Pariet, 20 mg 28 pcs

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 the H+/K+ ATPase on the secretory surface of gastric parietal cells. H+/K+ ATPase is a protein complex that functions as a proton pump, so sodium rabeprazole 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 lasts until 48 h.

This duration of pharmacodynamic action is much longer than that predicted by T1/2 (approximately one hour). This effect can 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 1-2 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, gastritis severity, 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 (Cmax) 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 about 52%. In addition, the bioavailability does not change with repeated administration of rabeprazole. In healthy volunteers, the T1/2 period from plasma is about 1 h (varying from 0.7 to 1.5 h) and the 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 T1/2 from plasma is increased 2-3 times. Neither the time of drug intake during a day, nor antacids affect absorption of rabeprazole. Taking the drug with fatty food slows down absorption of rabeprazole by 4 hours or more, but neither Cmax nor 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 primarily as two metabolites: mercapturic acid conjugate (M5) and carboxylic acid (M6), and 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 rabeprazole sodium 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. AUC and Cmax in these patients were approximately 35% lower than in healthy volunteers. On average, the T1/2 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 Cmax is increased by 50% compared to healthy volunteers of the appropriate sex. Elderly patients The elimination of rabeprazole is slightly delayed in elderly patients. After 7 days of taking rabeprazole at 20 mg per day, AUC was approximately doubled and Cmax 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 taking rabeprazole at a dose of 20 mg daily, the AUC increased 1.9-fold and Cmax 1.6-fold compared to the same parameters in “fast metabolizers”, while Cmax increased by 40%.

Indications

Active ingredient

Composition

Active ingredients:

Rabeprazole sodium 20 mg, which corresponds to the content of rabeprazole 18.85 mg.

Auxiliary substances:

mannitol (mannitol) – 40.0 mg,

magnesium oxide – 63.0 mg,

p> hydroxypropylcellulose slightly substituted (hyprolose) – 19.5 mg,

hydroxypropyl cellulose (hyprolose) – 3.0 mg,

magnesium stearate – 1.5 mg,

ethylcellulose – 1.0 mg,

hypromellose phthalate – 12.0 mg,

diacetylated monoglyceride – 1.2 mg,

talc – 1.13 mg,

titanium dioxide (E171) – 0.6 mg,

iron oxide yellow – 0.07 mg,

Carnauba wax – 0.025 mg,

Food red ink A1 (white shellac, iron oxide red, carnauba wax, glyceric acid ester, dehydrated ethanol, 1-Butanol).

How to take, the dosage

Pariet tablets should be swallowed whole without chewing or crushing. It has been found that neither time of day nor food intake affect the activity of Rabeprazole sodium.

In acute peptic ulcer and anastomosis

It is recommended to take orally 20 mg once daily. Usually cure occurs after 6 weeks of therapy, but in some cases the duration of treatment may be extended for an additional 6 weeks.

In acute duodenal ulcer

It is recommended to take orally 20 mg once a day. The duration of treatment is from 2 to 4 weeks. If necessary, the duration of treatment can be increased for 4 more weeks.

In the treatment of erosive gastroesophageal reflux disease (GERD) or reflux esophagitis

It is recommended to take orally 20 mg once daily. The duration of treatment is 4 to 8 weeks. If necessary, the duration of treatment may be increased for 8 more weeks.

In maintenance therapy of gastroesophageal reflux disease (GERD)

It is recommended to take orally 20 mg once a day. The duration of treatment depends on the patient’s condition.

In non-erosive gastroesophageal reflux disease (NERD) without esophagitis

It is recommended to take orally 20 mg once daily.

If symptoms do not disappear after four weeks of treatment, further evaluation of the patient should be performed.

After symptoms have resolved, oral medication should be taken once daily on demand to prevent future symptoms.

To treat Zollinger-Elison syndrome and other conditions characterized by pathological hypersecretion

The dose is adjusted individually. The initial dose is 60 mg per day, then the dose is increased and the drug is prescribed up to 100 mg per day on a single dose or 60 mg twice a day. For some patients, fractional dosing is preferable.

Treatment should continue as clinically necessary. In some patients with Zollinger-Elison syndrome, the duration of treatment with rabeprazole has been up to one year.

For eradication of Helicobacter pylori

It is recommended to take orally 20 mg 2 times a day according to a certain scheme with an appropriate combination of antibiotics. The duration of treatment is 7 days.

Patients with renal and hepatic impairment

There is no need to adjust the dose in patients with renal impairment.

In patients with mild to moderate hepatic impairment the blood concentration of rabeprazole is usually higher than in healthy patients.

Caution should be exercised when prescribing Pariet in patients with severe hepatic impairment.

Elderly patients

Dose adjustment is not required.

Children

The safety and efficacy of rabeprazole sodium 20 mg for short-term (up to 8 weeks) treatment of GERD in children aged 12 years and older is supported by extrapolation of adequate and well-controlled studies supporting the effectiveness of rabeprazole sodium for adults and safety and pharmacokinetics studies for pediatric patients. The recommended dose for children aged 12 years and older is 20 mg once daily for up to 8 weeks.

The safety and efficacy of rabeprazole sodium for treatment of GERD in children under 12 years of age has not been established.

The safety and effectiveness of rabeprazole sodium for other indications has not been established for pediatric patients.

Interaction

The cytochrome P450 system

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

Studies in healthy volunteers have shown that sodium rabeprazole 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 heavily or weakly).

There has been a study of combination therapy with antibacterial drugs. This four-way crossover study involved 16 healthy volunteers who received 20 mg of rabeprazole, 1,000 mg of amoxicillin, 500 mg of clarithromycin or a combination of these three drugs (RAC – rabeprazole, amoxicillin, clarithromycin).

The AUC and Cmax values for clarithromycin and amoxicillin were similar when comparing combination therapy to monotherapy. The AUC and Cmax values for rabeprazole increased by 11% and 34%, respectively, and the AUC and Cmax for 14-hydroxy-clarithromycin (the active metabolite of clarithromycin) increased by 42% and 46%, respectively, for combination therapy compared with monotherapy. This increase in exposure rates for rabeprazole and clarithromycin was not found to be clinically significant.

Interactions due to inhibition of gastric juice secretion

Rabeprazole sodium has a sustained and prolonged suppression of gastric juice secretion. Thus, there may be an interaction with substances for which absorption is pH-dependent. When concomitant administration with rabeprazole sodium absorption of ketoconazole is reduced by 30%, and absorption of digoxin is increased by 22%.

Hence, some patients should be monitored to decide if a dose adjustment is necessary when concomitantly taking rabeprazole sodium with ketoconazole, digoxin or other drugs for which absorption is pH dependent.

Atazanavir

Atazanavir 300 mg/ritonavir 100 mg concomitantly taken with omeprazole (40 mg once daily) or atazanavir 400 mg with lansoprazole (60 mg once daily) in healthy volunteers showed significant reduction in atazanavir exposure. Atazanavir absorption is pH dependent.

While concomitant administration with rabeprazole has not been studied, similar results are also expected for other PPIs. Thus, concomitant administration of atazanavir with proton pump inhibitors, including rabeprazole, is not recommended.

Antacids

In clinical studies, antacids have been used in conjunction with rabeprazole sodium. No clinically significant interactions of rabeprazole sodium with aluminum hydroxide gel or with magnesium hydroxide were observed.

In a clinical study during administration of rabeprazole sodium with fat-dense foods no clinically significant interactions were observed. Administration of rabeprazole sodium concomitantly with fat-rich food may delay absorption of rabeprazole up to 4 hours or more, but Cmax and AUC are not changed.

Cyclosporine

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

Methotrexate

According to reports of adverse events, data from published pharmacokinetic studies and data from retrospective analysis, it can be assumed that simultaneous administration of PPI and methotrexate (especially in high doses), can lead to increased concentration of methotrexate and/or its metabolite hydroxytetrexate and increase T1/2. However, no special studies of drug interaction of methotrexate with PPIs have been conducted.

Special Instructions

Patient response to therapy with rabeprazole sodium does not rule out the presence of malignancy in the stomach.

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

In a specific study in patients with mild to moderate hepatic impairment no significant difference in the incidence of side effects of Pariet compared to that in age and sex matched healthy subjects was found, but nevertheless caution is recommended when first prescribing Pariet in patients with severe hepatic impairment. The AUC of rabeprazole sodium in patients with severe hepatic impairment is approximately twice as high as in healthy patients.

Patients with impaired renal or hepatic function do not require dose adjustment of Pariet.

Hypomagnesemia

In treatment with proton pump inhibitors (PPIs) for at least 3 months, cases of symptomatic or asymptomatic hypomagnesemia have rarely been reported. Most of these cases were reported one year after therapy.

Serious adverse events were tetany, arrhythmias, and seizures. Most patients required treatment for hypomagnesemia, which included magnesium replacement and withdrawal of proton pump inhibitor therapy.

In patients who will receive long-term treatment or who take PPIs with drugs such as digoxin or drugs that can cause hypomagnesemia (such as diuretics), health care providers should monitor magnesium concentrations before treatment with proton pump inhibitors and during treatment.

Patients should not take other acid-reducing drugs, such as H2-receptor 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 who received high-dose PPIs for a long period of time (one year or more).

The concomitant use of rabeprazole with methotrexate

According to the literature, concomitant use of PPIs with methotrexate (especially in high doses), can lead to increased concentration of methotrexate and/or its metabolite hydroxytetrexate and increase T1/2 period, which may lead to methotrexate toxicity. If high doses of methotrexate are necessary, temporary discontinuation of PPI therapy may be considered.

Clostridium difficile

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

Impact on the ability to drive vehicles and other mechanisms requiring increased attention

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

Contraindications

With caution: use in patients with severe renal insufficiency and in children.

Side effects

Based on the experience of clinical trials, it can be concluded that Pariet is usually well tolerated by patients. Side effects are generally mild to moderate and transient.

When taking Pariet, the following side effects have been reported in clinical studies: headache, abdominal pain, diarrhea, flatulence, constipation, dry mouth, dizziness, rash, peripheral edema.

The adverse reactions are systematized relative to each of the organ systems using the following frequency of occurrence classification:

Immune system disorders: rare – acute systemic allergic reactions.

Blood and lymphatic system disorders: rare – thrombocytopenia, neutropenia, leukopenia.

Metabolism and nutrition disorders: rarely – hypomagnesemia.

Hepatobiliary system disorders: increased activity of liver enzymes, rarely – hepatitis, jaundice, hepatic encephalopathy.

Repnal and urinary tract disorders: very rare – interstitial nephritis.

Skin and subcutaneous tissue disorders: rare – bullous rash, urticaria, very rare – erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Muscular system disorders: rarely – myalgia and arthralgia.

Reproductive system disorders: very rare – gynecomastia.

There have been no changes in other laboratory parameters during ribeprazole sodium administration. According to post-marketing observations, proton pump inhibitors (PPIs) may increase the risk of fractures.

Overdose

Symptoms: data on intentional or accidental overdose are minimal. No cases of severe overdose with rabeprazole have been reported.

Treatment: A specific antidote for Pariet is not known. Rabeprazole is well bound to plasma proteins, and therefore poorly excreted by dialysis. In case of overdose symptomatic and supportive treatment is necessary.

Pregnancy use

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

Reproduction studies in rats and rabbits have shown no evidence of fertility or fetal defects due to rabeprazole; however, in rats, small amounts of the drug penetrate the placental barrier. Pariet should not be used in pregnancy unless the expected benefits to the mother outweigh the possible harm to the fetus.

It is unknown whether rabeprazole is excreted with breast milk. Corresponding studies in breastfeeding women have not been conducted. However, rabeprazole is found in the milk of lactating rats, and therefore Pariet should not be prescribed to nursing women.

Similarities