Vimovo TM - instructions for use, dose, side effects, contraindications

Active substanceNaproxen + EsomeprazoleNaproxen + Esomeprazole

Similar drugsTo uncover

Vimovo TM

pills inwards

AstraZeneca UK Ltd United Kingdom

Dosage form: & nbspenteric coated tablets

Composition:

One tablet contains:

active substances: naproxen 500 mg, esomeprazole magnesium three hydrate 22.3 mg equivalent to 20 mg esomeprazole;

Excipients: croscarmellose sodium 22.0 mg, povidone K90 11.0 mg, silicon dioxide colloid 2.62 mg, magnesium stearate 1.38 mg, hypromellose 3 mPas 77.35 mg, macrogol 8000 5.85 mg, triethyl citrate 8.18 mg , Polysorbate 80 4.55 mg, glyceryl monostearate 40-55 2.69 mg, methyl parahydroxybenzoate (E218) about 0.02 mg, propyl parahydroxybenzoate (E216) about 0.01 mg, methacrylic acid and ethyl acrylate copolymer (1: 1), suspension 30% 54.6 mg, titanium dioxide 13.56 mg , polydextrose (E1200) 6.30 mg, hypromellose 6 mPas 10.85 mg, hypromellose 50 mPas 0.68 mg, iron oxide yellow (E172) 0.58 mg, carnauba wax 0.05 mg, black ink (Opacode black) q.s.
The composition of black ink (Opacode black): iron oxide black - 22%, hypromellose 6 mPas - 7%, propylene glycol - 10%, isopropanol - 12%, purified water - 49%. Removed during production.

Description:

Oval pills covered with a film membrane of yellow color, with the inscription "500/20" on one side, made with a black dye.

Pharmacotherapeutic group:NSAIDs + glands of the stomach with a sulfur-lowering agent - proton pump inhibitor

ATX: & nbsp

M.01.A.E.52 Naproxen and esomeprazole

Pharmacodynamics:

The drug Vimovo ™ is developed in the form of tablets with consecutive delivery of substances: the envelope contains esomeprazole magnesium immediate release, and in the nucleus - naproxen sustained release, coated with an enteric-coated membrane. As a result, esomeprazole is released in the stomach until naproxen dissolves in the small intestine. The enteric membrane prevents the release of naproxen at a pH below 5, providing protection against the possible negative effects of naproxen on the gastric mucosa.

Naproxen is a non-steroidal anti-inflammatory drug with analgesic and antipyretic other NSAIDs, is not fully understood, but may be associated with the suppression of prostaglandin synthetase. Esomeprazole is an S-isomer of omeprazole and reduces the secretion of hydrochloric acid in the stomach by specifically inhibiting the proton pump in parietal cells of the stomach. S- and R- omeprazole isomers have similar pharmacodynamic activity. Esomeprazole is a weak base that transforms into an active form in a highly acidic environment of the secretory tubules of parietal cells of the gastric mucosa and inhibits the proton pump - the enzyme H⁺/TO⁺- ATPase, with the inhibition of both basal and stimulated secretion of hydrochloric acid.

Effect on the secretion of hydrochloric acid in the stomach

After 9 days of taking two times a day, three combinations of Vimovo ™: naproxen 500 mg in combination with esomeprazole in doses of 10 mg, 20 mg or 30 mg, the stomach pH above 4 was maintained on average 9.8 hours, 17.1 hours and 18.4 hours, respectively, during the day in healthy volunteers. The variability of the individual values of the gastric pH keeping time is higher than 4, in the form of the coefficient of variability (CV), amounted to 55%, 18% and 16%, respectively. Other effects associated with inhibition of hydrochloric acid secretion.
During treatment with drugs that reduce secretion the concentration of gastrin in the plasma is increased as a result of decreased acid secretion.

Due to a decrease in the secretion of hydrochloric acid, the concentration of chromogranin A (CgA). Increase in concentration CgA can influence the results of examinations for the detection of neuroendocrine tumors.To prevent this effect, therapy with proton pump inhibitors should be stopped 5 to 14 days before the study concentration CgA. If during this time the concentration CgA did not return to the normal value, the study should be repeated.

Patients who received long-term esomeprazole, there is an increase in the number of enterochromaffin-like cells, probably associated with an increase in the concentration of gastrin in the plasma. Clinical significance of this phenomenon is not.

In patients taking drugs that reduce the secretion of the glands of the stomach, for a long period of time, the formation of glandular cysts in the stomach is more often noted. These phenomena are caused by physiological changes as a result of pronounced inhibition of the secretion of hydrochloric acid. Cysts benign and exposed reverse development.

The use of medicines, suppressing the secretion of hydrochloric acid in stomach, including inhibitors proton pump, accompanied by increased content in the stomach microbial flora, normal present in the gastrointestinal tract. Application of inhibitors proton pump can lead to a slight increase in the risk of infectious diseases of the gastro-of the intestinal tract caused by bacteria kind Salmonella spp. and Campylobacter spp., a in hospitalized patients, possibly also bacteria Clostridium difficile.

Clinical efficacy and security

Vimovo ™ at a dose of 500 mg / 20 mg twice a day day significantly reduced the frequency of ulcers, associated with the administration of NSAIDs patients who are not infected N. pylori, related to the risk group (elderly age, stomach ulcer, or duodenal ulcer in the anamnesis), according to compared with naproxen in tablets, coated with enteric coating, 500 mg twice daily for six months of therapy in combination with other proton pump inhibitors or in the monotherapy regime. Frequency the development of gastric ulcers with Vimovo ™ was 5.6, and with naproxen - 23.7. Admission Vimovo ™ also reduced the incidence of duodenal ulcers compared with naproxen therapy (0.7% and 5.4%, respectively).

Patients who used Vimovo ™ had a lower incidence of NSAID side effects from the upper GI tract compared with patients taking naproxen in tablets coated with an enteric coating (53.3% and 70.4%, respectively).

In patients taking Vimovo ™ and low-dose acetylsalicylic acid, a lower incidence of gastric and duodenal ulcers was observed compared with patients who took acetylsalicylic acid together with naproxen in enteric coated tablets (4% and 32.4%, respectively ).

Vimovo ™ was also effective in patients aged 60 years and older - the incidence of gastric and duodenal ulcers was 3.3%, and in patients receiving naproxen in tablets coated with enteric coating - 30.1 %.

In patients who took Vimovo ™ for 6 months, a lower incidence of dyspepsia was noted compared with naproxen in tablets coated with enteric-soluble shell.

Patients who received Vimovo ™, less often discontinued therapy because of the development of adverse effects (7.9%) compared with patients receiving naproxen at tablets, coated with enteric-soluble shell (12.5%). Frequency of termination therapy due to side effects of the upper parts of the gastro- intestinal tract was also lower with Vimovo ™ therapy (4.0% and 12.0%, respectively, respectively). Average duration of therapy Vimovo ™ was 152 days compared to 124 days of naproxen monotherapy.

In osteoarthritis of the knee joint, similar efficacy of Vimovo ™ in a dose of 500 mg / 20 mg twice a day and celecoxib at a dose of 200 mg per day with admission for 12 weeks of therapy was noted. The frequency of cancellation of therapy because of the development of side effects was also similar.

Pharmacokinetics:

Absorption

Naproxen

In the equilibrium state after two-time reception of Vimovo ™ The maximum concentrations of naproxen in plasma levels are achieved on average in 3 hours after the morning and evening dose. Time until the maximum concentrations of naproxen in the plasma a little longer on the first day of therapy, while medians of time after the morning and the maximum concentration of naproxen in plasma (C_max), the bioequivalence of Wimovo ™ and naproxen was proved, covered enteric coating.

Naproxen quickly and completely absorbed from the gastrointestinal tract (bioavailability of 95%). The equilibrium concentration of naproxen is reached after 4-5 days of admission.

Esomeprazole

After twice taking Vimovo ™ esomeprazole quickly absorbed, reaching a maximum concentration in blood plasma, on average, 0.5-0.75 hours after the morning and evening doses on the first day and after reaching the equilibrium state. The maximum plasma esomeprazole concentrations are higher in the equilibrium state compared to the concentration on the first day of administration of Vimovo ™. This is partly due to increased absorption due to pharmacodynamic effect esomeprazole, increasing the pH of the stomach, which leads to a decrease in the acidic disintegration of esomeprazole in the stomach. Decreased presystemic metabolism and systemic clearance of esomeprazole on the background of repeated administration of the drug also contributes to an increase in the plasma concentrations of esomeprazole in the equilibrium state.

Reception with food

Taking Vimovo ™ with food does not affect the degree of absorption of naproxen, but it significantly inhibits (by 8 hours) absorption and reduces by 12% the maximum maximum plasma concentration, respectively.

The intake of Vimovo ™ 30 minutes prior to meals did not, or had a minimal effect on, the amount and time of absorption of naproxen, and did not significantly affect the rate and extent of absorption of esomeprazole compared to the administration of Vimovo ™ during meals.

Distribution

Naproxen

The volume of naproxen distribution is 0.16 l / kg. Naproxen in therapeutic concentrations more than 99% binds to serum albumin. When taking naproxen in doses of more than 500 mg per day, plasma concentrations increase less than proportionally to the dose due to increased clearance as a result of saturable communication 500, 1000 and 1500 mg, respectively). An anion of naproxen was found in the milk of lactating women at a concentration of approximately 1% of the maximum concentration of naproxen in plasma.

Esomeprazole

The apparent volume of distribution in the equilibrium state in healthy volunteers is approximately 0.22 l / kg body weight. Esomeprazole 97% bound to plasma proteins.

Metabolism

Naproxen

Naproxen is widely metabolized in the liver by the cytochrome P450 system (CYP), basically, an enzyme CYP2C9, to 6-O-desmethylnaproxen. The initial drug or metabolites do not induce metabolic enzymes. Naproxen and 6-O-desmethylnaproxene are further metabolized to the corresponding acylglucuronides conjugated metabolites. In accordance with the half-life of naproxen AUC increases with the repeated admission of Vimovo ™ twice a day.

Esomeprazole

Esomeprazole is completely metabolized by the cytochrome P450 system (CYP). A significant part of the metabolism of esomeprazole depends on the polymorphic enzyme CYP2C19, which is responsible for the formation of hydroxy- and desmethyl metabolites of esomeprazole. The rest is dependent on another specific isoform, CYP3A4, which is responsible for the formation AUC Esomeprazole increases with the repeated admission of Vimovo ™ twice daily. This increase depends on the dosage and explains the non-linear dose relationship with AUC after repeated taking the drug. This time and dose dependence is partly due to a decrease in presystemic metabolism and systemic clearance, probably due to inhibition of the enzyme CYP2C19 esomeprazole and / or its sulfonic metabolite. The increased absorption of esomeprazole with the repeated admission of Vimovo ™ probably also contributes to this time and dose dependence.

Excretion

Naproxen

After twice taking Vimovo ™, the average half-life of naproxen is approximately 9 hours and 15 hours after the morning and evening doses, respectively, and does not change with repeated use of the drug.

The clearance for naproxen is 0.13 ml / min / kg. Approximately 95% of naproxen from any dose is excreted in the urine, mainly in the form of naproxen (<1%), 6-O-desmethylnaproxen (<1%) or their conjugates (66% to 92%). Small amounts, 3% or less of the dose taken, are excreted with feces. In patients with renal insufficiency, metabolites can accumulate. Esomeprazole After receiving Vimovo ™ twice period half-life Esomeprazole is approximately 1 hour after the morning and evening doses in the first Almost 80% of the dose of esomeprazole after ingestion is excreted as metabolites in the urine, the rest with feces. Less than 1% of the original (unchanged) drug is excreted in the urine.

Special patient groups

Patients with renal insufficiency

Not were conducted research pharmacokinetics of Vimovo ™ in patients with renal insufficiency.

Naproxen: parameters of pharmacokinetics of naproxen in patients with renal insufficiency were not determined.

As naproxen, its metabolites and conjugates are mainly excreted in the urine, in the case of renal failure, a cumulation of naproxen metabolites is possible. In patients with severe renal failure, the elimination of naproxen is reduced.It is not recommended to apply Vimovo ™ in patients with severe renal insufficiency (creatinine clearance <30 mL / min).

Esomeprazole: There have been no studies of esomeprazole in patients with reduced renal function. Since the excretion of metabolites of esomeprazole, rather than the parent drug, is performed by the kidneys, it is not expected that in patients with impaired renal function the metabolism of esomeprazole will change.

Patients from hepatic insufficiency

Not were conducted research pharmacokinetics of Vimovo ™ in patients with hepatic insufficiency.

Naproxen: parameters of pharmacokinetics of naproxen in patients with hepatic insufficiency were not determined. Alcoholic cirrhosis and, probably, other forms of cirrhosis reduce the total concentration of naproxen in blood plasma, but increase the concentration unbound naproxen in plasma.

The applicability of these data to naproxen in Vimovo ™ is not known, but in it is reasonable to appoint such situations the lowest effective dose of the drug.

Esomeprazole: Weak or moderate hepatic failure may affect the metabolism of esomeprazole.

The level of metabolism is lower in patients with severe hepatic insufficiency that leads to a doubling AUC esomeprazole.

Therefore, do not exceed the maximum daily dose of esomeprazole 20 mg in patients with severe hepatic insufficiency. Do not prescribe Vimovo ™ to patients with severe hepatic insufficiency.

Application in elderly patients

There are no specific data on Vimovo ™ pharmacokinetics in patients over 65 years of age.

Naproxen: Studies show that Although the total concentration of naproxen in plasma does not change, unrelated the proportion of naproxen in blood plasma increases in elderly patients, but The unbound fraction is less than 1% of the total naproxen concentration.

The minimum concentrations of unbound naproxen in elderly patients ranged from 0.12% to 0.19% of the total concentrations of naproxen compared to 0.05% -0.075% in young patients. The clinical significance of this data is not known, although it is possible that an increase in the concentration of free naproxen may be accompanied by an increase in the incidence of adverse events with a specific dose in some elderly patients.

Esomeprazole: Metabolism of esomeprazole does not change significantly in elderly patients (aged 71 to 80 years).

Peculiarities of pharmacokinetics in some groups patients.

Approximately 2.9 ± 1.5% of the population has decreased isoenzyme activity CYP2C19. In such patients, the metabolism of esomeprazole is mainly due to the action of CYP3A4. With the systematic administration of 40 mg of esomeprazole, once a day, the mean AUC 100% higher than this parameter in patients with increased isoenzyme activity CYP2C19. The mean values of maximum plasma concentrations in patients with reduced isoenzyme activity were increased by approximately 60%. These features do not affect the dose and method of application of Vimovo ™.

Floor

Esomeprazole: After a single dose of esomeprazole 40 mg, the average area under the concentration ratio curve plasma in time by almost 30% higher in women than in men. After repeated use of esomeprazole once in day there was no difference in the dependence from the sex of patients. These data do not have values for the application mode Vimovo ™.

Indications:

Relieving Symptoms in Treatment osteoarthritis (osteoarthritis), rheumatoid arthritis and ankylosing spondylitis in patients with risk of developing gastric ulcers and / or duodenum, associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs).

Contraindications:

Hypersensitivity to nalroxen, esomeprazole, substituted benzimidazoles or other ingredients included in the preparation.

Children under 18 years of age (efficacy and safety of use not studied). Patients with a history of bronchial asthma, urticaria and allergic reactions when taking acetylsalicylic acid and other NSAIDs (complete or incomplete combination of intolerance to acetylsalicylic acid, rhinosinusitis, urticaria, angioedema, polyposis of the nasal mucosa and bronchial asthma).

Third trimester of pregnancy.

Breastfeeding period.

Severe hepatic insufficiency (Child-Pugh class C) or active liver disease.

Severe uncontrolled heart failure.

Severe renal insufficiency (creatinine clearance less than 30 ml / min.). Confirmed hyperkalemia.

Peptic ulcer of the stomach or duodenum in the stage of exacerbation.Gastrointestinal bleeding, cerebral hemorrhage or other bleeding. Inflammatory bowel disease in the phase of exacerbation (ulcerative colitis, Crohn's disease).

Conditions after coronary artery bypass grafting.

Vimovo ™ should not be taken with atazanavir and nelfinavir (see section "Interaction with other drugs and other types of drug interactions").

Carefully:

FROM caution - chronic heart failure (II-IV functional class by classification NYHA), elderly age; side effects from the gastrointestinal tract when taking acetylsalicylic acid or NSAIDs in history; Arterial hypertension, IBO, peripheral arterial disease, cerebral circulation disorder; simultaneous administration of oral corticosteroids, anticoagulants, selective serotonin reuptake inhibitors or antithrombotic agents (eg, acetylsalicylic acid), ACE inhibitors, diuretics; patients with risk factors for the development of cardiovascular diseases (eg, hypertension, hyperlipidemia, diabetes mellitus,smoking); Diseases of the gastrointestinal tract in the anamnesis (Crohn's disease, ulcerative colitis); hypovolemia; mild to moderate renal insufficiency; mild and moderate hepatic insufficiency.

Pregnancy and lactation:

Fertility

The use of NSAIDs, such as naproxen, may adversely affect the fertility. Research on animals showed that the intake of NSAIDs, such as naproxen, can suppress ovulation. AT several cases of infertility in women, taking NSAIDs, such as naproxen, restoration of fertility after their cancellation. Before appointment Vimovo ™ to women, who are trying to become pregnant, should assess the benefit / risk ratio (see subsection Pregnancy).

Pregnancy

Naproxen:

Studies naproxen conducted on animals, did not reveal any direct or indirect adverse effects on the development of the embryo / fetus. Epidemiological data research indicate an increased risk of miscarriage in women with NSAIDs in the early stages of pregnancy. Congenital anomalies were noted in the use of NSAIDs in humans; However, they developed rarely and were not specific.As with the use of other drugs of this type, naproxen inhibits labor in animals and affects the cardiovascular system of the human fetus (premature closure of the arterial duct). Contraindicated in the use of naproxen in the last trimester of pregnancy. NSAIDs should not be given to women attempting to become pregnant, or during the first two trimesters of pregnancy, unless the possible benefit to the mother outweighs the potential risk to the fetus.

Preparations containing in their composition naproxen, it is not recommended to be used in labor clashes and childbirth in connection with the suppression of synthesis of prostaglandins by naproxen; naproxen can adversely affect the blood circulation of the fetus and inhibit contractions, increasing bleeding in the mother and child. Esomeprazole:

Clinical evidence of effects esomeprazole for pregnancy is not enough. In studies on of animals esomeprazole did not provide direct or indirect adverse effects on embryo / fetus development. AT research on animals racemic the mixture did not directly or indirectly adverse impact on pregnancy, childbirth or postnatal development. Caution should be exercised assign esomeprazole pregnant women.

Breastfeeding period

Naproxen is excreted into breast milk of women. It is not known whether esomeprazole with breast milk, because there were no studies on women during lactation. Admission Vimovo ™ during breastfeeding is contraindicated.

Dosing and Administration:

Inside, 1 tablet (500 mg / 20 mg) twice a day. The tablet should be swallowed whole, washed down with water, not chewing, not breaking in half and not crushing. It is recommended to take Vimovo ™ at least 30 minutes before meals.

Renal insufficiency

Caution should be used to assign Vimovo ™ to patients with mild or moderate renal failure, while carefully monitoring renal function. You may need to reduce the daily dose of naproxen. If the daily dose of naproxen 1000 mg is not acceptable, then alternative therapies should be used.
It is not recommended to appoint Vimovo ™ to patients with severe renal insufficiency (creatinine clearance <30 ml / min) due to the observed accumulation of naproxen metabolites in patients with severe renal insufficiency and in patients on hemodialysis.

Liver failure

Care should be taken to administer Vimovo ™ to patients with mild to moderate hepatic impairment with careful monitoring and careful monitoring of liver function. You may need to reduce the daily dose of naproxen. If the daily dose of naproxen 1000 mg is not acceptable, then alternative therapies should be used.

Rimove ™ is contraindicated in patients with severe hepatic insufficiency, since these patients are not recommended to take more than 20 mg of esomeprazole per day.

Elderly patients

At elderly patients the risk of development of serious complications from undesirable reactions is raised.

Side effects:

The composition of the drug Vimovo ™ includes naproxen and esomeprazole, and therefore can To develop the same undesirable effects, which were observed in the application of these active substances separately.

Undesirable effects from the gastrointestinal tract, such as indigestion, stomach pain, nausea and vomiting, most often develop with the use of naproxen.

When developing Vimovo ™ in its composition included esomeprazole to reduce frequency of gastrointestinal side effects of naproxen. It is shown, that when taking Vimovo ™ significantly the incidence of stomach ulcers and adverse events in the upper gastrointestinal tract, associated with NSAIDs, compared with naproxen alone.

In the course of placebo-controlled studies most frequent The adverse events with Vimovo ™ (n = 490) compared with placebo (n = 246) included diarrhea, upper abdominal pain, constipation, dizziness, and peripheral edema, which are undesirable medicinal reactions with the use of active substances alone. No new safety data were obtained for Vimovo ™ in the general population of patients (n = 1157) compared to the well-known safety profiles of active substances naproxen and esomeprazole.

There were no differences in the types of adverse events with the use of the drug for 12 months compared with short-term therapy. Patients who took Vimovo ™ had significantly less early termination of therapy because of the development of adverse events compared with patients taking one naproxen, covered with an enteric coating (7.9% compared to 12.5%, respectively).The proportion of patients who discontinued treatment due to development of any undesirable phenomenon in upper gastrointestinal tract (including duodenal ulcers guts) with application of Vimovo was 4.0% compared to 12.0% patients receiving one naproxen, covered with enteric coating.

Undesirable phenomena are classified on the frequency of development and organs, and systems.

Frequencies of development of undesirable effects were defined as:

very frequent (≥1/10); frequent (≥1 / 100 to <1/10); infrequent (≥1/1000 to <1/100); rare (≥ 1/10000 to <1/1000); very rare (<1/10000); unknown (can not be estimated by received data).

Naproxen

The following undesirable phenomena were noted in patients who received naproxen during clinical research and post-marketing period.

	Frequent	Infrequent / rare
Laboratory		enlargement
indicators		activity
		Enzymes
		liver,
		enlargement
		time
		bleeding,
		rise
		level of
		whey
		creatinine

Violations from	heartbeatthe	arrhythmia, stagnant
hand hearts		cardiac
		failure,
		infarction
		myocardium,
		tachycardia
Violations from		agranulocytosis,
hand		aplastic
blood and		anemia,
lymphatic		eosinophilia,
system		granulocytopenia.
		hemolytic
		anemia,
		leukopenia,
		lymphadenopathy,
		pancytopenia,
		thrombocytopenia
Violations from	dizziness	cognitive
hand	tion,	dysfunction,
nervous	drowsiness,	coma, convulsions,
systems	head	decline
	pain,	concentrations
	pre-brahmo	attention, neuritis
	the	optic nerve,
	state,	paresthesia,
	vertigo	syncope, tremor
Violations from	violation of	blurred vision,
hand	view	conjunctivitis,
organ of vision		clouding
		cornea, swelling
		disk of the visual
		nerve
Violations from	ringing in	hearing impairment
hand	ears,
organ of hearing and	violation of
labyrinthine	hearing
violations

Violations from	dyspnea	bronchial
hand		asthma,
respiratory		bronchospasm,
system,		eosinophilic
bodies		pneumonitis,
thoracic		pneumonia, swelling
cells and		lungs, oppression
the mediastinum		breathing
Violations from	dyspepsia,	dry mouth,
hand	pain in	esophagitis, ulcers
gastro-	belly,	stomach, gastritis,
intestinal	nausea,	glossitis,
tract	vomiting,	eructation,
	diarrhea,	flatulence, ulcers
	constipation,	stomach and
	heartburn,	twelve fingers
	pepticus	bowel,
	ulcers,	gastro-
	stomatitis	intestinal
		bleeding and
		perforation,
		melena, bloody
		vomiting,
		pancreatitis,
		colitis,
		exacerbation
		inflammatory
		diseases
		intestines
		(ulcerative colitis,
		Crohn's disease),
		non-peptic
		ulcer GASTROINTESTINAL TRACT,
		rectal
		bleeding,
		ulcerative
		stomatitis

Violations from		glomerulonephritis,
the kidneys		hematuria,
and urination		interstitial
pathways		nephritis,
		nephrotic
		syndrome,
		oliguria / polyuria,
		proteinuria,
		renal
		failure,
		medullary
		necrosis of the kidney,
		necrosis of the kidneys
		tubules
Violations from	itching,	alopecia,
side of the skin	bruise	exanthema,
and subcutaneous	tech,	hives,
fabrics	purpura,	toxic
	cutaneous	epidermal
	rash	necrolysis,
		multiform
		erythema, nodosum
		erythema, persistent
		medicinal
		erythema, red
		flat lichen,
		system red
		lupus erythematosus, syndrome
		Stevens-
		Johnson,
		photosensitizer
		dermatitis,
		reactions
		photosensitizer
		including
		cases of rash
		like late

		porphyria of the skin
		(pseudoporphyria),
		exfoliative
		dermatitis,
		angioedema
		edema
Violations from		muscular
hand		weakness,
skeletal-		myalgia
muscular
apparatus and
connector
tissue
Violations from		violation of
hand		appetite, delay
metabolism and		liquid,
supply		hyperglycemia,
		hyperkalemia,
		hyperuricemia,
		hypoglycemia,
		change in mass
		body (associated with
		swelling / delay
		liquid)
Infections and	diverticus	aseptic
infestations	litas	meningitis,
		infection, sepsis
Violations from		rise
hand		arterial
vessels		pressure,
		decline
		arterial
		pressure,
		vasculitis

Are common	wearily	asthenia,
disorders	edema, edema,	malaise,
and reaction in	sweating,	fever
place	thirst
introduction of
Violations from		anaphylactic
hand		reaction,
immune		anaphylactoid
systems		reactions, reactions
		hypersensitivity
		of the
Violations from		cholestasis, hepatitis,
hand		jaundice,
liver and		hepatic
biliary excretion		failure
pathways
Violations from		infertility,
hand		violation of
reproductive		menstrual
function		cycle
and dairy
glands
Mental	depression,	excitation,
disorders	insomnia	anxiety,
		confusion
		consciousness,
		unusual
		dreams,
		hallucinations,
		nervousness

Esomeprazole

The following are undesirable medicinal reactions were identified or patients, who received esomeprazole, coated with enteric coating, during clinical trials and / or postmarketing period. None of these adverse reactions were dose dependent.

	Frequent	Chechasty	Rare	Highly rare
Narush with hand blood and lymphatics the systems			leucope tion, thrombotic cytope the	agranulo cytosis, pancy-tip the
Violations from the nervous system	goals naya pain	heads ruces tion, pareste iza, drowsy ity	rasstra ostvo taste
Disturbances on the part of the organ of vision			odd bone view
Narush with hand body hearing and labyrinth the upset the		vertigo
Disturbances from the respiratory side			broncho spasm

Noah
system,
bodies
thoracic
cells and
Wednesday
the
Narush	pain in	dryness	stomate	microscopy
with	lively	in the mouth	it,	picnic
hand	those,		gastric	colitis
ventricular	diarrhea,		Fractional-
but-	weather		intestine
intestinal	rhizm,		the
th tract	sickeningly		candi
	ta /		doses
	vomiting,
	constipation
Narush				intersti
with				social
hand				nephritis
kidney and
urinating
those who
ways
Narush		dermatitis	alopa	polyphore
with		it, itching,	tion,	a lot of
hand		nettles	flashing	erythema,
skin and		nitsa,	vvits	syndrome
subcutaneous		rash	the	Stevens-
th				Johnson,
fabrics				toxic
				cue
				epidermis
				flax
				necrolysis
Narush			arthral	muscular
with			GIIA,	weakness

hand		myalgia
skeletal-
muscularly
th
apparatus
and
connect
substantive
fabrics
Narush	peripheral	hyponate	hypomagnet
with	riches	rheemia	The empire,
hand	swelling		hypocal
metabolism			cesium
and			due to
supply			heavy
			hypomagnet
			emii,
			hypocal
			power
			due to
			hypomagnet
			emii
Are common		nedomosti
frustrated		gt;
and		reinforced
reactions		no
in place		sweat
introduction of		division
Narush		reactions
with		hyper
hand		vvits
immune		on the one hand,
Noah		for example
systems		measures,
		fever
		ka,
		angione

		vrotic
		the
		edema and
		anaphylaxis
		ktiches
		kaya
		reaction/
		shock
Narush	higher	hepatitis	hepatic
with	the	with / without	naya
hand	active	jaundice	lack of
liver and	ti		punctuality,
bile	truss		hepatic
leading	the		naya
ways	liver		encephalopa
			atia
			patients with
			before
			diagnostician
			the
			disease
			the
			liver
Narush			gynecoma
with			line
hand
reproductions
effective
function
and
milky
glands
Psychiche	sleepless	excited	aggression
skye	egg	tion,	tion,
frustrated		confused	hallucin
the		awn	tions.
		consciousness, depressing and I

Overdose:

There is no information about an overdose of Vimovo ™.

Any effects of an overdose of Vimovo ™ will mainly reflect the effects of Naproxen overdose.

Overdose Symptoms Overdose associated with naproxen

A significant overdose of naproxen can be characterized by the development of lethargy, dizziness, drowsiness, epigastric pain, abdominal discomfort, heartburn, digestive disorders, nausea, transient changes in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, disorientation or vomiting. Gastrointestinal bleeding may develop. In more rare cases, increased blood pressure, acute renal failure, respiratory failure and coma may develop. Seizures were observed in some patients, but the connection with the drug was not reliably established. Also, it is not known what dose of the drug will threaten the life of the patient.

Overdosage associated with esomeprazole

Symptoms of deliberate overdose with esomeprazole (limited experience with doses above 240 mg / day) are temporary.Oral administration of esomeprazole at a dose of 280 mg was accompanied by general weakness and symptoms from the gastrointestinal tract. With a single administration of esomeprazole at a dose of 80 mg, there was no overdose development.

Treatment of overdose Overdose associated with naproxen

After an overdose of NSAIDs, symptomatic and supportive therapy should be given, especially with the development of gastrointestinal effects and kidney damage. Specific antidotes are absent, hemodialysis does not reduce the concentration of naproxen in the plasma due to the high degree of its binding to plasma proteins. Stimulating vomiting and / or taking activated charcoal (60-100 g for adults, 1-2 g / kg for children) and / or using osmotic laxatives can be given to patients 4 hours after taking the drug if symptoms occur or after a significant overdose. Forced diuresis, alkalinization of urine or hemoperfusion are not effective because of high binding of the drug to plasma proteins.

Overdosage associated with esomeprazole

The specific antidote is unknown. Esomeprazole is widely associated with plasma proteins, so it is not excreted by hemodialysis. In case of an overdose of esomeprazole, symptomatic and maintenance therapy should be given.

Interaction:

Not recommended concomitant use Antiretroviral drugs

Shown, that omeprazole, and its racemate - esomeprazole, interact with some antiretroviral drugs. The clinical significance and mechanisms of these interactions are not completely clear. An increase in the pH of the stomach during the administration of omeprazole may alter the absorption of the antiretroviral drug. Other possible mechanisms of interaction are mediated CYP2C19. When using some antiretroviral drugs, such as atazanavir and nelfinavir, concomitantly with omeprazole, the concentrations of these drugs in the blood serum decreased. In this regard, it is not recommended to take omeprazole simultaneously with such drugs as atazanavir and nelfinavir. When omeprazole is used concomitantly with other antiretroviral drugs, such as saquinavir, there was an increase in serum concentration of the latter. Concentrations of some other antiretroviral drugs in serum did not change with concomitant use with omeprazole. In connection with the similar pharmacodynamic - and pharmacokinetic properties of omeprazole and esomeprazole, it is contraindicated to take esomeprazole at the same time as antiretroviral drugs, such as atazanavir and nelfinavir.

Use with caution

Acetylsalicylic acid

Vimovo ™ can be taken concomitantly with acetylsalicylic acid at a low dosage (<325 mg / day). In clinical trials, the frequency of gastric ulcers did not increase in patients taking Vimovo ™ in combination with low-dose acetylsalicylic acid compared with patients receiving only Vimovo ™. However, concomitant use of acetylsalicylic acid and Vimovo ™ may increase the risk of serious adverse events.

With the simultaneous use of naproxen with acetylsalicylic acid in high doses, its binding to plasma proteins is reduced, but without affecting the clearance of free naproxen. The clinical significance of this interaction is unknown.

Diuretics

Clinical studies, as well as postmarketing observation, have shown that in some patients, NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics. This is due to the suppression of the synthesis of renal prostaglandins.With the concomitant use of diuretics with NSAIDs, carefully monitor the signs of renal failure, and monitor the effectiveness of diuretic therapy.

Selective serotonin reuptake inhibitors

According to epidemiological studies, there is a link between the use of psychotropic drugs that affect serotonin reuptake, and the development of bleeding from the upper sections of the gastrointestinal tract. Therefore, caution should be taken to prescribe NSAIDs, including selective COX-2 inhibitors, along with selective serotonin reuptake inhibitors.

Corticosteroids

With simultaneous use of corticosteroids with NSAIDs, including selective COX-2 inhibitors, increases the risk of gastrointestinal bleeding. Caution should be given to NSAIDs simultaneously with corticosteroids. ACE Inhibitors NSAIDs can reduce the antihypertensive effect of ACE inhibitors. This interaction should be considered when prescribing NSAIDs simultaneously with ACE inhibitors.

Lithium preparations

NSAIDs increase the concentration of lithium in the blood plasma and reduce the kidney clearance of lithium.The average minimum concentration of lithium is increased by 15%, and the renal clearance is reduced by 20%. These effects were due to the inhibition of NSAIDs in the synthesis of prostaglandins in the kidneys. Therefore, with the simultaneous use of NSAIDs and lithium preparations, you should closely monitor the signs of lithium toxicity.

Methotrexate

NSAIDs competitively inhibit methotrexate cumulation and decrease the secretion of methotrexate in the renal tubules on animal models. This may indicate a possible increase in toxicity of methotrexate when used concomitantly with NSAIDs. In this regard, caution should be exercised in the combined use of NSAIDs and methotrexate.

Derivatives of sulfonylurea, hydantoin

Naproxen binds to a high degree with blood plasma albumin, therefore it is theoretically possible to interact with other albumin binding drugs, such as sulfonylurea derivatives and hydantoin. Patients receiving concomitantly naproxen and hydantoin derivatives, sulfonamide or sulfonyl urea derivatives, if necessary, adjust the dose of the drug.

Warfarin

NSAIDs can enhance the effect of oral anticoagulants (eg, warfarin and acenocoumarol) and heparin.

With simultaneous use of esomeprazole in a dose of 40 mg with warfarin, despite an insignificant increase in the minimum plasma concentration of less potent R- isomer of warfarin, the coagulation time remained within the permissible norm. However, post-marketing surveillance revealed cases of a clinically significant increase in the International Normalized Ratio (INR) with concomitant use with warfarin. Therefore, it is recommended to carefully monitor the initiation and completion of therapy with warfarin or other coumarin derivatives.

Beta-blockers

Naproxen and other NSAIDs can reduce the antihypertensive effect of propranolol and other beta-blockers.

Cyclosporin / tacrolimus

Due to the increased risk of nephrotoxicity, caution should be exercised when taking cyclosporine or tacrolimus simultaneously with any NSAID.

Probenecid

Concomitant therapy with probenecid increases plasma concentrations of the anion of naproxen and significantly extends the half-life from plasma.

Preparations, the absorption of which depends on the pH of the stomach

Reducing the acidity of gastric juice with esomeprazole may increase or decrease absorption of drugs if the absorption mechanism of these drugs depends on the acidity of the gastric juice. As with other drugs suppressing the secretion of hydrochloric acid, or antacid agents, treatment with esomeprazole may lead to a reduction in absorption of ketoconazole or itraconazole, as well as increased absorption of digoxin. Joint reception of omeprazole at a dose of 20 mg once a day and digoxin increases the bioavailability of digoxin by 10% (bioavailability of digoxin was increased by up to 30% in 20% of patients).

Other information about drug interactions

Studies of the combined use of esomeprazole and naproxen (nonselective NSAIDs) or rofecoxib (selective COX-2 inhibitor) have not revealed clinically significant interactions.

As with other NSAIDs, the concomitant use of colestyramine may inhibit naproxen absorption.

Esomeprazole suppresses CYP2C19, the main enzyme that metabolizes esomeprazole. Esomeprazole also metabolized by enzyme CYP3A4, The following observations related to these enzymes were obtained:

- Joint use of esomeprazole in a dose of 30 mg reduces by 45% the clearance of diazepam, the substrate CYP2C19. It is unlikely that this interaction has clinical relevance.

- The combined use of esomeprazole at a dose of 40 mg by 13% increases the minimum concentrations of phenytoin in the blood plasma in patients with epilepsy.

- Joint use of esomeprazole and a combined inhibitor CYP2C19 and CYP3A4, such as voriconazole, can almost double the concentration of esomeprazole.

- Joint use of esomeprazole and an inhibitor CYP3A4, clarithromycin (500 mg twice daily), twice the exposure (AUC) esomeprazole.

You do not need to change the dose of esomeprazole in these cases.

Medicines that induce isoenzymes CYP2C19 and CYP3A4, such as rifampicin and preparations of St. John's wort penetrated, when combined with esomeprazole may lead to a decrease in the concentration of esomeprazole in the blood plasma by accelerating the metabolism of esomeprazole.

Impact on laboratory performance

Naproxen can reduce platelet aggregation and prolong bleeding time. This should be remembered in determining the time of bleeding.

Naproxen can increase the levels of 17-ketosteroids in urine when determined by interaction of the drug and / or its metabolites with m-dinitrobenzene used in this assay. Although measurements of 17-hydroxy corticosteroids (test Porter- Silber) were not changed, Naproxen therapy was temporarily suspended for 72 hours until the adrenal gland function tests were performed, if a test Porter- Silber.

Naproxen can enter into interactions with certain substances used in the analysis of urine for 5-hydroxyindoleacetic acid.

Special instructions:

Elderly patients

Naproxen: In elderly patients, there was an increased incidence of adverse reactions with NSAIDs, in particular gastrointestinal bleeding, ulceration and perforation of the gastrointestinal tract, which could lead to the death of the patient. During clinical trials of the Vimovo ™ preparation, elderly patients did not have an increased incidence of gastric and duodenal ulcers compared to patients younger than 60 years, and a decrease in the risk of ulceration persisted in this population of elderly patients.However, complications of ulcers, such as bleeding, perforation and gastrointestinal obstruction, have not been studied in these studies by Vimovo ™. Effect on the gastrointestinal tract Naproxen: Gastrointestinal bleeding, ulceration, or perforation of the gastrointestinal tract, which can lead to the patient's death, were observed with all NSAIDs at any time during treatment, with or without symptoms, in the presence of serious gastro-intestinal diseases in the anamnesis or without.

The composition of the drug Vimovo ™ is included esomeprazole to reduce the frequency development of gastrointestinal by-products effects of naproxen, including ulceration.

Despite the fact that Vimovo ™ is substantially reduces the incidence of stomach ulcers by compared with one naproxen,the development of ulcers and accompanying their complications. Risk development of gastrointestinal bleeding, ulceration and perforation Gastrointestinal tract when using NSAIDs increases when doses are increased in patients with a history of ulcer, especially if the ulcer is complicated by bleeding or perforation, and in elderly patients. Thus, patients should be prescribed therapy with the lowest dosage.

Patients with gastrointestinal undesirable phenomena in the anamnesis, especially elderly patients, should report any unusual symptoms in The abdominal cavity (especially, about the gastro-intestinal bleeding) and, especially, in beginning of treatment.

It should be cautious to prescribe NSAIDs patients already taking drugs, which can increase the risk of development ulcers or bleeding, such as oral corticosteroids, anticoagulants, for example, warfarin, selective inhibitors of re-uptake serotonin or antithrombotic drugs, such as acetylsalicylic acid.

With the development of gastrointestinal bleeding or ulcers, the use of Vimovo ™ should be discontinued.

Caution should be used to prescribe NSAIDs in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) due to possible exacerbation of the disease. Esomeprazole: With the development of any alarming symptom (for example, significant, unintended weight loss, recurrent vomiting, dysphagia, bloody vomiting or melena) and the presence of an assumption or confidence in the development of a stomach ulcer, it is necessary to exclude a malignant tumor, since esomeprazole magnesium can relieve symptoms and delay the diagnosis.

Therapy with proton pump inhibitors may slightly increase the risk of infection of the gastrointestinal tract with microorganisms such as Salmonella and Campylobacter.

Effects on cardiovascular and cerebrovascular systems Naproxen: As with any NSAID, it is necessary to monitor and advise patients with hypertension and / or chronic cardiac insufficiency in the history, since therapy with NSAIDs is accompanied by fluid retention and development of edema.

Patients with uncontrolled hypertension, chronic heart failure, ischemic heart disease, peripheral arterial disease and / or cerebral circulation disorder should be prescribed naproxen only after a thorough examination. The same examination should be performed before the beginning of long-term therapy of patients with risk factors for the development of cardiovascular diseases (eg, hypertension, hyperlipidemia, diabetes, smoking).

According to the results of clinical and epidemiological studies, naproxen therapy (1000 mgper day) may be accompanied by a lower risk of developing thrombosis of the arteries than selective inhibitors of COX-2, but this small risk can not be ruled out. In general, the data do not confirm a cardioprotective effect.

Effects on the kidneys

Naproxen: Prolonged use of NSAIDs led to the development of medullary necrosis and other kidney lesions. Nephrotoxicity was also observed in patients with renal prostaglandins playing a compensatory role in maintaining renal perfusion. Have these patients, the use of NSAIDs can lead to a dose-dependent decrease synthesis of prostaglandins, and the second turn, to a decrease in renal blood flow, which can accelerate the development of explicit renal failure. The largest The risk of such a reaction is present in patients with impaired renal function, hypovolemia, cardiac insufficiency, hepatic insufficiency, with excess removal of sodium chloride from the body, patients taking diuretics, ACE inhibitors or antagonists receptors of angiotensin II, and in the elderly patients. After the abolition of therapy with NSAIDs the condition of patients usually is restored to the original one.

Application the patients with renal insufficiency As naproxen in a greater degree (95%) is excreted by the kidneys by glomerular filter, with great care should be prescribed to patients with renal failure, and It is recommended that serum creatinine and / or the clearance of creatinine in these patients. Not it is recommended to appoint Vimovo ™ patients with initial clearance creatinine less than 30 ml / min.

Hemodialysis does not reduce plasma The concentration of naproxen due to high binding with plasma proteins. Certain patients, especially those with impaired renal blood flow due to a decrease in the volume of the intercellular fluid, cirrhosis of the liver, limited salt intake, chronic heart failure and pre-existing kidney disease, should assess the kidney function before and during the administration of Vimovo ™. Some elderly patients with suspected renal dysfunction, as well as patients taking diuretics, ACE inhibitors or angiotensin II receptor antagonists, also fall into this category. To prevent possible excessive cumulation of naproxen metabolites in these patients, the daily dose of the drug should be reduced.

Influence on the hemopoietic system

Naproxen: It is necessary to prescribe with caution the preparations containing in its composition naproxen, patients with coagulation disorders or receiving therapy, affecting hemostasis.

The risk of bleeding in patients with a high risk of bleeding or receiving complete anticoagulation therapy (for example, dicumarol derivatives) increases with the concomitant use of drugs containing naproxen. Naproxen reduces aggregation

platelets and lengthens bleeding time. This should be remembered when determining bleeding time.

With the development of active or clinically significant bleeding in any area in patients taking Vimovo ™, therapy should be discontinued.

Dermatological effects

Naproxen: Very rarely, with NSAIDs, serious skin reactions developed, some of which led to the death of patients, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis. The greatest risk of such reactions exists at the beginning of therapy, and in most cases the onset of development of such reactions occurs in the first month of treatment.At the first signs of skin rash, lesions of mucous membranes or other symptoms of hypersensitivity, it is necessary to stop taking Vimovo ™.

Influence on visual function

If visual disturbances occur while taking Vimovo ™, consultation with an ophthalmologist is recommended.

Anaphylactic (anaphylactoid) reactions

Naproxen: Hypersensitivity reactions may develop in patients predisposed to them. Anaphylactic (anaphylactoid) reactions can develop in patients with or without hypersensitivity, or with or without hypersensitivity to acetylsalicylic acid, other NSAIDs or naproxen-containing drugs. These reactions can develop in patients with angioneurotic edema, bronchospasm (eg, bronchial asthma), rhinitis and polyposis rhinosinusopathy in history.

Patients with bronchial asthma

Naproxen: The use of acetylsalicylic acid in patients with aspirin asthma was accompanied by the development of severe bronchospasm, which can lead to the death of the patient. Since patients with hypersensitivity to acetylsalicylic acid have cross-reactivity, including bronchospasm,between acetylsalicylic acid and other NSAIDs, it is not recommended to appoint Vimovo ™ to patients with this hypersensitivity to acetylsalicylic acid and with caution to prescribe to patients with bronchial asthma.

Inflammation

Naproxen: Antipyretic and anti-inflammatory properties of naproxen can reduce fever and other signs of inflammation, thereby reducing their suitability as diagnostic factors.

Combinations with other medicinal drugs

It is not recommended to apply Wimovo ™ simultaneously with NSAIDs (except acetylsalicylic acid), including selective inhibitors of COX-2, due to the cumulative risks of developing serious adverse events related to NSAIDs.

Pharmacokinetic / pharmacodynamic interaction between clopidogrel (loading dose 300 mg and maintenance dose 75 mg / day) and esomeprazole (40 mg / day inwards), which leads to a decrease in exposure to the active metabolite of clopidogrel, on average 40 % and a decrease in the maximum inhibition of ADP-induced platelet aggregation by an average of 14%. Therefore, simultaneous use of esomeprazole and clopidogrel should be avoided.section "Interaction with other drugs and other types of drug interactions").

Fertility in women

Naproxen: There is some evidence that cyclooxygenase inhibiting / prostaglandin synthesis drugs can reduce fertility in women, affecting ovulation. This effect is reversible after the abolition of therapy. In connection with this, women who have problems with conception or undergoing infertility screening, should consider the possibility of lifting Vimovo ™ (see section "Use during pregnancy and during breastfeeding").

Are common

If the daily dose of naproxen 1000 mg is not acceptable, then alternative therapies should be used.

For patients receiving long-term therapy (especially more than 1 year), it is necessary to conduct constant monitoring. Separate observational studies indicate that proton pump inhibitor therapy may slightly increase the risk of osteoporosis-related fractures, but other similar studies have not shown an increased risk.

In a randomized, double-blind, controlled clinical trial of omeprazole and esomeprazole,including two open long-term studies (more than 12 years), the connection of fractures against the background of osteoporosis with the use of proton pump inhibitors was not confirmed.

Although the causal relationship between the use of omeprazole / esomeprazole with fractures against osteoporosis is not established, patients at risk for developing osteoporosis or fractures against it should be placed under appropriate clinical observation.

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

Due to the fact that during dasg treatment with Vimovo ™, dizziness, visual impairment and drowsiness may occur, caution should be exercised when driving vehicles and other mechanisms.

Form release / dosage:

Intestine-soluble tablets shell, 500 mg + 20 mg.

Packaging:By 6, 10, 30 or 60 tablets with desiccant in plastic vial with screwed plastic cover with the control of the first autopsy.

Each vial is packed in cardboard pack of instructions for use.

Storage conditions:

At a temperature of no higher than 30 ° C. Store in the original packaging, in a tightly closed bottle to protect from moisture. Keep out of the reach of children.

Shelf life:

2 years.Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001426

Date of registration:12.01.2012 / 15.01.2013

Expiration Date:12.01.2017

Date of cancellation:2016-03-14

The owner of the registration certificate:AstraZeneca UK LtdAstraZeneca UK Ltd United Kingdom

Manufacturer: & nbsp

PATHEON PHARMACEUTICALS, Inc. USA

Representation: & nbspAstraZeneca Pharmaceuticals Ltd.AstraZeneca Pharmaceuticals Ltd.

Information update date: & nbsp15.02.2017

Illustrated instructions

Instructions

Vimovo TM (VimovoTM)