Pariet, 10 mg 14 pc

Pharmacodynamics

A gastric gland secretion reducing agent – proton pump inhibitor.

The mechanism of action

Rabeprazole sodium belongs to the class of antisecretory agents, benzimidazole derivatives. Rabeprazole sodium inhibits gastric juice secretion by specifically inhibiting H⁺/K⁺ ATPase on the secretory surface of gastric parietal cells. H⁺/K⁺ ATPase is a protein complex that functions as a proton pump, thus rabeprazole sodium is a proton pump inhibitor in the stomach and blocks the final stage of acid production.

This effect is dose-dependent and results in suppression of both basal and stimulated acid secretion regardless of the stimulus. Rabeprazole sodium has no anticholinergic properties.

Antisecretory effects

After oral administration of 20 mg of rabeprazole sodium, the antisecretory effect develops within one hour. Inhibition of basal and stimulated acid secretion 23 h after the first dose of rabeprazole sodium is 69% and 82%, respectively, and continues up to 48 h. This duration of pharmacodynamic action is much longer than that predicted by T_1/2 (approximately one hour).

This effect may be explained by the prolonged binding of the drug substance to the H⁺/K⁺ ATPase of the gastric parietal cells. The magnitude of the inhibitory effect of rabeprazole sodium on acid secretion reaches a plateau after three days of taking rabeprazole sodium. When discontinued, secretory activity is restored within 1-2 days.

The effect on plasma gastrin levels

In clinical studies, patients were treated with 10 or 20 mg of rabeprazole sodium daily for a treatment duration of up to 43 months. Plasma gastrin levels were elevated for the first 2 to 8 weeks, reflecting an inhibitory effect on acid secretion. Gastrin concentrations returned to baseline levels usually within 1 to 2 weeks after discontinuation of treatment.

The effect on enterochromaffin-like cells

. In a study of human gastric biopsy specimens from the antrum and gastric fundus of 500 patients treated with rabeprazole sodium or a comparison drug for 8 weeks, no consistent changes were found in the morphological structure of enterochromaffin-like cells, the severity of gastritis, the frequency of atrophic gastritis, intestinal metaplasia, or the spread of Helicobacter pylori infection.

In a study involving more than 400 patients receiving rabeprazole sodium (10 mg/day or 20 mg/day) for up to 1 year, the incidence of hyperplasia was low and comparable to that of omeprazole (20 mg/kg). No cases of adenomatous changes or carcinoid tumors were reported in rats.

Systemic effects of rabeprazole sodium on the central nervous system, cardiovascular or respiratory systems have not been found at this time. Rabeprazole sodium has been shown to have no effect on thyroid function, carbohydrate metabolism, blood levels of parathyroid hormone, and levels of cortisol, estrogen, testosterone, prolactin, glucagon, follicle stimulating hormone (FSH), luteinizing hormone (LH), renin, aldosterone and somatotropic hormone when taken orally in a dose of 20 mg for 2 weeks.

Pharmacokinetics

Intake

Rabeprazole is rapidly absorbed from the gut, and its peak plasma concentrations are reached approximately 3.5 h after a dose of 20 mg. Changes in peak plasma concentrations (C_max) and values of area under the curve “concentration-time” (AUC) of rabeprazole are linear in the dose range from 10 to 40 mg.

The absolute bioavailability after oral administration of 20 mg (compared to intravenous administration) is approximately 52%. In addition, bioavailability does not change with repeated administration of rabeprazole. In healthy volunteers, the T_1/2 period from plasma is about 1 h (varying from 0.7 to 1.5 h) and total clearance is 3.8 ml/min/kg.

In patients with chronic liver damage, the AUC is doubled compared to healthy volunteers, indicating decreased first-pass metabolism, and the T_1/2 from plasma is increased 2 to 3 times. Neither the time of intake of the drug during the day, nor antacids affect the absorption of rabeprazole. Taking the drug with fatty food slows down absorption of rabeprazole by 4 hours or more, but neither C_max nor the degree of absorption is changed.

Distribution

In humans, the degree of binding of rabeprazole to plasma proteins is about 97%.

Metabolism and excretion

In healthy subjects

After a single oral dose of 20 mg of 14C-labeled rabeprazole sodium, no unchanged drug was found in the urine. About 90% of rabeprazole is excreted in the urine mainly as two metabolites: mercapturic acid conjugate (M5) and carboxylic acid (M6), and also in the form of two unknown metabolites identified in the toxicological analysis. The remainder of rabeprazole sodium taken is excreted in the feces.

The total excretion is 99.8%. These data indicate a small excretion of metabolites of sodium rabeprazole with bile. The main metabolite is thioether (M1). The only active metabolite is desmethyl (M3), but it was observed in low concentration only in one study participant after administration of 80 mg of rabeprazole.

Terminal renal failure

In patients with stable, terminal renal failure who require maintenance hemodialysis (creatinine clearance < 5ml/min/1.73m²), excretion of rabeprazole sodium is similar to that of healthy volunteers. The AUC and C_max in these patients were approximately 35% lower than in healthy volunteers. The mean T_1/2 of rabeprazole was 0.82 h in healthy volunteers, 0.95 h in patients during hemodialysis, and 3.6 h after hemodialysis. Clearance of the drug in patients with kidney disease requiring hemodialysis was approximately twice as high as in healthy volunteers.

Chronic compensated cirrhosis

Patients with chronic compensated cirrhosis tolerate rabeprazole sodium at a dose of 20 mg once daily, although AUC is doubled and C_max is increased by 50% compared to healthy volunteers of the respective sex. Elderly patients The elimination of rabeprazole is somewhat delayed in elderly patients.

After 7 days of taking rabeprazole at 20 mg daily, the AUC was approximately twice as high and C_max was increased by 60% compared to young healthy volunteers. However, no evidence of rabeprazole cumulation was observed.

CYP2C19 polymorphism

In patients with delayed CYP2C19 metabolism, after 7 days of rabeprazole at a dose of 20 mg daily, the AUC increased 1.9-fold, and C_max was increased by 60%.sub>max 1.6-fold compared to the same parameters in “fast metabolizers,” while C_max is increased by 40%.

Indications

Symptoms of dyspepsia associated with increased acidity of gastric juice, incl. symptoms of gastroesophageal reflux disease (heartburn, sour belching).

Pharmacological effect

Pharmacodynamics

A remedy that ­reduces­ secretion of ­glands ­stomach ­–­ proton­ pump ­inhibitor.

Mechanism of action

Rabeprazole sodium belongs to the class of antisecretory substances, benzimidazole derivatives. Rabeprazole sodium suppresses gastric acid secretion by specifically inhibiting H+/K+ ATPase on the secretory surface of gastric parietal cells. H+/K+ ATPase is a protein complex that functions as a proton pump, thus rabeprazole sodium is an inhibitor of the proton pump in the stomach and blocks the final stage of acid production.

This effect is dose-dependent and leads to suppression of both basal and stimulated acid secretion, regardless of the stimulus. Rabeprazole sodium does not have anticholinergic properties.

Antisecretory action

After oral administration of 20 mg of rabeprazole sodium, the antisecretory effect develops within an hour. Inhibition of basal and stimulated acid secretion 23 hours after taking the first dose of rabeprazole sodium is 69% and 82%, respectively, and lasts up to 48 hours. This duration of pharmacodynamic action far exceeds that predicted by T1/2 (approximately one hour).

This effect can be explained by prolonged binding of the drug to the H+/K+ ATPase of gastric parietal cells. The magnitude of the inhibitory effect of rabeprazole sodium on acid secretion reaches a plateau after three days of taking rabeprazole sodium. When you stop taking it, secretory activity is restored within 1-2 days.

Effect on plasma gastrin levels

In clinical studies, patients took 10 or 20 mg of rabeprazole sodium daily for treatment durations of up to 43 months. Plasma gastrin levels were elevated in the first 2–8 weeks, reflecting an inhibitory effect on acid secretion. Gastrin concentrations returned to baseline levels usually within 1-2 weeks after cessation of treatment.

Effect on enterochromaffin-like cells

In a study of human gastric biopsy specimens from the antrum and fundus of 500 patients treated with rabeprazole sodium or a comparator for 8 weeks, no consistent changes were found in the morphological structure of enterochromaffin-like cells, the severity of gastritis, the incidence of atrophic gastritis, intestinal metaplasia, or the prevalence of Helicobacter pylori infection.

In a study of more than 400 patients treated with rabeprazole sodium (10 mg/day or 20 mg/day) for up to 1 year, the incidence of hyperplasia was low and comparable to that of omeprazole (20 mg/kg). There have been no reported cases of adenomatous changes or carcinoid tumors observed in rats.

Other effects

Systemic effects of rabeprazole sodium on the central nervous system, cardiovascular or respiratory systems have not currently been detected. It has been shown that rabeprazole sodium, when taken orally at a dose of 20 mg for 2 weeks, has no effect on thyroid function, carbohydrate metabolism, the level of parathyroid hormone in the blood, as well as on the levels of cortisol, estrogens, testosterone, prolactin, glucagon, follicle-stimulating hormone (FSH), luteinizing hormone (LH), renin, aldosterone and somatotropic hormone.

Pharmacokinetics

Suction

Rabeprazole is rapidly absorbed from the intestine and peak plasma concentrations are achieved approximately 3.5 hours after a 20 mg dose. Changes in peak plasma concentrations (Cmax) and area under the concentration-time curve (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 approximately 52%. In addition, bioavailability does not change with repeated dosing of rabeprazole. In healthy volunteers, the plasma T1/2 period is about 1 hour (ranging from 0.7 to 1.5 hours), and the total clearance is 3.8 ml/min/kg.

In patients with chronic liver damage, AUC is doubled compared to healthy volunteers, indicating a decrease in first-pass metabolism, and T1/2 from plasma is increased by 2-3 times. Neither the time of taking the drug during the day nor antacids affect the absorption of rabeprazole. Taking the drug with fatty foods slows down the absorption of rabeprazole by 4 hours or more, but neither Cmax nor the degree of absorption changes.

Distribution

In humans, the degree of binding of rabeprazole to plasma proteins is about 97%.

Metabolism and excretion

In healthy people

After taking a single oral dose of 20 mg of 14C-labeled rabeprazole sodium, no unchanged drug was found in the urine. About 90% of rabeprazole is excreted in the urine mainly in the form of two metabolites: a conjugate of mercapturic acid (M5) and carboxylic acid (M6), as well as in the form of two unknown metabolites identified during toxicological analysis. The remainder of the rabeprazole sodium taken is excreted in the feces.

The total elimination is 99.8%. These data indicate a small excretion of rabeprazole sodium metabolites in bile. The main metabolite is thioester (M1). The only active metabolite is desmethyl (M3), but this was observed at low concentrations in only one study participant after taking 80 mg rabeprazole.

End stage renal failure

In patients with stable end-stage renal disease who require maintenance hemodialysis (creatinine clearance <5 ml/min/1.73 m2), the elimination of rabeprazole sodium is similar to that of healthy volunteers. AUC and Cmax in these patients were approximately 35% lower than in healthy volunteers. On average, T1/2 of rabeprazole was 0.82 hours in healthy volunteers, 0.95 hours in patients during hemodialysis and 3.6 hours after hemodialysis. Clearance of the drug in patients with kidney disease requiring hemodialysis was approximately twice as high as in healthy volunteers.

Chronic compensated cirrhosis

Patients with chronic compensated liver cirrhosis tolerate rabeprazole sodium 20 mg once daily, although AUC is doubled and Cmax is increased by 50% compared to sex-matched healthy volunteers. Elderly patients In elderly patients, the elimination of rabeprazole is somewhat slower.

After 7 days of rabeprazole 20 mg daily in elderly subjects, AUC was approximately twice as high and Cmax was increased by 60% compared to young healthy volunteers. However, there were no signs of rabeprazole accumulation.

CYP2C19 polymorphism

In patients with slow metabolism of CYP2C19, after 7 days of taking rabeprazole at a dose of 20 mg per day, AUC increases by 1.9 times and Cmax by 1.6 times compared with the same parameters in “rapid metabolizers,” while Cmax increases by 40%.

Special instructions

The patient’s response to therapy with rabeprazole sodium does not exclude the presence of malignant neoplasms in the stomach.

Pariet tablets should not be chewed or crushed. The tablets should be swallowed whole. It has been established that neither time of day nor food intake affects the activity of rabeprazole sodium.

In a special study in patients with mild or moderate liver dysfunction, no significant difference was found in the frequency of side effects of the drug Pariet from that of healthy individuals matched by gender and age, but despite this, caution is recommended when first prescribing the drug Pariet to patients with severe liver dysfunction. The AUC of rabeprazole sodium in patients with severe hepatic impairment is approximately two times higher than in healthy patients.

For patients with impaired renal or liver function, no dose adjustment of Pariet is required.

Hypomagnesemia

Rare cases of symptomatic or asymptomatic hypomagnesemia have been reported during treatment with proton pump inhibitors (PPIs) for at least 3 months. In most cases, these reports were received one year after therapy. Serious adverse events included tetany, arrhythmia, and seizures. Most patients required treatment for hypomagnesemia, including magnesium replacement and discontinuation of proton pump inhibitor therapy. In patients who will be receiving long-term treatment or who are taking PPIs with drugs such as digoxin or drugs that can cause hypomagnesemia (eg, diuretics), health care providers should monitor magnesium concentrations before starting treatment with proton pump inhibitors and during treatment.

Patients should not take other acid-reducing agents, such as H2 blockers or PPIs, at the same time as Pariet.

Bone fractures

Observational studies suggest that PPI therapy may increase the risk of osteoporosis-related fractures of the hip, wrist, or spine. The risk of fractures was increased in patients receiving high doses of PPIs for a long time (a year or more).

Concomitant use of rabeprazole with methotrexate

According to the literature, simultaneous use of PPIs with methotrexate (primarily in high doses) can lead to increased concentrations of methotrexate and/or its metabolite hydroxymethotrexate and increase the T1/2 period, which can lead to methotrexate toxicity. If high doses of methotrexate are required, temporary discontinuation of PPI therapy may be considered.

Clostridium difficile

PPI therapy may lead to an increased risk of gastrointestinal infections such as Clostridium difficile.

Patients taking Pariet for short-term symptomatic treatment of manifestations of GERD and NERD (for example, heartburn) without a prescription should consult a doctor in the following cases:

using medications to relieve symptoms of heartburn and indigestion for 4 weeks or more;
the appearance of new symptoms or a change in previously observed symptoms in patients over 55 years of age;
cases of unintentional weight loss, anemia, bleeding in the gastrointestinal tract, dysphagia, pain when swallowing, persistent vomiting or vomiting with blood and epigastric contents, cases of stomach ulcers or gastric surgery with a history, jaundice, etc. (including impaired liver and kidney function).

Patients suffering from recurring symptoms of indigestion or heartburn for a long time should be monitored regularly by a doctor. Patients over 55 years of age who take over-the-counter medications daily to relieve symptoms of heartburn and indigestion should tell their healthcare provider.

Patients should not take other acid-reducing agents, such as H2 receptor blockers or proton pump inhibitors, at the same time as Pariet.

If using other medications, patients should consult their pharmacist or physician before starting therapy with the over-the-counter drug Pariet. Patients should inform their doctor before starting to use Pariet without a prescription if they are scheduled for an endoscopic examination.

You should avoid taking Pariet before performing a urea breath test.

Patients with severe hepatic impairment should consult a physician before initiating over-the-counter treatment with Pariet for short-term symptomatic treatment of manifestations of GERD and NERD (eg, heartburn).

Impact on the ability to drive vehicles and other mechanisms that require increased concentration

Based on the pharmacodynamics of rabeprazole and its adverse effect profile, it is unlikely that Pariet has an effect on the ability to drive a car and operate machinery. However, if drowsiness occurs, these activities should be avoided.

Active ingredient

Rabeprazole

Composition

Active substance:

rabeprazole sodium, 10 mg, which corresponds to 9.42 mg of rabeprazole, respectively.

Excipients:

mannitol (mannitol) – 26.0 mg,

magnesium oxide – 44.7 mg,

weakly substituted hydroxypropylcellulose (hyprolose) – 13 mg,

Hydroxypropylcellulose (hyprolose) – 4.0 mg,

magnesium stearate – 1.0 mg,

ethylcellulose – 0.7 mg,

hypromellose phthalate – 8.5 mg,

diacetylated monoglyceride – 0.85 mg,

talc – 0.80 mg, titanium dioxide (E171) – 0.43 mg,

iron oxide red (E172) – 0.02 mg,

carnauba wax – 0.0015 mg,

food ink gray F6 (white shellac, black iron oxide, dehydrated ethanol, 1-Butanol).

Pregnancy

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

Reproduction studies in rats and rabbits showed no evidence of impaired fertility or fetal developmental defects associated with rabeprazole; however, in rats the drug crosses the placental barrier in small quantities. Pariet should not be used during pregnancy unless the expected positive effect for the mother outweighs the possible harm to the fetus.

It is not known whether rabeprazole is excreted in breast milk. Appropriate studies have not been conducted in lactating women. However, rabeprazole was found in the milk of lactating rats, and therefore Pariet should not be prescribed to lactating women.

Contraindications

Hypersensitivity to the components of the drug;
children under 18 years of age.

With caution: use in patients with severe renal failure.

Side Effects

Based on the experience of clinical studies, we can conclude that Pariet is usually well tolerated by patients. Side effects are generally mild or moderate and are transient.

During clinical studies: headache, abdominal pain, diarrhea, flatulence, constipation, dry mouth, dizziness, rash, peripheral edema.

Determination of the frequency of adverse reactions:

very often (≥1/10);
often (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), including isolated cases.

From the immune system: rarely – acute systemic allergic reactions.

From the hematopoietic system: rarely – thrombocytopenia, neutropenia, leukopenia.

Metabolism: rarely – hypomagnesemia.

From the hepatobiliary system: increased activity of liver enzymes; rarely – hepatitis, hepatic encephalopathy.

From the urinary system: very rarely – interstitial nephritis.

From the skin and subcutaneous tissues: rarely – bullous rashes, urticaria; very rarely – erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.

From the musculoskeletal system: rarely – myalgia, arthralgia.

From the reproductive system: very rarely – gynecomastia.

No changes in other laboratory parameters were observed while taking rabeprazole. According to post-marketing observations, taking proton pump inhibitors may increase the risk of fractures.

Interaction

Cytochrome P450 system

Rabeprazole sodium, like other proton pump inhibitors (PPIs), is metabolized by the cytochrome P450 (CYP450) system in the liver. In vitro studies on human liver microsomes have shown that rabeprazole sodium is metabolized by the isoenzymes CYP2C19 and CYP3A4.

Studies in healthy volunteers have shown that rabeprazole sodium has no pharmacokinetic or clinically significant interactions with drugs that are metabolized by the cytochrome P450 system – warfarin, phenytoin, theophylline and diazepam (regardless of whether patients metabolize diazepam extensively or poorly). A study of combination therapy with antibacterial drugs was conducted.

This four-way crossover study involved 16 healthy volunteers who received rabeprazole 20 mg, amoxicillin 1000 mg, clarithromycin 500 mg, or a combination of these three drugs (RAC – rabeprazole, amoxicillin, clarithromycin). AUC and Cmax values ​​for clarithromycin and amoxicillin were similar when combination therapy was compared with monotherapy. The AUC and Cmax for rabeprazole increased by 11% and 34%, respectively, and for 14-hydroxy-clarithromycin (the active metabolite of clarithromycin), the AUC and Cmax increased by 42% and 46%, respectively, for combination therapy compared with monotherapy. This increase in exposure rates for rabeprazole and clarithromycin was not considered clinically significant.

Interactions due to inhibition of gastric acid secretion

Rabeprazole sodium provides a stable and long-lasting suppression of gastric acid secretion. Thus, interactions may occur with substances for which absorption is pH dependent. When taken simultaneously with rabeprazole sodium, the absorption of ketoconazole is reduced by 30%, and the absorption of digoxin is increased by 22%. Therefore, some patients should be monitored to determine whether dose adjustments are necessary when taking rabeprazole sodium concomitantly with ketoconazole, digoxin, or other drugs for which absorption is pH dependent.

Atazanavir

When atazanavir 300 mg/ritonavir 100 mg was coadministered with omeprazole (40 mg once daily) or atazanavir 400 mg with lansoprazole (60 mg once daily) in healthy volunteers, a significant reduction in atazanavir exposure was observed. Absorption of atazanavir is pH dependent. Although concomitant use with rabeprazole has not been studied, similar results are expected for other PPIs. Therefore, concomitant use of atazanavir with proton pump inhibitors, including rabeprazole, is not recommended.

Antacids

In clinical studies, antacid substances were used in conjunction with rabeprazole sodium. Clinically significant interactions of rabeprazole sodium with aluminum hydroxide gel or magnesium hydroxide were not observed.

Eating

In a clinical study, no clinically significant interactions were observed when rabeprazole sodium was taken with a low-fat meal. Taking rabeprazole sodium concomitantly with a fat-enriched meal may slow down the absorption of rabeprazole by up to 4 hours or more, but Cmax and AUC do not change.

Cyclosporine

In vitro experiments using human liver microsomes showed that rabeprazole inhibits the metabolism of cyclosporine with an IC50 of 62 μmol, i.e., at a concentration 50 times the Cmax for healthy volunteers after 20 days of administration of 20 mg rabeprazole. The degree of inhibition is similar to that of omeprazole for equivalent concentrations.

Methotrexate

Based on reports of adverse events, published pharmacokinetic studies and retrospective analysis, it can be assumed that the simultaneous use of PPIs and methotrexate (primarily in high doses) may lead to increased concentrations of methotrexate and/or its metabolite hydroxymethotrexate and increase T1/2. However, no specific drug interaction studies have been conducted between methotrexate and PPIs.

Overdose

Symptoms: There is minimal evidence of intentional or accidental overdose. There have been no cases of severe overdose of rabeprazole.

Treatment: symptomatic and supportive therapy. A specific antidote is unknown. Rabeprazole binds well to plasma proteins and is therefore poorly excreted during dialysis.

Storage conditions

At a temperature not exceeding 25 °C (do not freeze)

Shelf life

2 years

Manufacturer

Bushu Pharmaceuticals Ltd., Misato Factory, Japan