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medicalmeds.eu Medicines Inhibitors of the protonew pump. Nekspro-40

Nekspro-40

Препарат Некспро-40. Torrent Pharmaceuticals Ltd (Торрент Фармасьютикалс Лтд) Индия


Producer: Torrent Pharmaceuticals Ltd (Torrent Pharmasyyutikals Ltd) India

Code of automatic telephone exchange: A02BC04

Release form: Firm dosage forms. Tablets.

Indications to use: Reflux esophagitis. Eradikation N. pylori. Prevention of aggravations of a peptic ulcer. Gastrointestinal bleeding. Zollingera-Ellison's syndrome.


General characteristics. Structure:

Active ingredient: 20 mg or 40 mg of esomeprazole (in the form of esomeprazole of magnesium of kishkovorochinny pellets).

Excipients: sugar spherical, ethyl cellulose, magnesium stearate, povidone, magnesium oxide easy, methacrylate copolymer dispersion, diethyl phthalate, talc, cellulose microcrystallic, lactoses monohydrate, starch corn, коповидон, polyethyleneglycol 8000, кросповидон, silicon dioxide colloid anhydrous, a gipromelloza, titanium dioxide (Е 171), ferrous oxide red (Е 172), blackened black OPACODE S-1-1-17823: shellac, ferrous oxide black (Е 172), propylene glycol, ammonium hydroxide.




Pharmacological properties:

Pharmacodynamics. Esomeprazole is S-isomer of an omeprazol which reduces secretion of a gastric juice thanks to specifically directed action mechanism. It is specific inhibitor of the proton pump in covering cell. R - and S-isomers of an omeprazol have identical pharmakodinamichesky activity.

Esomeprazole is a weak basis, it concentrates and passes into an active form in visokokislotny to the environment of secretory tubules of covering cell where it inhibits enzyme of N-K-Atfazy – the acid pump, and also suppresses basal and stimulated secretion of acid.

Influence on secretion of a gastric juice. After oral administration of 20 mg and 40 mg of esomeprazole action comes within an hour. After repeated reception of 20 mg of esomeprazole of 1 times a day within 5 days the average peak of emission of acid after stimulation by Pentagastrinum decreases by 90% when determining this indicator in 6-7 hours after reception of a dose for the 5th day.

In 5 days of reception of esomeprazole on 20 mg and 40 mg orally level рН a stomach was more than 4 on average for 13 both 17 hours respectively and more than 24 hours – at patients with symptomatic a reflux esophagitis. Made a part of patients who рН a stomach had a level more than 4 within 8, 12 and 16 hours respectively after reception of 20 mg of esomeprazole

76%, 54% and 24%. The corresponding proportions for esomeprazole of 40 mg made 97%, 92% and 56%.

When using an indirect indicator of AUC of plasma concentration dependence of oppression of secretion of acid on drug exposure was shown.

Therapeutic effects of oppression of secretion of acid. A reflux esophagitis esomeprazole of 40 mg 70% of patients had a successful treatment approximately after 4 weeks of treatment and at 93% – after 8 weeks of treatment.

Use of esomeprazole of 20 mg twice a day within one week together with the corresponding antibiotics led to a successful eradikation of Helicobacter pylori approximately at 90% of patients. After such treatment within one week there was no need for performing further monotherapy by anti-secretory drugs for successful healing of an ulcer and elimination of symptoms of an uncomplicated ulcer of a duodenum.

Other effects connected with acid secretion oppression. During use of anti-secretory drugs concentration of gastrin in a blood plasma increases in response to decrease in secretion of acid.

Increase in quantity of ECL cells, perhaps, is connected with increase in level of gastrin in a blood plasma that was observed at some patients at prolonged use of esomeprazole.

Messages on several cases of increase in frequency of developing of granular cysts of a stomach at long use of anti-secretory drugs were received. These phenomena are a physiological consequence of long suppression of secretion of acid and have high-quality and reversible character.

Decrease in secretion of a gastric juice owing to use of any inhibitor of the proton pump increases in a stomach the quantity of the bacteria which are present at a gastrointestinal path is normal. Treatment by inhibitors of the proton pump can lead to increase in risk of the gastrointestinal infection caused, for example, Salmonella or Campilobacter.

Pharmacokinetics. Esomeprazole is kislotolab_lny and is applied orally in a kishechnorastvorimy cover. Conversion in in vivo R-isomer is insignificant. Absorption of esomeprazole happens quickly, the maximum concentration in a blood plasma are reached approximately in 1-2 hours after reception of a dose. Absolute bioavailability makes 64% after a single dose of 40 mg and increases to 89% after repeated reception of 1 times a day. 20 mg of esomeprazole correspond to value of 50% and 68%. Distribution volume at healthy volunteers in equilibrium state makes 0,22 l/kg of body weight. Esomeprazole for 97% contacts plasma proteins.

Meal slows down and reduces esomeprazole absorption, however it does not influence effect of esomeprazole on acidity in a gastric cavity.

Metabolism and removal. Esomeprazole is completely metabolized with the help tsitokhromno ї the P450 (CYP) systems. The main part of metabolism of esomeprazole depends on polymorphic SUR2S19, the hydroxy which is responsible for emergence - and дезметилметаболітів esomeprazole. Other part depends on the second specific isoform, SURZA4 which is responsible for emergence to an ezomeprazolsulfon – the main metabolite in a blood plasma.

The parameters specified below mainly display pharmacokinetics at persons with functional SUR2S19 enzyme (extensive metabolizator).

The general clearance of a blood plasma makes about 17 l/hour after a single dose and about 9 l/hour after repeated reception. Plasma elimination half-life makes about 1,3 h after repeated reception of a dose of 1 times a day. The pharmacokinetics of esomeprazole was studied in doses to 40 mg twice a day. The area limited to a curve of dependence of concentration in a blood plasma from time increases at repeated reception of esomeprazole. This increase is dozozavisimy and gives more than dozoproportsionalny increase in AUC after repeated use. These the vremyazavisimost and a dozozavisimost are explained by the decrease in metabolism of the first passing and system clearance connected with SUR2S19 enzyme oppression by esomeprazole and/or its sulfmetabolity. Esomeprazole is completely removed from plasma between doses without tendency to accumulation at administration of drug of 1 times a day.

The main metabolites of esomeprazole do not influence secretion of a gastric juice. About 80% of a peroral dose of esomeprazole are removed in the form of metabolites with urine, others – with excrements. Less than 1% of initial medicinal substance are found in urine.

Special groups больныхю About 2,9±1,5% of group of patients have insufficiency of SUR2S19 enzyme (they are called weak metabol_zator). At these persons esomeprazole metabolism, respectively, is generally carried out by SURZA4. After repeated reception of 1 times in days of 40 mg of esomeprazole average value of the area, a limited curve of dependence of concentration in a blood plasma from time, in weak is about 100% higher than metabolizator, than at persons with normal functioning of SUR2S19 enzyme (extensive metabolizator). Average maximum concentration in a blood plasma increases approximately by 60%. These results have no influence on esomeprazole dosing.

Metabolism of esomeprazole does not undergo essential changes at patients of advanced age (from 71 to 80 years).

After a single dose of esomeprazole of 40 mg average value of the area, a limited curve of dependence of concentration in a blood plasma from time, at women is 30% above in comparison with men. No difference connected with a floor was observed at repeated administration of drug of 1 times a day. These results do not influence esomeprazole dosing.

Patients with dysfunction of livers/kidneys. Patients with weak and moderate dysfunction of a liver can have a broken metabolism of esomeprazole. Speed of metabolism decreases at patients with heavy abnormal liver functions that leads to increase in the area, a limited curve of dependence of concentration in a blood plasma from time, twice. Thus, the maximum dose for patients with serious violations of function of a liver makes 20 mg. Esomeprazole and its metabolites do not tend to cumulation at administration of drug of 1 times a day.

Researches at patients with an impaired renal function were not conducted. As kidneys are responsible for removal of metabolites of esomeprazole, but not main initial connection, changes in metabolism at patients with a renal failure are not expected.

Use in pediatrics. Children at the age of 12-18 years: after repeated use of 20 mg and 40 mg of esomeprazole the general influence and time of achievement of the maximum concentration of drug in plasma was same, as well as at adults.


Indications to use:

Gastroesophageal reflux disease:

• treatment erosive reflux esophagitis,
• for prolonged treatment for the purpose of prevention of a recurrence,
• symptomatic treatment of a gastroesophageal reflux disease.

In a combination with antibacterial agents for Helicobacter pylori eradikation:

• treatment of an ulcer of the duodenum tied with Helicobacter pylori
• prevention of a recurrence of round ulcers at patients of an ulcer, the caused Helicobacter pylori.

Treatment and prevention of the ulcers caused by prolonged use of non-steroidal anti-inflammatory drugs (NPVS):

• treatment of the ulcers caused by therapy of NPVS
• prevention of stomach ulcers and a duodenum at patients of risk group in connection with reception of NPVP.

Prevention of a recurrence of bleeding from stomach ulcers or a duodenum after treatment by esomeprazole (solution for infusions).

Treatment of a syndrome of Zollingera-Ellison.


Route of administration and doses:

It is necessary to swallow of tablets whole, washing down with enough liquid. Tablets cannot be chewed or crushed.

Patients who have difficulties with swallowing can recommend to dissolve a tablet in 100 ml of still water. It is impossible to use any other liquids as they can damage a kishechnorastvorimy cover. Water in a glass should be shaken up that the tablet was dissolved. To drink liquid with microgranules at once or within 30 minutes. It is necessary to gather still a half-glass of water, to rinse walls with water and to drink. Microgranules should not be chewed or split up.

Patients who have difficulties with swallowing can enter a tablet via the nazogastralny probe, previously having dissolved it in half of glass of still water. It is very important that the syringe and the probe for this procedure were corresponding.

Administration of drug via the nazogastralny probe:

1. To put a tablet in the corresponding syringe and to fill it about 25 ml of water and 5 ml of air. For some probes 50 ml of water can be necessary for difficulty of passing of a tablet for prevention via the probe.

2. To stir up the syringe within 2 minutes that the tablet broke up.

3. To hold the syringe vertically, a tip up, to check passability of a tip.

4. To put the syringe to the probe, holding it vertically.

5. To stir up the syringe and to turn it a tip down. To quickly enter 5-10 ml of liquid. To turn the syringe after introduction and again to stir up (the syringe should be held vertically not to hammer a tip).

6. To turn the syringe again and enter 5-10 more ml of liquid into the probe. To repeat the procedure until the syringe becomes empty.

7. For washing off of any remains of drug it is necessary to fill the syringe of 25 ml of water and 5 ml of air, to stir up the syringe, to turn and to quickly enter liquid. 50 ml of water can be necessary for some probes.

Adults and children age of 12 years. Gastroesophageal reflux disease. Treatment erosive reflux esophagitis: 40 mg of 1 times a day within 4 weeks. Additional 4 weeks are recommended for patients at whom the esophagitis was not cured or its symptoms remain.

Prolonged treatment of a recurrence at patients with the cured esophagitis: on 20 mg of 1 times a day.

Symptomatic treatment of a gastroesophageal reflux disease: 20 mg of 1 times a day to patients without esophagitis. If control of symptoms is not reached within 4 weeks of treatment, the patient should be inspected. At elimination of symptoms for further control there can be enough use of 20 mg of 1 times a day. It is possible to apply the scheme "in case of need" to adults, accepting 20 mg of 1 times a day. At patients who applied NPVS and who have a risk of development of stomach ulcers or a duodenum further control of symptoms with use of the scheme "in case of need" is not recommended.

Adults. In a combination with antibacterial agents for Helicobacter pylori eradikation Treatment of an ulcer of the duodenum tied with Helicobacter pylori: 20 mg of drug with 1 g of amoxicillin and 500 mg of a klaritromitsin 2 times a day within 7 days.

Prevention of a recurrence of round ulcers at patients of an ulcer, the caused Helicobacter pylori: 20 mg of drug with 1 g of amoxicillin and 500 mg of a klaritromitsin 2 times a day within 7 days.

Treatment and prevention of the ulcers caused by prolonged use of NPVP. Treatment of the stomach ulcers caused by therapy of NPVS: the recommended dose makes 20 mg of 1 times a day. Treatment duration – 4-8 weeks.

Prevention of the stomach ulcers and duodenum associated with treatment of NPVP at patients of risk group: the recommended dose makes 20 mg of 1 times a day.

Prevention of a recurrence of bleeding from stomach ulcers or a duodenum after treatment by esomeprazole, solution for infusions. On 40 mg of 1 times a day within 4 weeks. The period of peroral treatment by drug the therapy directed to suppression of acidity which consists in use of esomeprazole, solution for infusions precedes.

Treatment of a syndrome of Zollingera-Ellison: 40 mg 2 times a day. The dosage should be selected individually, duration of treatment is defined by clinical indications. Most of patients can have a controlled at reception from 80 to 160 mg of esomeprazole a day disease. If the dose exceeds 80 mg/days, it needs to be distributed on two receptions.

Renal failure. Dose adjustment for patients with a renal failure is not required. Due to the lack of experience of use of drug for treatment of patients with a heavy renal failure such patients should appoint drug with care (see the section "Pharmacological Properties").

Abnormal liver function. Patients with a weak and moderate abnormal liver function do not need dose adjustment. For patients with serious violations of function of a liver the maximum dose of drug should not exceed 20 mg (cm. section "Pharmacological Properties").

Patients of advanced age. Dose adjustment for patients of advanced age is not required.

Children aged up to 12 years. Drug should not be used to children aged up to 12 years as data on such use are absent.


Features of use:

Use during pregnancy or feeding by a breast. Data on use of drug for treatment of pregnant women are limited. Experiences did not show a direct or mediate negative impact on development of an embryo/fruit. It is necessary to appoint with care drug to pregnant women.

It is unknown whether esomeprazole gets into breast milk. Researches concerning esomeprazole use to women who nurse therefore drug should not be used during feeding by a breast were not conducted.

Children. Drug should not be used to children aged up to 12 years as data on such use are absent.

Features of use. In case of existence of alarming symptoms (for example the expressed body degrowth, nausea, a dysphagy, a hematemesis or a melena) and in cases when stomach ulcer is suspected or available, it is necessary to exclude a zlokachestvennost as use of drug can change symptoms and delay definition of the correct diagnosis.

To patients who use drug for a long time (especially the persons accepting it it is more than a year), it is necessary to be under regular observation.

Patients who use the drug "in case of need" should tell the doctor in case of change of character of symptoms. At purpose of esomeprazole it is necessary to take into account its interaction with other medicines which can influence concentration of esomeprazole in a blood plasma.

At purpose of esomeprazole for an eradikation of Helicobacter pylori it is necessary to consider possible medicinal interactions of all components of triple therapy. Klaritromitsin is powerful CYP3A4 inhibitor, and it is necessary to consider its contraindications and interaction (if triple therapy to patients who accept along with esomeprazole other medicines which are metabolized by CYP3A4, such as цизаприд is applied).

This medicine contains sucrose. Patients with rare hereditary intolerance of fructose, insufficient absorption of a glyukozo-galactose or insufficiency of invertase-isomaltase should not appoint this drug.

Use of inhibitors of a proton pomp can increase several risk of gastrointestinal infections, such as Salmonella and Campylobacter.

It is not recommended to apply in parallel esomeprazole and атазанавир. If the combination of an atazanavir with inhibitors of a proton pomp cannot be avoided, it is recommended to watch carefully patients in the conditions of a hospital, and also to raise a dose of an atazanavir to 400 mg from 100 mg of a ritonavir a dose of esomeprazole of 20 mg it is not necessary to exceed.

At healthy faces it was noted pharmacokinetic / фармакодинамическое interaction between klopidogrely (a load dose of 300 mg / a daily maintenance dose of 75 mg) and esomeprazole (40 mg in days orally) that led to reduction of exposure of an active metabolite of a klopidogrel on average for 40% and reduction of the maximum inhibiting activity (ADF-indutsirovannoy) concerning aggregation of thrombocytes on average for 14%. Respectively, use separately esomeprazole and to a klop_dogrel should be avoided.

Ability to influence speed of response at control of motor transport or work with other mechanisms. Treatment by drug does not influence ability to drive the car or work with other mechanisms. In cases if during treatment drug observes dizziness and an illegibility of sight, it is necessary to refrain from control of vehicles and work with mechanisms.


Side effects:

Disturbances of system of a hemopoiesis: leukopenia, thrombocytopenia, агрунолоцитоз, pancytopenia.

Disturbances of immune system: hypersensitivity reactions, such as fever, Quincke's disease and anaphylactic reaction / shock.

Metabolism disturbances: peripheral hypostases, a hyponatremia, a hypomagnesiemia, a heavy hypomagnesiemia can lead to a gipoltsiyemiya.

Mental disorders: sleeplessness, excitement, depression, confusion of consciousness, aggression, hallucinations.

Disturbances of a nervous system: headache, weakness, paresthesia, drowsiness, taste disturbance.

Vision disorder: sight illegibility.

Disturbances from an acoustic organ: dizziness.

Disturbances of respiratory system: bronchospasm.

Digestion disturbances: an abdominal pain, locks, diarrhea, abdominal distention, nausea, vomiting, dryness in a mouth, stomatitis, digestive tract candidiasis, microscopic colitis.

Disturbances of gepatobiliarny system: increase in levels of liver enzymes, hepatitis with or without jaundice, a liver failure, encephalopathy at patients with liver diseases.

Disturbances of skin and soft tissues: dermatitis, itch, urticaria, rash, allopecia, photo sensitivity, multiformny erythema, Stephens-Johnson's syndrome, toxic epidermal necrolysis.

Skeletal and muscular disturbances: arthralgia, mialgiya, muscular weakness.

Disturbances from kidneys and an urinary system: intersticial nephrite.

Disturbance of reproductive system: gynecomastia.

General disturbances: weakness, sweating strengthening.


Interaction with other medicines:

Influence of esomeprazole on pharmacokinetics of other medicines. The lowered acidity of a gastric juice at use of esomeprazole can increase or reduce absorption of medicinal substances if their absorption depends on acidity of a gastric juice.

As well as in a case with other drugs which reduce intragastric acidity, absorption of such drugs as кетоконазол, итраконазол, and also ерлотиниб can decrease whereas absorption of such drugs as digoxin, can increase during treatment by esomeprazole and acetylsalicylic acid. Simultaneous use of an omeprazol (20 mg a day) and digoxin at healthy faces increased bioavailability of digoxin for 10% (in two of ten people – for 30%).

It was noted interaction of an omeprazol with some inhibitors of protease. The clinical importance and mechanisms of such interactions are unknown. Raised рН a stomach during treatment omeprazoly can change absorption of inhibitors of protease. Other possible mechanism of interaction consists in oppression of CYP 2C19. It was reported that at simultaneous use with omeprazoly levels of an atazanavir and nelfinavir in blood serum decreased therefore their simultaneous use is not recommended. Despite similarity of pharmakodinamichesky effects and pharmacokinetic properties of an omeprazol and esomeprazole, it is not recommended to apply esomeprazole along with atazanaviry. The accompanying use of esomeprazole with nelfinaviry is contraindicated.

Esomeprazole inhibits SUR2S19 – the main enzyme which metabolizes esomeprazole. Therefore at use of esomeprazole in a combination with drugs which are metabolized by SUR2S19 (such as diazepam, to tsitalopra, Imipraminum, кломипрамин, Phenytoinum) concentration of these drugs in a blood plasma can be increased therefore reduction of their dose can be necessary. It should be considered, especially at purpose of esomeprazole "in case of need". Simultaneous use of 30 mg of esomeprazole leads to decrease in clearance of CYP2C19 of substrate of diazepam by 45%.

Simultaneous use of 40 mg of esomeprazole leads to increase in level of Phenytoinum in a blood plasma for 13% at patients with epilepsy. It is recommended to control concentration of Phenytoinum in a blood plasma at appointment or cancellation of therapy as esomeprazole. Use of 40 mg of esomeprazole by patients which accepted warfarin showed that time of coagulation was within norm. Experience of oral administration of esomeprazole testifies about several isolated cases of clinically significant increase in the international normalized relation (INR) during simultaneous use of esomeprazole and warfarin. It is recommended to carry out monitoring of INR at the beginning and at the end of simultaneous treatment by esomeprazole and warfarin or other derivatives of coumarin.

Omeprazol, as well as esomeprazole, acts as CYP 2C19 inhibitor. Use of an omeprazol in a dose of 40 mg by healthy volunteers during the research led to increase in Cmax and the area under a curve of dependence of concentration from time (AUC) for a tsilostazola for 18% and 26% respectively, and for one of its active metabolites for 29% and 69% respectively.

Simultaneous use of 40 mg of esomeprazole with tsizapridy led to increase in the area under a curve of dependence of concentration from time (AUC) for 32% and increase in time of semi-removal (t1/2) for 31%, but there was no noticeable increase in peak level of a tsizaprid in a blood plasma. Moderately prolonged QT interval was observed after reception of a tsizaprid separately, did not increase at use of a tsizaprid in a combination with esomeprazole further.

At simultaneous use of esomeprazole it was informed on increase in level of serum of a takrolimus.

It was reported about increase in level of a methotrexate in blood at some patients at a concomitant use with inhibitors of a proton pomp. If necessary to enter a methotrexate in high doses it is necessary to consider a question of temporary cancellation of esomeprazole.

It was noted that омепразол interacts with some anti-retrovirus means. The clinical importance and the mechanism of such interaction are not always known. Increase gastric рН during use of an omeprazol can change absorption of anti-retrovirus drugs. Other mechanisms of interaction, perhaps, are connected with CYP 2C19 enzyme. In case of use of some anti-retrovirus drugs, such as атазанавир and нелфинавир, noted reduced levels of the last in blood serum at simultaneous use with omeprazoly. For this accompanying use of an omeprazol and such drugs as атазанавир and нелфинавир, it is not recommended. It was reported about increase in levels in serum of other anti-retrovirus means, such as саквинавир. There are also other anti-retrovirus drugs, at simultaneous use with omeprazoly levels of which in blood serum remained invariable. Through similar pharmakodinamichesky effects and pharmacokinetic properties of an omeprazol and esomeprazole simultaneous use of esomeprazole and anti-retrovirus drugs, such as атазанавир and нелфинавир, it is not recommended.

Use of an omeprazol (40 mg of 1 times a day) from atazanaviry 300 mg and ritonaviry 100 mg caused essential weakening of action of an atazanavir in healthy volunteers (approximately

75% reduction of AUC, Cmax, Cmin). Increase in a dose of an atazanavir to 400 mg did not compensate influence of an omeprazol on efficiency of an atazanavir. Inhibitors of the proton pump, including esomeprazole, should not be applied together with atazanaviry.

Esomeprazole did not show clinically significant effect on pharmacokinetics of amoxicillin or quinidine. At simultaneous short-term use of esomeprazole and Naproxenum or to a rofekoksib of clinically significant pharmacokinetic interactions it was not noted.

Influence of other medicines on esomeprazole pharmacokinetics. Esomeprazole is metabolized SUR2S19 and SURZA4. Simultaneous use of esomeprazole and SURZA4 inhibitor of a klaritromitsin (500 mg 2 times a day) led to increase in exposure of esomeprazole twice. Simultaneous use of esomeprazole and komb_novanny SUR2S19 and SURZA4 inhibitor, such as вориконазол, can cause increase in exposure of esomeprazole more than twice.

CYP2C19 and CYP3A4 inhibitor вориконазол led to increase in AUCτ of an omeprazol for 280%.

Dose adjustment of esomeprazole should be considered at patients with heavy hepatic disturbance and in case of purpose of prolonged treatment.

The drugs inducing CYP2C19, CYP3A4 or both enzymes (such as rifampicin or grass of a St. John's Wort), can lead to decrease in levels of esomeprazole in blood serum by acceleration of his metabolism.


Contraindications:

The known hypersensitivity to esomeprazole, replaced benzimidazole or to other components of drug. Drug, as well as other inhibitors of the proton pump, it is not necessary to apply together with atazanaviry, nelfinaviry.

Children's age up to 12 years.


Overdose:

The overdoses given relatively are limited. Gastrointestinal symptoms and weakness are described after reception of 280 mg of esomeprazole. The single dose of esomeprazole of 80 mg will not cause heavy side effects. The special antidote is unknown.

Esomeprazole considerably contacts blood plasma proteins and therefore not діалізується. Treatment – symptomatic.


Storage conditions:

To store at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 2 years.


Issue conditions:

According to the recipe


Packaging:

On 7 tablets in the blister, on 2 blisters in cardboard packaging. On 10 tablets in the blister, on 2 blisters in cardboard packaging.



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