Нофлюкс - instructions for use, doses, side effects, contraindications

Ingredients of the enteric coating tablet: hypromellose phthalate - 8.8 mg; dibutyl sebacate 0.9 mg; ferric oxide red oxide - 0.02 mg; titanium dioxide - 0.4 mg; talc 0.9 mg.

Description:

Tablets 10 mg: round biconvex tablets, covered with an enteric-insoluble coat of pink color. Cross-sectional view: the core is white.

Pharmacotherapeutic group:Gastric secretion reducing agent - proton pump inhibitor

ATX: & nbsp

A.02.B.C Proton pump inhibitors

A.02.B.C.04 Rabeprazole

Pharmacodynamics:

Mechanism of action

Rabeprazole sodium belongs to the class of antisecretory substances, derivatives of benzimidazole. Rabeprazole sodium suppresses the secretion of gastric juice by specific inhibition H+ / K. + ATPase on the secretory surface of parietal cells of the stomach. H + / K + ATPase is a protein complex that functions as a proton pump, 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 irrespective of the stimulus. Rabeprazole sodium does not possess 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 the first dose of rabeprazole sodium is 69% and 82%, respectively, and lasts up to 48 hours. This duration of pharmacodynamic action is much greater than predicted on the basis of the half-life (approximately one hour). This effect can be explained by prolonged binding of the drug substance to the H + / K + ATPase of parietal cells of the stomach. The magnitude of the inhibitory effect of rabeprazole sodium on acid secretion reaches a plateau after three days of taking rabeprazole sodium. At the termination of reception, secretory activity is restored within 1-2 days.

Effect on the level of gastrin in plasma

In clinical trials, patients took 10 or 20 mg of rabeprazole sodium daily for up to 43 months. The level of gastrin in the plasma was increased in the first 2-8 weeks, which reflects the inhibitory effect on acid secretion. The concentration of gastrin returned to baseline usually within 1-2 weeks after discontinuation of treatment.

Effect on enterochromafin-like cells

In the study of human stomach biopsy specimens from the antrum and stomach bottom area, 500 patients who received rabeprazole sodium or a reference preparation for 8 weeks, stable changes in the morphological structure of enterochromachine-like cells, the degree of gastritis, the frequency of atrophic gastritis, intestinal metaplasia, or the spread of infection Helicobacter pylori were not detected.

In a study involving more than 400 patients who received 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 case of adenomatous changes or carcinoid tumors observed in rats was recorded.

Other effects

The systemic effects of rabeprazole sodium in relation to the central nervous system, cardiovascular or respiratory systems are currently not detected. It was shown that rabeprazole sodium at oral intake in a dose of 20 mg for 2 weeks does not affect the function of the thyroid gland, carbohydrate metabolism, the level of parathyroid hormone in the blood, as well as the level of cortisol, estrogens, testosterone, prolactin.glucagon, follicle-stimulating hormone (FSH), luteinizing hormone (LH), renin, aldosterone and growth hormone.

Pharmacokinetics:

Absorption.

Rabeprazole is rapidly absorbed from the intestine, and its peak plasma concentrations are reached about 3.5 hours after taking a dose of 20 mg. Change in peak plasma concentrations (Сmах) and the values of the area under the curve "concentration-time" (AUC) Rabeprazole are linear in the dose range of 10 to 40 mg. Absolute bioavailability after oral administration of 20 mg (but compared with intravenous administration) is about 52%. In addition, bioavailability does not change with multiple administration of rabeprazole. In healthy volunteers, the half-life of plasma is about 1 hour (varying from 0.7 to 1.5 hours), and the total clearance is 3.8 ml / min / kg. In patients with chronic liver disease AUC doubled Pcompared with healthy volunteers, which indicates a decrease in the metabolism of the first passage, and the half-life of 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 food slows the absorption of rabeprazole by 4 hours or more, but neither Сmах, nor the degree of absorption is changed.

Distribution.

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

In healthy people

PAfter receiving a single oral dose of 20 mg ¹⁴C-labeled rabeprazole sodium unchanged drug in the urine was found. About 90% of rabeprazole is excreted in the urine mainly in the form of two metabolites: mercuric acid conjugate (M5) and carboxylic acid (M6), and also in the form of two unknown metabolites detected during the toxicological analysis. The rest of the accepted rabeprazole sodium is excreted with feces.

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

Terminal stage of renal failure

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

Chronic compensated cirrhosis

Patients with chronic compensated cirrhosis transfer rabeprazole sodium in a dose of 20 mg once a day, although AUC doubled and Сmах increased by 50% compared with healthy volunteers of the corresponding sex.

Elderly patients.

In elderly patients, the elimination of rabeprazole is somewhat slowed down. After 7 days of taking rabeprazole 20 mg per day in the elderly AUC was approximately twice as large, and Stach was increased by 60% compared to young healthy volunteers. However, there were no signs of cumulation of rabeprazole.

CYP2C19 polymorphism

In patients with delayed metabolism CYP2C19 after 7 days of taking rabeprazole at a dose of 20 mg per day AUC increases in 1,9 times, and the half-life is 1,6 times as compared with the same parameters for "fast metabolizers," while Сmах increases by 40%.

Indications:

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

Contraindications:

hypersensitivity to rabeprazole, substituted benzimidazoles or to any of the excipients of the drug;
pregnancy;
lactation period;
age to 18 lay.

Carefully:

Severe kidney failure.

Pregnancy and lactation:

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

Studies of reproductive performance in rats and rabbits showed no signs of impaired fertility or fetal developmental defects caused by rabeprazole; However, in rats in small quantities, the drug penetrates the placental barrier. Noflux® should not be used during pregnancy, except when the expected positive effect on the mother exceeds the possible harm to the fetus.

It is not known whether rabeprazole with breast milk. Appropriate studies in lactating women were not conducted. At the same time rabeprazole It is found in the milk of lactating rats, and therefore Noxflux® can not be administered to lactating women.

Dosing and Administration:

Inside, in a dose of 10 mg once a day. Nablux® tablets can not be chewed or grinded. Tablets should be swallowed whole. It is recommended to take the drug in the morning, before eating. It has been established that neither the time of day nor the intake of food affects the activity of rabenrazole sodium, but the recommended time of taking Noxflux® tablets promotes better adherence to the treatment regimen.

In the absence of effect during the first three days of treatment, a specialist examination is necessary. The maximum course of treatment without a doctor's consultation is 14 days.

Side effects:

Based on the experience of clinical studies, it can be concluded that Noflux® is usually tolerated by patients. Side effects are generally mild or moderate and of a transient nature.

When taking Noflux® in clinical trials, the following side effects were noted: headache, abdominal pain, diarrhea, flatulence, constipation, dry mouth, dizziness, rash, peripheral edema.

Undesirable reactions are systematized relative to each of the organ systems using the following frequency classification:

Very frequent (> 1/10)

Frequent (> 1/100, <1/10)

Infrequent (> 1/1000, <1/100)

Rare (> 1/10000, <1/1000) Very rare (<1/10000), including isolated cases.

In the course of clinical trials and post-marketing period, the following adverse reactions were reported:

Immune system disorders: rarely - acute systemic allergic reactions; Violations from the blood and lymphatic system: rarely - thrombocytopenia, neutropenia, leukopenia;

Disorders from the metabolism and nutrition: rarely - hypomagnesemia;

Disturbances from the nervous system - headache, dizziness

Disorders from the gastrointestinal tract - abdominal pain, diarrhea, flatulence,

constipation, dry mouth

Disorders from the hepatobiliary system: increased activity of hepatic enzymes, rarely - hepatitis, jaundice, patients with cirrhosis rarely reported on the development of hepatic encephalopathy;

Disorders from the kidneys and urinary tract: very rarely - interstitial nephritis;

Disturbances from the skin and subcutaneous tissues: a rash, rarely - bullous eruptions, hives, very rarely - erythema multiforme,toxic epidermal necrolysis, Stevens-Johnson syndrome.

Disorders from the musculoskeletal system: rarely - myalgia, arthralgia;

Disorders from the reproductive system and mammary glands: very rarely - gynecomastia;

General disorders and disorders at the site of administration - peripheral edema

Changes in other laboratory parameters during the use of rabeprazole sodium are not was observed.

According to the data of postmarketing observations when taking proton pump inhibitors (PPIs), it is possible to increase the risk of fractures (see section "Special instructions")

Overdose:

Symptoms

Data on intentional or accidental overdose are minimal. No cases of severe overdose with rabsprazole were observed.

Treatment

The specific antidote for Noflux® is unknown. Rabeprazole binds well to plasma proteins, and therefore is poorly excreted by dialysis. In case of an overdose, symptomatic and supportive treatment should be performed.

Interaction:

Cytochrome 450 system

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

Studies in healthy volunteers have shown that rabeprazole sodium does not have pharmacokinetic or clinically significant interactions with drugs that are metabolized by the cytochrome P450 system - warfarin, phenytoin, theophylline and diazepam (regardless of whether patients are metabolized diazepam intensely or weakly).

The study of combined therapy with antibacterial drugs was carried out. Sixteen healthy volunteers who received 20 mg of rabeprazole, 1000 mg of amoxicillin, 500 mg of clarithromycin, or a combination of these three drugs (PAK - rabeprazole, amoxicillin, clarithromycin). Indicators AUC and Сmах for clarithromycin and amoxicillin were similar when comparing combined therapy with monotherapy. Indicators AUC and Schemes for rabeprazole increased by 11% and 34%, respectively, and for 14-hydroxy-clarithromycin (the active metabolite of clarithromycin) AUC and Сmах increased by 42% and 46%, respectively, for combination therapy compared with monotherapy. This increase in exposure indices for rabeprazole and clarithromycin was not clinically significant.

Interactions due to inhibition of gastric juice secretion

Rabeprazole sodium provides a stable and prolonged suppression of gastric juice secretion. Thus, interaction with substances for which the absorption depends on pH can occur. At simultaneous reception with rabeirazole sodium absorption of ketoconazole decreases by 30%, and absorption of digoxia increases by 22%. Therefore, some patients should be monitored to decide whether dose adjustment is necessary while taking sodium rabeprasol with ketoconazole, digoxin, or other drugs for which absorption is pH dependent.

Atazanavir

With the simultaneous administration of atazanavir 300 mg / ritonavir 100 mg with omeprazole (40 mg once a day) or c Atazanavir 400 mg with laisoprazole (60 mg once a day) by healthy volunteers there was a significant reduction in the impact of atazanavir.Absorption of atazanavir depends on pH. Although simultaneous use with rabeprazole ns has been studied, similar results are also expected for other proton pump inhibitors. Thus, concurrent administration of atazanavir with proton pump inhibitors is not recommended, including rabeprazole.

Antacid agents

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

Food intake

In a clinical study, during the reception of rabeprazole sodium with depleted fat, no clinically significant interactions were observed. Reception of rabeprazole sodium simultaneously with enriched food can slow the absorption of rabeprazole up to 4 hours or more, however Сmах and AUC do not change.

Cyclosporin

Experiments in vitro using human liver microsomes showed that rabeprazole inhibits the metabolism of cyclosporine with IC50 62 μmol, i.e., in a concentration 50 times higher than C max 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, published pharmacokinetic studies and retrospective analysis data, simultaneous administration of PPI and methotrexate (especially in high doses) may lead to an increase in the concentration of methotrexate and / or its metabolite, hydroxymetostransate, and increase the half-life. However, no special studies have been conducted on the drug interaction of methotrexate with PPI.

Special instructions:

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

Tablets of the drug Hoflux® can not be chewed or grinded. Tablets should be swallowed whole. It has been established that neither the time of day nor the intake of food affects the activity of rabeprazole sodium.

In a special study in patients with mild or moderate liver function abnormalities, there was no significant difference in the incidence of the side effects of Noxflux® from that of healthy and healthy adults.but, despite this, it is recommended to be cautious when first prescribing Noflux® to patients with severe liver function disorders. AUC Rabeprazole sodium in patients with severe impaired liver function is approximately twice as high as in healthy patients.

Patients with impaired renal or hepatic function are not required to adjust the dose of Noxflux®.

Hypomagiemia

In the treatment of proton pump inhibitors for at least 3 months, in rare cases, cases of symptomatic or asymptomatic hypomagnesemia were noted. In most cases, these reports were received one year after the therapy. Serious side effects were tetany, arrhythmia and convulsions. Most patients required treatment of hypomagnesemia, including the replacement of magnesium and the abolition of proton pump inhibitor therapy. In patients who will receive prolonged treatment or who take proton pump inhibitors with drugs such as digoxia or drugs that can cause hypomagnesemia (eg diuretics), health care providers should monitor the magnesium level before starting treatment with proton pump inhibitors and during treatment.

Patients should not take concomitantly with Noflux © other acid-reducing agents, such as H2 receptor blockers or proton pump inhibitors.

Fractures

According to observational studies, it can be assumed that proton pump inhibitor (PPI) therapy may lead to an increased risk of osteoporotic fractures of the hip, wrist, or spine. The risk of fractures was increased in patients who received high doses of PPI for a long time (a year or more).

The simultaneous use of rabeprazop with methotrexate

According to the literature, simultaneous reception of PPI with methotrexate (especially in high doses) may lead to an increase in the concentration of methotrexate and / or its metabolite, hydroxymototrexate, and increase the half-life, which may lead to toxicity of methotrexate. If it is necessary to use high doses of methotrexate, the possibility of temporary discontinuation of PPI therapy may be considered. Clostridium difficile

STI therapy may lead to an increased risk of gastrointestinal infections, such as infections caused by Clostridium difficile.

Patients taking Noflux® for short-term symptomatic treatment of GERD and NERD symptoms (eg, heartburn) without a prescription should consult a doctor in the following cases:

-Application of remedies for relieving 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 reduction in body weight, anemia, bleeding in the gastrointestinal tract, dysphagia, pain during swallowing, constant vomiting or vomiting with blood and epigastric contents, cases of stomach ulcers or stomach operations and a history of jaundice, etc. (including violations of the liver and kidneys).

Patients, long suffering from recurring symptoms of digestive disorders or heartburn, should be observed regularly by the doctor. Patients over 55 years of age who take OTC every day to relieve symptoms of heartburn and indigestion should inform their physician about this. Patients should not take other drugs that reduce acidity concomitantly with Noflux®, such as blockers H2 receptors or proton pump inhibitors.

When using other medications, patients should consult a pharmacist or physician before initiating therapy with Noflus® without prescription.

Patients should inform the physician before using Noflux® without a prescription if an endoscopic examination is prescribed.

Do not take Noflux® before taking a urea breath test.

Patients with severe liver dysfunction should consult a doctor before initiating therapy with Noxflux®, over-the-counter, for short-term symptomatic treatment of GERD and NERD symptoms (eg, heartburn).

Effect on the ability to drive transp. cf. and fur:

Based on the peculiarities of pharmacodynamics of rabeprazole and its profile of undesirable effects, it is unlikely that Noflux® influences the ability to drive a car and work with machinery. However, in the event of snotty, these activities should be avoided.

Form release / dosage:The tablets are covered with an enteric membrane.

Packaging:

Tablets coated with enteric coating 10 mg. 7 tablets are placed in AI / A1- blisskr. For 2 or 4 blisters together with instructions for medical use are placed in a cardboard box.

Storage conditions:At a temperature of no higher than 25 ° C.
Keep out of the reach of children.

Shelf life:3 years. Do not use after expiry date.

Terms of leave from pharmacies:Without recipe

Registration number:LP-001461

Date of registration:26.01.2012 /02.02.2015

Expiration Date:26.01.2017

The owner of the registration certificate:Egis Pharmaceutical Plant OJSCEgis Pharmaceutical Plant OJSC Hungary

Manufacturer: & nbsp

Laboratorios LICONSA, S.A. Spain

Representation: & nbspEGIS ZAO Pharmaceutical Plant EGIS ZAO Pharmaceutical Plant Hungary

Information update date: & nbsp02.02.2015

Illustrated instructions

Instructions

Noflux® (Noflux®)