Neksium lyophilisate

General characteristics. Structure:

Active agent:
Esomeprazole sodium 42,5 mg equivalent to 40 mg of esomeprazole.
Excipients:
Dinatrium эдетат dihydrate of 1,5 mg, sodium hydroxide of 0,2-1 mg.

Description. Lyophilisate of white or almost white color in the form of the pressed weight.
Pharmakoterapevtichesky group: stomach glands secretion the lowering means – the proton pump inhibitor.

Pharmacological properties:

Pharmacodynamics. Esomeprazole is S-isomer of an omeprazol and reduces secretion of hydrochloric acid in a stomach by specific inhibition of a proton pomp in covering cells of a stomach. S-and R-isomer of an omeprazol have similar pharmakodinamichesky activity.
Action mechanism
Esomeprazole is the weak basis which passes into an active form in strongly acid medium of secretory tubules of covering cells of a mucous membrane of a stomach and inhibits a proton pomp – H+/K enzyme +-to ATFAZ, at
it there is an inhibition of both basal, and stimulated secretion of hydrochloric acid.
Influence on secretion of hydrochloric acid in a stomach
After intake of esomeprazole in a dose of 20 mg or 40 mg within 5 days by patients with a gastroesophageal reflux disease (GERB) with existence of symptoms noted decrease in secretion of hydrochloric acid in a stomach for the most part of days. The effect was identical at intravenous
introduction and at intake. The analysis of pharmacokinetic data allowed to reveal interrelation between inhibition of secretion of hydrochloric acid and concentration of esomeprazole in plasma after intake (for assessment of concentration used the AUC parameter – the area under a curve "concentration – time"). Against the background of intravenous administration of 80 mg of esomeprazole within 30 minutes with the subsequent prolonged intravenous infusion of esomeprazole in a dose of 8 mg/h in
the current of 23,5 hours value gastric рН was higher than 4 within, on average, 21 hour, and higher than 6 – within 11-13 hours. The therapeutic effect reached as a result of secretion inhibition
hydrochloric acid. Healing a reflux esophagitis at oral administration of esomeprazole in a dose of 40 mg occurs approximately at 78% of patients in 4 weeks of therapy and at 93% of patients in 8 weeks of therapy.
Efficiency of the drug Neksium® at the bleeding from a round ulcer confirmed endoscopic is shown. Other effects connected with inhibition of secretion of hydrochloric acid during treatment by the drugs lowering secretion of glands of a stomach
concentration of gastrin in plasma increases as a result of decrease in secretion of hydrochloric acid. Owing to decrease in secretion of hydrochloric acid concentration of chromogranin A (CgA) increases. Increase in concentration of CgA can exert impact on results of inspections for detection of neuroendocrinal tumors. For prevention of this influence it is necessary to stop temporarily reception of esomeprazole in 5 days prior to carrying out a research of concentration of CgA.
At the patients accepting esomeprazole inside during a long period increase in quantity of enterokhromaffinopodobny cells was noted that it is probably connected with increase in concentration of gastrin in plasma.
At the patients accepting orally for a long time the drugs lowering secretion of glands of a stomach formation of ferruterous cysts in a stomach was more often noted. These phenomena are caused by physiological changes in result of inhibition of secretion of hydrochloric acid. Cysts high-quality are also exposed to involution.
Use of the medicines suppressing secretion of hydrochloric acid in a stomach including, inhibitors of a proton pomp, is followed by increase in contents in a stomach of the microbic flora which normal is present at digestive tract. Use of inhibitors of a proton pomp can lead to insignificant increase in risk of infectious diseases of the digestive tract caused by Salmonella spp., Campylobacter spp. and, the hospitalized patients have probably Clostridium difficile.
Pharmacokinetics. Distribution
The seeming distribution volume at an equilibrium state at healthy people makes about 0,22 l/kg of body weight. Esomeprazole contacts proteins of plasma for 97%.
Metabolism and removal
Esomeprazole is exposed to full metabolism with participation of system of P450 cytochrome. The main part is metabolized with the participation of a specific polymorphic isoenzyme of CYP2C19, at the same time hydroxylated and desmetilirovanny metabolites of esomeprazole are formed. Metabolism of the rest is carried out by CYP3A4 isoenzyme; at the same time it is formed sulfoderivative esomeprazole – the main metabolite defined in plasma.
The parameters specified below reflect, generally character of pharmacokinetics at patients with a superactivity of an isoenzyme of CYP2C19.
The general plasma clearance makes about 17 l/h after single administration of drug and 9 l/h – at repeated introductions. The elimination half-life makes 1,3 hours at repeated administrations of drug once a day. The area under a curve "concentration – time" (AUC) increases at repeated introduction. This increase is time - and dozozavisimy that is a consequence of decrease in metabolism at "the first passing" through a liver, and also decrease in system clearance probably caused by the fact that esomeprazole and/or its sulfoderivative inhibit CYP2C19 isoenzyme.
At daily use once a day esomeprazole is completely removed from plasma in a break between introductions, the tendency to cumulation of esomeprazole is not noted.
At repeated intravenous administration of esomeprazole in a dose of 40 mg average maximum concentration in plasma makes about 13,6 µmol/l. At intake of similar doses average plasma maximum concentration makes 4,6 µmol/l. Slightly less the general exposure increases (approximately by 30%) at intravenous administration of esomeprazole in comparison with oral administration.
At intravenous administration of esomeprazole in doses of 40 mg, 80 mg and 120 mg within 30 min. with the subsequent intravenous administration in a dose of 4 mg/h or 8 mg/h during 23,5 h linear dependence of AUC on the entered dose was shown.
The main metabolites of esomeprazole do not influence secretion of hydrochloric acid in a stomach. At oral administration to 80% of a dose of esomeprazole other part – intestines is removed in the form of metabolites by kidneys. In urine less than 1% of not changed esomeprazole are found.
Features of pharmacokinetics in some groups of patients
Approximately at 2,9±1,5% of the population activity of an isoenzyme of CYP2C19 is reduced. Such patients have an esomeprazole metabolism, is generally carried out by means of CYP3A4, and at repeated intake of 40 mg of esomeprazole once in days average area under a curve "concentration – time" is 100% higher, than patients with a superactivity of an isoenzyme have CYP2C19. Average values of the maximum concentration in plasma at patients with reduced activity of an isoenzyme are increased approximately for 60%. Similar distinctions are revealed at intravenous administration of esomeprazole. Noted features do not influence a dose and a route of administration of esomeprazole.
At patients of advanced age (71-80 years) esomeprazole metabolism significantly does not change.
At patients with an easy and moderate abnormal liver function metabolism of esomeprazole can be broken. At patients with a heavy abnormal liver function the speed of metabolism is reduced that concentration – time" for esomeprazole leads to doubling of the area under a curve ". The tendency to cumulation of esomeprazole and its main metabolites at administration of drug is not noted once a day.
Studying of pharmacokinetics at patients with reduced function of kidneys was not carried out. As through kidneys removal not of the esomeprazole, but its metabolites is carried out, it is possible to believe that metabolism of esomeprazole at patients with a renal failure does not change.

Indications to use:

- as an alternative peroral therapy at impossibility of its carrying out:
- at a gastroesophageal reflux disease at patients with an esophagitis and/or the expressed symptoms of a reflux disease
- for healing of the round ulcers connected with reception of non-steroidal anti-inflammatory drugs (NPVP)
- for prevention of the round ulcers connected with reception of NPVP at the patients belonging to risk group
- for prevention of a recurrence of bleeding from a round ulcer after an endoscopic hemostasis.

Route of administration and doses:

Adults
As an alternative peroral therapy at impossibility of its carrying out:
At impossibility of performing peroral therapy esomeprazole parenterally in a dose of 20-40 mg of 1 times a day can be recommended to patients.
At a gastroesophageal reflux disease at patients with an esophagitis esomeprazole in a dose of 40 mg of 1 times a day is recommended. To treatment of symptoms of GERB Neksium® it is applied in a dose of 20 mg of 1 times a day. For healing of the round ulcers connected with reception of NPVP at the patients belonging to risk group esomeprazole in a dose of 20 mg of 1 times a day is recommended.
For prevention of the round ulcers connected with reception of NPVP esomeprazole in a dose of 20 mg of 1 times a day is recommended.
As a rule, the treatment period an intravenous form is short, the patient should be transferred to oral administration of drug as soon as possible.
For prevention of a recurrence of bleeding from a round ulcer after an endoscopic hemostasis:
After an endoscopic hemostasis esomeprazole in a dose of 80 mg in the form of intravenous infusion within 30 minutes with the subsequent prolonged intravenous infusion of esomeprazole in a dose of 8 mg/h within 3 days (72 hours) is recommended. After the end of parenteral therapy for suppression of secretion of acid anti-secretory therapy is recommended (for example, esomeprazole of 40 mg of 1 times a day within 4 weeks).
Injections
Dose of 40 mg
The prepared solution of esomeprazole is entered intravenously within not less than 3 minutes.
Dose of 20 mg
A half of the prepared solution of esomeprazole is entered intravenously within not less than 3 minutes. The unused remains of solution have to be utilized.
Infusions
Dose of 40 mg
The prepared solution of esomeprazole is entered in the form of intravenous infusion within 10-30 minutes. Dose of 20 mg
A half of the prepared solution of esomeprazole is entered in the form of intravenous infusion within 10-30 minutes. The unused remains of solution have to be utilized.
Dose of 80 mg
The prepared solution of esomeprazole is entered in the form of intravenous infusion within 30 minutes.
Dose of 8 mg/h
The prepared solution of esomeprazole is entered in the form of the prolonged intravenous infusion within 71,5 hours (8 mg/h). (Conditions and a period of storage of the prepared solution - see in the section "Solution Preparation".)
Children
It is not recommended to apply Neksium® at children due to the lack of data on use.
Renal failure
Dose adjustment of the drug Neksium® with a renal failure is not required from patients. Due to the limited experience of use of the drug Neksium® for patients with a heavy renal failure, it is necessary to be careful at treatment of such patients (see the section "Pharmacokinetics").
Abnormal liver function
GERB: dose adjustment of the drug Neksium® with an abnormal liver function easy and moderate severity is not required from patients. At patients with a heavy abnormal liver function the maximum daily dose makes 20 mg (see the section "Pharmacokinetics").
Bleeding from a round ulcer: dose adjustment of the drug Neksium® with an abnormal liver function easy and moderate severity is not required from patients. At patients with a heavy abnormal liver function the following mode of administration of the drug Neksium® is recommended: 80 mg in the form of intravenous infusion within 30 minutes with the subsequent prolonged intravenous infusion in the maximum dose of 4 mg/h within 71,5 hours (see the section "Pharmacokinetics").
Patients of advanced age
Dose adjustment of the drug Neksium® is not required from patients of advanced age.
Solution preparation
Degradation of the prepared solution mainly depends on value рН in this connection for dissolution of drug only 0,9% chloride sodium solution for intravenous administration has to be used.
The prepared solution should not mix up or be entered together with other medicines.
Before use solution should be estimated visually regarding lack of visible mechanical impurity and discoloration. Only transparent solution can be used. The prepared solution is recommended to be entered right after preparation (from the microbiological point of view).
The prepared solution should be used within 12 hours. To store at a temperature not over 30C.
At purpose of 20 mg of esomeprazole a half of the prepared solution is entered. The unused remains of solution have to be utilized.
Injections
Solution for injections prepares by addition of 5 ml of 0,9% of solution of sodium of chloride for intravenous administration in a bottle with esomeprazole. Divorced solution of esomeprazole represents transparent liquid from colourless till pale yellow color.
Infusions
Infusion solution prepares by dissolution of contents of one bottle with esomeprazole in 100 ml of 0,9% of solution of sodium of chloride for intravenous administration.
Divorced solution of esomeprazole represents transparent liquid from colourless till pale yellow color. Infusion of 80 mg
Infusion solution prepares by dissolution of contents of two bottles with esomeprazole of 40 mg in 100 ml of 0,9% of solution of sodium of chloride for intravenous administration.

Features of use:

In the presence of any alarming symptoms (for example, such as considerable spontaneous loss of body weight, the repeating vomiting, a dysphagy, vomiting with blood or a melena), and also in the presence of stomach ulcer (or at suspicion of stomach ulcer), it is necessary to exclude existence of a malignant new growth as treatment by the drug Neksium® can lead to smoothing of symptomatology and delay diagnosis.
In rare instances at patients, a long time accepting омепразол, at a histologic research of bioptat of a mucous membrane of a body of a stomach atrophic gastritis came to light. INFLUENCE ON ABILITY to DRIVE the CAR AND OTHER MECHANISMS
Because during therapy dizziness, an illegibility of sight and drowsiness can be observed by the drug Neksium®, it is necessary to be careful at control of motor transport and other mechanisms.

Side effects:

The side effects noted at intravenous and oral administration of the drug Neksium® during conduct of clinical trials and at post-marketing studying of the drug Neksium® for intake are included below.
Often
(> 1/100, <1/10)
Headache, abdominal pain, diarrhea, meteorism, nausea/vomiting, lock, reactions in a drug injection site *
Infrequently
(> 1/1000, <1/100)
Dermatitis, itch, rash, urticaria, drowsiness, sleeplessness, dizziness, paresthesias, dryness in a mouth, peripheral hypostases, increase in activity of "hepatic" enzymes
Seldom
(> 1/10000, <1/1000)
Reactions of hyper feelings of Reaction of hypersensitivity (for example, fever, a Quincke's disease, anaphylactic reaction / an acute anaphylaxis), a bronchospasm, hepatitis (with jaundice or without), an arthralgia, a mialgiya, a leukopenia, thrombocytopenia, a depression, a hyponatremia, excitement, confusion, taste disturbance, stomatitis, digestive tract candidiasis, an alopecia, a photosensitization, an indisposition, perspiration, a sight illegibility
Very seldom
(<1/10000)
Agranulocytosis, pancytopenia, hallucinations, agressive behavior, liver failure, encephalopathy at patients with liver diseases, muscular weakness, intersticial nephrite, a gynecomastia, Stephens-Johnson's syndrome, a toxic epidermal necrolysis, a multiformny erythema, a hypomagnesiemia, the microscopic colitis (confirmed histologically).
* Reactions in a drug injection site, were generally noted in clinical trial at purpose of esomeprazole in a high dose within 3 days (72 hours). At preclinical studying of esomeprazole for intravenous administration of irritant action it was not revealed, however the weak inflammatory reaction at hypodermic administration of drug depending on concentration of esomeprazole was noted.
It was reported about separate cases of an irreversible vision disorder at intravenous administration of an omeprazol to patients in a critical state, especially at introduction of high doses, relationship of cause and effect with administration of drug it is not established.

Interaction with other medicines:

Influence of esomeprazole on pharmacokinetics of other medicines
Decrease in secretion of hydrochloric acid in a stomach at treatment by esomeprazole and other inhibitors of the proton pump can lead to decrease or increase in absorption of other drugs which absorption depends on acidity of the environment. Like other drugs reducing acidity of a gastric juice, treatment by esomeprazole can lead to decrease in absorption of a ketokonazol, itrakonazol and erlotinib, and also to increase in absorption of such drugs as digoxin. Joint reception of an omeprazol in a dose of 20 mg and digoxin increases once a day bioavailability of digoxin for 10% (bioavailability of digoxin increased at a size up to 30% at 20% of patients).
It was shown what омепразол interacts with some anti-retrovirus drugs. Mechanisms and clinical value of these interactions are not always known. Increase in value рН against the background of therapy omeprazoly can influence absorption of anti-retrovirus drugs. Interaction at the level of CYP2C19 isoenzyme is also possible. At combined use of an omeprazol and some anti-retrovirus drugs, such as атазанавир and нелфинавир, against the background of therapy omeprazoly, decrease in their concentration in serum is noted. Therefore their simultaneous use is not recommended. Combined use of an omeprazol (40 mg once a day) from atazanaviry 300 mg / to healthy volunteers led ritonaviry 100 mg to essential reduction of bioavailability of an atazanavir (the area under a curve "concentration – time", maximum (Cmax) and minimum (Cmin) of concentration decreased approximately by 75%). Increase in a dose of an atazanavir up to 400 mg did not compensate impact of an omeprazol on bioavailability of an atazanavir.
At simultaneous use of an omeprazol and sakvinavir increase in concentration of a sakvinavir in serum was noted, at use with some other anti-retrovirus drugs their concentration did not change. Considering similar pharmacokinetic and pharmakodinamichesky properties of an omeprazol and esomeprazole, combined use of esomeprazole with anti-retrovirus drugs, such as атазанавир and нелфинавир, it is not recommended.
Esomeprazole inhibits CYP2C19 – the main isoenzyme participating in his metabolism. Combined use of esomeprazole with other drugs in which metabolism CYP2C19 isoenzyme takes part such as diazepam, to tsitalopra, Imipraminum, кломипрамин, Phenytoinum, etc., can lead to increase in concentration of these drugs in plasma and demand a dose decline. At oral joint administration of 30 mg of esomeprazole and diazepam the clearance of diazepam which is CYP2C19 isoenzyme substrate decreases by 45%.
At joint reception of esomeprazole orally in a dose of 40 mg and Phenytoinum at patients with epilepsy residual concentration of Phenytoinum in plasma increased by 13%. In this regard control of concentration of Phenytoinum in plasma in an initiation of treatment is recommended by esomeprazole and at its cancellation. Use of an omeprazol in a dose of 40 mg led to increase in the area under a curve once a day "concentration – time" and Cmax of a vorikonazol (CYP2C19 isoenzyme substrate) for 15% and 41%, respectively.
At esomeprazole use orally in a dose of 40 mg to the patients receiving warfarin, time of coagulation remained within admissible values. However INR (the international normalized relation) at combined use of warfarin and esomeprazole was reported about several cases of clinically significant increase. In this regard monitoring of MNO at the beginning and upon termination of combined use of these drugs is recommended.
Use of an omeprazol in a dose of 40 mg led to increase in Cmax and the area under a curve once a day "concentration – time" a tsilostazol for 18% and 26%, respectively; for one of active metabolites of a tsilostazol increase made 29% and 69%, respectively.
Healthy volunteers have a joint oral administration of esomeprazole in a dose of 40 mg and a tsizaprida for 32% increased area size under a curve "concentration – time" (AUC) and increased an elimination half-life (t1/2) for a tsizaprid by 31%; the maximum concentration of a tsizaprid in plasma at the same time considerably did not change. Insignificant lengthening of an interval of QT which was observed at monotherapy tsizapridy at addition of esomeprazole did not increase (see the section "Special Instructions").
At some patients noted increase in concentration of a methotrexate against the background of combined use with inhibitors of the proton pump. At purpose of high doses of a methotrexate it is necessary to consider the possibility of temporary cancellation of esomeprazole.
It is shown that esomeprazole does not cause clinically significant changes of pharmacokinetics of amoxicillin and quinidine.
Researches on studying of interaction of esomeprazole with other medicines at its intravenous use in high doses (80 mg with the subsequent introduction in a dose of 8 mg/h) were not conducted. Perhaps, at such mode of dosing esomeprazole exerts more expressed impact on pharmacokinetics of substrates of an isoenzyme of CYP2C19. Therefore patients have to be under fixed medical observation during intravenous administration of esomeprazole.
Influence of medicines on drug Neksium® pharmacokinetics
Isoenzymes of CYP2C19 and CYP3A4 participate in metabolism of esomeprazole. Combined oral administration of esomeprazole and inhibitor of an isoenzyme CYP3A4, a klaritromitsina (500 mg 2 times a day) leads to double increase in AUC value for esomeprazole. Combined use of esomeprazole and the combined inhibitor of isoenzymes of CYP3A4 and CYP2C19, for example, of a vorikonazol, can lead more than to 2-fold increase in AUC value for esomeprazole. As a rule, in such cases esomeprazole dose adjustment is not required. Dose adjustment of esomeprazole can be required at patients with a heavy abnormal liver function and at its prolonged use.
The medicines inducing isoenzymes of CYP2C19 and CYP3A4 such as, rifampicin and drugs of the St. John's Wort which is made a hole at combined use with esomeprazole can lead to decrease in concentration of esomeprazole in a blood plasma due to esomeprazole metabolism acceleration.
For dissolution of drug only the medicines mentioned in the section "Solution Preparation" have to be used.

Contraindications:

Hypersensitivity to esomeprazole, the replaced benzimidazoles or other ingredients of drug. Children's age (due to the lack of data on use of drug for this group of patients).
Esomeprazole should not be accepted together with atazanaviry and nelfinaviry (see the section "Interaction with Other Medicines and Other Types of Interaction").
With CARE: patients with a heavy renal failure.
PREGNANCY AND PERIOD OF THE LACTATION
Now data on use of esomeprazole during pregnancy are limited. In researches on animals any direct or indirect negative impact of the drug Neksium® on development of an embryo or a fruit is not revealed. Administration of racemic mix of drug also did not make any negative impact on animals during pregnancy, childbirth, and also during post-natal development.
It is necessary to appoint drug during pregnancy only in that case when the expected advantage for mother exceeds possible risk for a fruit.
There are no data on drug use by women in the period of a lactation. It is not known whether esomeprazole with breast milk therefore it is not necessary to appoint Neksium® during feeding a breast is emitted. In case of need therapy by the drug Neksium® in the period of a lactation should consider the possibility of the termination of breastfeeding.

Overdose:

Extremely exceptional cases of intentional overdose are currently described. At oral administration of 280 mg of esomeprazole weakness and symptoms from digestive tract were described. One-time reception of 80 mg of esomeprazole inside and intravenous administration of 308 mg within 24 hours did not cause any negative effects.
The antidote of esomeprazole is unknown. Esomeprazole well contacts proteins of plasma therefore dialysis is ineffective. At overdose it is necessary to carry out the symptomatic and general supporting treatment.

Storage conditions:

To store in the place protected from light in original packaging at a temperature not above 30 °C. To store in the places unavailable to children. It is possible to store a bottle without cardboard pack at room lighting no more than 24 hours.

Issue conditions:

According to the recipe

Packaging:

Lyophilisate for preparation of solution for intravenous administration of 40 mg.
On 40 mg of esomeprazole in the transparent glass bottle of 5 ml corked by a brombutilovy rubber bung, which is rolled up by an aluminum blooming ring with a plastic cover.
10 bottles in a paper support with the application instruction in a cardboard pack with control of the first opening.
When packaging on Korden Pharm Gmbh, Germany: 10 bottles in a paper support in a cardboard pack with the application instruction.