Raso, 10 mg 15 pcs

Pharmacokinetics

Eabsorption

Rabeprazole is rapidly absorbed from the gut. After taking a dose of 20 mg, the Cmax of rabeprazole in plasma is reached after about 3.5 hours. Changes in Cmax and AUC are linear in the dose range from 10 to 40 mg. Absolute bioavailability after oral administration of 20 mg (compared with intravenous administration) is about 52% largely due to metabolism during “first passage” through the liver. In addition, bioavailability does not change with repeated administration of rabeprazole. Food intake and time of taking the drug during a day have no effect on absorption of rabeprazole.

Distribution

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

Metabolism

. The major metabolites present in plasma in humans are thioether (M1) and carboxylic acid (M6), and the minor metabolites present in low concentrations are sulfone (M2), demethylthioether (M4), and mercapturic acid conjugate (M5). Only the dimethyl metabolite (M3) has minor antisecretory activity, but it is not detected in plasma.

Evacuation

In healthy volunteers, the T1/2 is approximately 1 h (0.7-1.5 h) and total clearance is 283 ± 98 ml/min.

About 90% is excreted in the urine mainly as two metabolites: M5 and M6, about 10% is excreted in the feces.

Pharmacokinetics

in special clinical cases

In patients with stable terminal renal failure requiring maintenance hemodialysis (CK≤5 mL/min/1.73 m2) the distribution of rabeprazole was very close to that of healthy volunteers. AUC and Cmax in these patients were approximately 35% lower than in healthy volunteers. The average 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 2 times higher than in healthy volunteers.

After a single dose of rabeprazole 20 mg in patients with chronic hepatic failure AUC was increased 2-fold and T1/2 was increased 2-3-fold compared to healthy volunteers. However, after taking rabeprazole at a dose of 20 mg/day for 7 days, AUC increased only 1.5 times, and Cmax – 1.2 times. T1/2 in patients with hepatic impairment was 12.3 h, compared with 2.1 h in healthy volunteers. Pharmacodynamic response (gastric pH control) was clinically comparable in both groups.

In elderly patients the excretion of rabeprazole is slightly delayed. In 7 days after taking rabeprazole sodium 20 mg/day in this category of patients the AUC was about 2 times higher and Cmax was 60% higher compared to young healthy volunteers. However, there were no signs of cumulation of rabeprazole.

In the case of delayed CYP2C19 metabolism, after taking rabeprazole at 20 mg/day for 7 days, AUC was 1.9 times higher and T1/2 was 1.6 times higher compared to the same parameters in “fast” metabolizers, while Cmax was increased by 40%.

Pharmacodynamics

Rabeprazole sodium belongs to the class of antisecretory compounds, which are chemically substituted benzimidazoles. Rabeprazole inhibits the activity of the enzyme H+-K+-ATPase, thus blocking the final stage of hydrochloric acid synthesis. This effect is dose-dependent and leads to inhibition of both basal and stimulated acid secretion regardless of the stimulant. As a weak base, rabeprazole at any dose is rapidly absorbed and concentrated in the acidic environment of the parietal cells.

Antisecretory activity. After oral administration of rabeprazole at a dose of 20 mg, the antisecretory effect occurs within 1 h and reaches a maximum after 2 – 4 h. Inhibition of basal and food stimulated acid secretion 23 h after the first dose of rabeprazole sodium was 62 and 82%, respectively, and the duration of this action reached 48 h.

The inhibitory effect of rabeprazole sodium on acid secretion increases slightly during daily administration of 1 tablet, stable inhibition of secretion is achieved 3 days after the start of the drug. After termination of rabeprazole administration, secretory activity is restored in 2-3 days.

Indications

Active ingredient

Composition

How to take, the dosage

The drug is taken orally in a dose of 10 mg (1 tablet) once a day.

The tablets should be swallowed whole without chewing or crushing.

It is recommended that the drug is taken in the morning, before meals.

The time of day and meal have not been found to affect the activity of rabeprazole, but the recommended times of taking Razo® tablets improve patient compliance.

If there is no effect within the first 3 days of treatment, a specialist should be seen. The maximum course of treatment without a physician’s consultation is 14 days.

Interaction

Cytochrome 450 system

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

Studies in healthy volunteers have shown that 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 were increased by 11% and 34%, respectively, for rabeprazole, and the AUC and Cmax were increased by 42% and 46%, respectively, for 14-hydroxy-clarytromycin (the active metabolite of clarithromycin) 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 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, absorption of ketoconazole is reduced by 30%, and absorption of digoxin is increased by 22%. Consequently, for some patients observation should be carried out to decide whether it is necessary to adjust the dose when concomitant use of rabeprazole with ketoconazole, digoxin or other drugs for which absorption depends on pH.

Atazanavir

. When atazanavir 300 mg/ritonavir 100 mg was taken concomitantly 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. Atazanavir absorption is pH dependent. Although concomitant administration with rabeprazole has not been studied, similar results are expected for other proton pump inhibitors. Thus, concomitant use of atazanavir with proton pump inhibitors, including rabeprazole, is not recommended.

Antacid agents

In clinical trials antacid agents were used together with rabeprazole. No clinically significant interaction of rabeprazole with aluminum hydroxide gel or with magnesium hydroxide was observed.

Eating

In a clinical study during the use of rabeprazole with fat-dense foods no clinically significant interaction was observed. Administration of rabeprazole 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 the metabolism of cyclosporine with an IC50 of 62 μmol, ie.i.e. at a concentration 50 times the 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 PPIs and methotrexate (especially in high doses), can lead to increased concentration of methotrexate and/or its metabolite hydroxymethotrexate and increase T1/2. However, there have been no specific studies of drug interactions between methotrexate and PPIs.

Contraindications

With caution: severe renal failure.

Side effects

Rabeprazole is generally well tolerated by patients.

The side effects are generally mild to moderate and transient.

The following side effects have been reported with rabeprazole in clinical studies: headache, abdominal pain, diarrhea, flatulence, constipation, dry mouth, dizziness, rash, peripheral edema.

Frequency of side effects is outlined according to the following gradation:

very often (>1/10);

often (1/10-1/100);

infrequently (1/100-1/1000);

Overdose

The evidence for intentional or accidental overdose is minimal.

Symptoms:

The administration of 60 mg twice daily or 160 mg once daily has been reported, and side effects were minimal and reversible and did not require medical intervention.

Treatment:

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

Similarities