of H. pylori: In patients with H. pylori, the drug should be used in combination with eradication therapy. It is recommended to administer for 7 days:

Pariet® 20 mg 2 times a day + clarithromycin 500 mg 2 times a day and amoxicillin 1 g 2 times a day.

For indications requiring only once-daily administration, Pariet® tablets should be taken in the morning before meals. Although neither midday administration nor food intake has been shown to affect the action of rabeprazole sodium, this regimen is 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 application.

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

Children.

Pariet® is not recommended for use in children, as there is currently no experience with its use in patients of this age group.

Overdose

Experience with intentional or accidental overdose is limited. The maximum dose studied did not exceed 60 mg rabeprazole sodium 2 times a day or 160 mg rabeprazole sodium 1 time a day. Symptoms that occur with overdose are generally minimal, typical of the profile of known adverse events and resolve without the need for further medical intervention. A specific antidote for Pariet® is unknown. Rabeprazole sodium is highly bound to plasma proteins and is not removed by dialysis. In case of overdose, symptomatic and supportive treatment is necessary.

Side effects

In controlled clinical trials, the most frequently reported adverse reactions were headache, diarrhea, abdominal pain, asthenia, flatulence, rash, and dry mouth. The adverse reactions observed in clinical trials were mostly mild, moderate, and self-limiting.

The adverse reactions listed below have been reported during clinical trials 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), unknown (cannot be estimated from the available data).

Infections and infestations:

often - infections.

Blood and lymphatic system disorders:

rarely - neutropenia, leukopenia, thrombocytopenia, leukocytosis.

On the part of the immune system:

rarely – hypersensitivity1,2.

Metabolism and nutrition:

rarely – anorexia;

unknown – hyponatremia, hypomagnesemia4;

From the psyche:

often – insomnia;

infrequently – nervousness;

rarely – depression;

unknown – confusion of consciousness.

From the nervous system:

often - headache, dizziness;

infrequently - drowsiness.

On the part of the organs of vision:

rarely - visual disturbances.

From the vascular side:

not known – peripheral edema.

On the part of the respiratory system:

often - cough, pharyngitis, rhinitis;

infrequently - bronchitis, sinusitis.

From the digestive tract:

often – diarrhea, vomiting, nausea, abdominal pain, constipation, flatulence, benign fungicidal polyp;

infrequently - dyspepsia, dry mouth, belching;

rarely – gastritis, stomatitis, taste disturbance;

unknown – microscopic colitis.

From the hepatobiliary system:

rarely – hepatitis, jaundice, hepatic encephalopathy3.

Skin and subcutaneous tissue disorders:

uncommon – rash, erythema2;

rarely - itching, sweating, bullous reactions2;

very rarely - erythema multiforme, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome.

unknown – subacute cutaneous lupus erythematosus4.

From the musculoskeletal system:

often – nonspecific pain, back pain;

uncommon – myalgia, leg cramps, arthralgia, fracture of the femoral neck, wrist or spine4.

From the kidneys and urinary system:

infrequently - urinary tract infections;

rarely - interstitial nephritis.

From the reproductive system:

unknown – gynecomastia.

General disorders:

often – asthenia, flu-like syndrome;

uncommon – chest pain, chills, pyrexia.

Laboratory studies:

uncommon – increased liver enzymes3;

rarely - weight gain.

1 Including facial edema, hypotension, and dyspnea.

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

3 In isolated cases, hepatic encephalopathy has been observed in patients with cirrhosis. Caution should be exercised when prescribing Pariet® to patients with severe hepatic impairment (see section 4.4).

4 See the section "Features of application".

Adverse reactions of clinical significance:

shock and anaphylactic reactions;

pancytopenia, leukopenia, agranulocytosis and hemolytic anemia;

fulminant form of hepatitis, liver dysfunction, jaundice;

interstitial pneumonia;

toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme;

acute renal failure, interstitial nephritis;

hyponatremia;

rhabdomyolysis.

Adverse reactions that are clinically significant and specific to proton pump inhibitors:

visual impairment;

angioedema, bronchial spasm;

confusion of consciousness.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product has been authorised is important. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Expiration date

2 years.

Storage conditions

Store in 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, 1 blister in a cardboard box.

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

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

Vacation category

According to the recipe.

Producer

Responsible for the release of the series.

Cilag AG.

Lusomedicamenta Sociedade Tecnica Farmaceutica, SA/Lusomedicamenta Sociedade Tecnica Farmaceutica, SA

Address

Hochstrasse 201, 8200 Schaffhausen, Switzerland.

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